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Background Prostate MRI is used widely in clinical care for guiding tissue sampling, active surveillance, and staging. The Prostate Imaging Reporting and Data System (PI-RADS) helps provide a standardized probabilistic approach for identifying clinically significant prostate cancer. Despite widespread use, the variability in performance of prostate MRI across practices remains unknown. Purpose To estimate the positive predictive value (PPV) of PI-RADS for the detection of high-grade prostate cancer across imaging centers. Materials and Methods This retrospective cross-sectional study was compliant with the HIPAA. Twenty-six centers with members in the Society of Abdominal Radiology Prostate Cancer Disease-focused Panel submitted data from men with suspected or biopsy-proven untreated prostate cancer. MRI scans were obtained between January 2015 and April 2018. This was followed with targeted biopsy. Only men with at least one MRI lesion assigned a PI-RADS score of 2-5 were included. Outcome was prostate cancer with Gleason score (GS) greater than or equal to 3+4 (International Society of Urological Pathology grade group ≥2). A mixed-model logistic regression with institution and individuals as random effects was used to estimate overall PPVs. The variability of observed PPV of PI-RADS across imaging centers was described by using the median and interquartile range. Results The authors evaluated 3449 men (mean age, 65 years ± 8 [standard deviation]) with 5082 lesions. Biopsy results showed 1698 cancers with GS greater than or equal to 3+4 (International Society of Urological Pathology grade group ≥2) in 2082 men. Across all centers, the estimated PPV was 35% (95% confidence interval [CI]: 27%, 43%) for a PI-RADS score greater than or equal to 3 and 49% (95% CI: 40%, 58%) for a PI-RADS score greater than or equal to 4. The interquartile ranges of PPV at these same PI-RADS score thresholds were 27%-44% and 27%-48%, respectively. Conclusion The positive predictive value of the Prostate Imaging and Reporting Data System was low and varied widely across centers. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Milot in this issue.

OBJECTIVE. The purpose of this article is to evaluate restriction spectrum imaging (RSI) in men undergoing MRI-ultrasound fusion biopsy for suspected prostate cancer (PCa) and to compare the performance of RSI with that of conventional DWI. MATERIALS AND METHODS. One hundred ninety-eight biopsy-naïve men enrolled in a concurrent prospective clinical trial evaluating MRI-targeted prostate biopsy underwent multiparametric MRI with RSI. Clinical and imaging features were compared between men with and without clinically significant (CS) PCa (MRI-ultrasound fusion biopsy Gleason score ≥ 3 + 4). RSI z score and apparent diffusion coefficient (ADC) were correlated, and their diagnostic performances were compared. RESULTS. CS PCa was detected in 109 of 198 men (55%). Using predefined thresholds of ADC less than or equal to 1000 μm2/s and RSI z score greater than or equal to 3, sensitivity and specificity for CS PCa were 86% and 38%, respectively, for ADC and 61% and 70%, respectively, for RSI. In the transition zone (n = 69), the sensitivity and specificity were 94% and 17%, respectively, for ADC and 59% and 69%, respectively, for RSI. Among lesions with CS PCa, RSI z score and ADC were significantly inversely correlated in the peripheral zone (ρ = -0.4852; p < 0.01) but not the transition zone (ρ = -0.2412; p = 0.17). Overall diagnostic accuracies of RSI and DWI were 0.70 and 0.68, respectively (p = 0.74). CONCLUSION. RSI and DWI achieved equivalent diagnostic performance for PCa detection in a large population of men undergoing first-time prostate biopsy for suspected PCa, but RSI had superior specificity for transition zone lesions.

PurposeWe present a method for generating a T2 MR-based probabilistic model of tumor occurrence in the prostate to guide the selection of anatomical sites for targeted biopsies and serve as a diagnostic tool to aid radiological evaluation of prostate cancer.Materials and methodsIn our study, the prostate and any radiological findings within were segmented retrospectively on 3D T2-weighted MR images of 266 subjects who underwent radical prostatectomy. Subsequent histopathological analysis determined both the ground truth and the Gleason grade of the tumors. A randomly chosen subset of 19 subjects was used to generate a multi-subject-derived prostate template. Subsequently, a cascading registration algorithm involving both affine and non-rigid B-spline transforms was used to register the prostate of every subject to the template. Corresponding transformation of radiological findings yielded a population-based probabilistic model of tumor occurrence. The quality of our probabilistic model building approach was statistically evaluated by measuring the proportion of correct placements of tumors in the prostate template, i.e., the number of tumors that maintained their anatomical location within the prostate after their transformation into the prostate template space.ResultsProbabilistic model built with tumors deemed clinically significant demonstrated a heterogeneous distribution of tumors, with higher likelihood of tumor occurrence at the mid-gland anterior transition zone and the base-to-mid-gland posterior peripheral zones. Of 250 MR lesions analyzed, 248 maintained their original anatomical location with respect to the prostate zones after transformation to the prostate.ConclusionWe present a robust method for generating a probabilistic model of tumor occurrence in the prostate that could aid clinical decision making, such as selection of anatomical sites for MR-guided prostate biopsies.

PurposeWe assessed focal therapy eligibility in men who underwent multiparametric magnetic resonance imaging and targeted biopsy with correlation to whole mount histology after radical prostatectomy.Materials and methodsSubjects were selected from among the 454 men in whom targeted biopsy proven prostate cancer was derived from regions of interest on multiparametric magnetic resonance imaging from 2010 to 2016. Focal therapy eligibility was limited to a maximum Gleason score of 4 + 3 in regions of interest with or without other foci of low risk prostate cancer (Gleason score 3 + 3 and less than 4 mm). Men who did not meet NCCN® intermediate risk criteria were classified as ineligible for focal therapy. Of the 454 men 64 underwent radical prostatectomy and biopsy findings were compared to final pathology findings.ResultsOf the 454 men with a biopsy proven region of interest 175 (38.5%) were eligible for focal therapy. Fusion biopsy, which combined targeted and template biopsy, had 80.0% sensitivity (12 of 15 cases), 73.5% specificity (36 of 49) and 75.0% accuracy (48 of 64) for focal therapy eligibility. Targeted cores alone yielded 73.3% sensitivity (11 of 15 cases), 47.9% specificity (23 of 48) and 54.7% accuracy (35 of 64). Gleason score and extension across the midline differed in 4 and 9, respectively, of the 13 cases that showed discordant biopsy and whole mount histology.ConclusionsUsing intermediate risk eligibility criteria more than a third of men with a targeted biopsy proven lesion identified on multiparametric magnetic resonance imaging would have been eligible for focal therapy. Eligibility determined by fusion biopsy was concordant with whole mount histology in 75% of cases. Improved selection criteria are needed to reliably determine focal therapy eligibility.

