Receptor tyrosine kinase inhibition leads to regression of acral melanoma by targeting the tumor microenvironment.

Acral melanoma (AM) is an aggressive melanoma variant that arises from palmar, plantar, and nail unit melanocytes. Compared to non-acral cutaneous melanoma (CM), AM is biologically distinct, has an equal incidence across genetic ancestries, typically presents in advanced stage disease, is less responsive to therapy, and has an overall worse prognosis. Independent analysis of published genomic and transcriptomic sequencing identified that receptor tyrosine kinase (RTK) ligands and adapter proteins are frequently amplified, translocated, and/or overexpressed in AM. To target these unique genetic changes, a zebrafish acral melanoma model was exposed to a panel of narrow and broad spectrum multi-RTK inhibitors, revealing that dual FGFR/VEGFR inhibitors decrease acral-analogous melanocyte proliferation and migration. The potent pan-FGFR/VEGFR inhibitor, Lenvatinib, uniformly induces tumor regression in AM patient-derived xenograft (PDX) tumors but only slows tumor growth in CM models. Unlike other multi-RTK inhibitors, Lenvatinib is not directly cytotoxic to dissociated AM PDX tumor cells and instead disrupts tumor architecture and vascular networks. Considering the great difficulty in establishing AM cell culture lines, these findings suggest that AM may be more sensitive to microenvironment perturbations than CM. In conclusion, dual FGFR/VEGFR inhibition may be a viable therapeutic strategy that targets the unique biology of AM.

Venoarterial Extracorporeal Membrane Oxygenation for "Protected" Percutaneous Coronary Intervention Secondary to Refractory Polymorphic Ventricular Tachycardia and Cardiac Arrest.

ABSTRACT: We present a case of cardiogenic shock secondary to refractory polymorphic ventricular tachycardia associated with coronary ischemia resulting in cardiac arrest. Following the return of spontaneous circulation, the patient was cannulated for peripheral venoarterial extracorporeal membrane oxygenation (V-A ECMO) in anticipation of high-risk "protected" percutaneous coronary intervention (PCI). Under full V-A ECMO support, inotropes and vasopressors were weaned off, and the patient underwent uneventful PCI of left circumflex and obtuse marginal lesions. After 48 hours, the patient was decannulated and could be discharged home alive 16 days after his initial cardiac arrest.

Distinct Comorbidity Clusters in Patients With Acute Heart Failure: Data From RELAX-AHF-2.

BACKGROUND: Multimorbidity frequently occurs in patients with acute heart failure (AHF). The co-occurrence of comorbidities often follows specific patterns. OBJECTIVES: This study investigated multimorbidity subtypes and their associations with clinical outcomes. METHODS: From the prospective RELAX-AHF-2 (Relaxin for the Treatment of Acute Heart Failure-2) trial, 6,545 patients (26% with HF with preserved ejection fraction, defined as LVEF ≥50%) were classified into multimorbidity groups using latent class analysis. The association between subgroups and clinical outcomes was examined. Validation of these findings was conducted in the RELAX-AHF trial, which comprised 1,161 patients. RESULTS: Five distinct multimorbidity groups emerged: 1) diabetes and chronic kidney disease (CKD) (often male, high prevalence of CKD and diabetes mellitus); 2) ischemic (ischemic HF); 3) elderly/atrial fibrillation (AF) (oldest, high prevalence of AF); 4) metabolic (obese, hypertensive, more often HF with preserved ejection fraction); and 5) young (fewest comorbidities). After adjusting for confounders, patients in the diabetes and CKD (HR: 1.80; 95% CI: 1.50-2.20), elderly/AF (HR: 1.42; 95% CI: 1.20-1.70), and metabolic (HR: 1.40; 95% CI: 1.20-1.80) groups had higher rates of the composite outcome than patients in the young group, primarily driven by differences in rehospitalization. Treatment allocation (placebo or serelaxin) modified these associations (Pinteraction <0.001). Serelaxin-treated patients in the young group were associated with a lower risk for all-cause mortality (HR: 0.59; 95% CI: 0.40-0.90). Similarly, patients from the RELAX-AHF trial clustered in 5 multimorbidity groups. The clinical characteristics and associations with outcomes could also be validated. CONCLUSIONS: Comorbidities naturally clustered into 5 mutually exclusive groups in RELAX-AHF-2, showing variations in clinical outcomes. These data emphasize that the specific combination of comorbidities can influence adverse outcomes and treatment responses in patients with AHF.

