Evaluation of Hepatocellular Carcinoma Surveillance with Contrast-enhanced MRI in a High-Risk Western European Cohort.

AIM: To investigate the utilization of MRI using a MRI liver protocol with extracellular contrast-enhanced series for hepatocellular carcinoma (HCC) surveillance in high-risk patients. METHODS: Consecutive high-risk patients of a western European cohort who underwent repeated liver MRI for HCC screening were included. Lesions were registered according to the Liver Reporting & Data System (LIRADS) 2018. HCC was staged as very early stage HCC (BCLC stage 0) and more advanced stages of HCC (BCLC stage A-D). Differences in time interval between MRI's for BCLC stage 0 and stage A-D were calculated with the Mann-Whitney U test. The HCC cumulative incidence at one-, three- and five years was calculated with the Kaplan Meier estimator. RESULTS: From 2010 to 2019 a total of 240 patients were included (71% male; median age: 57 years; IQR: 50-64 years) with 1350 MRI's. Most patients (83 %) had cirrhosis with hepatitis C as the most common underlying cause. Patients underwent on average four MRI's (IQR: 3-7). Forty-two patients (17.5%) developed HCC (52 HCC lesions: 43 LIRADS-5, eight LIRADS-4, and one LIRADS-TIV). Eighteen patients (43%) had BCLC stage 0 HCC with a significant shorter screening time interval (10 months; IQR: 6-21) compared to patients with BCLC stage A-D (21 months; IQR: 10-32) (p = 0.03). Thirty seven percent of patients with a LIRADS-3 lesion (n=43) showed HCC development within twelve months (median: 7.4 months). One, three- and five-year HCC cumulative incidence in cirrhotic patients was 1%, 10% and 17%, respectively. CONCLUSION: High-risk patients who underwent surveillance with contrast-enhanced MRI developed HCC in 17.5 % during a follow up period of over 4 years median. Very early stage HCC was seen in compensated cirrhosis after a median time interval of 10 months. Later stages of HCC were related to prolonged screening time interval (median 21 months).

Identification of Small-Molecule Inhibitors Targeting Different Signaling Pathways in Cancer-Associated Fibroblast Reprogramming under Tumor-Stroma Interaction.

Cancer-associated fibroblasts (CAFs) interact reciprocally with tumor cells through various signaling pathways in many cancer types, including cutaneous squamous cell carcinoma. Among normal fibroblast subtypes, papillary fibroblasts (PFs) and reticular fibroblasts (RFs) respond distinctly to tumor cell signaling, eventuating the differentiation of RFs rather than PFs into CAFs. The regulation of subtype differentiation in fibroblasts remains poorly explored. In this study, we assessed the differences between PFs, RFs, and CAFs and examined the effects of small-molecule inhibitors targeting the TGFß, phosphoinositide 3-kinase/protein kinase B/mTOR, and NOTCH pathways on the tumor-promoting property of CAFs and CAF reprogramming in 2-dimensional and 3-dimensional cultures. Blocking TGFß and phosphoinositide 3-kinase strongly deactivated and concurrently induced a PF phenotype in RFs and CAFs. Three-dimensional coculturing of a cutaneous squamous cell carcinoma cell line MET2 with RFs or CAFs led to enhanced tumor invasion, RF-CAF transition, and cytokine production, which were further repressed by blocking TGFß and phosphoinositide 3-kinase/mTOR pathways but not NOTCH pathway. In conclusion, the study identified biomarkers for PFs, RFs, and CAFs and displayed different effects of blocking key signaling pathways in CAFs and tumor cell-CAF interplay. These findings prompted a CAF-to-PF therapeutic strategy and provided perspectives of using included inhibitors in CAF-based cancer therapy.

