Patient-reported outcomes before treatment for localized prostate cancer: are there differences among countries? Data from the True North Global Registry.

INTRODUCTION: Similar Patient-Reported Outcomes (PROs) at diagnosis for localized prostate cancer among countries may indicate that different treatments are recommended to the same profile of patients, regardless the context characteristics (health systems, medical schools, culture, preferences…). The aim of this study was to assess such comparison. METHODS: We analyzed the EPIC-26 results before the primary treatment of men diagnosed of localized prostate cancer from January 2017 onwards (revised data available up to September 2019), from a multicenter prospective international cohort including seven regions: Australia/New Zealand, Canada, Central Europe (Austria / Czech Republic / Germany), United Kingdom, Italy, Spain, and the United States. The EPIC-26 domain scores and pattern of three selected items were compared across regions (with Central Europe as reference). All comparisons were made stratifying by treatment: radical prostatectomy, external radiotherapy, brachytherapy, and active surveillance. RESULTS: The sample included a total of 13,483 men with clinically localized or locally advanced prostate cancer. PROs showed different domain patterns before treatment across countries. The sexual domain was the most impaired, and the one with the highest dispersion within countries and with the greatest medians' differences across countries. The urinary incontinence domain, together with the bowel and hormonal domains, presented the highest scores (better outcomes) for all treatment groups, and homogeneity across regions. CONCLUSIONS: Patients with localized or locally advanced prostate cancer undergoing radical prostatectomy, EBRT, brachytherapy, or active surveillance presented mainly negligible or small differences in the EPIC-26 domains before treatment across countries. The results on urinary incontinence or bowel domains, in which almost all patients presented the best possible score, may downplay the baseline data role for evaluating treatments' effects. However, the heterogeneity within countries and the magnitude of the differences found across countries in other domains, especially sexual, support the need of implementing the PRO measurement from diagnosis.

Cortical oxygen extraction fraction using quantitative BOLD MRI and cerebral blood flow during vasodilation.

Introduction: We aimed to demonstrate non-invasive measurements of regional oxygen extraction fraction (OEF) from quantitative BOLD MRI modeling at baseline and after pharmacological vasodilation. We hypothesized that OEF decreases in response to vasodilation with acetazolamide (ACZ) in healthy conditions, reflecting compensation in regions with increased cerebral blood flow (CBF), while cerebral metabolic rate of oxygen (CMRO2) remained unchanged. We also aimed to assess the relationship between OEF and perfusion in the default mode network (DMN) regions that have shown associations with vascular risk factors and cerebrovascular reactivity in different neurological conditions. Material and methods: Eight healthy subjects (47 ± 13 years, 6 female) were scanned on a 3 T scanner with a 32-channel head coil before and after administration of 15 mg/kg ACZ as a pharmacological vasodilator. The MR imaging acquisition protocols included: 1) A Gradient Echo Slice Excitation Profile Imaging Asymmetric Spin Echo scan to quantify OEF, deoxygenated blood volume, and reversible transverse relaxation rate (R2 ') and 2) a multi-post labeling delay arterial spin labeling scan to measure CBF. To assess changes in each parameter due to vasodilation, two-way t-tests were performed for all pairs (baseline versus vasodilation) in the DMN brain regions with Bonferroni correction for multiple comparisons. The relationships between CBF versus OEF and CBF versus R2' were analyzed and compared across DMN regions using linear, mixed-effect models. Results: During vasodilation, CBF significantly increased in the medial frontal cortex (P=0.004), posterior cingulate gyrus (pCG) (P=0.004), precuneus cortex (PCun) (P=0.004), and occipital pole (P=0.001). Concurrently, a significant decrease in OEF was observed only in the pCG (8.8%, P=0.003) and PCun (8.7%,P=0.001). CMRO2 showed a trend of increased values after vasodilation, but these differences were not significant after correction for multiple comparisons. Although R2' showed a slightly decreasing trend, no statistically significant changes were found in any regions in response to ACZ. The CBF response to ACZ exhibited a stronger negative correlation with OEF (ß=-0.104±0.027; t=-3.852,P<0.001), than with R2' (ß=-0.016±0.006; t=-2.692,P=0.008). Conclusion: Quantitative BOLD modeling can reliably measure OEF across multiple physiological conditions and captures vascular changes with higher sensitivity than R2' values. The inverse correlation between OEF and CBF across regions in DMN, suggests that these two measurements, in response to ACZ vasodilation, are reliable indicators of tissue health in this healthy cohort.

