Rationale and design of the Early valve replacement in severe ASYmptomatic Aortic Stenosis Trial.

BACKGROUND: Aortic valve replacement in asymptomatic severe aortic stenosis is controversial. The Early valve replacement in severe ASYmptomatic Aortic Stenosis (EASY-AS) trial aims to determine whether early aortic valve replacement improves clinical outcomes, quality of life and cost-effectiveness compared to a guideline recommended strategy of 'watchful waiting'. METHODS: In a pragmatic international, open parallel group randomized controlled trial (NCT04204915), 2844 patients with severe aortic stenosis will be randomized 1:1 to either a strategy of early (surgical or transcatheter) aortic valve replacement or aortic valve replacement only if symptoms or impaired left ventricular function develop. Exclusion criteria include other severe valvular disease, planned cardiac surgery, ejection fraction <50%, previous aortic valve replacement or life expectancy <2 years. The primary outcome is a composite of cardiovascular mortality or heart failure hospitalization. The primary analysis will be undertaken when 663 primary events have accrued, providing 90% power to detect a reduction in the primary endpoint from 27.7% to 21.6% (hazard ratio 0.75). Secondary endpoints include disability-free survival, days alive and out of hospital, major adverse cardiovascular events and quality of life. RESULTS: Recruitment commenced in March 2020 and is open in the UK, Australia, New Zealand and Serbia. Feasibility requirements were met in July 2022, and the main phase opened in October 2022, with additional international centers in set-up. CONCLUSIONS: The EASY-AS trial will establish whether a strategy of early aortic valve replacement in asymptomatic patients with severe aortic stenosis reduces cardiovascular mortality or heart failure hospitalization and improves other important outcomes.

The ASPREE Healthy Ageing Biobank: Methodology and participant characteristics.

ASPirin in Reducing Events in the Elderly (ASPREE), a placebo-controlled prevention trial of low dose aspirin, provided the opportunity to establish a biospecimen biobank from initially healthy persons aged 70+ years for future research. The ASPREE Healthy Ageing Biobank (ASPREE Biobank) collected, processed and stored blood and urine samples at -80degC or under nitrogen vapour at two timepoints, three years apart, from a willing subset of Australian ASPREE participants. Written informed consent included separate opt-in questions for biomarker and genetic testing. Fractionated blood and urine were aliquoted into multiple low-volume, barcoded cryotubes for frozen storage within 4 hours of collection. Specially designed and outfitted mobile laboratories provided opportunities for participation by people in regional and rural areas. Detailed, high quality demographic, physiological and clinical data were collected annually through the ASPREE trial. 12,219 participants contributed blood/urine at the first timepoint, 10,617 of these older adults provided 3-year follow-up samples, and an additional 1,712 provided saliva for DNA. The mean participant age was 74 years, 54% were female and 46% lived outside major cities. Despite geographical and logistical challenges, nearly 100% of blood/urine specimens were processed and frozen within 4 hours of collection into >1.4 million aliquots. After a median of 4.7 years, major clinical events among ASPREE Biobank participants included 332 with dementia, 613 with cardiovascular disease events, 1259 with cancer, 357 with major bleeds and 615 had died. The ASPREE Biobank houses and curates a large number of biospecimens collected prior to the clinical manifestations of major disease, and 3-year follow-up samples, all linked to high quality, extensive phenotypic information. This provides the opportunity to identify or validate diagnostic, prognostic and predictive biomarkers, and potentially study biological effectors, of ageing-related diseases or maintenance of older-age good health.

Ancient proteins resolve controversy over the identity of Genyornis eggshell.

The realization that ancient biomolecules are preserved in "fossil" samples has revolutionized archaeological science. Protein sequences survive longer than DNA, but their phylogenetic resolution is inferior; therefore, careful assessment of the research questions is required. Here, we show the potential of ancient proteins preserved in Pleistocene eggshell in addressing a longstanding controversy in human and animal evolution: the identity of the extinct bird that laid large eggs which were exploited by Australia's indigenous people. The eggs had been originally attributed to the iconic extinct flightless bird Genyornis newtoni (†Dromornithidae, Galloanseres) and were subsequently dated to before 50 ± 5 ka by Miller et al. [Nat. Commun. 7, 10496 (2016)]. This was taken to represent the likely extinction date for this endemic megafaunal species and thus implied a role of humans in its demise. A contrasting hypothesis, according to which the eggs were laid by a large mound-builder megapode (Megapodiidae, Galliformes), would therefore acquit humans of their responsibility in the extinction of Genyornis. Ancient protein sequences were reconstructed and used to assess the evolutionary proximity of the undetermined eggshell to extant birds, rejecting the megapode hypothesis. Authentic ancient DNA could not be confirmed from these highly degraded samples, but morphometric data also support the attribution of the eggshell to Genyornis. When used in triangulation to address well-defined hypotheses, paleoproteomics is a powerful tool for reconstructing the evolutionary history in ancient samples. In addition to the clarification of phylogenetic placement, these data provide a more nuanced understanding of the modes of interactions between humans and their environment.

