Category: Statistics

J Natl Cancer Inst. 2024 Jun 10:djae091. doi: 10.1093/jnci/djae091. Online ahead of print.

ABSTRACT

BACKGROUND: Breast cancer brain metastasis is a rising occurrence, necessitating a better understanding of the mechanisms involved for effective management. Breast cancer brain metastases diverge notably from the primary tumor, with gains in kinase and concomitant losses of steroid signaling observed. In this study, we explored the role of the kinase receptor RET in promoting breast cancer brain metastases and provide a rationale for targeting this receptor.

METHODS: RET expression was characterized in a cohort of patients with primary and brain metastatic tumors. RET functionality was assessed using pharmacological inhibition and gene silencing in patient-derived brain metastatic tumor explants and in vivo models, organoid models, and brain organotypic cultures. RNA sequencing was used to uncover novel brain metastatic relevant RET mechanisms of action.

RESULTS: A statistically significant enrichment of RET in brain metastases was observed in estrogen receptor-positive breast cancer, where it played a role in promoting cancer cell adhesion, survival, and outgrowth in the brain. In vivo, RET overexpression enhanced brain metastatic competency in patient-derived models. At a mechanistic level, RET overexpression was found to enhance the activation of gene programs involved in cell adhesion, requiring EGFR cooperation to deliver a pro-brain metastatic phenotype.

CONCLUSION: Our results illustrate, for the first time, the role of RET in regulating colonization and outgrowth of breast cancer brain metastasis and provide data to support the use of RET inhibitors in the management strategy for patients with breast cancer brain metastases.

PMID:38852945 | DOI:10.1093/jnci/djae091

Mol Phylogenet Evol. 2024 Jun 7:108117. doi: 10.1016/j.ympev.2024.108117. Online ahead of print.

ABSTRACT

The Least Nighthawk Chordeiles pusillus is widespread wherever there are savannas in the South American tropics, often in isolated patches, such as white-sands savannas in the Amazon rainforest realm. Here, we investigate genetic relationships between populations of the Least Nighthawk to understand historical processes leading to its diversification and to determine dispersal routes between northern and southern savannas by way of three hypothesized dispersal corridors by comparing samples from white-sand savannas to samples from other savannas outside of the Amazon rainforest region. We use 32 mtDNA samples from the range of C. pusillus to infer a dated phylogeny. In a subset of 17 samples, we use shotgun sequences to infer a distance-based phylogeny and to estimate individual admixture proportions. We calculate gene flow and shared alleles between white-sand and non-Amazonian populations using the ABBA-BABA test (D statistics), and Principal Component Analysis (PCA) to examine genetic structure within and between lineages. Finally, we use species distribution modelling (SDM) of conditions during the Last Glacial Maximum (LGM), currently, and in the future (2050-2080) to predict potential species occurrence under a climate change scenario. Two main clades (estimated to have diverged around 1.07 million years ago) were recovered with mtDNA sequences and Single Nucleotide Polymorphism (SNPs) and were supported by NGSadmix and PCA: one in the Amazon basin white-sand savannas, the other in the non-Amazonian savannas. Possible allele sharing between these clades was indicated by the D-statistics between northern non-Amazonian populations and the white-sand savanna population, but this was not corroborated by the admixture analyses. Dispersal among northern non-Amazonian populations may have occurred in a dry corridor between the Guianan and the Brazilian Shield, which has since moved eastward. Our data suggest that the lineages separated well before the Last Glacial Maximum, consequently dispersal could have happened at any earlier time during similar climatic conditions. Subsequently, non-Amazonian lineages became more divergent among themselves, possibly connecting and dispersing across the mouth of the Amazon River across Marajó island during favourable climatic conditions in the Pleistocene.

PMID:38852908 | DOI:10.1016/j.ympev.2024.108117

Mol Phylogenet Evol. 2024 Jun 7:108120. doi: 10.1016/j.ympev.2024.108120. Online ahead of print.

