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Despite multiple studies suggesting that low 25(OH)D-vitamin levels are associated with worse outcomes in critically ill individuals, attempts to mitigate the outcomes by fixed dose enteral supplementation unguided by baseline or target blood levels have been unsuccessful. Since a single measurement of 25(OH)D may not optimally reflect an individual's vitamin D status, we studied the plasma concentration of different vitamin D metabolites and their recovery during and following resolution of acute critical illness.A prospective observational study including patients 18 years and older admitted to a mixed medical-surgical ICU in Reykjavik, Iceland, located at a high-northern altitude (64° N). Vitamin D metabolites were measured at three timepoints; On admission (S1), 3-5 days following admission (S2) and after recovery from acute illness (median 178 days) (S3). Concentrations of total 25(OH)D-vitamin, cholecalciferol (DMost individuals were vitamin D deficient when assessed during critical illness, with 25(OH)D-vitamin levels under 30 ng/ml for 37/40 individuals at timepoint S1 and 34/38 at S2. After recovery, 18/30 patients were deficient at S3. Levels of all vitamin D metabolites measured were low during critical illness but rose substantially following resolution of acute illness. No strong correlation was found between markers of acute illness severity or duration and resolution of vitamin D metabolites in the interval between acute illness and recovery.In critically ill patients, levels of multiple vitamin D metabolites are low but substantial recovery occurs following resolution of acute illness. It is unclear whether a single metabolite is sufficient to assess vitamin D status of critically ill patients and guide potential supplementation.

Blood-based Alzheimer's disease (AD) biomarkers show promise, but pre-analytical protocol differences may pose problems. We examined seven AD blood biomarkers (amyloid beta [Plasma and serum were obtained from cerebrospinal fluid or amyloid positron emission tomography-positive and -negative participants (N = 38) in the Wisconsin Registry for Alzheimer's Prevention. We modeled AD biomarker values observed in EDTA plasma versus heparin plasma and serum, and assessed correspondence with brain amyloidosis.Results suggested bias due to tube type, but crosswalks are possible for some analytes, with excellent model fit for NfL (AD biomarker concentrations vary by tube type. However, correlations for some biomarkers support harmonization across types, suggesting cautious optimism for use in banked blood.

Bupropion is primarily metabolized in human liver by cytochrome P450 (CYP) 2B6, an isoform that shows high interindividual variability in expression and catalysis. The aim of this study was to identify mechanisms underlying this variability through comprehensive phenotype-genotype analysis of a well-characterized human liver bank (n = 54). There was substantial variability in microsomal bupropion hydroxylation activities (over 45-fold) and CYP2B6 protein content (over 288-fold), with excellent correlation between protein and activity values (rs = 0.88). CYP2B6 mRNA levels showed less variability (13-fold) and poorer correlation (rs = 0.44) to CYP2B6 protein resulting from 20-30% of livers that contained substantial CYP2B6 mRNA, but low CYP2B6 protein. Livers were genotyped for the common coding polymorphisms (Q172H, K262R and R487C) and 14 additional variations identified by sequencing of the gene promoter to -3000 bp. Of 14 haplotypes that were inferred, *1A (reference), *1H (-2320t>c; -750t>c) and *6B (-1456t>c; -750t>c; Q172H; K262R) were most common with frequencies of 0.28, 0.20 and 0.26, respectively. Alcohol use history (P = 0.011) and *6B haplotype (P = 0.011) were identified as significant predictors of bupropion hydroxylation. A consideration of the effects of these variables on CYP2B6 mRNA and protein levels suggests that alcohol use is associated with enhanced CYP2B6 gene transcription, but the presence of at least one *6B allele reduces this effect on bupropion hydroxylation at the post-transcriptional level. In conclusion, the results of this study indicate that interindividual variability in bupropion hydroxylation is a consequence of interactions between environmental and genetic influences on CYP2B6 gene function.

We report a previously apparently undescribed, X-linked recessive basal ganglia disorder segregating in three generations of one family. The affected patients were variably mentally retarded, although some showed strengths in oral reading and memory. Most affected males had frontal bossing and increased head circumference with large calvaria in relation to facial bones. Their height and weight did not differ from that of other relatives; testicular size was average, chromosomes were normal, and results of laboratory investigations for known metabolic disorders were normal. All patients examined had neurological impairment, including persistent frontal lobe reflexes, cogwheel rigidity, postural changes, and Parkinsonian-type tremors. Some had strabismus; several had seizures. Although carriers of the condition were not consistently abnormal, two had suggestive signs. No definitive indication of the disorder was documented in infancy in any affected male, and it is possible that this could be due to lack of careful prospective clinical evaluation rather than to the absence of symptoms in early life.