Symptomatic Phenotype Research Articles

Newborn screening algorithm distinguishing potential symptomatic isovaleric acidemia from asymptomatic newborns.

Newborn screening (NBS) for isovaleric acidemia (IVA) reduces mortality and morbidity; however, it has also resulted in the detection of individuals with an asymptomatic or mild presentation for which early detection via newborn screening has not been proven to alter neurological outcome. We reevaluated biochemical and molecular data for newborns flagged positive for IVA in aim of developing a new screening algorithm to exclude the latter from positive screening. Among 2 794 365 newborns underwent routine newborn screening in Israel, 412 flagged positive for IVA, of which, 371 were false positives on recall sample testing and 41 positive newborns were referred to the clinic. 38/41 have biochemical and molecular confirmation in keeping with IVA. Among the 38 patients, 32% (12/38) were classified as symptomatic while, 68% (26/38) were classified as asymptomatic. 69% of the latter group harbor the known variant associated with mild potentially asymptomatic phenotype, c.932C>T; p. Ala311Val. Among asymptomatic patients, only 46% (12/26) are currently treated. Two novel variants have been detected in the IVD gene: c.487G>A; p. Ala163Thr and c.985A>G; p. Met329Val. Cut-off recalculation, of referred newborns' initial biochemical results, after classifying the referred patients to two binary groups of symptomatic and asymptomatic, resulted in an improved NBS algorithm comprising of C5 >5 μM and C5/C2>0.2 and C5/C3>4 flagging only those likely to have the classic symptomatic phenotype.

Genetic variants in FCGR2A, PTPN2, VDR as predictive signatures of aggressive phenotypes in cerebral cavernous malformation

ObjectiveThe biological behavior of Cerebral Cavernous Malformation (CCM) is still controversial, lacking a clear-cut signature for a mechanistic explanation of lesion aggressiveness. In this study, we evaluated the predictive capacity of genetic variants concerning the aggressive behavior of CCM and their implications in biological processes. MethodsWe genotyped the variants in VDRrs7975232, VDRrs731236, VDRrs11568820, PTPN2rs72872125 and FCGR2Ars1801274 genes using TaqMan Genotyping Assays in a cohort study with 103 patients, 42 of whom had close follow-up visits for 4 years, focusing on 2 main aspects of the disease: (1) symptomatic events, which included both intracranial bleeding or epilepsy, and (2) the onset of symptoms. The genotypes were correlated with the levels of several cytokines quantified in peripheral blood, measured using the x-MAP method. ResultsWe report a novel observation that the PTPN2rs72872125 CT and the VDRrs7975232 CC genotype were independently associated with an asymptomatic phenotype. Additionally, PTPN2rs72872125 CC genotype and serum level of GM-CSF could predict a diagnostic association with symptomatic phenotype in CCM patients, while the FCGR2Ars1801274 GG genotype could predict a symptomatic event during follow-up. The study also found a correlation between VDRrs731236 AA and VDRrs11568820 CC genotype to the time to the first symptomatic event. ConclusionsThese genetic markers could pave the way for precision medicine strategies for CCM, enhancing patient outcomes by enabling customized therapeutic approaches.

A new hiPSC-based viral expression system to study virus host-cell interaction in hiPSC-derived cardiomyocytes

Abstract Coxsackievirus B3 (CVB3) belongs to the Picornaviridae family and is a member of the enterovirus genus. CVB3 is the most frequently detected pathogen in viral myocarditis, which leads to acute heart infections in 20-40% of cases and to dilated cardiomyopathy (DCM) in cases of prolonged viral persistence. Complex arrhythmias and sudden deaths due to CVB infections have also been reported, particularly in newborns and children. Observed arrhythmias include bradycardia, AV block and junctional ectopic tachycardia, suggesting that in addition to the functioning myocardium, the pacemaker cells and cardiac conduction system may also be impaired by CVB3 infection. The symptomatic phenotype is highly variable and depends on unclear host factors. It ranges from inconspicuous inflammation and rapid healing to acute congestive heart failure or viral persistence with progressive chronic disease. Despite the increasing and profound knowledge about viral myocarditis, it is still a challenge to identify further host factors that contribute to acute and chronic myocarditis, as science lacks sensitive and controllable disease models. The presented project shows the generation of a controlled, inducible virus-expressing hiPSC line that provides a solution for the beforementioned problems. The new human induced pluripotent stem cell line (hiPSC) i can be used to carry out virologic experiments in a controlled manner and without risk to the user. For this purpose, the modified and non-infectious genome of the enterovirus Coxsackievirus B3 (CVB3) is stably integrated into the genome of a wild-type hiPSC line. The CVB3 genome to be stably integrated was modified to prevent the formation of functional capsids by a DVP0 mutation. In addition, the 3'UTR and 5'UTR regions of the CVB3 genome were removed, which prevents uncontrolled self-replication of viral RNA. As a result, work with this CVB3DVP0-UTR genome is classified as S1 compliant. The expression of the CVB3DP0-UTR virus genome can be controlled by adding doxycycline to the cell culture medium by a TeT-On System. The transfected cells are then cultivated as clones and tested for virus expression. The dose-dependent CVB3DVP0 expression is verified using qPCR and FACS after 1 day of doxycycline application in the cell culture medium. Clones isolated and positively tested for CVB3 expression are used to carry out initial experiments on the interaction of the expressed viral proteins with the cell. Particular focus is placed on the induction of cell death, remodelling of the cytoskeleton and increase of reactive oxygen species (ROS) in mitochondria after CVB3DVP0-UTR induction in order to validate the cell system for application. Differentiation of the CVB3-expressing hiPSC-line into cardiomyocytes with subsequent virus induction results in the elevation of mitochondrial ROS, degradation of the cytoskeleton and arrhythmic behaviour of the cells.