The genome sequence of the grey wolf, Canis lupus Linnaeus 1758.

We present a genome assembly from an individual male Canis lupus orion (the grey wolf, subspecies: Greenland wolf; Chordata; Mammalia; Carnivora; Canidae). The genome sequence is 2,447 megabases in span. The majority of the assembly (98.91%) is scaffolded into 40 chromosomal pseudomolecules, with the X and Y sex chromosomes assembled.

Ancient microRNA profiles of a 14,300-year-old canid samples confirm taxonomic origin and give glimpses into tissue-specific gene regulation from the Pleistocene.

DNA sequencing is the current key technology for historic or ancient biological samples and has led to many exciting discoveries in the field of paleogenomics. However, functional insights into tissue identity, cellular composition or gene regulation cannot be gained from DNA. Recent analyses have shown that, under favorable conditions, RNA can also be sequenced from ancient samples, enabling studies at the transcriptomic and regulatory level. Analyzing ancient RNA data from a Pleistocene canid, we find hundreds of intact microRNAs that are taxonomically informative, show tissue-specificity and have functionally predictive characteristics. With an extraordinary age of 14,300 years, these microRNA sequences are by far the oldest ever reported. The authenticity of the sequences is further supported by a) the presence of canid / Caniformia-specific sequences that never evolved outside of this clade, b) tissue-specific expression patterns (cartilage, liver and muscle) that resemble those of modern dogs and c) RNA damage patterns that are clearly distinct from those of fresh samples. By performing computational microRNA-target enrichment analyses on the ancient sequences, we predict microRNA functions consistent with their tissue pattern of expression. For instance, we find a liver-specific microRNA that regulates carbohydrate metabolism and starvation responses in canids. In summary, we show that straightforward paleotranscriptomic microRNA analyses can give functional glimpses into tissue identity, cellular composition and gene regulatory activity of ancient samples and biological processes that took place in the Pleistocene, thus holding great promise for deeper insights into gene regulation in extinct animals based on ancient RNA sequencing. .

Testosterone and Estrone Increase From the Age of 70 Years: Findings From the Sex Hormones in Older Women Study.

CONTEXT: There is a lack of understanding of what is normal in terms of sex steroid levels in older women. OBJECTIVE: To determine whether sex steroid levels vary with age in and establish reference ranges for women >70 years of age. DESIGN AND SETTING: Cross-sectional, community-based study. PARTICIPANTS: Included 6392 women ≥70 years of age. MAIN OUTCOME MEASURES: Sex steroids measured by liquid chromatography-tandem mass spectrometry. A reference group, to establish sex steroid age-specific reference ranges, excluded women using systemic or topical sex steroid, antiandrogen or glucocorticoid therapy, or an antiglycemic agent. RESULTS: The reference group of 5326 women had a mean age of 75.1 (±4.2) years, range of 70 to 94.7 years. Median values (range) were 181.2 pmol/L (3.7 to 5768.9) for estrone (E1), 0.38 nmol/L (0.035 to 8.56) for testosterone (T), 2.60 nmol/L (0.07 to 46.85) for dehydroepiandrosterone (DHEA), and 41.6 nmol/L (2.4 to 176.6) for SHBG. Estradiol and DHT were below method sensitivity in 66.1% and 72.7% of the samples, respectively. Compared with women aged 70 to 74 years, women aged ≥85 years had higher median levels of E1 (11.7%, P = 0.01), T (11.3%, P = 0.02), and SHBG (22.7%, P < 0.001) and lower DHEA (30% less, P < 0.001). Women with overweight and obesity had higher E1 (P < 0.001) and T (P < 0.03) and lower SHBG (P < 0.001) than did women with normal body mass index. Smokers had 17.2% higher median T levels (P = 0.005). CONCLUSION: From the age of 70 years, T and E1 increase with age, despite a steady decline in DHEA. Whether E1 and T are biomarkers for longevity or contribute to healthy aging merits investigation.

Age-related macular degeneration in a randomized controlled trial of low-dose aspirin: Rationale and study design of the ASPREE-AMD study.

PURPOSE: Although aspirin therapy is used widely in older adults for prevention of cardiovascular disease, its impact on the incidence, progression and severity of age-related macular degeneration (AMD) is uncertain. The effect of low-dose aspirin on the course of AMD will be evaluated in this clinical trial. DESIGN: A sub-study of the 'ASPirin in Reducing Events in the Elderly' (ASPREE) trial, ASPREE-AMD is a 5-year follow-up double-blind, placebo-controlled, randomized trial of the effect of 100 mg daily aspirin on the course of AMD in 5000 subjects aged 70 years or older, with normal cognitive function and without cardiovascular disease at baseline. Non-mydriatic fundus photography will be performed at baseline, 3-year and 5-year follow-up to determine AMD status. PRIMARY OUTCOME MEASURES: The incidence and progression of AMD. Exploratory analyses will determine whether aspirin affects the risk of retinal hemorrhage in late AMD, and whether other factors, such as genotype, systemic disease, inflammatory biomarkers, influence the effect of aspirin on AMD. CONCLUSION: The study findings will be of significant clinical and public interest due to a potential to identify a possible low cost therapy for preventing AMD worldwide and to determine risk/benefit balance of the aspirin usage by the AMD-affected elderly. The ASPREE-AMD study provides a unique opportunity to determine the effect of aspirin on AMD incidence and progression, by adding retinal imaging to an ongoing, large-scale primary prevention randomized clinical trial.

