Anatomical Phenotypes Research Articles

Deep Screening for X Chromosome Parent-of-Origin Effects on Neurobehavioral and Neuroanatomical Phenotypes in 47,XXY Klinefelter Syndrome

BackgroundX chromosome parent of origin (POX) has been proposed as a source of phenotypic variation within sex chromosome aneuploidies such as Klinefelter syndrome (XXY/KS) and between XX and XY individuals. However, previous studies have yielded conflicting results regarding the presence and nature of POX effects, which we sought to clarify in an expanded sample with deeper neurobehavioral phenotyping. MethodsA cohort of 58 individuals with XXY/KS underwent duo or trio genome sequencing with parents (n = 151), measurement of 66 neurobehavioral phenotypes by standardized research assessments, and measurement of over 1000 anatomical phenotypes by structural magnetic resonance imaging. We developed a novel algorithm, the uniparental disomy visualization for variant call format files, to determine proband POX and then systematically tested for POX associations with all neurobehavioral and neuroanatomical outcomes. ResultsThe uniparental disomy visualization for variant call format files algorithm showed maternal POX in 35 of 58 cases (60.3%). There were no statistically significant POX effects on any of the 66 subscale measures of cognition, psychopathology, or behavior. Neuroimaging analysis identified 2 regions in the right hemisphere with significantly higher surface area (mean effect size = 1.20) among individuals with paternal versus maternal POX (q = .021). ConclusionsUsing deeper phenotyping in an expanded sample, we did not find evidence for substantial POX effects on neurobehavioral variability, except for localized unilateral modulations of surface area in the absence of co-occurring behavioral associations. These findings help to clarify previous inconsistencies in POX research and direct attention toward other sources of clinical variability in sex chromosome aneuploidies.

Root Anatomical Imaging and Phenotyping in Maize.

Root anatomy plays a crucial role in regulating essential processes such as the absorption and movement of water and nutrients in plants. Root anatomy also impacts the energy costs of building and sustaining root tissues, tissue mechanics, and interactions with other organisms. Although several studies in maize have confirmed the functional utility of numerous root anatomical traits, such as that of cortical cell size and number for stress adaptation, there have been significant obstacles in measuring and analyzing root anatomical characteristics. This has resulted in gaps in our understanding of the genetic control and range of phenotypic variations among different cultivars, and how this diversity relates to overall fitness. Here, we review root anatomical phenotypes in maize and their function in stress adaptation, and briefly discuss phenotyping methods available for root anatomy. We further introduce a simple and accessible phenotyping approach that enables a comprehensive investigation of maize root anatomy. Detailed characterization of root traits and the implementation of robust methods for root anatomical phenotyping could have wide-ranging benefits across various areas of plant science, from fundamental research to enhancing crop breeding efforts.

Pain with orgasm in endometriosis: potential etiologic factors and clinical correlates.