Online phenotypes of depression symptoms are associated with polygenic risk scores of somatic diseases in a population-based cohort

To test an associations of online phenotypes of depressive symptoms with polygenic risk scores (PRS) for selected somatic diseases in a population-based cohort. Participants in a Russian population-based cohort (n=4520) underwent online phenotyping based on the originally developed questionnaire using DSM-5 criteria (DSM phenotypes) and the Hospital Anxiety and Depression Scale (HADS) questionnaire (HADS phenotypes). After DNA genotyping with microarrays, PRS were calculated using summary statistics from large-scale GWASs (mostly from UK Biobank) for irritable bowel syndrome (IBS), coronary heart disease (narrow and broad phenotypes) (CHD), ischemic stroke (IS),diabetes mellitus type 2 (DT2) and migraine (MG). Then we assessed associations of PRS for somatic diseases with online phenotypes of depressive symptoms in a population-based cohort. Highly specific associations of PRS for somatic diseases with online phenotypes of depressive symptoms in a population cohort were identified: positive associations of PRS IBS with «DSM depression» (p=0.0035) and PRS CHD (narrow phenotype) with «DSM bipolar disorder» (p=0.0207), as well as a negative association of PRS IS with the symptomatic DSM phenotype «Hyperphagia» (p=0.0262). All the HADS phenotypes (clinical depression, subclinical depression, and HADS-D total score) showed a positive association with PRS for IBS and DT2, and at the same time were negatively associated with PRS IS. The DSM phenotype «Hypersomnia and hyperphagia» was positively associated with PRS for DT2 and IS, and negatively associated with PRS CHD (narrow phenotype). The DSM phenotypes «Subclinical Depression», «Hypersomnia», and «Anhedonia» showed exclusively negative associations with PRSs for DT2, IS, and IBS. Three maximum informative PRS by explained variance (PRS.R2) were found for the single DSM phenotype «Hypersomnia and hyperphagia»: PRS for IS and DT2 are positively associated and increase the risk of this phenotype, and PRS CHD (narrow phenotype) has a negative association and reduces the risk of this phenotype. Our study confirmed the presence of possible genetic comorbidity of depression and chronic somatic diseases and showed different effectiveness of online phenotyping of depressive symptoms as markers of genetic risk of somatic diseases in the population cohort. Further research is needed to construct various versions of online phenotyping test systems for population-based screening of cohorts at high genetic risk for genetically comorbid diseases.

Changes in cognitive function and daytime sleepiness in patients with chronic heart failure and Cheyne-Stokes respiration with adaptive servo ventilation treatment

Study objectivesCheyne - Stokes respiration (CSR) is prevalent in patients with chronic heart failure (CHF). Adaptive Servo Ventilation (ASV) alleviates CSR and improves objective sleep quality. We investigated the effects of ASV on neurocognitive function in the symptomatic phenotype of patients with CSR and CHF. MethodsThis case series included patients diagnosed with stable CHF (NYHA ≥ II) and CSR (N = 8). Sleep and neurocognitive function were assessed at baseline and after 1- and 6-months following initiation of ASV treatment. ResultsIn CHF patients (n = 8, median age 78.0[64.5–80.8] years and BMI 30.0[27.0–31.5] kg/m2, median ejection fraction 30[24–45]%, Epworth Sleepiness Scale (ESS) score 11.5[9.0–15.0]), ASV markedly improved respiration during sleep (Apnea-Hypopnea Index (AHI) 44.1[39.0–51.5]n/h at baseline, 6.3[2.4–9.7]n/h at 6 months treatment, respectively, p < 0.01). The 6-min-walk test distance increased by treatment from (295.0[178.8–385.0] m to 356.0[203.8–495.0] m (p = 0.05)). Sleep structure was modified, and Stage 3 increased markedly from 6.4[1.7–20.1] % to 20.8[14.2–25.3] %, p < 0.02). Sleep latency in the Maintenance of Wakefulness Test increased from 12.0[6.0–30.0] min to 26.3[12.0–30.0] min, (p = 0.04). In the Attention Network Test, evaluating neurocognition, the number of lapses decreased from 6.0[1.0–44.0] to 2.0[0.3–8.0], (p = 0.05) and the overall number of responses to a preset stimulus increased after treatment (p = 0.04). ConclusionsASV treatment in CHF patients with CSR may improve sleep quality, neurocognition and daytime performance.

Predictors of Unrelieved Symptoms in All of Us Research Program Participants With Chronic Conditions.

Over half of American adults are diagnosed with a chronic condition, with an increasing prevalence being diagnosed with multiple chronic conditions. These adults are at higher risk for having unrelieved, co-occurring symptoms, known as symptom clusters. To identify symptom phenotypes of patients diagnosed with four common chronic conditions, specifically, cancer, chronic obstructive pulmonary disease, heart failure, and/or type 2 diabetes mellitus, and to understand factors that predict membership in symptomatic phenotypes. We conducted a retrospective, cross-sectional analysis using participant responses (N=14,127) to All of Us Research Program, a National Institutes of Health biomedical database, survey questions. We performed hierarchical clustering to generate symptom phenotypes of fatigue, emotional distress, and pain and used multinomial regression to determine if demographic, healthcare access and utilization, and health-related variables predict symptom phenotype. Four phenotypes, one asymptomatic or mildly symptomatic and three highly symptomatic (characterized by severe symptoms, severe pain, and severe emotional distress), were identified. The percentage of participants belonging to the severe symptoms phenotype increased with the number of chronic conditions. Most notably, foregoing or delaying medical care and rating mental health as poor or fair increased the odds of belonging to a highly symptomatic phenotype. We found meaningful relationships between demographic, healthcare access and utilization, and health-related factors and symptom phenotypes. With the increasing trends of American adults with one or more chronic conditions and a demand to individualize care in the precision health era, it is critical to understand the factors that lead to unrelieved symptoms.

Trajectory of Functional Recovery from 6 to 12 Months in Persons Hospitalized for Severe SARS-CoV-2 Illness

<h3>Research Objectives</h3> To identify distinct post-acute COVID-19 phenotypes among adults hospitalized for severe SARS-CoV-2 infection and describe multidimensional outcomes and trajectories at 6 and 12 months post-hospitalization. <h3>Design</h3> Prospective, longitudinal data collection in functional, physical, cognitive, and psychological domains at 3, 6, and 12 months post-hospitalization. Retrospective data collection from the acute care and post-acute care settings. <h3>Setting</h3> Acute care and post-acute telephone follow-up. <h3>Participants</h3> English- and Spanish- speaking adults, with decision-making capacity, admitted for inpatient rehabilitation following inpatient rehabilitation for acute COVID-19 related illness (N = 61). <h3>Interventions</h3> N/A. <h3>Main Outcome Measures</h3> Physical, cognitive, and psychological symptoms; self-reported employment status and assistance with ADLs. <h3>Results</h3> Median age 60.8 years; 59% male; 72.1% white; 72.1% non-Hispanic; 26.2% preferred assessment in Spanish. 83% required mechanical ventilation in acute care. Comorbidities were common. We found a high prevalence of persistent symptoms at 6- and 12- months across physical, cognitive, and emotional health outcome domains. Three post-acute phenotypes were identified at 6 months; a "minimally symptomatic" subgroup with minimal symptom endorsement across all domains relative to other subjects (22.95%, n = 14), a "predominantly physical symptoms" subgroup (47.54%, n = 29), and a "globally symptomatic" subgroup (29.51%, n = 18). A similar pattern for phenotypes emerges at 12-months, with 67.21% of subjects falling into the same phenotype at both time points. In the Predominantly Physical Symptom phenotype, 31.0% declined into the Globally Symptomatic Phenotype and 10.3% improved. In the Globally Symptomatic phenotype, 11.1% of participants transitioned to the Minimally Symptomatic phenotype and 16.7% to the Predominantly Physical Symptom phenotype. Compared to premorbid level of employment (50.8%), 24.6% of participants were employed at 12-months. Phenotype at 6-months was a significant predictor of employment at 12-months (B = 2.26, p = .05, OR = 9.6). <h3>Conclusions</h3> Persons with severe COVID-19 illness experience persistent functional limitations and reduced employment up to 12 months post-hospitalization. Distinct recovery subgroups were found suggesting the need for comprehensive assessment and tailored treatment for recovery. <h3>Author(s) Disclosures</h3> The authors declare no relevant conflicts of interest.

