Tag: pubmed

Mod Pathol. 2023 Sep 22:100336. doi: 10.1016/j.modpat.2023.100336. Online ahead of print.

ABSTRACT

Phosphaturic mesenchymal tumors (PMT) are uncommon neoplasms that cause hypophosphatemia/osteomalacia mainly by secreting fibroblast growth factor 23. We previously identified FN1::FGFR1/FGF1 fusions in nearly half of PMTs, and frequent KL (Klotho or α-Klotho) overexpression only in those with no known fusion. Here, we studied a larger cohort of PMTs for KL expression and alterations. By FN1 break-apart FISH and reappraisal of previous RNA sequencing data, 6 tumors previously considered “fusion-negative” (defined by negative results of FISH for FN1::FGFR1 fusion and FGF1 break-apart and/or of RNA sequencing) were reclassified as fusion-positive PMTs, including one containing a novel FN1::ZACN fusion. The final cohort of fusion-negative PMTs included 33 tumors from 32 patients, which occurred in bone (N=18), soft tissue (10), sinonasal tract (4) and brain. In combination with previous work, RNA sequencing, RNA in situ hybridization, and immunohistochemistry showed largely concordant results and demonstrated KL/α-Klotho overexpression in 17 of the 28 fusion-negative and none of the 10 fusion-positive PMTs studied. Prompted by a patient in this cohort harboring germline KL upstream translocation with systemic α-Klotho overexpression and multifocal PMTs, FISH was performed and revealed KL rearrangement in 16 of the 33 fusion-negative PMTs (one also with amplification), including 14 of the 17 cases with KL/α-Klotho overexpression and none of the 11 KL/α-Klotho-low fusion-negative and 11 fusion-positive cases studied. Whole genomic sequencing confirmed in 2 FISH-positive cases translocation and inversion, respectively, involving KL upstream region, warranting further investigation into the mechanism whereby these rearrangements may lead to KL upregulation. Methylated DNA immunoprecipitation and sequencing suggested no major role of promoter methylation in KL regulation in PMT. Interestingly, KL-high/-rearranged cases seemed to form a clinicopathologically homogeneous group, showing a predilection for skeletal/sinonasal locations and typically matrix-poor, cellular solitary fibrous tumor-like morphology. Importantly, FGFR1 signaling pathways were upregulated in fusion-negative PMTs regardless of the KL status compared with non-PMT mesenchymal tumors by gene set enrichment analysis, perhaps justifying FGFR1 inhibition in treating this subset of PMTs.

PMID:37742927 | DOI:10.1016/j.modpat.2023.100336

Mod Pathol. 2023 Sep 22:100335. doi: 10.1016/j.modpat.2023.100335. Online ahead of print.

ABSTRACT

Tumor cell fraction (TCF) estimation is a common clinical task with well-established large inter-observer variability. It thus provides an ideal testbed to evaluate potential impacts of employing a computer-aided diagnostic (TCFCAD) tool to support pathologists’ evaluation. During a National Slide Seminar event, pathologists (n=69) were asked to visually estimate TCF in 10 regions of interest (ROI) from hematoxylin and eosin (H&E) colorectal cancer images intentionally curated for diverse tissue compositions, cellularity, and stain intensities. Next, they re-evaluated the same ROIs while being provided a TCFCAD created overlay highlighting predicted tumor versus non-tumor cells, together with the corresponding TCF percentage. Participants also reported confidence levels in their assessments using a 5-tiers scale, indicating no confidence to high confidence, respectively. The TCF ground truth (GT) was defined by manual cell-counting by experts. When assisted, inter-observer variability significantly decreased, showing estimates converging to the GT. This improvement remained even when TCFCAD predictions deviated slightly from the GT. The standard-deviation of estimated TCF to the GT across ROIs was 9.9% vs 5.8% with TCFCAD, p < 0.0001. The intraclass correlation coefficient increased from 0.8 to 0.93 (CI95% [0.65, 0.93] vs [0.86, 0.98]) and pathologists stated feeling more confident when aided (3.67 ± 0.81 vs. 4.17 ± 0.82 with CAD). TCFCAD estimation support demonstrated improved scoring accuracy, inter-pathologist agreement and scoring confidence. Interestingly, pathologists also expressed more willingness to use such a CAD tool at the end of the survey, highlighting the importance of training/education to increase adoption of CAD systems.

PMID:37742926 | DOI:10.1016/j.modpat.2023.100335

J Pain. 2023 Sep 22:S1526-5900(23)00541-2. doi: 10.1016/j.jpain.2023.09.011. Online ahead of print.

ABSTRACT

The ATP-gated channel P2X7 is encoded by a gene enriched for common nonsynonymous variants. Many of these variants have functional cellular effects, and some been implicated in chronic pain. In this study, we first systematically characterized all 17 common nonsynonymous variants using whole-cell patch clamp electrophysiology. Then, we analyzed these variants for statistical association with chronic pain phenotypes using both individual P2RX7 variants as predictors and cumulative allele counts of same-direction cellular effect in univariate models. Association and validation analyses were conducted in the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) cohort (N=3260) and in the Complex Persistent Pain Conditions (CPPC) cohort (N= 900), respectively. Our results showed an association between allele A of rs7958311 and an increased risk of chronic pelvic pain, with convergent evidence for contribution to fibromyalgia and irritable bowel syndrome (IBS), confirmed in meta-analysis. This allelic variant produced a unique cellular phenotype: a gain-of-function (GOF) in channel opening, and loss-of-function (LOF) in pore opening. Computational study using a 12-state Markov model of ATP binding to the P2X7 receptor suggested that this cellular phenotype arises from an increased ATP binding affinity and an increased open channel conductance combined with a loss of sensitization. Cumulative allele count analysis did not provide additional insights. In conclusion, our results go beyond reproducing association for rs7958311 with chronic pain and suggest that its unique combination of GOF in channel and LOF in pore activity may explain why it is likely the only common P2RX7 variant with contribution to chronic pain. PERSPECTIVE: This study characterizes all common P2RX7 variants using cellular assays and statistical association analyses with chronic pain, with Markov state modeling of the most robustly associated variant.

PMID:37742908 | DOI:10.1016/j.jpain.2023.09.011

Crit Rev Oncol Hematol. 2023 Sep 22:104143. doi: 10.1016/j.critrevonc.2023.104143. Online ahead of print.

ABSTRACT

With increasing reliance on technology in oncology, the impact of digital clinical decision support (CDS) tools needs to be examined. A systematic review update was conducted and peer-reviewed literature from 2016 to 2022 were included if CDS tools were used for live decision making and comparatively assessed quantitative outcomes. 3,369 studies were screened and 19 were included in this updated review. Combined with a previous review of 24 studies, a total of 43 studies were analyzed. Improvements in outcomes were observed in 42 studies, and 34 of these were of statistical significance. Computerised physician order entry and clinical practice guideline systems comprise the greatest number of evaluated CDS tools (13 and 10 respectively), followed by those that utilize patient-reported outcomes (8), clinical pathway systems (8) and prescriber alerts for best-practice advisories (4). Our review indicates that CDS can improve guideline adherence, patient-centered care, and care delivery processes in oncology.

PMID:37742884 | DOI:10.1016/j.critrevonc.2023.104143

Mol Phylogenet Evol. 2023 Sep 22:107916. doi: 10.1016/j.ympev.2023.107916. Online ahead of print.

ABSTRACT

With the rapid growth of entire genome data, phylogenomics focuses on analyzing evolutionary histories and relationships of species, i.e., the tree of life. For decades it has been realized that the genome-wide phylogenetic inference can be approached based upon the dynamic pattern of gene content (the presence/absence of gene families), or extended gene content (absence, presence as a single-copy, or duplicates). Those methods, conceptually or technically, invoked the birth-and-death process to model the evolutionary process (gene duplication or gene loss. One common drawback is that the mechanism of new gene input, including de novo origin of new genes and the lateral gene transfer, has not been explicitly considered. In this paper, the author developed a new genome distance approach for genome phylogeny inference under the origin-birth-death stochastic process. The model takes gene duplication, gene loss and new gene input into account simultaneously. Computer simulations found that the two-genome approach is statistically difficult to distinguish between two proliferation parameters, i.e., the rate of gene duplication and the rate of new gene input. Nevertheless, it has also demonstrated the statistical feasibility for using the loss-genome distance to infer the genome phylogeny, which can avoid the large sampling problem. The strategy to study the universal tree of life was discussed and exemplified by an example.

PMID:37742882 | DOI:10.1016/j.ympev.2023.107916

Ann Epidemiol. 2023 Sep 22:S1047-2797(23)00180-1. doi: 10.1016/j.annepidem.2023.09.006. Online ahead of print.

ABSTRACT

PURPOSE: To assess the distribution and clustering of COVID-19 testing and incidence over space and time, U.S. Department of Veteran’s Affairs (VA) data were used to describe where and when Veterans experienced highest proportions of test positivity.