Association of Complement Factors With Disability Progression in Primary Progressive Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: The complement system is known to play a role in multiple sclerosis (MS) pathogenesis. However, its contribution to disease progression remains elusive. The study investigated the role of the complement system in disability progression of patients with primary progressive MS (PPMS). METHODS: Sixty-eight patients with PPMS from 12 European MS centers were included in the study. Serum and CSF levels of a panel of complement components (CCs) were measured by multiplex enzyme-linked immunosorbent assay at a baseline time point (i.e., sampling). Mean (SD) follow-up time from baseline was 9.6 (4.8) years. Only one patient (1.5%) was treated during follow-up. Univariable and multivariable logistic regressions adjusted for age, sex, and albumin quotient were performed to assess the association between baseline CC levels and disability progression in short term (2 years), medium term (6 years), and long term (at the time of the last follow-up). RESULTS: In short term, CC played little or no role in disability progression. In medium term, an elevated serum C3a/C3 ratio was associated with a higher risk of disability progression (adjusted OR 2.30; 95% CI 1.17-6.03; p = 0.040). By contrast, increased CSF C1q levels were associated with a trend toward reduced risk of disability progression (adjusted OR 0.43; 95% CI 0.17-0.98; p = 0.054). Similarly, in long term, an elevated serum C3a/C3 ratio was associated with higher risk of disability progression (adjusted OR 1.81; 95% CI 1.09-3.40; p = 0.037), and increased CSF C1q levels predicted lower disability progression (adjusted OR 0.41; 95% CI 0.17-0.86; p = 0.025). DISCUSSION: Proteins involved in the activation of early complement cascades play a role in disability progression as risk (elevated serum C3a/C3 ratio) or protective (elevated CSF C1q) factors after 6 or more years of follow-up in patients with PPMS. The protective effects associated with C1q levels in CSF may be related to its neuroprotective and anti-inflammatory properties.

Lesions hyper- to isointense to surrounding liver in the hepatobiliary phase of gadoxetic acid-enhanced MRI.

OBJECTIVES: Hyper- or isointensity in the hepatobiliary phase (HBP) of gadoxetic acid-enhanced MRI has high specificity for focal nodular hyperplasia (FNH) but may be present in hepatocellular adenoma and carcinoma (HCA/HCC). This study aimed to identify imaging characteristics differentiating FNH and HCA/HCC. MATERIALS AND METHODS: This multicenter retrospective cohort study included patients with pathology-proven FNH or HCA/HCC, hyper-/isointense in the HBP of gadoxetic acid-enhanced MRI between 2010 and 2020. Diagnostic performance of imaging characteristics for the differentiation between FNH and HCA/HCC were reported. Univariable analyses, multivariable logistic regression analyses, and classification and regression tree (CART) analyses were conducted. Sensitivity analyses evaluated imaging characteristics of B-catenin-activated HCA. RESULTS: In total, 124 patients (mean age 40 years, standard deviation 10 years, 108 female) with 128 hyper-/isointense lesions were included. Pathology diagnoses were FNH and HCA/HCC in 64 lesions (50%) and HCA/HCC in 64 lesions (50%). Imaging characteristics observed exclusively in HCA/HCC were raster and atoll fingerprint patterns in the HBP, sinusoidal dilatation on T2-w, hemosiderin, T1-w in-phase hyperintensity, venous washout, and nodule-in-nodule partification in the HBP and T2-w. Multivariable logistic regression and CART additionally found a T2-w scar indicating FNH, less than 50% fat, and a spherical contour indicating HCA/HCC. In our selected cohort, 14/48 (29%) of HCA were B-catenin activated, most (13/14) showed extensive hyper-/isointensity, and some had a T2-w scar (4/14, 29%). CONCLUSION: If the aforementioned characteristics typical for HCA/HCC are encountered in lesions extensively hyper- to isointense, further investigation may be warranted to exclude B-catenin-activated HCA. CLINICAL RELEVANCE: Hyper- or isointensity in the HBP of gadoxetic acid-enhanced MRI is specific for FNH, but HCA/HCC can also exhibit this feature. Therefore, we described imaging patterns to differentiate these entities. KEY POINTS: FNH and HCA/HCC have similar HBP intensities but have different malignant potentials. Six imaging patterns exclusive to HCA/HCC were identified in this lesion population. These features in liver lesions hyper- to isointense in the HBP warrant further evaluation.