Abstract 12354: Novel Coronavirus Disease 2019 Infection in a Cohort of Patients With Phenotypic Hypertrophic Cardiomyopathy: An Extended Report

Background: Patients with preexisting heart disease suffer more severe outcomes after COVID-19. Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac conditions. We previously reported incidence and outcomes of COVID-19 in HCM in early days of the pandemic. We report results from an expanded and extended HCM cohort. Methods: 343 patients with HCM [age 59±17 years, 55% men, 19% NYHA class &gt;1, 63% obstructive, 14% septal reduction therapy, 24% positive family history, 42% selectively genotyped (43% positive for pathogenic mutations), 22% implantable cardioverter-defibrillator (ICD) implants, 27% paroxysmal or permanent atrial fibrillation (AF), 4% AF ablation] were evaluated for COVID-19 from December 2019 to May 2022. Results. Overall, 54 (16%) patients were diagnosed with COVID-19 [56% men, age 55±17 years, 60% obstructive HCM, 5.5% dilated phase HCM, 28% positive family history, 15% genotype positive, 28% with ICD, 17% NYHA class &gt;1, 31% AF]. There were 289 patients without COVID-19 [55% men, age 58±17 years, 63% obstructive HCM, 3% dilated phase HCM, 23% positive family history, 17% genotype positive, 21% with ICD, 19% NYHA class &gt;1, 27% AF]. Patients with COVID-19 were slightly younger (55±17 vs 58±17 years, p 0.046) and more often had dilated phase HCM (5.5% vs 3%) and more often had ICD (28% vs 21%). Eleven (20%) patients with COVID-19 were hospitalized and 1 (2%) died of the disease. Compared to those with mild disease, hospitalized patients with COVID-19 were more often men (82% vs 49%, p 0.04), older (age 59±15 vs. 54±18 years), with obstructive phenotype (73% vs 56%) and with NYHA class &gt;1 symptoms (27% vs 12%). In the studied patient cohort 70% had at least one dose of COVID-19 vaccine. Prior to the infection 63% of patients had no vaccination against SARS-CoV2. Among hospitalized patients 9 (82%) had no vaccination and 2 (18%) were vaccinated and had mild disease. Conclusions. Although Covid-19 infection rate (16%) in studied cohort was slightly lower than in general US population (~25%), hospitalization rate was higher (20% vs 9%) with similar death rates (1-2%). Older man with symptomatic obstructive HCM phenotype noted to have higher risk for hospitalization. Patients with vaccination against SARS-Cov2 tended to require less hospitalization.

To Modify or Not to Modify: Allele-Specific Effects of 3'UTR-KCNQ1 Single Nucleotide Polymorphisms on Clinical Phenotype in a Long QT 1 Founder Population Segregating a Dominant-Negative Mutation.

Background There are conflicting reports with regard to the allele-specific gene suppression effects of single nucleotide polymorphisms (SNPs) in the 3'untranslated region (3'UTR) of the KCNQ1 gene in long QT syndrome type 1 (LQT1) populations. Here we assess the allele-specific effects of 3 previously published 3'UTR-KCNQ1's SNPs in a LQT1 founder population segregating a dominant-negative mutation. Methods and Results Bidirectional sequencing of the KCNQ1's 3'UTR was performed in the p.Y111C founder population (n=232, 147 genotype positive), with a minor allele frequency of 0.1 for SNP1 (rs2519184) and 0.6 for linked SNP2 (rs8234) and SNP3 (rs107980). Allelic phase was assessed in trios aided by haplotype data, revealing a high prevalence of derived SNP2/3 in cis with p.Y111C (89%). Allele-specific association analyses, corrected using a relatedness matrix, were performed between 3'UTR-KCNQ1 SNP genotypes and clinical phenotypes. SNP1 in trans was associated with a significantly higher proportion of symptomatic phenotype compared with no derived SNP1 allele in trans (58% versus 32%, corrected P=0.027). SNP2/3 in cis was associated with a significantly lower proportion of symptomatic phenotype compared with no derived SNP2/3 allele in cis (32% versus 69%, corrected P=0.010). Conclusions Allele-specific modifying effects on symptomatic phenotype of 3'UTR-KCNQ1 SNPs rs2519184, rs8234, and rs107980 were seen in a LQT1 founder population segregating a dominant-negative mutation. The high prevalence of suppressive 3'UTR-KCNQ1 SNPs segregating with the founder mutation could contribute to the previously documented low incidence of cardiac events in heterozygous carriers of the p.Y111C KCNQ1 mutation.

Comorbid insomnia and sleep apnea in children: a preliminary explorative study.