The radiologist's role extends far beyond interpretation and reporting of medical imaging. In this manuscript, we describe the role of the Director of Prostate Imaging. We believe that this model can and should be implemented at other institutions, ultimately serving to improve the care for prostate cancer patients. Moreover, this model can be translated to support the development of an array of patient-centered service lines not only in abdominal imaging, but throughout radiology practices at large.

Purpose To determine the diagnostic yield of in-bore 3-T magnetic resonance (MR) imaging-guided prostate biopsy and stratify performance according to Prostate Imaging Reporting and Data System (PI-RADS) versions 1 and 2. Materials and Methods This study was HIPAA compliant and institution review board approved. In-bore 3-T MR-guided prostate biopsy was performed in 134 targets in 106 men who (a) had not previously undergone prostate biopsy, (b) had prior negative biopsy findings with increased prostate-specific antigen (PSA) level, or (c) had a prior history of prostate cancer with increasing PSA level. Clinical, diagnostic 3-T MR imaging was performed with in-bore guided prostate biopsy, and pathology data were collected. The diagnostic yields of MR-guided biopsy per patient and target were analyzed, and differences between biopsy targets with negative and positive findings were determined. Results of logistic regression and areas under the curve were compared between PI-RADS versions 1 and 2. Results Prostate cancer was detected in 63 of 106 patients (59.4%) and in 72 of 134 targets (53.7%) with 3-T MR imaging. Forty-nine of 72 targets (68.0%) had clinically significant cancer (Gleason score ≥ 7). One complication occurred (urosepsis, 0.9%). Patients who had positive target findings had lower apparent diffusion coefficient values (875 × 10-6 mm2/sec vs 1111 × 10-6 mm2/sec, respectively; P < .01), smaller prostate volume (47.2 cm3 vs 75.4 cm3, respectively; P < .01), higher PSA density (0.16 vs 0.10, respectively; P < .01), and higher proportion of PI-RADS version 2 category 3-5 scores when compared with patients with negative target findings. MR targets with PI-RADS version 2 category 2, 3, 4, and 5 scores had a positive diagnostic yield of three of 23 (13.0%), six of 31 (19.4%), 39 of 50 (78.0%), and 24 of 29 (82.8%) targets, respectively. No differences were detected in areas under the curve for PI-RADS version 2 versus 1. Conclusion In-bore 3-T MR-guided biopsy is safe and effective for prostate cancer diagnosis when stratified according to PI-RADS versions 1 and 2. ©RSNA, 2016.

PurposeTo compare the diagnostic performance of restriction spectrum imaging (RSI), with that of conventional multi-parametric (MP) magnetic resonance imaging (MRI) for prostate cancer (PCa) detection in a blinded reader-based format.MethodsThree readers independently evaluated 100 patients (67 with proven PCa) who underwent MP-MRI and RSI within 6 months of systematic biopsy (N = 67; 23 with targeting performed) or prostatectomy (N = 33). Imaging was performed at 3 Tesla using a phased-array coil. Readers used a five-point scale estimating the likelihood of PCa present in each prostate sextant. Evaluation was performed in two separate sessions, first using conventional MP-MRI alone then immediately with MP-MRI and RSI in the same session. Four weeks later, another scoring session used RSI and T2-weighted imaging (T2WI) without conventional diffusion-weighted or dynamic contrast-enhanced imaging. Reader interpretations were then compared to prostatectomy data or biopsy results. Receiver operating characteristic curves were performed, with area under the curve (AUC) used to compare across groups.ResultsMP-MRI with RSI achieved higher AUCs compared to MP-MRI alone for identifying high-grade (Gleason score greater than or equal to 4 + 3=7) PCa (0.78 vs. 0.70 at the sextant level; P

BackgroundThe current study was conducted to evaluate the performance of magnetic resonance (MR)-ultrasound-guided fusion biopsy in diagnosing clinically significant prostate cancer (csCaP).MethodsA total of 1042 men underwent multiparametric MR imaging (mpMRI) and fusion biopsy consecutively in a prospective trial (2009-2014). An expert reader graded mpMRI regions of interest (ROIs) as 1 to 5 using published protocols. The fusion biopsy device was used to obtain targeted cores from ROIs (when present) followed by a fusion image-guided, 12-core systematic biopsy in all men, even if no suspicious ROI was noted. The primary endpoint of the study was the detection of csCaP (ie, Gleason score ≥ 7).ResultsAmong 825 men with ≥ 1 suspicious ROI of ≥ grade 3, 289 (35%) were found to have csCaP. Powerful predictors of csCaP were ROI grade (grade 5 vs grade 3: odds ratio, 6.5 [P

PurposeDiffusion imaging in the prostate is susceptible to distortion from B0 inhomogeneity. Distortion correction in prostate imaging is not routinely performed, resulting in diffusion images without accurate localization of tumors. We performed and evaluated distortion correction for diffusion imaging in the prostate.Materials and methods28 patients underwent pre-operative MRI (T2, Gadolinium perfusion, diffusion at b=800 s/mm(2)). The restriction spectrum protocol parameters included b-values of 0, 800, 1500, and 4000 s/mm(2) in 30 directions for each nonzero b-value. To correct for distortion, forward and reverse trajectories were collected at b=0 s/mm(2). Distortion maps were generated to reflect the offset of the collected data versus the corrected data. Whole-mount histology was available for correlation.ResultsAcross the 27 patients evaluated (excluding one patient due to data collection error), the average root mean square distortion distance of the prostate was 3.1 mm (standard deviation, 2.2mm; and maximum distortion, 12 mm).ConclusionImproved localization of prostate cancer by MRI will allow better surgical planning, targeted biopsies and image-guided treatment therapies. Distortion distances of up to 12 mm due to standard diffusion imaging may grossly misdirect treatment decisions. Distortion correction for diffusion imaging in the prostate improves tumor localization.

