In vivo lymph node CEST-Dixon MRI in breast cancer patients with metastatic lymph node involvement.

PURPOSE: Axillary lymph nodes (LNs) often present a reservoir for metastatic breast cancer, yet metastatic LN involvement cannot be discerned definitively using diagnostic imaging. This study investigated whether in vivo CEST may discriminate LNs with versus without metastatic involvement. METHODS: 3T MRI was performed in patients with breast cancer before clinically-indicated mastectomy or lumpectomy with LN removal, after which LN metastasic involvement was determined using histological evaluation. Non-contrast anatomical imaging, as well as B0 and B1 field maps, were acquired in sequence with three-point CEST-Dixon (3D turbo-gradient-echo; factor = 25; TR/TE1/ΔTE = 851/1.35/1.1 ms; spatial-resolution = 2.5 × 2.5 × 6 mm; slices = 10; four sinc-gauss pulses with duty-cycle = 0.5, total saturation duration = 701.7 ms; B1 = 1.5 µT; saturation offsets = -5.5 to +5.5 ppm; stepsize = 0.2 ppm; scan duration = 6 min 30 s). The mean z-spectrum from LNs with (n = 20) versus without (n = 22) metastatic involvement were analyzed and a Wilcoxon rank-sum test (significance: p < 0.05) was applied to evaluate differences in B0, B1 , and magnetization transfer ratio (MTR) in differing spectral regions of known proton exchange (nuclear Overhauser effect [NOE], amide, amine, and hydroxyl) between cohorts. RESULTS: No difference in axillary B1 (p = 0.634) or B0 (p = 0.689) was observed between cohorts. Elevated MTR was observed for the NOE (-1.7 ppm; MTR = 0.285 ± 0.075 vs. 0.248 ± 0.039; p = 0.048), amine (+2.5 ppm; MTR = 0.284 ± 0.067 vs. 0.234 ± 0.31; p = 0.005), and hydroxyl (+1 ppm; MTR = 0.394 ± 0.075 vs. 0.329 ± 0.055; p = 0.002) protons in LNs from participants with versus without metastatic involvement. CONCLUSIONS: Findings are consistent with a unique metastatic LN microenvironment detectable by CEST-Dixon and suggest that CEST MRI may have potential for mapping LN metastasis non-invasively in vivo.

National survey of patient symptoms and therapies among 707 women with a lipedema phenotype in the United States.

BACKGROUND: National survey data exploring the patient experience with lipedema are lacking. METHODS: We conducted national surveys from 2016 to 2022 of women with lipedema as well as female controls. Surveys collected information on symptomatology, pain, and therapies. We performed logistic regression comparing symptoms among those with lipedema versus controls adjusting for age and BMI. RESULTS: A total of 707 women with lipedema and 216 controls completed the surveys. Those with lipedema had a mean age of 48.6 years and mean BMI of 40.9 kg/m2. Lipedema symptom onset occurred frequently at puberty (48.0%) or pregnancy (41.2%). Compared to controls, women with lipedema were more likely to report leg swelling in heat (odds ratio [OR], 66.82; 95% CI, 33.04-135.12; p < 0.0001), easy bruising (OR, 26.23; 95% CI, 15.58-44.17; p < 0.0001), altered gait (OR, 15.54; 95% CI, 7.58-31.96; p < 0.0001), flu-like symptoms (OR, 12.99; 95% CI, 4.27-39.49; p < 0.0001), joint hypermobility (OR, 12.88; 95% CI, 6.68-24.81; p < 0.0001), cool skin (OR, 12.21; 95% CI, 5.20-28.69; p < 0.0001), varicose veins (OR, 11.29; 95% CI, 6.71-18.99; p < 0.0001), and fatigue (OR, 9.59; 95% CI, 6.10-15.09; p < 0.0001). Additionally, 70.3% had upper arm involvement, 21.2% reported foot swelling, and 16.6% reported foot pain. Most (52.2%) reported no symptom improvement with diet or exercise. Common therapies used included compression therapy (45.0%), gastric bypass (15.7%), and lower-extremity liposuction (14.0%). CONCLUSION: In a large, national, symptom survey, women with lipedema reported excess pain, swelling, and fat in the legs along with numerous symptoms beyond those classically described. Symptom responses to common therapies remain understudied.

COMPREHENSIVE MOLECULAR PROFILING OF UVEAL MELANOMA EVALUATED WITH GENE EXPRESSION PROFILING, PREFERENTIALLY EXPRESSED ANTIGEN IN MELANOMA EXPRESSION, AND NEXT-GENERATION SEQUENCING.

