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Germline pathogenic TP53 variants predispose individuals to a high lifetime risk of developing multiple cancers and are the hallmark feature of Li-Fraumeni syndrome (LFS). Our group has previously shown that LFS patients harbor shorter plasma cell-free DNA fragmentation; independent of cancer status. To understand the functional underpinning of cfDNA fragmentation in LFS, we conducted a fragmentomic analysis of 199 cfDNA samples from 82 TP53 mutation carriers and 30 healthy TP53-wildtype controls. We find that LFS individuals exhibit an increased prevalence of A/T nucleotides at fragment ends, dysregulated nucleosome positioning at p53 binding sites, and loci-specific changes in chromatin accessibility at development-associated transcription factor binding sites and at cancer-associated open chromatin regions. Machine learning classification resulted in robust differentiation between TP53 mutant versus wildtype cfDNA samples (AUC-ROC = 0.710-1.000) and intra-patient longitudinal analysis of ctDNA fragmentation signal enabled early cancer detection. These results suggest that cfDNA fragmentation may be a useful diagnostic tool in LFS patients and provides an important baseline for cancer early detection.
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Ácidos Nucleicos Libres de Células , Fragmentación del ADN , Mutación de Línea Germinal , Síndrome de Li-Fraumeni , Proteína p53 Supresora de Tumor , Humanos , Proteína p53 Supresora de Tumor/genética , Masculino , Femenino , Síndrome de Li-Fraumeni/genética , Ácidos Nucleicos Libres de Células/genética , Ácidos Nucleicos Libres de Células/sangre , Adulto , Adulto Joven , Persona de Mediana Edad , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/sangre , Adolescente , Neoplasias/genética , Neoplasias/patología , Cromatina/genética , Cromatina/metabolismo , Aprendizaje Automático , Heterocigoto , Niño , Nucleosomas/metabolismo , Nucleosomas/genética , Detección Precoz del CáncerRESUMEN
BACKGROUND: Right ventricular (RV) dysfunction is known to impact prognosis, but its determinants in coronary artery disease are poorly understood. Stress cardiac magnetic resonance (CMR) has been used to assess ischemia and infarction in relation to the left ventricle (LV); the impact of myocardial tissue properties on RV function is unknown. METHODS: Vasodilator stress CMR was performed in patients with known coronary artery disease at 7 sites between May 2005 and October 2018. Myocardial infarction was identified on late gadolinium enhancement-CMR, and infarct transmurality was graded on a per-segment basis. Ischemia was assessed on stress CMR based on first-pass perfusion and localized by using segment partitions corresponding to cine and late gadolinium enhancement analyses. RV function was evaluated by CMR-feature tracking for primary analysis with a global longitudinal strain threshold of 20% used to define impaired RV strain (RVIS); secondary functional analysis via RV ejection fraction was also performed. RESULTS: A total of 2604 patients were studied, among whom RVIS was present in 461 patients (18%). The presence and magnitude of RVIS were strongly associated with LV dysfunction, irrespective of whether measured by LV ejection fraction or wall motion score (P<0.001 for all). Regarding tissue substrate, regions of ischemic and dysfunctional myocardium (ie, hibernating myocardium) and infarct size were each independently associated with RVIS (both P<0.001). During follow-up (median, 4.62 [interquartile range, 2.15-7.67] years), 555 deaths (21%) occurred. Kaplan-Meier analysis for patients stratified by presence and magnitude of RV dysfunction by global longitudinal strain and RV ejection fraction each demonstrated strong prognostic utility for all-cause mortality (P<0.001). RVIS conferred increased mortality risk (hazard ratio, 1.35 [95% CI, 1.11-1.66]; P=0.003) even after controlling for LV function, infarction, and ischemia. CONCLUSIONS: RVIS in patients with known coronary artery disease is associated with potentially reversible LV processes, including LV functional impairment due to ischemic and predominantly viable myocardium, which confers increased mortality risk independent of LV function and tissue substrate.
