Tag: pubmed

J Clin Oncol. 2024 Nov 22:JCO2400979. doi: 10.1200/JCO.24.00979. Online ahead of print.

ABSTRACT

PURPOSE: To investigate whether intermittent treatment after an induction phase of first-line schedule of fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus panitumumab (PAN) prevents or delays the onset of resistance and improves safety and compliance with treatment in patients with unresectable RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC).

PATIENTS AND METHODS: IMPROVE (ClinicalTrials.gov identifier: NCT04425239) was an open-label, multicenter, randomized phase II noncomparative trial. Patients with unresectable RAS/BRAF wt mCRC were randomly assigned (1:1) to receive FOLFIRI plus PAN continuously until progression (arm A) or intermittently, with treatment-free intervals (arm B) until progression on treatment, toxicity, or death. The primary end point was progression-free survival on treatment (PFSot) at 12 months. Assuming a null hypothesis of median PFSot time ≤7 months and target PFSot ≥10 months, 65 patients per arm were needed to achieve 80% power and 10% type I error, according to the binomial test.

RESULTS: Between May 2018 and June 2021, 69 patients were randomly assigned to arm A and 68 to arm B. The median number of treatment cycles was 13 in arm A and 16 in arm B. At a median follow-up of 43.2 months (IQR, 35.0-50.5), median PFSot was 11.2 and 17.5 months with 12-month PFSot rates of 45.7% and 58.5%, for arms A and B, respectively. The overall response rates were 68.1% and 61.2%, and median overall survival rates were 36.3 and 35.1 months in arms A and B, respectively. The overall rate of grade >2 skin PAN-related adverse events was 30.3% in arm A and 17.9% in arm B.

CONCLUSION: Intermittent FOLFIRI plus PAN after the induction phase was feasible, and the primary end point was met with reduced toxicity while allowing patients more time off treatment.

PMID:39576946 | DOI:10.1200/JCO.24.00979

Rev Med Inst Mex Seguro Soc. 2024 Sep 2;62(5):1-6. doi: 10.5281/zenodo.12668053.

ABSTRACT

BACKGROUND: Acute respiratory distress syndrome (ARDS) secondary to COVID-19 crowded intensive care units in the world with high mortality. Mechanical ventilation was fundamental in the treatment; however, the evidence of ventilatory markers associated with mortality is not entirely clear. In 2021 it was described the linear power, which was superior to other markers. At the moment its possible utility in patients with ARDS due to COVID-19 has not been described.

OBJECTIVE: To evaluate linear power as a risk factor for mortality in patients with ARDS due to COVID-19 in intensive care.

MATERIAL AND METHODS: Retrospective cohort study in patients admitted to intensive care with ARDS secondary to COVID-19. Linear power was calculated for patients who died and patients who survived in intensive care. Mann-Whitney U test and multivariable Cox regression (hazard ratio [HR] with 95% confidence intervals [95% CI]) were performed.

RESULTS: 60 patients were studied with a mortality of 43.3%. Those who died had a higher linear power (89.5 vs. 78, p = 0.031) and the best cut-off point was 84 cmH2O/rpm (AUC 0.663, p = 0.031, LR 2.02); in addition, those with linear power < 84 (p = 0.050) had a better cumulative survival.

CONCLUSIONS: Linear power is a possible risk factor for mortality in patients with ARDS secondary to COVID-19 in intensive care.

PMID:39576935 | DOI:10.5281/zenodo.12668053

Phys Rev Lett. 2024 Nov 8;133(19):196302. doi: 10.1103/PhysRevLett.133.196302.

ABSTRACT

Many-body localization (MBL) hinders the thermalization of quantum many-body systems in the presence of strong disorder. In this Letter, we study the MBL regime in bond-disordered spin-1/2 XXZ spin chain, finding the multimodal distribution of entanglement entropy in eigenstates, sub-Poissonian level statistics, and revealing a relation between operators and initial states required for examining the breakdown of thermalization in the time evolution of the system. We employ a real space renormalization group scheme to identify these phenomenological features of the MBL regime that extend beyond the standard picture of local integrals of motion relevant for systems with disorder coupled to on-site operators. Our results pave the way for experimental probing of MBL in bond-disordered spin chains.

