DNA methylation profiles of cancer-related fatigue associated with markers of inflammation and immunometabolism.

Cancer patients are commonly affected by fatigue. Herein, we sought to examine epigenetic modifications (i.e., DNA methylation) related to fatigue in peripheral blood among patients during and after treatment for head and neck cancer (HNC). Further, we determined whether these modifications were associated with gene expression and inflammatory protein markers, which we have previously linked to fatigue in HNC. This prospective, longitudinal study enrolled eligible patients with data collected at pre-radiotherapy, end of radiotherapy, and six months and one-year post-radiotherapy. Fatigue data were reported by patients using the Multidimensional Fatigue Inventory (MFI)-20. DNA methylation (Illumina MethylationEPIC) and gene expression (Applied Biosystems Clariom S) arrays and assays for seven inflammatory markers (R&D Systems multiplex) were performed. Mixed models and enrichment analyses were applied to establish the associations. A total of 386 methylation loci were associated with fatigue among 145 patients (False Discovery Rate [FDR] < 0.05). Enrichment analyses showed the involvement of genes related to immune and inflammatory responses, insulin and lipid metabolism, neuropsychological disorders, and tumors. We further identified 16 methylation-gene expression pairs (FDR < 0.05), which were linked to immune and inflammatory responses and lipid metabolism. Ninety-one percent (351) of the 386 methylation loci were also significantly associated with inflammatory markers (e.g., interleukin 6, c-reactive protein; FDR < 0.05), which further mediated the association between methylation and fatigue (FDR < 0.05). These data suggest that epigenetic modifications associated with inflammation and immunometabolism, in conjunction with relevant gene expression and protein markers, are potential targets for treating fatigue in HNC patients. The findings also merit future prospective studies in other cancer populations as well as interventional investigations.

Splinting of Low-Risk Pediatric Fractures.

ABSTRACT: This review covers common orthopedic injuries seen after acute traumatic injury. A thorough physical examination and radiographic review of these injuries are key to ensuring appropriate management. Although many injuries may require urgent or emergent orthopedic consultation and management, this review focuses on injuries that are low-risk and amenable to splinting with outpatient orthopedic follow-up. This review covers key physical examination features, radiographic findings that help providers assess injuries, as well as reviewing splinting application to help facilitate rapid management of these injuries in the acute care setting.

Noninvasive Ventilation or CPAP in the Initial Treatment Phase of Small Infants With Respiratory Failure.

BACKGROUND: Respiratory failure in infants is a common reason for admission to the pediatric ICU (PICU). Although high-flow nasal cannula (HFNC) is the preferred first-line treatment at our institution, some infants require CPAP or noninvasive ventilation (NIV). Here we report our experience using CPAP/NIV in infants < 10 kg. METHODS: We conducted a retrospective review of infants < 10 kg treated with CPAP/NIV in our PICUs between July 2017-May 2021 in the initial phase of treatment. Demographic, support type and settings, vital signs, pulse oximetry, and intubation data were extracted from the electronic health record. We compared subjects successfully treated with CPAP/NIV with those who required intubation. RESULTS: We studied 62 subjects with median (interquartile range) age 96 [6.5-308] d and weight 4.5 (3.4-6.6) kg. Of these, 22 (35%) required intubation. There were no significant differences in demographics, medical history, primary interface, pre-CPAP/NIV support, and device used to deliver CPAP/NIV. HFNC was used in 57 (92%) subjects before escalation to CPAP/NIV. Subjects who failed CPAP/NIV were less likely to have bronchiolitis (27% vs 60%, P = .040), less likely to be discharged from the hospital to home (68% vs 93%, P = .02), had a longer median hospital length of stay (LOS) (26.9 [21-50.5] d vs 10.4 [5.6-28.4] d, P = .002), and longer median ICU LOS (14.6 [7.9-25.2] d vs 5.8 [3.8-12.4] d, P = .004). Initial vital signs and FIO2 were similar, but SpO2 was lower and FIO2 higher at 6 h and 12 h after support initiation for subjects who failed CPAP/NIV. Initial CPAP/NIV settings were similar, but subjects who failed CPAP/NIV had higher maximum and final inspiratory/expiratory pressure. CONCLUSIONS: Most infants who failed initial HFNC support were successfully managed without intubation using NIV or CPAP. Bronchiolitis was associated with a lower rate of CPAP/NIV failure, whereas lower SpO2 and higher FIO2 levels were associated with higher rates of intubation.