PurposeThree-dimensional (3D) T2 -weighted fast spin echo (FSE) imaging of the prostate currently requires long acquisition times. Our objective was to develop a fast 3D T2 -weighted sequence for prostate imaging at 3T using a variable flip angle transition into driven equilibrium (T2 -TIDE) scheme.Methods3D T2 -TIDE uses interleaved spiral-out phase encode ordering to efficiently sample the ky -kz phase encodes and also uses the transient balanced steady-state free precession signal to acquire the center of k-space for T2 -weighted imaging. Bloch simulations and images from 10 healthy subjects were acquired to evaluate the performance of 3D T2 -TIDE compared to 3D FSE.Results3D T2 -TIDE images were acquired in 2:54 minutes compared to 7:02 minutes for 3D FSE with identical imaging parameters. The signal-to-noise ratio (SNR) efficiency was significantly higher for 3D T2 -TIDE compared to 3D FSE in nearly all tissues, including periprostatic fat (45 ± 12 vs. 31 ± 7, P

PurposeWe evaluate a novel magnetic resonance imaging (MRI) technique to improve detection of aggressive prostate cancer (PCa).Materials and methodsWe performed a retrospective analysis of pre-surgical prostate MRI scans using an advanced diffusion-weighted imaging technique called restriction spectrum imaging (RSI), which can be presented as a normalized z-score statistic. Scans were acquired prior to radical prostatectomy. Prostatectomy specimens were processed using whole-mount sectioning and regions of interest (ROIs) were drawn around individual PCa tumors. Corresponding ROIs were drawn on the MRI imaging and paired with ROIs in regions with no pathology. RSI z-score and conventional apparent diffusion coefficient (ADC) values were recorded for each ROI. Paired t-test, ANOVA, and logistic regression analyses were performed.ResultsWe evaluated 28 patients with 64 ROIs (28 benign and 36 PCa). The mean difference in RSI z-score (PCa ROI-Benign ROI) was 2.17 (SE = 0.11; p

PurposeWe explored the impact of magnetic resonance imaging-ultrasound fusion prostate biopsy on the prediction of final surgical pathology.Materials and methodsA total of 54 consecutive men undergoing radical prostatectomy at UCLA after fusion biopsy were included in this prospective, institutional review board approved pilot study. Using magnetic resonance imaging-ultrasound fusion, tissue was obtained from a 12-point systematic grid (mapping biopsy) and from regions of interest detected by multiparametric magnetic resonance imaging (targeted biopsy). A single radiologist read all magnetic resonance imaging, and a single pathologist independently rereviewed all biopsy and whole mount pathology, blinded to prior interpretation and matched specimen. Gleason score concordance between biopsy and prostatectomy was the primary end point.ResultsMean patient age was 62 years and median prostate specific antigen was 6.2 ng/ml. Final Gleason score at prostatectomy was 6 (13%), 7 (70%) and 8-9 (17%). A tertiary pattern was detected in 17 (31%) men. Of 45 high suspicion (image grade 4-5) magnetic resonance imaging targets 32 (71%) contained prostate cancer. The per core cancer detection rate was 20% by systematic mapping biopsy and 42% by targeted biopsy. The highest Gleason pattern at prostatectomy was detected by systematic mapping biopsy in 54%, targeted biopsy in 54% and a combination in 81% of cases. Overall 17% of cases were upgraded from fusion biopsy to final pathology and 1 (2%) was downgraded. The combination of targeted biopsy and systematic mapping biopsy was needed to obtain the best predictive accuracy.ConclusionsIn this pilot study magnetic resonance imaging-ultrasound fusion biopsy allowed for the prediction of final prostate pathology with greater accuracy than that reported previously using conventional methods (81% vs 40% to 65%). If confirmed, these results will have important clinical implications.

PurposeTo assess the ability of multiparametric (mp) MRI (mp-MRI) to identify, stratify, and localize biopsy-proven prostate cancer lesions in a risk-stratified patient population.Methods and materialsWe retrospectively analyzed 57 patients who had mp-MRI and core needle biopsy during diagnostic prostate cancer evaluation. The MRI sequences were scored for suspicion of cancer with a previously described system. Distributions of mp-MRI scores were compared across National Comprehensive Cancer Network prostate cancer risk groups. The mp-MRI-identified lesions were compared with the location of positive core needle biopsies to assess mp-MRI localization of true lesions.ResultsThe mp-MRI scoring system identified lesions in 84% (48/57) of the patients, including 100% (12/12) in the high-risk group. Scores assigned to lesions in patients in intermediate- and high-risk groups were statistically higher than those in the low-risk group, with a relative risk of 6.72 (95% confidence interval: 2.32-19.51, p

ObjectiveTo determine whether multiparametric magnetic resonance imaging might improve the identification of patients with higher risk disease at diagnosis and thereby reduce the incidence of undergrading or understaging.MethodsWe retrospectively reviewed the clinical records of 115 patients who underwent multiparametric magnetic resonance imaging before radical prostatectomy. We used Epstein's criteria of insignificant disease with and without a magnetic resonance imaging (MRI) parameter (apparent diffusion coefficient) to calculate sensitivity, specificity, as well as negative and positive predictive values [NPV and PPV] across varying definitions of clinically significant cancer based on Gleason grade and tumor volume (0.2 mL, 0.5 mL, and 1.3 mL) on whole-mount prostate specimens. Logistic regression analysis was performed to determine the incremental benefit of MRI in delineating significant cancer.ResultsThe majority had a prostate-specific antigen from 4.1-10.0 (67%), normal rectal examinations (90%), biopsy Gleason score ≤ 6 (68%), and ≤ 2 cores positive (55%). Of the 58 patients pathologically staged with Gleason 7 or pT3 disease at prostatectomy, Epstein's criteria alone missed 12 patients (sensitivity of 79% and NPV of 68%). Addition of apparent diffusion coefficient improved the sensitivity and NPV for predicting significant disease at prostatectomy to 93% and 84%, respectively. MRI improved detection of large Gleason 6 (≥ 1.3 mL, P = .006) or Gleason ≥ 7 lesions of any size (P