Impact of C-reactive protein levels on lipoprotein(a)-associated aortic stenosis incidence and progression.

Aims: Elevated lipoprotein(a) [Lp(a)] levels are associated with the risk of coronary artery disease (CAD) and calcific aortic valve stenosis (CAVS). Observational studies revealed that Lp(a) and C-reactive protein (CRP) levels, a biomarker of systemic inflammation, may jointly predict CAD risk. Whether Lp(a) and CRP levels also jointly predict CAVS incidence and progression is unknown. Methods and results: We investigated the association of Lp(a) with CAVS according to CRP levels in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk study (n = 18 226, 406 incident cases) and the UK Biobank (n = 438 260, 4582 incident cases), as well as in the ASTRONOMER study (n = 220), which assessed the haemodynamic progression rate of pre-existing mild-to-moderate aortic stenosis. In EPIC-Norfolk, in comparison to individuals with low Lp(a) levels (<50 mg/dL) and low CRP levels (<2.0 mg/L), those with elevated Lp(a) (>50 mg/dL) and low CRP levels (<2.0 mg/L) and those with elevated Lp(a) (>50 mg/dL) and elevated CRP levels (>2.0 mg/L) had a higher CAVS risk [hazard ratio (HR) = 1.86 (95% confidence intervals, 1.30-2.67) and 2.08 (1.44-2.99), respectively]. A comparable predictive value of Lp(a) in patients with vs. without elevated CRP levels was also noted in the UK Biobank. In ASTRONOMER, CAVS progression was comparable in patients with elevated Lp(a) levels with or without elevated CRP levels. Conclusion: Lp(a) predicts the incidence and possibly progression of CAVS regardless of plasma CRP levels. Lowering Lp(a) levels may warrant further investigation in the prevention and treatment of CAVS, regardless of systemic inflammation.

To mask or not to mask mosaicism? The impact of reporting embryo mosaicism on reproductive potential.

PURPOSE: To evaluate euploidy rates and probability of having at least one euploid embryo for transfer per cycle when mosaicism is reported compared to when it is masked. METHODS: Women age 18-46 years who underwent PGT-A with next generation sequencing of blastocyst biopsies were analyzed. When reported, mosaic embryos were classified as low-level, 20-40% mosaic, or high-level, 41-80% mosaic. When masked, low-level mosaics were categorized as euploid and high-level mosaics were considered aneuploid. Comparative analyses were performed with χ2 tests and t-tests. RESULTS: A total of 22,504 PGT-A biopsy cycles from 18,401 patients were included. These cycles were from 293 different clinics with a mean of 1.22 cycles per patient. The majority of cycles (94.8%) reported mosaicism, and only 5.2% cycles were masked. The euploidy rate was significantly lower when mosaicism was reported versus masked (38.7% v 47.4%, p < 0.0001), which remained significant for age 40 years old and younger. The mosaic reporting cohort was less likely to have at least one euploid embryo for transfer (68.8%) compared to the masked cohort (75.7%) (p < 0.0001); however, this was no longer significant after stratification by age. CONCLUSION: Mosaicism reporting shows an overall expected reduction in euploidy rate. In turn, the probability of having a euploid embryo to transfer depends on clinic transfer practices and patient preference. If mosaic embryos are not transferred, we observe a reduction in probability of having an embryo for transfer. Although the magnitude of these differences is small, our data show that mosaic reporting may contribute to embryo attrition rate.

Natural History of Mitral Annular Calcification and Calcific Mitral Valve Disease.