Pelvic pain worsened by orgasm is a poorly understood symptom in patients with endometriosis. To assess the prevalence of pelvic pain worsened by orgasm in patients with endometriosis and explore its association with potential etiologic factors, including pelvic floor myalgia, uterine tenderness and adenomyosis, and central nervous system sensitization. An analysis was done of a prospective data registry based at a tertiary referral center for endometriosis. Eligible participants were patients aged 18 to 50 years who were referred between January 1, 2018, and December 31, 2019, diagnosed with endometriosis, and subsequently underwent surgery at the center. Clinical features were compared between participants reporting worsening pelvic pain with orgasm and those without worsening pain with orgasm, including patient-reported variables, physical examination findings, and anatomic phenotyping at the time of surgery. Pelvic floor myalgia and uterine tenderness were assessed by palpation on pelvic examination, adenomyosis by ultrasound, and central nervous system sensitization via the Central Sensitization Inventory (range, 0-100). Outcomes included pelvic or lower abdominal pain in the last 3months that worsened with orgasm (yes/no). Among 358 participants with endometriosis, 14% (49/358) reported pain worsened by orgasm while 86% (309/358) did not. Pain with orgasm was significantly associated with pelvic floor myalgia (55% [27/49] vs 35% [109/309]; Cohen's h = 0.40, P = .01) and higher scores on the Central Sensitization Inventory (mean ± SD, 53.3 ± 17.0 vs 42.7 ± 18.2; Cohen's d = 0.60, P < .001) but not with uterine tenderness or adenomyosis. Other clinical features associated with pain with orgasm were poorer sexual health (higher scores: deep dyspareunia, Cohen's h = 0.60; superficial dyspareunia, Cohen's h = 0.34; and Female Sexual Distress Scale-Revised, Cohen's d = 0.68; all P < .05) and poorer mental health (higher scores: Patient Health Questionnaire-9, 12.9 ± 6.7 vs 9.1 ± 6.3, Cohen's d = 0.59, P < .001; Generalized Anxiety Disorder-7, 9.4 ± 5.6 vs 6.8 ± 5.5, Cohen's d = 0.48, P = .002). Anatomic findings at the time of surgery did not significantly differ between the groups. Interventions targeting pelvic floor myalgia and central nervous system sensitization may help alleviate pain worsened by orgasm in patients with endometriosis. A strength is that pain worsened by orgasm was differentiated from dyspareunia. However, pain with orgasm was assessed by only a binary question (yes/no). Also, the study is limited to a single center, and there were limited data on sexual function. Pelvic pain exacerbated by orgasm in people with endometriosis may be related to concurrent pelvic floor myalgia and central sensitization.

Globus sensation in obstructive sleep apnea patients; A cross-sectional study of 120 patients.

Globus pharyngeus (GP) is a common complaint in many disciplines, especially otolaryngology. Pharyngeal symptoms and abnormalities, including GP, are frequent in obstructive sleep apnea (OSA) patients. This study aims to investigate globus sensation in non-operated OSA patients. After translation and validation, the Laryngopharyngeal Measure of Perceived Sensation (LUMP) was administered to 120 untreated OSA patients. All patients underwent polysomnography and thorough physical examination. The association between LUMP scores and OSA measures was evaluated. LUMP score had a significant correlation with the Epworth Sleepiness Scale (ESS) (Spearman's ρ = 0.269, p = 0.004), and BMI (Spearman's ρ = 0.249, p = 0.007), the anatomical position of the tongue (ρ = -0.191, p = 0.04) and the Friedman grade of tonsils (ρ = 0.241, p = 0.01). It correlated with SpO2 nadir, though it did not reach statistical significance. The results of our study depict a relationship between a self-report measure of globus sensation and daytime sleepiness, BMI and tonsil size. In the absence of a direct relationship between OSA severity parameters and GP, we hypothesize a role for shared comorbidities and anatomical phenotypes. The increased frequency of GP in OSA patients should be considered when evaluating the complications of surgical interventions in these patients.

Preoperative prolapse phenotype is predictive of surgical outcome with minimally invasive sacrocolpopexy

