Variability In Disease Progression Research Articles

Forskolin-induced organoid swelling is associated with long-term cystic fibrosis disease progression.

RationaleCystic fibrosis (CF) is a monogenic life-shortening disease associated with highly variable individual disease progression which is difficult to predict. Here we assessed the association of forskolin-induced swelling (FIS) of patient-derived organoids with long-term CF disease progression in multiple organs and compared FIS with the golden standard biomarker sweat chloride concentration (SCC).MethodsWe retrieved 9-year longitudinal clinical data from the Dutch CF Registry of 173 people with mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Individual CFTR function was defined by FIS, measured as the relative size increase of intestinal organoids after stimulation with 0.8 µM forskolin, quantified as area under the curve (AUC). We used linear mixed-effect models and multivariable logistic regression to estimate the association of FIS with long-term forced expiratory volume in 1 s % predicted (FEV1pp) decline and development of pancreatic insufficiency, CF-related liver disease and diabetes. Within these models, FIS was compared with SCC.ResultsFIS was strongly associated with longitudinal changes of lung function, with an estimated difference in annual FEV1pp decline of 0.32% (95% CI 0.11–0.54%; p=0.004) per 1000-point change in AUC. Moreover, increasing FIS levels were associated with lower odds of developing pancreatic insufficiency (adjusted OR 0.18, 95% CI 0.07–0.46; p<0.001), CF-related liver disease (adjusted OR 0.18, 95% CI 0.06–0.54; p=0.002) and diabetes (adjusted OR 0.34, 95% CI 0.12–0.97; p=0.044). These associations were absent for SCC.ConclusionThis study exemplifies the prognostic value of a patient-derived organoid-based biomarker within a clinical setting, which is especially important for people carrying rare CFTR mutations with unclear clinical consequences.

Study of Clinical Profile and Comparison of Various Dimensions of Chronic Otitis Media among the Adult and Paediatric Population from Rural Area

Background: The term Chronic Suppurative Otitis Media (CSOM) is characterized as "chronic middle ear and mastoid cavity infection, which occurs through tympanic membrane perforation with recurrent ear discharge or otorrhoea . Though there are many similarities between adult and pediatric CSOM in terms of disease progression and pathological changes, there are certain notable differences stemming from temporal bone anatomy and extent of pneumatization, the immaturity of Eustachian Tube in terms of its function and variable progression of disease. Pediatric temporal bone being more pneumatized makes the disease to spread more extensively. Childhood cholesteatoma has much greater rates of residual and recurrence disease than seen in adults. This study is aimed to compare various dimensions of CSOM among the paediatric and adult age group in rural population.&#x0D; Methods: This cross-sectional comparative study is scheduled from November 2020 to November 2023 in ENT Department of AVBRH, Wardha. Total 50 patients with chronic Otitis Media in the paediatric and adult age group will be enrolled. Baseline investigations will be performed for all patients and compared.&#x0D; Expected Results: Clinical profile and behavior of chronic otitis media in adult and paediatric population in rural areas will be outlined, emphasizing middle ear changes, grade and extent of retraction pockets and cholesteatoma respectively. Pneumatization of the temporal bone and audiological status will be reported.&#x0D; Conclusion: Differentiating characteristics of chronic otitis media in adult and paediatric population with specified features will be concluded.

Burden of cystic fibrosis in children

BackgroundCystic fibrosis (CF) is a genetic, multisystemic, progressive and life-shortening disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Different genotypes have been linked to variations in...

A screening tool to identify risk for bronchiectasis progression in children with cystic fibrosis.

