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1.
Transl Lung Cancer Res ; 13(8): 1907-1917, 2024 Aug 31.
Article in English | MEDLINE | ID: mdl-39263016

ABSTRACT

Background: Radiomics has shown promise in improving malignancy risk stratification of indeterminate pulmonary nodules (IPNs) with many platforms available, but with no head-to-head comparisons. This study aimed to evaluate transportability of radiomic models across platforms by comparing performances of a commercial radiomic feature extractor (HealthMyne) with an open-source extractor (PyRadiomics) on diagnosis of lung cancer in IPNs. Methods: A commercial radiomic feature extractor was used to segment IPNs from computed tomography (CT) scans, and a previously validated radiomic model based on commercial features was used as baseline (ComRad). Using same segmentation masks, PyRadiomics, an open-source feature extractor was used to build three open-source radiomic models (OpenRad) using different methods: de novo open-source model derived using least absolute shrinkage and selection operator (LASSO) for feature selection, selecting open-source features matched to ComRad features based upon Imaging Biomarker Standardization Initiative (IBSI) nomenclature, and selecting open-source features most highly correlated to ComRad features. Radiomic models were trained on an internal cohort (n=161) and externally validated on 3 cohorts (n=278). We added Mayo clinical risk score to OpenRad and ComRad models, creating integrated clinical radiomic (ClinRad) models. All models were compared using area under the curve (AUC) and evaluated for clinical improvement using bias-corrected clinical net reclassification indices (cNRIs). Results: ComRad AUC was 0.76 [95% confidence interval (CI): 0.71-0.82], and OpenRad AUC was 0.75 (95% CI: 0.69-0.81) for LASSO model, 0.74 (95% CI: 0.68-0.79) for Spearman's correlation, and 0.71 (95% CI: 0.65-0.77) for IBSI. Mayo scores were added to OpenRad LASSO model, which performed best, forming open-source ClinRad model with AUC of 0.80 (95% CI: 0.74-0.86), identical to commercial ClinRad's AUC. Both ClinRad models showed clinical improvement compared to Mayo alone, with commercial ClinRad achieving cNRI of 0.09 (95% CI: 0.02-0.15) for benign and 0.07 (95% CI: 0.00-0.13) for malignant, and open-source ClinRad achieving cNRI of 0.09 (95% CI: 0.02-0.15) for benign and 0.06 (95% CI: 0.00-0.12) for malignant. Conclusions: Transportability of radiomic models across platforms directly does not conserve performance, but radiomic platforms can provide equivalent results when building de novo models allowing for flexibility in feature selection to maximize prediction accuracy.

2.
JAMA Cardiol ; 2024 Sep 04.
Article in English | MEDLINE | ID: mdl-39230897

ABSTRACT

Importance: Understanding of the genetics of accessory atrioventricular pathways (APs) and affiliated arrhythmias is limited. Objective: To investigate the genetics of APs and affiliated arrhythmias. Design, Setting, and Participants: This was a genome-wide association study (GWAS) of APs, defined by International Classification of Diseases (ICD) codes and/or confirmed by electrophysiology (EP) study. Genome-wide significant AP variants were tested for association with AP-affiliated arrhythmias: paroxysmal supraventricular tachycardia (PSVT), atrial fibrillation (AF), ventricular tachycardia, and cardiac arrest. AP variants were also tested in data on other heart diseases and measures of cardiac physiology. Individuals with APs and control individuals from Iceland (deCODE Genetics), Denmark (Copenhagen Hospital Biobank, Danish Blood Donor Study, and SupraGen/the Danish General Suburban Population Study [GESUS]), the US (Intermountain Healthcare), and the United Kingdom (UK Biobank) were included. Time of phenotype data collection ranged from January 1983 to December 2022. Data were analyzed from August 2022 to January 2024. Exposures: Sequence variants. Main Outcomes and Measures: Genome-wide significant association of sequence variants with APs. Results: The GWAS included 2310 individuals with APs (median [IQR] age, 43 [28-57] years; 1252 [54.2%] male and 1058 [45.8%] female) and 1 206 977 control individuals (median [IQR] year of birth, 1955 [1945-1970]; 632 888 [52.4%] female and 574 089 [47.6%] male). Of the individuals with APs, 909 had been confirmed in EP study. Three common missense variants were associated with APs, in the genes CCDC141 (p.Arg935Trp: adjusted odds ratio [aOR], 1.37; 95% CI, 1.24-1.52, and p.Ala141Val: aOR, 1.55; 95% CI 1.34-1.80) and SCN10A (p.Ala1073Val: OR, 1.22; 95% CI, 1.15-1.30). The 3 variants associated with PSVT and the SCN10A variant associated with AF, supporting an effect on AP-affiliated arrhythmias. All 3 AP risk alleles were associated with higher heart rate and shorter PR interval, and have reported associations with chronotropic response. Conclusions and Relevance: Associations were found between sequence variants and APs that were also associated with risk of PSVT, and thus likely atrioventricular reentrant tachycardia, but had allele-specific associations with AF and conduction disorders. Genetic variation in the modulation of heart rate, chronotropic response, and atrial or atrioventricular node conduction velocity may play a role in the risk of AP-affiliated arrhythmias. Further research into CCDC141 could provide insights for antiarrhythmic therapeutic targeting in the presence of an AP.

