Efficacy of Acoramidis on All-Cause Mortality and Cardiovascular Hospitalization in Transthyretin Amyloid Cardiomyopathy.

Background: Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underdiagnosed chronic disease associated with progressive heart failure that results in impaired quality of life, repeated hospitalizations, and premature death. Acoramidis is a selective, oral transthyretin stabilizer recently approved by the U.S.

Evaluation of Women with Peripartum or Dilated Cardiomyopathy and Their First-Degree Relatives: The DCM Precision Medicine Study.

Background: Peripartum cardiomyopathy (PPCM) presents substantial risk of maternal mortality, but underlying cause remains unsettled.

Methods: We compared the prevalence of dilated cardiomyopathy (DCM)-relevant genetic variants in 452 female patients (probands) of African and European ancestry (AA, EA) with PPCM or DCM who had been pregnant at least once. Pathogenic and likely pathogenic (P/LP) variants were identified in DCM-associated genes.

Arrhythmic Risk Stratification of Carriers of Filamin C Truncating Variants.

Importance: Filamin C truncating variants (FLNCtv) are a rare cause of cardiomyopathy with heterogeneous phenotypic presentations. Despite a high incidence of life-threatening ventricular arrhythmias and sudden cardiac death (SCD), reliable risk predictors to stratify carriers of FLNCtv are lacking.

Objective: To determine factors predictive of SCD/major ventricular arrhythmias (MVA) in carriers of FLNCtv.

Using technology to increase reach and optimize consent experience for a large-scale research program.

The consent process for research studies can be burdensome for potential participants due to complex information and lengthy consent forms. This pragmatic study aimed to improve the consent experience and evaluate its impact on participant decision making, study knowledge, and satisfaction with the In Our DNA SC program, a population-based genomic screening initiative. We compared two consent procedures: standard consent (SC) involving a PDF document and enhanced consent (EC) incorporating a pictograph and true or false questions.

Implementing Precision Medicine for Dilated Cardiomyopathy: Insights from The DCM Consortium.

Background: Clinical genetic evaluation of dilated cardiomyopathy (DCM) is implemented variably or not at all. Identifying needs and barriers to genetic evaluations will enable strategies to enhance precision medicine care.

Methods: An online survey was conducted in June 2024 among cardiologist investigators of the DCM Consortium from US advanced heart failure/transplant (HF/TX) programs to collect demographics, training, program characteristics, genetic evaluation practices for DCM, and implementation needs.

Arrhythmogenic Cardiomyopathy: Towards Genotype Based Diagnoses and Management.

Arrhythmogenic cardiomyopathy (ACM) is a genetically heterogeneous inherited cardiomyopathy with an estimated prevalence of 1:5000-10 000 that predisposes patients to life-threatening ventricular arrhythmias (VA) and sudden cardiac death (SCD). ACM diagnostic criteria and risk prediction models, particularly for arrhythmogenic right ventricular cardiomyopathy (ARVC), the most common form of ACM, are typically genotype-agnostic, but numerous studies have established clinically meaningful genotype-phenotype associations. Early signs of ACM onset differ by genotype indicating the need for genotype-specific diagnostic criteria and family screening paradigms.

Underestimated risk of secondary complications in pathogenic and glucose-elevating GCK variant carriers with type 2 diabetes.

Background: Natural HbA1c levels in GCK Maturity-onset diabetes of the young (GCK-MODY) patients often sit above the diagnostic threshold for type 2 diabetes (T2D). Treatments to lower HbA1c levels show reduced effectiveness in these individuals, yet in case studies to date, GCK-MODY patients often evade secondary T2D complications. Given these deviations, genetic screening of GCK may be clinically useful, but population studies are needed to more broadly understand T2D-related complications in GCK variant carriers.

Long-Term Efficacy and Safety of Acoramidis in ATTR-CM: Initial Report From the Open-Label Extension of the ATTRibute-CM Trial.

Background: In the phase 3 randomized controlled study ATTRibute-CM (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy), acoramidis, a transthyretin stabilizer, demonstrated significant efficacy on the primary end point. Participants with transthyretin amyloid cardiomyopathy who completed ATTRibute-CM were invited to enroll in an open-label extension study (OLE). We report the efficacy and safety data of acoramidis in participants who completed ATTRibute-CM and enrolled in the ongoing OLE.

Examining the burden and relationship between stunting and wasting among Timor-Leste under five rural children.

