Apixaban Level and Its Influence on Immunosuppression and Graft Outcome in Kidney Transplant Recipients With Atrial Fibrillation.

BACKGROUND: Currently, there is limited information on the level of apixaban in kidney transplant (KT) patients with atrial fibrillation and the influence of apixaban therapy on the level of immunosuppression and graft function. METHODS: This was a cross-sectional prospective study of 19 KT patients treated with apixaban. The levels of apixaban were measured using a chromogenic assay calibrated for apixaban and compared with those predicted by the manufacturer. Mean immunosuppression trough levels before and after apixaban treatment initiation were calculated using 3 consecutive measurements. Apixaban levels were compared with a historical control group comprising of 20 nontransplant patients with atrial fibrillation who were treated with the standard 5-mg bid apixaban dosage. RESULTS: All KT patients should have been treated with the standard 5-mg bid apixaban dosage according to the clinical parameters; however, 7 were inappropriately treated with a reduced dosage (2.5-mg bid). There was no significant difference in apixaban level between KT patients treated with the 5-mg bid dosage and nontransplant patients. No KT patient administered the standard dose had out-of-range levels. Peak GM level was significantly lower in KT patients administered an inappropriately reduced dose (P = 0.05). Two patients had below-range peak levels. Apixaban treatment initiation had minimal influence on the level of immunosuppression. Furthermore, it had no adverse impact on graft function. CONCLUSIONS: Similar to nontransplant patients, KT patients administered the standard 5-mg bid dosage had apixaban levels that were well within the recommended manufacturers' expected ranges. In addition, this dosage had minimal influence on immunosuppression and no effect on graft function.

Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability.

Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.

Mild cognitive impairment is associated with mild parkinsonian signs in a door-to-door study.

Mild cognitive impairment (MCI) and healthy aging have been shown to be associated with mild parkinsonian signs (MPS). We performed a door-to-door observational and follow-up study amongst consenting residents of Wadi Ara Arab villages in northern Israel aged ≥65 years (n=687) to examine whether MPS represent a risk factor for MCI and/or conversion from MCI to Alzheimer's disease (AD). In Phase 1, 223 cognitively normal (CN) and 173 MCI subjects were assessed by interview for medical history, neurological examination, motor part of the Unified Parkinson Disease Rating Scale (mUPDRS) (divided into item-clusters: axial, limb bradykinesia, tremor and rigidity) and cognitive tests. MCI subjects (n=111) were re-evaluated in Phase 2 for conversion to AD at least one year after initial assessment. MCI subjects had a higher frequency of axial dysfunction (8.7% vs. 1.3%) and limb bradykinesia (10.4% vs. 1.3%) than CN subjects (p<0.001, both). Stepwise logistic regression analysis estimating the probability of MCI vs. CN revealed higher mUPDRS (OR =1.19, 95% CI, 1.05 to 1.35, p=0.006) and higher limb bradykinesia scores (OR=1.75, 95% CI, 1.2 to 2.56, p=0.003) and not age as explanatory variables. Presence of MPS did not predict conversion to AD after adjustment for age and time-interval. These results suggest that axial and bradykinetic parkinsonian signs represent risk factors for MCI but MPS may not predict conversion from MCI to AD.