Frailty and Renal Cell Carcinoma: Integration of Comprehensive Geriatric Assessment into Shared Decision-making.

CONTEXT: Frailty, a geriatric syndrome characterized by decreased resilience and physiological reserve, impacts the prognosis and management of older adults significantly, particularly in the context of surgical and oncological care. OBJECTIVE: To provide an overview of frailty assessment in the management of older patients with a renal mass/renal cell carcinoma (RCC), focusing on its implications for diagnostic workup, treatment decisions, and clinical outcomes. EVIDENCE ACQUISITION: A narrative review of the literature was conducted, focusing on frailty definitions, assessment tools, and their application in geriatric oncology, applied to the field of RCC. Relevant studies addressing the prognostic value of frailty, its impact on treatment outcomes, and potential interventions were summarized. EVIDENCE SYNTHESIS: Frailty is a poor prognostic factor and can influence decision-making in the management of both localized and metastatic RCC. Screening tools such as the Geriatric Screening Tool 8 (G8) and the Mini-COG test can aid clinicians to select older patients (ie, aged ≥65 yr) for a further comprehensive geriatric assessment (CGA) performed by dedicated geriatricians. The CGA provides insights to risk stratify patients and guide subsequent treatment pathways. As such, the involvement of geriatricians in multidisciplinary tumor boards emerges as an essential priority to address the complex needs of frail patients and optimize clinical outcomes. Herein, we propose a dedicated care pathway as a first key step to implement frailty assessment in clinical practice and research for RCC. CONCLUSIONS: Frailty has emerged as a crucial factor influencing the management and outcomes of older patients with RCC. Involvement of geriatricians in diagnostic and therapeutic pathways represents a pragmatic approach to screen and assess frailty, fostering individualized treatment decisions according to holistic patient risk stratification. PATIENT SUMMARY: Frailty, a decline in resilience and physiological reserve, influences treatment decisions and outcomes in elderly patients with renal cell carcinoma, guiding personalized care. In this review, we focused on pragmatic strategies to screen patients with a renal mass suspected for renal cell carcinoma, who are older than 65 yr, for frailty and on personalized management algorithms integrating geriatric input beyond patient- and tumor-related factors.

A polarized FGF8 source specifies frontotemporal signatures in spatially oriented cell populations of cortical assembloids.

Organoids generating major cortical cell types in distinct compartments are used to study cortical development, evolution and disorders. However, the lack of morphogen gradients imparting cortical positional information and topography in current systems hinders the investigation of complex phenotypes. Here, we engineer human cortical assembloids by fusing an organizer-like structure expressing fibroblast growth factor 8 (FGF8) with an elongated organoid to enable the controlled modulation of FGF8 signaling along the longitudinal organoid axis. These polarized cortical assembloids mount a position-dependent transcriptional program that in part matches the in vivo rostrocaudal gene expression patterns and that is lost upon mutation in the FGFR3 gene associated with temporal lobe malformations and intellectual disability. By producing spatially oriented cell populations with signatures related to frontal and temporal area identity within individual assembloids, this model recapitulates in part the early transcriptional divergence embedded in the protomap and enables the study of cortical area-relevant alterations underlying human disorders.

HLA alleles associated to susceptibility to gliptin-associated bullous pemphigoid in Italian patients.

Bullous pemphigoid (BP), although a rare disease, is the most frequent subepidermal autoimmune disorder. Treatment with gliptins, used for type 2 diabetes, was reported as associated with BP onset. To identify HLA alleles that may reflect a higher susceptibility to BP in the Italian population, we analysed 30 patients affected by idiopathic bullous pemphigoid (IBP) and 86 gliptin-associated BP (GABP) patients. A significant association between HLA-DQB1*03:01 allele and IBP and GABP patients was found. Of note, both IBP and GABP were significantly associated with one of the following haplotypes: DRB1*11:01, DRB3*02:02, DQA1*05:05, DQB1*03:01 or DRB1*11:04, DRB3*02:02, DQA1*05:05 and DQB1*03:01. These data identify, for the first time, potential markers of susceptibility to BP in the Italian population, especially when associated with gliptin intake.