The gold-standard treatment for advanced pelvic organ prolapse is sacrocolpopexy. However, the preoperative features of prolapse that predict optimal outcomes are unknown. This study aimed to develop a clinical prediction model that uses preoperative scores on the Pelvic Organ Prolapse Quantification examination to predict outcomes after minimally invasive sacrocolpopexy for stages 2, 3, and 4 uterovaginal prolapse and vaginal vault prolapse. A 2-institution database of pre- and postoperative variables from 881 cases of minimally invasive sacrocolpopexy was analyzed. Data from patients were analyzed in the following 4 groups: stage 2 uterovaginal prolapse, stage 3 to 4 uterovaginal prolapse, stage 2 vaginal vault prolapse, and stage 3 to 4 vaginal vault prolapse. Unsupervised machine learning was used to identify clusters and investigate associations between clusters and outcome. The k-means clustering analysis was performed with preoperative Pelvic Organ Prolapse Quantification points and stratified by previous hysterectomy status. The "optimal" surgical outcome was defined as postoperative Pelvic Organ Prolapse Quantification stage <2. Demographic variables were compared by cluster with Student t and chi-square tests. Odds ratios were calculated to determine whether clusters could predict the outcome. Age at surgery, body mass index, and previous prolapse surgery were used for adjusted odds ratios. Five statistically distinct prolapse clusters (phenotypes C, A, A>P, P, and P>A) were found. These phenotypes reflected the predominant region of prolapse (apical, anterior, or posterior) and whether support was preserved in the nonpredominant region. Phenotype A (anterior compartment prolapse predominant, posterior support preserved) was found in all 4 groups of patients and was considered the reference in the analysis. In 111 patients with stage 2 uterovaginal prolapse, phenotypes A and A>P (greater anterior prolapse than posterior prolapse) were found, and patients with phenotype A were more likely than those with phenotype A>P to have an optimal surgical outcome. In 401 patients with stage 3 to 4 uterovaginal prolapse, phenotypes C (apical compartment predominant, prolapse in all compartments), A, and A>P were found, and patients with phenotype A>P were more likely than those with phenotype A to have ideal surgical outcome. In 72 patients with stage 2 vaginal vault prolapse, phenotypes A, A>P, and P (posterior compartment predominant, anterior support preserved) were found, and those with phenotype A>P were less likely to have an ideal outcome than patients with phenotype A. In 297 patients with stage 3 to 4 vaginal vault prolapse, phenotypes C, A, and P>A (prolapse greater in posterior than in anterior compartment) were found, but there were no significant differences in rate of ideal outcome between phenotypes. Five anatomic phenotypes based on preoperative Pelvic Organ Prolapse Quantification scores were present in patients with stages 2 and 3 to 4 uterovaginal prolapse and vaginal vault prolapse. These phenotypes are predictive of surgical outcome after minimally invasive sacrocolpopexy. Further work needs to confirm the presence and predictive nature of these phenotypes. In addition, whether the phenotypes represent a progression of prolapse or discrete prolapse presentations resulting from different anatomic and life course risk profiles is unknown. These phenotypes may be useful in surgical counseling and planning.

Relationship between OSA pathophysiological phenotypes and treatment response to mandibular advancement devices: a pilot study.

We assessed whether critical pathophysiological phenotypes predict treatment response in patients with obstructive sleep apnea using a mandibular advancement device (MAD). Thirty-one patients with obstructive sleep apnea were treated with a MAD. Individuals were categorized and graded into 4 pathophysiological phenotypes based on polysomnographic features (anatomical, ventilatory control, arousal threshold, and muscle responsiveness). Morpho-anthropometric data were additionally assessed. Patients were classified as responders or nonresponders. Associations between polysomnographic phenotypes and treatment response were documented, as were morpho-anthropometric data and their impact on therapeutic success. There was a male predominance (64.5%), with a median age of 49 years (25th percentile: 40; 75th percentile: 55), body mass index = 27.4 kg/m2 (25th percentile: 26; 75th percentile: 28.8), and apnea-hypopnea index of 18.2 events/h (25th percentile: 11.7; 75th percentile: 27.6). The majority of patients treated with a MAD (58%) were good responders (68.0% mild and moderate vs 16.7% severe). Treatment response was associated with shorter intermolar and interpremolar distances in the lower arch (P = .0092 and .0129). Rapid eye movement sleep apnea-hypopnea index and MAD-related treatment response were inversely correlated (P = .0013). Favorable anatomical (P = .0339) and low muscle response (P = .0447) phenotypes were correlated with outcomes. According to our results, a favorable response occurred in a better "anatomical phenotype" and in the worse "muscular responsiveness phenotype" according to polysomnographic data. Furthermore, other favorable predictors, such as a rapid eye movement sleep apnea-hypopnea index < 16 events/h and a smaller distance between lower molars and premolars, were found. These findings indicate that clinical and polysomnographic aspects can discriminate phenotypes that may guide decisions on MAD treatment for obstructive sleep apnea. Manetta IP, Duarte BB, Nucci LB, Enes CC. Relationship between OSA pathophysiological phenotypes and treatment response to mandibular advancement devices: a pilot study. J Clin Sleep Med. 2024;20(8):1321-1330.