PMID:39576929 | DOI:10.1103/PhysRevLett.133.196302

Phys Rev Lett. 2024 Nov 8;133(19):191002. doi: 10.1103/PhysRevLett.133.191002.

ABSTRACT

We present the first measurement of nuclear recoils from solar ^{8}B neutrinos via coherent elastic neutrino-nucleus scattering with the XENONnT dark matter experiment. The central detector of XENONnT is a low-background, two-phase time projection chamber with a 5.9 t sensitive liquid xenon target. A blind analysis with an exposure of 3.51 t×yr resulted in 37 observed events above 0.5 keV, with (26.4_{-1.3}^{+1.4}) events expected from backgrounds. The background-only hypothesis is rejected with a statistical significance of 2.73σ. The measured ^{8}B solar neutrino flux of (4.7_{-2.3}^{+3.6})×10^{6} cm^{-2} s^{-1} is consistent with results from the Sudbury Neutrino Observatory. The measured neutrino flux-weighted CEνNS cross section on Xe of (1.1_{-0.5}^{+0.8})×10^{-39} cm^{2} is consistent with the Standard Model prediction. This is the first direct measurement of nuclear recoils from solar neutrinos with a dark matter detector.

PMID:39576901 | DOI:10.1103/PhysRevLett.133.191002

ACS Appl Bio Mater. 2024 Nov 22. doi: 10.1021/acsabm.4c01301. Online ahead of print.

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is a cancer of the epithelia comprising the ductal network of the pancreas. During disease progression, PDAC tumors recruit fibroblasts that promote fibrosis, increasing local tissue stiffness and subjecting epithelial cells to increased compressive forces. Previous in vitro studies have documented cytoskeletal and nuclear adaptation following compressive stresses in two-dimensional (2D) and three-dimensional (3D) environments. However, a comparison of the responses of normal and tumor-derived ductal epithelia to physiologically relevant confinement remains underexplored, especially in 3D organoids. Here we control confinement with an engineered 3D microenvironment composed of Matrigel mixed with a low yield stress granular microgel. Normal and tumor-derived murine pancreas organoids (normal and tumor) were cultured for 48 h within this composite 3D environment or in pure Matrigel to investigate the effects of confinement on morphogenesis and lumen expansion. In confinement, tumor organoids (mT) formed a lumen that expanded rapidly, whereas normal organoids (mN) expanded more slowly. Moreover, a majority of normal organoids in more-confined conditions exhibited an inverted apicobasal polarity compared to those in less-confined conditions. Tumor organoids exhibited a collective “pulsing” behavior that increased in confinement. These pulses generated forces sufficient to locally overcome the yield stress of the microgels in the direction of organoid expansion. Normal organoids more commonly exhibit unidirectional rotation. Our in vitro microgel confinement platform enabled the discovery of two distinct modes of collective force generation in organoids that may shed light on the mutual interactions between tumors and the microenvironment. These insights into in vitro dynamics may deepen our understanding of how the confinement of healthy cells within a fibrotic tumor niche disrupts tissue organization and function in vivo.

PMID:39576883 | DOI:10.1021/acsabm.4c01301

Sci Adv. 2024 Nov 22;10(47):eadr9891. doi: 10.1126/sciadv.adr9891. Epub 2024 Nov 22.

ABSTRACT

The subthalamic nucleus (STN) modulates basal ganglia output and plays a fundamental role in the pathophysiology of Parkinson’s disease (PD). Blockade/ablation of the STN improves motor signs in PD. We assessed the topography of focused ultrasound subthalamotomy (n = 39) by voxel-based lesion-symptom mapping to identify statistically validated brain voxels with the optimal effect against each cardinal feature and their respective cortical connectivity patterns by diffusion-weighted tractography. Bradykinesia and rigidity amelioration were associated with ablation of the rostral motor STN subregion connected to the supplementary motor and premotor cortices, whereas antitremor effect was explained by lesioning the posterolateral STN projection to the primary motor cortex. These findings were corroborated prospectively in another PD cohort (n = 12). This work concurs with recent deep brain stimulation findings that suggest different corticosubthalamic circuits underlying each PD cardinal feature. Our results provide sound evidence in humans of segregated anatomy of subthalamic-cortical connections and their distinct role in PD pathophysiology and normal motor control.

