Telomere Length Shows No Association with BRCA1 and BRCA2 Mutation Status

This study aimed to determine whether telomere length (TL) is a marker of cancer risk or genetic status amongst two cohorts of BRCA1 and BRCA2 mutation carriers and controls. The first group was a prospective set of 665 male BRCA1/2 mutation carriers and controls (mean age 53 years), all healthy at time of enrolment and blood donation, 21 of whom have developed prostate cancer whilst on study. The second group consisted of 283 female BRCA1/2 mutation carriers and controls (mean age 48 years), half of whom had been diagnosed with breast cancer prior to enrolment. TL was quantified by qPCR from DNA extracted from peripheral blood lymphocytes. Weighted and unweighted Cox regressions and linear regression analyses were used to assess whether TL was associated with BRCA1/2 mutation status or cancer risk. We found no evidence for association between developing cancer or being a BRCA1 or BRCA2 mutation carrier and telomere length. It is the first study investigating TL in a cohort of genetically predisposed males and although TL and BRCA status was previously studied in females our results don''t support the previous finding of association between hereditary breast cancer and shorter TL.     

Cost-effectiveness analysis of administering tranexamic acid to bleeding trauma patients using evidence from the CRASH-2 trial

Objective

To assess the cost effectiveness of giving tranexamic acid (TXA) to bleeding trauma patients in low, middle and high income settings.

Methods

The CRASH-2 trial showed that TXA administration reduces the risk of death in bleeding trauma patients with a small but statistically significant increase in non-intensive care stay. A Markov model was used to assess the cost effectiveness of TXA in Tanzania, India and the United Kingdom (UK). The health outcome was the number of life years gained (LYs). Two costs were considered: the cost of administering TXA and the cost of additional days in hospital. Cost data were obtained from hospitals, World Health Organization (WHO) database and UK reference costs. Cost-effectiveness was measured in international dollars ($) per LY. Both deterministic and probabilistic sensitivity analyses were performed to test the robustness of the results to model assumptions.

Findings

Administering TXA to bleeding trauma patients within three hours of injury saved an estimated 372, 315 and 755 LYs per 1,000 trauma patients in Tanzania, India and the UK respectively. The cost of giving TXA to 1,000 patients was $17,483 in Tanzania, $19,550 in India and $30,830 in the UK. The incremental cost of giving TXA versus not giving TXA was $18,025 in Tanzania, $20,670 in India and $48,002 in the UK. The estimated incremental cost per LY gained of administering TXA is $48, $66 and $64 in Tanzania, India and the UK respectively.

Conclusion

Early administration of TXA to bleeding trauma patients is likely to be highly cost effective in low, middle and high income settings.

Trial Registration

This paper uses data collected by the CRASH 2 trial: Controlled-Trials.com ISRCTN86750102, Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00375258","term_id":"NCT00375258"}}NCT00375258 and South African Clinical Trial Register DOH-27-0607-1919.     

Survival times in people with dementia: analysis from population based cohort study with 14 year follow-up

Objectives To provide estimates of survival after onset of dementia by age, sex, self reported health, disability, and severity of cognitive impairment.Design Analysis of participants from prospective population based cohort study in 1991-2003, with follow-up of dementia status in all individuals after two and six years (in one centre) and 10 years and in subsamples additionally at six and eight years and mortality until 2005.Setting Multicentre population based study in England and Wales: two rural and three urban centres.Participants 438 participants who developed dementia from a population based study of 13 004 individuals aged 65 years and over drawn from primary care population registers.Main outcome measures Sociodemographic factors, cognitive function, specific health conditions, and self reported health collected at each interview. Cox’s proportional hazards regression models were used to identify predictors of mortality from the selected variables in people who received diagnosis of dementia according the study’s criteria.Results By December 2005, 356 of the 438 (81%) participants who developed dementia during the study had died. Estimated median survival time from onset of dementia to death was 4.1 years (interquartile range 2.5-7.6) for men and 4.6 years (2.9-7.0) for women. There was a difference of nearly seven years in survival between the younger old and the oldest people with dementia: 10.7 (25th centile 5.6) for ages 65-69; 5.4 (interquartile range 3.4-8.3) for ages 70-79; 4.3 (2.8-7.0) for ages 80-89, and 3.8 (2.3-5.2) years for ages ≥90. Significant factors that predicted mortality in the presence of dementia during the follow-up included sex, age of onset, and disability.Conclusion These analyses give a population based estimated median survival for incident dementia of 4.5 years. Such estimates can be used for prognosis and planning for patients, carers, service providers, and policy makers.     