Abstract 3767: A novel method to minimize HIER-induced alterations on H&amp;E staining in an integrated mIF-H&amp;E workflow

Abstract Background: Hematoxylin and eosin staining (H&amp;E) is widely used as an anatomical assay for clinical diagnosis. Researchers and clinicians also rely on molecular in situ techniques, such as multiplexed immunofluorescence (mIF), to gain deeper insights on cellular phenotypes and tissue microenvironment. As a result, there has been significant interest in combining anatomical stains with molecular imaging techniques, most commonly by using a terminal H&amp;E stain after mIF staining. This allows a combination of the two assays but has been observed to show alterations in the H&amp;E staining pattern. In this work we identify heat-induced epitope retrieval (HIER) as the root cause of alterations of the terminal H&amp;E stain after mIF. We further demonstrate a new workflow combining an initial H&amp;E stain with subsequent InSituPlex assay, to avoid these alterations and thus enable co-registration of highly sensitive multiplexed immunofluorescence with an unaltered H&amp;E stain. Methods: FFPE tissue slides were stained using a standard HIER protocol or a full mIF assay, followed by a standard H&amp;E stain. Slides were imaged using a Zeiss Axioscan.Z1 scanner. Additional H&amp;E-stained slides were prepared, and the H&amp;E stain removed using a destaining protocol before carrying out InSituPlex® mIF staining for multiple markers. Fluorescence and brightfield images of the same slide were overlaid using UltiStacker® to assess qualitative differences between pre- and post-mIF H&amp;E, and UltiAnalyzer.AI® was used to quantify cell densities and signal intensities between mIF image pre- and post-H&amp;E. Results: Alterations in H&amp;E staining were observed between slides directly stained with H&amp;E and slides stained with a terminal H&amp;E after HIER alone or a full mIF assay. Calculated cell counts and tissue area were consistent throughout, but some tissue microstructures could be difficult to resolve after either HIER or full mIF. Our destaining protocol was successful in removing hematoxylin and eosin from directly-stained H&amp;E slides and allowing subsequent mIF staining. For most biomarkers, qualitative and quantitative differences in InSituPlex mIF staining were minimal. Brightfield and fluorescent images were co-registered with sub-micron accuracy using UltiStacker, enabling molecularly defined cellular phenotyping within a traditional H&amp;E image. Conclusions: While the mIF to H&amp;E workflow is widely used and is capable of allowing combined anatomical and cellular phenotyping, alterations in the H&amp;E stain exist due to the use of HIER in most mIF protocols. An alternative method is possible in which H&amp;E-stained slides are destained and then restained for mIF or other spatial assays, providing the same valuable combination of assay information but without the HIER-induced alterations in H&amp;E staining pattern. Citation Format: Kevin Hwang, Grace Vezeau, Edyta Olejnik, Douglas Wood, Ruben Cardenes, Lauren Duro, Gourab Chatterjee, Je H. Lee. A novel method to minimize HIER-induced alterations on H&amp;E staining in an integrated mIF-H&amp;E workflow [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3767.