Insomnia and sleep-disordered breathing (SDB) are prevalent sleep disorders. These disorders can therefore be concurrently present - comorbid insomnia and sleep apnea (COMISA). The prevalence of COMISA in the paediatric age range is unclear. As such, phenotypic constructs should help better define this comorbid condition if it exists in children and improve both diagnostic sensitivity and ultimately clinical care outcomes. We aimed to evaluate the frequency of insomnia in children and adolescents referred for evaluation of sleep symptoms suggestive of SDB in one initial (Cohort#1) and verify such findings in an independent cohort (Cohort#2) using a retrospective cross-sectional approach in patients aged 9-19 years presenting at a sleep centre to be evaluated for symptoms of SDB. Cohort #1 comprised 50 consecutive children (58% males; mean [SD] age 13.6[3.3]years; median [interquartile range, IQR] Epworth Sleepiness Scale score 10[6-12]) who were evaluated using validated SDB and insomnia questionnaires. Cohort#2 was extracted from electronic medical records and included 384 polysomnographically evaluated children (mean [SD] age 12.9[3.6]years; mean [SD] body mass index z score 1.27[0.28]; median Epworth Sleepiness Scale score 9.7[4-17]). In Cohort #1, 56% were at high risk of SDB, 36% had insomnia alone, and 18% were at high risk of COMISA. The prevalence of COMISA in Cohort #2 was 16%, 72% had SDB alone, and 12% had insomnia alone. In both cohorts, COMISA manifested as increased propensity for sleepiness and fatigue during both waking and daytime. Thus, the presence of COMISA is frequent in the paediatric age range and accompanied by a more prominent symptomatic phenotype.

Analysis of Chinese Medical Syndrome Features of Ischemic Stroke Based on Similarity of Symptoms Subgroup.

To derive the Chinese medicine (CM) syndrome classification and subgroup syndrome characteristics of ischemic stroke patients. By extracting the CM clinical electronic medical records (EMRs) of 7,170 hospitalized patients with ischemic stroke from 2016 to 2018 at Weifang Hospital of Traditional Chinese Medicine, Shandong Province, China, a patient similarity network (PSN) was constructed based on the symptomatic phenotype of the patients. Thereafter the efficient community detection method BGLL was used to identify subgroups of patients. Finally, subgroups with a large number of cases were selected to analyze the specific manifestations of clinical symptoms and CM syndromes in each subgroup. Seven main subgroups of patients with specific symptom characteristics were identified, including M3, M2, M1, M5, M0, M29 and M4. M3 and M0 subgroups had prominent posterior circulatory symptoms, while M3 was associated with autonomic disorders, and M4 manifested as anxiety; M2 and M4 had motor and motor coordination disorders; M1 had sensory disorders; M5 had more obvious lung infections; M29 had a disorder of consciousness. The specificity of CM syndromes of each subgroup was as follows. M3, M2, M1, M0, M29 and M4 all had the same syndrome as wind phlegm pattern; M3 and M0 both showed hyperactivity of Gan (Liver) yang pattern; M2 and M29 had similar syndromes, which corresponded to intertwined phlegm and blood stasis pattern and phlegm-stasis obstructing meridians pattern, respectively. The manifestations of CM syndromes often appeared in a combination of 2 or more syndrome elements. The most common combination of these 7 subgroups was wind-phlegm. The 7 subgroups of CM syndrome elements were specifically manifested as pathogenic wind, pathogenic phlegm, and deficiency pathogens. There were 7 main symptom similarity-based subgroups in ischemic stroke patients, and their specific characteristics were obvious. The main syndromes were wind phlegm pattern and hyperactivity of Gan yang pattern.

PD21-06 INFLAMMATORY MYOFIBROBLASTIC TUMOR OF THE GENITOURINARY TRACT: A SYSTEMATIC REVIEW

You have accessJournal of UrologyCME1 May 2022PD21-06 INFLAMMATORY MYOFIBROBLASTIC TUMOR OF THE GENITOURINARY TRACT: A SYSTEMATIC REVIEW Nikolas Moring, Daniel Swerdloff, Mahmut Akgul, Tipu Nazeer, and Badar Mian Nikolas MoringNikolas Moring More articles by this author , Daniel SwerdloffDaniel Swerdloff More articles by this author , Mahmut AkgulMahmut Akgul More articles by this author , Tipu NazeerTipu Nazeer More articles by this author , and Badar MianBadar Mian More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002559.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Inflammatory myofibroblastic tumor (IMT) is a rare tumor that has been described in nearly every organ system in the body. IMT generally lack metastatic potential, but these tumors often exhibit locally invasive and progressive disease which can mimic locally advanced malignancy. In the genitourinary tract (GU), IMT can manifest with signs and symptoms (mass, hematuria, pain) of common GU cancers such as renal cell carcinoma, testicular mass, or transitional cell carcinoma of the bladder. Due to its novel nature and lack of a singularly agreed upon definition, IMT prevalence and incidence are difficult to ascertain. We conducted a comprehensive systematic review with the aim to identify all reports of IMT in the GU tract, and describe the presenting symptoms, contemporary management, and pathologic features. METHODS: Systematic review using the following search terms were performed: “Inflammatory Pseudotumor” OR “Pseudosarcoma” OR “Inflammatory Pseudo-Tumor” OR “Inflammatory Myofibroblastic Tumor” AND “Urology” OR “Urologic” OR “Genitourinary”. Two reviewers performed independent initial screening of all abstracts. All potentially eligible articles underwent full text review and data extraction. The data for each GU organ site was analyzed separately. RESULTS: Of the 259 articles initially identified, and 101 were used in the systematic review. The articles consisted primarily of small case series and case reports, for a total of 110 cases of GU IMT. Pediatric IMT accounted for 9% of GU IMT cases. Most common presenting symptoms included pain, mass, hematuria and voiding symptoms. The most frequently involved sites and treatment included bladder (63 cases; 52% had radical/partial cystectomy), kidney (19; 93% had radical/partial nephrectomy), epididymis (6), urachus (6), ureter (5), prostate (4), testis (4), and spermatic cord (3). Anti-inflammatory, antibiotic and antineoplastic therapy used in 8% of cases was ineffective. Anaplastic lymphoma kinase expression, noted in half the cases, is a favorable prognostic indicator. Incomplete excision is associated with risk of recurrence while complete surgical excision provides excellent disease control with rare recurrence or metastatic transformation (<2%). CONCLUSIONS: IMT exhibit locally invasive, symptomatic and progressive phenotype that can affect all GU organs, especially bladder, kidney and scrotal contents. Clinical and radiologic features mimic GU malignancy. IMT require complete surgical excision since incomplete resection increases the risk of symptomatic recurrence. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e362 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Nikolas Moring More articles by this author Daniel Swerdloff More articles by this author Mahmut Akgul More articles by this author Tipu Nazeer More articles by this author Badar Mian More articles by this author Expand All Advertisement PDF DownloadLoading ...