We have developed a system for evaluating magnetic resonance imaging of prostate cancer, using patient-specific 3D printed molds to facilitate MR-histology correlation. Prior to radical prostatectomy a patient receives a multiparametric MRI, which an expert genitourinary radiologist uses to identify and contour regions suspicious for disease. The same MR series is used to generate a prostate contour, which is the basis for design of a patient-specific mold. The 3D printed mold contains a series of evenly spaced parallel slits, each of which corresponds to a known MRI slice. After surgery, the patient's specimen is enclosed within the mold, and all whole-mount levels are obtained simultaneously through use of a multi-bladed slicing device. The levels are then formalin fixed, processed, and delivered to an expert pathologist, who identifies and grades all lesions within the slides. Finally, the lesion contours are loaded into custom software, which elastically warps them to fit the MR prostate contour. The suspicious regions on MR can then be directly compared to lesions on histology. Furthermore, the false-negative and false-positive regions on MR can be retrospectively examined, with the ultimate goal of developing methods for improving the predictive accuracy of MRI. This work presents the details of our analysis method, following a patient from diagnosis through the MR-histology correlation process. For this patient MRI successfully predicted the presence of cancer, but true lesion volume and extent were underestimated. Most cancer-positive regions missed on MR were observed to have patterns of low T2 signal, suggesting that there is potential to improve sensitivity.

Magnetic resonance spectroscopic imaging (MRSI) detects alterations in major prostate metabolites, such as citrate (Cit), creatine (Cr), and choline (Ch). We evaluated the sensitivity and accuracy of three-dimensional MRSI of prostate using an endorectal compared to an external phased array "receive" coil on a 3T MRI scanner. Eighteen patients with prostate cancer (PCa) who underwent endorectal MR imaging and proton (1H) MRSI were included in this study. Immediately after the endorectal MRSI scan, the PCa patients were scanned with the external phased array coil. The endorectal coil-detected metabolite ratio [(Ch+Cr)/Cit] was significantly higher in cancer locations (1.667 ± 0.663) compared to non-cancer locations (0.978 ± 0.420) (P < 0.001). Similarly, for the external phased array, the ratio was significantly higher in cancer locations (1.070 ± 0.525) compared to non-cancer locations (0.521 ± 0.310) (P < 0.001). The sensitivity and accuracy of cancer detection were 81% and 78% using the endorectal 'receive' coil, and 69% and 75%, respectively using the external phased array 'receive' coil.

Abstract Objectives The primary metabolite contents of ripe fruits result from complex regulations during their development. For Solanaceae, these regulations have been widely studied in tomato. The fruit metabolite contents of other fruit species, such as pepper (Capsicum annuum L.) and eggplant (Solanum melongena L.), constitute a valuable resource for the community to study the regulation of fruit metabolism and identify common or species-dependent regulations. This dataset about major polar metabolites is part of a larger project that integrates other omics data for pepper and eggplant, and other fruit species for metabolomics and other omics. Data description We provide quantitative metabolite data of pepper and eggplant fruit along development. We sampled pepper and eggplant fruit cultivated in a tunnel or a greenhouse at 10 or 11 stages from anthesis to ripe fruit. We used proton nuclear magnetic resonance (1H-NMR) metabolomic profiling of polar extracts to quantify the major metabolites and expressed the data in µmol per g fresh weight. Twenty-four metabolites were determined in pepper and 27 in eggplant. Nineteen common metabolites were quantified in both fruit species including three soluble sugars and one sugar-alcohol, five organic acids and nine free amino acids. These data can be combined with similar quantitative data on other species or complemented with other omics data to perform cross-species or cross-omics comparisons.

Abstract Desmin intermediate filaments play a crucial role in stress transmission and mechano-protection. The loss of its integrity triggers myofibril breakdown and muscle atrophy for which desmin phosphorylation (pDes) is a priming factor. We investigated whether eccentric accentuated resistance exercise (RE) influences the regulation of pDes, effecting its susceptibility to cleavage. Ten healthy persons performed 14 RE-sessions (2 per week). Muscle biopsies were collected in both untrained and trained conditions at rest (pre 1, pre 14) and one hour after RE (post 1, post 14). Western blotting and immunohistochemistry were utilized to assess desmin content, phosphorylation at several sites and susceptibility to cleavage. In untrained condition (pre 1, post 1), RE induced dephosphorylation of serin 31 and 60. Trained muscle exhibited more pronounced dephosphorylation at Serin 31 post-RE. Dephosphorylation was accompanied by reduced susceptibility of desmin to cleavage. Additionally, training increased total desmin content, upregulated baseline serine 31 phosphorylation and attenuated pDes at serine 60 and threonine 17. Our findings suggest that acute and repeated RE changes the phosphorylation pattern of desmin and its susceptibility to cleavage, highlighting pDes as an adaptive mechanism in skeletal muscle, contributing to the proteostatic regulation in response to recurring stress.

Abstract Cerebral cavernous malformations (CCMs) are anomalies of the cerebral vasculature. Loss of the CCM proteins CCM1/KRIT1, CCM2, or CCM3/PDCD10 trigger a MAPK-Krüppel-like factor 2 (KLF2) signaling cascade, which induces a pathophysiological pattern of gene expression. The downstream target genes that are activated by KLF2 are mostly unknown. Here we show that Chromobox Protein Homolog 7 (CBX7), component of the Polycomb Repressive Complex 1, contributes to pathophysiological KLF2 signaling during zebrafish cardiovascular development. CBX7/cbx7a mRNA is strongly upregulated in lesions of CCM patients, and in human, mouse, and zebrafish CCM-deficient endothelial cells. The silencing or pharmacological inhibition of CBX7/Cbx7a suppresses pathological CCM phenotypes in ccm2 zebrafish, CCM2-deficient HUVECs, and in a pre-clinical murine CCM3 disease model. Whole-transcriptome datasets from zebrafish cardiovascular tissues and human endothelial cells reveal a role of CBX7/Cbx7a in the activation of KLF2 target genes including TEK, ANGPT1, WNT9, and endoMT-associated genes. Our findings uncover an intricate interplay in the regulation of Klf2-dependent biomechanical signaling by CBX7 in CCM. This work also provides insights for therapeutic strategies in the pathogenesis of CCM.