PMID:39576853 | DOI:10.1126/sciadv.adr9891

PLoS One. 2024 Nov 22;19(11):e0314133. doi: 10.1371/journal.pone.0314133. eCollection 2024.

ABSTRACT

The purpose of this study is to explore nonlinear and threshold effects of traffic statuses and road geometries, as well as their interactions, on traffic accident severity. In contrast to earlier research that primarily defined road alignment qualitatively as straight or curved, flat or slope, this study focused on the design elements of road geometry at accident locations. Additionally, this study considers the traffic conditions on the day of the accident, rather than the average annual traffic data as previous studies have done. To achieve this, we collected road design documents, traffic-related data, and 2023 accident data from the Suining section of the G42 Expressway in China. Using this dataset, we tested the classification performance of four machine learning models, including eXtreme Gradient Boosting, Gradient Boosted Decision Tree, Random Forest, and Light Gradient Boosting Machine. The optimal Random Forest model was employed to identify the key factors infulencing traffic accident severity, and the partial dependence plot was introduced to visualize the relationship between severity and various single and two-factor variables. The results indicate that the percentage of trucks, daily traffic volume, slope length, road grade, curvature, and curve length all exhibit significant nonlinear and threshold effects on accident severity. This reveals sepecific road and traffic features associated with varying levels of accident severity along the highway section examined in this study. The findings of this study will provide data-driven recommendations for highway design and daily safety management to reduce the severity of traffic accidents.

PMID:39576833 | DOI:10.1371/journal.pone.0314133

Genomics Proteomics Bioinformatics. 2024 Nov 22:qzae083. doi: 10.1093/gpbjnl/qzae083. Online ahead of print.

ABSTRACT

Mass spectrometry (MS) is a technique widely employed for the identification and characterization of proteins, with personalized medicine, systems biology, and biomedical applications. The application of MS-based proteomics advances our understanding of protein function, cellular signaling, and complex biological systems. MS data analysis is a critical process that includes identifying and quantifying proteins and peptides and then exploring their biological functions in downstream analysis. To address the complexities associated with MS data analysis, we developed ProtPipe to streamline and automate the processing and analysis of high-throughput proteomics and peptidomics datasets with DIA-NN preinstalled. The pipeline facilitates data quality control, sample filtering, and normalization, ensuring robust and reliable downstream analyses. ProtPipe provides downstream analyses, including protein and peptide differential abundance identification, pathway enrichment analysis, protein-protein interaction analysis, and Major histocompatibility complex (MHC) -peptide binding affinity analysis. ProtPipe generates annotated tables and visualizations by performing statistical postprocessing and calculating fold changes between predefined pairwise conditions in an experimental design. It is an open-source, well-documented tool available online at https://github.com/NIH-CARD/ProtPipe, with a user-friendly web interface.

PMID:39576693 | DOI:10.1093/gpbjnl/qzae083

Interact J Med Res. 2024 Nov 22;13:e60942. doi: 10.2196/60942.

ABSTRACT

BACKGROUND: Chronically elevated inflammation is implicated in many conditions, including obesity, metabolic syndrome, and cardiovascular disease, and has been associated with increased mortality risk. Whole-body cryotherapy (W-BC) is a promising modality to treat inflammation with demonstrated benefits for clinical subpopulations including those with arthritis, obesity, and type 2 diabetes. However, it is unclear whether the benefit from W-BC extends to healthy individuals prior to chronic disease-related inflammation. In addition, the long-term durability of W-BC effect is unknown.

OBJECTIVE: This study investigates the inflammatory response to W-BC in healthy adults with a biomarker of inflammation, high-sensitivity C-reactive protein (hsCRP), and clinical biomarkers of metabolism including fasting glucose, hemoglobin A_1c (HbA_1c), low-density lipoprotein (LDL) and high-density lipoprotein (HDL), and triglycerides.

METHODS: Fifteen individuals (n=9 female) participated in frequent recreational W-BC (3 minutes of cold exposure at -110 ℃) over approximately 9 months and had blood draws at baseline plus follow-up visits. Biomarkers were modeled as linear functions of W-BC sessions received in the month prior to blood draw.