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Enfermedad de la Arteria Coronaria , Imagen por Resonancia Cinemagnética , Imagen de Perfusión Miocárdica , Disfunción Ventricular Derecha , Función Ventricular Derecha , Humanos , Masculino , Femenino , Enfermedad de la Arteria Coronaria/fisiopatología , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Persona de Mediana Edad , Anciano , Imagen por Resonancia Cinemagnética/métodos , Disfunción Ventricular Derecha/fisiopatología , Disfunción Ventricular Derecha/etiología , Disfunción Ventricular Derecha/diagnóstico por imagen , Función Ventricular Derecha/fisiología , Imagen de Perfusión Miocárdica/métodos , Valor Predictivo de las Pruebas , Volumen Sistólico/fisiología , Función Ventricular Izquierda/fisiología , Pronóstico , Estados Unidos/epidemiologíaRESUMEN
OBJECTIVE: Whether or not women who harbor a germline pathogenic variant ('mutation') in the BRCA1 or BRCA2 genes are at elevated risk of developing endometrial cancer is yet to be determined. METHODS: We conducted a prospective analysis of 4959 BRCA mutation carriers with no prior history of cancer (except for breast or melanoma) and an intact uterus. RESULTS: After a mean of 6.7 years of follow-up there were 38 incident cases of endometrial cancer diagnosed; 30 among BRCA1 carriers and eight among BRCA2 carriers. The mean age at diagnosis was 58.4 years (range 46.8-76.1). The majority were of the endometrioid subtype (n = 16), followed by mixed endometroid and serous (n = 4), serous (n = 3) or clear cell (n = 1) (missing = 13). The cumulative incidence from age 40 to age 70 was 3.4% for BRCA1 carriers and was 1.6% for BRCA2 mutation carriers. Prior tamoxifen use was associated with a significant two-fold increased risk (HR = 2.24; 95% CI 1.10-4.55). There was no significant association between exogenous hormone use, oophorectomy, smoking or BMI at age 40 and risk (P ≥ 0.32). CONCLUSIONS: Compared to the general population, we observed higher rates of endometrial cancer among young BRCA1 mutation carriers; however, lifetime risks were similar. Women with prior tamoxifen exposure were at a significantly increased risk. These findings were based. on a small number of incident cases and require confirmation with additional follow-up of our aging cohort.
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Neoplasias Endometriales , Genes BRCA1 , Humanos , Femenino , Neoplasias Endometriales/genética , Neoplasias Endometriales/epidemiología , Persona de Mediana Edad , Incidencia , Anciano , Estudios Prospectivos , Adulto , Genes BRCA2 , Heterocigoto , Mutación de Línea Germinal , Tamoxifeno , Mutación , Predisposición Genética a la EnfermedadRESUMEN
BACKGROUND AND AIMS: Fully covered self-expandable metal stents (FCSEMSs) are widely used in benign upper gastrointestinal (GI) conditions, but stent migration remains a limitation. An over-the-scope clip (OTSC) device (Ovesco Endoscopy) for stent anchoring has been recently developed. The aim of this study was to evaluate the effect of OTSC fixation on SEMS migration rate. METHODS: A retrospective review of consecutive patients who underwent FCSEMS placement for benign upper GI conditions between 1/2011 and 10/2022 at 16 centers. The primary outcome was rate of stent migration. The secondary outcomes were clinical success and adverse events. RESULTS: A total of 311 (no fixation 122, OTSC 94, endoscopic suturing 95) patients underwent 316 stenting procedures. Compared to the no fixation (NF) group (n=49, 39%), the rate of stent migration was significantly lower in the OTSC (SF) (n=16, 17%, p=0.001) and endoscopic suturing (ES) group (n=23, 24%, p=0.01). The rate of stent migration was not different between the SF and ES groups (p=0.2). On multivariate analysis, SF (OR 0.34, CI 0.17-0.70, p<0.01) and ES (OR 0.46, CI 0.23-0.91, p=0.02) were independently associated with decreased risk of stent migration. Compared to the NF group (n=64, 52%), there was a higher rate of clinical success in the SF (n=64, 68%; p=0.03) and ES group (n=66, 69%; p = 0.02). There was no significant difference in the rate of adverse events between the three groups. CONCLUSION: Stent fixation using OTSC is safe and effective at preventing stent migration and may also result in improved clinical response.