A multi-layered integrative analysis reveals a cholesterol metabolic program in outer radial glia with implications for human brain evolution.

The definition of molecular and cellular mechanisms contributing to brain ontogenetic trajectories is essential to investigate the evolution of our species. Yet their functional dissection at an appropriate level of granularity remains challenging. Capitalizing on recent efforts that have extensively profiled neural stem cells from the developing human cortex, we develop an integrative computational framework to perform trajectory inference and gene regulatory network reconstruction, (pseudo)time-informed non-negative matrix factorization for learning the dynamics of gene expression programs, and paleogenomic analysis for a higher-resolution mapping of derived regulatory variants in our species in comparison with our closest relatives. We provide evidence for cell type-specific regulation of gene expression programs during indirect neurogenesis. In particular, our analysis uncovers a key role for a cholesterol program in outer radial glia, regulated by zinc-finger transcription factor KLF6. A cartography of the regulatory landscape impacted by Homo sapiens-derived variants reveals signals of selection clustering around regulatory regions associated with GLI3, a well-known regulator of radial glial cell cycle, and impacting KLF6 regulation. Our study contributes to the evidence of significant changes in metabolic pathways in recent human brain evolution.

Engineering Toxoplasma gondii secretion systems for intracellular delivery of multiple large therapeutic proteins to neurons.

Delivering macromolecules across biological barriers such as the blood-brain barrier limits their application in vivo. Previous work has demonstrated that Toxoplasma gondii, a parasite that naturally travels from the human gut to the central nervous system (CNS), can deliver proteins to host cells. Here we engineered T. gondii's endogenous secretion systems, the rhoptries and dense granules, to deliver multiple large (>100 kDa) therapeutic proteins into neurons via translational fusions to toxofilin and GRA16. We demonstrate delivery in cultured cells, brain organoids and in vivo, and probe protein activity using imaging, pull-down assays, scRNA-seq and fluorescent reporters. We demonstrate robust delivery after intraperitoneal administration in mice and characterize 3D distribution throughout the brain. As proof of concept, we demonstrate GRA16-mediated brain delivery of the MeCP2 protein, a putative therapeutic target for Rett syndrome. By characterizing the potential and current limitations of the system, we aim to guide future improvements that will be required for broader application.

Geriatricians' role in the management of aortic stenosis in frail older patients: a decade later.

INTRODUCTION: Increasing evidence supports the implementation of geriatric assessment in the workup of older patients with aortic stenosis (AS). In 2012, an online European survey revealed that geriatricians were rarely involved in the assessment of candidates for transcatheter aortic valve implantation (TAVI). After a "call to action" for early involvement of geriatricians in AS evaluation, the survey was repeated in 2022. Our aim was to investigate whether geriatricians' role changed in the last decade. METHODS: Online survey conducted between December 16th, 2021, and December 15th, 2022. All members of the European Geriatric Medicine Society were invited to participate. The survey included 26 questions regarding geriatricians' experience with AS and TAVI. RESULTS: Among 193 respondents (79.8% geriatricians), 73 (38%) reported to be involved in AS evaluation at least once a week. During 2 years prior to the survey, 43 (22.3%) had referred > 50% of their patients with severe AS for TAVI. Age influenced TAVI referral in a considerable proportion of respondents (36.8%). TAVI candidates were mainly referred to specialised cardiac centres with multidisciplinary teams (91.8%), including (47.2%) or not including (44.6%) a geriatrician. A total of 38.9% of respondents reported to be part of a multidisciplinary heart team. Geriatricians were less frequently involved (37%) than cardiologists (89.6%) and surgeons (53.4%) in pre-procedural TAVI management. Cardiologists were more frequently involved (85.5%) than geriatricians (33.7%) and surgeons (26.9%) in post-procedural management. CONCLUSIONS: Geriatricians' involvement in AS management and multidisciplinary heart teams remains scarce. More efforts should be devoted to implement geriatricians' role in AS decision-making.