Opposing roles of resident and infiltrating immune cells in the defense against Legionella longbeachae via IL-18R/IFN-γ/ROS axis in mice.

The immune response against Legionella longbeachae, a causative agent of the often-fatal Legionnaires' pneumonia, is poorly understood. Here, we investigated the specific roles of tissue-resident alveolar macrophages (AMs) and infiltrating phagocytes during infection with this pathogen. AMs were the predominant cell type that internalized bacteria 1 day after infection. A total of 3 and 5 days after infection, AM numbers were greatly reduced, whereas there was an influx of neutrophils and, later, monocyte-derived cells (MCs) into lung tissue. AMs carried greater numbers of viable L. longbeachae than neutrophils and MCs, which correlated with a higher capacity of L. longbeachae to translocate bacterial effector proteins required for bacterial replication into the AM cytosol. Cell ablation experiments demonstrated that AM promoted infection, whereas neutrophils and MC were required for efficient bacterial clearance. Interleukin (IL)-18 was important for interferon-γ production by IL-18R+ natural killer cells and T cells, which, in turn, stimulated reactive oxygen species-mediated bactericidal activity in neutrophils, resulting in the restriction of L. longbeachae infection. Ciliated bronchiolar epithelial cells also expressed IL-18R but did not play a role in IL-18-mediated L. longbeachae clearance. Our results have identified opposing innate functions of tissue-resident and infiltrating immune cells during L. longbeachae infection that may be manipulated to improve protective responses.

A Retrospective Comparison of Multiple Approaches to Anatomically Informed Contact Selection in Subthalamic Deep Brain Stimulation for Parkinson's Disease.

Background: Conventional deep brain stimulation (DBS) programming via trial-and-error warrants improvement to ensure swift achievement of optimal outcomes. The definition of a sweet spot for subthalamic DBS in Parkinson's disease (PD-STN-DBS) may offer such advancement. Objective: This investigation examines the association of long-term motor outcomes with contact selection during monopolar review and different strategies for anatomically informed contact selection in a retrospective real-life cohort of PD-STN-DBS. Methods: We compared contact selection based on a monopolar review (MPR) to multiple anatomically informed contact selection strategies in a cohort of 28 PD patients with STN-DBS. We employed a commercial software package for contact selection based on visual assessment of individual anatomy following two predefined strategies and two algorithmic approaches with automatic targeting of either the sensorimotor STN or our previously published sweet spot. Similarity indices between chronic stimulation and contact selection strategies were correlated to motor outcomes at 12 months follow-up. Results: Lateralized motor outcomes of chronic DBS were correlated to the similarity between chronic stimulation and visual contact selection targeting the dorsal part of the posterior STN (rho = 0.36, p = 0.007). Similar relationships could not be established for MPR or any of the other investigated strategies. Conclusions: Our data demonstrates that a visual contact selection following a predefined strategy can be linked to beneficial long-term motor outcomes in PD-STN-DBS. Since similar correlations could not be observed for the other approaches to anatomically informed contact selection, we conclude that clear definitions and prospective validation of any approach to imaging-based DBS-programming is warranted.

Engaging stimulatory immune checkpoint interactions in the tumour immune microenvironment of primary liver cancers - how to push the gas after having released the brake.

Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the first and second most common primary liver cancer (PLC). For decades, systemic therapies consisting of tyrosine kinase inhibitors (TKIs) or chemotherapy have formed the cornerstone of treating advanced-stage HCC and CCA, respectively. More recently, immunotherapy using immune checkpoint inhibition (ICI) has shown anti-tumour reactivity in some patients. The combination regimen of anti-PD-L1 and anti-VEGF antibodies has been approved as new first-line treatment of advanced-stage HCC. Furthermore, gemcibatine plus cisplatin (GEMCIS) with an anti-PD-L1 antibody is awaiting global approval for the treatment of advanced-stage CCA. As effective anti-tumour reactivity using ICI is achieved in a minor subset of both HCC and CCA patients only, alternative immune strategies to sensitise the tumour microenvironment of PLC are waited for. Here we discuss immune checkpoint stimulation (ICS) as additional tool to enhance anti-tumour reactivity. Up-to-date information on the clinical application of ICS in onco-immunology is provided. This review provides a rationale of the application of next-generation ICS either alone or in combination regimen to potentially enhance anti-tumour reactivity in PLC patients.

Unrecognized myocardial scar by late-gadolinium-enhancement cardiovascular magnetic resonance: Insights from the population-based Hamburg City Health Study.

BACKGROUND: The presence of myocardial scar is associated with poor prognosis in several underlying diseases. Late-gadolinium-enhancement (LGE) cardiovascular magnetic resonance (CMR) imaging reveals clinically silent "unrecognized myocardial scar" (UMS), but the etiology of UMS often remains unclear. This population-based CMR study evaluated prevalence, localization, patterns, and risk factors of UMS. METHODS: The study population consisted of 1064 consecutive Hamburg City Health Study participants without a history of coronary heart disease or myocarditis. UMS was assessed by standard-phase-sensitive-inversion-recovery LGE CMR. RESULTS: Median age was 66 [quartiles 59, 71] years and 37% (388/1064) were females. UMS was detected in 244 (23%) participants. Twenty-five participants (10%) had ischemic, and 217 participants (89%) had non-ischemic scar patterns, predominantly involving the basal inferolateral left-ventricular (LV) myocardium (75%). Two participants (1%) had coincident ischemic and non-ischemic scar. The presence of any UMS was independently associated with LV ejection fraction (odds ratios (OR) per standard deviation (SD) 0.77 (confidence interval (CI) 0.65-0.90), p = 0.002) and LV mass (OR per SD 1.54 (CI 1.31-1.82), p < 0.001). Ischemic UMS was independently associated with LV ejection fraction (OR per SD 0.58 (CI 0.39-0.86), p = 0.007), LV mass (OR per SD 1.74 (CI 1.25-2.45), p = 0.001), and diabetes (OR 4.91 (CI 1.66-13.03), p = 0.002). Non-ischemic UMS was only independently associated with LV mass (OR per SD 1.44 (CI 1.24-1.69), p < 0.001). CONCLUSION: UMS, in particular with a non-ischemic pattern, is frequent in individuals without known cardiac disease and predominantly involves the basal inferolateral LV myocardium. Presence of UMS is independently associated with a lower LVEF, a higher LV mass, and a history of diabetes.

Cryptogenic non-cirrhotic HCC: Clinical, prognostic and immunologic aspects of an emerging HCC etiology.

The incidence of hepatocellular carcinoma (HCC) in non-cirrhotic livers is rising significantly, but clear risk factors for screening remain elusive. This study sought to characterize non-cirrhotic HCC etiologies. HCC cases from 2009 to 2020 in a Dutch referral center were examined, revealing 371 out of 1654 cases (22%) as non-cirrhotic. Notably, the incidence of non-cirrhotic HCC increased by 61% in the time frame between 2009 and 2020. Interestingly 39% of non-cirrhotic HCC cases had cryptogenic origins. Cryptogenic non-cirrhotic HCC exhibited similarities with non-cirrhotic NAFLD HCC, but displayed advanced tumor stages, lower surgical rates, and a more frequent presence of symptoms, which substantiated in poor survival rates. Advanced cryptogenic non-cirrhotic HCC stages exhibited elevated serum interleukin-6 levels compared to non-cirrhotic HCC with defined etiologies. Comparative analysis encompassing cryptogenic and NAFLD non-cirrhotic HCC cohorts and controls unveiled comparable circulating immune biomarker profiles and PNPLA3 polymorphisms. To conclude, the primary etiology of non-cirrhotic HCC in our cohort has not defined risk factors. This cryptogenic variant exhibits distinct traits, such as advanced tumors and increased symptoms, and most resemble burned-out NAFLD. Understanding this HCC variant is crucial for improving screening and management strategies.