Seis-ing up the Super-Morrison formation sauropods.

The Upper Jurassic Morrison Formation sauropods Diplodocus (formerly "Seismosaurus") hallorum and Supersaurus vivianae are quantifiably the largest dinosaurian taxa from the formation, as well as being among the largest dinosaurs in the world. Their extreme body size (in particular body length, c. 50+ m) has fascinated the paleontological community since their discoveries and has sparked an ongoing discussion on the trends and limits of Morrison Formation sauropod body size. Although not an undeviating proxy, often the largest and skeletally most mature specimens are among the rarest (as exemplified in Triceratops). While their body size has no phylogenetic bearing, the extreme size and potential eco and biological significance of these two sauropod taxa are frequently discussed. Whether these rare and titanically proportioned sauropod specimens are large-bodied, senescent or both is an often-repeating rhetoric. To definitively make maturational inferences about these taxa, we osteohistologically sampled the holotype of D. hallorum (NMMNH P-25079) and the second known specimen of S. vivianae (WDC DMJ-021). Our age-determinant and maturational assessments indicate that both specimens were skeletally mature at their respective age of death. Retrocalculation methods for D. hallorum NMMNH P-25079 produce a maximum age-at-death estimation of 60 years, whereas S. vivianae WDC DMJ-021 lived well past skeletal maturity-so much so that reliable retrocalculated ages cannot be accurately determined at this time. Additionally, the rarity of such large sauropods within the Morrison Formation might be more parsimoniously explained as relating to their maturity as opposed to representing aberrant taxa on the Morrison landscape.

Validation of the Subaxial Cervical Spine Injury Classification score in children: a single-institution experience at a level 1 pediatric trauma center.

OBJECTIVE: The Subaxial Cervical Spine Injury Classification (SLIC) score has not been previously validated for a pediatric population. The authors compared the SLIC treatment recommendations for pediatric subaxial cervical spine trauma with real-world pediatric spine surgery practice. METHODS: A retrospective cohort study at a pediatric level 1 trauma center was conducted in patients < 18 years of age evaluated for trauma from 2012 to 2021. An SLIC score was calculated for each patient, and the subsequent recommendations were compared with actual treatment delivered. Percentage misclassification, sensitivity, specificity, positive (PPV) and negative predictive value (NPV), and area under the receiver operating characteristic (ROC) curve (AUC) were calculated. RESULTS: Two hundred forty-three pediatric patients with trauma were included. Twenty-five patients (10.3%) underwent surgery and 218 were managed conservatively. The median SLIC score was 2 (interquartile range = 2). Sixteen patients (6.6%) had an SLIC score of 4, for which either conservative or surgical treatment is recommended; 27 children had an SLIC score ≥ 5, indicating a recommendation for surgical treatment; and 200 children had an SLIC score ≤ 3, indicating a recommendation for conservative treatment. Of the 243 patients, 227 received treatment consistent with SLIC score recommendations (p < 0.001). SLIC sensitivity in determining surgically treated patients was 79.2% and the specificity for accurately determining who underwent conservative treatment was 96.1%. The PPV was 70.3% and the NPV was 97.5%. There was a 5.7% misclassification rate (n = 13) using SLIC. Among patients for whom surgical treatment would be recommended by the SLIC, 29.6% (n = 8) did not undergo surgery; similarly, 2.5% (n = 5) of patients for whom conservative management would be recommended by the SLIC had surgery. The ROC curve for determining treatment received demonstrated excellent discriminative ability, with an AUC of 0.96 (OR 3.12, p < 0.001). Sensitivity decreased when the cohort was split by age (< 10 and ≥ 10 years old) to 0.5 and 0.82, respectively; specificity remained high at 0.98 and 0.94. CONCLUSIONS: The SLIC scoring system recommended similar treatment when compared with the actual treatment delivered for traumatic subaxial cervical spine injuries in children, with a low misclassification rate and a specificity of 96%. These findings demonstrate that the SLIC can be useful in guiding treatment for pediatric patients with subaxial cervical spine injuries. Further investigation into the score in young children (< 10 years) using a multicenter cohort is warranted.