Hermey Wants to Be a Dentist.

I hope you had a festive and enjoyable holiday season. The American Dental Association tried to liven up the holidays with a public service campaign to remind us all to be careful when we are indulging in our sugary snacks. They enlisted the services of Hermey the Elffrom the Rudolf the Red-Nosed Reindeer cartoon.

Genome sequences of two stress-tolerant Campylobacter jejuni poultry strains, 305 and DFVF1099.

Campylobacter jejuni is a food-borne pathogen with a high prevalence in poultry meat, which in fresh unfrozen condition is the major source of campylobacteriosis. C. jejuni strains DFVF1099 and 305 are considered tolerant to several environmental stresses (T. Birk et al., J. Food Prot. 73:258-265, 2010; S. L. On et al., Int. J. Med. Microbiol. 296:353-363, 2006). Here, we report the genome sequences of C. jejuni 305 and DFVF1099, a turkey and a chicken isolate, respectively.

Genome Sequence of Campylobacter jejuni strain 327, a strain isolated from a turkey slaughterhouse.

Campylobacter is one of the leading causes of food-borne gastroenteritis and has a high prevalence in poultry. Campylobacter jejuni subsp. jejuni 327 is a subspecies of the genus Campylobacter of the family Campylobacteraceae in the phylum Proteobacteria. The microaerophilic, spiral shaped, catalase positive bacterium obtains energy from the metabolism of amino acids and Krebs cycle intermediates. Strain 327 was isolated from a turkey slaughter production line and is considered environmentally sensitive to food processing (cold, heat, drying) and storage conditions. The 327 whole genome shotgun sequence of 1,618,613 bp long consists of 1,740 protein-coding genes, 46 tRNA genes and 3 rRNA operons. A protein based BLAST analysis places the turkey isolate 327 close to the human clinical strain 81116 (NCTC 11828).

Rapid intradermal delivery of liquid formulations using a hollow microstructured array.

PURPOSE: The purpose of this work is to demonstrate rapid intradermal delivery of up to 1.5 mL of formulation using a hollow microneedle delivery device designed for self-application. METHODS: 3M's hollow Microstructured Transdermal System (hMTS) was applied to domestic swine to demonstrate delivery of a variety of formulations including small molecule salts and proteins. Blood samples were collected after delivery and analyzed via HPLC or ELISA to provide a PK profile for the delivered drug. Site evaluations were conducted post delivery to determine skin tolerability. RESULTS: Up to 1.5 mL of formulation was infused into swine at a max rate of approximately 0.25 mL/min. A red blotch, the size of the hMTS array, was observed immediately after patch removal, but had faded so as to be almost indistinguishable 10 min post-patch removal. One-mL deliveries of commercial formulations of naloxone hydrochloride and human growth hormone and a formulation of equine anti-tetanus toxin were completed in swine. With few notable differences, the resulting PK profiles were similar to those achieved following subcutaneous injection of these formulations. CONCLUSIONS: 3M's hMTS can provide rapid, intradermal delivery of 300-1,500 µL of liquid formulations of small molecules salts and proteins, compounds not typically compatible with passive transdermal delivery.

Reasons for hospital admissions among youth and young adults with cerebral palsy.

OBJECTIVE: To identify the most common reasons for acute care hospital admissions among youth (age range, 13-17.9y) and young adults (age range, 23-32.9y) with cerebral palsy (CP). DESIGN: We completed a secondary analysis of data from the Canadian Institute for Health Information (CIHI) to determine the most frequently observed reasons for admissions and the associated lengths of stay (LOS). SETTING: Participants were identified from 6 children's treatment centers in Ontario, Canada. PARTICIPANTS: Health records data from youth with CP (n=587) and young adults with CP (n=477) contributed to this study. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The most common reasons for hospital admission, relative frequencies of admissions for each reason, and mean LOS were reported. RESULTS: The analysis of CIHI records identified epilepsy and pneumonia as the top 2 reasons for admissions in both age groups. Both age groups were commonly admitted because of infections other than pneumonia and urinary tract infections (UTIs), gastrointestinal (GI) problems such as malabsorption, and mental illness. The reasons that were unique to youth included orthopedic and joint-related issues, other respiratory problems, and scoliosis. In young adults, mental illness was the third most common reason for admission, followed by lower GI or constipation problems, malnutrition or dehydration, upper GI problems, fractures, and UTIs. CONCLUSIONS: This article provides important clinical information that can be used in the training of physicians and health care providers, and to guide future planning of ambulatory care services to support the clinical management of persons with CP over their lifespan.