Efficacy of therapies for post dural puncture headache.

PURPOSE OF REVIEW: Clinical management of postdural puncture headache (PDPH) remains an interdisciplinary challenge with significant impact on both morbidity and quality of life. This review aims to give an overview of the most recent literature on prophylactic and therapeutic measures and to discuss novel findings with regard to currently published consensus practice guideline recommendations. RECENT FINDINGS: Although current evidence does not support a recommendation of any specific prophylactic measure, new data is available on the use of intrathecal catheters to prevent PDPH and/or to avoid invasive procedures. In case of disabling or refractory symptoms despite conservative treatments, the epidural blood patch (EBP) remains the therapeutic gold standard and its use should not be delayed in the absence of contraindications. However, recent clinical studies and meta-analyses provide additional findings on the therapeutic use of local anesthetics as potential noninvasive alternatives for early symptom control. SUMMARY: There is continuing research focusing on both prophylactic and therapeutic measures offering promising data on potential alternatives to invasive procedures, although there is currently no treatment option that comes close to the effectiveness of an EBP. A better understanding of PDPH pathophysiology is not only necessary to identify new therapeutic targets, but also to recognize patients who benefit most from current treatments, as this might enhance their therapeutic efficacy.

Successful adult domino living donor liver transplantation in methylmalonic acidemia: case report.

Background: Liver transplantation (LT) is a therapeutic option in multiple inherited metabolic diseases (IMDs), including methylmalonic acidemia (MMA), as LT reduces the risk of acute metabolic decompensations and long-term complications associated with these diseases. In certain IMDs, such as maple syrup urine disease (MSUD), domino liver transplant (DLT) is an accepted and safe method which expands the donor pool. However, only one adult case of DLT using an MMA donor liver has been reported; outcome and safety are still unknown and questioned. Case Description: In this case report, we describe our experience with DLT using MMA livers. Two adult MMA patients underwent living donor liver transplant (LDLT); their MMA livers were consecutively transplanted into two patients on the liver transplant waiting list who had limited chance of receiving a liver transplant in the short term due to their low model for end-stage liver disease (MELD) scores. No severe peri- or postoperative complications occurred, however the recipients of the MMA livers biochemically now have mild MMA. Conclusions: DLT using MMA grafts is a feasible strategy to treat end-stage liver disease and expand the donor organ pool. However, the recipient of the MMA domino liver may develop mild MMA which could affect quality of life, and long-term safety remains unclear. Further long-term of outcomes for domino recipients of MMA livers, focusing on quality of life and any metabolic complications of transplantation are needed to better define the risks and benefits.

Functional Analysis of TRPA1, TRPM3, and TRPV1 Channels in Human Dermal Arteries and Their Role in Vascular Modulation.