Sustained delivery of celecoxib from nanoparticles embedded in hydrogel injected into the biopsy cavity to prevent biopsy-induced breast cancer metastasis.

PURPOSE: We have previously reported that protracted Cyclooxygenase-2 (COX-2) activity in bone marrow-derived cells (BMDCs) infiltrating into biopsy wounds adjacent to the biopsy cavity of breast tumors in mice promotes M2-shift of macrophages and pro-metastatic changes in cancer cells, effects which were suppressed by oral administration of COX-2 inhibitors. Thus, local control of COX-2 activity in the biopsy wound may mitigate biopsy-induced pro-metastatic changes. METHODS: A combinatorial delivery system-thermosensitive biodegradable poly(lactic acid) hydrogel (PLA-gel) incorporating celecoxib-encapsulated poly(lactic-co-glycolic acid) nanoparticles (Cx-NP/PLA-gel)-was injected into the biopsy cavity of Py230 murine breast tumors to achieve local control of COX-2 activity in the wound stroma. RESULTS: A single intra-biopsy cavity injection of PLA-gel loaded with rhodamine-encapsulated nanoparticles (NPs) showed sustained local delivery of rhodamine preferentially to infiltrating BMDCs with minimal to no rhodamine uptake by the reticuloendothelial organs in mice. Moreover, significant reductions in M2-like macrophage density, cancer cell epithelial-to-mesenchymal transition, and blood vessel density were observed in response to a single intra-biopsy cavity injection of Cx-NP/PLA-gel compared to PLA-gel loaded with NPs containing no payload. Accordingly, intra-biopsy cavity injection of Cx-NP/PLA-gel led to significantly fewer metastatic cells in the lungs than control-treated mice. CONCLUSION: This study provides evidence for the feasibility of sustained, local delivery of payload preferential to BMDCs in the wound stroma adjacent to the biopsy cavity using a combinatorial delivery system to reduce localized inflammation and effectively mitigate breast cancer cell dissemination.

Wildfires and Human Health.

This JAMA Insights explores the adverse effects of wildfires on human health and health care systems and offers suggestions on how clinicians can help mitigate the health threats posed by wildfires.

Differential Components of Bradykinesia in Parkinson Disease Revealed by Deep Brain Stimulation.

Bradykinesia is a term describing several manifestations of movement disruption caused by Parkinson's disease (PD), including movement slowing, amplitude reduction, and gradual decrease of speed and amplitude over multiple repetitions of the same movement. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves bradykinesia in patients with PD. We examined the effect of DBS on specific components of bradykinesia when applied at two locations within the STN, using signal processing techniques to identify the time course of amplitude and frequency of repeated hand pronation-supination movements performed by participants with and without PD. Stimulation at either location increased movement amplitude, increased frequency, and decreased variability, though not to the range observed in the control group. Amplitude and frequency showed decrement within trials, which was similar in PD and control groups and did not change with DBS. Decrement across trials, by contrast, differed between PD and control groups, and was reduced by stimulation. We conclude that DBS improves specific aspects of movement that are disrupted by PD, whereas it does not affect short-term decrement that could reflect muscular fatigue.

Application of high-dimensional propensity score methods to the National Health and Aging Trends Study.

BACKGROUND: High-dimensional propensity scoring (HDPS) is a method for empirically identifying potential confounders within large healthcare databases such as administrative claims data. However, this method has not yet been applied to large national health surveys such as the National Health and Aging Trends Study (NHATS), an ongoing nationally representative survey of older adults in the U.S and important resource in gerontology research. METHODS: In this Research Practice article, we present an overview of HDPS and describe the specific data transformation steps and analytic considerations needed to apply it to national health surveys. We applied HDPS within NHATS to investigate the association between self-reported visual difficulty and incident dementia, comparing HDPS to conventional confounder selection methods. RESULTS: Among 7,207 dementia-free NHATS wave 1 respondents, 528 (7.3%) had self-reported visual difficulty. In an unadjusted discrete time proportional hazards model accounting for the complex survey design of NHATS, self-reported visual difficulty was strongly associated with incident dementia (OR 2.34, 95% CI: 1.95-2.81). After adjustment for standard investigator-selected covariates via inverse probability weighting, the magnitude of this association decreased, but evidence of an association remained (OR 1.44, 95% CI: 1.11-1.85). Adding 75 HDPS-prioritized variables to the investigator-selected propensity score model resulted in further attenuation of the association between visual impairment and dementia (OR 0.94, 95% CI: 0.70-1.23). CONCLUSIONS: HDPS can be successfully applied to national health surveys such as NHATS and may improve confounder adjustment. We hope developing this framework will encourage future consideration of HDPS in this setting.

