Search Results (456)

Background: More than 1500 genes are associated with developmental delay and intellectual disability, with variants in many of these genes contributing to a shared phenotype. The discovery of variants of uncertain significance (VUS) found in these genes during genetic testing can lead to ambiguity and further delay in diagnosis and medical management. Phenotyping, additional genetic testing, and functional studies can all add valuable information to help reclassify these variants. Here we demonstrate the clinical utility of epigenetic signatures in prioritizing variants of uncertain significance in genes associated with developmental delay (DD) and intellectual disability (ID). Methods: Genome sequencing was performed in a male with developmental delay. He was found to have VUSs in both PHF6 and DDB1 genes, linked with Börjeson–Forssman–Lehmann syndrome (BFLS) and White–Kernohan syndrome (WHIKERS), respectively. These two disorders share a similar phenotype but have distinct inheritance patterns and molecular pathogenic mechanisms. DNA methylation profiling (DNAm) of whole blood was performed using the clinically validated EpiSign assay. Results: The proband’s methylation profile demonstrated a strong correlation with the BFLS methylation signature, supporting the PHF6 variant as a likely cause of his neurodevelopmental disorder. Conclusions: Epigenetic testing for disorders with distinct methylation patterns can provide diagnostic utility when a patient presents with variants of uncertain significance in genes associated with developmental delay. Epigenetic signatures can also guide genetic counselling and family planning. Full article

Class D β-lactamases (DBLs) represent a major threat to antibiotic efficacy by hydrolyzing β-lactam drugs, including last-resort carbapenems, thereby driving antimicrobial resistance in Gram-negative bacteria. The enzymes share a structurally conserved two-domain α/β architecture with seven active-site motifs and three flexible extended loops (the P-loop, Ω-loop, and newly designated B-loop) that surround the active site. While each of these loops is known to influence enzyme function, their coordinated roles have not been fully elucidated. To investigate the significance of their interplay, we compared the sequences and crystal structures of 40 DBLs from clinically relevant Gram-negative pathogens and performed molecular dynamics simulations on selected representatives. Combined structural and dynamical analyses revealed a strong correlation between B-loop architecture and carbapenemase activity in the pathogens Klebsiella and Acinetobacter, particularly regarding loop length and spatial organization. These findings emphasize the B-loop’s critical contribution, in concert with the P- and Ω-loops, in tuning active site versatility, substrate recognition, catalytic activity, and structural stability. A deeper understanding of how these motifs and loops govern DBL function may inform the development of novel antibiotics and inhibitors targeting this class of enzymes. Full article

Background: Aortic stenosis (AS) has long been considered a degenerative disease and is typically diagnosed in older men at an advanced stage. However, accumulating evidence has highlighted the similarities between AS and atherosclerosis, particularly regarding shared risk factors and overlapping pathophysiological mechanisms. This connection has led to a paradigm shift, suggesting that AS may be preventable in its early stages. Methods: This narrative review synthesizes the existing literature exploring the parallels between AS and atherosclerosis, focusing on common risk factors, pathogenic pathways, and evolving therapeutic strategies. Clinical trials and translational studies were examined to assess the effectiveness of atherosclerosis-based treatments for AS. Results: Multiple studies have confirmed the shared inflammatory, lipid-mediated, and calcific mechanisms of AS and atherosclerosis. Despite these similarities, therapeutic strategies effective in atherosclerosis, such as statin therapy, have not consistently shown benefits in AS. New medical approaches aim to delay aortic valve replacement and reduce the associated morbidity. The partially overlapping pathogenesis continues to guide future research. Conclusions: While AS and atherosclerosis share several pathogenic features, their clinical courses and treatment responses diverge. Understanding the limits and potential of their overlap may inform future preventive and therapeutic strategies. Earlier detection and targeted intervention in AS remain key goals, drawing on insights from cardiovascular disease management. Full article