BACKGROUND: The natural history of mitral annular calcification (MAC) and risk for developing calcific mitral valve disease (CMVD) have been poorly defined. The aim of this study was to evaluate the progression rate of MAC and of the development of CMVD. METHODS: Patients with MAC and paired echocardiograms ≥1 year apart between 2005 and 2019 were included. Progression rates from mild or moderate to severe MAC and to CMVD (defined as severe MAC and significant mitral stenosis and/or regurgitation) were assessed, along with potential association with sex. RESULTS: A total of 11,605 patients (mean age, 73 ± 10 years; 51% men) with MAC (78% mild, 17% moderate, 5% severe) were included and underwent follow-up echocardiography at 4.2 ± 2.7 years. Among patients with mild or moderate MAC, 33% presented with severe MAC at 10 years. The rate of severe MAC was higher in women than in men (41% vs 24% [P < .001]; hazard ratio, 1.3; P < .001) and in patients with moderate versus mild MAC (71% vs 22% [P < .001]; hazard ratio, 6.1; P < .001). At 10 years, 10% presented with CMVD (4%, 23%, and 60% in patients with mild, moderate, and severe MAC, respectively), which was predicted by female sex (15% vs 5%; P < .0001), even after adjustment for MAC severity (hazard ratio, 1.9; P < .001). CONCLUSION: In this large cohort of patients with MAC, progression to severe MAC was common and frequently resulted in CMVD. Female sex was associated with higher progression rates. MAC and CMVD are expected to dramatically increase as the population ages, highlighting the importance of a better understanding of the pathophysiology of MAC to develop effective preventive medical therapies.

The role of high-risk HPV testing in cervical cancer surveillance.

OBJECTIVES: While high-risk HPV (hrHPV) testing is not formally recommended as a surveillance modality in patients with a history of cervical cancer, it is often performed in routine practice. It is unclear whether the presence of hrHPV infection after cervical cancer treatment is associated with recurrent disease. METHODS: Patients with a cervical cancer diagnosis who were seen in a single institution between May 2012 and December 2019 were retrospectively identified. Squamous cell, adenocarcinoma, adenosquamous, and neuroendocrine histologies were included. Those with cancer progression within 3 months of treatment or < 1 year of documented surveillance were excluded. Patients who had hrHPV testing performed were included in the primary outcome analysis. RESULTS: Of the 262 patients meeting inclusion criteria, 58 (22%) recurrences were diagnosed, and recurrence was most commonly detected by a surveillance imaging study (71%). Among the 169 patients that were tested for hrHPV during the surveillance period, 41 (24%) had at least one positive hrHPV test. Recurrent disease was diagnosed in 24 (14%). Of the 24 patients with recurrent disease, 5 (21%) had at least one positive hrHPV test during surveillance, versus 36 (24%) of 145 patients without recurrent disease (p = 0.67). No recurrences were detected by hrHPV testing. CONCLUSIONS: Positive hrHPV testing in the surveillance setting was not associated with cervical cancer recurrence but did lead to additional studies and procedures. Our findings do not support the routine use of hrHPV testing for the evaluation of cervical cancer recurrence.

Improvement in dyspareunia after vaginal mesh removal measured by a validated questionnaire.

INTRODUCTION AND HYPOTHESIS: The objective was to examine the effect of the surgical removal of vaginally placed prolapse and incontinence mesh on sexual function. We hypothesize that patients with painful complications of mesh will experience improvement in dyspareunia and sexual function after mesh removal. METHODS: The eligible cohort consisted of 133 women who presented with a new onset of pain attributed to mesh-augmented incontinence or prolapse surgery and who elected to undergo mesh removal between 1 August 2012 and 1 July 2013. Sexual function symptoms were assessed before and after mesh removal surgery using the Pelvic Organ Prolapse and Urinary Incontinence Sexual Function Questionnaire short form (PISQ-12). Multivariate analysis was performed to identify predictors of improvement in dyspareunia. RESULTS: Ninety-four patients undergoing mesh removal completed a pre-operative questionnaire, 63 of whom also completed a post-operative questionnaire. After mesh removal, there was a nearly 50% reduction in the proportion of women reporting always experiencing post-operative pain with intercourse among those experiencing pre-operative pain. There was a statistically significant quantitative improvement in pain with intercourse after mesh removal based on mean change score of PISQ-12 question 5 "How often do you experience pain with intercourse?". In multivariate analysis, only history of vaginal delivery was associated with symptom improvement. CONCLUSION: Removal of transvaginal prolapse mesh is associated with improvement in self-reported dyspareunia based on a standardized question on a validated instrument in a small cohort of women. Although larger studies are needed to confirm the relationship between mesh-augmented surgeries and post-procedural dyspareunia, these data suggest that consideration of mesh removal is a reasonable step for patients with painful intercourse attributed to mesh-augmented prolapse and incontinence surgeries.