3.
Neurology ; 103(7): e209797, 2024 Oct 08.
Article in English | MEDLINE | ID: mdl-39231380

ABSTRACT

BACKGROUND AND OBJECTIVES: Traumatic brain injury (TBI) is frequently characterized by chronic motor deficits. Therefore, this clinical trial assessed whether intracranial implantation of allogeneic modified mesenchymal stromal (SB623) cells can improve chronic motor deficits after TBI. METHODS: Post hoc analysis of the double-blind, randomized, prospective, surgical sham-controlled, phase 2, STEMTRA clinical trial (June 2016 and March 2019) with 48 weeks of follow-up was conducted. In this international, multicenter clinical trial, eligible participants had moderate-to-severe TBI, were ≥12 months postinjury, and had chronic motor deficits. Participants were randomized in a 1:1:1:1 ratio to stereotactic surgical intracranial implantation of SB623 cells (2.5 × 106, 5.0 × 106, 10 × 106) or surgical sham-controlled procedure. The prespecified primary efficacy end point was significantly greater change from baseline of the Fugl-Meyer Motor Scale (FMMS) score, a measure of motor status, for the SB623 pooled vs control arm at 24 weeks. RESULTS: A total of 211 participants were screened, 148 were excluded, and 63 underwent randomization, of which 61 (97%; mean age, 34 [SD, 12] years; 43 men [70.5%]) completed the trial. Single participants in the SB623 2.5 × 106 and 5.0 × 106 cell dose groups discontinued before surgery. Safety and efficacy (modified intent-to-treat) were assessed in participants who underwent surgery (N = 61; SB623 = 46, controls = 15). The primary efficacy end point (FMMS) was achieved (least squares mean [SE] SB623: +8.3 [1.4]; 95% CI 5.5-11.2 vs control: +2.3 [2.5]; 95% CI -2.7 to 7.3; p = 0.04), with faster improvement of the FMMS score in SB623-treated groups than in controls at 24 weeks and sustained improvement at 48 weeks. At 48 weeks, improvement of function and activities of daily living (ADL) was greater, but not significantly different in SB623-treated groups vs controls. The incidence of adverse events was equivalent in SB623-treated groups and controls. There were no deaths or withdrawals due to adverse events. DISCUSSION: Intraparenchymal implantation of SB623 cells was safe and significantly improved motor status at 24 weeks in participants with chronic motor deficits after TBI, with continued improvement of function and ADL at 48 weeks. Cell therapy can modify chronic neurologic deficits after TBI. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02416492. Submitted to registry: April 15, 2015. First participant enrolled: July 6, 2016. Available at: classic.clinicaltrials.gov/ct2/show/NCT02416492. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that intracranial implantation of allogeneic stem (SB623) cells in adults with motor deficits from chronic TBI improves motor function at 24 weeks.


Subject(s)
Brain Injuries, Traumatic , Mesenchymal Stem Cell Transplantation , Humans , Brain Injuries, Traumatic/complications , Brain Injuries, Traumatic/surgery , Brain Injuries, Traumatic/therapy , Male , Adult , Female , Double-Blind Method , Mesenchymal Stem Cell Transplantation/methods , Middle Aged , Prospective Studies , Treatment Outcome , Young Adult
5.
J Neurotrauma ; 2024 Sep 12.
Article in English | MEDLINE | ID: mdl-39264867

ABSTRACT

Traumatic brain injury (TBI), a global leading cause of mortality and disability, lacks effective treatments to enhance recovery. Synaptic remodeling has been postulated as one mechanism that influences outcomes after TBI. We sought to investigate whether common mechanisms affecting synapse maintenance are shared between TBI and other neuropsychiatric conditions using pathway enrichment tools and genome-wide genotype data, with the goal of highlighting novel treatment targets. We leveraged an integrative approach, combining data from Genome-Wide Association Studies (GWAS) with pathway and gene-set enrichment analyses. Literature review-based and Reactome database-driven approaches were combined to identify synapse-related pathways of interest in TBI outcome, and to assess for shared associations with conditions in which synapse-related pathobiological mechanisms have been implicated, including Alzheimer's disease (AD), schizophrenia (SCZ), major depressive disorder (MDD), post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Gene and pathway-level enrichment analyses were conducted using MAGMA and its extensions, e- and H-MAGMA, followed by Mendelian Randomization (MR) to investigate potential causal associations. Of the 98 pathways tested, 32 were significantly enriched in the included conditions. In TBI outcome, we identified significant enrichment in five pathways: "Serotonin clearance from the synaptic cleft" (p-value = 0.0001), "Presynaptic nicotinic acetylcholine receptors" (p-value = 0.0003), "Postsynaptic nicotinic acetylcholine receptors" (p-value = 0.0003), "Highly sodium permeable postsynaptic acetylcholine nicotinic receptors" (p-value = 0.0001), and "Acetylcholine binding and downstream events" pathways (p-value = 0.0003). These associations highlight potential involvement of the cholinergic and serotonergic systems in post-TBI recovery. Three of those pathways were shared between TBI and schizophrenia, suggesting possible pathophysiologic commonalities. In this study we utilize comparative and integrative genomic approaches across brain conditions that share synaptic mechanisms to explore the pathophysiology of TBI outcome. Our results implicate associations between TBI outcome and synaptic pathways as well as pathobiologic overlap with other neuropsychiatric diseases.

6.
ACS Energy Lett ; 9(8): 4180-4187, 2024 Aug 09.
Article in English | MEDLINE | ID: mdl-39144811

ABSTRACT

To explore the possibility of oxygen dimerization-particularly, the formation of molecular oxygen-like species-in the bulk of LiNiO2 lithium ion cathode materials at high states of charge, we conduct a redox-product structure search inspired by recent methodological developments for point-defect structure prediction. We find that (1) delithiated Li1-x NiO2 (x = 1) has good kinetic stability toward decomposition into molecular oxygen and reduced transition-metal oxides but (2) defects can act as nucleation sites for oxygen dimerization. These results help reconcile conflicting reports on the formation of bulk molecular oxygen in LiNiO2 and other nickel-rich cathode materials, highlighting the role of defect chemistry in driving the bulk degradation of these compounds.

7.
Foodborne Pathog Dis ; 2024 Aug 02.
Article in English | MEDLINE | ID: mdl-39093865

ABSTRACT

The study was conducted to determine the proportion and concentration of enterohemorrhagic Escherichia coli (EHEC) O157 and six non-O157 (O26, O45, O103, O111, O121, and O145) serogroups and identify seasonal and processing plant differences in feces and on hides of cull dairy cattle processed in commercial slaughterhouses in the United States. Approximately 60 rectal and 60 hide-on samples from matched carcasses were collected in each of three processing plants, in two periods; summer of 2017 and spring of 2018. Samples before enrichment were spiral plated to quantify EHEC, and postenriched samples underwent culture methods that included immuno-magnetic separation, plating on selective media, and PCR assays for identification and serogroup confirmation of putative isolates. An isolate was considered EHEC O157 positive if it harbored serogroup-specific (rfbE), Shiga toxin (stx1 and/or stx2), and intimin (eae) genes and EHEC non-O157 positive if at least one of the non-O157 serogroup-specific, stx1 and/or stx2, and eae genes was identified. Generalized linear mixed models were fitted to estimate overall proportion of positives for EHEC O157 and non-O157 EHEC serogroups, as well as seasonal and processing plant differences in fecal and hide-on proportion of positives. The fecal EHEC proportion at the sample level was 1.8% (95% CI = 0.0-92.2%) and 4.2% (95% CI = 0.0-100.0%) for EHEC O157 and EHEC non-O157, respectively. Hide sample level proportion of positives was 3.0% (95% CI = 0.0-99.9%) for EHEC O157 and 1.6% (95% CI = 0.0-100.0%) for EHEC non-O157. The proportion of EHEC O157 and non-O157 significantly differed by processing plant and sample type (hide vs. feces), but not by season. The association between proportion of EHEC serogroups in feces with the proportion on hides collected from matched cattle was 7.8% (95% CI = 0.6-53.3%) and 3.8% (95% CI = 0.3-30.8%) for EHEC O157 and non-O157, respectively. Taken together, our findings provide evidence of a low proportion of EHEC serogroups in the feces and on hides of cull dairy cattle and that their proportion varies across processing plants.

8.
Neurocrit Care ; 2024 Aug 13.
Article in English | MEDLINE | ID: mdl-39138718

ABSTRACT

BACKGROUND: Interventions to reduce intracranial pressure (ICP) in patients with traumatic brain injury (TBI) are multimodal but variable, including sedation-dosing strategies. This article quantifies the different sedation intensities administered in patients with moderate to severe TBI (msTBI) using the therapy intensity level (TIL) across different intensive care units (ICUs), including the use of additional ICP-lowering therapies. METHODS: Within the prospective Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study, we performed a retrospective analysis of adult patients with msTBI admitted to an ICU for a least 5 days from seven US level 1 trauma centers who received invasive ICP monitoring and intravenous sedation. Sedation intensity was classified prospectively as one of three ordinal levels as part of the validated TIL score, which were collected at least once a day. RESULTS: A total of 127 patients met inclusion criteria (mean age 41.6 ± 17.7 years; 20% female). The median Injury Severity Score was 27 (interquartile range 17-33), with a median admission Glasgow Coma Score of 3 (interquartile range 3-7); 104 patients had severe TBI (82%), and 23 patients had moderate TBI (18%). The sedation intensity score was highest on the first ICU day (2.69 ± 1.78), independent of patient severity. Time to reaching each sedation intensity level varied by site. Sedation level I was reached within 24 h for all sites, but sedation levels II and III were reached variably between days 1 and 3. Sedation level III was never reached by two of seven sites. The total TIL score was highest on the first ICU day, with a modest decrease for each subsequent ICU day, but there was high site-specific practice-pattern variation. CONCLUSIONS: Intensity of sedation and other therapies for elevated ICP for patients with msTBI demonstrate large practice-pattern variation across level 1 trauma centers within the TRACK-TBI cohort study, independent of patient severity. Optimizing sedation strategies using patient-specific physiologic and pathoanatomic information may optimize patient outcomes.

9.
Nutrients ; 16(15)2024 Aug 03.
Article in English | MEDLINE | ID: mdl-39125422

ABSTRACT

One in ten Americans suffers from type 2 diabetes, which, if not managed well, can result in severe complications, disability, and premature death. Diabetes education classes can play a pivotal role in providing practical education on diabetes and self-care behaviors, with a particular emphasis on dietary management, which is often regarded as the most demanding diabetes self-care behavior. The Texas A&M AgriLife Extension Service developed Cooking Well with Diabetes (CWWD), a four-week interactive diabetes education series, with each week consisting of a lecture on healthy eating coupled with cooking lessons featuring diabetes-friendly recipes. The current study aimed to examine the effectiveness of CWWD in improving the frequency of healthy food preparation and consumption of program participants. Secondary data from 2017 to 2023 was analyzed involving 1574 adults from 59 predominantly rural Texas counties. Data from self-reported pre and post evaluations showed improvements in healthy food preparation and consumption behaviors. The curriculum enabled Extension Educators to introduce healthful dietary behaviors to a diverse group of clients. The curriculum can be adapted by Extension Educators in other states reaching a broader audience. The findings will inform future research aimed at planning and implementing successful diabetes education programs.


Subject(s)
Cooking , Diabetes Mellitus, Type 2 , Diet, Healthy , Humans , Cooking/methods , Diabetes Mellitus, Type 2/prevention & control , Male , Female , Texas , Middle Aged , Adult , Curriculum , Aged , Patient Education as Topic/methods , Self Care , Feeding Behavior
10.
Circ Arrhythm Electrophysiol ; : e012926, 2024 Aug 28.
Article in English | MEDLINE | ID: mdl-39193716

ABSTRACT

BACKGROUND: Catheter ablation (CA) improves clinical outcomes in patients with atrial fibrillation (AF) and heart failure (HF) with reduced ejection fraction (HFrEF). We aimed to evaluate the impact of CA on clinical and quality-of-life outcomes across HF subtypes. METHODS: All patients undergoing AF ablation at a tertiary center were enrolled in a prospective registry and included in this study (2013-2021). The primary end point was AF recurrence. Secondary end points included AF-related hospitalizations and quality-of-life outcomes. Patients were categorized according to their HF status: no HF, HFrEF, HF with mildly reduced ejection fraction (HFmrEF), and HF with preserved ejection fraction (HFpEF). RESULTS: 7020 patients were included (80% no HF, 8% HFrEF, 7% HFmrEF, and 5% HFpEF). Over 3 years, the cumulative incidence of AF recurrence after ablation was as follows: HFpEF (53%), HFmrEF (41%), HFrEF (41%), and no HF (34%); P<0.01. Multivariable Cox analyses confirmed these findings using no HF group as reference (HFpEF: hazard ratio, 1.47 [95% CI, 1.21-1.78]; HFmrEF: hazard ratio, 1.23 [95% CI, 1.04-1.45]; and HFrEF: hazard ratio, 1.17 [95% CI, 1.01-1.37]; P<0.05 for all). In all groups, CA resulted in a significant reduction of AF-related hospitalization (mean rate per 1 patient-years [before and after CA]; HFpEF [1.8 versus 0.3], HFmrEF [1.1 versus 0.2], HFrEF [1.1 versus 0.2], and no HF [1 versus 0.1]; P<0.01 for each comparison) and significant improvement in quality of life as measured by both the AF symptom severity score and the AF burden score (P<0.01 for the comparison between baseline and follow-up for each score when tested separately). CONCLUSIONS: AF recurrence rates after CA were higher in patients with HF compared with those without HF, with patients with HFpEF being at the highest risk of recurrence. Nonetheless, CA was associated with a significant reduction in AF symptoms, AF-related hospitalization, and HF symptoms in most patients irrespective of HF subtypes.

11.
Molecules ; 29(15)2024 Jul 27.
Article in English | MEDLINE | ID: mdl-39124947

ABSTRACT

Three new tridentate copper(II) N-heterocyclic carbene (NHC) complexes have been obtained and characterized with symmetrical C-4 substitutions on their pendent pyridine rings. Substitutions including methyl (Me), methoxy (OMe), and chloro (Cl) groups, which extend the library pincer Cu-NHC complexes under investigation, modify the impact of pyridinyl basicity on NCN pincer complexes. Both ligand precursors and copper(II) complexes are characterized using a range of techniques, including nuclear magnetic resonance (NMR) spectroscopy for 1H, 13C, 31P, and 19F nuclei, electrospray ionization mass spectrometry (ESI-MS), X-ray crystallography, cyclic voltammetry, and UV-Vis spectroscopy. The pyridine substitutions lead to minimal changes to bond lengths and angles in the X-ray crystal structures of these related complexes; there is a pronounced impact on the electrochemical behavior of both the ligand precursors and copper complexes in the solution. The substitution in the pyridinyl units of these complexes show an impact on the catalytic reactivity of these complexes as applied to a model C-N bond-forming reaction (CEL cross-coupling) under well-established conditions; however, this observation does not correlate to the expected change in basicity in these ligands.

12.
Cells ; 13(16)2024 Aug 22.
Article in English | MEDLINE | ID: mdl-39195287

ABSTRACT

The high-affinity IgE receptor, FcεRI, is typically associated with type 2 effectors such as mast cells (MC). The relatively unique expression profile of FcεRI and accumulating evidence from pre-clinical and clinical settings, such as MC interactions with tumors, have led us to study MCs as a potential therapeutic target in breast cancer. Our work identified MCs interacting with tumor cells at primary sites using the 4T1 (BALB/c) adenocarcinoma model in vivo. However, this analysis was complicated by a surprising finding that the tumor cells intrinsically and strongly expressed FcεRI. We further studied the expression and function of FcεRI in breast cancer cells in vitro. The 4T1 cells expressed FcεRI to a level similar to mouse bone marrow-derived MC (BMMC). Additionally, two established breast cancer cultures derived from human T-47D cells, one estrogen-dependent (E3) and the other estrogen-withdrawn (EWD8), also expressed FcεRI with EWD8 cells showing the greatest abundance. Functional analyses indicated that IgE-mediated antigen stimulation did not elicit classic Ca2+ flux in breast cancer cells as seen in the respective species' MCs; however, FcεRI crosslinking could stimulate IL-6 production from the T-47D derivatives. Preliminary analysis of primary breast cancer biopsy datasets using R2: Genomics Analysis and Visualization Platform was discordant with our in vivo model and in vitro observations. Indeed, FcεRI mRNA abundance declined in metastatic breast cancers compared to non-cancerous breast tissue. Altogether, we report a previously unidentified and immunologically substantive difference between breast cancer models and human primary tumors. Investigators pursuing FcεRI-relevant therapeutics in this context should be aware of this translational barrier.


Subject(s)
Breast Neoplasms , Receptors, IgE , Receptors, IgE/metabolism , Receptors, IgE/genetics , Breast Neoplasms/pathology , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Humans , Female , Cell Line, Tumor , Animals , Mice , Mast Cells/metabolism , Mice, Inbred BALB C , Gene Expression Regulation, Neoplastic , Interleukin-6/metabolism , Immunoglobulin E/metabolism
13.
J Neurol Sci ; 464: 123159, 2024 Sep 15.
Article in English | MEDLINE | ID: mdl-39094434

ABSTRACT

Activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a moderating factor between obesity and cognitive impairment in animals, but this has never been tested in humans following mild traumatic brain injury (mTBI). This is a retrospective cohort analysis of subjects enrolled at a single level 1 trauma center (n = 172). Participants completed Trail Making Test Part A and B (TMT-A and B) at six- and twelve-months, Blood samples were obtained within 24 h of mTBI and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, interleukin-18 (IL-18), and IL-1ß were assayed. Obese participants (BMI = 30-34.9) were associated with higher IL-18 (p = 0.03) and IL-1ß (p = 0.05) and severely obese participants (BMI > 35.0) were associated with higher IL-1ß (p = 0.005) than healthy weight participants. IL-1ß was associated with TMT-A at six- (p = 0.01) and twelve-months (p = 0.03) and TMT-B at twelve-months (p = 0.046). The interaction of severely obese BMI and IL-1ß was associated with TMT-B at six- (p = 0.049) and twelve-months (p = 0.02). ASC (p = 0.03) and the interaction of ASC with severely obese BMI was associated with TMTB at six- (p = 0.02) and twelve-months (p = 0.02). Obesity may augment acute inflammasome response to mTBI and influence worse long-term cognitive outcomes up to one-year post-injury.


Subject(s)
Biomarkers , Body Mass Index , Inflammasomes , Obesity , Humans , Male , Female , Obesity/blood , Obesity/complications , Obesity/psychology , Inflammasomes/blood , Adult , Biomarkers/blood , Middle Aged , Retrospective Studies , Brain Injuries, Traumatic/blood , Brain Injuries, Traumatic/complications , Brain Injuries, Traumatic/psychology , Glasgow Coma Scale , Interleukin-18/blood , Interleukin-1beta/blood , Young Adult , Cohort Studies , Neuropsychological Tests , Brain Concussion/blood , Brain Concussion/complications , Brain Concussion/psychology
14.
J Pathol ; 264(2): 212-227, 2024 Oct.
Article in English | MEDLINE | ID: mdl-39177649

ABSTRACT

WT1 encodes a podocyte transcription factor whose variants can cause an untreatable glomerular disease in early childhood. Although WT1 regulates many podocyte genes, it is poorly understood which of them are initiators in disease and how they subsequently influence other cell-types in the glomerulus. We hypothesised that this could be resolved using single-cell RNA sequencing (scRNA-seq) and ligand-receptor analysis to profile glomerular cell-cell communication during the early stages of disease in mice harbouring an orthologous human mutation in WT1 (Wt1R394W/+). Podocytes were the most dysregulated cell-type in the early stages of Wt1R394W/+ disease, with disrupted angiogenic signalling between podocytes and the endothelium, including the significant downregulation of transcripts for the vascular factors Vegfa and Nrp1. These signalling changes preceded glomerular endothelial cell loss in advancing disease, a feature also observed in biopsy samples from human WT1 glomerulopathies. Addition of conditioned medium from murine Wt1R394W/+ primary podocytes to wild-type glomerular endothelial cells resulted in impaired endothelial looping and reduced vascular complexity. Despite the loss of key angiogenic molecules in Wt1R394W/+ podocytes, the pro-vascular molecule adrenomedullin was upregulated in Wt1R394W/+ podocytes and plasma and its further administration was able to rescue the impaired looping observed when glomerular endothelium was exposed to Wt1R394W/+ podocyte medium. In comparative analyses, adrenomedullin upregulation was part of a common injury signature across multiple murine and human glomerular disease datasets, whilst other gene changes were unique to WT1 disease. Collectively, our study describes a novel role for altered angiogenic signalling in the initiation of WT1 glomerulopathy. We also identify adrenomedullin as a proangiogenic factor, which despite being upregulated in early injury, offers an insufficient protective response due to the wider milieu of dampened vascular signalling that results in endothelial cell loss in later disease. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.