A Thy-1-negative immunofibroblast population emerges as a key determinant of fibrotic outcomes to biomaterials.

Fibrosis-associated fibroblasts have been identified across various fibrotic disorders, but not in the context of biomaterials, fibrotic encapsulation, and the foreign body response. In other fibrotic disorders, a fibroblast subpopulation defined by Thy-1 loss is strongly correlated with fibrosis yet we do not know what promotes Thy-1 loss. We have previously shown that Thy-1 is an integrin regulator enabling normal fibroblast mechanosensing, and here, leveraging nonfibrotic microporous annealed particle (MAP) hydrogels versus classical fibrotic bulk hydrogels, we demonstrate that Thy1-/- mice mount a fibrotic response to MAP gels that includes inflammatory signaling. We found that a distinct and cryptic α-smooth muscle actin-positive Thy-1- fibroblast population emerges in response to interleuklin-1ß (IL-1ß) and tumor necrosis factor-α (TNFα). Furthermore, IL-1ß/TNFα-induced Thy-1- fibroblasts consist of two distinct subpopulations that are strongly proinflammatory. These findings illustrate the emergence of a unique proinflammatory, profibrotic fibroblast subpopulation that is central to fibrotic encapsulation of biomaterials.

Recruitment and Retention Issues in a Technology-Based Intervention Among Korean American Midlife Women With Depressive Symptoms'.

The number of health technology-based intervention studies has grown significantly. However, issues in the recruitment and retention for such studies, especially of Asian Americans, have rarely been discussed. The purpose of this paper was to discuss issues in the recruitment and retention of a specific group of Asian Americans-Korean American midlife women with depressive symptoms-into a technology-based intervention study using computers and mobile devices with a measurement device and to provide directions for future participant recruitment and retention in technology-based intervention studies. The written memos of research team members and the written records of research team meetings were analyzed using a content analysis. The issues in the recruitment and retention process included (1) low recruitment and retention rates; (2) the perceived long intervention period; (3) strict inclusion/exclusion criteria; (4) concerns related to the use of a measurement device; and (5) the perceived adequacy of monetary incentives. Based on the issues identified in the study, several suggestions are made for future recruitment and retention of racial/ethnic minorities in technology-based intervention studies (eg, appropriate intervention period, innovative and creative motivation strategies, acceptable measurement scales and devices, and adequate monetary reimbursement).

Computational Docking as a Tool in Guiding the Drug Design of Rutaecarpine Derivatives as Potential SARS-CoV-2 Inhibitors.

COVID-19 continues to spread around the world. This is mainly because new variants of the SARS-CoV-2 virus emerge due to genomic mutations, evade the immune system and result in the effectiveness of current therapeutics being reduced. We previously established a series of detection platforms, comprising computational docking analysis, S-protein-based ELISA, pseudovirus entry, and 3CL protease activity assays, which allow us to screen a large library of phytochemicals from natural products and to determine their potential in blocking the entry of SARS-CoV-2. In this new screen, rutaecarpine (an alkaloid from Evodia rutaecarpa) was identified as exhibiting anti-SARS-CoV-2 activity. Therefore, we conducted multiple rounds of structure-activity-relationship (SAR) studies around this phytochemical and generated several rutaecarpine analogs that were subjected to in vitro evaluations. Among these derivatives, RU-75 and RU-184 displayed remarkable inhibitory activity when tested in the 3CL protease assay, S-protein-based ELISA, and pseudovirus entry assay (for both wild-type and omicron variants), and they attenuated the inflammatory response induced by SARS-CoV-2. Interestingly, RU-75 and RU-184 both appeared to be more potent than rutaecarpine itself, and this suggests that they might be considered as lead candidates for future pharmacological elaboration.

Efficacy and Safety of Xanomeline-Trospium Chloride in Schizophrenia: A Randomized Clinical Trial.

