We investigated the pathogenicity of a homozygous intronic variant in CDK5RAP3, a key UFMylation adapter, in three individuals from two unrelated families with a lethal neurodevelopmental disorder. CDK5RAP3 variants have not been linked to human disorders to date; however, murine Cdk5rap3 knockout is embryonic lethal and variants in five other UFMylation components cause severe neurodevelopmental conditions. A segregating homozygous variant, chr17(GRCh38):g.47974691G > A, CDK5RAP3 NM_176096.3:c.334 + 243G > A, was identified by trio whole-genome and proband RNA sequencing in Family A and by trio whole-exome sequencing data reanalysis in Family B. Variant pathogenicity investigations included RT-PCR, Western blot, co-immunoprecipitation and (phospho)proteomics to assess transcript, protein and UFMylation complex effects. Antisense oligonucleotide-mediated rescue of CDK5RAP3 expression combined with proteomics and phosphoproteomics defined the mechanistic impact of CDK5RAP3 deficiency and rescue in amniocytes from an affected individual. All three affected individuals showed foetal growth restriction, foetal akinesia, pontocerebellar hypoplasia, arthrogryposis and hepatic pathology. CDK5RAP3 c.334 + 243G > A activates a cryptic donor splice-site causing pseudoexon/intron inclusion triggering nonsense-mediated decay and deficiency of full-length CDK5RAP3 (NP_788276.1), while potentially allowing retained expression of C-terminal alternative isoforms. Co-immunoprecipitation revealed only full-length CDK5RAP3 binds UFL1, whereas C-terminal isoforms cannot. Primary amniocytes showed CDK5RAP3 deficiency was associated with impaired UFMylation of known substrates, RPL26 and UFBP1. Proteomic and phosphoproteomic analyses revealed dysregulation of extracellular matrix organisation, cell adhesion, mitotic/genome stability pathways, cytoskeletal networks and neuronal guidance, which were reversed by restoration of canonical CDK5RAP3 expression via splice-correcting antisense oligonucleotides. Phosphoproteomic data implicate CDK5RAP3 as an upstream regulator of UFL1 S462 phosphorylation, known to be regulated by Ataxia-telangiectasia mutated (ATM) signalling. Our findings provide strong evidence linking deficiency of full-length CDK5RAP3 to severe neurodevelopmental, liver and muscle dysfunction. This study further highlights the therapeutic potential of ASO-based deep-intronic splicing defect correction.
Frailty is a state of diminished physiological reserve and heightened vulnerability to stressors. Strong observational evidence shows that frailty is common in critically ill patients and is associated with prolonged hospitalization, functional decline, and increased mortality. To address these challenges, an international, multidisciplinary group of experts in critical care, frailty, rehabilitation, outcomes, and research methodology convened to review current evidence, identify gaps, and outline a research agenda to improve the recognition, management, and outcomes of critically ill patients with frailty. The consensus was that further research is needed to identify frailty assessment tools suitable for widespread use, determine which patient populations should undergo screening, and evaluate whether frailty assessments improve clinical outcomes. Additional priorities include investigating the biological mechanisms of frailty and their interaction with critical illness, and understanding how these factors influence treatment response. The development and evaluation of frailty-informed interventions, spanning acute care through post-ICU and after hospital recovery, are essential to improving function and quality of life. Finally, there is a need to refine outcome measures and determine which outcomes matter most to older adults living with frailty. Advancing care for this population will require high-quality evidence on how frailty-informed care can support decision-making and improve outcomes.
Obstructive sleep apnea (OSA) is reported to be more prevalent in posttraumatic stress disorder (PTSD) compared to the general population for unknown reasons. Most prior studies have assessed military populations who commonly possess other OSA risk factors. This study aimed to determine whether: 1) OSA prevalence is increased in young adults with PTSD symptoms exposed to non-military traumas; and 2) the ventilatory response to arousal from sleep - an OSA pathogenic trait - differs according to PTSD symptoms. Individuals with a range of PTSD symptoms (PTSD symptom checklist for DSM-5, PCL-5) completed an overnight sleep study. OSA prevalence and the ventilatory response to brief spontaneous arousals were compared between those with Likely PTSD (trauma exposure, intrusions and PCL-5 > 33), Subsyndromal PTSD (trauma exposure, intrusions and PCL-5 15-33) and No PTSD (PCL-5 < 15). Data were obtained in 60 individuals, 18 with Likely PTSD, 19 Subsyndromal PTSD and 23 No PTSD. The number found to have OSA (4 in Likely PTSD, 3 in Subsyndromal PTSD and 1 in No PTSD, p = .21) and the mean apnea-hypopnea index did not differ between groups (p < .98). The ventilatory response to arousal was assessed in 29 individuals without OSA who had good nasal pressure traces and was significantly larger in individuals with Likely PTSD and subsyndromal PTSD than No PTSD (p < .001). Although these young individuals with Likely PTSD did not commonly have OSA, the ventilatory response to arousal was elevated, which when combined with other OSA risk factors may predispose to OSA. Obstructive sleep apnea has been reported to be much more common in military veterans with posttraumatic stress disorder (PTSD) than in the general population. Whether this is a result of factors specific to military veterans or due to other reasons was unknown. This study found that young adults with non-military trauma exposure and likely PTSD did not have elevated rates of OSA. However, their ventilatory response to brief spontaneous arousal from sleep was elevated, which may contribute to OSA development when other risk factors are present (older age, obesity etc) and may also represent a PTSD-specific OSA treatment pathway.
To compare perioperative, oncological, and survival outcomes of total gastrectomy (TG) versus subtotal gastrectomy (SG) in patients with locally advanced distal diffuse gastric adenocarcinoma treated with perioperative 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) chemotherapy. Diffuse distal gastric cancer is characterized by infiltrative growth patterns and early nodal metastasis. Whilst radical resection remains the cornerstone of curative treatment, the optimal extent of surgery with TG or SG, remains debated. This international multicenter cohort study analyzed data from patients with histologically confirmed diffuse gastric adenocarcinoma, located > 5 cm from the gastroesophageal junction. Endpoints included surgical margin status, nodal yield, perioperative morbidity, recurrence patterns, time-to-recurrence (TTR), and overall survival (OS). Outcomes were compared using multivariate analyses. In total, 188 (39.0
Although the Woven EndoBridge (WEB) device is increasingly used for the treatment of wide-neck intracranial aneurysms, including in the acute rupture setting, comparative evidence assessing the impact of rupture status remains limited. This study compared angiographic, safety, and clinical outcomes between ruptured and unruptured intracranial aneurysms treated with WEB. We conducted a retrospective analysis of prospectively collected data from the multicenter cohort registry WorldWideWEB, including consecutive adult patients with intracranial aneurysms treated with the WEB. Patients were stratified into groups of ruptured and unruptured aneurysms. Propensity score matching was used to balance baseline characteristics between both groups. Retreatment rate was the primary outcome. Secondary outcomes included mRS, safety events (thromboembolic complications) and angiographic outcomes (periprocedurally and last follow-up). Among 1,220 patients, 342 (28.0