Abstract Collagenous connective tissue, found throughout the bodies of metazoans, plays a crucial role in maintaining structural integrity. This versatile tissue has the potential for numerous biomedical applications, including the development of innovative collagen-based biomaterials. Inspiration for such advancements can be drawn from echinoderms, a group of marine invertebrates that includes sea stars, sea cucumbers, brittle stars, sea urchins, and sea lilies. Through their nervous system, these organisms can reversibly control the pliability of their connective tissue components (i.e., tendons and ligaments) that are composed of mutable collagenous tissue (MCT). The variable tensile properties of the MCT allow echinoderms to perform unique functions, including postural maintenance, reduction of muscular energy use, autotomy to avoid predators, and asexual reproduction through fission. The changes in the tensile strength of MCT structures are specifically controlled by specialized neurosecretory cells called juxtaligamental cells. These cells release substances that either soften or stiffen the MCT. So far, only a few of these substances have been purified and characterized, and the genetic underpinning of MCT biology remains unknown. Therefore, we have conducted this research to identify MCT-related genes in echinoderms as a first step towards a better understanding of the MCT molecular control mechanisms. Our ultimate goal is to unlock new biomaterial applications based on this knowledge. In this project, we used RNA-Seq to identify and annotate differentially expressed genes in the MCT structures of the brittle star Ophiomastix wendtii. As a result, we present a list of 16 putative MCT modulator genes, which will be validated and characterized in forthcoming functional analyses.

Abstract Background Perivascular space (PVS) enlargement in ageing and Alzheimer’s disease (AD) and the drivers of such a structural change in humans require longitudinal investigation. Elucidating the effects of demographic factors, hypertension, cerebrovascular dysfunction, and AD pathology on PVS dynamics could inform the role of PVS in brain health function as well as the complex pathophysiology of AD. Methods We studied PVS in centrum semiovale (CSO) and basal ganglia (BG) computationally over three to four annual visits in 503 participants (255 females; meanage = 70.78 ± 5.78) of the ongoing observational multicentre “DZNE Longitudinal Cognitive Impairment and Dementia Study” (DELCODE) cohort. We analysed data from subjects who were cognitively unimpaired (n = 401), had amnestic mild cognitive impairment (n = 71), or had AD (n = 31). We used linear mixed-effects modelling to test for changes of PVS volumes in relation to cross-sectional and longitudinal age, as well as sex, years of education, hypertension, white matter hyperintensities, AD diagnosis, and cerebrospinal-fluid-derived amyloid (A) and tau (T) status (available for 46.71%; A-T-/A + T-/A + T + n = 143/48/39). Results PVS volumes increased significantly over follow-ups (CSO: B = 0.03 [0.02, 0.05], p A-T-, p FDR = 0.004) or who were amyloid positive but tau negative (A + T + > A + T-, p FDR = 0.07). CSO-PVS volumes increased at a faster rate with amyloid positivity as compared to amyloid negativity (A + T-/A + T + > A-T-, p FDR = 0.021). Conclusion Our longitudinal evidence supports the relevance of PVS enlargement in presumably healthy ageing as well as in AD pathology. We further discuss the region-specific involvement of white matter hyperintensities and neurotoxic waste accumulation in PVS enlargement and the possibility of additional factors contributing to PVS progression. A comprehensive understanding of PVS dynamics could facilitate the understanding of pathological cascades and might inform targeted treatment strategies. Trial registration German Clinical Trials Register DRKS00007966. Registered 04.05.2015 – retrospectively registered, https://drks.de/search/en/trial/DRKS00007966 .

Abstract Background For over three decades, the concomitance of cortical neurodegeneration and white matter hyperintensities (WMH) has sparked discussions about their coupled temporal dynamics. Longitudinal studies supporting this hypothesis nonetheless remain scarce. Methods We applied global and regional bivariate latent growth curve modelling to determine the extent to which WMH and cortical thickness were interrelated over a four-year period. For this purpose, we leveraged longitudinal MRI data from 451 cognitively unimpaired participants (DELCODE; median age 69.71 [IQR 65.51, 75.50] years; 52.32% female). Participants underwent MRI sessions annually over a four-year period (1815 sessions in total, with roughly four MRI sessions per participant). We adjusted all models for demographics and cardiovascular risk. Results Our findings were three-fold. First, larger WMH volumes were linked to lower cortical thickness (σ = -0.165, SE = 0.047, Z = -3.515, P

The recent elevation of the Western Grass Snake, Natrix helvetica, from subspecies status prompted an assessment of its natural history and ecological traits compared to closely related species. We report an unusual predation attempt by the freshwater crab Potamon fluviatile on N. helvetica sicula from Sicily, indicating an ecological interaction previously overlooked in this species. The observation suggests that this crab may utilise snakes’ muscle tissue as an additional nutrient source. This predator-prey interaction, although probably rare, adds to the understanding of the dynamics between crabs and snakes, shedding light on their interaction in freshwater habitats. To provide context for our observation and highlight its rarity, we searched through scientific literature and online sources to generate a comprehensive review of the phenomenon that examines the predatory behaviour of crabs on snakes.

Abstract The sequencing of a kidney sample (KW2013002) from a stranded Megaptera novaeangliae (Humpback whale) calf is the first chromosome-level reference genome for this species1. The calf, a 457 cm and 2,500 lbs male, was found stranded in Hawai’i Kai, HI, in 2013 and was marked as abandoned/orphaned. In 2023, 1 g of kidney was sequenced with PacBio long-read DNA sequencing, chromatin conformation capture (Hi-C), RNA sequencing, and mitochondrial sequencing to comprehensively characterize the genome and transcriptome of M. novaeangliae. Data validation includes a synteny analysis, mitochondrial annotation, and a comparison of BUSCO scores (scaffold v. reference genome and Balaenoptera musculus (Blue whale) v. M. novaeangliae). BUSCO analysis was performed on an M. novaeangliae scaffold-level assembly to determine genomic completeness of the reference genome, with a scaffold BUSCO score of 91.2% versus a score of 95.4%. Synteny analysis was performed using the B. musculus genome as comparison to determine chromosome-level coverage and structure. Further, a time-based phylogenetic tree was constructed using the sequenced data and publicly available genomes.