The Effects of Suicide Prevention Gatekeeper Training on Behavioral Intention and Intervention Behavior: A Systematic Review and Meta-Analysis.

To understand the current state of research, a systematic review and meta-analysis were conducted to synthesize the effects of suicide prevention gatekeeper training (GKT) on participant behavioral intention to intervene and participant suicide intervention behaviors. Included studies examined GKT with adult participants and measured either behavioral intention to conduct a suicide intervention or the utilization of suicide intervention skills. Searches yielded a total of 43 studies from 46 reports, comprising 21,720 participants. To quantify change over time, the standardized mean gain effect size metric was utilized. Large effect sizes were found for behavioral intention from pre-training to post-training (1.03, 95% CI [0.80, 1.25]) and short-term follow-up (0.78, 95% CI [0.59, 0.97]). Smaller effect sizes were found for intervention behavior from pre-training to short-term (0.33, 95% CI [0.21, 0.46]) and long-term follow-up (0.22, 95% CI [0.14, 0.30]). Although this meta-analysis reveals a positive effect for GKT on behavioral outcomes, the low methodological quality of the currently available evidence limits the ability to draw conclusions from the synthesis. This work informs policymakers and interventionists on best practices for GKT and highlights that additional, rigorous research is needed.

Long-term impact of COVID-19 hospitalisation among individuals with pre-existing airway diseases in the UK: a multicentre, longitudinal cohort study - PHOSP-COVID.

Background: The long-term outcomes of COVID-19 hospitalisation in individuals with pre-existing airway diseases are unknown. Methods: Adult participants hospitalised for confirmed or clinically suspected COVID-19 and discharged between 5 March 2020 and 31 March 2021 were recruited to the Post-hospitalisation COVID-19 (PHOSP-COVID) study. Participants attended research visits at 5 months and 1 year post discharge. Clinical characteristics, perceived recovery, burden of symptoms and health-related quality of life (HRQoL) of individuals with pre-existing airway disease (i.e., asthma, COPD or bronchiectasis) were compared to the non-airways group. Results: A total of 615 out of 2697 (22.8%) participants had a history of pre-existing airway diseases (72.0% diagnosed with asthma, 22.9% COPD and 5.1% bronchiectasis). At 1 year, the airways group participants were less likely to feel fully recovered (20.4% versus 33.2%, p<0.001), had higher burden of anxiety (29.1% versus 22.0%, p=0.002), depression (31.2% versus 24.7%, p=0.006), higher percentage of impaired mobility using short physical performance battery ≤10 (57.4% versus 45.2%, p<0.001) and 27% had a new disability (assessed by the Washington Group Short Set on Functioning) versus 16.6%, p=0.014. HRQoL assessed using EQ-5D-5L Utility Index was lower in the airways group (mean±SD 0.64±0.27 versus 0.73±0.25, p<0.001). Burden of breathlessness, fatigue and cough measured using a study-specific tool was higher in the airways group. Conclusion: Individuals with pre-existing airway diseases hospitalised due to COVID-19 were less likely to feel fully recovered, had lower physiological performance measurements, more burden of symptoms and reduced HRQoL up to 1 year post-hospital discharge.

Carbon, nitrogen, and sulfur elemental and isotopic variations in mouse hair and bone collagen during short-term graded calorie restriction.