The European Health Technology Assessment (HTA) regulation (HTAR) came into effect in January 2025 and impacts the HTA process in all European Member States. Member States must give due consideration to the joint clinical assessment (JCA) report. This may require adaptations at the national level. This paper describes the anticipated changes to the Dutch national HTA process and how the Dutch National Health Care Institute (Zorginstituut Nederland, ZIN) prepared for this, because sharing experience between Member States can be of general interest for future expansion of the EU HTAR. ZIN’s implementation activities were facilitated by a project-governance structure and by a continuous gap analysis of the current national assessment and appraisal process of medicinal products, resulting in a concrete action plan. The implementation of the HTAR has two major implications for ZIN’s HTA process, namely that the scoping phase starts much earlier and that the JCA report is the starting point for the national assessment. Gaps, challenges and issues were identified in the categories: information and knowledge, IT and template, communication and stakeholder engagement, capacity and resources, and financial aspects. Based on a thorough and well-defined implementation plan, ZIN is ready to implement the HTAR in national HTA processes and to take on (co-)assessor roles for JCA of medicinal products in 2025. Full article

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing lung disease characterized by chronic inflammation, vascular remodeling, and immune dysregulation. COVID-19, caused by SARS-CoV-2, shares several systemic immunohematologic disturbances with IPF, including cytokine storms, endothelial injury, and prothrombotic states. Unlike general comparisons of viral infections and chronic lung disease, this review offers a focused analysis of the shared hematologic and immunologic mechanisms between COVID-19 and IPF. Our aim is to better understand how SARS-CoV-2 infection may worsen disease progression in IPF and identify converging pathophysiological pathways that may inform clinical management. We conducted a narrative synthesis of the peer-reviewed literature from PubMed, Scopus, and Web of Science, focusing on clinical, experimental, and pathological studies addressing immune and coagulation abnormalities in both COVID-19 and IPF. Both diseases exhibit significant overlap in inflammatory and fibrotic signaling, particularly via the TGF-β, IL-6, and TNF-α pathways. COVID-19 amplifies coagulation disturbances and endothelial dysfunction already present in IPF, promoting microvascular thrombosis and acute exacerbations. Myeloid cell overactivation, impaired lymphocyte responses, and fibroblast proliferation are central to this shared pathophysiology. These synergistic mechanisms may accelerate fibrosis and increase mortality risk in IPF patients infected with SARS-CoV-2. This review proposes an integrative framework for understanding the hematologic and immunologic convergence of COVID-19 and IPF. Such insights are essential for refining therapeutic targets, improving prognostic stratification, and guiding early interventions in this high-risk population. Full article

Background/Objectives: Neurofibromatosis type 1 (NF1) and Noonan syndrome spectrum disorders (NSSD) are the most common RASopathies, resulting from germline mutations that affect the RAS-MAPK signaling pathway. Both are associated with increased risk for neurodevelopmental and psychiatric conditions, yet few studies have used structured diagnostic interviews to compare their psychiatric comorbidities. Methods: We conducted clinician-administered DSM-5 diagnostic assessments (KSADS) in 123 children with RASopathies (NF1 = 29, NSSD = 94; ages 5–15). Diagnosis prevalence was compared within each group and to population-based estimates. Results: Psychiatric diagnoses were highly prevalent, at 79.3% in NF1 and 76.6% in NSSD, with ADHD (NF1 = 72.4%, NSSD = 51.1%) and anxiety disorders (NF1 = 37.9% and NSSD = 43.6%) being the most common, rates substantially higher than those reported in general population estimates. Behavioral and sleep disorders were identified in approximately 25% of both groups. Notably, social anxiety disorder was identified in 14.9% of NSSD but not in NF1. Full-scale IQ did not significantly differ by diagnosis status. Specific anxiety disorders, elimination disorders, obsessive–compulsive disorder, and post-traumatic stress disorder were characterized, expanding the known psychiatric phenotype of RASopathies. Conclusions: Children with NF1 and NSSD demonstrate similarly high rates of ADHD, anxiety, and behavioral disorders compared to the general population; in addition, we report sleep disorders in NSSD and characterize psychiatric disorders not previously described in RASopathies. The shared psychiatric profiles may reflect the common effect of RAS-MAPK pathway dysregulation on psychiatric outcomes. These findings highlight the need for early, syndrome-informed mental health screening and intervention in the clinical care of individuals with RASopathies. Full article