Identification of the novel HLA-A*30:221 allele by next-generation sequencing.

The novel HLA-A*30:221 allele differs from HLA-A*30:01:01:01 by one nucleotide substitution in Exon 7.

Multiscale modeling uncovers 7q11.23 copy number variation-dependent changes in ribosomal biogenesis and neuronal maturation and excitability.

Copy number variation (CNV) at 7q11.23 causes Williams-Beuren syndrome (WBS) and 7q microduplication syndrome (7Dup), neurodevelopmental disorders (NDDs) featuring intellectual disability accompanied by symmetrically opposite neurocognitive features. Although significant progress has been made in understanding the molecular mechanisms underlying 7q11.23-related pathophysiology, the propagation of CNV dosage across gene expression layers and their interplay remains elusive. Here we uncovered 7q11.23 dosage-dependent symmetrically opposite dynamics in neuronal differentiation and intrinsic excitability. By integrating transcriptomics, translatomics, and proteomics of patient-derived and isogenic induced neurons, we found that genes related to neuronal transmission follow 7q11.23 dosage and are transcriptionally controlled, while translational factors and ribosomal genes are posttranscriptionally buffered. Consistently, we found phosphorylated RPS6 (p-RPS6) downregulated in WBS and upregulated in 7Dup. Surprisingly, p-4EBP was changed in the opposite direction, reflecting dosage-specific changes in total 4EBP levels. This highlights different dosage-sensitive dyregulations of the mTOR pathway as well as distinct roles of p-RPS6 and p-4EBP during neurogenesis. Our work demonstrates the importance of multiscale disease modeling across molecular and functional layers, uncovers the pathophysiological relevance of ribosomal biogenesis in a paradigmatic pair of NDDs, and uncouples the roles of p-RPS6 and p-4EBP as mechanistically actionable relays in NDDs.

miRNA-mediated inhibition of an actomyosin network in hippocampal pyramidal neurons restricts sociability in adult male mice.

Social deficits are frequently observed in patients suffering from neurodevelopmental disorders, but the molecular mechanisms regulating sociability are still poorly understood. We recently reported that the loss of the microRNA (miRNA) cluster miR-379-410 leads to hypersocial behavior and anxiety in mice. Here, we show that ablating miR-379-410 in excitatory neurons of the postnatal mouse hippocampus recapitulates hypersociability, but not anxiety. At the cellular level, miR-379-410 loss in excitatory neurons leads to larger dendritic spines, increased excitatory synaptic transmission, and upregulation of an actomyosin gene network. Re-expression of three cluster miRNAs, as well as pharmacological inhibition of the actomyosin activator ROCK, is sufficient to reinstate normal sociability in miR-379-410 knockout mice. Several actomyosin genes and miR-379-410 family members are reciprocally dysregulated in isogenic human induced pluripotent stem cell (iPSC)-derived neurons harboring a deletion present in patients with Williams-Beuren syndrome, characterized by hypersocial behavior. Together, our results show an miRNA-actomyosin pathway involved in social behavior regulation.

Multimodal Prehabilitation for Patients with Crohn's Disease Scheduled for Major Surgery: A Narrative Review.

Approximately 15-50% of patients with Crohn's disease (CD) will require surgery within ten years following the diagnosis. The management of modifiable risk factors before surgery is essential to reduce postoperative complications and to promote a better postoperative recovery. Preoperative malnutrition reduced functional capacity, sarcopenia, immunosuppressive medications, anemia, and psychological distress are frequently present in CD patients. Multimodal prehabilitation consists of nutritional, functional, medical, and psychological interventions implemented before surgery, aiming at optimizing preoperative status and improve postoperative recovery. Currently, studies evaluating the effect of multimodal prehabilitation on postoperative outcomes specifically in CD are lacking. Some studies have investigated the effect of a single prehabilitation intervention, of which nutritional optimization is the most investigated. The aim of this narrative review is to present the physiologic rationale supporting multimodal surgical prehabilitation in CD patients waiting for surgery, and to describe its main components to facilitate their adoption in the preoperative standard of care.