Clinical implications of left atrial size adjustment: Impact of obesity.

BACKGROUND: American and European societies recommend using left atrial (LA) volume adjusted to body surface area (BSA) as the means of indexing LA volume to the patient's body size irrespective of morphometric characteristics. AIM: To evaluate the impact of obesity on LA volume indexation to BSA on the presence and degree of LA enlargement. METHODS: From our echocardiography database, we extracted all consecutive adults referred for a transthoracic echocardiography in 2019 (n=28,725; 64±17 years; 55% male; 31% obese [body mass index≥30kg/m2]). LA volume indexed to BSA was calculated using measured weight (LAMeas) and ideal weight (LAIdeal) calculated using the Devine Formula. RESULTS: LAMeas and LAIdeal were 35±17mL/m2 and 40±19mL/m2, respectively (P<0.0001); 13% were classified as having a normal LAMeas but LAIdeal enlargement overall, 25% in obese patients and 7% in non-obese patients (P<0.0001). The percentages of patients with no, mild, moderate and severe LA dilatation were 57%, 19%, 9% and 16%, respectively, using LAMeas, and 45%, 20%, 11% and 24%, respectively, using LAIdeal (kappa=0.57). Degree of LA enlargement differed in 8194 patients (29%); 96% of the disagreement was related to underestimation of the degree of LA enlargement using LAMeas. Agreement for the degree of LA enlargement was poor in obese and good in non-obese patients (kappa=0.28 and 0.71, respectively). As illustrative clinical implications, diastolic function grade was modified in 8.3% of patients with preserved ejection fraction and 10.8% of patients with reduced left ventricular ejection fraction/myocardial disease, and timing for intervention was potentially different in 12.9% of patients with primary mitral regurgitation. CONCLUSIONS: Indexing LA volume to measured BSA versus ideal BSA markedly underestimates the presence and severity of LA enlargement, especially in obese patients, with potential important clinical implications.

Size-adjusted aortic valve area: refining the definition of severe aortic stenosis.

AIMS: Severe aortic valve stenosis (AS) is defined by an aortic valve area (AVA) <1 cm2 or an AVA indexed to body surface area (BSA) <0.6 cm/m2, despite little evidence supporting the latter approach and important intrinsic limitations of BSA indexation. We hypothesized that AVA indexed to height (H) might be more applicable to a wide range of populations and body morphologies and might provide a better predictive accuracy. METHODS AND RESULTS: In 1298 patients with degenerative AS and preserved ejection fraction from three different countries and continents (derivation cohort), we aimed to establish an AVA/H threshold that would be equivalent to 1.0 cm2 for defining severe AS. In a distinct prospective validation cohort of 395 patients, we compared the predictive accuracy of AVA/BSA and AVA/H. Correlations between AVA and AVA/BSA or AVA/H were excellent (all R2 > 0.79) but greater with AVA/H. Regressions lines were markedly different in obese and non-obese patients with AVA/BSA (P < 0.0001) but almost identical with AVA/H (P = 0.16). AVA/BSA values that corresponded to an AVA of 1.0 cm2 were markedly different in obese and non-obese patients (0.48 and 0.59 cm2/m2) but not with AVA/H (0.61 cm2/m for both). Agreement for the diagnosis of severe AS (AVA < 1 cm2) was significantly higher with AVA/H than with AVA/BSA (P < 0.05). Similar results were observed across the three countries. An AVA/H cut-off value of 0.6 cm2/m [HR = 8.2(5.6-12.1)] provided the best predictive value for the occurrence of AS-related events [absolute AVA of 1 cm2: HR = 7.3(5.0-10.7); AVA/BSA of 0.6 cm2/m2 HR = 6.7(4.4-10.0)]. CONCLUSION: In a large multinational/multiracial cohort, AVA/H was better correlated with AVA than AVA/BSA and a cut-off value of 0.6 cm2/m provided a better diagnostic and prognostic value than 0.6 cm2/m2. Our results suggest that severe AS should be defined as an AVA < 1 cm2 or an AVA/H < 0.6 cm2/m rather than a BSA-indexed value of 0.6 cm2/m2.