Abstract Background Post-cardiac arrest syndrome (PCAS) presents a multifaceted challenge in clinical practice, characterized by severe neurological injury and high mortality rates despite advancements in management strategies. One of the important critical aspects of PCAS is post-arrest lung injury (PALI), which significantly contributes to poor outcomes. PALI arises from a complex interplay of pathophysiological mechanisms, including trauma from chest compressions, pulmonary ischemia–reperfusion (IR) injury, aspiration, and systemic inflammation. Despite its clinical significance, the pathophysiology of PALI remains incompletely understood, necessitating further investigation to optimize therapeutic approaches. Methods This review comprehensively examines the existing literature to elucidate the epidemiology, pathophysiology, and therapeutic strategies for PALI. A comprehensive literature search was conducted to identify preclinical and clinical studies investigating PALI. Data from these studies were synthesized to provide a comprehensive overview of PALI and its management. Results Epidemiological studies have highlighted the substantial prevalence of PALI in post-cardiac arrest patients, with up to 50% of survivors experiencing acute lung injury. Diagnostic imaging modalities, including chest X-rays, computed tomography, and lung ultrasound, play a crucial role in identifying PALI and assessing its severity. Pathophysiologically, PALI encompasses a spectrum of factors, including chest compression-related trauma, pulmonary IR injury, aspiration, and systemic inflammation, which collectively contribute to lung dysfunction and poor outcomes. Therapeutically, lung-protective ventilation strategies, such as low tidal volume ventilation and optimization of positive end-expiratory pressure, have emerged as cornerstone approaches in the management of PALI. Additionally, therapeutic hypothermia and emerging therapies targeting mitochondrial dysfunction hold promise in mitigating PALI-related morbidity and mortality. Conclusion PALI represents a significant clinical challenge in post-cardiac arrest care, necessitating prompt diagnosis and targeted interventions to improve outcomes. Mitochondrial-related therapies are among the novel therapeutic strategies for PALI. Further clinical research is warranted to optimize PALI management and enhance post-cardiac arrest care paradigms. Graphical Abstract

Abstract The Western Palearctic harbours a diverse snake fauna, including numerous endemic species and yet unnamed clades, identified through molecular analyses. However, morphological characteristics of these clades, even of common species, often remain relatively unexplored. In this study, we provide an examination of the morphology and cranial anatomy of the semi-aquatic snake species Natrix tessellata (Laurenti, 1768), with a focus on populations of the so-called ‘Europe’ and ‘Greece’ clades. Utilising both museum collections and field data, we first morphologically examined 541 individuals of N. tessellata, categorising them according to previously established clades and lineages that resulted in relatively low morphometric and meristic variation across the species’ range. When assessing the 448 specimens from the ‘Europe’ and the ‘Greece’ clades separately, we similarly observed little variation in meristic characteristics. On the other hand, individuals of the ‘Greece’ clade displayed smaller and more slender body and head proportions compared to those of the ‘Europe’ clade and the pigmentation of the labial scales is distinctively paler in the ‘Greece’ clade, whereas the overall body colouration remains largely similar between the two. Our osteological analysis of 47 N. tessellata skulls also indicated slight differences in the frontoparietal portion of the braincase between the ‘Europe’ and the ‘Greece’ clades, warranting further examination with a larger dataset and extending to other skull components. These findings hold significance for ongoing enquiries into the species’ biogeography, morphology and ecological adaptations. In summary, the integration of morphological and osteological data with genetic information offers a promising avenue for potential taxonomic revisions of N. tessellata in the future.

Introduction: Emergency departments are the primary entry point for emergencies in the public healthcare system. Resource constraints burden a large proportion of the public hospital emergency departments, which includes limited access to radiological services. Emergency point-of-care ultrasound provides a tool capable of bridging this gap. The Eastern Cape is yet to describe the utilisation of emergency point-of-care ultrasound in any of its emergency departments. Methods: Frere Hospital initiated a clinical audit to assess the utilisation of emergency point-of-care ultrasound in its emergency department in 2022. This study was a retrospective review of the audit between 01 November 2022 until 28 February 2023. Data from the handwritten register regarding patient's presenting complaints and provisional diagnoses was also captured during the study period to draw comparisons between burden of disease and use of emergency point-of-care ultrasound. Results: A total of 9501 patients attended Frere Hospital's emergency department over the study period with 492 emergency point-of-care ultrasounds performed (overall utilisation rate 5.2 %). The five credentialed emergency point-of-care ultrasound providers performed the majority (n = 360, 73.2 %) of the applications, compared to 132 (26.8 %) performed by the seven non-credentialed providers. The extended focused abdominal sonography in trauma (eFAST) was the most frequently performed application (n = 140, 28.5 %). Conclusion: Emergency point-of-care ultrasound is underutilised in Frere Hospital's emergency department. The varied casemix requires upskilling of clinicians in emergency point-of-care ultrasound to suit the burden of disease experienced in the department. Ongoing emergency point-of-care ultrasound training, credentialing and research is important to ensure appropriate and quality emergency point-of-care ultrasound utilisation.

Light–oxygen–voltage (LOV) domains are small photosensory flavoprotein modules that allow the conversion of external stimuli (sunlight) into intracellular signals responsible for various cell behaviors (e.g. phototropism and chloroplast relocation). This ability relies on the light-induced formation of a covalent thioether adduct between a flavin chromophore and a reactive cysteine from the protein environment, which triggers a cascade of structural changes that result in the activation of a serine/threonine (Ser/Thr) kinase. Recent developments in time-resolved crystallography may allow the activation cascade of the LOV domain to be observed in real time, which has been elusive. In this study, we report a robust protocol for the production and stable delivery of microcrystals of the LOV domain of phototropin Phot-1 from Chlamydomonas reinhardtii (CrPhotLOV1) with a high-viscosity injector for time-resolved serial synchrotron crystallography (TR-SSX). The detailed process covers all aspects, from sample optimization to data collection, which may serve as a guide for soluble protein preparation for TR-SSX. In addition, we show that the crystals obtained preserve the photoreactivity using infrared spectroscopy. Furthermore, the results of the TR-SSX experiment provide high-resolution insights into structural alterations of CrPhotLOV1 from Δt = 2.5 ms up to Δt = 95 ms post-photoactivation, including resolving the geometry of the thioether adduct and the C-terminal region implicated in the signal transduction process.