Discriminating mild from critical COVID-19 by innate and adaptive immune single-cell profiling of bronchoalveolar lavages

How the innate and adaptive host immune system miscommunicate to worsen COVID-19 immunopathology has not been fully elucidated. Here, we perform single-cell deep-immune profiling of bronchoalveolar lavage (BAL) samples from 5 patients with mild and 26 with critical COVID-19 in comparison to BALs from non-COVID-19 pneumonia and normal lung. We use pseudotime inference to build T-cell and monocyte-to-macrophage trajectories and model gene expression changes along them. In mild COVID-19, CD8⁺ resident-memory (T_RM) and CD4⁺ T-helper-17 (T_H17) cells undergo active (presumably antigen-driven) expansion towards the end of the trajectory, and are characterized by good effector functions, while in critical COVID-19 they remain more naïve. Vice versa, CD4⁺ T-cells with T-helper-1 characteristics (T_H1-like) and CD8⁺ T-cells expressing exhaustion markers (T_EX-like) are enriched halfway their trajectories in mild COVID-19, where they also exhibit good effector functions, while in critical COVID-19 they show evidence of inflammation-associated stress at the end of their trajectories. Monocyte-to-macrophage trajectories show that chronic hyperinflammatory monocytes are enriched in critical COVID-19, while alveolar macrophages, otherwise characterized by anti-inflammatory and antigen-presenting characteristics, are depleted. In critical COVID-19, monocytes contribute to an ATP-purinergic signaling-inflammasome footprint that could enable COVID-19 associated fibrosis and worsen disease-severity. Finally, viral RNA-tracking reveals infected lung epithelial cells, and a significant proportion of neutrophils and macrophages that are involved in viral clearance.Subject terms: Genome-wide analysis of gene expression, Innate immunity, Bioinformatics     

Consent for Brain Tissue Donation after Intracerebral Haemorrhage: A Community-Based Study

Background

Spontaneous intracerebral haemorrhage is a devastating form of stroke and its incidence increases with age. Obtaining brain tissue following intracerebral haemorrhage helps to understand its cause. Given declining autopsy rates worldwide, the feasibility of establishing an autopsy-based collection and its generalisability are uncertain.

Methods

We used multiple overlapping sources of case ascertainment to identify every adult diagnosed with intracerebral haemorrhage between 1^st June 2010-31^st May 2012, whilst resident in the Lothian region of Scotland. We sought consent from patients with intracerebral haemorrhage (or their nearest relative if the patient lacked mental capacity) to conduct a research autopsy.

Results

Of 295 adults with acute intracerebral haemorrhage, 110 (37%) could not be approached to consider donation. Of 185 adults/relatives approached, 91 (49%) consented to research autopsy. There were no differences in baseline demographic variables or markers of intracerebral haemorrhage severity between consenters and non-consenters. Adults who died and became donors (n = 46) differed from the rest of the cohort (n = 249) by being older (median age 80, IQR 76–86 vs. 75, IQR 65–83, p = 0.002) and having larger haemorrhages (median volume 23ml, IQR 13–50 vs. 13ml, IQR 4–40; p = 0.002).

Conclusions

Nearly half of those approached consent to brain tissue donation after acute intracerebral haemorrhage. The characteristics of adults who gave consent were comparable to those in an entire community, although those who donate early are older and have larger haemorrhage volumes.     

New taxa from the Venezuelan Guayana

Seven new taxa, mainly from the Guayana Highland of Venezuela, are described. These include four new species (Cottendorfia atrorosea, Navia emergens, Navia ovoidea, and Pitcairnia nematophora) and one new variety (Cottendorfia brachyphylla var. angustior) of Bromeliaceae, one new species (Swartzia cowanii) of Leguminosae, and one new species (Marlierea pudica) of Myrtaceae.