Proxy-analysis of the genetics of cognitive decline in Parkinson’s disease through polygenic scores

Cognitive decline is common in Parkinson’s disease (PD) and its genetic risk factors are not well known to date, besides variants in the GBA and APOE genes. However, variation in complex traits is caused by numerous variants and is usually studied with genome-wide association studies (GWAS), requiring a large sample size, which is difficult to achieve for outcome measures in PD. Taking an alternative approach, we computed 100 polygenic scores (PGS) related to cognitive, dementia, stroke, and brain anatomical phenotypes and investigated their association with cognitive decline in six longitudinal cohorts. The analysis was adjusted for age, sex, genetic ancestry, follow-up duration, GBA and APOE status. Then, we meta-analyzed five of these cohorts, comprising a total of 1702 PD participants with 6156 visits, using the Montreal Cognitive Assessment as a cognitive outcome measure. After correction for multiple comparisons, we found four PGS significantly associated with cognitive decline: intelligence (p = 5.26e–13), cognitive performance (p = 1.46e–12), educational attainment (p = 8.52e–10), and reasoning (p = 3.58e–5). Survival analyses highlighted an offset of several years between the first and last quartiles of PGS, with significant differences for the PGS of cognitive performance (5 years) and educational attainment (7 years). In conclusion, we found four PGS associated with cognitive decline in PD, all associated with general cognitive phenotypes. This study highlights the common genetic factors between cognitive decline in PD and the general population, and the importance of the participant’s cognitive reserve for cognitive outcome in PD.

Ventricular Septal Defects: Molecular Pathways and Animal Models.

Ventricular septation is a complex process which involves the major genes of cardiac development, acting on myocardial cells from first and second heart fields, and on mesenchymal cells from endocardial cushions. These genes, coding for transcription factors, interact with each other, and their differential expression conditions the severity of the phenotype. In this chapter, we will describe the formation of the ventricular septum in the normal heart, as well as the molecular mechanisms leading to the four main anatomic types of ventricular septal defects: outlet, inlet, muscular, and central perimembranous, resulting from failure of development of the different parts of the ventricular septum. Experiments on animal models, particularly transgenic mouse lines, have helped us to decipher the molecular determinants of ventricular septation. However, a precise description of the anatomic phenotypes found in these models is mandatory to achieve a better comprehension of the complex mechanisms responsible for the various types of VSDs.

Human Genetics of d-Transposition of Great Arteries.

Although several genes underlying occurrence of transposition of the great arteries have been found in the mouse, human genetics of the most frequent cyanotic congenital heart defect diagnosed in neonates is still largely unknown. Development of the outflow tract is a complex process which involves the major genes of cardiac development, acting on myocardial cells from the anterior second heart field, and on mesenchymal cells from endocardial cushions. These genes, coding for transcription factors, interact with each other, and their differential expression conditions the severity of the phenotype. A precise description of the anatomic phenotypes is mandatory to achieve a better comprehension of the complex mechanisms responsible for transposition of the great arteries.

Micro-CT and high-field MRI for studying very early post-mortem human fetal anatomy at 8weeks of gestation.

This study involved very early post-mortem (PM) examination of human fetal anatomy at 8weeks of gestation (WG) using whole-body multimodal micro-imaging: micro-CT and high-field MRI (HF-MRI). We discuss the potential place of this imaging in early first-trimester virtual autopsy. We performed micro-CT after different contrast-bath protocols including diffusible iodine-based contrast-enhanced (dice) and HF-MRI with a 9.4T machine with qualitative and quantitative evaluation and obtained histological sections. Nine fetuses were included: the crown-rump length was 10-24mm and corresponded to 7 and 9 WG according to the Robinson formula. The Carnegie stages were 17-21. Dice micro-CT and HF-MRI presented high signal to noise ratio, >5, according to the Rose criterion, and for allowed anatomical phenotyping in these specimens. Imaging did not alter the histology, allowing immunostaining and pathological examination. PM non-destructive whole-body multimodal micro-imaging: dice micro-CT and HF-MRI allows for PM human fetal anatomy study as early as 8 WG. It paves the way to virtual autopsy in the very early first trimester. Obtaining a precision phenotype, even regarding miscarriage products, allows a reverse phenotyping to select variants of interest in genome-wide analysis, offering potential genetic counseling for bereaved parents.