Importance: A significant need exists for new antipsychotic medications with different mechanisms of action, greater efficacy, and better tolerability than existing agents. Xanomeline is a dual M1/M4 preferring muscarinic receptor agonist with no direct D2 dopamine receptor blocking activity. KarXT combines xanomeline with the peripheral muscarinic receptor antagonist trospium chloride with the goal of reducing adverse events due to xanomeline-related peripheral muscarinic receptor activation. In prior trials, xanomeline-trospium chloride was effective in reducing symptoms of psychosis and generally well tolerated in people with schizophrenia. Objective: To evaluate the efficacy and safety of xanomeline-trospium vs placebo in adults with schizophrenia. Design, Setting, and Participants: EMERGENT-3 (NCT04738123) was a phase 3, multicenter, randomized, double-blind, placebo-controlled, 5-week trial of xanomeline-trospium in people with schizophrenia experiencing acute psychosis, conducted between April 1, 2021, and December 7, 2022, at 30 inpatient sites in the US and Ukraine. Data were analyzed from February to June 2023. Interventions: Participants were randomized 1:1 to receive xanomeline-trospium chloride (maximum dose xanomeline 125 mg/trospium 30 mg) or placebo for 5 weeks. Main Outcomes and Measures: The prespecified primary end point was change from baseline to week 5 in Positive and Negative Syndrome Scale (PANSS) total score. Secondary outcome measures were change from baseline to week 5 in PANSS positive subscale score, PANSS negative subscale score, PANSS Marder negative factor score, Clinical Global Impression-Severity score, and proportion of participants with at least a 30% reduction in PANSS total score. Safety and tolerability were also evaluated. Results: A total of 256 participants (mean [SD] age, 43.1 [11.8] years; 191 men [74.6%]; 156 of 256 participants [60.9%] were Black or African American, 98 [38.3%] were White, and 1 [0.4%] was Asian) were randomized (125 in xanomeline-trospium group and 131 in placebo group). At week 5, xanomeline-trospium significantly reduced PANSS total score compared with placebo (xanomeline-trospium , -20.6; placebo, -12.2; least squares mean difference, -8.4; 95% CI, -12.4 to -4.3; P < .001; Cohen d effect size, 0.60). Discontinuation rates due to treatment-emergent adverse events (TEAEs) were similar between the xanomeline-trospium (8 participants [6.4%]) and placebo (7 participants [5.5%]) groups. The most common TEAEs in the xanomeline-trospium vs placebo group were nausea (24 participants [19.2%] vs 2 participants [1.6%]), dyspepsia (20 participants [16.0%] vs 2 participants [1.6%]), vomiting (20 participants [16.0%] vs 1 participant [0.8%]), and constipation (16 participants [12.8%] vs 5 participants [3.9%]). Measures of extrapyramidal symptoms, weight gain, and somnolence were similar between treatment groups. Conclusions and Relevance: Xanomeline-trospium was efficacious and well tolerated in people with schizophrenia experiencing acute psychosis. These findings, together with the previously reported and consistent results from the EMERGENT-1 and EMERGENT-2 trials, support the potential of xanomeline-trospium to be the first in a putative new class of antipsychotic medications without D2 dopamine receptor blocking activity. Trial Registration: ClinicalTrials.gov Identifier: NCT04738123.

Endotracheal Intubation Outside the Operating Room: Year in Review 2023.

Endotracheal intubation is a common lifesaving procedure that often is performed outside the operating room in a variety of clinical scenarios. Providers who perform intubation outside the operating room have variable degrees of training, skill development, and experience. A large number of studies were published in 2023 on the topic of intubations outside the operating room across a wide variety of settings and patient populations. Here, we review relevant papers on this topic published in 2023.

The Performance of ChatGPT on the American Society for Surgery of the Hand Self-Assessment Examination.