Background/Objectives: Tongue thrust (TT) occurs when abnormal tongue movements cause anterior tongue placement with pressure and contact against or between the teeth, potentially affecting the oral phase of swallowing, impacting eating, breathing and speaking. There is limited literature on the diagnostic and treatment approaches for TT, as well as involvement of health practitioners in its management. This study aims to examine the current knowledge and practices related to TT diagnosis and treatment among health professionals in Australia. Methods: A two-phase explanatory sequential mixed methods approach was adopted, comprising an online survey that collected participants’ demographic information and details on assessment, diagnosis, management, referral practices, and relevant experience and training. Phase one involved 47 health professionals from various disciplines in Australia who completed an online survey in its entirety. Phase two included in-depth interviews with seven speech-language pathologists (SLPs) to gain further insights into their experiences in managing TT. Survey data were analysed descriptively, and interview data was analysed thematically. Results: Most participants diagnosed TT using clinical assessments, such as general observation and oral motor examinations. Treatment approaches commonly included orofacial myofunctional therapy and the use of myofunctional devices. Interviews with SLPs identified four key themes: tongue thrust as a symptom rather than a diagnosis, facilitators to effective treatment, multidisciplinary approaches to management, and training and education gaps in clinical practice. Conclusions: This study provides valuable insights into how TT is identified, assessed, diagnosed, and managed by health professionals in Australia. It highlights the perspectives of SLPs on treatment approaches, as well as their views on the availability and adequacy of training and education in this field. The findings suggest the need for a broader understanding of TT management, emphasising the importance of multidisciplinary collaboration and professional development. These insights are globally relevant, as they stress the shared challenges and the value of international collaboration in improving TT diagnosis and treatment practices. Full article

Background/Objectives: Endometriosis and high-grade serous ovarian cancer (HGS-OC) share common features within the peritoneal immune microenvironment, yet they exhibit divergent clinical outcomes. This study aimed to dissect the immune–metabolic landscape of the peritoneal cavity in patients with endometriosis and ovarian cancer by evaluating macrophage polarization, intracellular signaling pathways, and iron-driven oxidative stress. Methods: A prospective cohort study enrolled 40 patients with endometriosis, 198 with ascitic ovarian cancer (178 HGS-OC), and 200 controls with benign gynecological conditions. Peritoneal and peripheral blood samples were analyzed via flow cytometry for macrophage (M1/M2) polarization markers, mTOR/AKT expression, and glucose uptake. Inflammatory markers (IL-6, CRP), oxidative stress (ROS), and iron metabolism parameters (hepcidin, ferritin, transferrin, serum/free iron) were quantified. Results: HGS-OC displayed a predominance of M1-polarized tumor-associated macrophages (TAMs) (CD14⁺/CD80⁺/Glut1⁺) and a high M1/M2 ratio (2.5 vs. 0.8 and 0.9; p = 0.019), correlating positively with IL-6 (p = 0.015), ROS (p = 0.023), hepcidin (p = 0.038), and ferritin (p = 0.043). Conversely, endometriosis showed a dominant M2 profile (CD14⁺/CD163⁺), elevated intracellular mTOR and AKT expression in both TAMs and epithelial cells (p < 0.01), and significantly higher ascitic ROS and free iron levels (p = 0.047 and p < 0.0001, respectively). In endometriosis, the M1/M2 ratio correlated inversely with free iron (p = 0.041), while ROS levels were directly associated with iron overload (p = 0.0034). Conclusions: Endometriosis exhibits a distinct immune–metabolic phenotype characterized by M2 macrophage predominance and iron-induced oxidative stress, contrasting with the inflammatory, M1-rich profile of HGS-OC. These findings suggest that iron metabolism and macrophage plasticity contribute to disease persistence in endometriosis and may inform future immunomodulatory strategies. Full article

Patient-generated health data (PGHD) enhance traditional healthcare by enabling continuous monitoring and supporting personalized care, yet concerns over privacy, security, and integration into existing systems hinder broader adoption. This study examined the perceptions, awareness, and concerns of patients and caregivers regarding PGHD and assessed their willingness to share such data for clinical, research, and commercial purposes. A cross-sectional survey was conducted from 6 to 12 November 2023, involving 400 individuals with experience using PGHD. Participants completed structured questionnaires addressing health information management, PGHD usage, and attitudes toward its application. PGHD was most commonly used by patients with chronic conditions and guardians of minors, with tethered personal health record apps frequently utilized. Respondents identified improved self-management and better access to information as key benefits. However, significant concerns about data privacy and security emerged, especially regarding non-clinical use. Younger adults, particularly those in their 20s, showed lower willingness to engage with PGHD due to heightened privacy concerns. These findings suggest that, while support for clinical use of PGHD is strong, barriers related to trust and consent remain. Addressing privacy concerns and simplifying consent processes will be essential to promote equitable and responsible PGHD utilization across diverse patient populations. Full article