Accuracy of automated three-dimensional ultrasound imaging technique for fetal head biometry.

OBJECTIVES: To evaluate the accuracy of an automated three-dimensional (3D) ultrasound technique for fetal intracranial measurements compared with manual acquisition. METHODS: This was a prospective observational study of patients presenting for routine anatomical survey between 18 + 0 and 22 + 6 weeks' gestation. After providing informed consent, each patient underwent two consecutive ultrasound examinations of the fetal head, one by a sonographer and one by a physician. Each operator obtained manual measurements of the biparietal diameter (BPD), head circumference (HC), transcerebellar diameter (TCD), cisterna magna (CM) and posterior horn of the lateral ventricle (Vp), followed by automated measurements of these structures using an artificial intelligence-based tool, SonoCNS® Fetal Brain. Both operators repeated the automated approach until all five measurements were obtained in a single sweep, up to a maximum of three attempts. The accuracy of automated measurements was compared with that of manual measurements using intraclass correlation coefficients (ICC) by operator type, accounting for patient and ultrasound characteristics. RESULTS: One hundred and forty-three women were enrolled in the study. Median body mass index was 24.0 kg/m2 (interquartile range (IQR), 22.5-26.8 kg/m2 ) and median subcutaneous thickness was 1.6 cm (IQR, 1.3-2.0 cm). Fifteen (10%) patients had at least one prior Cesarean delivery, 17 (12%) had other abdominal surgery and 78 (55%) had an anterior placenta. Successful acquisition of the automated measurements was achieved on the first, second and third attempts in 70%, 22% and 3% of patients, respectively, by sonographers and in 76%, 16% and 3% of cases, respectively, by physicians. The automated algorithm was not able to identify and measure all five structures correctly in six (4%) and seven (5%) patients scanned by the sonographers and physicians, respectively. The ICCs reflected good reliability (0.80-0.88) of the automated compared with the manual approach for BPD and HC and poor to moderate reliability (0.23-0.50) for TCD, CM and Vp. Fetal lie, head position, placental location, maternal subcutaneous thickness and prior Cesarean section were not associated with the success or accuracy of the automated technique. CONCLUSIONS: Automated 3D ultrasound imaging of the fetal head using SonoCNS reliably identified and measured BPD and HC but was less consistent in accurately identifying and measuring TCD, CM and Vp. While these results are encouraging, further optimization of the automated technology is necessary prior to incorporation of the technique into routine sonographic protocols. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Detailed Phenotyping and Therapeutic Strategies for Intronic ABCA4 Variants in Stargardt Disease.

Stargardt disease is a progressive retinal disorder caused by bi-allelic mutations in the ABCA4 gene that encodes the ATP-binding cassette, subfamily A, member 4 transporter protein. Over the past few years, we and others have identified several pathogenic variants that reside within the introns of ABCA4, including a recurrent variant in intron 36 (c.5196+1137G>A) of which the pathogenicity so far remained controversial. Detailed clinical characterization of this variant confirmed its pathogenic nature, and classified it as an allele of intermediate severity. Moreover, we discovered several additional ABCA4 variants clustering in intron 36. Several of these variants resulted in aberrant splicing of ABCA4, i.e., the inclusion of pseudoexons, while the splicing defects caused by the recurrent c.5196+1137G>A variant strongly increased upon differentiation of patient-derived induced pluripotent stem cells into retina-like cells. Finally, all splicing defects could be rescued by the administration of antisense oligonucleotides that were designed to specifically block the pseudoexon insertion, including rescue in 3D retinal organoids harboring the c.5196+1137G>A variant. Our data illustrate the importance of intronic variants in ABCA4 and expand the therapeutic possibilities for overcoming splicing defects in Stargardt disease.

Presentation and management of calcific mitral valve disease.