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AIMS: The heterogeneous phenotype of hypertrophic cardiomyopathy (HCM) is still not fully understood. Clonal haematopoiesis (CH) is emerging as a cardiovascular risk factor potentially associated with adverse clinical events. The prevalence, phenotype and outcomes related to CH in HCM patients were evaluated. METHODS AND RESULTS: Patients with HCM and available biospecimens from the Peter Munk Cardiac Centre Cardiovascular Biobank were subjected to targeted sequencing for 35 myeloid genes associated with CH. CH prevalence, clinical characteristics, morphological phenotypes assessed by echocardiogram and cardiac magnetic resonance and outcomes were assessed. All patients were evaluated for a 71-plex cytokines/chemokines, troponin I and B-type natriuretic peptide analysis. Major adverse cardiovascular events (MACE) were defined as appropriate implantable cardioverter-defibrillator shock, stroke, cardiac arrest, orthotopic heart transplant and death. Among the 799 patients, CH was found in 183 (22.9%) HCM patients with sarcomeric germline mutations. HCM patients with CH were more symptomatic and with a higher burden of fibrosis than those without CH. CH was associated with MACE in those HCM patients with sarcomeric germline mutations (adjusted hazard ratio [HR] 6.89, 95% confidence interval [CI] 1.78-26.6; p = 0.005), with the highest risk among those that had DNMT3A, TET2 and ASXL1 mutations (adjusted HR 5.76, 95% CI 1.51-21.94; p = 0.010). Several cytokines (IL-1ra, IL-6, IL-17F, TGFα, CCL21, CCL1, CCL8, and CCL17), and troponin I were upregulated in gene-positive HCM patients with CH. CONCLUSIONS: These results indicate that CH in patients with HCM is associated with worse clinical outcomes. In the absence of CH, gene-positive patients with HCM have lower rates of MACE.
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OBJECTIVE: Endoscopic retrograde cholangiopancreatography (ERCP) may be unsuccessful in patients with duodenal stenosis or malignant ampullary infiltration. Endoscopic ultrasound-guided biliary drainage (EUS-BD) has been proposed as an alternative. We aimed to assess the efficacy and safety of EUS-BD for malignant distal bile duct obstruction using the newly introduced smaller caliber 6 or 8 mm cautery-enhanced lumen-apposing metal stent. METHODS: A multicenter retrospective study was performed on patients with unresectable malignant distal bile duct obstruction who underwent EUS-BD between 2021 and 2022 after unsuccessful ERCP. RESULTS: Thirty-two patients were included [7 (53.13%) males], with a mean age of 72.2 ± 12.5 years. The technical success rate was 100%. Altered anatomy was present in 2 (6.25%). The indication for drainage was biliary obstruction from pancreatic cancer in 26 patients (84.5%), cholangiocarcinoma in 3 (9.4%), and ampullary mass in 3 (9.4%). The procedure was performed mostly in an outpatient setting (n = 19, 59.38%). The clinical success rate was 92.3% [bilirubin: 14.1 (SD: 8.9) preprocedure vs 4.9 (SD: 1.1) postprocedure; P = 0.0001]. There was one early adverse event of a perforation, which was closed endoscopically and drained percutaneously. Delayed adverse events included food impaction of the stent (n = 1), which was resolved with a repeat procedure and insertion of a double pigtail stent. CONCLUSION: This study demonstrates the feasibility of EUS-BD drainage using smaller caliber 6 or 8 mm lumen-apposing metal stent to relieve malignant distal bile duct obstruction in patients who fail conventional ERCP.