Transient receptor potential (TRP) channels are pivotal in modulating vascular functions. In fact, topical application of cinnamaldehyde or capsaicin (TRPA1 and TRPV1 channel agonists, respectively) induces "local" changes in blood flow by releasing vasodilator neuropeptides. We investigated TRP channels' contributions and the pharmacological mechanisms driving vasodilation in human isolated dermal arteries. Ex vivo studies assessed the vascular function of artery segments and analyzed the effects of different compounds. Concentration-response curves to cinnamaldehyde, pregnenolone sulfate (PregS, TRPM3 agonist), and capsaicin were constructed to evaluate the effect of the antagonists HC030031 (TRPA1); isosakuranetin (TRPM3); and capsazepine (TRPV1). Additionally, the antagonists/inhibitors olcegepant (CGRP receptor); L-NAME (nitric oxide synthase); indomethacin (cyclooxygenase); TRAM-34 plus apamin (K+ channels); and MK-801 (NMDA receptors, only for PregS) were used. Moreover, CGRP release was assessed in the organ bath fluid post-agonist-exposure. In dermal arteries, cinnamaldehyde- and capsaicin-induced relaxation remained unchanged after the aforementioned antagonists, while PregS-induced relaxation was significantly inhibited by isosakuranetin, L-NAME and MK-801. Furthermore, there was a significant increase in CGRP levels post-agonist-exposure. In our experimental model, TRPA1 and TRPV1 channels seem not to be involved in cinnamaldehyde- or capsaicin-induced relaxation, respectively, whereas TRPM3 channels contribute to PregS-induced relaxation, possibly via CGRP-independent mechanisms.

Human fertilization in vivo and in vitro requires the CatSper channel to initiate sperm hyperactivation.

The infertility of many couples rests on an enigmatic dysfunction of the man's sperm. To gain insight into the underlying pathomechanisms, we assessed the function of the sperm-specific multisubunit CatSper-channel complex in the sperm of almost 2,300 men undergoing a fertility workup, using a simple motility-based test. We identified a group of men with normal semen parameters but defective CatSper function. These men or couples failed to conceive naturally and upon medically assisted reproduction via intrauterine insemination and in vitro fertilization. Intracytoplasmic sperm injection (ICSI) was, ultimately, required to conceive a child. We revealed that the defective CatSper function was caused by variations in CATSPER genes. Moreover, we unveiled that CatSper-deficient human sperm were unable to undergo hyperactive motility and, therefore, failed to penetrate the egg coat. Thus, our study provides the experimental evidence that sperm hyperactivation is required for human fertilization, explaining the infertility of CatSper-deficient men and the need of ICSI for medically assisted reproduction. Finally, our study also revealed that defective CatSper function and ensuing failure to hyperactivate represents the most common cause of unexplained male infertility known thus far and that this sperm channelopathy can readily be diagnosed, enabling future evidence-based treatment of affected couples.

Workplace ostracism influencing turnover intentions: Moderating roles of perceptions of organizational virtuousness and authentic leadership.

Workplace Ostracism is known to be a physically and emotionally painful experience. Even if it has a temporary and minor impact, it strongly predicts employee turnover intentions. Therefore, the purpose of this paper is to examine the moderating effects of perceptions of Organizational Virtuousness (OV) and Authentic Leadership (AL) in explaining the relationship between Workplace Ostracism (WO) and employees' Turnover Intentions (TI). Data were collected from 686 full-time employees using a non-probabilistic convenience sampling in India's Information Technology (IT) companies. The reliability and validity of scales were assessed using confirmatory factor analysis. Multiple hierarchical regression modeling was used to test the proposed hypotheses using IBM SPSS 23.0 with Process Macro 3.5. The present study's findings suggest that workplace ostracism is significantly related to employees' turnover intentions. Furthermore, perceptions of organizational virtuousness and authentic leadership moderated the relationship between workplace ostracism and employee turnover intentions. Employee turnover is a gigantic problem for IT firms in India. The present study offers valuable insights to managers to create awareness of workplace ostracism. Implementing managerial strategies rooted in positive psychology can help organizations create a more inclusive, supportive, and psychologically healthy work environment. This, in turn, can reduce the occurrence of workplace ostracism and turnover intentions.

Automated Assessment of T2-Weighted MRI to Differentiate Malignant and Benign Primary Solid Liver Lesions in Noncirrhotic Livers Using Radiomics.

RATIONALE AND OBJECTIVES: Distinguishing malignant from benign liver lesions based on magnetic resonance imaging (MRI) is an important but often challenging task, especially in noncirrhotic livers. We developed and externally validated a radiomics model to quantitatively assess T2-weighted MRI to distinguish the most common malignant and benign primary solid liver lesions in noncirrhotic livers. MATERIALS AND METHODS: Data sets were retrospectively collected from three tertiary referral centers (A, B, and C) between 2002 and 2018. Patients with malignant (hepatocellular carcinoma and intrahepatic cholangiocarcinoma) and benign (hepatocellular adenoma and focal nodular hyperplasia) lesions were included. A radiomics model based on T2-weighted MRI was developed in data set A using a combination of machine learning approaches. The model was internally evaluated on data set A through cross-validation, externally validated on data sets B and C, and compared to visual scoring of two experienced abdominal radiologists on data set C. RESULTS: The overall data set included 486 patients (A: 187, B: 98, and C: 201). The radiomics model had a mean area under the curve (AUC) of 0.78 upon internal validation on data set A and a similar AUC in external validation (B: 0.74 and C: 0.76). In data set C, the two radiologists showed moderate agreement (Cohen's κ: 0.61) and achieved AUCs of 0.86 and 0.82. CONCLUSION: Our T2-weighted MRI radiomics model shows potential for distinguishing malignant from benign primary solid liver lesions. External validation indicated that the model is generalizable despite substantial MRI acquisition protocol differences. Pending further optimization and generalization, this model may aid radiologists in improving the diagnostic workup of patients with liver lesions.

Contrast-enhanced cardiac MRI is superior to non-contrast mapping to predict left ventricular remodeling at 6 months after acute myocardial infarction.

OBJECTIVES: Parametric mapping constitutes a novel cardiac magnetic resonance (CMR) technique enabling quantitative assessment of pathologic alterations of left ventricular (LV) myocardium. This study aimed to investigate the clinical utility of mapping techniques with and without contrast agent compared to standard CMR to predict adverse LV remodeling following acute myocardial infarction (AMI). MATERIALS AND METHODS: A post hoc analysis was performed on sixty-four consecutively enrolled patients (57 ± 12 years, 54 men) with first-time reperfused AMI. Baseline CMR was obtained at 8 ± 5 days post-AMI, and follow-up CMR at 6 ± 1.4 months. T1/T2 mapping, T2-weighted, and late gadolinium enhancement (LGE) acquisitions were performed at baseline and cine imaging was used to determine adverse LV remodeling, defined as end-diastolic volume increase by 20% at 6 months. RESULTS: A total of 11 (17%) patients developed adverse LV remodeling. At baseline, patients with LV remodeling showed larger edema (30 ± 11 vs. 22 ± 10%LV; p < 0.05), infarct size (24 ± 11 vs. 14 ± 8%LV; p < 0.001), extracellular volume (ECVinfarct; 63 ± 12 vs. 47 ± 11%; p < 0.001), and native T2infarct (95 ± 16 vs. 78 ± 17 ms; p < 0.01). ECVinfarct and infarct size by LGE were the best predictors of LV remodeling with areas under the curve (AUCs) of 0.843 and 0.789, respectively (all p < 0.01). Native T1infarct had the lowest AUC of 0.549 (p = 0.668) and was inferior to edema size by T2-weighted imaging (AUC = 0.720; p < 0.05) and native T2infarct (AUC = 0.766; p < 0.01). CONCLUSION: In this study, ECVinfarct and infarct size by LGE were the best predictors for the development of LV remodeling within 6 months after AMI, with a better discriminative performance than non-contrast mapping CMR. CLINICAL RELEVANCE STATEMENT: This study demonstrates the predictive value of contrast-enhanced and non-contrast as well as conventional and novel CMR techniques for the development of LV remodeling following AMI, which might help define precise CMR endpoints in experimental and clinical myocardial infarction trials. KEY POINTS: • Multiparametric CMR provides insights into left ventricular remodeling at 6 months following an acute myocardial infarction. • Extracellular volume fraction and infarct size are the best predictors for adverse left ventricular remodeling. • Contrast-enhanced T1 mapping has a better predictive performance than non-contrast standard CMR and T1/T2 mapping.