METHODS: Data for 6,342,455 Veterans who utilized VA services between January 1, 2018 and September 30, 2021 were assessed for COVID-19 testing and test positivity. Testing and positivity proportions by county were mapped and focused-cluster tests identified significant clustering aroung VA facilities. Spatial cluster analysis also identified where and when Veterans experienced highest proportions of test positivity.

RESULTS: Within the Veterans study population and our time window, 21.3% received at least one COVID-19 test, and 20.4% of those tested had at least one positive test. There was statistically significant clustering of testing around VA facilities, revealing regional variation in testing practices. Veterans experienced highest test positivity proportions between November 2020 and January 2021 in a cluster of states in the Midwest, compared to those who received testing outside of the identified cluster (RR: 3.45).

CONCLUSION: Findings reflect broad regional trends in COVID-19 positivity which can inform VA policy and resource allocation. Additional analysis is needed to understand patterns during Delta and Omicron variant periods.

PMID:37742880 | DOI:10.1016/j.annepidem.2023.09.006

Ann Epidemiol. 2023 Sep 22:S1047-2797(23)00181-3. doi: 10.1016/j.annepidem.2023.09.007. Online ahead of print.

ABSTRACT

BACKGROUND: We developed a predictive model to estimate the risk of sub-optimal HIV clinical outcomes among people living with HIV and mental illness or substance use disorders in Texas.

METHODS: The Texas Medical Monitoring Project (MMP) data obtained from June 2015 to May 2020 was used to develop and internally validate the predictive model. Univariate descriptive and bivariate inferential statistics were performed to describe the characteristics of the study population and unadjusted associations with HIV clinical outcomes. Multivariable logistic regression was used to develop the prediction model. Internal validation was performed using the bootstrap method.

RESULTS: A total of 518 respondents aged 18 years and above, representing 27,255 adults living with HIV and mental illness or substance use disorders in Texas were included. Most participants were male (77.04%), less than 50 years of age (56.98%), had mild diagnosed mental illness and substance use disorder (56.59%). The risk predictive model contained 8 predictors, which together yielded an AUC of 0.727. Nonretention in care appeared to be the strongest predictor for having suboptimal HIV clinical outcome (aOR = 3.27; 95% CI = 1.45, 7.42).

CONCLUSION: The predictive model had good discrimination between persons at risk of poor HIV clinical outcomes and those not at risk.

PMID:37742879 | DOI:10.1016/j.annepidem.2023.09.007

J Neurol Sci. 2023 Sep 19;453:120813. doi: 10.1016/j.jns.2023.120813. Online ahead of print.

ABSTRACT

BACKGROUND: Conventional MRI scans have limited usefulness in monitoring Parkinson’s disease as they typically do not show any disease-specific brain abnormalities. This study aimed to identify an imaging biomarker for tracking motor symptom progression by using a multivariate statistical approach that can combine gray matter volume information from multiple brain regions into a single score specific to each PD patient.

METHODS: A cohort of 150 patients underwent MRI at baseline and had their motor symptoms tracked for up to 10 years using MDS-UPDRS-III, with motor symptoms focused on total and subscores, including rigidity, bradykinesia, postural instability, and gait disturbances, resting tremor, and postural-kinetic tremor. Gray matter volume extracted from MRI data was summarized into a patient-specific summary score using Mahalanobis distance, M_GMV. MDS-UPDRS-III’s progression and its association with M_GMV were modeled via linear mixed-effects models over 5- and 10-year follow-up periods.

RESULTS: Over the 5-year follow-up, there was a significant increase (P < 0.05) in MDS-UPDRS-III total and subscores, except for postural-kinetic tremor. Over the 10-year follow-up, all MDS-UPDRS-III scores increased significantly (P < 0.05). A higher baseline M_GMV was associated with a significant increase in MDS-UPDRS-III total, bradykinesia, postural instability and gait disturbances, and resting tremor (P < 0.05) over the 5-year follow-up, but only with total, bradykinesia, and postural instability and gait disturbances during the 10-year follow-up (P < 0.05).

CONCLUSIONS: Higher M_GMV scores were linked to faster motor symptom progression, suggesting it could be a valuable marker for clinicians monitoring Parkinson’s disease over time.

PMID:37742348 | DOI:10.1016/j.jns.2023.120813

Med Phys. 2023 Sep 24. doi: 10.1002/mp.16753. Online ahead of print.