ABSTRACT

Ochrophyta is a photosynthetic lineage that crowns the phylogenetic tree of stramenopiles, one of the major eukaryotic supergroups. Due to their ecological impact as a major primary producer, ochrophytes are relatively well-studied compared to the rest of the stramenopiles, yet their evolutionary relationships remain poorly understood. This is in part due to a number of missing lineages in large-scale multigene analyses, and an apparently rapid radiation leading to many short internodes between ochrophyte subgroups in the tree. These short internodes are also found across deep-branching lineages of stramenopiles with limited phylogenetic signal, leaving many relationships controversial overall. We have addressed this issue with other deep-branching stramenopiles recently, and now examine whether contentious relationships within the ochrophytes may be resolved with the help of filling in missing lineages in an updated phylogenomic dataset of ochrophytes, along with exploring various gene filtering criteria to identify the most phylogenetically informative genes. We generated ten new transcriptomes from various culture collections and a single-cell isolation from an environmental sample, added these to an existing phylogenomic dataset, and examined the effects of selecting genes with high phylogenetic signal or low phylogenetic noise. For some previously contentious relationships, we find a variety of analyses and gene filtering criteria consistently unite previously unstable groupings with strong statistical support. For example, we recovered a robust grouping of Eustigmatophyceae with Raphidophyceae-Phaeophyceae-Xanthophyceae while Olisthodiscophyceae formed a sister-lineage to Pinguiophyceae. Selecting genes with high phylogenetic signal or data quality recovered more stable topologies. Overall, we find that adding under-represented groups across different lineages is still crucial in resolving phylogenetic relationships, and discrete gene properties affect lineages of stramenopiles differently. This is something which may be explored to further our understanding of the molecular evolution of stramenopiles.

PMID:38852907 | DOI:10.1016/j.ympev.2024.108120

Microbes Infect. 2024 Jun 7:105376. doi: 10.1016/j.micinf.2024.105376. Online ahead of print.

ABSTRACT

Host heterogeneity in pulmonary tuberculosis leads to varied responses to infection and drug treatment. The present portfolio of anti-TB drugs needs to be boosted with new drugs and drug regimens. Macozinone, a clinical-stage molecule targeting the essential enzyme, DprE1, represents an attractive option. Mice (I/St, B6, (AKRxI/St)F1, B6.I-100 and B6.I-139) genetically diverse susceptibility to M. tuberculosis (Mtb) H37Rv infection were subjected to aerosol- or intravenous infection to determine the efficacy of macozinone (MCZ). They were treated with macozinone or reference drugs (isoniazid, rifampicin). Lung and spleen bacterial burdens were measured at four and eight weeks post-infection. Lung histology was evaluated at four weeks of treatment. Treatment with macozinone resulted in a statistically significant reduction in the bacterial load in the lungs and spleen as early as four weeks after treatment initiation in mice susceptible or resistant to Mtb infection. In the TB hypoxic granuloma model, macozinone was more potent than rifampicin in reducing the CFU counts. However, histopathological analysis revealed significant lung changes in I/St mice after eight weeks of treatment initiation. Macozinone demonstrated efficacy to varying degrees across all mouse models of Mtb infection used. These results should facilitate its further development and potential introduction into clinical practice.

PMID:38852904 | DOI:10.1016/j.micinf.2024.105376

J Nucl Cardiol. 2024 Jun 7:101889. doi: 10.1016/j.nuclcard.2024.101889. Online ahead of print.

ABSTRACT

BACKGROUND: We developed an explainable deep learning-based classifier to identify flow-limiting coronary artery disease (CAD) by O-15 H2O perfusion PET/CT and coronary CT angiography (CTA) imaging. The classifier uses polar map images with numerical data and visualizes data findings.

METHODS: A deep learning (DL) model was implemented and evaluated on 138 subjects, consisting of a combined image- and data-based classifier considering 35 clinical, CTA and PET variables. Data from invasive coronary angiography was used as reference. Performance was evaluated with clinical classification using accuracy (ACC), area under the receiver operating characteristic curve (AUC), F1 score (F1S), sensitivity (SEN), specificity (SPE), precision (PRE), net benefit and Cohen’s Kappa. Statistical testing was conducted using McNemar’s test.

RESULTS: The DL model had a median ACC 0.8478, AUC 0.8481, F1S 0.8293, SEN 0.8500, SPE 0.8846 and PRE 0.8500. Improved detection of TP and FN cases, increased net benefit in thresholds up to 34 %, and comparable Cohen’s kappa was seen, reaching similar performance to clinical reading. Statistical testing revealed no significant differences between DL model and clinical reading.

CONCLUSIONS: The combined DL model is a feasible and an effective method in detection of CAD, allowing to highlight important data findings individually in interpretable manner.

PMID:38852900 | DOI:10.1016/j.nuclcard.2024.101889

Int J Cardiol. 2024 Jun 7:132239. doi: 10.1016/j.ijcard.2024.132239. Online ahead of print.

