Citations

Transcription factor E3-rearranged renal cell carcinoma (TFE3-RCC) has heterogenous morphologic and immunohistochemical (IHC) features. 131 pathologists with genitourinary expertise were invited in an online survey containing 23 questions assessing their experience on TFE3-RCC diagnostic work-up. Fifty (38%) participants completed the survey. 46 of 50 participants reported multiple patterns, most commonly papillary pattern (almost always 9/46, 19.5%; frequently 29/46, 63%). Large epithelioid cells with abundant cytoplasm were the most encountered cytologic feature, with either clear (almost always 10/50, 20%; frequently 34/50, 68%) or eosinophilic (almost always 4/49, 8%; frequently 28/49, 57%) cytology. Strong (3+) or diffuse (>75% of tumour cells) nuclear TFE3 IHC expression was considered diagnostic by 13/46 (28%) and 12/47 (26%) participants, respectively. Main TFE3 IHC issues were the low specificity (16/42, 38%), unreliable staining performance (15/42, 36%) and background staining (12/42, 29%). Most preferred IHC assays other than TFE3, cathepsin K and pancytokeratin were melan A (44/50, 88%), HMB45 (43/50, 86%), carbonic anhydrase IX (41/50, 82%) and CK7 (32/50, 64%). Cut-off for positive TFE3 fluorescent in situ hybridisation (FISH) was preferably 10% (9/50, 18%), although significant variation in cut-off values was present. 23/48 (48%) participants required TFE3 FISH testing to confirm TFE3-RCC regardless of the histomorphologic and IHC assessment. 28/50 (56%) participants would request additional molecular studies other than FISH assay in selected cases, whereas 3/50 participants use additional molecular cases in all cases when TFE3-RCC is in the differential. Optimal diagnostic approach on TFE3-RCC is impacted by IHC and/or FISH assay preferences as well as their conflicting interpretation methods.

Abstract This International Consensus Classification and Nomenclature for the congenital bicuspid aortic valve condition recognizes 3 types of bicuspid valves: 1. The fused type (right-left cusp fusion, right-non-coronary cusp fusion and left-non-coronary cusp fusion phenotypes); 2. The 2-sinus type (latero-lateral and antero-posterior phenotypes); and 3. The partial-fusion (forme fruste) type. The presence of raphe and the symmetry of the fused type phenotypes are critical aspects to describe. The International Consensus also recognizes 3 types of bicuspid valve-associated aortopathy: 1. The ascending phenotype; 2. The root phenotype; and 3. Extended phenotypes.

Abstract This International evidence-based nomenclature and classification consensus on the congenital bicuspid aortic valve and its aortopathy recognizes 3 types of bicuspid aortic valve: 1. Fused type, with 3 phenotypes: right-left cusp fusion, right-non cusp fusion and left-non cusp fusion; 2. 2-sinus type with 2 phenotypes: Latero-lateral and antero-posterior; and 3. Partial-fusion or forme fruste. This consensus recognizes 3 bicuspid-aortopathy types: 1. Ascending phenotype; root phenotype; and 3. extended phenotypes.

Purpose: To investigate candidate genes associated with familial strabismus and propose a theory of their interaction in familial strabismus associated with early neurodevelopment. Methods: Eighteen families, including 53 patients diagnosed with strabismus and 34 unaffected family members, were analyzed. All patients with strabismus and available unaffected family members were evaluated using whole exome sequencing. The primary outcome was to identify rare occurring variants among affected individuals and investigate the evidence of their genetic heterogeneity. These results were compared with exome sequencing analysis to build a comprehensive genetic profile of the study families. Results: We observed 60 variants from 58 genes in 53 patients diagnosed with strabismus. We prioritized the most credible risk variants, which showed clear segregation in family members affected by strabismus. As a result, we found risk variants in four genes (FAT3, KCNH2, CELSR1, and TTYH1) in five families, suggesting their role in development of familial strabismus. In other families, there were several rare genetic variants in affected cases, but we did not find clear segregation pattern across family members. Conclusion: Genomic sequencing holds great promise in elucidating the genetic causes of strabismus; further research with larger cohorts or other related approaches are warranted.

Background Myocardial fibrosis is an important contributor for development of diastolic dysfunction. We investigated the impact of sirolimus as primary immunosuppression on diastolic dysfunction and fibrosis progression among heart transplantation recipients. Methods and Results In 100 heart transplantation recipients who were either treated with a calcineurin inhibitor (CNI) (n=51) or converted from CNI to sirolimus (n=49), diastolic function parameters were assessed using serial echocardiograms and right heart catheterizations. Myocardial fibrosis was quantified on serial myocardial biopsies. After 3 years, lateral e′ increased within the sirolimus group but decreased in the CNI group (0.02±0.04 versus −0.02±0.04 m/s delta change; P =0.003, respectively). Both pulmonary capillary wedge pressure and diastolic pulmonary artery pressure significantly decreased in the sirolimus group but remained unchanged in the CNI group (−1.50±2.59 versus 0.20±2.20 mm Hg/year; P =0.02; and −1.72±3.39 versus 0.82±2.59 mm Hg/year; P =0.005, respectively). A trend for increased percentage of fibrosis was seen in the sirolimus group (8.48±3.17 to 10.10±3.0%; P =0.07) as compared with marginally significant progression in the CNI group (8.76±3.87 to 10.56±4.34%; P =0.04). The percent change in fibrosis did not differ significantly between the groups (1.62±4.67 versus 1.80±5.31%, respectively; P =0.88). Conclusions Early conversion to sirolimus is associated with improvement in diastolic dysfunction and filling pressures as compared with CNI therapy. Whether this could be attributed to attenuation of myocardial fibrosis progression with sirolimus treatment warrants further investigation.

