Bird evolution: testing the Metaves clade with six new mitochondrial genomes

Background Evolutionary biologists are often misled by convergence of morphology and this has been common in the study of bird evolution. However, the use of molecular data sets have their own problems and phylogenies based on short DNA sequences have the potential to mislead us too. The relationships among clades and timing of the evolution of modern birds (Neoaves) has not yet been well resolved. Evidence of convergence of morphology remain controversial. With six new bird mitochondrial genomes (hummingbird, swift, kagu, rail, flamingo and grebe) we test the proposed Metaves/Coronaves division within Neoaves and the parallel radiations in this primary avian clade. Results Our mitochondrial trees did not return the Metaves clade that had been proposed based on one nuclear intron sequence. We suggest that the high number of indels within the seventh intron of the β-fibrinogen gene at this phylogenetic level, which left a dataset with not a single site across the alignment shared by all taxa, resulted in artifacts during analysis. With respect to the overall avian tree, we find the flamingo and grebe are sister taxa and basal to the shorebirds (Charadriiformes). Using a novel site-stripping technique for noise-reduction we found this relationship to be stable. The hummingbird/swift clade is outside the large and very diverse group of raptors, shore and sea birds. Unexpectedly the kagu is not closely related to the rail in our analysis, but because neither the kagu nor the rail have close affinity to any taxa within this dataset of 41 birds, their placement is not yet resolved. Conclusion Our phylogenetic hypothesis based on 41 avian mitochondrial genomes (13,229 bp) rejects monophyly of seven Metaves species and we therefore conclude that the members of Metaves do not share a common evolutionary history within the Neoaves

Is severe hypocalcemia immediately life threatening?

Objective: Severe hypocalcemia (Ca <1.9 mmol/L) is often considered an emergency because of a potential risk of cardiac arrest or seizures. However, there is little evidence to support this. The aim of our study was to assess whether severe hypocalcemia was associated with immediately life-threatening cardiac arrhythmias or neurological complications. Methods: A retrospective observational study was carried out over a 2-year period in the Adult Emergency Department (ED) of Nantes University Hospital. All patients who had a protein-corrected calcium concentration measure were eligible for inclusion. Patients with multiple myeloma were excluded. The primary outcome was the number of life-threatening cardiac arrhythmias and/or neurological complications during the stay in the ED. Results: A total of 41,823 patients had protein-corrected calcium (pcCa) concentrations measured, 155 had severe hypocalcemia, 22 were excluded because of myeloma leaving 133 for analysis. Median pcCa concentration was 1.73 mmol/L (1.57–1.84). Seventeen (12.8%) patients presented a life-threatening condition, 14 (10.5%) neurological and 3 (2.2%) cardiac during ED stay. However, these complications could be explained by the presence of underlying co-morbidities and or electrolyte disturbances other than hypocalcemia. Overall, 24 (18%) patients died in hospital. Vitamin D deficiency, chronic kidney disease and hypoparathyroidism were the most frequently found causes of hypocalcemia. Conclusion: Thirteen percent of patients with severe hypocalcemia presented a life-threatening cardiac or neurological complication on the ED. However, a perfectly valid alternative cause could account for these complications. Further research is warranted to define the precise role of hypocalcemia

Genome-Wide Studies of Histone Demethylation Catalysed by the Fission Yeast Homologues of Mammalian LSD1

In order to gain a more global view of the activity of histone demethylases, we report here genome-wide studies of the fission yeast SWIRM and polyamine oxidase (PAO) domain homologues of mammalian LSD1. Consistent with previous work we find that the two S. pombe proteins, which we name Swm1 and Swm2 (after SWIRM1 and SWIRM2), associate together in a complex. However, we find that this complex specifically demethylates lysine 9 in histone H3 (H3K9) and both up- and down-regulates expression of different groups of genes. Using chromatin-immunoprecipitation, to isolate fragments of chromatin containing either H3K4me2 or H3K9me2, and DNA microarray analysis (ChIP-chip), we have studied genome-wide changes in patterns of histone methylation, and their correlation with gene expression, upon deletion of the swm1+ gene. Using hyper-geometric probability comparisons we uncover genetic links between lysine-specific demethylases, the histone deacetylase Clr6, and the chromatin remodeller Hrp1. The data presented here demonstrate that in fission yeast the SWIRM/PAO domain proteins Swm1 and Swm2 are associated in complexes that can remove methyl groups from lysine 9 methylated histone H3. In vitro, we show that bacterially expressed Swm1 also possesses lysine 9 demethylase activity. In vivo, loss of Swm1 increases the global levels of both H3K9me2 and H3K4me2. A significant accumulation of H3K4me2 is observed at genes that are up-regulated in a swm1 deletion strain. In addition, H3K9me2 accumulates at some genes known to be direct Swm1/2 targets that are down-regulated in the swm1¿ strain. The in vivo data indicate that Swm1 acts in concert with the HDAC Clr6 and the chromatin remodeller Hrp1 to repress gene expression. In addition, our in vitro analyses suggest that the H3K9 demethylase activity requires an unidentified post-translational modification to allow it to act. Thus, our results highlight complex interactions between histone demethylase, deacetylase and chromatin remodelling activities in the regulation of gene expression

The mechanics of explosive seed dispersal in orange jewelweed (Impatiens capensis)