ABSTRACT

BACKGROUND: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are anti-hyperglycemic drugs and have been proven to have cardiovascular protective effects for patients with heart failure regardless of their diabetes status. However, the benefit of SGLT2i following myocardial infarction (MI) remains incompletely established. This review aimed to investigate the impact of SGLT2i on NT-proBNP levels and structural changes post-MI.

METHOD: Medline, ClinicalTrial.gov, Scopus, and Directory of open-access journals were searched to retrieve the relevant articles. Eligible studies were randomized clinical trials that assessed NT-proBNP and cardiac structural changes in patients who received SGLT2i compared to placebo following MI. Two reviewers independently screened articles, extracted data, and assessed study quality.

RESULT: Four studies were included in this review, including patients with and without diabetes. While two studies showed no marked decrease from the baseline in NT-proBNP levels between the SGLT2i group and the control group, two studies reported a substantial reduction. The meta-analysis included three of these studies, with a total of 238 participants. The meta-analysis did not find a statistically significant drop in NT-proBNP levels post-MI in the SGLT2 inhibitors group compared to placebo (pooled SMD = 0.16, 95% CI 0.57-0.26, P 0.45). Furthermore, different echocardiographic parameters were reported in the included trials, yet no meta-analysis could be conducted to assess the influence of SGLT2i on cardiac remodeling post-MI.

CONCLUSION: SGLT2i did not result in a statistically significant reduction of NT-proBNP level subsequent to myocardial infarction. A knowledge gap exists regarding the impact of these agents on cardiac remodeling post-MI. Future high-quality clinical trials are needed to provide more robust evidence.

PMID:38852858 | DOI:10.1016/j.ijcard.2024.132239

Am J Obstet Gynecol. 2024 Jun 7:S0002-9378(24)00661-6. doi: 10.1016/j.ajog.2024.06.001. Online ahead of print.

ABSTRACT

BACKGROUND: Studies that have compared induction of labor in individuals with one prior cesarean delivery to expectant management have shown conflicting results.

OBJECTIVE: To determine the association between clinical outcomes and induction of labor at 39 weeks in a national sample of low-risk patients with one prior cesarean delivery.

STUDY DESIGN: This cross-sectional study analyzed 2016 to 2021 US Vital Statistics birth certificate data. Individuals with vertex, singleton pregnancies and one prior cesarean delivery were included. Patients with prior vaginal deliveries, delivery at 42 weeks and 6 days of gestation, and medical comorbidities were excluded. The primary exposure of interest was induction of labor at 39 weeks 0 days to 39 weeks 6 days compared to expectant management with delivery from 40 weeks 0 days to 42 weeks 6 days. The primary outcome was vaginal delivery. The main secondary outcomes were separate maternal and neonatal morbidity composites. The maternal morbidity composite included uterine rupture, operative vaginal delivery, peripartum hysterectomy, intensive care unit admission, and transfusion. The neonatal morbidity composite included neonatal intensive care unit admission, Apgar score less than 5 at 5 minutes, immediate ventilation, prolonged ventilation, and seizure or serious neurological dysfunction. Unadjusted and adjusted log binomial regression models accounting for demographic variables and the exposure of interest (induction versus expectant management) were performed. Results are presented as unadjusted (RR) and adjusted risk ratios (aRR) with 95% confidence intervals (CI).

RESULTS: From 2016 to 2021, a total of 198,797 individuals with vertex, singleton pregnancies and one prior cesarean were included in the primary analysis. Of these individuals, 25,915 (13.0%) underwent induction of labor from 39 weeks 0 days to 39 weeks 6 days and 172,882 (87.0%) were expectantly managed with deliveries between 40 weeks 0 days and 42 weeks 6 days. In adjusted analyses, patients induced at 39 weeks were more likely to have a vaginal delivery when compared to those expectantly managed (38.0% vs. 31.8%; aRR 1.32, 95% CI 1.28 to 1.36). Among those who had vaginal deliveries, induction of labor was associated with increased likelihood of operative vaginal delivery (11.1% vs. 10.0; aRR 1.15, 95% CI 1.07, 1.24). The maternal morbidity composite occurred in 0.9% of individuals in both the induction and expectant management groups (aRR 0.92, 95% CI 0.79, 1.06). The rates of uterine rupture (0.3%), peripartum hysterectomy (0.04% vs. 0.05%), and intensive care unit admission (0.1% vs. 0.2%) were all relatively low and did not differ significantly between groups. There was also no significant difference in the neonatal morbidity composite between the induction and expectant management groups (7.3% vs. 6.7%; aRR 1.04, 95% CI 0.98, 1.09).

CONCLUSIONS: When compared to expectant management, elective induction of labor at 39 weeks in low-risk patients with one prior cesarean delivery was associated with a significantly higher likelihood of vaginal delivery with no difference in composite maternal and neonatal morbidity outcomes. Prospective studies are needed to better elucidate the risks and benefits of induction of labor in this patient population.

PMID:38852849 | DOI:10.1016/j.ajog.2024.06.001

J Food Prot. 2024 Jun 7:100310. doi: 10.1016/j.jfp.2024.100310. Online ahead of print.

ABSTRACT

The utilization of Cold Plasma (CP) technology for decontamination and disinfection has garnered considerable attention across diverse industries. This study aims to investigate the interaction between pH and electrical conductivity (EC) (μS/cm) in Cold Plasma-Activated Water (CPAW) enriched with metal cations and its potential as an antifungal agent against two Penicillium (P.) mold strains. The investigation focuses on elucidating the augmented chemical interactions induced by plasma between radicals, charged particles, and microorganisms’ cell membranes within an aqueous environment. Our findings demonstrate a positive correlation between the inactivation potential of CPAW (operating at 10 kV voltage, 2.5 kHz high frequency, and 500 mA current intensity) and pH and EC(μS/cm) values. Notably, the relative chemical reactivity and solubility of calcium oxide emerge as significant factors, highlighting the pronounced link between P. Italicum and Plasma-Activated Water containing Copper cations (CPAW+Cu⁺²) (p<0.05). Our study distinctly emphasizes: 1) the substantial impact of both activated water type and mold species on CFU/mL values (p < 0.05); 2) the mold-specific effect of activated water on CFU/mL; and 3) the noteworthy EC(μS/cm) enhancement and pH decrease with prolonged activation time, attaining statistical significance (p < 0.01).

PMID:38852818 | DOI:10.1016/j.jfp.2024.100310

Clin Immunol. 2024 Jun 7:110270. doi: 10.1016/j.clim.2024.110270. Online ahead of print.

ABSTRACT

Inflammation is a hallmark of amyotrophic lateral sclerosis (ALS) and is often assessed through biological samples. Due to the easier access, peripheral blood is more commonly phenotyped instead of cerebrospinal fluid (CSF) or affected tissues in ALS. Here, using flow cytometry, we compared the composition of T cell subsets in blood and CSF in ALS patients. We found consistent but weak correlations between blood and CSF for all T cell subsets examined. This finding implies that blood and CSF offer complementary information when characterizing T cell immunity in ALS and blood may not be used as a surrogate for CSF.

PMID:38852806 | DOI:10.1016/j.clim.2024.110270

Life Sci. 2024 Jun 7:122796. doi: 10.1016/j.lfs.2024.122796. Online ahead of print.

ABSTRACT

AIMS: Long-term oral anticoagulation is the primary therapy for preventing ischemic stroke in patients with atrial fibrillation (AF). Different types of oral anticoagulant drugs can have specific effects on the metabolism of patients. Here we characterize, for the first time, the serum metabolomic and lipoproteomic profiles of AF patients treated with anticoagulants: vitamin K antagonists (AVKs) or direct oral anticoagulants (DOACs).

MATERIALS AND METHODS: Serum samples of 167 AF patients (median age 78 years, 62 % males, 70 % on DOACs treatment) were analyzed via high resolution ¹H nuclear magnetic resonance (NMR) spectroscopy. Data on 25 metabolites and 112 lipoprotein-related fractions were quantified and analyzed with multivariate and univariate statistical approaches.

KEY FINDINGS: Our data provide evidence that patients treated with AVKs and DOACs present significant differences in their profiles: lower levels of alanine and lactate (odds ratio: 1.72 and 1.84), free cholesterol VLDL-4 subfraction (OR: 1.75), triglycerides LDL-1 subfraction (OR: 1.80) and 4 IDL cholesterol fractions (ORs ~ 1.80), as well as higher levels of HDL cholesterol (OR: 0.48), apolipoprotein A1 (OR: 0.42) and 7 HDL cholesterol fractions/subfractions (ORs: 0.40-0.51) are characteristic of serum profile of patients on DOACs’ therapy.

SIGNIFICANCE: Our results support the usefulness of NMR-based metabolomics for the description of the effects of oral anticoagulants on AF patient circulating metabolites and lipoproteins. The higher serum levels of HDL cholesterol observed in patients on DOACs could contribute to explaining their reduced cardiovascular risk, suggesting the need of further studies in this direction to fully understand possible clinical implications.

PMID:38852797 | DOI:10.1016/j.lfs.2024.122796