Tracing the invisible mutant ADNP protein in Helsmoortel-Van der Aa syndrome patients.

Heterozygous de novo mutations in the Activity-Dependent Neuroprotective Homeobox (ADNP) gene underlie Helsmoortel-Van der Aa syndrome (HVDAS). Most of these mutations are situated in the last exon and we previously demonstrated escape from nonsense-mediated decay by detecting mutant ADNP mRNA in patient blood. In this study, wild-type and ADNP mutants are investigated at the protein level and therefore optimal detection of the protein is required. Detection of ADNP by means of western blotting has been ambiguous with reported antibodies resulting in non-specific bands without unique ADNP signal. Validation of an N-terminal ADNP antibody (Aviva Systems) using a blocking peptide competition assay allowed to differentiate between specific and non-specific signals in different sample materials, resulting in a unique band signal around 150 kDa for ADNP, above its theoretical molecular weight of 124 kDa. Detection with different C-terminal antibodies confirmed the signals at an observed molecular weight of 150 kDa. Our antibody panel was subsequently tested by immunoblotting, comparing parental and homozygous CRISPR/Cas9 endonuclease-mediated Adnp knockout cell lines and showed disappearance of the 150 kDa signal, indicative for intact ADNP. By means of both a GFPSpark and Flag-tag N-terminally fused to a human ADNP expression vector, we detected wild-type ADNP together with mutant forms after introduction of patient mutations in E. coli expression systems by site-directed mutagenesis. Furthermore, we were also able to visualize endogenous ADNP with our C-terminal antibody panel in heterozygous cell lines carrying ADNP patient mutations, while the truncated ADNP mutants could only be detected with epitope-tag-specific antibodies, suggesting that addition of an epitope-tag possibly helps stabilizing the protein. However, western blotting of patient-derived hiPSCs, immortalized lymphoblastoid cell lines and post-mortem patient brain material failed to detect a native mutant ADNP protein. In addition, an N-terminal immunoprecipitation-competent ADNP antibody enriched truncating mutants in overexpression lysates, whereas implementation of the same method failed to enrich a possible native mutant protein in immortalized patient-derived lymphoblastoid cell lines. This study aims to shape awareness for critical assessment of mutant ADNP protein analysis in Helsmoortel-Van der Aa syndrome.

In and out: Benchmarking in vitro, in vivo, ex vivo, and xenografting approaches for an integrative brain disease modeling pipeline.

Human cellular models and their neuronal derivatives have afforded unprecedented advances in elucidating pathogenic mechanisms of neuropsychiatric diseases. Notwithstanding their indispensable contribution, animal models remain the benchmark in neurobiological research. In an attempt to harness the best of both worlds, researchers have increasingly relied on human/animal chimeras by xenografting human cells into the animal brain. Despite the unparalleled potential of xenografting approaches in the study of the human brain, literature resources that systematically examine their significance and advantages are surprisingly lacking. We fill this gap by providing a comprehensive account of brain diseases that were thus far subjected to all three modeling approaches (transgenic rodents, in vitro human lineages, human-animal xenografting) and provide a critical appraisal of the impact of xenografting approaches for advancing our understanding of those diseases and brain development. Next, we give our perspective on integrating xenografting modeling pipeline with recent cutting-edge technological advancements.

Tumor microenvironment-induced FOXM1 regulates ovarian cancer stemness.