Little is known about the prevalence, presentation and management of calcific mitral valve disease (CMVD). We identified 167 patients (80 ± 10 years; 79% women) with significant CMVD undergoing transthoracic echocardiography at our institution in 2016. Patients presented with significant co-morbidities, 47% had moderate/severe mitral stenosis, 38% had 3+/4+ mitral regurgitation and 15% had a combination of both. Fifty-eight percent were symptomatic. Most symptomatic patients were managed conservatively and incurred higher mortality and mortality/heart failure admission rates than those managed surgically. These data highlight the importance of gaining mechanistic insights into CMVD to prevent its occurrence and avoid the need for high-risk surgery, which is seldom performed in contemporary practice.

Low-dose corticosteroid and mycophenolate for primary treatment of minimal change disease.

BACKGROUND: Mycophenolate has been shown to be effective in glomerular disease. However, the role of mycophenolate in the first-line treatment of adult-onset idiopathic minimal change disease (MCD) has not been systematically studied in a randomized fashion. AIM: To evaluate the therapeutic efficacy of enteric-coated mycophenolate sodium combined with low-dose corticosteroid as first-line treatment for MCNS. DESIGN: A prospective, open-label, randomized clinical trial. METHODS: Twenty adult patients with biopsy proven MCD were recruited and randomly assigned to receive either enteric-coated Mycophenolate Sodium (EC-MPS) plus low-dose prednisolone (Group 1: Prednisolone 0.25 mg/kg/day, n = 10) or standard-dose prednisolone (Group 2: Prednisolone 1 mg/kg/day, n = 10). RESULTS: After 24 weeks of therapy, eight patients in Group 1 vs. seven of patients in Group 2 achieved complete remission (P = 0.606). Both groups showed a significant reduction of urine protein excretion (P < 0.05) and increased serum albumin (P < 0.001) vs. baseline levels. However, no significant between-group differences were demonstrated. The relapse rate was also similar in both groups. Both treatment regimens were well tolerated but there were more patient reported adverse effects in the standard-dose prednisolone group. CONCLUSION: EC-MPS plus low-dose prednisolone is non-inferior to standard-dose prednisolone therapy in inducing clinical remission and preventing relapse in adult-onset idiopathic MCD and is associated with better tolerability and less adverse effects. This trial is registered with the ClinicalTrials.gov number NCT01185197.

The myopic shift associated with hyperbaric oxygen administration is reduced when using a mask delivery system compared to a hood - a randomised controlled trial.

INTRODUCTION: A temporary myopic shift is a well-recognized complication of hyperbaric oxygen treatment (HBOT). Oxidation of proteins in the crystalline lens is the likely cause. Direct exposure of the eye to hyperbaric oxygen may exacerbate the effect. Our aim was to measure the magnitude of the myopic shift over a course of HBOT when using two different methods of oxygen delivery. METHODS: We conducted a randomised trial of oxygen delivery via hood versus oronasal mask during a course of 20 and 30 HBOT sessions. Subjective refraction was performed at baseline and after 20 and 30 sessions. We repeated these measurements at four and 12 weeks after completion of the course in those available for assessment. RESULTS: We enrolled 120 patients (mean age 57.6 (SD 11.2) years; 81% male). The myopic shift was significantly greater after both 20 and 30 sessions in those patients using the hood. At 20 treatments: refractory change was -0.92 D with hood versus -0.52 D with mask, difference 0.40 D (95% CI 0.22 to 0.57, P < 0.0001); at 30 treatments: -1.25 D with hood versus -0.63 with mask, difference 0.62 D (95% CI 0.39 to 0.84, P < 0.0001). Recovery was slower and less complete in the hood group at both four and 12 weeks. CONCLUSIONS: Myopic shift is common following HBOT and more pronounced using a hood system than an oronasal mask. Recovery may be slower and less complete using a hood. Our data support the use of an oronasal mask in an air environment when possible.

Magnetic resonance imaging of mouse brain networks plasticity following motor learning.