ABSTRACT

BACKGROUND: Accurate delineations of regions of interest (ROIs) on multi-parametric magnetic resonance imaging (mpMRI) are crucial for development of automated, machine learning-based prostate cancer (PCa) detection and segmentation models. However, manual ROI delineations are labor-intensive and susceptible to inter-reader variability. Histopathology images from radical prostatectomy (RP) represent the “gold standard” in terms of the delineation of disease extents, for example, PCa, prostatitis, and benign prostatic hyperplasia (BPH). Co-registering digitized histopathology images onto pre-operative mpMRI enables automated mapping of the ground truth disease extents onto mpMRI, thus enabling the development of machine learning tools for PCa detection and risk stratification. Still, MRI-histopathology co-registration is challenging due to various artifacts and large deformation between in vivo MRI and ex vivo whole-mount histopathology images (WMHs). Furthermore, the artifacts on WMHs, such as tissue loss, may introduce unrealistic deformation during co-registration.

PURPOSE: This study presents a new registration pipeline, MSERgSDM, a multi-scale feature-based registration (MSERg) with a statistical deformation (SDM) constraint, which aims to improve accuracy of MRI-histopathology co-registration.

METHODS: In this study, we collected 85 pairs of MRI and WMHs from 48 patients across three cohorts. Cohort 1 (D₁ ), comprised of a unique set of 3D printed mold data from six patients, facilitated the generation of ground truth deformations between ex vivo WMHs and in vivo MRI. The other two clinically acquired cohorts (D₂ and D₃ ) included 42 patients. Affine and nonrigid registrations were employed to minimize the deformation between ex vivo WMH and ex vivo T2-weighted MRI (T2WI) in D₁ . Subsequently, ground truth deformation between in vivo T2WI and ex vivo WMH was approximated as the deformation between in vivo T2WI and ex vivo T2WI. In D₂ and D₃ , the prostate anatomical annotations, for example, tumor and urethra, were made by a pathologist and a radiologist in collaboration. These annotations included ROI boundary contours and landmark points. Before applying the registration, manual corrections were made for flipping and rotation of WMHs. MSERgSDM comprises two main components: (1) multi-scale representation construction, and (2) SDM construction. For the SDM construction, we collected N = 200 reasonable deformation fields generated using MSERg, verified through visual inspection. Three additional methods, including intensity-based registration, ProsRegNet, and MSERg, were also employed for comparison against MSERgSDM.

RESULTS: Our results suggest that MSERgSDM performed comparably to the ground truth (p > 0.05). Additionally, MSERgSDM (ROI Dice ratio = 0.61, landmark distance = 3.26 mm) exhibited significant improvement over MSERg (ROI Dice ratio = 0.59, landmark distance = 3.69 mm) and ProsRegNet (ROI Dice ratio = 0.56, landmark distance = 4.00 mm) in local alignment.

CONCLUSIONS: This study presents a novel registration method, MSERgSDM, for mapping ex vivo WMH onto in vivo prostate MRI. Our preliminary results demonstrate that MSERgSDM can serve as a valuable tool to map ground truth disease annotations from histopathology images onto MRI, thereby assisting in the development of machine learning models for PCa detection on MRI.

PMID:37742344 | DOI:10.1002/mp.16753

J Sports Sci. 2023 Sep 24:1-18. doi: 10.1080/02640414.2023.2257513. Online ahead of print.

ABSTRACT

Badminton footwork has been characterised with jump-landing, cross step, side side and lunges, which requires movement agility to facilitate on-court performance. A novel badminton shoe design with systematic increase of lateral wedge hardness (Asker C value of 55, 60, 65, and 70) was developed and investigated in this study, aiming to analyse the dose-response effect of incremental wedge hardness on typical badminton footwork. Stance time and joint stiffness were employed to investigate the footwork performance, and the factorial Statistical non-Parametric Mapping and Principal Component Analysis (PCA) were used to quantify the biomechanical responses over the stance. As reported, shorter contact times (decreased by 8.9%-13.5%) and increased joint stiffness (in side step) of foot-ankle complex were found, suggesting improved footwork stability and agility from increased hardness. Time-varying differences were noted during the initial landing and driving-off phase of cross and side steps and drive-off returning of lunges, suggesting facilitated footwork performance. The reconstructed modes of variations from PCA further deciphered the biomechanical response to the wedge dosage, especially during drive-off, to understand the improved footwork agility and stability.

PMID:37742342 | DOI:10.1080/02640414.2023.2257513