In ovarian tumors, the omental microenvironment profoundly influences the behavior of cancer cells and sustains the acquisition of stem-like traits, with major impacts on tumor aggressiveness and relapse. Here, we leverage a patient-derived platform of organotypic cultures to study the crosstalk between the tumor microenvironment and ovarian cancer stem cells. We discovered that the pro-tumorigenic transcription factor FOXM1 is specifically induced by the microenvironment in ovarian cancer stem cells, through activation of FAK/YAP signaling. The microenvironment-induced FOXM1 sustains stemness, and its inactivation reduces cancer stem cells survival in the omental niche and enhances their response to the PARP inhibitor Olaparib. By unveiling the novel role of FOXM1 in ovarian cancer stemness, our findings highlight patient-derived organotypic co-cultures as a powerful tool to capture clinically relevant mechanisms of the microenvironment/cancer stem cells crosstalk, contributing to the identification of tumor vulnerabilities.

Comparison of different frailty instruments for prediction of functional decline in older hypertensive outpatients (HYPER-FRAIL pilot study 2).

BACKGROUND AND AIMS: Few studies have evaluated frailty in older hypertensive individuals and the most appropriate tools to identify frailty in this population have yet to be identified. This study compared the performance of six frailty instruments in the prediction of 1-year functional decline in older hypertensive outpatients. METHODS: The HYPERtension and FRAILty in Older Adults (HYPER-FRAIL) longitudinal pilot study involved hypertensive participants ≥75 years from two geriatric outpatient clinics at Careggi Hospital, Florence, Italy, undergoing identification of frailty with four frailty scales (Fried Frailty Phenotype, Frailty Index [FI], Clinical Frailty Scale [CFS], Frailty Postal Score) and two physical performance tests (Short Physical Performance Battery [SPPB] and gait speed). Prediction of 1-year functional decline (i.e. a ≥ 10-point Barthel Index decrease between baseline and follow-up) was examined based on ROC curve analysis and multivariable logistic regression. RESULTS: Among 116 participants, 24 % reported functional decline. In the ROC curve analyses, FI (AUC=0.76), CFS (AUC=0.77), gait speed (AUC=0.73) and the SPPB (AUC=0.77) achieved the best predictive performance, with FI ≥0.21 and CFS ≥4 showing the highest sensitivity (82 %) and negative predictive value (91 %). Frailty identified with FI, CFS or physical performance tests was associated with an increased risk of 1-year functional decline, independently of baseline functional status and comorbidity burden. CONCLUSIONS: FI, CFS and physical performance tests showed similar predictive ability for functional decline in hypertensive outpatients. The CFS and gait speed might be more suitable for clinical use and may be useful to identify non-frail individuals at lower risk of functional decline.

Tolerability of Antihypertensive Medications: The Influence of Age.

INTRODUCTION: Despite high prevalence of hypertension, few studies have analysed the adverse effects (AEs) of antihypertensive medications, especially in older patients. AIM: To investigate the prevalence and associated factors of antihypertensive-related AEs, focusing on the influence of age on treatment tolerability. METHODS: We retrospectively investigated antihypertensive-related AEs in patients evaluated at the Hypertension Clinic of Careggi Hospital, Florence, Italy, between January 2017 and July 2020. Multivariable regression models were generated to analyse variables associated with AEs in the overall sample and in participants ≥75 years. RESULTS: Among 622 subjects (mean age 64.8 years, 51.4% female), the most frequently reported AEs were calcium-channel blockers (CCB)-related ankle swelling (26.8%) and ACEi-induced cough (15.1%). Ankle swelling was more common in older patients (35.7% vs 22.3%, p = 0.001; odds ratio [OR] 1.94, 95%CI 1.289-2.912) and was independently associated with Body Mass Index (BMI, adjOR 1.073) and angiotensin-receptor antagonists (adjOR 1.864). The association with BMI was confirmed in older patients (adjOR 1.134). ACEi-induced cough showed similar prevalence in younger and older patients (13.9% vs 15.6%, p = 0.634), being independently associated with female sex (adjOR 2.118), gastroesophageal reflux disease (GERD, adjOR 2.488) and SNRI therapy (adjOR 8.114). The association with GERD was confirmed in older patients (adjOR 3.238). CONCLUSIONS: CCB-related ankle swelling and ACEi-induced cough represent the most common antihypertensive-related AEs, also at old age. Older patients showed a two-fold increased risk of ankle swelling, that was also independently associated with BMI. ACEi-induced cough had similar prevalence at younger and old ages, being independently associated with GERD.