We do not have a full understanding of the mechanisms underlying plasticity in the human brain. Mouse models have well controlled environments and genetics, and provide tools to help dissect the mechanisms underlying the observed responses to therapies devised for humans recovering from injury of ischemic nature or trauma. We aimed to detect plasticity following learning of a unilateral reaching movement, and relied on MRI performed with a rapid structural protocol suitable for in vivo brain imaging, and a longer diffusion tensor imaging (DTI) protocol executed ex vivo. In vivo MRI detected contralateral volume increases in trained animals (reachers), in circuits involved in motor control, sensory processing, and importantly, learning and memory. The temporal association area, parafascicular and mediodorsal thalamic nuclei were also enlarged. In vivo MRI allowed us to detect longitudinal effects over the ~25 days training period. The interaction between time and group (trained versus not trained) supported a role for the contralateral, but also the ipsilateral hemisphere. While ex vivo imaging was affected by shrinkage due to the fixation, it allowed for superior resolution and improved contrast to noise ratios, especially for subcortical structures. We examined microstructural changes based on DTI, and identified increased fractional anisotropy and decreased apparent diffusion coefficient, predominantly in the cerebellum and its connections. Cortical thickness differences did not survive multiple corrections, but uncorrected statistics supported the contralateral effects seen with voxel based volumetric analysis, showing thickening in the somatosensory, motor and visual cortices. In vivo and ex vivo analyses identified plasticity in circuits relevant to selecting actions in a sensory-motor context, through exploitation of learned association and decision making. By mapping a connectivity atlas into our ex vivo template we revealed that changes due to skilled motor learning occurred in a network of 35 regions, including the primary and secondary motor (M1, M2) and sensory cortices (S1, S2), the caudate putamen (CPu), visual (V1) and temporal association cortex. The significant clusters intersected tractography based networks seeded in M1, M2, S1, V1 and CPu at levels > 80%. We found that 89% of the significant cluster belonged to a network seeded in the contralateral M1, and 85% to one seeded in the contralateral M2. Moreover, 40% of the M1 and S1 cluster by network intersections were in the top 80th percentile of the tract densities for their respective networks. Our investigation may be relevant to studies of rehabilitation and recovery, and points to widespread network changes that accompany motor learning that may have potential applications to designing recovery strategies following brain injury.

Clinical characteristics and outcomes of methamphetamine-associated intracerebral hemorrhage.

OBJECTIVE: To compare the clinical characteristics and outcomes of primary intracerebral hemorrhage (ICH) with and without methamphetamine exposure. METHODS: We performed a retrospective analysis of patients diagnosed with spontaneous, nontraumatic ICH over a 3-year period between January 2013 and December 2016. Demographics, clinical measures, and outcomes were compared between ICH patients with positive methamphetamine toxicology tests vs those with negative methamphetamine toxicology tests. RESULTS: Methamphetamine-positive ICH patients were younger than methamphetamine-negative ICH patients (52 vs 67 years, p < 0.001). Patients with methamphetamine-positive ICH had higher diastolic blood pressure (115 vs 101, p = 0.003), higher mean arterial pressure (144 vs 129, p = 0.01), longer lengths of hospital (18 vs 8 days, p < 0.001) and intensive care unit (ICU) stay (10 vs 5 days, p < 0.001), required more days of IV antihypertensive medications (5 vs 3 days, p = 0.02), and had more subcortical hemorrhages (63% vs 46%, p = 0.05). The methamphetamine-positive group had better premorbid modified Rankin Scale (mRS) scores (p < 0.001) and a greater change in functional ability as measured by mRS at the time of hospital discharge (p = 0.001). In multivariate analyses, methamphetamine use predicted both hospital length of stay (risk ratio [RR] 1.54, confidence interval [CI] 1.39-1.70, p < 0.001) and ICU length of stay (RR 1.36, CI 1.18-1.56, p < 0.001), but did not predict poor outcome (mRS 4-6). CONCLUSIONS: Methamphetamine use is associated with earlier age at onset of ICH, longer hospital stays, and greater change in functional ability, but did not predict outcome.

Association of Mild to Moderate Aortic Valve Stenosis Progression With Higher Lipoprotein(a) and Oxidized Phospholipid Levels: Secondary Analysis of a Randomized Clinical Trial.