BackgroundThe marked heterogeneity in cystic fibrosis (CF) disease complicates the selection of those most likely to benefit from existing or emergent treatments.ObjectiveWe aimed to predict the progression of bronchiectasis in preschool children with CF.MethodsUsing data collected up to 3 years of age, in the Australian Respiratory Early Surveillance Team for CF cohort study, clinical information, chest computed tomography (CT) scores, and biomarkers from bronchoalveolar lavage were assessed in a multivariable linear regression model as predictors for CT bronchiectasis at age 5–6.ResultsFollow‐up at 5–6 years was available in 171 children. Bronchiectasis prevalence at 5–6 was 134/171 (78%) and median bronchiectasis score was 3 (range 0–12). The internally validated multivariate model retained eight independent predictors accounting for 37% (adjusted R 2) of the variance in bronchiectasis score. The strongest predictors of future bronchiectasis were: pancreatic insufficiency, repeated intravenous treatment courses, recurrent lower respiratory infections in the first 3 years of life, and lower airway inflammation. Dichotomizing the resulting prediction score at a bronchiectasis score of above the median resulted in a diagnostic odds ratio of 13 (95% confidence interval [CI], 6.3–27) with positive and negative predictive values of 80% (95% CI, 72%–86%) and 77% (95% CI, 69%–83%), respectively.ConclusionEarly assessment of bronchiectasis risk in children with CF is feasible with reasonable precision at a group level, which can assist in high‐risk patient selection for interventional trials. The unexplained variability in disease progression at individual patient levels remains high, limiting the use of this model as a clinical prediction tool.

P64.02 EMERGE 402 Phase 4 Observational Study: Safety and Outcomes in Patients With SCLC Receiving Treatment With Lurbinectedin

Lurbinectedin, a selective inhibitor of oncogenic transcription, was approved on June 15, 2020 by the US Food and Drug Administration for the treatment of adult patients with metastatic small-cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy; accelerated approval was based on the overall response rate (ORR; 35.2%) and duration of response (5.3 months) observed in a phase 2 clinical trial (NCT02454972). This trial, however, included a limited number of patients with metastatic SCLC who progressed on first-line platinum-based chemotherapy in combination with immunotherapy, which has since become standard of care. Thus, it is important to understand the effectiveness of lurbinectedin in patients with first-line immunotherapy exposure among a broader population with variable disease state and progression, and sensitivity to various treatments, as well as to collect data on health-related quality of life (HRQOL). Accordingly, the EMERGE 402 study will assess the effectiveness, safety, and HRQOL with lurbinectedin in a real-world setting among patients with SCLC who progressed on or after prior platinum-containing chemotherapy, with or without immunotherapy. EMERGE 402 is a prospective, observational, multicenter, phase 4 trial with a target enrollment of 300 patients with SCLC who have previously received ≥1 line of a platinum-based chemotherapy regimen at approximately 50 community- and academic-based centers throughout the United States. After a physician has prescribed lurbinectedin (in line with US prescribing information: 3.2 mg/m2 by intravenous infusion over 60 minutes every 21 days), the patient may be assessed for enrollment in the study. Data will be collected at baseline and during the normal course of patient care from first infusion until death, withdrawal of consent, loss to follow-up, or until 24 months has elapsed, whichever occurs first. An ad hoc analysis is planned after the first 120 patients have been followed for ≥6 months after initial lurbinectedin infusion. Primary and secondary endpoints are listed in the Table. Additional analyses will be performed for key subgroups of interest: patients receiving prior immunotherapy (including specific immune checkpoint inhibitors); chemotherapy-free intervals of >180, >90, <90, and <30 days before lurbinectedin treatment; brain metastasis (baseline and progression); limited- versus extensive-stage disease at initial diagnosis; use of granulocyte colony-stimulating factor as prophylaxis (primary versus secondary and number of administrations); ages ≥65 versus <65 years; and current therapies, including lurbinectedin monotherapy, lurbinectedin in combination with other anti-cancer agents, line of lurbinectedin treatment, and lurbinectedin treatment through progression.TablePrimary and Secondary Objectives and Endpoint Assessments in EMERGE 402Primary objective• Assess effectiveness of lurbinectedin monotherapy by ORR (CR or PR) as assessed by the investigator according to the RECIST v.1.1 in the study populationSecondary objectives• Assess other effectiveness measures (OS, PFS, DoR, and DCR) of lurbinectedin monotherapy in the study population • Assess patterns of lurbinectedin utilization (dose and number of lurbinectedin cycles, and previous, concomitant, and subsequent treatments) in the study population • Assess safety and tolerability (SAE and AESI) of lurbinectedin monotherapy in the study population • Assess HRQOL with lurbinectedin monotherapy in the study population using PRO questionnaires (EORTC-QLQ-C30 and EORTC-QLQ-LC13) • Assess time to confirmed response (CR or PR) with lurbinectedin monotherapy in the study population • Assess effectiveness, safety, and HRQOL with lurbinectedin monotherapy in the second-line setting • Assess effectiveness (OS, PFS, ORR, DoR, and DCR) and safety in other subgroups of interestORR, overall response rate; CR, complete response; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; OS, overall survival; PFS, progression-free survival; DoR, duration of response; DCR, disease control rate; SAE, serious adverse event; AESI, adverse event of special interest; HRQOL, health-related quality of life; PRO, patient-reported outcomes; EORTC-QLQ, European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire. Open table in a new tab ORR, overall response rate; CR, complete response; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; OS, overall survival; PFS, progression-free survival; DoR, duration of response; DCR, disease control rate; SAE, serious adverse event; AESI, adverse event of special interest; HRQOL, health-related quality of life; PRO, patient-reported outcomes; EORTC-QLQ, European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire. ▪▪▪ ▪▪▪

ASXL1 and STAG2 are common mutations in GATA2 deficiency patients with bone marrow disease and myelodysplastic syndrome

AbstractPatients with GATA2 deficiencyharbor de novo or inherited germline mutations in the GATA2 transcription factor gene, predisposing them to myeloid malignancies. There is considerable variation in disease progression, even among family members with the same mutation in GATA2. We investigated somatic mutations in 106 patients with GATA2 deficiency to identify acquired mutations that are associated with myeloid malignancies. Myelodysplastic syndrome (MDS) was the most common diagnosis (∼44%), followed by GATA2 bone marrow immunodeficiency disorder (G2BMID; ∼37%). Thirteen percent of the cohort had GATA2 mutations but displayed no disease manifestations. There were no correlations between age or sex with disease progression or survival. Cytogenetic analyses showed a high incidence of abnormalities (∼43%), notably trisomy 8 (∼23%) and monosomy 7 (∼12%), but the changes did not correlate with lower survival. Somatic mutations in ASXL1 and STAG2 were detected in ∼25% of patients, although the mutations were rarely concomitant. Mutations in DNMT3A were found in ∼10% of patients. These somatic mutations were found similarly in G2BMID and MDS, suggesting clonal hematopoiesis in early stages of disease, before the onset of MDS. ASXL1 mutations conferred a lower survival probability and were more prevalent in female patients. STAG2 mutations also conferred a lower survival probability, but did not show a statistically significant sex bias. There was a conspicuous absence of many commonly mutated genes associated with myeloid malignancies, including TET2, IDH1/2, and the splicing factor genes. Notably, somatic mutations in chromatin-related genes and cohesin genes characterized disease progression in GATA2 deficiency.

Leukodystrophies in Children: Diagnosis, Care, and Treatment.

Leukodystrophies are a group of genetically determined disorders that affect development or maintenance of central nervous system myelin. Leukodystrophies have an incidence of at least 1 in 4700 live births and significant morbidity and elevated risk of early death. This report includes a discussion of the types of leukodystrophies; their prevalence, clinical presentation, symptoms, and diagnosis; and current and future treatments. Leukodystrophies can present at any age from infancy to adulthood, with variability in disease progression and clinical presentation, ranging from developmental delay to seizures to spasticity. Diagnosis is based on a combination of history, examination, and radiologic and laboratory findings, including genetic testing. Although there are few cures, there are significant opportunities for care and improvements in patient well-being. Rapid advances in imaging and diagnosis, the emergence of and requirement for timely treatments, and the addition of leukodystrophy screening to newborn screening, make an understanding of the leukodystrophies necessary for pediatricians and other care providers for children.

Childhood Hypertrophic Cardiomyopathy: A Disease of the Cardiac Sarcomere.

Hypertrophic cardiomyopathy is the second most common cause of cardiomyopathy presenting during childhood and whilst its underlying aetiology is variable, the majority of disease is caused by sarcomeric protein gene variants. Sarcomeric disease can present at any age with highly variable disease phenotype, progression and outcomes. The majority have good childhood-outcomes with reported 5-year survival rates above 80%. However, childhood onset disease is associated with considerable life-long morbidity and mortality, including a higher SCD rate during childhood than seen in adults. Management is currently focused on relieving symptoms and preventing disease-related complications, but the possibility of future disease-modifying therapies offers an exciting opportunity to modulate disease expression and outcomes in these young patients.

Fluctuating biomarkers in primary sclerosing cholangitis: A longitudinal comparison of alkaline phosphatase, liver stiffness, and ELF

Background & AimsPrimary sclerosing cholangitis (PSC) is a progressive liver disease characterised by fluctuating liver biochemistries and highly variable disease progression. The Enhanced Liver Fibrosis (ELF®) test and liver stiffness measurements (LSMs) reflect fibrosis and predict clinical outcomes in PSC; however, longitudinal assessments are missing. We aimed to characterise the systematic change in ELF and LSM over time in a prospective cohort of patients with PSC, along with their longitudinal relationship to alkaline phosphatase (ALP) and bilirubin.MethodsWe included 113 non-transplant PSC patients (86 males [76.1%]; mean age 43.3 ± 15.7 years) with annual study visits between 2013 and 2019 at 2 Norwegian centres. ELF test, LSM, clinical data, liver biochemistries, and revised Mayo risk score were measured. We used linear mixed-effects models to estimate change over time, intraclass correlations (ICCs), and their relationship with ALP and bilirubin.ResultsAt baseline, the median (range) ELF test was 9.3 (7.5–12.9) and median LSM 1.26 m/s (0.66–3.04 m/s). ELF and LSM increased over time (0.09 point/year, 95% CI [0.03, 0.15], p = 0.005, vs. 0.12 point/year, 95% CI [0.03, 0.21], p = 0.009). Between-patient effects explained 78% of ELF variation (ICC 0.78) and 56% of LSM variation (ICC 0.56). ALP also increased and showed the highest ICC (0.86).ConclusionsELF and LSM increased over a 5-year period. Longitudinal analyses demonstrated differences regarding within- and between-patient effects, suggesting that the ELF test may have superior reliability for risk stratification compared with LSM in PSC.Lay summaryPrimary sclerosing cholangitis (PSC) is characterised by substantial disease variability between patients and fluctuating liver biochemistries. Hence, new biomarkers are needed to identify individuals with an increased risk of developing end-stage liver disease. We explore the change over time of 2 putative prognostic biomarkers in PSC, the serum Enhanced Liver Fibrosis (ELF®) test and LSMs by ultrasound, demonstrating differences that may reflect differing abilities to discriminate risk.

Update on pain in arthritis.

Osteoarthritis is a degenerative joint disease that features pain as a hallmark symptom. This review summarises progress and obstacles in our understanding of pain mechanisms in arthritis. Pain phenotypes in osteoarthritis are poorly characterized in clinical studies and animal studies are largely carti-centric. Different animal models incur variable disease progression patterns and activation of distinct pain pathways, but studies reporting both structural and pain outcomes permit better translational insights. In patients, classification of osteoarthritis disease severity is only based on structural integrity of the joint, but pain outcomes do not consistently correlate with joint damage. The complexity of this relationship underlines the need for pain detection in criteria for osteoarthritis classification and patient-reported outcome measures. Variable inflammatory and neuropathic components and spatiotemporal evolution underlie the heterogeneity of osteoarthritis pain phenotypes, which must be considered to adequately stratify patients. Revised classification of osteoarthritis at different stages encompassing both structural and pain outcomes would significantly improve detection and diagnosis at both early and late stages of disease. These are necessary advancements in the field that would also improve trial design and provide better understanding of basic mechanisms of disease progression and pain in osteoarthritis.

Predictors of sinonasal disease onset, progression, and severity in pediatric cystic fibrosis patients

PurposePediatric cystic fibrosis (CF) patients have a variable onset, severity, and progression of sinonasal disease. The objective of this study was to identify genotypic and phenotypic factors associated with CF that are predictive of sinonasal disease, recurrent nasal polyposis, and failure to respond to standard treatment. MethodsA retrospective case series was conducted of 30 pediatric patients with CF chronic rhinosinusitis with and without polyps. Patient specific mutations were divided by class and categorized into high risk (Class I-III) and low risk (Class IV-V). Severity of pulmonary and pancreatic manifestations of CF, number of sinus surgeries, nasal polyposis and recurrence, age at presentation to Otolaryngology, and Pediatric Sinonasal Symptom Survey (SN-5)/Sinonasal Outcome Test (SNOT-22) scores were examined. Results27/30 patients (90%) had high risk mutations (Class I-III). 21/30 (70.0%) patients had nasal polyposis and 10/30 (33.3%) had recurrent nasal polyposis. Dependence on pancreatic enzymes (23/27, 85.2% vs 0/3, 0.0%, p = 0.009) and worse forced expiratory volumes (FEV1%) (mean 79, SD 15 vs mean 105, SD 12, p = 0.009) were more common in patients with high risk mutations. Insulin-dependence was more common in those with recurrent polyposis (5/10, 50% vs 2/20, 10%, p = 0.026). There was no statistical difference in ages at presentation, first polyps, or sinus surgery, or in polyposis presence, recurrence, or extent of sinus surgery based on high risk vs. low risk classification. ConclusionCF-related diabetes was associated with nasal polyposis recurrence. Patients with more severe extra-pulmonary manifestations of CF may also be at increased risk of sinonasal disease.

An unusual cause of "reverse batwing" sign.

An unusual cause of "reverse batwing" sign.

Recent Advances in Integrative Multi-Omics Research in Breast and Ovarian Cancer.

The underlying molecular heterogeneity of cancer is responsible for the dynamic clinical landscape of this disease. The combination of genomic and proteomic alterations, including both inherited and acquired mutations, promotes tumor diversity and accounts for variable disease progression, therapeutic response, and clinical outcome. Recent advances in high-throughput proteogenomic profiling of tumor samples have resulted in the identification of novel oncogenic drivers, tumor suppressors, and signaling networks; biomarkers for the prediction of drug sensitivity and disease progression; and have contributed to the development of novel and more effective treatment strategies. In this review, we will focus on the impact of historical and recent advances in single platform and integrative proteogenomic studies in breast and ovarian cancer, which constitute two of the most lethal forms of cancer for women, and discuss the molecular similarities of these diseases, the impact of these findings on our understanding of tumor biology as well as the clinical applicability of these discoveries.

The Sclerosing Cholangitis Outcomes in Pediatrics (SCOPE) Index: A Prognostic Tool for Children.

