Clinical characteristics of HFrEF patients with rare pathogenic variants in DCM-associated genes: a subgroup analysis of the PARADIGM-HF trial

Aims: To evaluate the prevalence of pathogenic variants in genes associated with dilated cardiomyopathy (DCM) in a clinical trial population with heart failure and reduced ejection fraction (HFrEF) and describe the baseline characteristics by variant carrier status. Methods and results: This was a post hoc analysis of the Phase 3 PARADIGM-HF trial. Forty-four genes, divided into three tiers, based on definitive, moderate or limited evidence of association with DCM, were assessed for rare predicted loss-of-function (pLoF) variants, which were prioritised using ClinVar annotations, measures of gene transcriptional output and evolutionary constraint, and pLoF confidence predictions. Prevalence was reported for pLoF variant carriers based on DCM-associated gene tiers. Clinical features were compared between carriers and non-carriers. Of the 1412 HFrEF participants with whole-exome sequence data, 68 (4.8%) had at least one pLoF variant in the 8 tier-1 genes (definitive/strong association with DCM), with Titin being most commonly affected. The prevalence increased to 7.5% when considering all 44 genes. Among patients with idiopathic aetiology, 10.0% (23/229) had tier-1 variants only and 12.6% (29/229) had tier-1, -2 or -3 variants. Compared to non-carriers, tier-1 carriers were younger (4 years; adjusted p-value [padj]=4×10−3), leaner (27.8 kg/m2 vs. 29.4 kg/m2; padj=3.2x10−3), had lower EF (27.3% vs. 29.8%; padj=5.8x10−3), and less likely to have ischaemic aetiology (37.3% vs 67.4%; padj=4×10−4). Conclusion: Deleterious pLoF variants in genes with definitive/strong association to DCM were identified in ~5% of HFrEF patients from a PARADIGM-HF trial subset, who were younger, had lower EF and were less likely to have had an ischaemic aetiology

Changes in coronal alignment of the hip joint after medial opening wedge high tibial osteotomy.

PURPOSE: An observation was made by the senior author of this paper that patients reported changes in their hip function after a medial opening wedge high tibial osteotomy (MOHTO) for varus pattern osteoarthritis. Alignment changes at the hip after MOHTO have not been previously documented. This study assesses coronal alignment changes at the hip after MOHTO. METHODS: We retrospectively analysed pre- and post-operative lower limb alignment radiographs of patients who underwent MOHTO. The medial proximal tibial angle (MPTA) and mechanical axis deviation (MAD) were measured to assess the alignment changes created by the MOHTO. The coronal alignment changes at the hip were evaluated using the mechanical greater trochanter angle (MGTA). RESULTS: 29 osteotomies in 27 patients were included in this study. Results showed MOHTO created alignment changes at the hip. A positive correlation was found between the size of the correction at the knee and the subsequent changes at the hip. The change in the MGTA had a stronger correlation with the MAD than with the change in MPTA (r = 0.684 vs. 0.585). It was found that age, weight, height and BMI had no significant influence on these correlations. CONCLUSIONS: Increased correction by the MOHTO lead to increased change in the coronal alignment of the hip. These changes are likely to result in an alteration in the weight bearing portion of the femoral head and the function of the abductors and we recommend assessing the hip joint as part of pre-operative planning. LEVEL OF EVIDENCE: Prognostic level IV

Exploring the Potential of Nanoparticles in the Treatment of Breast Cancer: Current Applications and Future Directions

Breast cancer (BC) ranks among the most diagnosed solid tumors worldwide. For decades, significant research efforts have been dedicated to finding selective treatments for these solid tumors. Currently, the primary treatment method for BC involves surgery, with the subsequent utilization of radiotherapy and chemotherapy. However, these subsequent treatments often fall short of effectively treating BC due to their side effects and harm to healthy tissues. Today, a range of nanoparticles are being developed to target BC cells without affecting the surrounding healthy tissues. This in-depth review, based on studies, seeks to shed light on these specially designed nanoparticles and their potential in BC treatment. Typically, therapeutic drugs or naturally occurring bioactive compounds are incorporated into precisely crafted nanoparticles. This enhances their solubility, longevity in the bloodstream, and distribution in the body while also minimizing side effects and immune reactions. Nanoparticles have been designed to address the shortcomings of standalone therapeutics and traverse various biological obstacles spanning the systemic, microenvironmental, and cellular that differ among patients and diseases. We prioritize breakthroughs in nanoparticle design to surpass diverse delivery obstacles and believe that smart nanoparticle engineering not only enhances effectiveness for general delivery but also allows customized solutions for specific needs, ultimately leading to better outcomes for patients

miR-483-5p offsets functional and behavioural effects of stress in male mice through synapse-targeted repression of Pgap2 in the basolateral amygdala

Abstract Severe psychological trauma triggers genetic, biochemical and morphological changes in amygdala neurons, which underpin the development of stress-induced behavioural abnormalities, such as high levels of anxiety. miRNAs are small, non-coding RNA fragments that orchestrate complex neuronal responses by simultaneous transcriptional/translational repression of multiple target genes. Here we show that miR-483-5p in the amygdala of male mice counterbalances the structural, functional and behavioural consequences of stress to promote a reduction in anxiety-like behaviour. Upon stress, miR-483-5p is upregulated in the synaptic compartment of amygdala neurons and directly represses three stress-associated genes: Pgap2, Gpx3 and Macf1. Upregulation of miR-483-5p leads to selective contraction of distal parts of the dendritic arbour and conversion of immature filopodia into mature, mushroom-like dendritic spines. Consistent with its role in reducing the stress response, upregulation of miR-483-5p in the basolateral amygdala produces a reduction in anxiety-like behaviour. Stress-induced neuromorphological and behavioural effects of miR-483-5p can be recapitulated by shRNA mediated suppression of Pgap2 and prevented by simultaneous overexpression of miR-483-5p-resistant Pgap2. Our results demonstrate that miR-483-5p is sufficient to confer a reduction in anxiety-like behaviour and point to miR-483-5p-mediated repression of Pgap2 as a critical cellular event offsetting the functional and behavioural consequences of psychological stress

Aptamer Proteomics for Biomarker Discovery in Heart Failure with Reduced Ejection Fraction.

no abstrac

Aptamer Proteomics for Biomarker Discovery in Heart Failure With Reduced Ejection Fraction.

No abstract part in this lette

Aptamer proteomics for biomarker discovery in heart failure with reduced ejection fraction

no abstrac