Towards a common definition of surgical prehabilitation: a scoping review of randomised trials.

BACKGROUND: There is no universally accepted definition for surgical prehabilitation. The objectives of this scoping review were to (1) identify how surgical prehabilitation is defined across randomised controlled trials and (2) propose a common definition. METHODS: The final search was conducted in February 2023 using MEDLINE, Embase, PsycINFO, Web of Science, CINAHL, and Cochrane. We included randomised controlled trials (RCTs) of unimodal or multimodal prehabilitation interventions (nutrition, exercise, and psychological support) lasting at least 7 days in adults undergoing elective surgery. Qualitative data were analysed using summative content analysis. RESULTS: We identified 76 prehabilitation trials of patients undergoing abdominal (n=26, 34%), orthopaedic (n=20, 26%), thoracic (n=14, 18%), cardiac (n=7, 9%), spinal (n=4, 5%), and other (n=5, 7%) surgeries. Surgical prehabilitation was explicitly defined in more than half of these RCTs (n=42, 55%). Our findings consolidated the following definition: 'Prehabilitation is a process from diagnosis to surgery, consisting of one or more preoperative interventions of exercise, nutrition, psychological strategies and respiratory training, that aims to enhance functional capacity and physiological reserve to allow patients to withstand surgical stressors, improve postoperative outcomes, and facilitate recovery.' CONCLUSIONS: A common definition is the first step towards standardisation, which is needed to guide future high-quality research and advance the field of prehabilitation. The proposed definition should be further evaluated by international stakeholders to ensure that it is comprehensive and globally accepted.

Outcomes reported in randomised trials of surgical prehabilitation: a scoping review.

BACKGROUND: Heterogeneity of reported outcomes can impact the certainty of evidence for prehabilitation. The objective of this scoping review was to systematically map outcomes and assessment tools used in trials of surgical prehabilitation. METHODS: MEDLINE, EMBASE, PsychInfo, Web of Science, CINAHL, and Cochrane were searched in February 2023. Randomised controlled trials of unimodal or multimodal prehabilitation interventions (nutrition, exercise, psychological support) lasting at least 7 days in adults undergoing elective surgery were included. Reported outcomes were classified according to the International Society for Pharmacoeconomics and Outcomes Research framework. RESULTS: We included 76 trials, mostly focused on abdominal or orthopaedic surgeries. A total of 50 different outcomes were identified, measured using 184 outcome assessment tools. Observer-reported outcomes were collected in 86% of trials (n=65), with hospital length of stay being most common. Performance outcomes were reported in 80% of trials (n=61), most commonly as exercise capacity assessed by cardiopulmonary exercise testing. Clinician-reported outcomes were included in 78% (n=59) of trials and most frequently included postoperative complications with Clavien-Dindo classification. Patient-reported outcomes were reported in 76% (n=58) of trials, with health-related quality of life using the 36- or 12-Item Short Form Survey being most prevalent. Biomarker outcomes were reported in 16% of trials (n=12) most commonly using inflammatory markers assessed with C-reactive protein. CONCLUSIONS: There is substantial heterogeneity in the reporting of outcomes and assessment tools across surgical prehabilitation trials. Identification of meaningful outcomes, and agreement on appropriate assessment tools, could inform the development of a prehabilitation core outcomes set to harmonise outcome reporting and facilitate meta-analyses.

Immunotherapy use in older adults with cancer with frailty: A young SIOG review paper.

