Atenolol versus losartan in children and young adults with Marfan's syndrome

BACKGROUND : Aortic-root dissection is the leading cause of death in Marfan's syndrome. Studies suggest that with regard to slowing aortic-root enlargement, losartan may be more effective than beta-blockers, the current standard therapy in most centers. METHODS : We conducted a randomized trial comparing losartan with atenolol in children and young adults with Marfan's syndrome. The primary outcome was the rate of aortic-root enlargement, expressed as the change in the maximum aortic-root-diameter z score indexed to body-surface area (hereafter, aortic-root z score) over a 3-year period. Secondary outcomes included the rate of change in the absolute diameter of the aortic root; the rate of change in aortic regurgitation; the time to aortic dissection, aortic-root surgery, or death; somatic growth; and the incidence of adverse events. RESULTS : From January 2007 through February 2011, a total of 21 clinical centers enrolled 608 participants, 6 months to 25 years of age (mean [+/- SD] age, 11.5 +/- 6.5 years in the atenolol group and 11.0 +/- 6.2 years in the losartan group), who had an aorticroot z score greater than 3.0. The baseline-adjusted rate of change (+/- SE) in the aortic-root z score did not differ significantly between the atenolol group and the losartan group (-0.139 +/- 0.013 and -0.107 +/- 0.013 standard-deviation units per year, respectively; P = 0.08). Both slopes were significantly less than zero, indicating a decrease in the degree of aortic-root dilatation relative to body-surface area with either treatment. The 3-year rates of aortic-root surgery, aortic dissection, death, and a composite of these events did not differ significantly between the two treatment groups. CONCLUSIONS : Among children and young adults with Marfan's syndrome who were randomly assigned to losartan or atenolol, we found no significant difference in the rate of aorticroot dilatation between the two treatment groups over a 3-year period

Differential transcriptomic responses to heat stress in surface and subterranean diving beetles

Subterranean habitats are generally very stable environments, and as such evolutionary transitions of organisms from surface to subterranean lifestyles may cause considerable shifts in physiology, particularly with respect to thermal tolerance. In this study we compared responses to heat shock at the molecular level in a geographically widespread, surface-dwelling water beetle to a congeneric subterranean species restricted to a single aquifer (Dytiscidae: Hydroporinae). The obligate subterranean beetle Paroster macrosturtensis is known to have a lower thermal tolerance compared to surface lineages (CTmax 38 °C cf. 42–46 °C), but the genetic basis of this physiological diference has not been characterized. We experimentally manipulated the thermal environment of 24 individuals to demonstrate that both species can mount a heat shock response at high temperatures (35 °C), as determined by comparative transcriptomics. However, genes involved in these responses difer between species and a far greater number were diferentially expressed in the surface taxon, suggesting it can mount a more robust heat shock response; these data may underpin its higher thermal tolerance compared to subterranean relatives. In contrast, the subterranean species examined not only diferentially expressed fewer genes in response to increasing temperatures, but also in the presence of the experimental setup employed here alone. Our results suggest P. macrosturtensis may be comparatively poorly equipped to respond to both thermally induced stress and environmental disturbances more broadly. The molecular fndings presented here have conservation implications for P. macrosturtensis and contribute to a growing narrative concerning weakened thermal tolerances in obligate subterranean organisms at the molecular level.Perry G. Beasley-Hall, Terry Bertozzi, Tessa M. Bradford, Charles S. P. Foster, Karl Jones, Simon M.Tierney, William F. Humphreys, Andrew D.Austin, Steven J. B. Coope

Multilaboratory evaluation of methods for detecting enteric viruses in soils.

Two candidate methods for the recovery and detection of viruses in soil were subjected to round robin comparative testing by members of the American Society for Testing and Materials D19:24:04:04 Subcommittee Task Group. Selection of the methods, designated "Berg" and "Goyal," was based on results of an initial screening which indicated that both met basic criteria considered essential by the task group. Both methods utilized beef extract solutions to achieve desorption and recovery of viruses from representative soils: a fine sand soil, an organic muck soil, a sandy loam soil, and a clay loam soil. One of the two methods, Goyal, also used a secondary concentration of resulting soil eluants via low-pH organic flocculation to achieve a smaller final assay volume. Evaluation of the two methods was simultaneously performed in replicate by nine different laboratories. Each of the produced samples was divided into portions, and these were respectively subjected to quantitative viral plaque assay by both the individual, termed independent, laboratory which had done the soil processing and a single common reference laboratory, using a single cell line and passage level. The Berg method seemed to produce slightly higher virus recovery values; however, the differences in virus assay titers for samples produced by the two methods were not statistically significant (P less than or equal to 0.05) for any one of the four soils. Despite this lack of a method effect, th

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

Frequency of social nesting in the sweat bee Megalopta genalis (Halictidae) does not vary across a rainfall gradient, despite disparity in brood production and body size

Local environmental conditions can facilitate or preclude the development of eusocial colonies in insects that facultatively express behavioural-caste polyphenism. To explore how environmental variability relates to the expression of social behaviour, we collected 120 nests of the facultatively social sweat bee, Megalopta genalis (Halictidae: Augochlorini), along a nearly twofold rainfall gradient in central Panama. Brood rearing activity of bees in seasonal neotropical forests should track flowering phenologies, which are typically set by rainfall and phylogenetic patterns. Nests were collected at roughly similar times of year from three sites comprising wet, moist and dry lowland tropical forests. There were significant differences in ovarian development, brood production and body size across sites for some comparisons, but no effect on the proportion of social colonies collected at each site. Results show that phenotypes of M. genalis relevant to social behaviour (ovarian development, brood production, body size) may be responsive to variation in local environment over distances of <20 km.S. M. Tierney, C. N. Fischer, S. M. Rehan, K. M. Kapheim, W. T. Wcisl