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Advances in our understanding of the genetic landscape of hereditary breast and ovarian cancer (HBOC) have led to the clinical adoption of multi-gene panel testing. Panel testing introduces new sources of genetic uncertainty secondary to the inclusion of moderate- and low-penetrance genes, as well as the increased likelihood of identifying a variant of uncertain significance (VUS). This cross-sectional study explored the post-test psychological functioning of women who underwent multi-gene panel testing for HBOC susceptibility genes. Two hundred and ninety-five women who underwent panel testing within the previous 2 years completed a study questionnaire to measure levels of cancer-related and genetic testing-related distress using the Impact of Events Scale (IES) and the Multidimensional Impact of Cancer Risk Assessment (MICRA), respectively. Multiple regression analyses were conducted to evaluate the relationship between genetic test results and levels of psychological distress captured by the IES and MICRA. In this cohort, a pathogenic variant (PV) was identified in 41 (14%) of participants, and 77 (26%) participants were found to have a VUS. In the multi-variate model, higher mean levels of genetic testing-related distress were observed in individuals with a PV (p < 0.001) or a VUS (p = 0.007) compared to those with a negative result. Furthermore, participants with a PV in a moderate-penetrance gene were found to have higher levels of genetic testing-related distress compared to those with a PV in a high-risk gene (p = 0.03). Overall, participants were highly satisfied with their genetic testing experience, with 92% of individuals reporting they would recommend testing to others. Our findings highlight differences in psychological outcomes based on both variant pathogenicity and gene penetrance, which contribute to our understanding of the impact of panel testing and sources of both cancer-related and genetic testing-related distress secondary to testing.
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KEY POINTS: Novel topical therapeutics require extensive pre-clinical testing to assess efficacy and safety. Antibiofilm or immunosuppressant agents can utilize ex vivo models to measure ciliotoxicity. Agents that are found to be effective and non-toxic ex vivo warrant further investigation in vivo.
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Valgus instability can occur after total knee arthroplasty (TKA) due to traumatic medial collateral ligament (MCL) injury, component malpositioning, or progressive ligamentous laxity. Although revision TKA with exchange of the polyethylene to a varus-valgus-constrained liner can reduce laxity due to MCL insufficiency, isolated liner exchange in the setting of collateral ligament insufficiency may lead to greater strain at the cement-bone or implant-cement interface and possibly a greater rate of aseptic loosening. Anatomic MCL reconstruction can be performed in conjunction with liner exchange to restore stability and reduce strain compared with liner exchange alone. The purpose of this Technical Note is to describe a technique for MCL reconstruction and liner exchange for treatment of valgus instability after TKA.
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Risk-stratified breast screening has been proposed as a strategy to overcome the limitations of age-based screening. A prospective cohort study was undertaken within the PERSPECTIVE I&I project, which will generate the first Canadian evidence on multifactorial breast cancer risk assessment in the population setting to inform the implementation of risk-stratified screening. Recruited females aged 40-69 unaffected by breast cancer, with a previous mammogram, underwent multifactorial breast cancer risk assessment. The adoption of multifactorial risk assessment, the effectiveness of methods for collecting risk factor information and the costs of risk assessment were examined. Associations between participant characteristics and study sites, as well as data collection methods, were assessed using logistic regression; all p-values are two-sided. Of the 4246 participants recruited, 88.4% completed a risk assessment, with 79.8%, 15.7% and 4.4% estimated at average, higher than average and high risk, respectively. The total per-participant cost for risk assessment was CAD 315. Participants who chose to provide risk factor information on paper/telephone (27.2%) vs. online were more likely to be older (p = 0.021), not born in Canada (p = 0.043), visible minorities (p = 0.01) and have a lower attained education (p < 0.0001) and perceived fair/poor health (p < 0.001). The 34.4% of participants requiring risk factor verification for missing/unusual values were more likely to be visible minorities (p = 0.009) and have a lower attained education (p ≤ 0.006). This study demonstrates the feasibility of risk assessment for risk-stratified screening at the population level. Implementation should incorporate an equity lens to ensure cancer-screening disparities are not widened.