Disease progression in children with primary sclerosing cholangitis (PSC) is variable. Prognostic and risk-stratification tools exist for adult-onset PSC, but not for children. We aimed to create a tool that accounts for the biochemical and phenotypic features and early disease stage of pediatric PSC. We used retrospective data from the Pediatric PSC Consortium. The training cohort contained 1,012 patients from 40 centers. We generated a multivariate risk index (Sclerosing Cholangitis Outcomes in Pediatrics [SCOPE] index) that contained total bilirubin, albumin, platelet count, gamma glutamyltransferase, and cholangiography to predict a primary outcome of liver transplantation or death (TD) and a broader secondary outcome that included portal hypertensive, biliary, and cancer complications termed hepatobiliary complications (HBCs). The model stratified patients as low, medium, or high risk based on progression to TD at rates of <1%, 3%, and 9% annually and to HBCs at rates of 2%, 6%, and 13% annually, respectively (P<0.001). C-statistics to discriminate outcomes at 1 and 5years were 0.95 and 0.82 for TD and 0.80 and 0.76 for HBCs, respectively. Baseline hepatic fibrosis stage was worse with increasing risk score, with extensive fibrosis in 8% of the lowest versus 100% with the highest risk index (P<0.001). The model was validated in 240 children from 11 additional centers and performed well. The SCOPE index is a pediatric-specific prognostic tool for PSC. It uses routinely obtained, objective data to predict a complicated clinical course. It correlates strongly with biopsy-proven liver fibrosis. SCOPE can be used with families for shared decision making on clinical care based on a patient's individual risk, and to account for variable disease progression when designing future clinical trials.

TGF344‐AD rats exhibit cognitive reserve despite continual Aβ and tau accumulation

AbstractBackgroundPatient to patient variability in Alzheimer’s disease progression complicates treatment efficacy. Furthermore, the presence of Aβ pathology does not always indicate cognitive impairments. Epidemiological evidence of cognitive reserve suggests some individuals exhibit enhanced neuronal and behavioural resilience, protecting against neurodegeneration and cognitive decline. However, Alzheimer’s disease models typically exhibit a correlation between accumulation of pathology and behavioural impairments, making cognitive reserve difficult to investigate preclinically.MethodTgF344‐AD rats recapitulate the amyloid cascade with a long‐term accumulation of Aβ and tau pathology leading to significant neurodegeneration and behavioural impairments. TgF344‐AD rats were assessed for cognitive and neuropathological alterations compared to age‐matched non‐transgenic littermates, across disease progression at 4, 6, 9, 12 and 15 months of age. Latency to escape and complexity of search strategies utilized in the Barnes maze spatial and reversal phases were assessed to determine learning, long‐term memory, and executive function. Neuropathological assessment included GABAergic and total neuronal counts, and quantification of Aβ and tau pathology.ResultTgF344‐AD rats demonstrate deficits in spatial memory and executive function beginning at 6 months which are not exacerbated at 9 or 12 months, but are at 15 months of age. GABAergic and total neuronal counts in the hippocampus and entorhinal cortex of TgF344‐AD rats exhibit a similar trend, with deficits not progressing between 9 and 12 months of age. Conversely, Aβ and tau pathology accumulate continually across disease progression. Non‐transgenic rats exhibit slight, yet consistent age‐related decline in cognitive and neuronal measures.ConclusionDisease‐bearing TgF344‐AD rats exhibit cognitive reserve before robust cognitive decline at 15 months, despite consistent increases in Aβ and tau deposition. Maintenance, and in certain hippocampal subregions a recovery, of neuronal loss at 12 months support this observation, and suggest the involvement of compensatory mechanisms such as hippocampal neurogenesis. Understanding the mechanisms underlying cognitive reserve in Alzheimer’s disease will help explain patient variability in disease progression and elucidate novel regenerative therapeutic targets.

Association of genetic mutations and loss of ambulation in childhood-onset dystrophinopathy.

Quantifying associations between genetic mutations and loss of ambulation (LoA) among males diagnosed with childhood-onset dystrophinopathy is important for understanding variation in disease progression and may be useful in clinical trial design. Genetic and clinical data from the Muscular Dystrophy Surveillance, Tracking, and Research Network for 358 males born and diagnosed from 1982 to 2011 were analyzed. LoA was defined as the age at which independent ambulation ceased. Genetic mutations were defined by overall type (deletion/duplication/point mutation) and among deletions, those amenable to exon-skipping therapy (exons 8, 20, 44-46, 51-53) and another group. Cox proportional hazards regression modeling was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Mutation type did not predict time to LoA. Controlling for corticosteroids, Exons 8 (HR = 0.22; 95% CI = 0.08, 0.63) and 44 (HR = 0.30; 95% CI = 0.12, 0.78) were associated with delayed LoA compared to other exon deletions. Delayed LoA in males with mutations amenable to exon-skipping therapy is consistent with previous studies. These findings suggest that clinical trials including exon 8 and 44 skippable males should consider mutation information prior to randomization.

