The Y chromosome has long been considered a ‘genetic wasteland’ on a trajectory to completely disappear from the human genome. The perception of its physiological function was restricted to sex determination and spermatogenesis. These views have been challenged in recent times with the identification of multiple ubiquitously expressed Y-chromosome genes and the discovery of several unexpected associations between the Y chromosome, immune system and complex polygenic traits. The collected evidence suggests that the Y chromosome influences immune and inflammatory responses in men, translating into genetically programmed susceptibility to diseases with a strong immune component. Phylogenetic studies reveal that carriers of a common European lineage of the Y chromosome (haplogroup I) possess increased risk of coronary artery disease. This occurs amidst upregulation of inflammation and suppression of adaptive immunity in this Y lineage, as well as inferior outcomes in human immunodeficiency virus infection. From structural analysis and experimental data, the UTY (Ubiquitously Transcribed Tetratricopeptide Repeat Containing, Y-Linked) gene is emerging as a promising candidate underlying the associations between Y-chromosome variants and the immunity-driven susceptibility to complex disease. This review synthesises the recent structural, experimental and clinical insights into the human Y chromosome in the context of men’s susceptibility to disease (with a particular emphasis on cardiovascular disease) and provides an overview of the paradigm shift in the perception of the Y chromosome.

ObjectiveAnticoagulation reversal, intensive blood pressure lowering, neurosurgery, and access to critical care might all be beneficial in acute intracerebral hemorrhage (ICH). We combined and implemented these as the “ABC” hyperacute care bundle and sought to determine whether the implementation was associated with lower case fatality.MethodsThe ABC bundle was implemented from June 1, 2015 to May 31, 2016. Key process targets were set, and a registry captured consecutive patients. We compared 30‐day case fatality before, during, and after bundle implementation with multivariate logistic regression and used mediation analysis to determine which care process measures mediated any association. Difference‐in‐difference analysis compared 30‐day case fatality with 32,295 patients with ICH from 214 other hospitals in England and Wales using Sentinel Stroke National Audit Programme data.ResultsA total of 973 ICH patients were admitted in the study period. Compared to before implementation, the adjusted odds of death by 30 days were lower in the implementation period (odds ratio [OR] = 0.62, 95% confidence interval [CI] = 0.38–0.97, p = 0.03), and this was sustained after implementation (OR = 0.40, 95% CI = 0.24–0.61, p < 0.0001). Implementation of the bundle was associated with a 10.8 percentage point (95% CI = −17.9 to −3.7, p = 0.003) reduction in 30‐day case fatality in difference‐in‐difference analysis. The total effect of the care bundle was mediated by a reduction in do‐not‐resuscitate orders within 24 hours (52.8%) and increased admission to critical care (11.1%).InterpretationImplementation of the ABC care bundle was significantly associated with lower 30‐day case fatality after ICH. ANN NEUROL 2019;86:495–503

Nephrons scar and involute during aging, increasing the risk of chronic kidney disease. Little is known, however, about genetic mechanisms of kidney aging. We sought to define the signatures of age on the renal transcriptome using 563 human kidneys. The initial discovery analysis of 260 kidney transcriptomes from the TRANScriptome of renaL humAn TissuE Study (TRANSLATE) and the Cancer Genome Atlas identified 37 age-associated genes. For 19 of those genes, the association with age was replicated in 303 kidney transcriptomes from the Nephroseq resource. Surveying 42 nonrenal tissues from the Genotype–Tissue Expression project revealed that, for approximately a fifth of the replicated genes, the association with age was kidney-specific. Seventy-three percent of the replicated genes were associated with functional or histological parameters of age-related decline in kidney health, including glomerular filtration rate, glomerulosclerosis, interstitial fibrosis, tubular atrophy, and arterial narrowing. Common genetic variants in four of the age-related genes, namely LYG1 , PPP1R3C , LTF and TSPYL5 , correlated with the trajectory of age-related changes in their renal expression. Integrative analysis of genomic, epigenomic, and transcriptomic information revealed that the observed age-related decline in renal TSPYL5 expression was determined both genetically and epigenetically. Thus, this study revealed robust molecular signatures of the aging kidney and new regulatory mechanisms of age-related change in the kidney transcriptome.

Reference curves demonstrating the relationship between serum or liver vitamin B12 and weight gain were derived from the examination of 16 published and 48 unpublished N.Z. trials. From these curves probability of obtaining an economic reponse (>10g/day body weight increase) for any serum or liver vitamin B12 can be determined. No significant (P<0.05) weight gain responses occurred to vitamin B12 or cobalt treatment in trials with mean serum vitamin B12 levels above 500 pmol/l or liver vitamin B12 levels greater than 500 nmol/kg. The reference curves were therefore derived from trials with vitamin B12 levels below these levels; 36 trials with serum vitamin B12 and 19 trials with liver vitamin B12 data. The mean vitamin B12 level at the mid point of the weight gain response period was selected from each trial. Examination of serum vitamin B12 reference curves for spring, summer, autumn and winter indicated that curves derived from data closest to the middle of January (summer) adequately reflected response to treatment at any time during the first year of life. Reference curves for liver vitamin B12 also used data closest to middle of January. This was partly because insufficient liver data was available to compare seasonal variations. The fitted response curve approached 0 gram/day at 500 pmol/l for serum vitamin B12 and 375 nmol/kg for liver vitamin B12. The minimum vitamin B12 level at which an economic response to treatment (>10 g/day) is not likely was 336 pmol/l for serum and 282 nmol/kg for liver.

Ageing of the kidney is a multi-dimensional process that occurs simultaneously at the molecular, cellular, histological, anatomical and physiological level. Nephron number and renal cortical volume decline, renal tubules become atrophic and glomeruli become sclerotic with age. These structural changes are accompanied by a decline in glomerular filtration rate, decreased sodium reabsorption and potassium excretion, reduced urinary concentrating capacity and alterations in the endocrine activity of the kidney. However, the pace of progression of these changes is not identical in everyone - individuals of the same age and seemingly similar clinical profile often exhibit stark differences in the age-related decline in renal health. Thus, chronological age poorly reflects the time-dependent changes that occur in the kidney. An ideal measure of renal vitality is biological kidney age – a measure of the age-related changes in physiological function. Replacing chronological age with biological age could provide numerous clinical benefits including improved prognostic accuracy in renal transplantation, better stratification of risk and identification of those who are on a fast trajectory to an age-related drop in kidney health.

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