Background: The treatment options for HER2-negative metastatic breast cancer include targeted therapies, cytotoxic chemotherapies, and immunotherapy. However, limited specificity and inevitable resistance highlight the need for novel agents. Antibody–drug conjugates (ADCs), such as trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG), represent a breakthrough by selectively delivering cytotoxic agents to tumor cells, potentially improving the therapeutic index. Despite demonstrated efficacy, ADCs present toxicity profiles similar to conventional chemotherapy, alongside unique adverse events. In clinical practice, oncologists may face scenarios where both T-DXd and SG are treatment options in HER2-negative mBC. To enable shared decision-making, it is crucial to present a comprehensive overview that includes both efficacy data and detailed toxicity profiles. Our objective was to provide a pooled and informative synthesis of toxicities from pivotal studies, including graphical representations, to support informed, patient-centered medical decisions. Methods: We reviewed safety data from phase 3 clinical trials in HER2-negative mBC: DESTINY-Breast04/DESTINY-Breast06 for T-DXd and ASCENT/TROPICS-02 for SG. Adverse event (AE) profiles, including frequency and severity, were extracted, and weighted means were calculated. Emerging ADCs such as datopotamab deruxtecan and patritumab deruxtecan were considered to contextualize future therapeutic decisions. Results: Tables, bar plots and radar plots were generated. T-DXd demonstrated high rates of nausea (69.2%), fatigue (47.2%), and neutropenia (35.6%), with 52.7% experiencing grade ≥ 3 AEs. Notably, pneumonitis occurred in 10.7%, with grade ≥ 3 in 2.6%. SG showed a distinct AE profile, with higher incidences of neutropenia (67.1%), with grade ≥ 3 in 51.3%, and diarrhea (60.8%). Conclusions: The choice between ADCs in HER2-negative metastatic BC when both T-DXd and SG are treatment options should consider toxicity profiles to optimize patient-centered treatment strategies. Tailoring ADC selection based on individual tolerance and preferences is critical for shared decision-making, and future research should focus on assessing the utility and acceptability of such clinical tools to guide treatment selection. Full article

Sexual dysfunction is a prevalent and often under-addressed concern among prostate cancer survivors, significantly affecting quality of life for patients and their partners. The True North Sexual Health and Rehabilitation eClinic (SHAReClinic) is a virtual, biopsychosocial intervention developed to improve access to sexual health support for prostate cancer survivors and their partners. This study used a qualitative descriptive design to examine barriers and facilitators influencing the integration of SHAReClinic into oncology care across nine Canadian health care centres. Semi-structured interviews were conducted with 17 knowledge users, including health care providers and institutional leaders. Data were analyzed using a hybrid deductive–inductive thematic approach guided by the Consolidated Framework for Implementation Research (CFIR) 2.0. Participants described SHAReClinic as a much-needed resource, particularly in the absence of standardized sexual health pathways in oncology care. The virtual format was seen as accessible and well suited to addressing sensitive topics. However, limited funding, lack of institutional support, and workflow integration challenges emerged as primary barriers to implementation. Findings offer practical, theory-informed guidance for integrating SHAReClinic into oncology care and highlight key considerations for developing sustainable and scalable survivorship care models. Full article

The high pathogenicity rate of carbapenem-resistant Pseudomonas aeruginosa (CRPA) has resulted in substantial economic losses for humans and the breeding industry. Consequently, there is an urgent need to develop new alternatives to mitigate antibiotic use. Phage therapy has demonstrated promising results in numerous studies. In this study, lytic phages targeting CRPA were isolated from feces and river water samples in Shandong, China. A total of 94 phage strains with CRPA as hosts were obtained, exhibiting lysis rates that ranged from 29% to 76% for P. aeruginosa derived from humans and different types of animals (n = 246). We further examined five representative phages, the host bacteria of which were CRPA from clinical patients and poultry, and these phages included two myoviruses and three podoviruses. Their optimal multiplicities of infection (MOIs) ranged from 10⁻³ to 10⁻⁵, with latent periods of less than 5 to 15 min and burst durations of 140 to 175 min, resulting in burst sizes of 133 to 352 PFU/cell. All five phages exhibited the ability to survive at temperatures up to 60 °C and within pH levels of 3 to 11. Whole-genome sequencing revealed that these five phages were all double-stranded DNA phages and did not possess resistance genes or virulence factors. The two myoviruses, sharing similar sequences, were classified into the genus Pakpunavirus, with a size of 92,509 bp and 92,293 bp, 149 to 152 ORFs and 20 to 22 tRNAs. In contrast, the three similar podoviruses belong to the genus Phikmvvirus and all contained a perforin–lyase system, with a size of 43.35 kb, a GC content of 62%, 49 to 50 ORFs and 16 to 20 tRNAs. A spray disinfection experiment demonstrated that the phage cocktail exhibited a high sterilization effect after spraying and showed good efficacy against cement and metal surfaces. This study provides foundational information for further research into the elimination of CRPA in the environment. Full article