BACKGROUND: This study aims to compare the performance of ChatGPT-3.5 (GPT-3.5) and ChatGPT-4 (GPT-4) on the American Society for Surgery of the Hand (ASSH) Self-Assessment Examination (SAE) to determine their potential as educational tools. METHODS: This study assessed the proportion of correct answers to text-based questions on the 2021 and 2022 ASSH SAE between untrained ChatGPT versions. Secondary analyses assessed the performance of ChatGPT based on question difficulty and question category. The outcomes of ChatGPT were compared with the performance of actual examinees on the ASSH SAE. RESULTS: A total of 238 questions were included in the analysis. Compared with GPT-3.5, GPT-4 provided significantly more correct answers overall (58.0% versus 68.9%, respectively; P = 0.013), on the 2022 SAE (55.9% versus 72.9%; P = 0.007), and more difficult questions (48.8% versus 63.6%; P = 0.02). In a multivariable logistic regression analysis, correct answers were predicted by GPT-4 (odds ratio [OR], 1.66; P = 0.011), increased question difficulty (OR, 0.59; P = 0.009), Bone and Joint questions (OR, 0.18; P < 0.001), and Soft Tissue questions (OR, 0.30; P = 0.013). Actual examinees scored a mean of 21.6% above GPT-3.5 and 10.7% above GPT-4. The mean percentage of correct answers by actual examinees was significantly higher for correct (versus incorrect) ChatGPT answers. CONCLUSIONS: GPT-4 demonstrated improved performance over GPT-3.5 on the ASSH SAE, especially on more difficult questions. Actual examinees scored higher than both versions of ChatGPT, but the margin was cut in half by GPT-4.

Ramomarthamyces octomerus sp. nov. and Insights into the Evolution and Diversification of Ramomarthamyces (Ascomycota, Leotiomycetes, Marthamycetales).

The apothecial fungus Ramomarthamyces octomerus sp. nov. is described from specimens collected in Mediterranean climate regions in southern Portugal, Spain (Canary Islands), and the Dalmatian region of Croatia. Presumably saprobic, R. octomerus occurs on intact, decorticated wood of Laurus novocanariensis and Olea europaea. Ascospores are cylindric-ellipsoid and seven-septate. Surprisingly, in our four-locus phylogenetic analysis (nuSSU, ITS1-5.8S-ITS2, LSU, mtSSU), this fungus clusters among species of Cyclaneusma, Marthamyces, Naemacyclus, and Ramomarthamyces in a core Marthamycetaceae clade that circumscribes primarily leaf-inhabiting, filiform-spored species. In addition, the asci of R. octomerus possess an amyloid pore, but the reaction varies between specimens collected in the Canary Islands and those collected in Portugal and Croatia. The occurrence of an amyloid reaction in the asci of R. octomerus challenges the characterization of Marthamycetales taxa as possessing inamyloid asci. In our discussion we provide background and analysis of these notable observations.

Survey of Ventilator Waveform Interpretation Among ICU Professionals.

BACKGROUND: The interpretation of ventilator waveforms is essential for effective and safe mechanical ventilation but requires specialized training and expertise. This study aimed to investigate the ability of ICU professionals to interpret ventilator waveforms, identify areas requiring further education and training, and explore the factors influencing their interpretation skills. METHODS: We conducted an international online anonymous survey of ICU professionals (physicians, nurses, and respiratory therapists [RTs]), with ≥ 1 y of experience working in the ICU. The survey consisted of demographic information and 15 multiple-choice questions related to ventilator waveforms. Results were compared between professions using descriptive statistics, and logistic regression (expressed as odds ratios [ORs; 95% CI]) was performed to identify factors associated with high performance, which was defined by a threshold of 60% correct answers. RESULTS: A total of 1,832 professionals from 31 countries or regions completed the survey; 53% of respondents answered ≥ 60% of the questions correctly. The 3 questions with the most correct responses were related to waveforms that demonstrated condensation (90%), pressure overshoot (79%), and bronchospasm (75%). Conversely, the 3 questions with the fewest correct responses were waveforms that demonstrated early cycle leading to double trigger (43%), severe under assistance (flow starvation) (37%), and early/reverse trigger (31%). Factors significantly associated with ≥ 60% correct answers included years of ICU working experience (≥ 10 y, OR 1.6 [1.2-2.0], P < .001), profession (RT, OR 2.8 [2.1-3.7], P < .001), highest degree earned (graduate, OR 1.7 [1.3-2.2], P < .001), workplace (teaching hospital, OR 1.4 [1.1-1.7], P = .008), and prior ventilator waveforms training (OR 1.7 [1.3-2.2], P < .001). CONCLUSIONS: Slightly over half respondents correctly identified ≥ 60% of waveforms demonstrating patient-ventilator discordance. High performance was associated with ≥ 10 years of ICU working experience, RT profession, graduate degree, working in a teaching hospital, and prior ventilator waveforms training. Some discordances were poorly recognized across all groups of surveyed professionals.