SCN5A gene variants as potential markers of the progression of chronic chagasic cardiac alterations.

Host genetic factors have been proposed as determinants of the variable progression of Chagas disease (ChD). Two polymorphisms, H558R and A572D, of the voltage-gated sodium channel α-subunit SCN5A gene were studied in chagasic patients in order to determine their contribution to the susceptibility to the development and/or to the progression of the cardiovascular disease. A total of 104 patients were classified as seronegative or seropositive for Trypanosoma cruzi antibodies. Clinical evaluation, electrocardiograms (ECG) and echocardiograms (Echo) were performed to detect any conduction and/or structural alteration. Patients were classified into: G1: without ECG and/or Echo alterations, G2: with ECG alterations and G3: with ECG and Echo alterations. H558R and A572D polymorphisms were detected by PCR. Cardiac alterations were more frequent in G2+G3 seropositive patients. For H558R polymorphism, the C allele was significantly increased in seropositive G2+G3 patients (P=0.049. OR=2.08; 95% CI=1.12-4.33). When comparing the disease cardiac progression (G2 vs G3), the genotypes from the H558R polymorphism were associated to more intense cardiac alterations (P=0.018). For A572D polymorphism, no associations were found. The results suggest a possible involvement of SCN5A polymorphisms in the susceptibility to chronic ChD and the disease progression, contributing to the elucidation of the molecular mechanism underlying this complex myocardiopathy. In this regard, this is the first work that studies this gene in the context of chagasic cardiomyopathy.

Experimental model of congestive heart failure induced by transverse aortic constriction in BALB/c mice

IntroductionMurine transverse aortic constriction (TAC) is a frequently used model of pressure overload-induced left ventricular (LV) remodeling. However, there is considerable variability in disease progression to overt heart failure (HF) development in the most commonly used strain of mice (i.e., C57BL/6J). Studies have shown that C57BL/6J mice are more resistant than BALB/c mice to congestive HF development following myocardial infarction or angiotensin II-induced hypertension. Therefore, we tested the hypothesis that BALB/c mice may be a better research model to study TAC-induced progressive HF. MethodsFollowing sham or TAC surgery in both C57BL/6J (n = 29) and BALB/c (n = 32) mice, we evaluated cardiac dimensions and function by echocardiography at 2, 4, 8, and 12 weeks and monitored survival throughout the study. In a separate cohort of BALB/c mice, we repeated the study in the presence of the angiotensin converting enzyme inhibitor enalapril or a vehicle initiated 2 weeks post-TAC and administered for 6 weeks. At the end of the studies, we assessed the heart weight, lung weight, and plasma brain natriuretic peptide (BNP) concentration. ResultsFollowing comparable TAC, both C57BL/6J and BALB/c mice showed significant LV remodeling compared with the sham control mice. BALB/c mice progressively developed systolic dysfunction, LV dilation, lung congestion, and significant mortality, whereas C57BL/6J mice did not. In the separate cohort of BALB/c TAC mice, enalapril significantly reduced the heart weight, lung weight, and plasma BNP concentration and improved survival compared with the vehicle control. DiscussionBALB/c mice uniformly developed congestive HF post-TAC. Enalapril was effective in improving survival and reducing lung congestion in this model. The data suggest that BALB/c mice may be a better research tool than C57BL/6J mice to study TAC-induced disease progression to HF and to evaluate novel therapies for the treatment of chronic HF with reduced ejection fraction.