Silent hypoxia is not an identifiable characteristic in patients with COVID-19 infection

BackgroundWe aimed to assess whether asymptomatic (“happy”) hypoxia was an identifiable physiological phenotype of COVID-19 acute respiratory distress syndrome (ARDS), and associated with need for ICU admission. MethodsWe performed an observational cohort study of all adult patients admitted with hypoxaemic respiratory failure to a large acute hospital Trust serving the East Midlands, UK. Patients with confirmed COVID-19 were compared to those without. Physiological response to hypoxaemia was modelled using a linear mixed effects model. ResultsOf 1,586 patients included, 75% tested positive for SARS-CoV-2. The ROX index was 2.08 min−1 lower (1.56–2.61, p < 0.001) in the COVID-19 cohort when adjusted for age and ethnicity, suggesting an enhanced respiratory response to hypoxia compared to the non-Covid-19 patients. There was substantial residual inter- and intra-patient variability in the respiratory response to hypoxaemia. 33% of the infected cohort required ICU, and of these 31% died within 60 days. ICU admission and mortality were both associated with an enhanced respiratory response for all degrees of hypoxaemia. ConclusionsPatients with COVID-19 display a more symptomatic phenotype in response to hypoxaemia than those with other causes of hypoxaemic respiratory failure, however individual patients exhibit a wide range of responses. As such although asymptomatic hypoxaemia may be a phenomenon in any individual patient with hypoxaemic respiratory failure, it is no more frequently observed in those with SARS-CoV-2 infection than without.

Primary hyperparathyroidism-related giant parathyroid adenoma (Review).

Primary hyperparathyroidism (PHPT), an endocrine condition caused by a parathyroid adenoma (PTA) in 80-85% of the cases, has shifted in the modern era to a mildly symptomatic phenotype due to the prompt recognition of hypercalcemia and to a minimally invasive surgical approach which has a curative potential. Clinical complications of PHTH are either related to high calcium or parathyroid hormone [also parathormone (PTH)] or both, while the originating tumor typically is small, without local mass effects. A distinct entity is represented by giant PTA (GPTA) which is considered at a weight of more than 3 (3.5) grams. The present article is a review of the literature involving practical points of non-syndromic PHPT-related GPTA. Most authors agree that pre-operatory calcium and PTH are higher in GPTA vs. non-GPTA. However, the clinical presentation of PHPT may be less severe, probably due to local mass effects that bring the patient to an early medical evaluation. Age distribution, sex ratio, rate of successful pre-operatory location do not differ from non-giant PTA. Hypovitaminosis D is more frequent in PTA of higher dimensions. Post-operative hypocalcemia, but not recurrent/persistent PHPT, is expected, even hungry bone disease. A higher rate of atypia is described although the tumor is mostly benign. Unusual presentations such as cystic transformation, initial diagnosis during pregnancy or auto-infarction have been reported. The ectopic localization of PTA presented in almost 15% of all cases may also be found in GPTA. What are the exact cutoffs for defining GPTA is still an open issue.

Association of Variants in FCGR2A, PTPN2, and GM-CSF with Cerebral Cavernous Malformation: Potential Biomarkers for a Symptomatic Disease.