Predicting academic productivity among American Shoulder and Elbow Surgeons fellowship faculty from publications acquired before and during surgical training.

BACKGROUND: Orthopedic residency and fellowship applicants with a strong research record are highly valued for their potential in continuing academic excellence. Despite this, the association between research productivity during training and future academic productivity as an attending orthopedic surgeon is not well-established. We assess the effects of research output during different periods of surgical training as well as residency location on long-term academic productivity as an attending shoulder and elbow surgeon. METHODS: A search of the 2022-2023 American Shoulder and Elbow Surgeons Fellowship Directory was conducted to identify a list of orthopedic shoulder and elbow fellowship faculty members. Each surgeon's residency, fellowship and current institution of practice were determined and stratified by geographic location. Total publication counts acquired before residency, during residency, during fellowship, and after fellowship were collected for each faculty member. Attending publication rates and H-indices were calculated. A multivariate linear regression model was created, and significance was set at a P value <.05. RESULTS: A total of 149 shoulder and elbow fellowship faculty members representing 34 fellowship programs were identified. The average number of total publications per surgeon was 88.8 ± 102. The average attending publication rate was 5.29 ± 6.89 publications per year. The average H-index for included surgeons was 27.8 ± 24.4. The number of publications acquired before residency (ß = 0.293; P < .001), during residency (ß = 0.110; P = .025) and during fellowship (ß = 0.593; P < .001) were significantly associated with an increased attending publication rate, but no association was observed with the H-index [before residency (ß = -0.221; P = .574), during residency (ß = 0.045; P = .866), during fellowship (ß = 0.198; P = .678)]. There were no significant differences in total publication count (P = .397), attending publication rate (P = .237), or H-index (P = .364) based on location of residency training. DISCUSSION: Research output before and during surgical training is predictive of continued academic productivity as a shoulder and elbow surgeon. In particular, greater productivity during surgical fellowship was most predictive of academic output as an attending. While long-term academic productivity does not seem to be influenced by the geographic location of residency training, attending surgeons practicing in the Midwest had significantly greater total publication counts and H-indices but similar annual publication rates.

Fibroblast and myofibroblast activation in normal tissue repair and fibrosis.

The term 'fibroblast' often serves as a catch-all for a diverse array of mesenchymal cells, including perivascular cells, stromal progenitor cells and bona fide fibroblasts. Although phenotypically similar, these subpopulations are functionally distinct, maintaining tissue integrity and serving as local progenitor reservoirs. In response to tissue injury, these cells undergo a dynamic fibroblast-myofibroblast transition, marked by extracellular matrix secretion and contraction of actomyosin-based stress fibres. Importantly, whereas transient activation into myofibroblasts aids in tissue repair, persistent activation triggers pathological fibrosis. In this Review, we discuss the roles of mechanical cues, such as tissue stiffness and strain, alongside cell signalling pathways and extracellular matrix ligands in modulating myofibroblast activation and survival. We also highlight the role of epigenetic modifications and myofibroblast memory in physiological and pathological processes. Finally, we discuss potential strategies for therapeutically interfering with these factors and the associated signal transduction pathways to improve the outcome of dysregulated healing.