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Objective: To investigate the features and outcomes of breast cancer in high-risk subgroups. Materials and Methods: REB approved an observational study of women diagnosed with breast cancer from 2010 to 2019. Three radiologists, using the BI-RADS lexicon, blindly reviewed mammogram and MRI screenings without a washout period. Consensus was reached with 2 additional reviewers. Inter-rater agreement was measured by Fleiss Kappa. Statistical analysis included Mann-Whitney U, Chi-square tests for cohort analysis, and Kaplan-Meier for survival rates, with a Cox model for comparative analysis using gene mutation as a reference. Results: The study included 140 high-risk women, finding 155 malignant lesions. Significant age differences noted: chest radiation therapy (median age 44, IQR: 37.0-46.2), gene mutation (median age 49, IQR: 39.8-58.0), and familial risk (median age 51, IQR: 44.5-56.0) (P = .007). Gene mutation carriers had smaller (P = .01), higher-grade tumours (P = .002), and more triple-negative ER- (P = .02), PR- (P = .002), and HER2- (P = .02) cases. MRI outperformed mammography in all subgroups. Substantial to near-perfect inter-rater agreement observed. Over 10 years, no deaths occurred in chest radiation group, with no significant survival difference between gene mutation and familial risk groups, HR = 0.93 (95% CI: 0.27, 3.26), P = .92. Conclusion: The study highlights the importance of age and specific tumour characteristics in identifying high-risk breast cancer subgroups. MRI is confirmed as an effective screening tool. Despite the aggressive nature of cancers in gene mutation carriers, early detection is crucial for survival outcomes. These insights, while necessitating further validation with larger studies, advocate for a move toward personalized medical care, strengthening the existing healthcare guidelines.
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Pathogenic variants in NOTCH1 are associated with non-syndromic congenital heart disease (CHD) and Adams-Oliver syndrome (AOS). The clinical presentation of individuals with damaging NOTCH1 variants is characterized by variable expressivity and incomplete penetrance; however, data on systematic phenotypic characterization are limited. We report the genotype and phenotype of a cohort of 33 individuals (20 females, 13 males; median age 23.4 years, range 2.5-68.3 years) from 11 families with causative NOTCH1 variants (9 inherited, 2 de novo; 9 novel), ascertained from a proband with CHD. We describe the cardiac and extracardiac anomalies identified in these 33 individuals, only four of whom met criteria for AOS. The most common CHD identified was tetralogy of Fallot, though various left- and right-sided lesions and septal defects were also present. Extracardiac anomalies identified include cutis aplasia (5/33), cutaneous vascular anomalies (7/33), vascular anomalies of the central nervous system (2/10), Poland anomaly (1/33), pulmonary hypertension (2/33), and structural brain anomalies (3/14). Identification of these findings in a cardiac proband cohort supports NOTCH1-associated CHD and NOTCH1-associated AOS lying on a phenotypic continuum. Our findings also support (1) Broad indications for NOTCH1 molecular testing (any familial CHD, simplex tetralogy of Fallot or hypoplastic left heart); (2) Cascade testing in all at-risk relatives; and (3) A thorough physical exam, in addition to cardiac, brain (structural and vascular), abdominal, and ophthalmologic imaging, in all gene-positive individuals. This information is important for guiding the medical management of these individuals, particularly given the high prevalence of NOTCH1 variants in the CHD population.