Cerebral Cavernous Malformations (CCM) predispose patients to a lifetime risk of seizures and symptomatic hemorrhage. Only a small percentage of people affected will develop clinical symptoms and the molecular mechanisms underlying lesional activity remain unclear. We analyzed a panel of Single Nucleotide Polymorphisms (SNPs) in CCM patients. We looked for plasmatic inflammatory cytokines, checking for a pattern of plasma expression heterogeneity and any correlation with genetic variations identified with different CCM clinical phenotypes. This was a case-control study from a long-term follow-up cohort including 23 CCM patients, of which 16 were symptomatic, and 7 were asymptomatic. A 200-SNP panel was considered through next-generation sequencing and 18 different plasma molecules were assessed through a suspension array system. Fcγ receptor IIa rs1801274 (FCGR2A) and protein tyrosine phosphatase non-receptor type 2 rs72872125 PTPN2 were statistically different between groups. Patients who had a combination of the presence of FCGR2A and the absence of PTPN2 also had symptoms earlier in life. The combination of genetic polymorphisms and serum level of GM-CSF showed the best diagnostic biomarker to distinguish symptomatic patients as formulated: [0.296*(FCGR2A)] + [-0.788*(PTPN2)] + [-0.107*(GM-CSF)]. We have shown that SNPs in inflammation genes might be related to a symptomatic phenotype in CCM. We also demonstrated that a formula based on two of these polymorphisms (FCGR2A+ and PTPN2+) is possibly capable of predicting a symptomatic phenotype during a patient's lifetime.

Echocardiography Study of Hypertrophic Cardiomyopathy Phenotypes

Background: Hypertrophic cardiomyopathy (HCM) is a genetic disorder with a heterogeneous phenotype. Historically, only obstructive and nonobstructive forms have been described. Improvements in imaging techniques have led to elaborative description of various new phenotypes, although there are limited epidemiological data regarding these phenotypes from within our population. Aims and Objectives: •To identify HCM patients from a cohort of cardiomyopathy patients. •To describe their demographic profile and mode of presentation based on the presenting symptoms. •To subclassify the selected HCM population into various phenotypes based on echocardiography. Results: There were 233 patients of HCM in this study. The mean age of the patients was 53 ± 14.5 years with male preponderance (70%). Thirty-six percent patients were asymptomatic, 37% mildly symptomatic (in class I-II), and 27% severely symptomatic (in class III-IV). Patients were classified into six phenotypes consisting of five classically described phenotypes and one atypical phenotype. Reverse curvature phenotype was most prevalent (49%) and symptomatic phenotype with 19.3% having significant resting left ventricular outflow tract (LVOT) obstruction. Other phenotypes were 19% apical mid, 11% neutral, 6% sigmoid, and 4% atypical. Male: female ratio for reverse curvature phenotype was 3:1, apical (mid) phenotype 2.4:1, and both apical and neutral phenotypes 2:1. Sigmoid phenotype had female-to-male ratio of 2.5:1. Conclusion: HCM patients require phenotype specific approach for complete assessment. Transthoracic echocardiography with myocardial contrast plays a pivotal role in identifying morphological phenotypes, effects on cardiac remodeling and hemodynamics which consequently influence mode of presentation. Reverse curvature, apical mid, and sigmoid phenotypes are comparatively more symptomatic, have larger left atrial size and segment thickness compared to less symptomatic apical and neutral phenotypes. Symptom status of the patient seems to be dependent on age, septal contour, severity of LVOT obstruction, left atrial volume, and maximal segment thickness.

Clinical phenotypes of primary hyperparathyroidism in hospitalized patients who underwent parathyroidectomy.

ObjectiveThe aim of our study was to investigate the distribution of the PHPT clinical manifestations and biochemical features in patients who underwent parathyroidectomy.Materials and methodsMedical records of 449 patients from three Medical Centers (Saint-Petersburg, Russia), hospitalized during a period from 2011 to 2018, were reviewed. History and anthropometric data, laboratory results (iPTH, total and iCa, phosphorus, ALP, 24-h urinary calcium, 25(OH)D) and imaging data (ultrasonography, scintigraphy, CT/MRI scan, DXA) were analyzed.ResultsThree hundred ninety-four patients were included in the final analysis. Median age was 60 years with 94.2% being women. Symptomatic disease was evident in 222 (56.4%) patients, asymptomatic in 172 (43.6%). Skeletal involvement was more common for women, while frequency of other manifestations did not differ in both genders. There was no difference between symptomatic and asymptomatic patients in age. Serum iPTH level was higher in symptomatic patients (202.9 and 181.0 pg/mL, P = 0.022). Serum 25(OH)D level was estimated in few patients and negatively correlated with PTH (r = ¯0.294, P = 0.005), iCa (r = ¯0.268, P = 0.010) and total Ca (r = ¯0.284, P = 0.014) levels. Manifestations of CVD were observed in 67.7% of cases and affected equally both symptomatic and asymptomatic patients (70.7 and 63.4%, P = 0.076). Both age and BMI were higher in patients with CVD, whether or not they were symptomatic (62 and 53 years, P < 0.0001; 30.4 vs 26.0 kg/m2, P < 0.0001, respectively).ConclusionsThis experience illustrates that symptomatic phenotype is still the most common form of PHPT.