A protective role for B-1 cells and oxidation-specific epitope IgM in lung fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a morbid fibrotic lung disease with limited treatment options. The pathophysiology of IPF remains poorly understood, and elucidation of the cellular and molecular mechanisms of IPF pathogenesis is key to the development of new therapeutics. B-1 cells are an innate B cell population which play an important role linking innate and adaptive immunity. B-1 cells spontaneously secrete natural IgM and prevent inflammation in several disease states. One class of these IgM recognize oxidation-specific epitopes (OSE), which have been shown to be generated in lung injury and to promote fibrosis. A main B-1 cell reservoir is the pleural space, adjacent to the typical distribution of fibrosis in IPF. In this study, we demonstrate that B-1 cells are recruited to the lung during injury where they secrete IgM to OSE (IgM OSE ). We also show that the pleural B-1 cell reservoir responds to lung injury through regulation of the chemokine receptor CXCR4. Mechanistically we show that the transcription factor Id3 is a novel negative regulator of CXCR4 expression. Using mice with B-cell specific Id3 deficiency, a model of increased B-1b cells, we demonstrate decreased bleomycin-induced fibrosis compared to littermate controls. Furthermore, we show that mice deficient in secretory IgM ( sIgM -/- ) have higher mortality in response to bleomycin-induced lung injury, which is partially mitigated through airway delivery of the IgM OSE E06. Additionally, we provide insight into potential mechanisms of IgM in attenuation of fibrosis through RNA sequencing and pathway analysis, highlighting complement activation and extracellular matrix deposition as key differentially regulated pathways.

Comprehensive Assessment of Artificial Intelligence Tools for Driver Monitoring and Analyzing Safety Critical Events in Vehicles.

Human factors are a primary cause of vehicle accidents. Driver monitoring systems, utilizing a range of sensors and techniques, offer an effective method to monitor and alert drivers to minimize driver error and reduce risky driving behaviors, thus helping to avoid Safety Critical Events (SCEs) and enhance overall driving safety. Artificial Intelligence (AI) tools, in particular, have been widely investigated to improve the efficiency and accuracy of driver monitoring or analysis of SCEs. To better understand the state-of-the-art practices and potential directions for AI tools in this domain, this work is an inaugural attempt to consolidate AI-related tools from academic and industry perspectives. We include an extensive review of AI models and sensors used in driver gaze analysis, driver state monitoring, and analyzing SCEs. Furthermore, researchers identified essential AI tools, both in academia and industry, utilized for camera-based driver monitoring and SCE analysis, in the market. Recommendations for future research directions are presented based on the identified tools and the discrepancies between academia and industry in previous studies. This effort provides a valuable resource for researchers and practitioners seeking a deeper understanding of leveraging AI tools to minimize driver errors, avoid SCEs, and increase driving safety.

A Master Protocol Template for Pediatric ARDS Studies.

BACKGROUND: Pediatric ARDS is associated with significant morbidity and mortality. High-quality data from clinical trials in children are limited due to numerous barriers to their design and execution. Here we describe the collaborative development of a master protocol as a tool to address some of these barriers and support the conduct of pediatric ARDS studies. METHODS: Using PubMed, we performed a literature search of randomized controlled trials (RCTs) in pediatric ARDS to characterize the current state and evaluate potential benefit of harmonized master protocols. We used a multi-stakeholder, collaborative, and team science-oriented process to develop a master protocol template with links to common data elements (CDEs) for pediatric ARDS trials. RESULTS: We identified 11 RCTs that enrolled between 14-200 total subjects per trial. Interventions included mechanical ventilation, prone positioning, corticosteroids, and surfactant. Studies displayed significant heterogeneity in ARDS definition, design, inclusion and exclusion criteria, and reported outcomes. Mortality was reported in 91% of trials and ventilator-free days in 73%. The trial heterogeneity made pooled analysis unfeasible. These findings underscore the need for a method to facilitate combined analysis of future trials through standardization of trial elements. As a potential solution, we developed a master protocol, iteratively revised with input from a multidisciplinary panel of experts and organized into 3 categories: instructions and general information, templated language, and a series of text options of common pediatric ARDS trial scenarios. Finally, we linked master protocol sections to relevant CDEs previously defined for pediatric ARDS and captured in a series of electronic case report forms. CONCLUSIONS: The majority of pediatric ARDS trials identified were small and heterogeneous in study design and outcome reporting. Using a master protocol template for pediatric ARDS trials with CDEs would support combining and comparing pediatric ARDS trial findings and increase the knowledge base.