Immune checkpoint inhibitors (ICIs) became a treatment option in most tumor types and improved survival in patients with cancer in the last decade. Older patients with cancer are underrepresented in the pivotal clinical trials with ICIs. Older patients with cancer often have significant comorbidities and geriatric syndromes like frailty, which can complicate cancer care and treatment decisions. Frailty is among the most prevalent geriatric syndromes in patients with cancer and could lead to inferior survival and a higher risk of complications in patients treated with chemotherapy. However, the effect of frailty on the efficacy and safety of ICIs is understudied. This review focuses on the available evidence regarding the association between frailty and ICI efficacy and safety. Although the survival benefits of ICIs have generally been shown to be independent of age, the available real-world data has generally suggested higher rates of immune-related adverse events (irAEs) and treatment discontinuation in older patients. While international organizations recommend conducting a comprehensive geriatric assessment CGA to assess and address frailty before the start of anti-cancer therapies, an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or higher is frequently used in clinical practice as synonymous with frailty, albeit with significant limitations. The available data has generally demonstrated diminished ICI efficacy in patients with an ECOG 2 or higher compared to patients with better performance status, while the incidence of high-grade irAEs were similar. Whilst evidence regarding outcomes with ICI in older patients and in those with sub-optimal performance status is growing, there is very limited data specifically evaluating the role of frailty with ICIs. These studies found a shortened overall survival, yet no evidence of a lower response rate to ICIs. These patients experienced more AEs, but they did not necessarily have a higher incidence of irAEs.

What is the association of polypharmacy with frailty in heart failure? A systematic review and meta-analysis.

This systematic review and meta-analysis aimed to explore the differences in the number of prescribed medications and polypharmacy risk between patients with heart failure (HF) and frailty vs. those with HF but without frailty. Eligible studies included observational or experimental studies in patients aged ≥50 years. Thirteen studies met the criteria and were included in the final analysis. Patients with frailty and HF exhibited a higher risk of polypharmacy (OR: 1.87, 95% CI 1.72 - 2.04, I2 = 0%, P < 0.01) compared to those without frailty. Results remained significant after adjusting for comorbidity status. Additionally, patients with frailty and HF were prescribed more medications compared to those without (k = 6; MD: 1.43, 95% CI 0.31 - 2.55, I2 = 94%, P = 0.01), with a high degree of heterogeneity. However, results were non-significant after adjustment for comorbidity status. Patients with HF and frailty have a higher need of polypharmacy compared to those without frailty, which may increase the risk of potentially inappropriate medications (PIM). Investigating the real-world prevalence of PIM may support clinicians in their routine assessment as part of a comprehensive management strategy in patients with HF and frailty.

YY1 mutations disrupt corticogenesis through a cell-type specific rewiring of cell-autonomous and non-cell-autonomous transcriptional programs.

Germline mutations of YY1 cause Gabriele-de Vries syndrome (GADEVS), a neurodevelopmental disorder featuring intellectual disability and a wide range of systemic manifestations. To dissect the cellular and molecular mechanisms underlying GADEVS, we combined large-scale imaging, single-cell multiomics and gene regulatory network reconstruction in 2D and 3D patient-derived physiopathologically relevant cell lineages. YY1 haploinsufficiency causes a pervasive alteration of cell type specific transcriptional networks, disrupting corticogenesis at the level of neural progenitors and terminally differentiated neurons, including cytoarchitectural defects reminiscent of GADEVS clinical features. Transcriptional alterations in neurons propagated to neighboring astrocytes through a major non-cell autonomous pro-inflammatory effect that grounds the rationale for modulatory interventions. Together, neurodevelopmental trajectories, synaptic formation and neuronal-astrocyte cross talk emerged as salient domains of YY1 dosage-dependent vulnerability. Mechanistically, cell-type resolved reconstruction of gene regulatory networks uncovered the regulatory interplay between YY1, NEUROG2 and ETV5 and its aberrant rewiring in GADEVS. Our findings underscore the reach of advanced in vitro models in capturing developmental antecedents of clinical features and exposing their underlying mechanisms to guide the search for targeted interventions.