2f:I[703058,["/_next/static/immutable/chunks/3bhq_5eh1d760.js","/_next/static/immutable/chunks/1855-ogyi8eh4.js","/_next/static/immutable/chunks/2pfsjpn6k6zlg.js","/_next/static/immutable/chunks/26c7v3_3uwnwu.js","/_next/static/immutable/chunks/25a3ozcrvi1ff.js","/_next/static/immutable/chunks/2r4wx50nvjh_4.js","/_next/static/immutable/chunks/23fsw06hsi5b1.js","/_next/static/immutable/chunks/06_yt270h41rg.js","/_next/static/immutable/chunks/3ezsiz-7shkna.js","/_next/static/immutable/chunks/20x2y96ldu5wx.js","/_next/static/immutable/chunks/2lxntcm3pd1_h.js","/_next/static/immutable/chunks/00dgco8irq3jw.js","/_next/static/immutable/chunks/00nwe-kq0rboc.js","/_next/static/immutable/chunks/2051ffx3xzio9.js"],"PaperListPageClient"] 30:T6b0,Human retinal organoids (ROs), derived from pluripotent stem cells, have emerged as versatile human-relevant systems for studying retinal development, modeling disease, and evaluating therapeutic strategies. This review summarizes the evolution of human RO technology, from early stem-cell-based differentiation protocols to advanced culture platforms that improve scalability, reproducibility, and functional maturation. We compare human ROs with native human retinas regarding developmental trajectory, cellular composition, and photoreceptor function, while also highlighting persistent gaps in vascularization, immune interactions, and inner-retinal connectivity. ROs have displayed substantial value in modeling inherited retinal disorders, toxic and infectious retinopathies, and selected pathogenic processes relevant to complex diseases. Applications in precision medicine include patient-specific drug testing, gene augmentation, antisense approaches, and gene/base-editing validation. In regenerative medicine, RO-derived photoreceptors and retinal sheets are promising donor sources, although clear clinical evidence of functional integration remains limited. Current limitations include the lack of a bona fide fovea, incomplete recapitulation of the outer retina-retinal pigment epithelium-choroid interface, and variability across protocols and cell lines. Emerging bioengineering strategies, coculture systems, and multilineage assembloids are starting to address these barriers. Overall, human ROs are advancing rapidly as a platform that bridges developmental biology and translational ophthalmology, while still requiring careful interpretation of their biological scope and clinical readiness.31:T4d9,Social isolation is a major environmental driver of anxiety disorders, yet its neurobiological underpinnings remain elusive. We report here that social isolation triggers "ferroplasticity"-a novel form of experience-dependent synaptic remodeling-in ventral hippocampus (vHip) pyramidal neurons via a glucocorticoid-initiated iron-α-synuclein (α-Syn) axis. Psychosocial stress specifically engages this pathway. Mechanistically, isolation-induced glucocorticoid receptor activation upregulates transferrin receptor 1 (TfR1), leading to neuronal iron accumulation, which boosts α-Syn expression via translational derepression. α-Syn then enhances glutamate release and spine density, driving vHip hyperexcitability and anxiety. Interventions targeting the TfR1-iron-α-Syn axis at any node prevent or reverse anxiety-like behaviors, establishing necessity and causality. Translationally, intranasal delivery of an iron chelator or α-Syn-targeting antisense oligonucleotide (ASO) normalizes vHip neural activity and alleviates anxiety, highlighting a direct and viable path to clinical translation. Our findings define ferroplasticity as a core mechanism in social stress pathology, bridging brain iron metabolism with affective disorders.32:T4c4,Inherited optic neuropathies (IONs), such as Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (ADOA), typically lead to irreversible severe vision loss due to mitochondrial dysfunction causing retinal ganglion cell degeneration. Although current treatment options are limited, substantial progress has been made recently in our understanding of the molecular genetic pathways that lead to retinal ganglion cell loss. Clinical trials for LHON have demonstrated the efficacy of idebenone, an oral neuroprotective agent, and gene replacement therapy using allotopic gene expression. Early phase clinical trials are underway for ADOA caused by variants in the nuclear gene OPA1 using innovative techniques to modulate gene expression in a variant-agnostic manner. In this review, we have critically appraised a range of therapeutic strategies, including gene editing and stem cell-based optic nerve regeneration, with a discussion of the barriers to translation. Future studies focussing on understanding genetic heterogeneity, disease variability and optimising patient selection for clinical trials are essential to improve patient management and fast track transformative therapies for IONs.33:T574,Abstract Inherited optic neuropathies (IONs), such as Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (ADOA), typically lead to irreversible severe vision loss due to mitochondrial dysfunction causing retinal ganglion cell degeneration. Although current treatment options are limited, substantial progress has been made recently in our understanding of the molecular genetic pathways that lead to retinal ganglion cell loss. Clinical trials for LHON have demonstrated the efficacy of idebenone, an oral neuroprotective agent, and gene replacement therapy using allotopic gene expression. Early phase clinical trials are underway for ADOA caused by variants in the nuclear gene OPA1 using innovative techniques to modulate gene expression in a variant-agnostic manner. In this review, we have critically appraised a range of therapeutic strategies, including gene editing and stem cell-based optic nerve regeneration, with a discussion of the barriers to translation. Future studies focussing on understanding genetic heterogeneity, disease variability and optimising patient selection for clinical trials are essential to improve patient management and fast track transformative therapies for IONs. 25:[[["$","script","0",{"type":"application/ld+json","dangerouslySetInnerHTML":{"__html":"{\"@context\":\"https://schema.org\",\"@type\":\"CollectionPage\",\"name\":\"Antisense Oligonucleotide: modality Research & Clinical Takeaways\",\"description\":\"Explore peer-reviewed papers on Antisense Oligonucleotide (modality). Clinician-written summaries and actionable practice insights. 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sample sizes referenced are from individual cited studies and vary widely.","value_numeric":null},{"paper_doi":"10.1007/s00702-026-03235-8","tag_type":"warning","value":"Several cited studies (e.g., AMULET trial, ASPIRE study, ATH434 phase 2, PAF meta-analysis) were published in 2026 and may not yet have undergone full peer scrutiny at time of this review's publication.","value_numeric":null},{"paper_doi":"10.1007/s00702-026-03235-8","tag_type":"warning","value":"This is a narrative review, not a systematic review or meta-analysis; evidence synthesis methods are not formally described and may reflect author perspective.","value_numeric":null}],"summaries":{"what_studied":"This narrative review covers the full spectrum of MSA — from genetics and pathophysiology to updated diagnostic criteria, emerging biomarkers, disease-modifying therapies, and evolving care models including telemedicine and multidisciplinary approaches.","key_result":"No disease-modifying therapy has yet demonstrated consistent clinical benefit in MSA. The Phase 2 AMULET trial of amlenetug (anti-α-synuclein monoclonal antibody) missed its primary endpoint, though a non-significant trend toward slowing progression was noted. ATH434 (iron-modulating agent) showed reduced brain iron accumulation and slower clinical progression over 52 weeks vs. placebo. Among patients with pure autonomic failure (PAF), a meta-analysis of 900 individuals found 30% phenoconverted to a central α-synucleinopathy over ~6 years (5.09/100 person-years); 12% converted specifically to MSA. Up to 38% of clinically diagnosed MSA cases are misdiagnosed at autopsy.","limitations":"No primary data are generated; findings are based on literature synthesis with inherent selection bias. Diagnostic gold standard remains neuropathology, introducing heterogeneity into all reviewed clinical and genetic studies. Many emerging biomarkers and therapies lack large, autopsy-confirmed trial cohorts.","practice_takeaway":"Autonomic dysfunction — especially orthostatic hypotension — requires active treatment alongside motor symptoms; clinicians should initiate advance care planning early, before cognitive or communication decline limits patient input. Telemedicine and multidisciplinary models can help maintain access to specialized care as mobility worsens."}},{"doi":"10.1210/clinem/dgag280","pmid":"42497031","title":"Treatment of severe hypertriglyceridemia: a new era dawns","journal_title":"The Journal of Clinical Endocrinology & Metabolism","journal_issn":"0021-972X","published_at":"2026-07-24T00:00:00.000Z","url":"https://doi.org/10.1210/clinem/dgag280","source_score":10,"is_retracted":false,"is_open_access":null,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":false},"created_at":"2026-08-04T18:18:10.395Z","updated_at":"2026-08-04T18:18:10.395Z","tags":[{"paper_doi":"10.1210/clinem/dgag280","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1210/clinem/dgag280","tag_type":"category","value":"Endocrinology & Metabolism","value_numeric":null},{"paper_doi":"10.1210/clinem/dgag280","tag_type":"condition","value":"Acute Pancreatitis","value_numeric":null},{"paper_doi":"10.1210/clinem/dgag280","tag_type":"condition","value":"Cardiovascular Disease","value_numeric":null},{"paper_doi":"10.1210/clinem/dgag280","tag_type":"condition","value":"Severe Hypertriglyceridemia","value_numeric":null},{"paper_doi":"10.1210/clinem/dgag280","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1210/clinem/dgag280","tag_type":"level_of_evidence","value":"7","value_numeric":null},{"paper_doi":"10.1210/clinem/dgag280","tag_type":"modality","value":"Antisense Oligonucleotide","value_numeric":null},{"paper_doi":"10.1210/clinem/dgag280","tag_type":"modality","value":"Gene Therapy","value_numeric":null},{"paper_doi":"10.1210/clinem/dgag280","tag_type":"modality","value":"RNA Interference","value_numeric":null},{"paper_doi":"10.1210/clinem/dgag280","tag_type":"study_design","value":"Narrative Review","value_numeric":null},{"paper_doi":"10.1210/clinem/dgag280","tag_type":"warning","value":"Age group defaulted to 'adult' as the population was not explicitly specified beyond general clinical context.","value_numeric":null},{"paper_doi":"10.1210/clinem/dgag280","tag_type":"warning","value":"'practice_changing' impact flag applied cautiously — the review signals a paradigm shift in the field, though most agents remain investigational.","value_numeric":null},{"paper_doi":"10.1210/clinem/dgag280","tag_type":"warning","value":"The abstract does not name specific agents, trial phases, or numeric efficacy data — tags and summaries reflect only what the text explicitly states.","value_numeric":null},{"paper_doi":"10.1210/clinem/dgag280","tag_type":"warning","value":"The paper is a narrative review; level of evidence is set to 7 (expert opinion/review). No RCT data were extractable.","value_numeric":null}],"summaries":{"what_studied":"This review evaluates emerging therapeutic targets and agents for severe hypertriglyceridemia (TG > 500 mg/dL) and extreme hypertriglyceridemia (TG > 1000 mg/dL), focusing on novel mechanisms of action including loss-of-function gene inhibition and newly identified proteins/hormones involved in TG metabolism.","key_result":"Multiple novel therapeutic strategies targeting TG-rich lipoprotein metabolism are in active clinical development; current approved use remains limited to selected patient populations, with broader indications still under investigation.","limitations":"As a narrative review, it does not provide original trial data, head-to-head comparisons, or pooled effect estimates; most therapies discussed are not yet broadly approved.","practice_takeaway":"Clinicians managing patients with severe or extreme hypertriglyceridemia should be aware of a rapidly expanding pipeline of targeted therapies beyond fibrates and omega-3 fatty acids. Referral to specialized lipid clinics or clinical trials may benefit patients who fail standard therapy."}},{"doi":"10.1002/epi.70354","pmid":"42470358","title":"Progress report on new epilepsy treatments: A summary of the Eighteenth Eilat Conference on New Antiepileptic Drugs and Devices (\n EILAT XVIII\n ). I. Treatments in preclinical and early clinical development","journal_title":"Epilepsia","journal_issn":"0013-9580","published_at":"2026-07-18T00:00:00.000Z","url":"https://doi.org/10.1002/epi.70354","source_score":68,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-08-04T18:17:42.881Z","updated_at":"2026-08-04T18:17:42.881Z","tags":[{"paper_doi":"10.1002/epi.70354","tag_type":"age_group","value":"mixed","value_numeric":null},{"paper_doi":"10.1002/epi.70354","tag_type":"brand","value":"PTI5803","value_numeric":null},{"paper_doi":"10.1002/epi.70354","tag_type":"category","value":"Clinical Neurology","value_numeric":null},{"paper_doi":"10.1002/epi.70354","tag_type":"condition","value":"Epilepsy","value_numeric":null},{"paper_doi":"10.1002/epi.70354","tag_type":"condition","value":"Focal Cortical Dysplasia","value_numeric":null},{"paper_doi":"10.1002/epi.70354","tag_type":"condition","value":"Focal Seizures","value_numeric":null},{"paper_doi":"10.1002/epi.70354","tag_type":"condition","value":"Lafora Disease","value_numeric":null},{"paper_doi":"10.1002/epi.70354","tag_type":"condition","value":"Mesial Temporal Lobe Epilepsy","value_numeric":null},{"paper_doi":"10.1002/epi.70354","tag_type":"condition","value":"Tuberous Sclerosis Complex","value_numeric":null},{"paper_doi":"10.1002/epi.70354","tag_type":"generic","value":"AUT00206","value_numeric":null},{"paper_doi":"10.1002/epi.70354","tag_type":"generic","value":"ION283","value_numeric":null},{"paper_doi":"10.1002/epi.70354","tag_type":"generic","value":"MSCA-7136","value_numeric":null},{"paper_doi":"10.1002/epi.70354","tag_type":"generic","value":"OV329","value_numeric":null},{"paper_doi":"10.1002/epi.70354","tag_type":"generic","value":"probenecid","value_numeric":null},{"paper_doi":"10.1002/epi.70354","tag_type":"generic","value":"simufilam","value_numeric":null},{"paper_doi":"10.1002/epi.70354","tag_type":"generic","value":"SN-2000","value_numeric":null},{"paper_doi":"10.1002/epi.70354","tag_type":"generic","value":"sodium selenate","value_numeric":null},{"paper_doi":"10.1002/epi.70354","tag_type":"impact_flag","value":"limited_evidence","value_numeric":null},{"paper_doi":"10.1002/epi.70354","tag_type":"level_of_evidence","value":"7","value_numeric":null},{"paper_doi":"10.1002/epi.70354","tag_type":"modality","value":"Antisense