Background/Objectives: Long QT Syndrome type 2 (LQT2) is a cardiac channelopathy linked to pathogenic variants in the KCNH2 gene, which encodes the Kv11.1 potassium channel, essential for cardiac repolarization. Variants affecting splice sites disrupt potassium ion flow, prolong QT interval, and increase the risk of arrhythmias and sudden cardiac death (SCD). Understanding genotype–phenotype correlations is key, given the variability of clinical manifestations even within families sharing the same variant. We aimed to evaluate new pathogenic variants by analyzing genotype–phenotype correlations in informative families. Methods: Genetic and clinical assessments were performed on index cases and family members carrying KCNH2 pathogenic variants, referred for genetic testing between 2010 and June 2023. The next-generation sequencing (NGS) of 210 cardiovascular-related genes was conducted. Clinical data, including demographic details, family history, arrhythmic events, electrocardiographic parameters, and treatments, were collected. Results: Among 390 patients (152 probands) tested for LQTS, only 2 KCNH2 variants had over 5 carriers. The detailed clinical information of 22 carriers of this KCNH2 p.Ser261fs. has already been reported by our research group. Moreover, we identified 12 carriers of the KCNH2 c.77-2del variant, predicted to disrupt a splice site and not previously reported. Segregation analysis showed its high penetrance, supporting its classification as pathogenic. Conclusions: The newly identified KCNH2 c.77-2del variant is a pathogenic, as strongly supported by the segregation analysis. Our findings underscore the importance of further research into splice site variants to enhance clinical management and genetic counseling for affected families. Full article

Chronic kidney disease (CKD) is associated with the systemic accumulation of uremic toxins (UTs) due to impaired renal elimination. Among these, indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are particularly challenging because of their high protein binding and limited removal by dialysis. In addition to renal excretion, the transport of IS and PCS, and their microbiota-derived precursors, indole and p-cresol, across key physiological barriers—the intestinal barrier, blood–brain barrier, and renal proximal tubule—critically influences their distribution and elimination. This review provides an overview of transporter-mediated mechanisms involved in the disposition of IS, PCS, and their microbial precursors, indole and p-cresol. It also examines how these UTs may interact with commonly prescribed drugs in CKD, particularly those that share transporter pathways as substrates or inhibitors. These drug–toxin interactions may influence the pharmacokinetics and toxicity of IS and PCS, but remain poorly characterized and largely overlooked in clinical settings. A better understanding of these processes may guide future efforts to optimize pharmacotherapy and support more informed management of CKD patients, particularly in the context of polypharmacy. Full article

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are linked by shared genetic mutations and overlapping clinical features, forming a clinical spectrum. This systematic review and meta-analysis analysed 97 studies, including 3212 patients with key ALS/FTD gene mutations, to identify gene-specific behavioural profiles. Chromosome 9 open reading frame 72 (C9orf72) mutations were strongly associated with psychotic symptoms and aggression, while superoxide dismutase 1 (SOD1) mutations had minimal cognitive effects. Progranulin (PGRN) mutations correlated with apathy and hallucinations, microtubule-associated protein tau (MAPT) mutations with disinhibition, and charged multivesicular body protein 2B (CHMP2B) with social impairments. Fused in sarcoma (FUS) mutations caused early sleep disturbances, TANK-binding kinase 1 (TBK1) led to disinhibition, and presenilin 1 and 2 (PSEN1/2) was linked to severe aggression. Prodromal cognitive changes in PGRN, MAPT, and CHMP2B mutations suggested early disease onset. Despite overlapping symptoms and clinical heterogeneity, understanding gene-specific patterns could inform tailored care strategies to enhance the quality of life for ALS and FTD patients. This study calls for refined guidelines integrating genetic behavioural profiles to improve patient and family support. Full article