Explosive dehiscence ballistically disperses seeds in a number of plant species. During dehiscence, mechanical energy stored in specialized tissues is transferred to the seeds to increase their kinetic and potential energies. The resulting seed dispersal patterns have been investigated in some ballistic dispersers, but the mechanical performance of a launch mechanism of this type has not been measured. The properties of the energy storage tissue and the energy transfer efficiency of the launch mechanism were quantified in Impatiens capensis. In this species the valves forming the seed pod wall store mechanical energy. Their mass specific energy storage capacity (124 J kg−1) was comparable with that of elastin and spring steel. The energy storage capacity of the pod tissues was determined by their level of hydration, suggesting a role for turgor pressure in the energy storage mechanism. During dehiscence the valves coiled inwards, collapsing the pod and ejecting the seeds. Dehiscence took 4.2±0.4 ms (mean ±SEM, n=13). The estimated efficiency with which energy was transferred to the seeds was low (0.51±0.26%, mean ±SEM, n=13). The mean seed launch angle (17.4±5.2, mean ±SEM, n=45) fell within the range predicted by a ballistic model to maximize dispersal distance. Low ballistic dispersal efficiency or effectiveness may be characteristic of species that also utilize secondary seed dispersal mechanisms

Ten-year mortality, disease progression, and treatment-related side effects in men with localised prostate cancer from the ProtecT randomised controlled trial according to treatment received

Background The ProtecT trial reported intention-to-treat analysis of men with localised prostate cancer randomly allocated to active monitoring (AM), radical prostatectomy, and external beam radiotherapy. Objective To report outcomes according to treatment received in men in randomised and treatment choice cohorts. Design, setting, and participants This study focuses on secondary care. Men with clinically localised prostate cancer at one of nine UK centres were invited to participate in the treatment trial comparing AM, radical prostatectomy, and radiotherapy. Intervention Two cohorts included 1643 men who agreed to be randomised and 997 who declined randomisation and chose treatment. Outcome measurements and statistical analysis Analysis was carried out to assess mortality, metastasis and progression and health-related quality of life impacts on urinary, bowel, and sexual function using patient-reported outcome measures. Analysis was based on comparisons between groups defined by treatment received for both randomised and treatment choice cohorts in turn, with pooled estimates of intervention effect obtained using meta-analysis. Differences were estimated with adjustment for known prognostic factors using propensity scores. Results and limitations According to treatment received, more men receiving AM died of PCa (AM 1.85%, surgery 0.67%, radiotherapy 0.73%), whilst this difference remained consistent with chance in the randomised cohort (p = 0.08); stronger evidence was found in the exploratory analyses (randomised plus choice cohort) when AM was compared with the combined radical treatment group (p = 0.003). There was also strong evidence that metastasis (AM 5.6%, surgery 2.4%, radiotherapy 2.7%) and disease progression (AM 20.35%, surgery 5.87%, radiotherapy 6.62%) were more common in the AM group. Compared with AM, there were higher risks of sexual dysfunction (95% at 6 mo) and urinary incontinence (55% at 6 mo) after surgery, and of sexual dysfunction (88% at 6 mo) and bowel dysfunction (5% at 6 mo) after radiotherapy. The key limitations are the potential for bias when comparing groups defined by treatment received and changes in the protocol for AM during the lengthy follow-up required in trials of screen-detected PCa. Conclusions Analyses according to treatment received showed increased rates of disease-related events and lower rates of patient-reported harms in men managed by AM compared with men managed by radical treatment, and stronger evidence of greater PCa mortality in the AM group. Patient summary More than 95 out of every 100 men with low or intermediate risk localised prostate cancer do not die of prostate cancer within 10 yr, irrespective of whether treatment is by means of monitoring, surgery, or radiotherapy. Side effects on sexual and bladder function are better after active monitoring, but the risks of spreading of prostate cancer are more common

Functional and quality of life outcomes of localised prostate cancer treatments (prostate testing for cancer and treatment [ProtecT] study)

Objective To investigate the functional and quality of life (QoL) outcomes of treatments for localised prostate cancer and inform treatment decision-making. Patients and Methods Men aged 50–69 years diagnosed with localised prostate cancer by prostate-specific antigen testing and biopsies at nine UK centres in the Prostate Testing for Cancer and Treatment (ProtecT) trial were randomised to, or chose one of, three treatments. Of 2565 participants, 1135 men received active monitoring (AM), 750 a radical prostatectomy (RP), 603 external-beam radiotherapy (EBRT) with concurrent androgen-deprivation therapy (ADT) and 77 low-dose-rate brachytherapy (BT, not a randomised treatment). Patient-reported outcome measures (PROMs) completed annually for 6 years were analysed by initial treatment and censored for subsequent treatments. Mixed effects models were adjusted for baseline characteristics using propensity scores. Results Treatment-received analyses revealed different impacts of treatments over 6 years. Men remaining on AM experienced gradual declines in sexual and urinary function with age (e.g., increases in erectile dysfunction from 35% of men at baseline to 53% at 6 years and nocturia similarly from 20% to 38%). Radical treatment impacts were immediate and continued over 6 years. After RP, 95% of men reported erectile dysfunction persisting for 85% at 6 years, and after EBRT this was reported by 69% and 74%, respectively (P < 0.001 compared with AM). After RP, 36% of men reported urinary leakage requiring at least 1 pad/day, persisting for 20% at 6 years, compared with no change in men receiving EBRT or AM (P < 0.001). Worse bowel function and bother (e.g., bloody stools 6% at 6 years and faecal incontinence 10%) was experienced by men after EBRT than after RP or AM (P < 0.001) with lesser effects after BT. No treatment affected mental or physical QoL. Conclusion Treatment decision-making for localised prostate cancer can be informed by these 6-year functional and QoL outcomes

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome