Tag: statistics

Exp Eye Res. 2023 Jul 18:109592. doi: 10.1016/j.exer.2023.109592. Online ahead of print.

ABSTRACT

Understanding the metabolic dysfunctions and underlying complex pathological mechanisms of neurodegeneration in glaucoma could help discover disease pathways, identify novel biomarkers, and rationalize newer therapeutics. Therefore, we aimed to investigate the local metabolomic alterations in the aqueous humor and plasma of primary glaucomatous patients. This study cohort comprised primary open-angle glaucoma (POAG), primary angle-closure glaucoma (PACG), and cataract control groups. Aqueous humor and plasma samples were collected from patients undergoing trabeculectomy or cataract surgery and subjected to high-resolution mass spectrometry (HRMS) analysis. Spectral information was processed, and the acquired data were subjected to uni-variate as well as multi-variate statistical analyses using MetaboAnalyst ver5.0. To further understand the localized metabolic abnormalities in glaucoma, metabolites affected in aqueous humor were distinguished from metabolites altered in plasma in this study. Nine and twelve metabolites were found to be significantly altered (p < 0.05, variable importance of projection >1 and log₂ fold change ≥0.58/≤ -0.58) in the aqueous humor of PACG and POAG patients, respectively. The galactose and amino acid metabolic pathways were locally affected in the PACG and POAG groups, respectively. Based on the observation of the previous findings, gene expression profiles of trace amine-associated receptor-1 (TAAR-1) were studied in rat ocular tissues. The pharmacodynamics of TAAR-1 were explored in rabbits using topical administration of its agonist, β-phenyl-ethylamine (β-PEA). TAAR-1 was expressed in the rat’s iris-ciliary body, optic nerve, lens, and cornea. β-PEA elicited a mydriatic response in rabbit eyes without altering intraocular pressure. Targeted analysis of β-PEA levels in the aqueous humor of POAG patients showed an insignificant elevation. This study provides new insights regarding alterations in both localized and systemic metabolites in primary glaucomatous patients. This study also demonstrated the propensity of β-PEA to cause an adrenergic response through the TAAR-1 pathway.

PMID:37474016 | DOI:10.1016/j.exer.2023.109592

Exp Eye Res. 2023 Jul 18:109590. doi: 10.1016/j.exer.2023.109590. Online ahead of print.

ABSTRACT

Animal models of choroidal neovascularization (CNV) are extensively used in translational studies of CNV formation and to evaluate angiostatic treatment strategies. However, the current paucity of large animal models compared with rodent models constitutes a knowledge gap regarding the clinical translation of findings. Ocular anatomical and physiological similarities to humans suggest the pig as a relevant model animal. Thus, a systematic survey of porcine CNV models was performed to identify pertinent model parameters and suggest avenues for model standardization and optimization. A systematic search was performed in PubMed and EMBASE on November 28, 2022 for porcine models of CNV. Following inclusion by two investigators, data from the articles were extracted according to a predefined protocol. A total of 14 articles, representing 19 independent porcine CNV models were included. The included models were almost equally divided between laser-induced (53%) and surgically-induced (47%) models. Different specified breeds of domestic pigs (71%) were most commonly used in the studies. All studies used normal animals. Female pigs were reported used in 43% of the studies, while 43% did not report on sex of the animals. Younger pigs were typically used. The surgical models reported consistent CNV induction following mechanical Bruch’s membrane rupture. The laser models used variants of the infrared diode laser (40%) or the frequency-doubled Nd:YAG laser (50%). Both lasers enabled successful CNV induction with reported induction rates ranging from 60 to 100%. Collateral damage to the neuroretina was reported for the infrared diode laser. CNV evaluation varied across studies with fluorescein angiography (50%) as the most used in vivo method and retinal sections (71%) as the most used ex vivo method. In interventional studies, quantification of lesions was in general performed between 7 and 14 days. The field of porcine CNV models is relatively small and heterogeneous and almost equally divided between surgically-induced and laser-induced models. Both methods have allowed successful modeling of CNV formation with induction rates comparable to those of non-human primates. However, the field would benefit from standardization of model parameters and reporting. This includes laser parameters and validation of CNV formation as well as methods of CNV evaluation and statistical analysis.

PMID:37474015 | DOI:10.1016/j.exer.2023.109590

Mod Pathol. 2023 Jul 18:100285. doi: 10.1016/j.modpat.2023.100285. Online ahead of print.

ABSTRACT

We have developed an artificial intelligence (AI)-based digital pathology model for the evaluation of histologic features related to eosinophilic esophagitis (EoE). In this study, we evaluate the performance of our AI model in a cohort of pediatric and adult patients for histologic features included in the Eosinophilic Esophagitis Histologic Scoring System (EoEHSS). We collected a total of 203 esophageal biopsies from patients with mucosal eosinophilia of any degree (91 adults, 112 pediatric patients) and 10 normal controls from a prospectively maintained database. All cases were assessed by a specialized gastrointestinal (GI) pathologist for features in the EoEHSS at the time of original diagnosis and re-scored by a central GI pathologist. We have subsequently analyzed whole-slide image digital slides using a supervised AI model operating in a cloud-based, deep-learning artificial intelligence platform (Aiforia Technologies, Helsinki, Finland) for peak eosinophil count (PEC) and several histopathologic features in the EoEHSS. The correlation and inter-observer agreement between the AI model and pathologists (r_s=0.89 and ICC=0.87 vs. original pathologist [OP]; r_s =0.91 and ICC=0.83 vs. central pathologist [CP]) was similar to the correlation and inter-observer agreement between pathologists for PEC (r_s=0.88 and ICC=0.91) and broadly similar for most other histologic features in the EoEHSS. The AI model PEC also accurately identified >15 eosinophils/HPF by the OP (AUC [area under the curve]=0.98) and CP (AUC=0.98) and had similar AUCs for the presence of EoE-related endoscopic features than pathologists’ assessment. Average eosinophils per epithelial unit area had similar performance compared to AI HPF-based analysis. Our newly developed AI model can accurately identify, quantify, and score several of the main histopathologic features in the EoE spectrum, with agreement regarding EoEHSS scoring, which was similar to that seen among GI pathologists.

PMID:37474003 | DOI:10.1016/j.modpat.2023.100285

J Thorac Cardiovasc Surg. 2023 Jul 18:S0022-5223(23)00612-8. doi: 10.1016/j.jtcvs.2023.07.008. Online ahead of print.

ABSTRACT

OBJECTIVE: We have recently reported the primary results of CALGB 140503 (Alliance), a randomized trial in patients with peripheral cT1aN0 NSCLC (AJCC 7^th) treated with either lobar (LR) or sublobar resection (SLR). Here we report differences in disease-free survival (DFS), overall survival (OS) and lung cancer specific survival (LCSS) between LR, segmental (SR) and wedge resections (WR). We also report differences between WR and SR in surgical margins, rates of locoregional recurrence (LRR) and expiratory flow rates at 6 months postoperatively.

METHODS: Between 6/2007 and 3/2017, 697 patients were randomized to LR (357) or SLR (340) stratified by clinical tumor size, histology and smoking history. Ten patients were converted from SLR to LR and 5 from LR to SLR. Survival end points were estimated by the Kaplan-Meier estimator and tested by the stratified Log rank test. Kruskal-Wallis testing was used to compare margins and FEV1 changes between groups; and a Chi-square test was used to test the association between recurrence and groups.

RESULTS: A total of 362 patients had LR, 131 had SR and 204 had WR. Basic demographic and clinical and pathological characteristics were similar between all three groups. Five-year DFS was 64.7% after LR [95% CI; 59.6-70.1%], 63.8% after SR [ 95% C; 55.6 – 73.2%] and 62.5% after WR [95% CI; 55.8 – 69.9%] (Log rank, p = 0.888). Five-year OS was 78.7% after LR, 81.9% after SR and 79.7% after WR (Log rank, p = 0.873). Five-year LCSS was 86.8% after LR, 89.2% after SR and 89.7% after WR (Log rank, p = 0.903). LRR occurred in 12% after SR and 14% after WR (p=0.295). At 6 months postoperatively, the median reduction in % FEV1 was 5% after WR and 3% after SR (p=0.930) CONCLUSIONS: In this large, randomized trial, LR, SR and WR were associated with similar survival outcomes. Although LRR was numerically higher after WR compared to SR, the difference was not clinically meaningful statistically significant. There was no significant difference in the reduction of FEV1 between the SR and WR groups.

PMID:37473998 | DOI:10.1016/j.jtcvs.2023.07.008

Neuroimage Clin. 2023 Jul 11;39:103471. doi: 10.1016/j.nicl.2023.103471. Online ahead of print.

ABSTRACT

BACKGROUND: Using multi-block methods we combined multimodal neuroimaging metrics of thalamic morphology, thalamic white matter tract diffusion metrics, and cortical thickness to examine changes in behavioural variant frontotemporal dementia. (bvFTD).

METHOD: Twenty-three patients with sporadic bvFTD and 24 healthy controls underwent structural and diffusion MRI scans. Clinical severity was assessed using the Clinical Dementia Rating scale and behavioural severity using the Frontal Behaviour Inventory by patient caregivers. Thalamic volumes were manually segmented. Anterior and posterior thalamic radiation fractional anisotropy and mean diffusivity were extracted using Tract-Based Spatial Statistics. Finally, cortical thickness was assessed using Freesurfer. We used shape analyses, diffusion measures, and cortical thickness as features in sparse multi-block partial least squares (PLS) discriminatory analyses to classify participants within bvFTD or healthy control groups. Sparsity was tuned with five-fold cross-validation repeated 10 times. Final model fit was assessed using permutation testing. Additionally, sparse multi-block PLS was used to examine associations between imaging features and measures of dementia severity.

RESULTS: Bilateral anterior-dorsal thalamic atrophy, reduction in mean diffusivity of thalamic projections, and frontotemporal cortical thinning, were the main features predicting bvFTD group membership. The model had a sensitivity of 96%, specificity of 68%, and was statistically significant using permutation testing (p = 0.012). For measures of dementia severity, we found similar involvement of regional thalamic and cortical areas as in discrimination analyses, although more extensive thalamo-cortical white matter metric changes.

CONCLUSIONS: Using multimodal neuroimaging, we demonstrate combined structural network dysfunction of anterior cortical regions, cortical-thalamic projections, and anterior thalamic regions in sporadic bvFTD.

PMID:37473493 | DOI:10.1016/j.nicl.2023.103471

Psychiatry Res. 2023 Jul 11;326:115343. doi: 10.1016/j.psychres.2023.115343. Online ahead of print.

ABSTRACT

Anxiety disorders are a group of prevalent and heritable neuropsychiatric diseases. We previously conducted a genome-wide association study (GWAS) which identified genomic loci associated with anxiety; however, the biological consequences underlying the genetic associations are largely unknown. Integrating GWAS and functional genomic data may improve our understanding of the genetic effects on intermediate molecular phenotypes such as gene expression. This can provide an opportunity for the discovery of drug targets for anxiety via drug repurposing. We used the GWAS summary statistics to determine putative causal genes for anxiety using MAGMA and colocalization analyses. A transcriptome-wide association study was conducted to identify genes with differential genetically regulated levels of gene expression in human brain tissue. The genes were integrated with a large drug-gene expression database (Connectivity Map), discovering compounds that are predicted to “normalise” anxiety-associated expression changes. The study identified 64 putative causal genes associated with anxiety (35 genes upregulated; 29 genes downregulated). Drug mechanisms adrenergic receptor agonists, sigma receptor agonists, and glutamate receptor agonists gene targets were enriched in anxiety-associated genetic signal and exhibited an opposing effect on the anxiety-associated gene expression signature. The significance of the project demonstrated genetic links for novel drug candidates to potentially advance anxiety therapeutics.

PMID:37473490 | DOI:10.1016/j.psychres.2023.115343

Clin Neurol Neurosurg. 2023 Jul 10;232:107887. doi: 10.1016/j.clineuro.2023.107887. Online ahead of print.

ABSTRACT

OBJECTIVE: To gauge resident knowledge in the socioeconomic aspects of neurosurgery and assess the efficacy of an asynchronous, longitudinal, web-based, socioeconomics educational program tailored for neurosurgery residents.

METHODS: Trainees completed a 20-question pre- and post-intervention knowledge examination including four educational categories: billing/coding, procedure-specific concepts, material costs, and operating room protocols. Structured data from 12 index cranial neurosurgical operations were organized into 5 online, case-based modules sent to residents within a single training program via weekly e-mail. Content from each educational category was integrated into the weekly modules for resident review.

RESULTS: Twenty-seven neurosurgical residents completed the survey. Overall, there was no statistically significant difference between pre- vs post-intervention resident knowledge of billing/coding (79.2 % vs 88.2 %, p = 0.33), procedure-specific concepts (34.3 % vs 39.2 %, p = 0.11), material costs (31.7 % vs 21.6 %, p = 0.75), or operating room protocols (51.7 % vs 35.3 %, p = 0.61). However, respondents’ accuracy increased significantly by 40.8 % on questions containing content presented more than 3 times during the 5-week study period, compared to an increased accuracy of only 2.2 % on questions containing content presented less often during the same time period (p = 0.05).

CONCLUSIONS: Baseline resident knowledge in socioeconomic aspects of neurosurgery is relatively lacking outside of billing/coding. Our socioeconomic educational intervention demonstrates some promise in improving socioeconomic knowledge among neurosurgery trainees, particularly when content is presented frequently. This decentralized, web-based approach to resident education may serve as a future model for self-driven learning initiatives among neurosurgical residents with minimal disruption to existing workflows.

PMID:37473488 | DOI:10.1016/j.clineuro.2023.107887

Clin Neurol Neurosurg. 2023 Jul 16;232:107898. doi: 10.1016/j.clineuro.2023.107898. Online ahead of print.

ABSTRACT

OBJECTIVE: It is unknown whether adjunctive intra-arterial thrombolysis (IAT) during mechanical thrombectomy (MT) improves outcomes in patients with large vessel occlusion (LVO) stroke. This systematic review and meta-analysis aimed to compare the safety and efficacy of MT with and without IAT for the treatment of LVO stroke.

METHODS: A systematic literature search of PubMed, Embase, and the Cochrane Library was conducted to identify studies that compared rates of 3-month functional independence (modified Rankin Scale score 0-2), successful revascularization, symptomatic intracranial hemorrhage, and 3-month mortality for MT+IAT and MT alone. Meta-analyses were performed using random effects models, and effect sizes were expressed as odds ratios (ORs) and 95% confidence intervals (CIs). Heterogeneity was assessed with Cochran’s Q test and I² statistic.

RESULTS: Twelve studies met eligibility criteria, comprising one randomized controlled trial and 11 observational cohort studies involving 2584 patients. Compared to MT alone, MT+IAT had a 43% higher odds of 3-month functional independence (OR 1.43, 95% CI 1.11-1.83; I² =21%) and a 23% decrease in odds for 3-month mortality (OR 0.77, 95% CI 0.60-0.99; I² =0%). There were no differences in successful revascularization (OR 1.39, 95% CI 0.89-2.17; I² =57%) or symptomatic intracranial hemorrhage (OR 0.87, 95% CI 0.56-1.35; I² =6%) between the two groups.

CONCLUSIONS: The present study has demonstrated that, compared with MT alone, the use of adjunct IAT during MT in patients with LVO stroke resulted in better functional outcomes and lower mortality.

PMID:37473487 | DOI:10.1016/j.clineuro.2023.107898

Clin Neurophysiol. 2023 Jul 5;153:88-101. doi: 10.1016/j.clinph.2023.06.015. Online ahead of print.