Abstract INTRODUCTION A biphasic model for brain structural changes in preclinical Alzheimer's disease (AD) could reconcile some conflicting and paradoxical findings in observational studies and anti‐amyloid clinical trials. METHODS In this study we tested this model fitting linear versus quadratic trajectories and computed the timing of the inflection points vertexwise of cortical thickness and cortical diffusivity—a novel marker of cortical microstructure—changes in 389 participants from the Dominantly Inherited Alzheimer Network. RESULTS In early preclinical AD, between 20 and 15 years before estimated symptom onset, we found increases in cortical thickness and decreases in cortical diffusivity followed by cortical thinning and cortical diffusivity increases in later preclinical and symptomatic stages. The inflection points 16 to 19 years before estimated symptom onset are in agreement with the start of tau biomarker alterations. DISCUSSION These findings confirm a biphasic trajectory for brain structural changes and have direct implications when interpreting magnetic resonance imaging measures in preventive AD clinical trials.

Background: Reduced left ventricular stroke work index (LVSWI) has been associated with adverse outcomes in several populations of patients with chronic heart disease, but no prior studies have examined this metric in cardiac intensive care unit (CICU) patients. We sought to determine whether a low LVSWI, as measured noninvasively using transthoracic echocardiography, is associated with higher mortality in CICU patients. Methods: Using a database of unique Mayo Clinic CICU admissions from 2007 to 2018, we identified patients with LVSWI measured by transthoracic echocardiography within 1 day of CICU admission. Hospital mortality was analyzed using multivariable logistic regression, and 1-year mortality was analyzed using multivariable Cox proportional-hazards analysis, adjusted for left ventricular ejection fraction and known predictors of hospital mortality. Results: We included 4536 patients with a mean age of 68±14 years (36% women). Admission diagnoses (not mutually exclusive) included acute coronary syndrome in 62%, heart failure in 46%, and cardiogenic shock in 11%. The mean LVSWI was 38±14 g×min/m 2 , and in-hospital mortality occurred in 6% of patients. LVSWI had better discrimination for hospital mortality than left ventricular ejection fraction ( P <0.001 by De Long test). Higher LVSWI was associated with lower in-hospital mortality (adjusted odds ratio, 0.72 per 10 g×min/m 2 higher [95% CI, 0.61–0.84]; P <0.001) and lower 1-year mortality (adjusted hazard ratio, 0.812 per 1 g×min/m 2 higher [95% CI, 0.759–0.868]; P <0.001). Stepwise decreases in hospital and 1-year mortality were observed with higher LVSWI. Conclusions: Low LVSWI, reflecting poor left ventricular systolic and diastolic performance, is associated with increased short-term and long-term mortality among CICU patients. This emphasizes the importance of Doppler transthoracic echocardiography as a predictor of outcomes among critically ill patients. Further study is required to determine whether early interventions to optimize LVSWI can improve outcomes in the CICU setting.

We present diagnostic criteria for mal de débarquement syndrome (MdDS) for inclusion into the International Classification of Vestibular Disorders. The criteria include the following: 1] Non-spinning vertigo characterized by an oscillatory perception (‘rocking,’ ‘bobbing,’ or ‘swaying’) present continuously or for most of the day; 2] Onset occurs within 48 hours after the end of exposure to passive motion, 3] Symptoms temporarily reduce with exposure to passive motion (e.g. driving), and 4] Symptoms persist for >48 hours. MdDS may be designated as “in evolution,” if symptoms are ongoing but the observation period has been less than 1 month; “transient,” if symptoms resolve at or before 1 month and the observation period extends at least to the resolution point; or “persistent” if symptoms last for more than 1 month. Individuals with MdDS may develop co-existing symptoms of spatial disorientation, visual motion intolerance, fatigue, and exacerbation of headaches or anxiety. Features that distinguish MdDS from vestibular migraine, motion sickness, and persistent postural perceptual dizziness (PPPD) are reviewed. Motion-moderated oscillatory vertigo can also occur without a motion trigger, typically following another vestibular disorder, a medical illness, heightened psychological stress, or metabolic disturbance. Terminology for this non-motion triggered presentation has been varied as it has features of both MdDS and PPPD. Further research is needed into its phenomenological and biological relationship to MdDS, PPPD, and other vestibular disorders.