Electrophysiological mechanisms underlying T wave pseudonormalisation on stress ECGs in hypertrophic cardiomyopathy

BackgroundPseudonormal T waves may be detected on stress electrocardiograms (ECGs) in hypertrophic cardiomyopathy (HCM). Either myocardial ischaemia or purely exercise-induced changes have been hypothesised to contribute to this phenomenon, but the precise electrophysiological mechanisms remain unknown. MethodsComputational models of human HCM ventricles (n = 20) with apical and asymmetric septal hypertrophy phenotypes with variable severities of repolarisation impairment were used to investigate the effects of acute myocardial ischaemia on ECGs with T wave inversions at baseline. Virtual 12-lead ECGs were derived from a total of 520 biventricular simulations, for cases with regionally ischaemic K+ accumulation in hypertrophied segments, global exercise-induced serum K+ increases, and/or increased pacing frequency, to analyse effects on ECG biomarkers including ST segments, T wave amplitudes, and QT intervals. ResultsRegional ischaemic K+ accumulation had a greater impact on T wave pseudonormalisation than exercise-induced serum K+ increases, due to larger reductions in repolarisation gradients. Increases in serum K+ and pacing rate partially corrected T waves in some anatomical and electrophysiological phenotypes. T wave morphology was more sensitive than ST segment elevation to regional K+ increases, suggesting that T wave pseudonormalisation may sometimes be an early, or the only, ECG feature of myocardial ischaemia in HCM. ConclusionsIschaemia-induced T wave pseudonormalisation can occur on stress ECG testing in HCM before significant ST segment changes. Some anatomical and electrophysiological phenotypes may enable T wave pseudonormalisation due to exercise-induced increased serum K+ and pacing rate. Consideration of dynamic T wave abnormalities could improve the detection of myocardial ischaemia in HCM.

Abstract 17273: Phenotypic Clustering of Patients With Heterotaxy Syndrome Predicts Outcomes of Mortality and Transplantation

Background: Current classifications of heterotaxy syndrome (HS) (e.g. left/right isomerism, polysplenia/asplenia) do not capture the heterogeneity of cardiac anomalies observed nor provide insight on risk stratification. We aimed to improve these classifications using cluster analysis to identify anatomic phenotypes in HS patients. Methods: Using a retrospective database of all HS patients seen at Boston Children’s Hospital from 1985-2014 (n=264), we performed principal component and cluster analyses on 47 cardiac anatomic variables and compared rates of mortality/transplantation across clusters. Results: Five clusters were identified ranging in size from 19 to 91 patients. Cluster #1 had a high prevalence of right-dominant complete atrioventricular canal defects (CAVC), double-outlet right ventricle (DORV), pulmonary stenosis/atresia (PS/PA), and total anomalous pulmonary venous connection (TAPVC); Cluster #2 of left-dominant CAVC, DORV, and TAPVC; Cluster #3 of left-sided obstructive lesions and interrupted IVC; Cluster #4 of transposition of the great arteries with PS/PA; and Cluster #5 of interrupted IVC with miscellaneous cardiac anomalies (Table). Over 80% of patients in clusters 1 and 2 underwent single ventricle palliation compared with only 16% of patients in cluster 5. Transplant-free survival was lowest in clusters 1, 2, and 3 but differed by single versus biventricular repair (Figure). Conclusions: Cluster analysis of cardiac anatomic variables identified 5 phenotypes of HS including 3 higher risk and 2 lower risk phenotypes. These findings highlight the need for improved phenotyping of HS to account for the high degree of disease heterogeneity.