Oligonucleotide","value_numeric":null},{"paper_doi":"10.1002/epi.70354","tag_type":"modality","value":"Filamin A Modulator","value_numeric":null},{"paper_doi":"10.1002/epi.70354","tag_type":"modality","value":"GABA Aminotransferase Inhibitor","value_numeric":null},{"paper_doi":"10.1002/epi.70354","tag_type":"modality","value":"MEK Inhibitor","value_numeric":null},{"paper_doi":"10.1002/epi.70354","tag_type":"modality","value":"Pannexin 1 Channel Blocker","value_numeric":null},{"paper_doi":"10.1002/epi.70354","tag_type":"modality","value":"Phosphodiesterase 4B Inhibitor","value_numeric":null},{"paper_doi":"10.1002/epi.70354","tag_type":"modality","value":"Potassium Channel Modulator","value_numeric":null},{"paper_doi":"10.1002/epi.70354","tag_type":"modality","value":"Tau Dephosphorylation Promoter","value_numeric":null},{"paper_doi":"10.1002/epi.70354","tag_type":"study_design","value":"Conference Proceedings / Narrative Review","value_numeric":null},{"paper_doi":"10.1002/epi.70354","tag_type":"warning","value":"Full text was behind a security wall and was not accessible — all extracted information is based solely on the abstract.","value_numeric":null},{"paper_doi":"10.1002/epi.70354","tag_type":"warning","value":"No clinical outcome data (efficacy, safety, sample sizes) were available; all eight agents are preclinical or in early clinical development.","value_numeric":null},{"paper_doi":"10.1002/epi.70354","tag_type":"warning","value":"PTI5803 is listed as a brand name for probenecid in the context of this repurposing program; confirm nomenclature as development proceeds.","value_numeric":null},{"paper_doi":"10.1002/epi.70354","tag_type":"warning","value":"Sex of study participants not reported in the abstract.","value_numeric":null},{"paper_doi":"10.1002/epi.70354","tag_type":"warning","value":"Study design categorized as 'Conference Proceedings / Narrative Review' as this is a conference summary report, not a primary trial.","value_numeric":null}],"summaries":{"what_studied":"This conference report summarizes eight investigational treatments for epilepsy — in preclinical and early clinical development — presented at the EILAT XVIII conference (Madrid, May 2026), covering novel mechanisms including potassium channel modulation, antisense oligonucleotides, MEK inhibition, GABA aminotransferase inhibition, pannexin 1 blockade, filamin A modulation, PDE4B inhibition, and tau dephosphorylation promotion.","key_result":"Eight agents were reviewed: AUT00206 (Kv3.1/3.2 PAM), ION283 (ASO for Lafora disease), MSCA-7136 (MEK inhibitor for focal/TSC seizures), OV329 (GABA aminotransferase inhibitor), PTI5803/probenecid (pannexin 1 blocker for focal cortical dysplasia), simufilam (filamin A modulator for TSC epilepsy), SN-2000 (PDE4B inhibitor for focal seizures), and sodium selenate (disease-modifying agent for mesial temporal lobe epilepsy); no clinical efficacy or safety outcome data are reported in the abstract.","limitations":"Full text was inaccessible — only the abstract was available; no quantitative efficacy, safety, or tolerability data are presented; all agents are preclinical or in early clinical stages, limiting clinical applicability.","practice_takeaway":"These agents represent a diverse pipeline of novel mechanisms for drug-resistant and rare epilepsies, but none are yet ready for clinical use — clinicians should monitor their progression in future trials."}},{"doi":"10.1016/j.jid.2026.05.023","pmid":"42417685","title":"History and future of RNA medicines","journal_title":"Journal of Investigative Dermatology","journal_issn":"0022-202X","published_at":"2026-07-07T00:00:00.000Z","url":"https://doi.org/10.1016/j.jid.2026.05.023","source_score":3,"is_retracted":false,"is_open_access":false,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-07-15T13:26:10.470Z","updated_at":"2026-07-15T13:26:10.470Z","tags":[{"paper_doi":"10.1016/j.jid.2026.05.023","tag_type":"age_group","value":"mixed","value_numeric":null},{"paper_doi":"10.1016/j.jid.2026.05.023","tag_type":"category","value":"Dermatology","value_numeric":null},{"paper_doi":"10.1016/j.jid.2026.05.023","tag_type":"condition","value":"Autoimmune Skin Disease","value_numeric":null},{"paper_doi":"10.1016/j.jid.2026.05.023","tag_type":"condition","value":"Chronic Wounds","value_numeric":null},{"paper_doi":"10.1016/j.jid.2026.05.023","tag_type":"condition","value":"Genetic Skin Disease","value_numeric":null},{"paper_doi":"10.1016/j.jid.2026.05.023","tag_type":"condition","value":"Metastatic Melanoma","value_numeric":null},{"paper_doi":"10.1016/j.jid.2026.05.023","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1016/j.jid.2026.05.023","tag_type":"level_of_evidence","value":"7","value_numeric":null},{"paper_doi":"10.1016/j.jid.2026.05.023","tag_type":"modality","value":"Antisense Oligonucleotide","value_numeric":null},{"paper_doi":"10.1016/j.jid.2026.05.023","tag_type":"modality","value":"Aptamer","value_numeric":null},{"paper_doi":"10.1016/j.jid.2026.05.023","tag_type":"modality","value":"MicroRNA","value_numeric":null},{"paper_doi":"10.1016/j.jid.2026.05.023","tag_type":"modality","value":"mRNA Vaccine","value_numeric":null},{"paper_doi":"10.1016/j.jid.2026.05.023","tag_type":"modality","value":"RNA Therapeutics","value_numeric":null},{"paper_doi":"10.1016/j.jid.2026.05.023","tag_type":"modality","value":"Small Interfering RNA","value_numeric":null},{"paper_doi":"10.1016/j.jid.2026.05.023","tag_type":"study_design","value":"Review Article","value_numeric":null},{"paper_doi":"10.1016/j.jid.2026.05.023","tag_type":"warning","value":"Only the abstract was available — no full text was accessible. Summary is based solely on abstract content; specific clinical outcomes, trial data, and mechanistic details could not be extracted.","value_numeric":null},{"paper_doi":"10.1016/j.jid.2026.05.023","tag_type":"warning","value":"The impact_flag 'practice_changing' reflects the field-level framing of the abstract (post-COVID mRNA acceleration) rather than a specific trial result.","value_numeric":null},{"paper_doi":"10.1016/j.jid.2026.05.023","tag_type":"warning","value":"The study_design is inferred as a narrative review based on abstract language; no explicit methods section was visible to confirm.","value_numeric":null}],"summaries":{"what_studied":"This review covers the history and future of RNA therapeutics — including antisense oligonucleotides, siRNAs, microRNAs, mRNAs, and aptamers — with a focus on their advantages over traditional drugs and their emerging applications in dermatology (chronic wounds, metastatic melanoma, autoimmune and genetic skin diseases).","key_result":"The success of mRNA vaccines against SARS-CoV-2 has accelerated clinical translation of RNA medicines; the review highlights faster development timelines and simplified manufacturing as key advantages over small-molecule drugs, protein drugs, and gene therapies.","limitations":"Only the abstract is available — full text could not be reviewed, so specific clinical data, trial outcomes, and detailed mechanistic findings cannot be assessed.","practice_takeaway":"RNA therapeutics are moving rapidly into dermatology; clinicians should watch for emerging approvals and trials targeting chronic wounds, melanoma, and genetic skin conditions. The mRNA platform's success sets a precedent for broader skin disease applications."}},{"doi":"10.1183/16000617.0334-2025","pmid":"42386312","title":"Preclinical human models of primary ciliary dyskinesia","journal_title":"European Respiratory Review","journal_issn":"0905-9180","published_at":"2026-07-01T00:00:00.000Z","url":"https://doi.org/10.1183/16000617.0334-2025","source_score":5,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-07-05T13:38:51.620Z","updated_at":"2026-07-05T13:38:51.620Z","tags":[{"paper_doi":"10.1183/16000617.0334-2025","tag_type":"age_group","value":"mixed","value_numeric":null},{"paper_doi":"10.1183/16000617.0334-2025","tag_type":"category","value":"Respiratory System","value_numeric":null},{"paper_doi":"10.1183/16000617.0334-2025","tag_type":"condition","value":"Primary Ciliary Dyskinesia","value_numeric":null},{"paper_doi":"10.1183/16000617.0334-2025","tag_type":"generic","value":"BMI-1","value_numeric":null},{"paper_doi":"10.1183/16000617.0334-2025","tag_type":"generic","value":"DNAI1 mRNA","value_numeric":null},{"paper_doi":"10.1183/16000617.0334-2025","tag_type":"generic","value":"hTERT","value_numeric":null},{"paper_doi":"10.1183/16000617.0334-2025","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1183/16000617.0334-2025","tag_type":"level_of_evidence","value":"5","value_numeric":null},{"paper_doi":"10.1183/16000617.0334-2025","tag_type":"modality","value":"Antisense Oligonucleotide","value_numeric":null},{"paper_doi":"10.1183/16000617.0334-2025","tag_type":"modality","value":"Gene Therapy","value_numeric":null},{"paper_doi":"10.1183/16000617.0334-2025","tag_type":"modality","value":"Genome Editing","value_numeric":null},{"paper_doi":"10.1183/16000617.0334-2025","tag_type":"modality","value":"Lipid Nanoparticle","value_numeric":null},{"paper_doi":"10.1183/16000617.0334-2025","tag_type":"modality","value":"mRNA Therapy","value_numeric":null},{"paper_doi":"10.1183/16000617.0334-2025","tag_type":"modality","value":"Small Molecule Readthrough Drug","value_numeric":null},{"paper_doi":"10.1183/16000617.0334-2025","tag_type":"study_design","value":"Narrative Review","value_numeric":null},{"paper_doi":"10.1183/16000617.0334-2025","tag_type":"warning","value":"No sample size tag applied — this is a review article with no primary patient cohort. The 'practice_changing' impact flag reflects the field-wide translational significance of the review's framework and emerging therapies, not a single trial result. The phase 1 LNP-DNAI1 mRNA trial outcome is described as expected 'this year' (2026) but results are not yet published in this paper.","value_numeric":null}],"summaries":{"what_studied":"This narrative review examines human preclinical model platforms for primary ciliary dyskinesia (PCD) — including air–liquid interface (ALI) cultures, organoids, spheroids, and lung-on-a-chip — evaluating their ability to recapitulate patient-specific genotypes/phenotypes and support scalable screening of emerging genetic therapies (small molecules, oligonucleotides, mRNA, gene replacement, genome editing).","key_result":"ALI culture remains the most widely used and scalable format, supporting 96-well high-throughput screening; patient-derived and CRISPR-edited models now exist for >15 PCD genes (e.g., DNAH5, DNAH11, DNAI1, CCDC39, CCDC40, RSPH4A). Mosaic data suggest ~30–75% functional cell correction may be needed to restore mucociliary clearance, but clinically meaningful thresholds remain undefined. Inhaled LNP-DNAI1 mRNA showed preclinical efficacy in human ALI models and a nonhuman primate, with a phase 1 trial underway.","limitations":"- No disease-modifying therapy is yet approved; thresholds of molecular, ultrastructural, or motility restoration required for clinical benefit are unknown.\n- Widespread protocol heterogeneity across labs limits reproducibility and cross-study comparisons; consensus reporting standards are lacking.\n- iPSC-derived ciliated cells more closely resemble fetal rather than adult epithelium, and primary cells have limited proliferative capacity, restricting longitudinal studies.","practice_takeaway":"No approved disease-modifying therapy exists for PCD today, but inhaled mRNA and gene-editing approaches are entering early clinical trials — clinicians should be aware that phase 1 data for LNP-DNAI1 mRNA are expected imminently. Field-wide standardisation of preclinical outcome measures and reporting criteria is urgently needed to support regulatory pathways analogous to those used for CFTR modulators in cystic fibrosis."}},{"doi":"10.1007/s00702-026-03208-x","pmid":"42319427","title":"Disease modification in advanced Parkinson’s disease: a review and roadmap for paving the way for next-generation interventions","journal_title":"Journal of Neural Transmission","journal_issn":"0300-9564","published_at":"2026-06-19T00:00:00.000Z","url":"https://doi.org/10.1007/s00702-026-03208-x","source_score":12,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-06-27T13:27:39.225Z","updated_at":"2026-06-27T13:27:39.225Z","tags":[{"paper_doi":"10.1007/s00702-026-03208-x","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1007/s00702-026-03208-x","tag_type":"age_group","value":"older_adult","value_numeric":null},{"paper_doi":"10.1007/s00702-026-03208-x","tag_type":"brand","value":"Lu AF82422","value_numeric":null},{"paper_doi":"10.1007/s00702-026-03208-x","tag_type":"category","value":"Clinical Neurology","value_numeric":null},{"paper_doi":"10.1007/s00702-026-03208-x","tag_type":"category","value":"Neurosciences","value_numeric":null},{"paper_doi":"10.1007/s00702-026-03208-x","tag_type":"condition","value":"Advanced Parkinson's Disease","value_numeric":null},{"paper_doi":"10.1007/s00702-026-03208-x","tag_type":"condition","value":"Parkinson's Disease","value_numeric":null},{"paper_doi":"10.1007/s00702-026-03208-x","tag_type":"generic","value":"amlenetug","value_numeric":null},{"paper_doi":"10.1007/s00702-026-03208-x","tag_type":"generic","value":"anle138b","value_numeric":null},{"paper_doi":"10.1007/s00702-026-03208-x","tag_type":"generic","value":"prasinezumab","value_numeric":null},{"paper_doi":"10.1007/s00702-026-03208-x","tag_type":"impact_flag","value":"limited_evidence","value_numeric":null},{"paper_doi":"10.1007/s00702-026-03208-x","tag_type":"level_of_evidence","value":"5","value_numeric":null},{"paper_doi":"10.1007/s00702-026-03208-x","tag_type":"modality","value":"Alpha-Synuclein Immunotherapy","value_numeric":null},{"paper_doi":"10.1007/s00702-026-03208-x","tag_type":"modality","value":"Antisense Oligonucleotide","value_numeric":null},{"paper_doi":"10.1007/s00702-026-03208-x","tag_type":"modality","value":"Deep Brain Stimulation","value_numeric":null},{"paper_doi":"10.1007/s00702-026-03208-x","tag_type":"modality","value":"GLP-1 Receptor Agonist","value_numeric":null},{"paper_doi":"10.1007/s00702-026-03208-x","tag_type":"modality","value":"Levodopa-Carbidopa Intestinal Gel","value_numeric":null},{"paper_doi":"10.1007/s00702-026-03208-x","tag_type":"modality","value":"Seed Amplification Assay","value_numeric":null},{"paper_doi":"10.1007/s00702-026-03208-x","tag_type":"modality","value":"Stem Cell Transplantation","value_numeric":null},{"paper_doi":"10.1007/s00702-026-03208-x","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1007/s00702-026-03208-x","tag_type":"study_design","value":"Narrative Review","value_numeric":null},{"paper_doi":"10.1007/s00702-026-03208-x","tag_type":"warning","value":"Lu AF82422 is the investigational code for amlenetug; the brand tag reflects the trial compound name as used in the paper, not a commercially approved brand name.","value_numeric":null},{"paper_doi":"10.1007/s00702-026-03208-x","tag_type":"warning","value":"The AMULET trial result cited (19% slowing on UMSARS) was non-statistically significant and pertains to MSA, not PD — generalizability to aPD is speculative as noted by the authors.","value_numeric":null},{"paper_doi":"10.1007/s00702-026-03208-x","tag_type":"warning","value":"The paper does not report a sample size, as it is a review article — sample_size tag omitted accordingly.","value_numeric":null},{"paper_doi":"10.1007/s00702-026-03208-x","tag_type":"warning","value":"This is a narrative expert review; conclusions reflect author consensus and literature synthesis, not systematic review or meta-analysis methodology. No original patient data were generated or analyzed.","value_numeric":null}],"summaries":{"what_studied":"This expert review proposes a multi-domain framework for disease modification in advanced Parkinson's disease (aPD), covering pathological targets (α-synuclein, mitochondrial dysfunction, neuroinflammation, gut-brain axis), biology-driven patient stratification using emerging biomarkers, and management of comorbidities, lifestyle, healthcare access, and caregiver well-being.","key_result":"No single consensus definition of aPD exists; three overlapping frameworks are identified (clinical milestone-based, treatment-based, biomarker-informed). The review concludes that single-target therapies are likely insufficient, and that multi-target strategies combined with precision stratification are needed. Co-pathologies are highly prevalent in long-standing PD: amyloid plaques in >40% of patients in their 60s and up to 85% in their 90s, TDP-43 (LATE) in 20–50%, and tau pathology in 40–60% at autopsy.","limitations":"This is a narrative expert review without systematic meta-analysis or original data; recommendations are consensus-based and not derived from prospective trials in aPD specifically. Biomarkers validated in early PD are not confirmed as surrogates for progression in aPD, and dedicated validation studies in this population are largely lacking.","practice_takeaway":"For patients with advanced PD, clinicians should address modifiable comorbidities (cardiometabolic risk, sleep apnea, polypharmacy/anticholinergic burden, sensory impairment) alongside optimizing dopaminergic therapy, as these factors independently shape functional trajectory. Caregiver strain—driven more by non-motor than motor burden—should be systematically assessed and supported, as caregiver capacity directly influences institutionalization timing and clinical outcomes."}},{"doi":"10.1111/dom.70944","pmid":"42244216","title":"Comparative Effects of Emerging Lp(a)‐Lowering Agents and\n PCSK9\n ‐Directed Therapies on Lipoprotein(a): A Network Meta‐Analysis of Randomised Clinical Trials","journal_title":"Diabetes, Obesity and Metabolism","journal_issn":"1462-8902","published_at":"2026-06-04T00:00:00.000Z","url":"https://doi.org/10.1111/dom.70944","source_score":1,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-06-09T13:50:35.173Z","updated_at":"2026-06-09T13:50:35.173Z","tags":[{"paper_doi":"10.1111/dom.70944","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1111/dom.70944","tag_type":"brand","value":"Praluent","value_numeric":null},{"paper_doi":"10.1111/dom.70944","tag_type":"brand","value":"Repatha","value_numeric":null},{"paper_doi":"10.1111/dom.70944","tag_type":"category","value":"Endocrinology & Metabolism","value_numeric":null},{"paper_doi":"10.1111/dom.70944","tag_type":"condition","value":"Atherosclerotic Cardiovascular Disease","value_numeric":null},{"paper_doi":"10.1111/dom.70944","tag_type":"condition","value":"Elevated Lipoprotein(a)","value_numeric":null},{"paper_doi":"10.1111/dom.70944","tag_type":"generic","value":"alirocumab","value_numeric":null},{"paper_doi":"10.1111/dom.70944","tag_type":"generic","value":"evolocumab","value_numeric":null},{"paper_doi":"10.1111/dom.70944","tag_type":"generic","value":"lepodisiran","value_numeric":null},{"paper_doi":"10.1111/dom.70944","tag_type":"generic","value":"muvalaplin","value_numeric":null},{"paper_doi":"10.1111/dom.70944","tag_type":"generic","value":"olpasiran","value_numeric":null},{"paper_doi":"10.1111/dom.70944","tag_type":"generic","value":"pelacarsen","value_numeric":null},{"paper_doi":"10.1111/dom.70944","tag_type":"generic","value":"zerlasiran","value_numeric":null},{"paper_doi":"10.1111/dom.70944","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1111/dom.70944","tag_type":"level_of_evidence","value":"1","value_numeric":null},{"paper_doi":"10.1111/dom.70944","tag_type":"modality","value":"Antisense Oligonucleotide","value_numeric":null},{"paper_doi":"10.1111/dom.70944","tag_type":"modality","value":"Oral Assembly Inhibitor","value_numeric":null},{"paper_doi":"10.1111/dom.70944","tag_type":"modality","value":"PCSK9 Inhibitor","value_numeric":null},{"paper_doi":"10.1111/dom.70944","tag_type":"modality","value":"Small Interfering RNA (siRNA)","value_numeric":null},{"paper_doi":"10.1111/dom.70944","tag_type":"sample_size","value":"n=17810","value_numeric":17810},{"paper_doi":"10.1111/dom.70944","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1111/dom.70944","tag_type":"study_design","value":"Network Meta-Analysis","value_numeric":null},{"paper_doi":"10.1111/dom.70944","tag_type":"warning","value":"High heterogeneity (I² = 90.9%) and funnel plot asymmetry substantially reduce certainty for individual treatment estimates; rankings should be interpreted directionally rather than as precise comparisons.","value_numeric":null},{"paper_doi":"10.1111/dom.70944","tag_type":"warning","value":"Most Lp(a)-targeted agents (olpasiran, zerlasiran, lepodisiran, muvalaplin) lack completed cardiovascular outcome trials; clinical benefit is inferred from Lp(a) reduction, not hard endpoints.","value_numeric":null},{"paper_doi":"10.1111/dom.70944","tag_type":"warning","value":"The impact_flag 'practice_changing' reflects the scale of Lp(a) reductions demonstrated, but should be viewed cautiously given the absence of outcomes data for emerging agents.","value_numeric":null}],"summaries":{"what_studied":"This network meta-analysis compared the efficacy and safety of emerging Lp(a)-targeted therapies (siRNAs: olpasiran, zerlasiran, lepodisiran; antisense oligonucleotide: pelacarsen; oral assembly inhibitor: muvalaplin) versus PCSK9-directed therapies (evolocumab, alirocumab) on percent change in Lp(a) from baseline across 51 RCTs (n=17,810 adults, ≥8-week follow-up) through December 2025.","key_result":"Olpasiran 225 mg Q12W showed the greatest Lp(a) reduction (MD −98.94 pp vs. placebo, 95% CI −114.36 to −83.52); pelacarsen, muvalaplin, zerlasiran, and lepodisiran also produced large reductions. PCSK9 inhibitors offered more modest Lp(a) lowering (evolocumab 140 mg Q2W: MD −31.58 pp) but greater LDL-C reduction. No agent was linked to more serious adverse events or discontinuations versus placebo; alirocumab 150 mg had more injection-site reactions.","limitations":"- Very high heterogeneity (I² = 90.9%) in the primary Lp(a) network, limiting confidence in point estimates.\n- Funnel plot asymmetry suggests possible publication bias or small-study effects.\n- No cardiovascular outcome trial data yet available for most Lp(a)-targeted agents, so clinical hard-endpoint benefit remains unproven.","practice_takeaway":"Emerging Lp(a)-specific agents (especially olpasiran, zerlasiran, lepodisiran, pelacarsen, muvalaplin) cut Lp(a) far more than PCSK9 inhibitors, but cardiovascular outcome trials are still needed before routine use. PCSK9 inhibitors remain the better choice when both LDL-C and Lp(a) lowering are priorities."}},{"doi":"10.1056/nejmoa2515131","pmid":"42206582","title":"Phase 3 Results of Bepirovirsen Treatment for Chronic Hepatitis B Virus Infection","journal_title":"New England Journal of Medicine","journal_issn":"0028-4793","published_at":"2026-05-28T00:00:00.000Z","url":"https://doi.org/10.1056/nejmoa2515131","source_score":874,"is_retracted":false,"is_open_access":false,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-06-01T13:39:31.176Z","updated_at":"2026-06-01T13:39:31.176Z","tags":[{"paper_doi":"10.1056/nejmoa2515131","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1056/nejmoa2515131","tag_type":"category","value":"Medicine, General & Internal","value_numeric":null},{"paper_doi":"10.1056/nejmoa2515131","tag_type":"condition","value":"Chronic Hepatitis B Virus Infection","value_numeric":null},{"paper_doi":"10.1056/nejmoa2515131","tag_type":"generic","value":"bepirovirsen","value_numeric":null},{"paper_doi":"10.1056/nejmoa2515131","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1056/nejmoa2515131","tag_type":"level_of_evidence","value":"1","value_numeric":null},{"paper_doi":"10.1056/nejmoa2515131","tag_type":"modality","value":"Antisense Oligonucleotide","value_numeric":null},{"paper_doi":"10.1056/nejmoa2515131","tag_type":"sample_size","value":"n=1834","value_numeric":1834},{"paper_doi":"10.1056/nejmoa2515131","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1056/nejmoa2515131","tag_type":"study_design","value":"Randomized Controlled Trial","value_numeric":null},{"paper_doi":"10.1056/nejmoa2515131","tag_type":"warning","value":"Full-text data (e.g., subgroup analyses, virologic rebound rates after NA discontinuation) are not available from the abstract alone; some details may be materially relevant to clinical interpretation.","value_numeric":null},{"paper_doi":"10.1056/nejmoa2515131","tag_type":"warning","value":"No brand name for bepirovirsen was available in the source text; it is an investigational agent funded by GSK.","value_numeric":null},{"paper_doi":"10.1056/nejmoa2515131","tag_type":"warning","value":"Total sample size of n=1834 is an approximation pooled from both trials (B-Well 1: 650+328=978; B-Well 2: 570+286=856; total=1834). Exact enrolled vs. randomized counts may differ slightly in the full text.","value_numeric":null}],"summaries":{"what_studied":"Two replicate phase 3 double-blind RCTs (B-Well 1 and B-Well 2) evaluated subcutaneous bepirovirsen 300 mg weekly for 24 weeks vs. placebo in noncirrhotic adults with chronic HBV on stable NA therapy (HBsAg 100–3000 IU/mL), with NA discontinuation at week 48 and primary outcome of functional cure (HBsAg loss + HBV DNA A p.(Gly70Glu) causes variable non-syndromic dominant retinal dystrophy with defective lipidated protein transport in human retinal stem cell models","journal-title":"Hum Mol Genet","doi-asserted-by":"crossref"},{"DOI":"10.1016/j.cell.2020.08.013","key":"10.1016/j.exer.2026.111051_bib19","year":"2020","issue":null,"author":"Cowan","volume":"182","first-page":null,"unstructured":null,"article-title":"Cell Types of the Human Retina and Its Organoids at Single-Cell Resolution","journal-title":"Cell","doi-asserted-by":"crossref"},{"DOI":"10.1016/j.ymthe.2024.10.004","key":"10.1016/j.exer.2026.111051_bib20","year":"2024","issue":null,"author":"Damodar","volume":"32","first-page":"4319","unstructured":null,"article-title":"Dual CRALBP isoforms unveiled: iPSC-derived retinal modeling and AAV2/5-RLBP1 gene transfer raise considerations for effective therapy","journal-title":"Mol Ther","doi-asserted-by":"crossref"},{"DOI":"10.7150/thno.87266","key":"10.1016/j.exer.2026.111051_bib21","year":"2023","issue":null,"author":"Deng","volume":"13","first-page":"4526","unstructured":null,"article-title":"Organ-on-a-chip meets artificial intelligence in drug evaluation","journal-title":"Theranostics","doi-asserted-by":"crossref"},{"DOI":"10.1017/S0952523800005605","key":"10.1016/j.exer.2026.111051_bib22","year":"1992","issue":null,"author":"Diaz-Araya","volume":"8","first-page":"505","unstructured":null,"article-title":"Evidence of photoreceptor migration during early foveal development: a quantitative analysis of human fetal retinae","journal-title":"Vis Neurosci","doi-asserted-by":"crossref"},{"DOI":"10.1038/s41587-021-00815-9","key":"10.1016/j.exer.2026.111051_bib23","year":"2021","issue":null,"author":"Drakhlis","volume":"39","first-page":"737","unstructured":null,"article-title":"Human heart-forming organoids recapitulate early heart and foregut development","journal-title":"Nat Biotechnol","doi-asserted-by":"crossref"},{"DOI":"10.1186/s13287-024-03767-4","key":"10.1016/j.exer.2026.111051_bib24","year":"2024","issue":null,"author":"Duan","volume":"15","first-page":"152","unstructured":null,"article-title":"Retinal organoids with X-linked retinoschisis RS1 (E72K) mutation exhibit a photoreceptor developmental delay and are rescued by gene augmentation therapy","journal-title":"Stem Cell Research & 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three-dimensional retinal tissue with functional photoreceptors from human iPSCs","journal-title":"Nat Commun","doi-asserted-by":"crossref"}],"short-title":[],"update-policy":"https://doi.org/10.1016/elsevier_cm_policy","alternative-id":["S0014483526002071"],"article-number":"111051","content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"original-title":[],"container-title":["Experimental Eye Research"],"published-print":{"date-parts":[[2026,5]]},"reference-count":115,"published-online":null,"references-count":115,"short-container-title":["Experimental Eye Research"],"is-referenced-by-count":0},"unpaywall":{"doi":"10.1016/j.exer.2026.111051","is_oa":false,"title":"Human retinal organoids: from developmental biology to translational 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Retinopathy","value_numeric":null},{"paper_doi":"10.1016/j.exer.2026.111051","tag_type":"impact_flag","value":"limited_evidence","value_numeric":null},{"paper_doi":"10.1016/j.exer.2026.111051","tag_type":"level_of_evidence","value":"7","value_numeric":null},{"paper_doi":"10.1016/j.exer.2026.111051","tag_type":"modality","value":"Antisense Oligonucleotide","value_numeric":null},{"paper_doi":"10.1016/j.exer.2026.111051","tag_type":"modality","value":"Base Editing","value_numeric":null},{"paper_doi":"10.1016/j.exer.2026.111051","tag_type":"modality","value":"Cell Transplantation","value_numeric":null},{"paper_doi":"10.1016/j.exer.2026.111051","tag_type":"modality","value":"Gene Therapy","value_numeric":null},{"paper_doi":"10.1016/j.exer.2026.111051","tag_type":"modality","value":"Stem Cell-Derived Retinal Organoid","value_numeric":null},{"paper_doi":"10.1016/j.exer.2026.111051","tag_type":"study_design","value":"Narrative Review","value_numeric":null},{"paper_doi":"10.1016/j.exer.2026.111051","tag_type":"warning","value":"No sample size is applicable as this is a review article; the level of evidence is set at the lowest tier accordingly.","value_numeric":null},{"paper_doi":"10.1016/j.exer.2026.111051","tag_type":"warning","value":"The paper is published in 2026 and references emerging assembloid and multilineage coculture systems that may not yet have broad peer-reviewed validation.","value_numeric":null},{"paper_doi":"10.1016/j.exer.2026.111051","tag_type":"warning","value":"This is a narrative review, not a systematic review or meta-analysis; conclusions reflect author synthesis rather than pooled quantitative evidence.","value_numeric":null}],"summaries":{"what_studied":"This review evaluates human retinal organoids (ROs) derived from pluripotent stem cells, covering their evolution from early differentiation protocols to advanced platforms, and their applications in developmental biology, disease modeling, precision medicine, and regenerative ophthalmology.","key_result":"ROs show meaningful utility for modeling inherited retinal disorders, toxic and infectious retinopathies, and for validating gene augmentation, antisense, and base-editing therapies; however, functional integration of RO-derived photoreceptors in regenerative settings lacks clear clinical evidence.","limitations":"- ROs lack a true fovea and do not fully recapitulate the outer retina–RPE–choroid interface.\n- Vascularization, immune cell interactions, and inner-retinal connectivity remain absent or incomplete.\n- Significant variability exists across differentiation protocols and cell lines, limiting reproducibility.","practice_takeaway":"ROs are a promising but not yet clinically mature platform; clinicians evaluating gene therapy or cell transplant pipelines should weigh RO validation data carefully, recognizing gaps in foveal modeling and functional integration evidence.\n\nEmerging assembloid and coculture systems may soon address key structural gaps, but current RO-based findings require cautious translation to patient care."}},{"doi":"10.1161/circheartfailure.126.014205","pmid":"42104840","title":"Rationale and Design of CARDIO-TTRansform, a Phase 3 Trial of Eplontersen in Transthyretin Amyloid Cardiomyopathy","journal_title":"Circulation: Heart Failure","journal_issn":"1941-3289","published_at":"2026-05-09T00:00:00.000Z","url":"https://doi.org/10.1161/circheartfailure.126.014205","source_score":22,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-06-22T13:24:14.749Z","updated_at":"2026-06-22T13:24:14.749Z","tags":[{"paper_doi":"10.1161/circheartfailure.126.014205","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1161/circheartfailure.126.014205","tag_type":"age_group","value":"older_adult","value_numeric":null},{"paper_doi":"10.1161/circheartfailure.126.014205","tag_type":"brand","value":"Wainua","value_numeric":null},{"paper_doi":"10.1161/circheartfailure.126.014205","tag_type":"category","value":"Cardiac & Cardiovascular Systems","value_numeric":null},{"paper_doi":"10.1161/circheartfailure.126.014205","tag_type":"condition","value":"Transthyretin Amyloid Cardiomyopathy","value_numeric":null},{"paper_doi":"10.1161/circheartfailure.126.014205","tag_type":"condition","value":"Transthyretin Amyloidosis","value_numeric":null},{"paper_doi":"10.1161/circheartfailure.126.014205","tag_type":"generic","value":"eplontersen","value_numeric":null},{"paper_doi":"10.1161/circheartfailure.126.014205","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1161/circheartfailure.126.014205","tag_type":"level_of_evidence","value":"1","value_numeric":null},{"paper_doi":"10.1161/circheartfailure.126.014205","tag_type":"modality","value":"Antisense Oligonucleotide","value_numeric":null},{"paper_doi":"10.1161/circheartfailure.126.014205","tag_type":"modality","value":"TTR Silencer","value_numeric":null},{"paper_doi":"10.1161/circheartfailure.126.014205","tag_type":"sample_size","value":"n=1432","value_numeric":1432},{"paper_doi":"10.1161/circheartfailure.126.014205","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1161/circheartfailure.126.014205","tag_type":"study_design","value":"Randomized Controlled Trial","value_numeric":null},{"paper_doi":"10.1161/circheartfailure.126.014205","tag_type":"warning","value":"Sample size was amended three times during the trial, which may affect interpretation of the final power assumptions when results are published.","value_numeric":null},{"paper_doi":"10.1161/circheartfailure.126.014205","tag_type":"warning","value":"The trial enrolled patients up to age 90, but age-specific subgroup results are not yet available.","value_numeric":null},{"paper_doi":"10.1161/circheartfailure.126.014205","tag_type":"warning","value":"This is a trial design/rationale paper only — no efficacy or safety outcome data are reported; the impact_flag 'practice_changing' reflects the trial's potential significance pending results.","value_numeric":null}],"summaries":{"what_studied":"CARDIO-TTRansform is a Phase 3, double-blind, placebo-controlled trial evaluating eplontersen 45 mg SC every 4 weeks vs. placebo for up to 140 weeks in 1,432 adults with variant or wild-type ATTR cardiomyopathy (NYHA class I–III), with unrestricted background use of TTR stabilizers.","key_result":"This is a design/rationale paper — no efficacy outcomes are yet reported. The trial is fully enrolled (n=1,432), making it the largest ATTR-CM trial to date. The primary endpoint is a composite of cardiovascular mortality and recurrent cardiovascular clinical events at 140 weeks; the trial is powered (~85%) to detect a 20% reduction, assuming a placebo CV death rate of 8.7% and 0.476 CV events/patient over 140 weeks.","limitations":"- No efficacy results available yet; this paper describes only design and rationale.\n- Protocol underwent multiple amendments (sample size increased from 700 → 1,000 → 1,400) due to lower-than-expected event rates in contemporary ATTR-CM populations, reflecting uncertainty in event rate projections.\n- Subgroup analysis of patients on background TTR stabilizers is a secondary endpoint, so it is not independently powered for a definitive conclusion.","practice_takeaway":"CARDIO-TTRansform will provide the first Phase 3 RCT evidence on whether eplontersen (an ASO TTR silencer, self-administered via autoinjector) improves CV outcomes on top of current standard of care — including tafamidis or acoramidis — in ATTR-CM. Clinicians should watch for results, as a positive trial could support adding TTR silencing to stabilizer therapy across both variant and wild-type ATTR-CM."}},{"doi":"10.1182/bloodadvances.2025018710","pmid":"41925579","title":"IL-6–driven POU2AF1 and ELL2 are key regulators of multiple myeloma–distinct transcriptional and splicing programs","journal_title":"Blood Advances","journal_issn":"2473-9529","published_at":"2026-04-02T00:00:00.000Z","url":"https://doi.org/10.1182/bloodadvances.2025018710","source_score":3,"is_retracted":false,"is_open_access":true,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-06-05T13:26:51.524Z","updated_at":"2026-06-05T13:26:51.524Z","tags":[{"paper_doi":"10.1182/bloodadvances.2025018710","tag_type":"age_group","value":"mixed","value_numeric":null},{"paper_doi":"10.1182/bloodadvances.2025018710","tag_type":"category","value":"Hematology","value_numeric":null},{"paper_doi":"10.1182/bloodadvances.2025018710","tag_type":"condition","value":"Multiple Myeloma","value_numeric":null},{"paper_doi":"10.1182/bloodadvances.2025018710","tag_type":"generic","value":"gapmer antisense oligonucleotide","value_numeric":null},{"paper_doi":"10.1182/bloodadvances.2025018710","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1182/bloodadvances.2025018710","tag_type":"level_of_evidence","value":"6","value_numeric":null},{"paper_doi":"10.1182/bloodadvances.2025018710","tag_type":"modality","value":"Antisense Oligonucleotide","value_numeric":null},{"paper_doi":"10.1182/bloodadvances.2025018710","tag_type":"modality","value":"CRISPR Knockout","value_numeric":null},{"paper_doi":"10.1182/bloodadvances.2025018710","tag_type":"modality","value":"JAK Inhibitor","value_numeric":null},{"paper_doi":"10.1182/bloodadvances.2025018710","tag_type":"study_design","value":"Preclinical Laboratory Study","value_numeric":null},{"paper_doi":"10.1182/bloodadvances.2025018710","tag_type":"warning","value":"No sample size is reported in the abstract; the study is preclinical with no patient cohort data, so sample_size tag was omitted.","value_numeric":null},{"paper_doi":"10.1182/bloodadvances.2025018710","tag_type":"warning","value":"Published date is listed as 2026-04-02, which is in the future relative to today's date (June 05, 2026) — this may reflect an online-ahead-of-print or issue date discrepancy.","value_numeric":null},{"paper_doi":"10.1182/bloodadvances.2025018710","tag_type":"warning","value":"Study design label 'Preclinical Laboratory Study' is an approximation; the paper combines multiple experimental approaches (CRISPR screen, ChIP-seq, xenograft) without a single canonical study design label.","value_numeric":null},{"paper_doi":"10.1182/bloodadvances.2025018710","tag_type":"warning","value":"The 'practice_changing' impact flag reflects novel therapeutic target identification at the preclinical stage only — clinical translation has not yet been demonstrated.","value_numeric":null}],"summaries":{"what_studied":"This study investigated how the IL-6/JAK/STAT3 pathway drives transcriptional and RNA splicing programs in multiple myeloma (MM), focusing on the B-cell lineage factors POU2AF1 and ELL2 as key downstream targets, using ChIP-seq, transcriptomics, CRISPR knockout screening, xenograft mouse models, and antisense oligonucleotide (ASO) targeting.","key_result":"POU2AF1 and ELL2 form an autoregulatory loop with IRF4 that sustains an MM-distinct immature transcriptional program; their genetic depletion suppressed MM cell growth in vitro and in IL-6 humanized xenograft models. Gapmer ASOs targeting POU2AF1 reduced MM cell growth even in the presence of bone marrow stromal factors including IL-6.","limitations":"Findings are largely based on cell line and xenograft models; clinical validation in patient cohorts is absent. The study does not address acquired resistance mechanisms to POU2AF1 targeting. Functional dissection of POU2AF1's roles in transcription vs. splicing was not fully separated mechanistically.","practice_takeaway":"POU2AF1 and ELL2 are emerging therapeutic vulnerabilities in MM that persist even in the bone marrow microenvironment. Gapmer ASOs targeting POU2AF1 show preclinical promise and may warrant further development as a novel MM treatment strategy."}},{"doi":"10.1161/circulationaha.126.080012","pmid":"41910513","title":"Effect of APOC3 Inhibition With Olezarsen on Coronary Atherosclerosis: Essence-TIMI 73b Imaging Study","journal_title":"Circulation","journal_issn":"0009-7322","published_at":"2026-03-30T00:00:00.000Z","url":"https://doi.org/10.1161/circulationaha.126.080012","source_score":105,"is_retracted":false,"is_open_access":false,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-05-24T13:23:13.961Z","updated_at":"2026-05-24T13:23:13.961Z","tags":[{"paper_doi":"10.1161/circulationaha.126.080012","tag_type":"age_group","value":"older_adult","value_numeric":null},{"paper_doi":"10.1161/circulationaha.126.080012","tag_type":"category","value":"Cardiac & Cardiovascular Systems","value_numeric":null},{"paper_doi":"10.1161/circulationaha.126.080012","tag_type":"condition","value":"Cardiovascular Disease","value_numeric":null},{"paper_doi":"10.1161/circulationaha.126.080012","tag_type":"condition","value":"Coronary Atherosclerosis","value_numeric":null},{"paper_doi":"10.1161/circulationaha.126.080012","tag_type":"condition","value":"Hypertriglyceridemia","value_numeric":null},{"paper_doi":"10.1161/circulationaha.126.080012","tag_type":"generic","value":"olezarsen","value_numeric":null},{"paper_doi":"10.1161/circulationaha.126.080012","tag_type":"impact_flag","value":"confirms_prior","value_numeric":null},{"paper_doi":"10.1161/circulationaha.126.080012","tag_type":"level_of_evidence","value":"2","value_numeric":null},{"paper_doi":"10.1161/circulationaha.126.080012","tag_type":"modality","value":"Antisense Oligonucleotide","value_numeric":null},{"paper_doi":"10.1161/circulationaha.126.080012","tag_type":"sample_size","value":"n=468","value_numeric":468},{"paper_doi":"10.1161/circulationaha.126.080012","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1161/circulationaha.126.080012","tag_type":"study_design","value":"Randomized Controlled Trial","value_numeric":null},{"paper_doi":"10.1161/circulationaha.126.080012","tag_type":"warning","value":"Level of evidence assigned as 2 (RCT imaging sub-study); primary hard-outcome RCT data not yet available.","value_numeric":null},{"paper_doi":"10.1161/circulationaha.126.080012","tag_type":"warning","value":"Median follow-up for imaging was 12 months — the trial's primary clinical outcomes (MACE) are not yet reported, so the lack of plaque change does not preclude a future cardiovascular event benefit.","value_numeric":null},{"paper_doi":"10.1161/circulationaha.126.080012","tag_type":"warning","value":"The imaging sub-study was nested within a larger RCT (Essence-TIMI 73b); it is unclear if the imaging cohort was pre-specified or powered for the plaque endpoint, which may limit the strength of the null result.","value_numeric":null}],"summaries":{"what_studied":"This imaging sub-study of Essence-TIMI 73b evaluated whether olezarsen (an APOC3-targeting antisense oligonucleotide) vs. placebo changed coronary noncalcified plaque volume over 12 months in 468 adults with largely moderate hypertriglyceridemia (median TG 249 mg/dL), high CV risk, and existing noncalcified plaque on baseline CCTA — 97% were already on lipid-lowering therapy.","key_result":"Despite reducing triglycerides by 63.9%, remnant cholesterol by 71.9%, and apoB by 16.0% vs. placebo at 6 months, olezarsen did not significantly change noncalcified plaque volume at 12 months (placebo-adjusted LS mean difference: +2.98% [95% CI, −3.4 to +9.3]; p=0.36). Calcified, low-attenuation, and total plaque volumes were also unchanged.","limitations":"- Short 12-month imaging window may be insufficient to detect plaque regression given the degree of lipid lowering achieved.\n- No effect on LDL-C, which is the dominant driver of plaque burden; apoB reduction was modest (~16%), limiting the ability to detect plaque benefit.\n- Imaging sub-study design (not pre-specified primary trial endpoint); results may not be powered to detect small but clinically meaningful plaque changes.","practice_takeaway":"Clinicians should not expect coronary plaque regression from triglyceride/remnant cholesterol lowering with olezarsen alone in 12 months, even with dramatic TG reduction, in patients already on standard lipid-lowering therapy. Targeting LDL-C and apoB more aggressively remains central to plaque-modifying strategies."}},{"doi":"10.1016/j.cmet.2025.12.022","pmid":"41605214","title":"Ferroplasticity drives social isolation-induced anxiety via a ventral hippocampal iron-α-synuclein axis","journal_title":"Cell Metabolism","journal_issn":"1550-4131","published_at":"2026-01-29T00:00:00.000Z","url":"https://doi.org/10.1016/j.cmet.2025.12.022","source_score":31,"is_retracted":false,"is_open_access":false,"raw_metadata":{"ooir":{"day":"2026-05-10","doi":"10.1016/j.cmet.2025.12.022","days":"7","issn":"1550-4131","rank":"4","field":"Clinical Medicine","score":"31","category":"Endocrinology & Metabolism","categories":["Endocrinology & Metabolism"],"_categories":["Endocrinology & Metabolism"]},"pubmed":{"doi":"10.1016/j.cmet.2025.12.022","title":"Ferroplasticity drives social isolation-induced anxiety via a ventral hippocampal iron-α-synuclein axis.","journal":"Cell 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