RESULTS: The mean amount of W-BC received was 6.78 (SD 4.26) times per month with the cumulative total ranging from 13 to 157 W-BC sessions over the course of the study. On average, participants completed 1-2 sessions per week throughout the intervention. The number of W-BC sessions were associated with decreased hsCRP (-0.14 mg/L in hsCRP per W-BC session; P<.01) and with durability of up to 9 months. Increased W-BC was also associated with a downward trend in fasting glucose. This trend failed to reach significance at 1 month (-0.73 mg/dL in fasting glucose per W-BC session; P<.10) but was significant for 2- and 3-month windows (P<.05). HbA_1c was increased significantly after 9 months (P<.01); however, the change occurred within normal ranges (difference=0.13% and <5.7%) and was not clinically significant. There was no association between W-BC and LDL cholesterol, HDL cholesterol, or triglycerides (P>.10), although LDL trended lower over the time period examined (P=.07).

CONCLUSIONS: These results suggest that W-BC beneficially impacts systemic inflammation by lowering hsCRP levels in healthy individuals and may also have some modulating effect on fasting glucose.

PMID:39576692 | DOI:10.2196/60942

JMIR Diabetes. 2024 Nov 22;9:e63434. doi: 10.2196/63434.

ABSTRACT

BACKGROUND: The management of type 2 diabetes mellitus (T2DM) includes mastery of complex care activities, self-management skills, and routine health care encounters to optimize glucose control and achieve good health. Given the lifelong course of T2DM, patients are faced with navigating complex medical and disease-specific information. This health-seeking behavior is a driver of health disparities and is associated with hospitalization and readmission. Given that health-seeking behavior is a potentially intervenable social determinant of health, a better understanding of how people navigate these complex systems is warranted.

OBJECTIVE: To address this need, we aimed to develop new patient-reported outcome (PRO) measures that evaluate health-seeking behavior in persons with T2DM. These new PROs were designed to be included in the Re-Engineered Discharge for Diabetes-Computer Adaptive Test (REDD-CAT) measurement system, which includes several other PROs that capture the importance of social determinants of health.

METHODS: Overall, 225 participants with T2DM completed 56 self-report items that examined health-seeking behaviors. Classical Test Theory and Item Response Theory were used for measurement development. Exploratory factor analysis (EFA; criterion ratio of eigenvalue 1 to eigenvalue 2 being >4; variance for eigenvalue 1 ≥40%) and confirmatory factor analysis (CFA; criterion 1-factor CFA loading <.50; 1-factor CFA residual correlation >.20; comparative fit index ≥0.90; Tucker-Lewis index ≥0.90; root mean square error of approximation <0.15) were used to determine unidimensional sets of items. Items with sparse responses, low-adjusted total score correlations, nonmonotonicity, low factor loading, and high residual correlations of high error modification indices were candidates for exclusion. A constrained graded response model was used to examine item misfit, and differential item functioning was examined to identify item bias. Cronbach α was used to examine internal consistency reliability for the new PROs (criterion ≥0.70), and floor and ceiling effects were examined (criterion ≤20%).

RESULTS: Four unidimensional sets of items were supported by EFA (all EFA eigenvalue ratios >4; variance for eigenvalue 1=41.4%-67.3%) and CFA (fit statistics all exceeded criterion values). This included (1) “Health-Seeking Behavior: PCP-Specific” (6 items); (2) “Health-Seeking Behavior: General Beliefs” (13 items); (3) “Health-Seeking Behavior: Family or Friends-Specific” (5 items); and (4) “Health-Seeking Behavior: Internet-Specific” (4 items). All items were devoid of differential item functioning for age, sex, education, or socioeconomic status factors. “Health-Seeking Behavior: General Beliefs” was developed to include both a computer adaptive test and a 6-item short form version; all other PROs were developed as static short forms. The psychometric reliability of these new PROs was supported; internal consistency ranged from acceptable to excellent (Cronbach α=.78-.91), and measures were free of significant floor or ceiling effects (floor effects range: 0%-8.9%; ceiling effects range: 0%-8.4%).

CONCLUSIONS: The new REDD-CAT Health-Seeking Behavior PROs provide reliable assessments of health-seeking behaviors among those with T2DM.

PMID:39576685 | DOI:10.2196/63434