Importance: Several studies have reported an association of levels of lipoprotein(a) (Lp[a]) and the content of oxidized phospholipids on apolipoprotein B (OxPL-apoB) and apolipoprotein(a) (OxPL-apo[a]) with faster calcific aortic valve stenosis (CAVS) progression. However, whether this association is threshold or linear remains unclear. Objective: To determine whether the plasma levels of Lp(a), OxPL-apoB, and OxPL-apo(a) have a linear association with a faster rate of CAVS progression. Design, Setting, and Participants: This secondary analysis of a randomized clinical trial tested the association of baseline plasma levels of Lp(a), OxPL-apoB, and OxPL-apo(a) with the rate of CAVS progression. Participants were included from the ASTRONOMER (Effects of Rosuvastatin on Aortic Stenosis Progression) trial, a multicenter study conducted in 23 Canadian sites designed to test the effect of statin therapy (median follow-up, 3.5 years [interquartile range, 2.9-4.5 years]). Patients with mild to moderate CAVS defined by peak aortic jet velocity ranging from 2.5 to 4.0 m/s were recruited; those with peak aortic jet velocity of less than 2.5 m/s or with an indication for statin therapy were excluded. Data were collected from January 1, 2002, through December 31, 2005, and underwent ad hoc analysis from April 1 through September 1, 2018. Interventions: After the randomization process, patients were followed up by means of echocardiography for 3 to 5 years. Main Outcomes and Measures: Progression rate of CAVS as assessed by annualized progression of peak aortic jet velocity. Results: In this cohort of 220 patients (60.0% male; mean [SD] age, 58 [13] years), a linear association was found between plasma levels of Lp(a) (odds ratio [OR] per 10-mg/dL increase, 1.10; 95% CI, 1.03-1.19; P = .006), OxPL-apoB (OR per 1-nM increase, 1.06; 95% CI, 1.01-1.12; P = .02), and OxPL-apo(a) (OR per 10-nM increase, 1.16; 95% CI, 1.05-1.27; P = .002) and faster CAVS progression, which is marked in younger patients (OR for Lp[a] level per 10-mg/dL increase, 1.19 [95% CI, 1.07-1.33; P = .002]; OR for OxPL-apoB level per 1-nM increase, 1.06 [95% CI, 1.02-1.17; P = .01]; and OR for OxPL-apo[a] level per 10-nM increase, 1.26 [95% CI, 1.10-1.45; P = .001]) and remained statistically significant after comprehensive multivariable adjustment (ß coefficient, ≥ 0.25; SE, ≤ 0.004 [P ≤ .005]; OR, ≥1.10 [P ≤ .007]). Conclusions and Relevance: This study demonstrates that the association of Lp(a) levels and its content in OxPL with faster CAVS progression is linear, reinforcing the concept that Lp(a) levels should be measured in patients with mild to moderate CAVS to enhance management and risk stratification. Trial Registration: ClinicalTrials.gov Identifier: NCT00800800.

Acute Stroke Despite Dabigatran Anticoagulation Treated with Idarucizumab and Intravenous Tissue Plasminogen Activator.

Dabigatran is a direct thrombin inhibitor used to reduce the risk of stroke in patients with nonvalvular atrial fibrillation. For patients who present with an acute stroke despite dabigatran therapy, clinical data on the use of intravenous tissue plasminogen activator (IV-tPA) is limited. There is an anticipated increased risk of symptomatic intracranial hemorrhage (sICH) when using IV-tPA in patients on dabigatran therapy. In 2015, the humanized monoclonal antibody fragment idarucizumab was approved for rapid (minutes) reversal of anticoagulant effects of dabigatran. Dabigatran reversal with idarucizumab before administration of IV-tPA might reduce the risk of sICH. We report a case of a 69-year-old stroke patient on dabigatran for paroxysmal atrial fibrillation who presented with an initial National Institutes of Health Stroke Scale (NIHSS) of 12. There was no early evidence of ischemic stroke or hemorrhage on head computed tomography, and coagulation studies implied therapeutic dabigatran levels. After controlling blood pressure, dabigatran was reversed with idarucizumab, and IV-tPA was administrated beginning 197 minutes after he was last seen at his baseline. Subsequent brain magnetic resonance imaging showed 2 punctate infarcts in the left temporal lobe and occipital lobe with no evidence of hemorrhage. The patient was discharged with an NIHSS of 1. Telephone follow-up 2 months later indicated that he was at his prestroke baseline, except for a complaint of worsened short-term memory. Idarucizumab reversal of dabigatran may reduce the risk of sICH and should be considered for acute stroke patients arriving in the IV-tPA time window.