Managing Hypertension in Older Adults.

PURPOSE OF REVIEW: The population of older adults 60-79 years globally is projected to double from 800 million to 1.6 billion between 2015 and 2050, while adults ≥ 80 years were forecast to more than triple from 125 to 430 million. The risk for cardiovascular events doubles with each decade of aging and each 20 mmHg increase of systolic blood pressure. Thus, successful management of hypertension in older adults is critical in mitigating the projected global health and economic burden of cardiovascular disease. RECENT FINDINGS: Women live longer than men, yet with aging systolic blood pressure and prevalent hypertension increase more, and hypertension control decreases more than in men, i.e., hypertension in older adults is disproportionately a women's health issue. Among older adults who are healthy to mildly frail, the absolute benefit of hypertension control, including more intensive control, on cardiovascular events is greater in adults ≥ 80 than 60-79 years old. The absolute rate of serious adverse events during antihypertensive therapy is greater in adults ≥ 80 years older than 60-79 years, yet the excess adverse event rate with intensive versus standard care is only moderately increased. Among adults ≥ 80 years, benefits of more intensive therapy appear non-existent to reversed with moderate to marked frailty and when cognitive function is less than roughly the twenty-fifth percentile. Accordingly, assessment of functional and cognitive status is important in setting blood pressure targets in older adults. Given substantial absolute cardiovascular benefits of more intensive antihypertensive therapy in independent-living older adults, this group merits shared-decision making for hypertension targets.

Morphometric Analyses of Macrophages.

Cell morphology and motility drive the cellular capabilities to interact with the environment. For example, microglia, the longest known tissue-resident macrophages, show a highly branched process tree with which they continuously scan their environment. Computational image analysis allows to quantify morphology and/or motility from images of tissue-resident macrophages. Here, I describe a step-by-step protocol for analyzing the morphology (and motility) of macrophages with our recently described, freely available software MotiQ, which provides a broad band of parameters and thereby serves as a versatile tool for studies of morphology and motility.

Quantifying the Disadvantage of Small Recipient Size on the Liver Transplantation Waitlist, a Longitudinal Analysis Within the Eurotransplant Region.

BACKGROUND: Small adult patients with end-stage liver disease waitlisted for liver transplantation may face a shortage of size-matched liver grafts. This may result in longer waiting times, increased waitlist removal, and waitlist mortality. This study aims to assess access to transplantation in transplant candidates with below-average bodyweight throughout the Eurotransplant region. METHODS: Patients above 16 y of age listed for liver transplantation between 2010 and 2015 within the Eurotransplant region were eligible for inclusion. The effect of bodyweight on chances of receiving a liver graft was studied in a Cox model corrected for lab-Model for End-stage Liver Disease (MELD) score updates fitted as time-dependent variable, blood type, listing for malignant disease, and age. A natural spline with 3 degrees of freedom was used for bodyweight and lab-MELD score to correct for nonlinear effects. RESULTS: At the end of follow-up, the percentage of transplanted, delisted, and deceased waitlisted patients was 49.1%, 17.9%, and 24.3% for patients with a bodyweight <60 kg (n = 1267) versus 60.1%, 15.1%, and 18.6% for patients with a bodyweight ≥60 kg (n = 10 520). To reach comparable chances for transplantation, 60-kg and 50-kg transplant candidates are estimated to need, respectively, up to 2.8 and 4.0 more lab-MELD points than 80-kg transplant candidates. CONCLUSIONS: Decreasing bodyweight was significantly associated with decreased chances to receive a liver graft. This resulted in substantially longer waiting times, higher delisting rates, and higher waitlist mortality for patients with a bodyweight <60 kg.