Mangroves are known for their carbon storage capacity, yet they are under immense pressure from human activities. This study assessed anthropogenic disturbances on mangroves’ aboveground biomass (AGB) in northern Borneo, Malaysia, using airborne light detection and ranging (LiDAR) data. Three global or pantropical allometries were compared in the development of an AGB estimation model by regressing LiDAR metrics against the AGB. The best model predicted AGB from Saenger and Snedaker allometry with an R2 of 0.85 and a root mean square error (RMSE) of 14.59 Mg/ha (relative RMSE: 7.24 %). The high-resolution AGB map revealed a natural AGB gradient in intact mangroves from the coast to the interior. However, only a weak correlation between the distance from shoreline and AGB in disturbed mangroves was found. The LiDAR estimated AGBs were 196.36 Mg/ha and 157.27 Mg/ha for intact mangroves and disturbed mangroves, respectively. Relatively high AGB areas were abundant in the intact mangroves but scarce in the disturbed mangroves. The LiDAR-based AGB assessment is accurate and high-resolution, supporting carbon stock conservation and sustainable management activities under climate change mitigation programs such as REDD + .

Recent phylogenetic studies in Himalayan lazy toads of the genus Scutiger Theobald, 1868 revealed the presence of genetically deeply divergent lineages. The taxonomy of S. nepalensis sensu lato was re-assessed based on museum material considering molecular and morphological data. The results strongly support the recognition of a new species, S. kanjiroba sp. nov. distributed along the Nepalese Kanjiroba massif. It is further shown that S. sikimmensis has an apparently much more restricted distribution range than previously thought. The frequent misidentification of Scutiger across large areas of the Himalaya-Tibet area highlights the significance of careful taxonomic evaluation of collection material and the need for the direct morphological comparison of closely related species when describing new species.

Abstract Environmental concerns and climate protection are gaining increasing emphasis nowadays. A growing number of industries and scientific fields are involved in this trend. Sustainable electronics is an emerging research strand. Environmentally friendly and biodegradable or biobased raw materials can be used for the development of green flexible electronic devices, which may serve to reduce the pollution generated by plastics and electronics waste. In this work, we present cytocompatible, electrically conductive structures of nanocarbon water-soluble composites based on starch films. To accomplish this goal, potato starch-based films with glycerol as a plasticiser were developed along with a water-soluble vehicle for nanocarbon-based electroconductive pastes specifically dedicated to screen printing technology. Films were characterized by optical microscopy, scanning electron microscopy (SEM) mechanical properties and surface free energy.

Abstract Background Compared with conventional cigarettes, electronic cigarettes are less harmful in some studies. However, recent research may indicate the opposite. This study aimed to determine whether e-cigarette use is related to myocardial health in adults in the U.S. Methods This study used data from the 2020 Behavioral Risk Factor Surveillance System (BRFSS), a cross-sectional survey of adult US residents aged 18 years or older. We examined whether e-cigarette use was related to myocardial infarction byapplying a logistic regression model to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Results The final analytical sample included 198,530 adults in the U.S. Logistic regression indicated that U.S. adults who reported being former and some days of e-cigarette use had 23% and 52% greater odds of ever having an MI, respectively, than did those who reported never using e-cigarettes (OR = 1.23, 95% CI 1.08–1.40, p = 0.001; OR = 1.52, 95% CI 1.10–2.09, p = 0.010). Conclusions The results suggest that former and someday users of e-cigarettes probably have increased odds of myocardial infarction in adults in the U.S. Further research is needed, including long-term follow-up studies on e-cigarettes, since it is still unknown whether they should be discouraged.

Abstract The black fungus Exophiala causes a wide range of infections from superficial to subcutaneous, but also invasive fungal infections in immunocompromised patients as well as healthy individuals. In addition, Exophiala, is a common colonizer of the air ways of patients with cystic fibrosis. However, the source of infection and mode of transmission is still unclear. The aim of this study was to investigate the presence of Exophiala in samples collected from Swedish indoor environments. We found that the Exophiala species were commonly found in dishwashers and that Exophiala dermatitidis was the most common Exophiala species, being identified in 70% (26 out of the 37) of samples. Almost all E. dermatitidis isolates had the ability to grow at 42 °C (P = 0.0002) and were catalase positive. Voriconazole and posaconazole exhibited the lowest MICs, while caspofungin and anidulafungin lack the antifungal activities in vitro. Future studies are needed to illuminate the transmission mode of the fungi.

Objectives: We aim to estimate geographic variability in total numbers of infections and infection fatality ratios (IFR; the number of deaths caused by an infection per 1,000 infected people) when the availability and quality of data on disease burden are limited during an epidemic. Methods: We develop a noncentral hypergeometric framework that accounts for differential probabilities of positive tests and reflects the fact that symptomatic people are more likely to seek testing. We demonstrate the robustness, accuracy, and precision of this framework, and apply it to the United States (U.S.) COVID-19 pandemic to estimate county-level SARS-CoV-2 IFRs. Results: The estimators for the numbers of infections and IFRs showed high accuracy and precision; for instance, when applied to simulated validation data sets, across counties, Pearson correlation coefficients between estimator means and true values were 0.996 and 0.928, respectively, and they showed strong robustness to model misspecification. Applying the county-level estimators to the real, unsimulated COVID-19 data spanning April 1, 2020 to September 30, 2020 from across the U.S., we found that IFRs varied from 0 to 44.69, with a standard deviation of 3.55 and a median of 2.14. Conclusions: The proposed estimation framework can be used to identify geographic variation in IFRs across settings.

From the nineteenth-century panorama to the emergence of the digital panoramic format in the 1990's, the visualization of large images frequently relies on panoramic viewing strategies. Originally rendered in the form of epic painted canvases, these strategies are now amplified through gigapixel imaging, computer vision and machine learning. Whether for scientific analysis, dissemination, or to visualize cultural big data, panoramic strategies pivot on the illusion of immersion. The latter is achieved through human-centered design situated within a large-scale environment combined with a multi-sensory experience spanning sight, sound, touch, and smell. In this article, we present the original research undertaken to realize a digital twin of the 1894 panorama of the battle of Murten. Following a brief history of the panorama, the methods and technological framework systems developed for Murten panorama's visualization are delineated. Novel visualization methodologies are further discussed, including how to create the illusion of immersion for the world's largest image of a single physical object and its cultural big data. We also present the visualization strategies developed for the augmentation of the layered narratives and histories embedded in the final interactive viewing experience of the Murten panorama. This article offers researchers in heritage big data new schemas for the visualization and augmentation of gigapixel images in digital panoramas.