Globally and in Timor-Leste, wasting and stunting remain major public health problems among 'under five years children, but the interrelationship between the two has been poorly investigated. A better understanding of this interrelationship is a prerequisite to improving wasting and stunting programming. In our study, we assessed the influence of age on the prevalence of wasting and stunting, the overlap between the two conditions, and the effect of wasting parameters on linear growth catch-up using the data of 401 children recruited at 0 to 54 months of age [median (IQR) of 17 (7-32) months] with repeated anthropometric assessments [median (IQR) follow-up time was 25 (16-39) months].

Desmoplakin mutations in cardiac fibroblasts cause TGFβ1-mediated pathological fibrogenesis in desmoplakin cardiomyopathy via beclin-1 regulation.

Background: Pathological fibrosis is a major finding in cardiovascular diseases and can result in arrhythmia and heart failure. Desmosome gene mutations can lead to arrhythmogenic cardiomyopathy (ACM). Among ACM, pathogenic desmoplakin ( ) variants cause a distinctive cardiomyopathy with excessive cardiac fibrosis that could precede ventricular dysfunction.

A power-based sliding window approach to evaluate the clinical impact of rare genetic variants in the nucleotide sequence or the spatial position of the folded protein.

Systematic determination of novel variant pathogenicity remains a major challenge, even when there is an established association between a gene and phenotype. Here we present Power Window (PW), a sliding window technique that identifies the impactful regions of a gene using population-scale clinico-genomic datasets. By sizing analysis windows on the number of variant carriers, rather than the number of variants or nucleotides, statistical power is held constant, enabling the localization of clinical phenotypes and removal of unassociated gene regions.

Establishing an infrastructure to optimize the integration of genomics into research: Results from a precision health needs assessment.

Researchers across the translational research continuum have emphasized the importance of integrating genomics into their research program. To date capacity and resources for genomics research have been limited; however, a recent population-wide genomic screening initiative launched at the Medical University of South Carolina in partnership with Helix has rapidly advanced the need to develop appropriate infrastructure for genomics research at our institution. We conducted a survey with researchers from across our institution (n = 36) to assess current knowledge about genomics health, barriers, and facilitators to uptake, and next steps to support translational research using genomics.

Using implementation science to evaluate a population-wide genomic screening program: Findings from the first 20,000 In Our DNA SC participants.

We use the implementation science framework RE-AIM (reach, effectiveness, adoption, implementation, and maintenance) to describe outcomes of In Our DNA SC, a population-wide genomic screening (PWGS) program. In Our DNA SC involves participation through clinical appointments, community events, or at home collection. Participants provide a saliva sample that is sequenced by Helix, and those with a pathogenic variant or likely pathogenic variant for CDC Tier 1 conditions are offered free genetic counseling.

The farnesyl transferase inhibitor (FTI) lonafarnib improves nuclear morphology in ZMPSTE24-deficient fibroblasts from patients with the progeroid disorder MAD-B.

Several related progeroid disorders are caused by defective post-translational processing of prelamin A, the precursor of the nuclear scaffold protein lamin A, encoded by . Prelamin A undergoes farnesylation and additional modifications at its C-terminus. Subsequently, the farnesylated C-terminal segment is cleaved off by the zinc metalloprotease ZMPSTE24.

Use of a multi-phased approach to identify and address facilitators and barriers to the implementation of a population-wide genomic screening program.

Introduction: Population-wide genomic screening for CDC Tier-1 conditions offers the ability to identify the 1-2% of the US population at increased risk for Hereditary Breast and Ovarian Cancer, Lynch Syndrome, and Familial Hypercholesterolemia. Implementation of population-wide screening programs is highly complex, requiring engagement of diverse collaborators and implementation teams. Implementation science offers tools to promote integration of these programs through the identification of determinants of success and strategies to address potential barriers.

Applying the R = MC implementation science heuristic to assess the impact of readiness on reach and implementation of a population-wide genomic screening program.

Population-wide genomic screening for genes that have high penetrance and clinical actionability enhances the opportunity to identify individuals at risk for developing hereditary conditions. Organizational readiness has been shown to influence the likelihood of successful implementation of complex initiatives such as the integration of population-wide genomic screening in clinical settings. We use the organizational readiness heuristic R = MC to better understand three factors that influence readiness for implementation of In Our DNA SC, a population-wide genomic screening program: motivation to implement, general capacity of an organization, and innovation-specific capacities.

Community-Acquired, Bacteraemic Acinetobacter Baumannii Pneumonia: A Retrospective Review of Cases in Tropical Queensland, Australia.

Background: Community-acquired pneumonia (CAAP) typically presents with rapid progression to fulminant disease and is complicated by high mortality. Australian epidemiological studies are few.

Methods: We conducted a retrospective study on bacteraemic cases of CAAP over twenty years (2000-2019) in North Queensland.