Subject(s)
Kidney Glomerulus , Podocytes , Signal Transduction , Single-Cell Analysis , Transcriptome , WT1 Proteins , Animals , Podocytes/metabolism , Podocytes/pathology , WT1 Proteins/metabolism , WT1 Proteins/genetics , Humans , Kidney Glomerulus/metabolism , Kidney Glomerulus/pathology , Kidney Glomerulus/blood supply , Endothelial Cells/metabolism , Endothelial Cells/pathology , Mice , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/metabolism , Disease Models, Animal , Mutation , Kidney Diseases/genetics , Kidney Diseases/metabolism , Kidney Diseases/pathology , Adrenomedullin/genetics , Adrenomedullin/metabolism , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor A/genetics , Cell Communication , Cells, Cultured
15.
Am J Sports Med ; 52(10): 2620-2627, 2024 Aug.
Article in English | MEDLINE | ID: mdl-39140729

ABSTRACT

BACKGROUND: Osteochondritis dissecans (OCD) of the humeral capitellum is a rare and challenging condition to treat. Several surgical options exist, but in the last few years, the pendulum has swung from debridement and microfracture to restoration of the articular surface. Osteochondral autografts from the rib and knee have been described, but donor-site morbidity is a concern. PURPOSE: To expand the results of fresh osteochondral allograft transplantation (FOCAT) in a previously published report with inclusion of additional patients and a longer follow-up period. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: After institutional review board approval, the charts of patients who underwent FOCAT for OCD of the capitellum between 2006 and 2022 by a single surgeon were reviewed. The majority of cases (94%) had unstable lesions (Minami grades 2 and 3). A trial of nonoperative treatment had failed in all. All patients underwent diagnostic arthroscopy, followed by a mini-open, ligament-sparing approach with grafting using commercially available guides and instruments. RESULTS: A total of 35 patients were identified, of whom 25 were male. The mean age was 16 ± 3.9 years (range, 11-32 years). There were 24 baseball players (19 pitchers and 5 position players), 5 gymnasts, 3 cheerleaders/tumblers, 1 tennis player, 1 student (who did not participate in athletics), and 1 patient with avascular necrosis from chemotherapy. Eighteen patients had a mean flexion contracture of 14.1°± 11.9°. A single osteochondral allograft plug was used in 23 patients (mean diameter, 11.3 ± 2.8 mm), and 12 patients required 2 plugs (Mastercard technique). The mean follow-up was 92.6 ± 54.5 months (range, 24-204 months). There was significant improvement in Oxford (from 25.5 ± 4.9 to 46.7 ± 3.5; P < .00001) and visual analog scale for pain (from 7.5 ± 2 to 0.3 ± 1.0; P < .0001) scores. The mean Single Assessment Numeric Evaluation score at the time of follow-up was 90.6 ± 10.8 (range, 60-100). In overhead athletes, there was significant improvement in the Kerlan-Jobe Orthopaedic Clinic score (from 40.8 ± 11.8 to 90.6 ± 10.8; P < .00001). A postoperative magnetic resonance imaging scan was obtained in 16 (46%) patients at a mean of 32.6 months. In all cases, the graft was incorporated. All overhead athletes were able to return to their sport and perform at the same level or higher for >2 years. Two elbows required a subsequent arthroscopy for loose-body removal; otherwise, there were no other complications. CONCLUSION: FOCAT is an excellent option for treating OCD lesions of the humeral capitellum. Excellent outcomes and high return-to-sport rates were observed, with midterm follow-up showing no graft failures. FOCAT eliminates donor-site morbidity.


Subject(s)
Osteochondritis Dissecans , Humans , Osteochondritis Dissecans/surgery , Male , Adolescent , Female , Child , Adult , Young Adult , Retrospective Studies , Bone Transplantation/methods , Humerus/surgery , Transplantation, Homologous , Arthroscopy/methods , Allografts , Elbow Joint/surgery , Treatment Outcome
16.
Ophthalmic Epidemiol ; : 1-8, 2024 Aug 30.
Article in English | MEDLINE | ID: mdl-39212488

