New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Compression for venous leg ulcers

Venous leg ulcers can occur when blood returning from veins in the legs to the heart is slow or obstructed. These ulcers can take a long time to heal (weeks or months) and can cause distress to patients, as well as being very costly to the health service. Compression bandages help blood to return to the heart from the legs, and there are a variety of types of bandage systems available; some are just a single bandage, while others require the application of several different types of bandages to the leg. Compression stockings are sometimes used as an alternative to compression bandages. This review examined the effectiveness of compression bandages versus no compression, and compared different types of compression bandages and stockings. We looked at how well these different treatments work in terms of ulcer healing. We found that applying compression was better than not using compression, and that multi-component bandages worked better than single-component systems. Multi-component systems (bandages or stockings) appear to perform better when one part is an elastic (stretchy) bandage. A very detailed analysis showed that a system called the 'four-layer bandage' or '4LB' (i.e. four different bandages applied to the leg, including an elastic one) heals ulcers faster than the 'short-stretch bandage' or 'SSB' (a type of bandage with very minimal stretch)

Effect of treatment on established osteoporosis in young women with amenorrhoea

Background and Objective - Amenorrhoea in women of reproductive age causes loss of bone mineral. This study assessed the effect of treatment of amenorrhoea on bone mineral density. Design - Serial measurements of bone mineral density were obtained in women receiving treatment for amenorrhoea. Patients - Eighty-five women aged 17-40 with a past or current history of amenorrhoea, from various causes, with median duration of 46.5 months (range 8 months-21 years). Measurements - Bone mineral density in the lumbar spine was measured by dual-energy X-ray absorptiometry. Results - Initial vertebral bone mineral density was low, mean 0.85 (SD 0.10) g/cm2. After an interval of 19.6 (SD 7.5) months on treatment there was a highly significant increase to 0.89 (SD 0.10) g/cm2 (P < 0.0005). This was equivalent to a gain in bone mass of 2.1% per year (95% confidence interval 1.5-2.8%). Improvement was seen in all diagnostic groups (except polycystic ovary syndrome) and with all types of therapy. We observed no difference in the response of previously untreated patients compared with those already on treatment, nor any change in response with increasing duration of treatment. No new fractures were reported during the study. Conclusions - Bone mineral density in young women with amenorrhoea is improved by appropriate treatment, but recovery is not substantial. Hence early diagnosis and therapy is essential to prevent bone loss