BackgroundFrailty, defined as multidimensional prognostic index (MPI), has been recently identified as strong predictor of disability and mortality in the elderly with acute ischemic stroke (AIS). The stress hyperglycemia ratio (SHR) is a recently introduced biomarker significantly associated with poor outcome in AIS.ObjectivesThis study aimed to investigate in what extent frailty, measured by MPI, and SHR affects the 3-months outcome of patients > 65 years-old with AIS.MethodsConsecutive patients with AIS >65 years-old who underwent intravenous thrombolysis (IVT) from 2015 to 2019 were enrolled in a German and an Italian Stroke Unit. The SHR was calculated by dividing the fasting plasma glucose at admission with glycated hemoglobin. Demographics and clinical premorbid data, stroke-related variables, including baseline and post-treatment NIHSS score were included in a logistic regression model. The 3-months functional outcome was evaluated by using modified Rankin scale (mRS); good outcome was defined as mRS 0–2, poor as mRS ≥ 3.ResultsOne hundred and fifty-five AIS patients were enrolled in the study. Median MPI was 0.19 [0.13–0.31]; 118 (76.1%) patients were classified as “robust” and 37 (23.9%) as “frail.” In regression analysis, age, NIHSS, and MPI demonstrated as the most significant predictor of 3-months good outcome in the whole cohort. In robust patients, SHR values were significantly associated with the outcome.ConclusionsMPI is associated with the 3-months outcome in our cohort, in particular with good outcome. Conversely, SHR seems to be associated with a 3-months poor outcome in “robust” patients but not in frail patients.

Asia is the center of Tilia (Malvaceae) species diversity. However, the ectomycorrhizal (ECM) relations of Asian Tilia are scarcely studied. This study provides the first description of ECM communities of Tilia kiusiana, a rare tree endemic to southwestern Japan. Across the natural distribution of T. kiusiana, ECM fungal communities hosted by the species were investigated in three study sites: Hyōgo (H) and Yamaguchi (Y) on Honshu Island, and Ōita (O) on Kyushu Island. Using molecular methods, T. kiusiana was revealed to host a high diversity of fungi belonging to 25 ECM lineages (16, 17, and 14 lineages on sites H, Y, and O, respectively). The ECM communities of T. kiusiana and the previously studied endemic T. japonica were compared to the available data on other ECM tree genera in Japan, revealing that three Ascomycota ECM lineages (/genea-humaria, marcelleina-peziza gerardii, /tuber-helvella) show a preference towards Tilia hosts. While the total lineage richness did not differ among the compared host tree genera, Tilia communities exhibited higher effective lineage richness at higher (less sensitive to rare taxa) diversity orders. Despite their relative rarity, Tilia trees might play an important role in mixed forests: maintaining the diversity of ECM Ascomycota and potentially buffering the ECM fungal biodiversity loss in cases of ECM tree host diversity decline.

Objective Hypertrophic cardiomyopathy (HCM), including obstructive HCM (oHCM), is the most common inherited cardiomyopathy causing lifestyle-limiting symptoms. Data are lacking about patients’ perspectives on the daily impact of their symptoms. This qualitative interview study was conducted to better understand patients’ experiences with oHCM.Methods In October 2019, telephone interviews were conducted with 20 US adults with oHCM identified by the Hypertrophic Cardiomyopathy Association. Using a semi-structured interview guide, key symptoms, impacts of oHCM and oHCM treatment goals were discussed.Results Median age was 54 years (range 29–78), 55% were women, 85% were white and 15% were Hispanic or Latino. Median time since diagnosis was 3 years. Symptoms included shortness of breath, dizziness/light-headedness, heart palpitations/fluttering (all 95%), fatigue (90%) and chest pain/pressure (80%). All participants reported limitations in physical functioning/activities; most reported additional impacts (emotional stress (80%), fear of dying (55%)). Shortness of breath and fatigue were among their most bothersome symptoms; an effective oHCM treatment would need to improve ≥1 of these symptoms (allowing increased physical/social activity).Conclusions Patients with oHCM experience a high symptom burden and psychosocial impacts, affecting health status. Improved shortness of breath, fatigue and physical functioning are highly valued by patients and represent important treatment goals.

Mathematical modeling of epidemic dynamics is crucial to understand its underlying mechanisms, quantify important parameters, and make predictions that facilitate more informed decision-making. There are three major types of models: mechanistic models including the SEIR-type paradigm, alternative data-driven (DD) approaches, and hybrid models that combine mechanistic models with DD approaches. In this paper, we summarize our work in the COVID-19 Scenario Modeling Hub (SMH) for more than 12 rounds since early 2021 for informed decision support. We emphasize the importance of deep learning techniques for epidemic modeling via a flexible DD framework that substantially complements the mechanistic paradigm to evaluate various future epidemic scenarios. We start with a traditional curve-fitting approach to model cumulative COVID-19 based on the underlying SEIR-type mechanisms. Hospitalizations and deaths are modeled as binomial processes of cases and hospitalization, respectively. We further formulate two types of deep learning models based on multivariate long short term memory (LSTM) to address the challenges of more traditional DD models. The first LSTM is structurally similar to the curve fitting approach and assumes that hospitalizations and deaths are binomial processes of cases. Instead of using a predefined exponential curve, LSTM relies on the underlying data to identify the most appropriate functions, and is capable of capturing both long-term and short-term epidemic behaviors. We then relax the assumption of dependent inputs among cases, hospitalizations, and death. Another type of LSTM that handles all input time series as parallel signals, the independent multivariate LSTM, is developed. Independent multivariate LSTM can incorporate a wide range of data sources beyond traditional case-based epidemiological surveillance. The DD framework unleashes its potential in big data era with previously neglected heterogeneous surveillance data sources, such as syndromic, environment, genomic, serologic, infoveillance, and mobility data. DD approaches, especially LSTM, complement and integrate with the mechanistic modeling paradigm, provide a feasible alternative approach to model today’s complex socio-epidemiological systems, and further leverage our ability to explore different scenarios for more informed decision-making during health emergencies.