This study characterized the effect of calorie restriction (CR) on elemental content and stable isotope ratio measurements of bone "collagen" and hair keratin. Adult mice on graded CR (10-40%; 84 days) showed decreased hair δ 15N, δ 13C, and δ 34S values (significantly for δ 15N) with increasing CR, alongside a significant increase in bone "collagen" δ 15N values and a decrease in "collagen" δ 13C values. We propose this was likely due to the intensified mobilization of endogenous proteins, as well as lipids in newly synthesized "collagen". Elemental analysis of bone "collagen" revealed decreased carbon, nitrogen, and sulfur % content with increasing CR which is attributed to a change in the in vivo bone "collagen" structure with extent of CR. This complexity challenges the use of elemental indicators in the assessment of collagen quality in archaeological studies where nutritional stress may be a factor.

An evaluation of the genotoxicity and 90-day repeated dose oral toxicity in rats of Porphyridium purpureum.

Interest in microalgae products for use in food is increasing, as demands for sustainable and cost-effective food choices grow due to the escalating global population and increase in climate-related struggles with agriculture. Toxicological assessments of some species of microalgae have been conducted, but there were little data available for the oral consumption of the red microalgae Porphyridium purpureum and no data on genotoxicity. This article articulates a genotoxicity assessment and a 90-day repeated dose oral toxicity study in rats performed according to OECD guidelines. Under the experimental conditions applied, the test item did not induce gene mutations by base pair changes or frameshifts in the genome of the strains used in the bacterial reverse mutation test. Similarly, the test item did not induce structural chromosomal aberrations in V79 hamster lung cells. The test item also did not cause chromosomal damage in bone marrow of mice in the mammalian micronucleus test. The no observed adverse effect level (NOAEL) of the 90-day repeated dose oral toxicity study in rats was determined to be the highest dose tested, 3000 mg/kg bw/day. These data add to the body of evidence regarding the safety of P. purpureum for human consumption.

Lymphedema vs lipedema: Similar but different.

Lymphedema and lipedema are chronic debilitating disorders that most commonly affect the upper and lower extremities. Although they can appear similar, they differ in important ways, which the authors of this article review and contrast.

Cardiac autonomic function in REM-related obstructive sleep apnoea: insights from nocturnal heart rate variability profiles.

PURPOSE: In light of the reported association between REM-related obstructive sleep apnoea (OSA) and heightened cardiovascular risk, this study aims to compare cardiac autonomic function in patients with REM-OSA and OSA independent of sleep stage. We hypothesized that REM-OSA patients would exhibit higher sympathetic cardiac modulation based on heart rate variability (HRV) profiles. METHODS: HRV was compared between the OSA group (AHI ≥ 5 events/h, n = 252) and the REM-OSA group (AHI ≥ 5 events/h, AHIREM:AHINREM ≥ 2, n = 137). Time- and frequency-domain measures of HRV were analysed during N2 and REM sleep. RESULTS: Clinical characteristics between the two test groups differed significantly, 45% of REM-OSA patients were female, with mild OSA (median, interquartile range (IQR)) AHI of 10 (7) events/h. Only 26% of the OSA cohort were female with moderate OSA (AHI = 17 (20) events/h, p < 0.001). Compared with the OSA group, the low frequency to high frequency ratio (LF:HF) and LF power were lower and HF power was higher in the REM-OSA group during N2 (LF:HF, p = 0.012; LF; p = 0.013; HF, p = 0.007) and in REM sleep (LF:HF, p = 0.002; LF, p = 0.004; HF, p < 0.001). Patient sex and OSA severity had a significant combined effect on average N to N interval, LF power, and LF:HF ratio during N2 and REM sleep (all p < 0.001). CONCLUSION: Contrary to our hypothesis, REM-OSA patients demonstrated consistently higher cardiac vagal modulation, reflecting better cardiac autonomic adaptation. These results were attributed to differences in OSA severity and sex in these two groups, both independently affecting HRV. This study emphasises the need for future research into the underlying pathophysiology of REM-OSA and the potential implications of sex and OSA severity on cardiovascular risk.

Outcomes of Biodegradable Temporizing Matrix for Soft Tissue Reconstruction of the Hand and Extremities.