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Cardiopatías Congénitas , Linaje , Fenotipo , Receptor Notch1 , Humanos , Receptor Notch1/genética , Masculino , Femenino , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/patología , Adulto , Adolescente , Preescolar , Niño , Persona de Mediana Edad , Anciano , Mutación , Displasia Ectodérmica/genética , Displasia Ectodérmica/patología , Displasia Ectodérmica/diagnóstico , Deformidades Congénitas de las Extremidades/genética , Deformidades Congénitas de las Extremidades/patología , Deformidades Congénitas de las Extremidades/diagnóstico , Dermatosis del Cuero Cabelludo/congénitoRESUMEN
The virus severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, is the causative agent of the current COVID-19 pandemic. It possesses a large 30 kilobase (kb) genome that encodes structural, non-structural, and accessory proteins. Although not necessary to cause disease, these accessory proteins are known to influence viral replication and pathogenesis. Through the synthesis of novel infectious clones of SARS-CoV-2 that lack one or more of the accessory proteins of the virus, we have found that one of these accessory proteins, ORF8, is critical for the modulation of the host inflammatory response. Mice infected with a SARS-CoV-2 virus lacking ORF8 exhibit increased weight loss and exacerbated macrophage infiltration into the lungs. Additionally, infection of mice with recombinant SARS-CoV-2 viruses encoding ORF8 mutations found in variants of concern reveal that naturally occurring mutations in this protein influence disease severity. Our studies with a virus lacking this ORF8 protein and viruses possessing naturally occurring point mutations in this protein demonstrate that this protein impacts pathogenesis.
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COVID-19 , SARS-CoV-2 , Animales , SARS-CoV-2/genética , COVID-19/virología , COVID-19/inmunología , COVID-19/patología , COVID-19/genética , Ratones , Humanos , Progresión de la Enfermedad , Proteínas Virales/genética , Proteínas Virales/metabolismo , Pulmón/virología , Pulmón/patología , Replicación Viral , Neumonía/virología , Neumonía/patología , Chlorocebus aethiops , Mutación , Células Vero , FemeninoRESUMEN
Background and study aims Endoscopic retrograde cholangiopancreatography (ERCP) poses the risk of radiation exposure (RE) to patients and staff and increases the risk of adverse biological effects such as cataracts, sterility, and cancer. Newer fluoroscopy equipment (C-Arm) provides options to limit radiation in the form of lower radiation dose and frame rate or time-limited "pulsed" settings. However, the impact of lower settings on image quality has not been assessed, and no standard protocol exists for fluoroscopy settings used during ERCP. Patients and methods This was a single-center, double-blind, prospective randomized study of consecutive adult patients undergoing standard-of-care ERCP at a tertiary academic medical center. Patients were randomized into two groups: 1) standard-dose pulsed and 2) low-dose pulsed. Pulsed mode (8 fps) was defined as x-ray exposure either in the manufacturer standard-dose or low-dose settings limited to 3 seconds each time the foot-operated switch was depressed. Results Seventy-eight patients undergoing ERCP were enrolled and randomized. No difference in age, gender, or body mass index was found between the two groups. No significant difference in image quality was found between standard-dose and low-dose fluoroscopy P = 0.925). The low-dose group was exposed to significantly less radiation when compared with standard-dose P < 0.05). Fluoroscopy time (minutes) was similar in both groups (2.0 vs 1.9), further suggesting that group assignment had no impact on image quality or procedure time. Conclusions Low-dose pulsed fluoroscopy is a reliable method that substantially reduces radiation without compromising image quality or affecting procedure or fluoroscopy times. This underscores the need for standardization in ERCP fluoroscopy settings to limit radiation exposure.