How blind are they? Phototactic responses in stygobiont diving beetles (Coleoptera: Dytiscidae) from calcrete aquifers of Western Australia

Subterranean water beetles endemic to groundwater calcretes of Western Australia exhibit convergent traits typical of troglomorphic arthropods, including loss of eyes, pigmentation and wings. As these dytiscid species are estimated to have been isolated underground in permanent darkness for over three million years, it is predicted that they will completely lack phototactic responses. We tested this hypothesis by analysing the behaviour of six subterranean beetle species within an observational arena with dark and light hemispheres. Scan samples at 1 min intervals and total time spent on each hemisphere were recorded over a 20 min period, testing at least 15 individuals per species. We quantified behaviour as an index (dark ratio) so that individual species in this, and future, studies can be consistently compared. Results analysed as both categorical and absolute proportion of time spent in each hemisphere suggest negative phototaxis in Paroster macrosturtensis. The remaining five species did not display any preference for either light or dark hemispheres. These results raise the possibility that some ancestral Par oster species may have exhibited negative phototactic behaviour prior to subterranean colonization. The retention of such a behavioural trait in lightless environments could represent the maintenance for some unknown pleiotropic function. Alternatively, it is possible that insufficient time has passed for neutral processes to render photoreception genes and phototactic behaviours non-functional. Our study adds to a growing body of evidence that implies highly troglomorphic animals may have evolved from ancestral species that exhibited negative phototaxis as a preadaptation to living in permanent darkness.Barbara L Langille, Simon M Tierney, Andrew D Austin, William F Humphreys and Steven J B Coope

Massive parallel regression: a precis of genetic mechanisms for vision loss in diving beetles

Two tribes of subterranean dytiscid diving beetles independently colonised groundwater systems of the Western Australian arid zone, a habitat transition that was most likely driven by the contraction of surface water bodies following late Neogene aridification of the Australian continent. These 'stygofauna' are now trapped within discrete calcrete aquifers that have formed in palaeodrainage valleys, resulting in the world's most diverse radiations of subterranean dytiscid beetles. Approximately 100 species from three genera exhibit partial or fully regressed visual systems and are essentially blind. This unique study system, with multiple independent transitions to subterranean life enables regressive and adaptive evolutionary processes to be studied in parallel at an unheralded comparative scale. Here we provide an overview of the progression of dytiscid beetle research and undertake a literature survey of published research within the field of regressive evolution as it applies to eye loss. We detail our exploration of insect vision genes for signatures of adaptive and neutral evolutionary mechanisms related to eye regression, largely within photoreceptor and eye pigment genes. Our project makes use of transcriptome data from five representative dytiscid beetle species (two surface and three subterranean) in order to design a customized set of RNA baits for use in a hybrid-capture method to target a pool of vision genes sequenced using high-throughput Illumina platforms. This methodological design permits the assessment of modifications in the genomic sequence of beetle vision genes at a much broader scale than Sanger sequencing, enabling a higher number of both target species and genes to be simultaneously assessed relative to research time-investments. Based on our literature search criteria of the research field ('regressive evolution' + 'eyes'), 81 papers have been published since the late 1980's accruing an h-index of 27 and a mean citation rate of 24.57. Collective annual citations for this field of research have surged over the past five years, an indication that broader scientific community interest is gaining momentum. The majority of publications (75%) have focused on the chordate clade Actinopterygii. Historically, research on variant subterranean taxa have faced difficulties inferring the evolutionary mechanisms of eye regression (and vision loss) using molecular approaches because only a handful of target genes could be feasibly addressed within grant funding cycles. From a comparative phylogenetic perspective, next-generation sequencing approaches applied to stygobiontic dytiscid beetles hold the potential to greatly improve our understanding of the genetic mechanisms underlying regressive evolution generally.Simon M. Tierney, Barbara Langille, William F. Humphreys, Andrew D. Austin, and Steven J.B. Coope

Preventing infection in general surgery: improvements through education of surgeons by surgeons

Surgical patients are at particular risk of healthcare-associated infection (HCAI) due to the presence of a surgical site leading to surgical site infection (SSI), and because of the need for intravascular access resulting in catheter-related bloodstream infection (CRBSI). A two-year initiative commenced with an initial audit of surgical practice; this was used to inform the development of a targeted educational initiative by surgeons specifically for surgical trainees. Parameters assessed during the initial audit and a further audit after the educational initiative were related to intra- and postoperative aspects of the prevention of SSIs, as well as care of peripheral venous catheters (PVCs) in surgical patients. The proportion of prophylactic antibiotics administered prior to incision across 360 operations increased from 30.0% to 59.1% (P&lt;0.001). Surgical site dressings were observed in 234 patients, and a significant decrease was found in the percentage of dressings that were tampered with during the initial 48h after surgery (16.5% vs 6.2%, P=0.030). In total, 574 PVCs were assessed over the two-year period. Improvements were found in the proportion of unnecessary PVCs in situ (37.9% vs 24.4%, P&lt;0.001), PVCs in situ for &gt;72h (10.6% vs 3.1%, P&lt;0.001) and PVCs covered with clean and intact dressings (87.3% vs 97.6%, P&lt;0.001). Significant improvements in surgical practice were established for the prevention of SSI and CRBSI through a focused educational programme developed by and for surgeons. Potentially, other specific measures may also be warranted to achieve further improvements in infection prevention in surgical practic