Background: NovoSorb biodegradable temporizing matrix (BTM) is a novel, bilayer, synthetic skin substitute made of biodegradable polyurethane foam covered with a sealing membrane. BTM has demonstrated excellent outcomes in burn literature; however, few studies have been published for hand and extremity soft tissue reconstruction. Methods: All patients who underwent extremity reconstruction with BTM from 2018 to 2023 were reviewed. Demographics, presentations, and clinical outcomes were recorded. Results: A total of 86 cases from 54 patients (53.7% pediatric; age range: 0-81 years) were included. Common indications included trauma (36%), infection (18.6%), and malignancy (11.6%). BTM was placed over exposed tendon (38.4%), bone (19%), joints (12.8%), nerves (8.1%), and/or blood vessels (7%). BTM served as temporary wound coverage in 26 cases. Complications included hematoma (8.1%), infection (4.7%), and spontaneous delamination (4.7%). Wound closure was successfully obtained without flap use in 93.3%. Poor BTM take was associated with peripheral vascular disease, hypertension, immunosuppression, and BTM hematoma and infection (<0.05). Conclusion: This study contributes to the growing body of evidence favoring BTM use in challenging reconstructive cases. Although prospective comparative studies are forthcoming, BTM likely has broad applications in reconstructive surgery.

The chromatin regulator Ankrd11 controls cardiac neural crest cell-mediated outflow tract remodeling and heart function.

ANKRD11 (Ankyrin Repeat Domain 11) is a chromatin regulator and a causative gene for KBG syndrome, a rare developmental disorder characterized by multiple organ abnormalities, including cardiac defects. However, the role of ANKRD11 in heart development is unknown. The neural crest plays a leading role in embryonic heart development, and its dysfunction is implicated in congenital heart defects. We demonstrate that conditional knockout of Ankrd11 in the murine embryonic neural crest results in persistent truncus arteriosus, ventricular dilation, and impaired ventricular contractility. We further show these defects occur due to aberrant cardiac neural crest cell organization leading to outflow tract septation failure. Lastly, knockout of Ankrd11 in the neural crest leads to impaired expression of various transcription factors, chromatin remodelers and signaling pathways, including mTOR, BMP and TGF-ß in the cardiac neural crest cells. In this work, we identify Ankrd11 as a regulator of neural crest-mediated heart development and function.

Resolving chaperone-assisted protein folding on the ribosome at the peptide level.

Protein folding in vivo begins during synthesis on the ribosome and is modulated by molecular chaperones that engage the nascent polypeptide. How these features of protein biogenesis influence the maturation pathway of nascent proteins is incompletely understood. Here, we use hydrogen-deuterium exchange mass spectrometry to define, at peptide resolution, the cotranslational chaperone-assisted folding pathway of Escherichia coli dihydrofolate reductase. The nascent polypeptide folds along an unanticipated pathway through structured intermediates not populated during refolding from denaturant. Association with the ribosome allows these intermediates to form, as otherwise destabilizing carboxy-terminal sequences remain confined in the ribosome exit tunnel. Trigger factor binds partially folded states without disrupting their structure, and the nascent chain is poised to complete folding immediately upon emergence of the C terminus from the exit tunnel. By mapping interactions between the nascent chain and ribosomal proteins, we trace the path of the emerging polypeptide during synthesis. Our work reveals new mechanisms by which cellular factors shape the conformational search for the native state.

PI3Kγ inhibition circumvents inflammation and vascular leak in SARS-CoV-2 and other infections.

Virulent infectious agents such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and methicillin-resistant Staphylococcus aureus (MRSA) induce tissue damage that recruits neutrophils, monocyte, and macrophages, leading to T cell exhaustion, fibrosis, vascular leak, epithelial cell depletion, and fatal organ damage. Neutrophils, monocytes, and macrophages recruited to pathogen-infected lungs, including SARS-CoV-2-infected lungs, express phosphatidylinositol 3-kinase gamma (PI3Kγ), a signaling protein that coordinates both granulocyte and monocyte trafficking to diseased tissues and immune-suppressive, profibrotic transcription in myeloid cells. PI3Kγ deletion and inhibition with the clinical PI3Kγ inhibitor eganelisib promoted survival in models of infectious diseases, including SARS-CoV-2 and MRSA, by suppressing inflammation, vascular leak, organ damage, and cytokine storm. These results demonstrate essential roles for PI3Kγ in inflammatory lung disease and support the potential use of PI3Kγ inhibitors to suppress inflammation in severe infectious diseases.