Abstract 12897: Automated Assessment of Left Ventricular Function in Tetralogy of Fallot - A Machine Learning Approach

Introduction: Congenital heart disease (CHD) is associated with significant cardiac anatomic and functional variability. This study tests the implementation and validation of a convolutional neural network algorithm (EchoNet-Dynamic) on a pediatric dataset via a transfer learning approach. We compare the echocardiographic systolic function measure, left ventricular ejection fraction (LVEF), with CMR as the gold standard. Methods: Patients ages 1-18 (44% female) who underwent a transthoracic echocardiographic evaluation and CMR for repaired Tetralogy of Fallot (TOF) were divided into 2 groups of EF &lt; and &gt;40%. 406 (2D-A4C views) videos with LVEF calculated using Bullet and Simpson method were identified. MRI EF as a ground truth label was compared with predicted EF data. Inference weights were derived from EchoNet-Dynamic and the weights from re-training the model on pediatric data. Correlation statistics were computed. The metrics included mean absolute error (MAE), root mean squared error (RMSE), and coefficient of determination (R2). Results: The R2 of actual vs predicted was 0.83 (0.71-0.89) with an MAE of 3.55. The predicted EF vs MRI EF resulted in an R2 of 0.48 and an MAE of 6.39 (Figure 1 a-c). Bland-Altman analysis between actual vs predicted EF estimates LVEF (bias = 1.64%) with 95% limits of agreement of -7.80% to 11.09%. MRI EF vs predicted values, the model estimates LVEF (bias = -3.12%) with 95% limits of agreement of -18.71% to 12.48%. The smaller body surface area and ages correlated with better model performance in both groups. Conclusions: EchoNet-Dynamic trained on a pediatric data set can accurately predict EF and this validates the model’s performance on a distinct CHD population. The predicted EF accurately compares with the MRI assessment. EchoNet Dynamic can be employed via a transfer learning method for automated real-time evaluations of cardiac function in CHD patients with compromised ventricular function and complex anatomical phenotypes.

Human Kidneys House Tissue-Resident B Cells with a Distinct Anatomical Location and Phenotype that Changes with Age

Human Kidneys House Tissue-Resident B Cells with a Distinct Anatomical Location and Phenotype that Changes with Age

P30 An unusual infective cause of inflammatory arthritis

P30 An unusual infective cause of inflammatory arthritis

Plasma Cell Neoplasms with Unusual Anatomic Locations, Morphology, Phenotype, and Review of Literature: A Case Series

Plasma Cell Neoplasms with Unusual Anatomic Locations, Morphology, Phenotype, and Review of Literature: A Case Series

Association of sex and cardiovascular risk factors with atherosclerosis distribution pattern in lower extremity peripheral artery disease.

Atherosclerosis expression varies across not only coronary, cerebrovascular, and peripheral arteries but also within the peripheral vascular tree. The underlying pathomechanisms of distinct atherosclerosis phenotypes in lower extremity peripheral artery disease (PAD) is poorly understood. We investigated the association of cardiovascular risk factors (CVRFs) and atherosclerosis distribution in a targeted approach analyzing symptomatic patients with isolated anatomic phenotypes of PAD. In a cross-sectional analysis of consecutive patients undergoing first-time endovascular recanalization for symptomatic PAD, data of patients with isolated anatomic phenotypes of either proximal (iliac) or distal (infrageniculate) atherosclerosis segregation were extracted. We performed a multivariable logistic regression model with backward elimination to investigate the association of proximal and distal PAD with CVRFs. Of the 637 patients (29% females) with endovascular recanalization, 351 (55%) had proximal and 286 (45%) had distal atherosclerosis. Female sex [odds ratio (OR) 0.33, 95% confidence interval (CI) 0.20-0.54, p = 0.01], active smoking (OR 0.16, 95% CI 0.09-0.28, p < 0.001), and former smoking (OR 0.33, 95% CI 0.20-0.57, p < 0.001) were associated with proximal disease. Diabetes mellitus (DM) (OR 3.25, 95% CI 1.93-5.46, p < 0.001), chronic kidney disease (CKD) (OR 1.18, 95% CI 1.08-1.28, p < 0.001), and older age (OR 1.31, 95% CI 1.06-1.61, p = 0.01) were associated with distal disease. Female sex, particularly in the context of smoking, is associated with clinically relevant, proximal atherosclerosis expression. Our additional findings that distal atherosclerosis expression is associated with DM, CKD, and older age suggest that PAD has at least two distinct atherosclerotic phenotypes with sex-specific and individual susceptibility to atherogenic risk factors.

