A comparison of peritoneal equilibration tests performed 1 and 4 weeks after PD commencement

Objective: The aim of this study was to prospectively evaluate the ability of a peritoneal equilibration test (PET) performed in the first week of peritoneal dialysis (PD) to predict subsequent transport status, as determined by a PET at 4 weeks and >1 year after PD commencement

CCCDTD5 recommendations on the deprescribing of cognitive enhancers in dementia

Abstract Introduction Cognitive enhancers (ie, cholinesterase inhibitors and memantine) can provide symptomatic benefit for some individuals with dementia; however, there are circumstances in which the risks of continuing treatment may potentially outweigh benefits. The decision to deprescribe cognitive enhancers must consider each patient's preferences, treatment indications, current clinical status and symptoms, prognosis, and dementia type. Methods The 5th Canadian Consensus Conference on the Diagnosis and Treatment of Dementia (CCCDTD5) established a subcommittee of experts to review current evidence on the deprescribing of cognitive enhancers. The questions answered by this group included: When should cognitive enhancers be deprescribed in persons with dementia and mild cognitive impairment? How should cognitive enhancers be deprescribed? And, what clinical factors should be considered when deprescribing cognitive enhancers? Results Patient and care‐partner preferences should be incorporated into all decisions to deprescribe cognitive enhancers. Cognitive enhancers should be discontinued in individuals without ongoing evidence of benefit or when the indication for cognitive enhancer use was inappropriate (eg, mild cognitive impairment). Deprescribing should occur gradually and cognitive enhancers should be reinitiated if patients’ cognition or function deteriorates. Cognitive enhancers should be continued in individuals whose neuropsychiatric symptoms improve in response to treatment. Clinicians should not deprescribe cognitive enhancers in individuals with significant neuropsychiatric symptoms until symptoms have stabilized. Conclusion CCCDTD5 deprescribing recommendations provide evidence‐informed recommendations related to cognitive enhancer deprescribing that will facilitate shared decision making among patients, care partners, and clinicians

POLR1A variants underlie phenotypic heterogeneity in craniofacial, neural, and cardiac anomalies

Heterozygous pathogenic variants in POLR1A, which encodes the largest subunit of RNA Polymerase I, were previously identified as the cause of acrofacial dysostosis, Cincinnati-type. The predominant phenotypes observed in the cohort of 3 individuals were craniofacial anomalies reminiscent of Treacher Collins syndrome. We subsequently identified 17 additional individuals with 12 unique heterozygous variants in POLR1A and observed numerous additional phenotypes including neurodevelopmental abnormalities and structural cardiac defects, in combination with highly prevalent craniofacial anomalies and variable limb defects. To understand the pathogenesis of this pleiotropy, we modeled an allelic series of POLR1A variants in vitro and in vivo. In vitro assessments demonstrate variable effects of individual pathogenic variants on ribosomal RNA synthesis and nucleolar morphology, which supports the possibility of variant-specific phenotypic effects in affected individuals. To further explore variant-specific effects in vivo, we used CRISPR-Cas9 gene editing to recapitulate two human variants in mice. Additionally, spatiotemporal requirements for Polr1a in developmental lineages contributing to congenital anomalies in affected individuals were examined via conditional mutagenesis in neural crest cells (face and heart), the second heart field (cardiac outflow tract and right ventricle), and forebrain precursors in mice. Consistent with its ubiquitous role in the essential function of ribosome biogenesis, we observed that loss of Polr1a in any of these lineages causes cell-autonomous apoptosis resulting in embryonic malformations. Altogether, our work greatly expands the phenotype of human POLR1A-related disorders and demonstrates variant-specific effects that provide insights into the underlying pathogenesis of ribosomopathies