ABSTRACT

OBJECTIVE: To evaluate the diagnostic accuracy of electromagnetic source imaging (EMSI) in localizing spikes and predict surgical outcome in children with drug resistant epilepsy (DRE) due to focal cortical dysplasia (FCD).

METHODS: We retrospectively analyzed magnetoencephalography (MEG) and high-density (HD-EEG) data from 23 children with FCD-associated DRE who underwent intracranial EEG and surgery. We localized spikes using equivalent current dipole (ECD) fitting, dipole clustering, and dynamical statistical parametric mapping (dSPM) on EMSI, electric source imaging (ESI), and magnetic source imaging (MSI). We calculated the distance from the seizure onset zone (D_SOZ) and resection (D_RES). We estimated receiver operating characteristic (ROC) curves with Youden’s index (J) to predict outcome.

RESULTS: EMSI presented shorter D_SOZ (15.18 ± 9.06 mm) and D_RES (8.56 ± 6.24 mm) compared to ESI (D_SOZ: 25.04 ± 16.20 mm, p < 0.009; D_RES: 18.88 ± 17.30 mm, p < 0.03) and MSI (D_SOZ: 23.37 ± 8.98 mm, p < 0.03; D_RES: 15.51 ± 10.11 mm, p < 0.02) for clustering in patients with good outcome. Clustering showed shorter D_SOZ and D_RES compared to ECD fitting and dSPM (p < 0.05). EMSI had higher performance as outcome predictor (J = 70.63%) compared to ESI (J = 41.27%) and MSI (J = 33.33%) for clustering.

CONCLUSIONS: EMSI provides superior localization and improved predictive performance than individual modalities.

SIGNIFICANCE: EMSI can help the surgical planning and facilitate the localization of epileptogenic foci.

PMID:37473485 | DOI:10.1016/j.clinph.2023.06.015

Talanta. 2023 Jul 13;266(Pt 1):124943. doi: 10.1016/j.talanta.2023.124943. Online ahead of print.

ABSTRACT

Near-infrared (NIR) spectroscopy is a rapid, non-invasive and cost-effective technique, for which sample pre-treatment is often not required. It is applied for both qualitative and quantitative analyses in various application fields. Often, large calibration sets are used, from which informative subsets can be selected without a loss of meaningful information. In this study, a new approach for sample subset selection is proposed and evaluated. The global PLS model, obtained with the original large global calibration set after FCAM-SIG variable selection, is used for the selection of the best fitting subset of calibration samples with optimally predictive ability. This best fitting calibration subset is called the optimally predictive calibration subset (OPCS). After ranking the global calibration samples according to increasing residuals, different enlarging fractions of the ranked calibration set are selected. For each fraction, the optimal predictive ability and the corresponding optimal PLS complexity are determined by cross model validation (CMV). After performing CMV with all fractions, the fraction with the best fitting samples and optimally predictive ability, i.e. the OPCS, is determined. The use of the best fitting samples from the global PLS model results in an OPCS-based model which is similar to the global PLS model and has a similar predictive ability. Because the best fitting samples do not need to be representative for the global calibration set, but only need to support the OPCS-based model, the number of samples in the OPCS model is mostly smaller than that selected by a traditional representative sample subset selection method. The new OPCS approach is tested on three real life NIR data sets with twelve X-y combinations to model. The results show that the number of selected samples obtained by the OPCS approach is statistically significantly lower than (i) that of the most suitable and widely used representative sample selection method of Kennard and Stone, and (ii) that suggested by the guideline that the optimal sample size N for reduced calibration sets should surpass the PLS model complexity A by a factor 12. An additional advantage of the OPCS approach is that no outliers are included in the subset because only the best fitting calibration samples are selected. In the new OPCS approach, two additional innovations are built in: (i) CMV is for the first time applied for sample selection and (ii) in CMV, the “one standard error rule”, adopted from “Repeated Double Cross Validation”, is for the first time used for the determination of the optimal PLS complexity of the OPCS-based models.

PMID:37473472 | DOI:10.1016/j.talanta.2023.124943