Conflict of interest statement. PLM, AR, EC, MSM, OM, GLG, DS, CC, FF, YM, and PS declare that they have no conflicts of interest. SL has received consulting fees from Viforpharma. KA has received lecturing and consulting fees from Braun, Astellas, and Fresenius. AbstractPurpose: Frailty is a recent concept used for evaluating elderly individuals. Our study determined the prevalence of frailty in intensive care unit (ICU) patients and its impact on the rate of mortality. Methods:A multicenter, prospective, observational study performed in four ICUs in France included 196 patients aged ≥65 years hospitalized for >24 hours during a 6-month study period. Frailty was determined using the frailty phenotype (FP) and the clinical frailty score (CFS). The patients were separated as follows: FP score <3 or ≥3 and CFS < 5 or ≥ 5.Results: Frailty was observed in 41% and 23% of patients based on a FP score ≥3 and a CFS ≥5, respectively. At admission to the ICU, the Simplified Acute Physiology Score II (SAPS II) and Sequential Organ Failure Assessment (SOFA) scores did not differ between the frail and nonfrail patients. In the multivariate analysis, the risk factors for ICU mortality were FP score ≥3 (hazard ratio [HR], 3.3; 95% confidence interval [CI], 1.6-6.6; p<0.001), male gender (HR, 2.4; 95% CI, 1.1-5.3; p=0.026), cardiac arrest before admission (HR, 2.8; 95% CI, 1.1-7.4; p=0.036), SAPS II score ≥ 46 (HR, 2.6; 95% CI, 1.2-5.3; p=0.011), and brain injury before admission (HR, 3.5; 95% CI, 1.6-7.7; p=0.002). The risk factors for 6-month mortality were a CFS ≥5 (HR, 2.4; 95% CI, 1.49-3.87; p<0.001) and a SOFA score ≥7 (HR, 2.2; 95% CI, 1.35-3.64; p=0.002). An increased CFS was associated with significant incremental hospital and 6-month mortalities. Conclusions:Frailty is a frequent occurrence and is independently associated with increased ICU and 6-month mortalities.Notably, the CFS predicts outcomes more effectively than the commonly used ICU illness scores.

Hereditary hemochromatosis is a genetically heterogeneous disease of iron metabolism. The most common form of the disorder is an adult-onset form that has mainly been associated with the HFE pC282Y/pC282Y genotype. The phenotypic expression of this genotype is very heterogeneous and could be modulated by both environmental factors and modifier genes. The non-HFE hereditary hemochromatosis forms include a juvenile onset form associated with mutations in HAMP. From a cohort of 392 C282Y homozygous patients, we found 5 carriers of an additional HAMP mutation at the heterozygous state (pR59G, pG71D, or pR56X). We found that iron indices of these 5 patients were among the most elevated of the cohort. Moreover, we specified that the HAMP mutations were not detected in 300 control subjects. These results revealed that mutations in HAMP might increase the phenotypic expression of the pC282Y/pC282Y genotype. From a cohort of 31 patients with at least one chromosome lacking an HFE mutation, we further identified 4 males carrying a heterozygous HAMP mutation (pR59G or pG71D). Based on a digenic model of inheritance, these data suggest that the association of heterozygous mutations in the HFE and HAMP genes could lead, at least in some cases, to an adultonset form of primary iron overload.

Variant interpretation is the key issue in molecular diagnosis. Spliceogenic variants exemplify this issue as each nucleotide variant can be deleterious via disruption or creation of splice site consensus sequences. Consequently, reliable in silico prediction of variant spliceogenicity would be a major improvement. Thanks to an international effort, a set of 395 variants studied at the mRNA level and occurring in 5′ and 3′ consensus regions (defined as the 11 and 14 bases surrounding the exon/intron junction, respectively) was collected for 11 different genes, including BRCA1, BRCA2, CFTR and RHD, and used to train and validate a new prediction protocol named Splicing Prediction in Consensus Elements (SPiCE). SPiCE combines in silico predictions from SpliceSiteFinder-like and MaxEntScan and uses logistic regression to define optimal decision thresholds. It revealed an unprecedented sensitivity and specificity of 99.5 and 95.2%, respectively, and the impact on splicing was correctly predicted for 98.8% of variants. We therefore propose SPiCE as the new tool for predicting variant spliceogenicity. It could be easily implemented in any diagnostic laboratory as a routine decision making tool to help geneticists to face the deluge of variants in the next-generation sequencing era. SPiCE is accessible at (https://sourceforge.net/projects/spicev2-1/).