Echocardiographic parameters differentiating heart failure with preserved ejection fraction from asymptomatic left ventricular diastolic dysfunction.

(LVDD) either remains latent or manifests as heart failure with preserved ejection fraction (HFpEF). Little is known about echocardiographic parameters associated with symptomatic phenotype. To investigate echocardiographic parameters associated with symptomatic state in LVDD. Three hundred and thirty patients with definite diagnosis of LVDD (according to ASE/EACVI recommendations 2016) were included and divided into asymptomatic LVDD and HFpEF groups according to presence of dyspnea and brain natriuretic peptide levels. We excluded patients with left ventricular ejection fraction <50%, significant valvular heart disease, chronic lung disease, or renal dysfunction. Mean age was 61.2±8.3years; 71% were females. Both groups were matched regarding age, gender, comorbidities, and drug history. HFpEF group showed significantly larger BMI (P=.04), significantly higher IVS thickness (P<.001), LA diameter (P<.001), LA volume index (P=.004), E velocity (P=.001), TR jet velocity (P=.03), and average E/e' ratio (P<.001).On the contrary, lateral e' velocity was significantly lower in HFpEF group (P<.001). By regression analysis, lateral e' velocity was the best independent predictor of symptomatic state. Area under ROC curve of lateral e' velocity was 0.789 (0.667-0.911, P<.001) to predict symptomatic state in LVDD with the best cutoff value of ≤8.2cm/s (76% sensitivity and 79% specificity). Moreover, lateral e' velocity was significantly negatively correlated with NYHA class in HFpEF group. Reduced lateral e' velocity was associated with symptomatic state in LVDD. Moreover, it was significantly negatively correlated with NYHA class in HFpEF.

On the use of circulating desphospho-uncarboxylated matrix gla-protein to determine symptomatic atherosclerotic calcification phenotype

AbstractThe rupture of atherosclerotic plaques is the prerequisite for adverse cardiovascular events. Calcification morphology plays a critical role in plaque stability, therefore accurate calcification classification is essential for favourable patient management. Blood biomarkers may be a worthwhile approach to stratify patients based on calcification phenotype. Vitamin K-dependent Matrix γ-carboxyglutamate (Gla) protein (MGP) is a potent inhibitor of vascular calcification. Recent studies have demonstrated the potential utility of circulating non-functional MGP (dp-ucMGP) measurements to determine arterial stiffness and calcification levels. The objective of this study was to examine the relationship between circulating dp-ucMGP and calcification phenotype within symptomatic atherosclerotic lesions. Consenting patients undergoing standard endarterectomy procedures were recruited (n = 29). Fasting venous blood was collected preoperatively. Circulating plasma levels of dp-ucMGP were quantified using the inaKtif MGP (dp-ucMGP) iSYS kit. A bicinchoninic acid assay was used to standardise the total protein content present in each sample. High-resolution micro-CT imaging was conducted on the excised atherosclerotic specimens postoperatively. ImageJ post-processing was used to accurately quantify the calcification volume (≥ 130 Hounsfield Units) and determine the total number of calcified particles (3D objects counter plugin). Thirteen carotid (average age 71 years, 9 male) and fourteen peripheral lower limb (average age 65 years, 12 male) patients were examined. One patient had a carotid and a peripheral lower limb plaque (age 79, male). Peripheral lower limb specimens have larger volumes of calcification and higher numbers of calcified particles than carotid samples (472 ± 310 vs 85 ± 113mm3, p &lt; 0.0005; 13919 ± 16034 vs 3476 ± 6208, p = 0.061.) While a higher dp-ucMGP value was noted in carotid than peripheral lower limb patients (214 ± 52 vs 169 ± 36pmol/L, p = 0.014) there was no correlation between circulating dp-ucMGP and calcification volume or number of calcified particles (rs = -0.329 and rs = 0.046). Previous research also found that peripheral lower limb lesions contain higher volumes of calcification than carotid lesions. There is currently no published data on calcified particle comparisons. Patients with symptomatic carotid disease are assumed to have a degree of peripheral arterial disease, this could explain the higher levels of circulating dp-ucMGP in carotid patients. The current study did not examine the dietary patterns of individuals with regards to Vitamin K intake or analyse other areas of the vasculature for additional calcification. This may interfere with dp-ucMGP measurements. This study serves as a preliminary investigation into the potential of dp-ucMGP as a blood based biomarker to distinguish between symptomatic atherosclerotic calcification phenotypes.

The Network Degeneration Hypothesis: Spread of Neurodegenerative Patterns Along Neuronal Brain Networks.

The network degeneration hypothesis suggests that neurodegenerative disorders are characterized by the spread of molecular neuropathologic features along specific neuronal brain networks, leading to functional impairment of these networks. Interestingly, the symptomatic phenotype of