The anatomy of neuroepithelial tumours.

Many neurological conditions conceal specific anatomical patterns. Their study contributes to the understanding of disease biology and to tailored diagnostics and therapy. Neuroepithelial tumours exhibit distinct anatomical phenotypes and spatiotemporal dynamics that differ from those of other brain tumours. Brain metastases display a preference for the cortico-subcortical boundaries of watershed areas and have a predominantly spherical growth. Primary CNS lymphomas localize to the white matter and generally invade along fibre tracts. In neuroepithelial tumours, topographic probability mapping and unsupervised topological clustering have identified an inherent radial anatomy and adherence to ventriculopial configurations of specific hierarchical orders. Spatiotemporal probability and multivariate survival analyses have identified a temporal and prognostic sequence underlying the anatomical phenotypes of neuroepithelial tumours. Gradual neuroepithelial de-differentiation and declining prognosis follow (i) an expansion into higher order radial units; (ii) a subventricular spread; and (iii) the presence of mesenchymal patterns (expansion along white matter tracts, leptomeningeal or perivascular invasion, CSF spread). While different pathophysiological hypotheses have been proposed, the cellular and molecular mechanisms dictating this anatomical behaviour remain largely unknown. Here we adopt an ontogenetic approach towards the understanding of neuroepithelial tumour anatomy. Contemporary perception of histo- and morphogenetic processes during neurodevelopment permit us to conceptualize the architecture of the brain into hierarchically organized radial units. The anatomical phenotypes in neuroepithelial tumours and their temporal and prognostic sequences share remarkable similarities with the ontogenetic organization of the brain and the anatomical specifications that occur during neurodevelopment. This macroscopic coherence is reinforced by cellular and molecular observations that the initiation of various neuroepithelial tumours, their intratumoural hierarchy and tumour progression are associated with the aberrant reactivation of surprisingly normal ontogenetic programs. Generalizable topological phenotypes could provide the basis for an anatomical refinement of the current classification of neuroepithelial tumours. In addition, we have proposed a staging system for adult-type diffuse gliomas that is based on the prognostically critical steps along the sequence of anatomical tumour progression. Considering the parallels in anatomical behaviour between different neuroepithelial tumours, analogous staging systems may be implemented for other neuroepithelial tumour types and subtypes. Both the anatomical stage of a neuroepithelial tumour and the spatial configuration of its hosting radial unit harbour the potential to stratify treatment decisions at diagnosis and during follow-up. More data on specific neuroepithelial tumour types and subtypes are needed to increase the anatomical granularity in their classification and to determine the clinical impact of stage-adapted and anatomically tailored therapy and surveillance.

A quantitative micro-tomographic gut atlas of the lepidopteran model insect Manduca sexta

The tobacco hornworm is used extensively as a model system for ecotoxicology, immunology and gut physiology. Here, we established a micro-computed tomography approach based on the oral application of the clinical contrast agent iodixanol, allowing for a high-resolution quantitative analysis of the Manduca sexta gut. This technique permitted the identification of previously unknown and understudied structures, such as the crop or gastric ceca, and revealed the underlying complexity of the hindgut folding pattern, which is involved in fecal pellet formation. The acquired data enabled the volume rendering of all gut parts, the reliable calculation of their volumes, and the virtual endoscopy of the entire alimentary tract. It can provide information for accurate orientation in histology uses, enable quantitative anatomical phenotyping in three dimensions, and allow the calculation of locally effective midgut concentrations of applied chemicals. This atlas will provide critical insights into the evolution of the alimentary tract in lepidopterans.