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PURPOSE: Studies have shown an increased risk of epilepsy in patients with neurofibromatosis type 1 (NF1). However, most reports focus on the pediatric population. In this study, we describe the trajectory of patients with NF1 and epilepsy beyond childhood. METHODS: Patients with NF1 ≥18 years-old consecutively seen at a multidisciplinary neurofibromatosis clinic during a four-year period were prospectively enrolled and offered routine EEG, MRI, and genetic testing. The lifelong and point prevalence of epilepsy in patients with NF1 were calculated. Demographic, genetic, radiological, and clinical features found to be statistically associated with having received a diagnosis of epilepsy were incorporated into a logistic regression model. RESULTS: Among 113 patients with NF1 included in this study (median age at study inclusion: 33 years), the lifelong prevalence of epilepsy was 11% (CI95%=6-18%) and point prevalence 7% (CI95%= 3-13%). Most patients (73%) were diagnosed with epilepsy before the age of 18 and achieved seizure-freedom by adulthood. At study inclusion, three-quarters of patients with a diagnosis of epilepsy had been seizure-free for more than one year and a third had resolved epilepsy. A routine EEG with epileptiform discharges had a sensitivity of 25% (CI95%=3-65) and specificity of 99% (CI95%=93-100) for identifying adult patients with NF1 and unresolved epilepsy. A history of epilepsy was associated with having a low-grade glioma (OR: 38.2; CI95%=2.2-674.7; p<0.01), learning disability (OR: 5.7; CI95%=1.0-31.5; p<0.05), and no plexiform neurofibroma (OR: 0.05; CI95%=0.0-0.8; p=0.04). No single mutation type was associated with the development of epilepsy. CONCLUSIONS: In patients with NF1, although resolution of epilepsy over time was observed in many cases, the prevalence of epilepsy was higher among adults with NF1 than that reported in the general population. Epileptogenesis in NF1 likely requires the combination of multiple genetic and environmental factors and suggests involvement of a network that spreads beyond the borders of a well-defined parenchymal lesion.
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Electroencefalografía , Epilepsia , Neurofibromatosis 1 , Fenotipo , Humanos , Neurofibromatosis 1/genética , Neurofibromatosis 1/complicaciones , Neurofibromatosis 1/epidemiología , Epilepsia/genética , Epilepsia/epidemiología , Masculino , Femenino , Adulto , Prevalencia , Adulto Joven , Persona de Mediana Edad , Genotipo , Adolescente , Imagen por Resonancia Magnética , Estudios ProspectivosRESUMEN
BACKGROUND: Cardiovascular disease (CVD) remains a leading cause of death in people living with HIV. Myocardial fibrosis is well-described in HIV infection acquired in adulthood. We evaluate the burden of fibrosis by cardiac magnetic resonance in people with perinatal HIV infection. METHODS: Individuals with perinatally acquired HIV (pnHIV) diagnosed before 10 years-old and on antiretroviral treatment for ≥ 6 months were matched with uninfected controls. Patients with significant cardiometabolic co-morbidities and pregnancy were excluded. Diffuse fibrosis was assessed by cardiac magnetic resonance (CMR) with native T1 mapping for calculation of extracellular volume fraction (ECV). Viability was assessed with late gadolinium enhancement. The normality of fibrosis was assessed using the Komogrov-Smirnov test. Fibrosis between the groups was analyzed using a Mann-Whitney U test, as the data was not normally distributed. Statistical significance was defined as a p-valve < 0.05. RESULTS: Fourteen adults with pnHIV group and 26 controls (71% female and 86% Black race) were assessed. The average (± standard deviation) age in the study group was 29 (± 4.3) years-old. All pnHIV had been on ART for decades. Demographic data, CMR functional/volumetric data, and pre-contrast T1 mapping values were similar between groups. Diastolic function was normal in 50% of pnHIV patients and indeterminate in most of the remainder (42%). There was no statistically significant difference in ECV between groups; p = 0.24. CONCLUSION: Perinatally-acquired HIV was not associated with diffuse myocardial fibrosis. Larger prospective studies with serial examinations are needed to determine whether pnHIV patients develop abnormal structure or function more often than unaffected controls.
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Infecciones por VIH , Adulto , Embarazo , Humanos , Femenino , Adulto Joven , Niño , Masculino , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Medios de Contraste , Estudios Prospectivos , Gadolinio , FibrosisRESUMEN
Commercial pharmacogenetic testing panels capture a fraction of the genetic variation underlying medication metabolism and predisposition to adverse reactions. In this study we compared variation in six pharmacogenes detected by whole genome sequencing (WGS) to a targeted commercial panel in a cohort of 308 individuals with family history of pediatric heart disease. In 1% of the cohort, WGS identified rare variants that altered the interpretation of metabolizer status and would thus prevent potential errors in gene-based dosing.