PURPOSE: To determine the association between gene-expression profiling (GEP), next-generation sequencing (NGS), preferentially expressed antigen in melanoma (PRAME) features, and metastatic risk in patients with uveal melanoma (UM). METHODS: A retrospective analysis of patients with UM treated by brachytherapy or enucleation by a single ocular oncologist was conducted from November 2020 and July 2022. Clinicopathologic features, patient outcomes, GEP classification, NGS, and PRAME results were recorded. RESULTS: Comprehensive GEP, PRAME, and NGS testing was performed on 135 UMs. The presence of eukaryotic translation initiation factor 1A, X-chromosomal and splicing factor 3B subunit 1 mutations was significantly associated with GEP class 1A and GEP class 1B, respectively. The presence of BRCA- associated protein-1 mutation was significantly associated with GEP class 2. The average largest basal diameter for tumors with eukaryotic translation initiation factor 1A, X-chromosomal mutations was significantly smaller than those with splicing factor 3B subunit 1 mutations and BRCA1-associated protein-1 mutations. Class 2 tumors metastasized sooner than GEP class 1 tumors. Tumors with splicing factor 3B subunit 1 and/or BRCA1-associated protein-1 mutations metastasized sooner compared with tumors that had either no driver mutation or no mutations at all. Tumors with splicing factor 3B subunit 1 did not have a significantly different time to metastasis compared with tumors with BRCA1-associated protein-1 (P value = 0.97). Forty tumors (30%) were PRAME positive, and the remaining 95 tumors (70%) were PRAME negative. Tumors with PRAME-positive status did not have a significantly different time to metastasis compared with tumors without PRAME-positive status (P value = 0.11). CONCLUSION: GEP, NGS, and PRAME expression analysis help determine different levels of metastatic risk in UM. Although other prognostic tests exist, the following study reports on the use of NGS for metastatic prognostication in UM. However, limitations of NGS exist, especially with small lesions that are technically difficult to biopsy.

Differential response to preoperative exercise training in patients candidates to cardiac valve replacement.

BACKGROUND: There is lack of evidence regarding safety, effectiveness and applicability of prehabilitation on cardiac surgery population, particularly in patients candidates to cardiac valve replacement. The aim of the study is to assess and compare the effect of a multimodal prehabilitation program on functional capacity in patients with severe aortic stenosis (AoS) and severe mitral regurgitation (MR) proposed for valve replacement surgery. METHODS: Secondary analysis from a randomised controlled trial whose main objective was to analyze the efficacy of a 4-6 weeks multimodal prehabilitation program in cardiac surgery on reducing postoperative complications. For this secondary analysis, only candidates for valve replacement surgery were selected. The primary outcome was the change in endurance time (ET) from baseline to preoperative assessment measured by a cycling constant work-rate cardiopulmonary exercise test. RESULTS: 68 patients were included in this secondary analysis, 34 (20 AoS and 14 MR) were allocated to the prehabilitation group and 34 (20 AoS and 14 MR) to control group. At baseline, patients with AoS had better left systolic ventricular function and lower prevalence of atrial fibrillation compared to MR (p = 0.022 and p = 0.035 respectively). After prehabilitation program, patients with MR showed greater improvement in ET than AoS patients (101% vs. 66% increase from baseline). No adverse events related to the prehabilitation program were observed. CONCLUSIONS: A 4-6 week exercise training program is safe and overall improves functional capacity in patients with severe AoS and MR. However, exercise response is different according to the cardiac valve type disfunction, and further studies are needed to know the factors that predispose some patients to have better training response. TRIAL REGISTRATION: The study has been registered on the Registry of National Institutes of Health ClinicalTrials.gov (NCT03466606) (05/03/2018).

Sport PRactice and its Effects on aortic size and valve function in bicuspid Aortic valve Disease: a cross-sectional report from the SPREAD study.

OBJECTIVE: Concerns exist about the possible detrimental effects of exercise training on aortic size and valve function in individuals with bicuspid aortic valve (BAV). This multicentre international study aimed to determine the characteristics of aortic size and valve function in athletes versus non-athletes with BAV and athletes with tricuspid aortic valve (TAV). METHODS: We enrolled competitive athletes with BAV and age- and sex-matched athletes with TAV and non-athletes with BAV. We assessed valve function, aortic size and biventricular measures using echocardiography. Individuals with established moderate-severe AV stenosis, regurgitation or significant aortic dilation were excluded from the study. RESULTS: The study population comprised 504 participants: 186 competitive athletes with BAV (84% males; age 30±11 years), 193 competitive athletes with TAV and 125 non-athletes with BAV. The aortic annulus was greater in athletes with BAV than athletes with TAV and non-athletes with BAV (p<0.001). Both athletic and non-athletic individuals with BAV had greater sinuses of Valsalva, sino-tubular junction and ascending aorta diameters than athletes with TAV (p<0.001). However, no significant differences were found between athletes and non-athletes with BAV. Left ventricular index volumes and mass were greater in athletes with BAV than in the other two groups (p<0.001). Individuals with BAV (athletes and non-athletes) had greater mean gradients than TAV athletes. CONCLUSION: This multicentre international study demonstrates no differences between athletes with BAV and non-athletes with BAV regarding aortic valve function or aortic dimensions. However, athletes with BAV have larger aortic diameters and a relatively worse valvular function than athletes with TAV.

Vascular space occupancy asymmetric spin echo (VASO-ASE) for non-invasive quantification of cerebral oxygen extraction fraction.

PURPOSE: Asymmetric spin echo (ASE) MRI is a method for measuring regional oxygen extraction fraction (OEF); however, extravascular tissue models have been shown to under-estimate OEF. The hypothesis investigated here is that the addition of a vascular-space-occupancy (VASO) pre-pulse will more fully suppress blood water signal and provide global OEF values more consistent with physiological expectation and 15 O positron emission tomography (PET)-validated T2 -relaxation-under-spin-tagging (TRUST) OEF measures. METHODS: Healthy adults (n = 14; age = 27.7 ± 5.2 y; sex = 7/7 male/female) were scanned at 3.0T. Multi-echo ASE without inter-readout refocusing (ASERF- ), multi-echo ASE with inter-readout refocusing (ASERF+ ), and single-echo VASO-ASE were acquired twice each with common spatial resolution = 3.44 × 3.44 × 3.0 mm and τ = 0-20 ms (interval = 0.5 ms). TRUST was acquired twice sequentially for independent global OEF assessment (τCPMG  = 10 ms; effective TEs = 0, 40, 80, and 160 ms; spatial resolution = 3.4 × 3.4 × 5 mm). OEF intraclass-correlation-coefficients (ICC), summary statistics, and group-wise differences were assessed (Wilcoxon rank-sum; significance: two-sided p < 0.05). RESULTS: ASERF+ (OEF = 36.8 ± 1.9%) and VASO-ASE (OEF = 34.4 ± 2.3%) produced OEF values similar to TRUST (OEF = 36.5 ± 4.6%, human calibration model; OEF = 32.7 ± 4.9%, bovine calibration model); however, ASERF- yielded lower OEF (OEF = 26.1 ± 1.0%; p < 0.01) relative to TRUST. VASO-ASE (ICC = 0.61) yielded lower ICC compared to other ASE variants (ICC >0.89). CONCLUSION: VASO-ASE and TRUST provide similar OEF values; however, VASO-ASE spatial coverage and repeatability improvements are required.

Red cell exchange transfusions increase cerebral capillary transit times and may alter oxygen extraction in sickle cell disease.

Persons with sickle cell disease (SCD) suffer from chronic hemolytic anemia, reduced blood oxygen content, and lifelong risk of silent and overt stroke. Major conventional stroke risk factors are absent in most individuals with SCD, yet nearly 50% have evidence of brain infarcts by the age of 30 years, indicating alternative etiologies for ischemia. We investigated whether radiological evidence of accelerated blood water transit through capillaries, visible on arterial spin labeling (ASL) magnetic resonance imaging, reduces following transfusion-induced increases in hemoglobin and relates to oxygen extraction fraction (OEF). Neurological evaluation along with anatomical and hemodynamic imaging with cerebral blood flow (CBF)-weighted pseudocontinuous ASL and OEF imaging with T2 -relaxation-under-spin-tagging were applied in sequence before and after blood transfusion therapy (n = 32) and in a comparator cohort of nontransfused SCD participants on hydroxyurea therapy scanned at two time points to assess stability without interim intervention (n = 13). OEF was calculated separately using models derived from human hemoglobin-F, hemoglobin-A, and hemoglobin-S. Gray matter CBF and dural sinus signal, indicative of rapid blood transit, were evaluated at each time point and compared with OEF using paired statistical tests (significance: two-sided p < 0.05). No significant change in sinus signal was observed in nontransfused participants (p = 0.650), but a reduction was observed in transfused participants (p = 0.034), consistent with slower red cell transit following transfusion. The dural sinus signal intensity was inversely associated with OEF pretransfusion (p = 0.011), but not posttransfusion. Study findings suggest that transfusion-induced increases in total hemoglobin may lengthen blood transit times through cerebral capillaries and alter cerebral OEF in SCD.

Subcutaneous Adipose Tissue Edema in Lipedema Revealed by Noninvasive 3T MR Lymphangiography.

BACKGROUND: Lipedema exhibits excessive lower-extremity subcutaneous adipose tissue (SAT) deposition, which is frequently misidentified as obesity until lymphedema presents. MR lymphangiography may have relevance to distinguish lipedema from obesity or lymphedema. HYPOTHESIS: Hyperintensity profiles on 3T MR lymphangiography can identify distinct features consistent with SAT edema in participants with lipedema. STUDY TYPE: Prospective cross-sectional study. SUBJECTS: Participants (48 females, matched for age [mean = 44.8 years]) with lipedema (n = 14), lipedema with lymphedema (LWL, n = 12), cancer treatment-related lymphedema (lymphedema, n = 8), and controls without these conditions (n = 14). FIELD STRENGTH/SEQUENCE: 3T MR lymphangiography (nontracer 3D turbo-spin-echo). ASSESSMENT: Review of lymphangiograms in lower extremities by three radiologists was performed independently. Spatial patterns of hyperintense signal within the SAT were scored for extravascular (focal, diffuse, or not apparent) and vascular (linear, dilated, or not apparent) image features. STATISTICAL TESTS: Interreader reliability was computed using Fleiss Kappa. Fisher's exact test was used to evaluate the proportion of image features between study groups. Multinomial logistic regression was used to assess the relationship between image features and study groups. The odds ratio (OR) and 95% confidence interval (CI) of SAT extravascular and vascular features was reported in groups compared to lipedema. The threshold of statistical significance was P < 0.05. RESULTS: Reliable agreement was demonstrated between three independent, blinded reviewers (P < 0.001). The frequency of SAT hyperintensities in participants with lipedema (36% focal, 36% diffuse), LWL (42% focal, 33% diffuse), lymphedema (62% focal, 38% diffuse), and controls (43% focal, 0% diffuse) was significantly distinct. Compared with lipedema, SAT hyperintensities were less frequent in controls (focal: OR = 0.63, CI = 0.11-3.41; diffuse: OR = 0.05, CI = 0.00-1.27), similar in LWL (focal: OR = 1.29, CI = 0.19-8.89; diffuse: OR = 1.05, CI = 0.15-7.61), and more frequent in lymphedema (focal: OR = 9.00, CI = 0.30-274.12; diffuse: OR = 5.73, CI = 0.18-186.84). DATA CONCLUSION: Noninvasive MR lymphangiography identifies distinct signal patterns indicating SAT edema and lymphatic load in participants with lipedema. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 1.

Elevated magnetic resonance imaging measures of adipose tissue deposition in women with breast cancer treatment-related lymphedema.

PURPOSE: Breast cancer treatment-related lymphedema (BCRL) is a common co-morbidity of breast cancer therapies, yet factors that contribute to BCRL progression remain incompletely characterized. We investigated whether magnetic resonance imaging (MRI) measures of subcutaneous adipose tissue were uniquely elevated in women with BCRL. METHODS: MRI at 3.0 T of upper extremity and torso anatomy, fat and muscle tissue composition, and T2 relaxometry were applied in left and right axillae of healthy control (n = 24) and symptomatic BCRL (n = 22) participants to test the primary hypothesis that fat-to-muscle volume fraction is elevated in symptomatic BCRL relative to healthy participants, and the secondary hypothesis that fat-to-muscle volume fraction is correlated with MR relaxometry of affected tissues and BCRL stage (significance criterion: two-sided p < 0.05). RESULTS: Fat-to-muscle volume fraction in healthy participants was symmetric in the right and left sides (p = 0.51); in BCRL participants matched for age, sex, and BMI, fat-to-muscle volume fraction was elevated on the affected side (fraction = 0.732 ± 0.184) versus right and left side in controls (fraction = 0.545 ± 0.221, p < 0.001). Fat-to-muscle volume fraction directly correlated with muscle T2 (p = 0.046) and increased with increasing level of BCRL stage (p = 0.041). CONCLUSION: Adiposity quantified by MRI is elevated in the affected upper extremity of women with BCRL and may provide a surrogate marker of condition onset or severity. CLINICAL TRIAL: NCT02611557.

Stem-cell transplantation for children with primary immune deficiencies: A retrospective study of 19 patients from one centre in Mexico.

INTRODUCTION: For many patients with primary immune deficiency (PID), stem-cell transplantation (SCT) may be life-saving. OBJECTIVE: To review our experience of 11 years transplanting children with PID in Mexico. METHODS: Chart review of patients who underwent SCT from 2008 to 2018, to describe their diagnoses, time to transplant, conditioning regime, survival rate and outcomes. All patients received post-transplant cyclophosphamide as graft-versus-host-disease (GVHD) prophylaxis. RESULTS: 19 patients with combined, phagocytic or syndromic PID from 5 states. Twelve of them were male (58%) and 14 survive (79%). Mean age at HSCT was 41.9 months; mean time from diagnosis was 31.2 months. Seven grafts were umbilical cord and 12 haploidentical. The conditioning regime was myeloablative, with five primary graft failures. Two patients had partial and 10 full chimerism. Five patients died within 2 months after transplant. Immune reconstitution was complete in 11 of 19 patients. We found a prevalence of 21% GVHD. DISCUSSION: We describe 19 patients from Mexico with 8 PID diagnoses who underwent allogenic HSCT over a period of 11 years. Survival rate and other outcomes compare well with industrialized countries. We recommend the use of post-transplant cyclophosphamide to prevent GVHD in scenarios of resource scarcity and a lack of HLA-identical donors.

Navigable Space and Traversable Edges Differentially Influence Reorientation in Sighted and Blind Mice.

Reorientation enables navigators to regain their bearings after becoming lost. Disoriented individuals primarily reorient themselves using the geometry of a layout, even when other informative cues, such as landmarks, are present. Yet the specific strategies that animals use to determine geometry are unclear. Moreover, because vision allows subjects to rapidly form precise representations of objects and background, it is unknown whether it has a deterministic role in the use of geometry. In this study, we tested sighted and congenitally blind mice (Ns = 8-11) in various settings in which global shape parameters were manipulated. Results indicated that the navigational affordances of the context-the traversable space-promote sampling of boundaries, which determines the effective use of geometric strategies in both sighted and blind mice. However, blind animals can also effectively reorient themselves using 3D edges by extensively patrolling the borders, even when the traversable space is not limited by these boundaries.

Presurgical Magnetic Resonance Imaging Indicators of Revascularization Response in Adults With Moyamoya Vasculopathy.

BACKGROUND: Moyamoya is a progressive intracranial vasculopathy, primarily affecting distal segments of the internal carotid and middle cerebral arteries. Treatment may comprise angiogenesis-inducing surgical revascularization; however, lack of randomized trials often results in subjective treatment decisions. HYPOTHESIS: Compensatory presurgical posterior vertebrobasilar artery (VBA) flow-territory reactivity, including greater cerebrovascular reactivity (CVR) and reduced vascular delay time, portends greater neoangiogenic response verified on digital subtraction angiography (DSA) at 1-year follow-up. STUDY TYPE: Prospective intervention cohort. SUBJECTS: Thirty-one patients with moyamoya (26 females; age = 45 ± 13 years; 41 revascularized hemispheres). METHODS: Anatomical MRI, hypercapnic CVR MRI, and DSA acquired presurgically in adult moyamoya participants scheduled for clinically indicated surgical revascularization. One-year postsurgery, DSA was repeated to evaluate collateralization. FIELD STRENGTH: 3 T. SEQUENCE: Hypercapnic T 2 * -weighted gradient-echo blood-oxygenation-level-dependent, T2 -weighted turbo-spin-echo fluid-attenuated-inversion-recovery, T1 -weighted magnetization-prepared-rapid-gradient-echo, and T2 -weighted diffusion-weighted-imaging. ASSESSMENT: Presurgical maximum CVR and response times were evaluated in VBA flow-territories. Revascularization success was determined using an ordinal scoring system of neoangiogenic collateralization from postsurgical DSA by two cerebrovascular neurosurgeons (R.V.C. with 8 years of experience; M.R.F. with 9 years of experience) and one neuroradiologist (L.T.D. with 8 years of experience). Stroke risk factors (age, sex, race, vasculopathy, and diabetes) were recorded. STATISTICAL TESTS: Fisher's exact and Wilcoxon rank-sum tests were applied to compare presurgical variables between cohorts with angiographically confirmed good (>1/3 middle cerebral artery [MCA] territory revascularized) vs. poor (<1/3 MCA territory revascularized) outcomes. SIGNIFICANCE: two-sided P < 0.05. Normalized odds ratios (ORs) were calculated. RESULTS: Criteria for good collateralization were met in 25 of the 41 revascularized hemispheres. Presurgical normalized VBA flow-territory CVR was significantly higher in those with good (1.12 ± 0.13 unitless) vs. poor (1.04 ± 0.05 unitless) outcomes. Younger (OR = -0.60 ± 0.67) and White (OR = -1.81 ± 1.40) participants had highest revascularization success (good outcomes: age = 42 ± 14 years, race = 84% White; poor outcomes: age = 49 ± 11 years, race = 44% White). DATA CONCLUSION: Presurgical MRI-measures of VBA flow-territory CVR are highest in moyamoya participants with better angiographic responses to surgical revascularization. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 4.

Sex as a main determinant of bi-atrial acute and chronic adaptation to exercise.

PURPOSE: Athlete's heart encompasses multiple physiological cardiac adaptations, although less is known at atrial level. How sex may influence the type and extent of atrial adaptations to exercise stimuli is also unknown. Our objective was to compare gender differences of echocardiographic atrial function indices in response to exercise in endurance athletes (EAs). METHODS: Highly trained (> 10 h/week) endurance athletes performed a maximal cardiopulmonary exercise test (CPET). Echocardiographic evaluation was performed at rest and immediately after exercise. Atria analysis consisted of standard and speckle-tracking echocardiographic assessment of atrial dimensions and contractile, reservoir, and conduit functions with myocardial deformation. RESULTS: 80 EAs (55% women) were enrolled and performed excellent CPET (129.6% of predicted VO2 maximal consumption). At rest, left atrial (LA) volumes and strain were similar between men and women. Women had lower right atrial (RA) volumes (26.7 vs 32.9 ml/m2, p < 0.001) and higher reservoir and conduit strain absolute values. After exercise, women exhibited a larger improvement in reservoir and conduit LA strain, and the same trend was observed for the RA. In EAs with LA dilatation on baseline (~ 50%), women persistently showed higher increase in reservoir and conduit strain profile with exercise compared to men. CONCLUSION: In highly trained EAs, women have similar or even lower atrial dimensions remodelling compared to men, but better function based on reservoir and conduit strain values both at rest and in response to exercise. This phenomenon should be confirmed in larger studies and its potential role in the development of supraventricular arrhythmias, addressed in a specifically designed protocol.

Distinctive Toll-like Receptors Gene Expression and Glial Response in Different Brain Regions of Natural Scrapie.

Prion diseases are chronic and fatal neurodegenerative diseases characterized by the accumulation of disease-specific prion protein (PrPSc), spongiform changes, neuronal loss, and gliosis. Growing evidence shows that the neuroinflammatory response is a key component of prion diseases and contributes to neurodegeneration. Toll-like receptors (TLRs) have been proposed as important mediators of innate immune responses triggered in the central nervous system in other human neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. However, little is known about the role of TLRs in prion diseases, and their involvement in the neuropathology of natural scrapie has not been studied. We assessed the gene expression of ovine TLRs in four anatomically distinct brain regions in natural scrapie-infected sheep and evaluated the possible correlations between gene expression and the pathological hallmarks of prion disease. We observed significant changes in TLR expression in scrapie-infected sheep that correlate with the degree of spongiosis, PrPSc deposition, and gliosis in each of the regions studied. Remarkably, TLR4 was the only gene upregulated in all regions, regardless of the severity of neuropathology. In the hippocampus, we observed milder neuropathology associated with a distinct TLR gene expression profile and the presence of a peculiar microglial morphology, called rod microglia, described here for the first time in the brain of scrapie-infected sheep. The concurrence of these features suggests partial neuroprotection of the hippocampus. Finally, a comparison of the findings in naturallyinfected sheep versus an ovinized mouse model (tg338 mice) revealed distinct patterns of TLRgene expression.

Indications of Peripheral Pain, Dermal Hypersensitivity, and Neurogenic Inflammation in Patients with Lipedema.

Lipedema is a disease with abnormally increased adipose tissue deposition and distribution. Pain sensations have been described in the clinical evaluation of lipedema, but its etiology remains poorly understood. We hypothesized that pain sensitivity measurements and ex vivo quantitation of neuronal cell body distribution in the skin would be lipedema stage-dependent, and could, thus, serve to objectively characterize neuropathic pain in lipedema. The pain was assessed by questionnaire and peripheral cutaneous mechanical sensitization (von-Frey) in lipedema (n = 27) and control (n = 23) consenting female volunteers. Dermal biopsies from (n = 11) Stages 1-3 lipedema and control (n = 10) participants were characterized for neuronal cell body and nociceptive neuropeptide calcitonin gene-related peptide (CGRP) and nerve growth factor (NGF) distribution. Stage 2 or 3 lipedema participants responded positively to von Frey sensitization in the calf and thigh, and Stage 3 participants also responded in the arm. Lipedema abdominal skin displayed reduced Tuj-1+ neuronal cell body density, compared to healthy controls, while CGRP and NGF was significantly elevated in Stage 3 lipedema tissues. Together, dermal neuronal cell body loss is consistent with hyper-sensitization in patients with lipedema. Further study of neuropathic pain in lipedema may elucidate underlying disease mechanisms and inform lipedema clinical management and treatment impact.

Assessment of myocardial deformation with CMR: a comparison with ultrasound speckle tracking.

OBJECTIVES: Myocardial deformation integrated with cardiac dimensions provides a comprehensive assessment of cardiac function, which has proven useful to differentiate cardiac pathology from physiological adaptation to situations such as chronic intensive training. Feature tracking (FT) can measure myocardial deformation from cardiac magnetic resonance (CMR) cine sequences; however, its accuracy is not yet fully validated. Our aim was to compare the accuracy and reproducibility of FT with speckle tracking echocardiography (STE) in highly trained endurance athletes. METHODS: Ninety-three endurance athletes (> 12-h training/week during the last 5 years, 52% male, 35 ± 5.1 years old) and 72 age-matched controls underwent resting CMR and transthoracic echocardiography to assess biventricular exercise-induced remodeling and biventricular global longitudinal strain (GLS) by CMR-FT and STE. RESULTS: Strain values were significantly lower when assessed by CMR-FT compared to STE (p < 0.001), with good reproducibility for the left ventricle (bias = 3.94%, limit of agreement [LOA] = ± 4.27 %) but wider variability for right ventricle strain. Strain values by both techniques proportionally decreased with increasing ventricular volumes, potentially depicting the functional biventricular reserve that characterizes athletes' hearts. CONCLUSIONS: Biventricular longitudinal strain values were lower when assessed by FT as compared to STE. Both methods were statistically comparable when measuring LV strain but not RV strain. These differences might be justified by the lower in-plane spatial and temporal resolution of FT, which is particularly relevant for the complex anatomy of the RV. KEY POINTS: • Strain values were significantly lower when assessed by FT as compared to STE, which was expected due to the lower in-plane spatial and temporal resolution of FT versus STE. • Both methods were statistically comparable when measuring LV strain but not for RV strain analysis. • Characterizing the normal ranges and reproducibility of strain metrics by FT is an important step toward its clinical applicability, since it can be assessed offline and applied to routinely acquired cine CMR images.

Recommendations for participation in leisure-time physical activity and competitive sports of patients with arrhythmias and potentially arrhythmogenic conditions. Part 2: ventricular arrhythmias, channelopathies, and implantable defibrillators.

This paper belongs to a series of recommendation documents for participation in leisure-time physical activity and competitive sports by the European Association of Preventive Cardiology (EAPC). Together with an accompanying paper on supraventricular arrhythmias, this second text deals specifically with those participants in whom some form of ventricular rhythm disorder is documented, who are diagnosed with an inherited arrhythmogenic condition, and/or who have an implanted pacemaker or cardioverter defibrillator. A companion text on recommendations in athletes with supraventricular arrhythmias is published in the European Journal of Preventive Cardiology. Since both texts focus on arrhythmias, they are the result of a collaboration between EAPC and the European Heart Rhythm Association (EHRA). The documents provide a framework for evaluating eligibility to perform sports, based on three elements, i.e. the prognostic risk of the arrhythmias when performing sports, the symptomatic impact of arrhythmias while performing sports, and the potential progression of underlying structural problems as the result of sports.

Vaccination Rates Among Patients Age 65 Years and Older Who Require Interpreter Services in the State of Minnesota.

In the United States, the growing population of older adults with limited English language proficiency (LEP) faces profound health care disparities. Previous research on vaccination of older adults has been based on self-reported data, without clinical verification. We compared pneumococcal vaccination rates between a patient group with LEP and a group of English speakers in an older community-dwelling population. A population-nested matched cohort of participants age 65 years and older was identified in Minnesota. Patients with LEP were identified through an electronic alert within the electronic health record, designed to determine the need for an interpreter. Patients were matched 1 to 1 for age, sex, and Charlson comorbidity index. We used conditional logistic regression for the final analysis. In total, 24,052 patients were identified as older patients (mean [SD] age, 74 [7] years). Of them, 617 patients (2.6%) had LEP. The most common primary languages were Somali (24%), Vietnamese (15%), and Spanish (13%). We found lower rates of vaccination with 13-valent pneumococcal conjugate vaccine (PCV13) in the LEP group compared with English speakers [62% vs 77%; odds ratio (OR) (95% CI) 2.07 (1.61-2.66); P < 0.001]. Results were similar for 23-valent pneumococcal polysaccharide vaccine (PPSV23) [60% vs 75%; OR (95% CI) 1.97 91.54-2.51); P < 0.001]. These data are suggestive that older adults who required a language interpreter during health care encounters were less likely to be vaccinated with PCV13 and PPSV23 than older adults who did not require an interpreter. Effectiveness studies are needed to determine which interventions can help improve vaccination rates in the LEP population of elderly patients.

Recommendations for participation in competitive sport in adolescent and adult athletes with Congenital Heart Disease (CHD): position statement of the Sports Cardiology & Exercise Section of the European Association of Preventive Cardiology (EAPC), the European Society of Cardiology (ESC) Working Group on Adult Congenital Heart Disease and the Sports Cardiology, Physical Activity and Prevention Working Group of the Association for European Paediatric and Congenital Cardiology (AEPC).

Improved clinical care has led to an increase in the number of adults with congenital heart disease (CHD) engaging in leisure time and competitive sports activities. Although the benefits of exercise in patients with CHD are well established, there is a low but appreciable risk of exercise-related complications. Published exercise recommendations for individuals with CHD are predominantly centred on anatomic lesions, hampering an individualized approach to exercise advice in this heterogeneous population. This document presents an update of the recommendations for competitive sports participation in athletes with cardiovascular disease published by the Sports Cardiology & Exercise section of the European Association of Preventive Cardiology (EAPC) in 2005. It introduces an approach which is based on the assessment of haemodynamic, electrophysiological and functional parameters, rather than anatomic lesions. The recommendations provide a comprehensive assessment algorithm which allows for patient-specific assessment and risk stratification of athletes with CHD who wish to participate in competitive sports.

Systems-thinking approach to identify and assess feasibility of potential interventions to reduce antibiotic use in tilapia farming in Egypt.

Antibiotics are used in aquaculture to maintain the health and welfare of stocks; however, the emergence and selection of antibiotic resistance in bacteria poses threats to humans, animals and the environment. Mitigation of antibiotic resistance relies on understanding the flow of antibiotics, residues, resistant bacteria and resistance genes through interconnecting systems, so that potential solutions can be identified and issues around their implementation evaluated. Participatory systems-thinking can capture the deep complexity of a system while integrating stakeholder perspectives. In this present study, such an approach was applied to Nile tilapia (Oreochromis niloticus) production in the Nile Delta of Egypt, where disease events caused by antibiotic-resistant pathogens have been reported. A system map was co-produced with aquaculture stakeholders at a workshop in May 2018 and used to identify hotspots of antibiotic use, exposure and fate and to describe approaches that would promote fish health and thus reduce antibiotic use. Antibiotics are introduced into the aquaculture system via direct application for example in medicated feed, but residues may also be introduced into the system through agricultural drainage water, which is the primary source of water for most fish farms in Egypt. A follow-up survey of stakeholders assessed the perceived feasibility, advantages and disadvantages of potential interventions. Interventions that respondents felt could be implemented in the short-term to reduce antibiotic usage effectively included: more frequent water exchanges, regular monitoring of culture water quality parameters, improved storage conditions for feed, use of probiotics and greater access to farmer and service providers training programmes. Other potential interventions included greater access to suitable and rapid diagnostics, high quality feeds, improved biosecurity measures and genetically-improved fish, but these solutions were expected to be achieved as long-term goals, with cost being of one of the noted barriers to implementation. Identifying feasible and sustainable interventions that can be taken to reduce antibiotic use, and understanding implementation barriers, are important for addressing antibiotic resistance and ensuring the continued efficacy of antibiotics. This is vital to ensuring the productivity of the tilapia sector in Egypt. The approach taken in the present study provides a means to identify points in the system where the effectiveness of interventions can be evaluated and thus it may be applied to other food production systems to combat the problem of antibiotic resistance.