P0036THE EFFECT OF CKD ASSOCIATED SNPS ON THE PROGRESSION OF AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE

Abstract Background and Aims Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most frequent, inherited, cystic kidney disease. It is characterized by formation and growth of renal cysts obstructing normal tubules leading to a decline in renal function and eventually end stage renal disease (ESRD). The disease is mainly caused by mutations in either PKD1 or PKD2. Both the involved genes and the type of mutation have been shown to provide significant prognostic information in relation to the risk of early progression to ESRD. However, even within families, progression of disease varies widely between individuals with the same disease causing mutation. This variation might be explained by other genetic components. Previous studies have suggested genetic components affect the progression of Chronic Kidney Disease (CKD) and ESRD. To explain the variation in disease progression, not accounted for by the disease causing gene, 15 Single Nucleotide Variants (SNPs) associated to CKD and/or ESRD were chosen for further analysis. In addition, 3 SNPs within CFTR was included, since variants within this gene is known to affect the progression of ADPKD. Method A cohort of 120 Danish individuals suffering from ADPKD was sequenced using targeted Next Generation Sequencing (NGS). The targeted NGS panel included PKD1, PKD2, rs13538, rs12460876, rs17319721, rs10109414, rs653178, rs267734, rs1260326, rs347685, rs11959928, rs6420094, rs7805747, rs4744712, rs626277, rs881858, rs12917707, rs213950, rs213965, rs1042180. If no causative variant was identified using the NGS panel, Multiplex Ligation-dependent Probe Amplification was performed to identify larger deletions and duplications. In addition, clinical information was obtained to divide patients into two established or predicted progression groups; fast or slow. Results Based on clinical information we identified 39 patients with established or predicted fast progression and 81 with slow progression. The distribution of SNPs in the fast progression group was compared to the distribution within a European population. Out of 18 SNPs, one was significantly different distributed among the fast progressive ADPKD patients, rs13538 (p=0.01); however, in contrast to expected the frequency of the SNP was lower in the fast progression group compared to the European population. To examine if the shift could be associated to a specific disease causing mutation type, the distribution of each SNP within different mutation types were analysed. The mutations were divided into three groups; PKD1 truncating, PKD1 nontruncating and PKD2. A significant difference was observed in all three groups. Conclusion A single SNP associated to progression of CKD was observed to have a different distribution in the fast progressive ADPKD patients. The distribution differed for all analysed mutation types, thus no specific mutation type or gene could explain the shift in distribution alone. Hence, none of the analysed SNPs seem to influence the rate of progression in the analysed cohort of ADPKD patients.

Accurate Genomic Predictions for Chronic Wasting Disease in U.S. White-Tailed Deer.

The geographic expansion of chronic wasting disease (CWD) in U.S. white-tailed deer (Odocoileus virginianus) has been largely unabated by best management practices, diagnostic surveillance, and depopulation of positive herds. Using a custom Affymetrix Axiom single nucleotide polymorphism (SNP) array, we demonstrate that both differential susceptibility to CWD, and natural variation in disease progression, are moderately to highly heritable ( among farmed U.S. white-tailed deer, and that loci other than PRNP are involved. Genome-wide association analyses using 123,987 quality filtered SNPs for a geographically diverse cohort of 807 farmed U.S. white-tailed deer (n = 284 CWD positive; n = 523 CWD non-detect) confirmed the prion gene (PRNP; G96S) as a large-effect risk locus (P-value < 6.3E-11), as evidenced by the estimated proportion of phenotypic variance explained (PVE ≥ 0.05), but also demonstrated that more phenotypic variance was collectively explained by loci other than PRNP. Genomic best linear unbiased prediction (GBLUP; n = 123,987 SNPs) with k-fold cross validation (k = 3; k = 5) and random sampling (n = 50 iterations) for the same cohort of 807 farmed U.S. white-tailed deer produced mean genomic prediction accuracies ≥ 0.81; thereby providing the necessary foundation for exploring a genomically-estimated CWD eradication program.