ABSTRACT

PURPOSE: To determine the incidence and clinical characteristics of ocular adnexaltumors in Olmsted County, Minnesota. METHODS: Retrospective population-based cohort study of all patients residing in Olmsted County, Minnesota diagnosed with any ocular tumor from January 1, 2006, to December 31, 2015. The medical records of all patients with an incident diagnosis of any ocular adnexal tumor were reviewed using the Rochester Epidemiology Project medical record linkage system for patient demographics, tumor type, and histopathologic confirmation. Incidence rates were calculated per 100,000 person-years. Poisson regression analysis was used to analyze changes in incidence over time. RESULTS: There were 717 patients diagnosed with ocular adnexal tumors during the 10-year study period, yielding an age- and sex-adjusted incidence rate of 59.7 per 100,000 (95% CI 55.4 to 64.0, p < 0.05) per year. In total, 764 tumors were diagnosed. Most tumors were eyelid lesions (N = 756, 99.0%), which were mostly benign (N = 512, 67.8%) with epidermal inclusion cysts (N = 275, 36.0%), hidrocystoma (N = 70, 9.2%), and eyelid sebaceous cysts (N = 46, 6.1%) accounting for the majority. Malignant eyelid lesions (N = 244, 31.9%) were relatively common with basal cell carcinoma (N = 184, 24.1%) and squamous cell carcinoma (N = 49, 6.4%) having the highest frequencies. Orbital tumors (N = 8, 1.0%) were infrequent. Of the orbital tumors, the most common was lacrimal gland adenoidcystic carcinoma (N = 2, 25.0%). CONCLUSIONS: In a population-based setting, most ocular adnexal tumors were benign eyelid lesions. Understanding the epidemiology of ocular adnexal tumors is important to aid providers in diagnosing and facilitating appropriate referrals of potentially vision- and life-threatening malignancies.

17.
Laryngoscope ; 2024 Aug 01.
Article in English | MEDLINE | ID: mdl-39087526

ABSTRACT

OBJECTIVES: Hearing loss (HL) is one of the most common chronic health conditions in the United States (US). This study aims to evaluate trends in HL prevalence among US adults over the past two decades. METHODS: Audiometric data of adults from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018 were analyzed in 2-year intervals to evaluate changes in HL (defined as pure tone average greater than 25 dB in at least one ear) over time in using odds ratios (ORs). Multivariate logistic regression was used to control for age and sex, and linear regression was used to evaluate trends in HL prevalence over time. RESULTS: The study included 13,468 participants. In adult participants (20-69 years old), HL remained stable over time, with some fluctuations ranging from 14.8% to 16.8%. In elderly participants (70-years and older), HL remained stable over time, with some fluctuations ranging from 71.7% to 77.1%. Based on univariate and linear regression analysis, there were no differences in HL rates in the adult and elderly cohorts. Subjects 40-49 years old and adults with education level of less than high school had significant downward trends in HL prevalence over two decades (p < 0.001 and p = 0.029). CONCLUSIONS: HL prevalence may be declining in the adult population when correcting for age and gender; however, there has not been a significant downward trend for the elderly population. HL may be decreasing over time among adults 40-49 years old and with shorter education backgrounds. LEVEL OF EVIDENCE: IV Laryngoscope, 2024.

19.
Simul Healthc ; 2024 Aug 16.
Article in English | MEDLINE | ID: mdl-39162794

ABSTRACT

INTRODUCTION: With increased incorporation of simulation-based methodologies into quality improvement activities, standards for reporting on simulation-specific elements in healthcare improvement research are needed. METHODS: We followed established consensus process methodology to iteratively create simulation-based extensions for SQUIRE 2.0 reporting guidelines. Initial steps involved forming a steering committee, defining the scope, and conducting premeeting activities with an expert panel of simulation and quality improvement researchers. Recommendations from the expert panel were brought to a consensus meeting where existing guidelines were reviewed and recommendations made. Steering Committee members reviewed all recommendations, reconciled differences, and made final recommendations, which were piloted by experienced simulation and quality improvement researchers. RESULTS: Fifteen Steering Committee members, 59 experts in simulation and quality improvement research, and 86 consensus meeting attendees reviewed SQUIRE 2.0 reporting guidelines and ultimately recommended simulation-based reporting guidelines for 22 of the 41 (54%) SQUIRE 2.0 guidelines. Those items for which simulation-based extensions were identified were: Notes to Authors, 1 (Title), 2a (Abstract), 2b (Abstract), 4 (Introduction: Available knowledge), 5 (Introduction: Rationale), 7 and 8a & b (Methods: Context and intervention), 9a (Methods - Study of the intervention), 9b (Methods - Study of the intervention), 10a (Methods - Measures), 10b (Methods-Measures), 10c (Methods-Measures), 11b (Methods- Analysis), 12 (Methods - Ethical considerations), 13a (Results), 13e (Results), 14b (Discussion - Summary), 15a-e (Discussion - Interpretation), 16a (Discussion - Limitations), 16b (Discussion - Limitations), 17c (Discussion - Conclusions), and 17d (Discussion - Conclusions). CONCLUSIONS: We created simulation-based extensions to SQUIRE 2.0 reporting guidelines to improve the quality and standardization of reporting on simulation-specific elements of healthcare improvement research.

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