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OBJECTIVE: The American Society of Clinical Oncology recommends all patients with high-grade serous ovarian carcinoma (HGSC) undergo germline genetic testing. Genetic consultation rates in Ontario, Canada, only reached 13.3% in 2011. In 2016, PARP inhibitor maintenance therapy became available in Ontario for BRCA-positive HGSC patients. Given expanding treatment options, we re-examined genetic consultation rates among HGSC patients. METHODS: This retrospective cohort study identified patients diagnosed with HGSC between 2012 and 2019 using population-based administrative data from Ontario. Genetics consultations were identified using Ontario Health Insurance Plan billing codes. Consultation rates over time were analyzed using Cochran-Armitage trend test and segmental regression analysis. Multivariable analysis identified factors associated with attending genetics consultation. RESULTS: This study included 4645 HGSC patients. The mean age was 64.2 years (±SD 12.3); 56.3% had stage 3-4 disease. Overall, approximately 35% attended genetics consultations. The genetic consultation rate per year increased significantly from 21.6% to 42.6% (P < 0.001). Shorter times between diagnosis and genetics consult were observed after PARP inhibitors became available (68.1 vs 34.1 weeks, P < 0.001). Patients treated at designated cancer centers (odds ratio [OR] 2.11, P < 0.001), diagnosed in later years (OR 1.33, P < 0.001), and from higher income groups (P < 0.05) were more likely to attend genetics consultation; older patients were less likely (OR 0.98, P < 0.001). After PARP inhibitors became available, consultation rates plateaued (P < 0.001). CONCLUSIONS: Between 2012 and 2019, genetic consultation rates improved significantly among HGSC patients; however, a large proportion of patients never attended consultation. Further exploration of barriers to care is warranted to improve consultation rates and ensure equitable access to care.
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Cistadenocarcinoma Seroso , Neoplasias Ováricas , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Derivación y Consulta , Humanos , Femenino , Persona de Mediana Edad , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Estudios Retrospectivos , Ontario , Anciano , Derivación y Consulta/estadística & datos numéricos , Cistadenocarcinoma Seroso/tratamiento farmacológico , Cistadenocarcinoma Seroso/genética , Pruebas Genéticas/estadística & datos numéricos , Adulto , Asesoramiento Genético/estadística & datos numéricosRESUMEN
BACKGROUND AND AIMS: Opioid-induced esophageal dysfunction (OIED) often presents as spastic esophageal disorders (SEDs) and esophagogastric junction outflow obstruction (EGJOO). The aim of this study was to evaluate and compare clinical outcomes of peroral endoscopic myotomy (POEM) for SEDs and EGJOO among opioid users and nonusers. METHODS: This propensity score (PS) matching study included consecutive opioid users and nonusers who underwent POEM for SEDs and EGJOO between January 2018 and September 2022. The following covariates were used for the PS calculation: age, sex, duration of symptoms, Eckardt score, type of motility disorder, and length of myotomy during POEM. Clinical response was defined as a post-POEM Eckardt score ≤3. RESULTS: A total of 277 consecutive patients underwent POEM during the study period. PS matching resulted in the selection of 64 pairs of patients strictly matched 1:1 (n = 128) with no statistically significant differences in demographic, baseline, or procedural characteristics or in the parameters considered for the PS between the 2 groups. Clinical response to POEM was significantly lower among opioid users (51 of 64 [79.7%]) versus nonusers (60 of 64 [93.8%]) (P = .03) at a median follow-up of 18 months. Among opioid users, higher opioid dose (>60 morphine milligram equivalents per day) was associated with a higher likelihood of failure to respond to POEM (odds ratio, 4.59; 95% confidence interval, 1.31-3.98; P = .02). CONCLUSIONS: Clinical response to POEM for SEDs and EGJOO is significantly lower among opioid users versus nonusers. There was a dose-relationship between opioids and response to POEM, with higher daily opioid usage associated with a higher likelihood of treatment failure.