What are the evolutionary constraints on larval growth in a trophically transmitted parasite?

For organisms with a complex life cycle, a large larval size is generally beneficial, but it may come at the expense of prolonged development. Individuals that grow fast may avoid this tradeoff and switch habitats at both a larger size and younger age. A fast growth rate itself can be costly, however, as it requires greater resource intake. For parasites, fast larval growth is assumed to increase the likelihood of host death before transmission to the next host occurs. Using the tapeworm Schistocephalus solidus in its copepod first intermediate host, I investigated potential constraints in the parasite’s larval life history. Fast-growing parasites developed infectivity earlier, indicating there is no functional tradeoff between size and developmental time. There was significant growth variation among full-sib worm families, but fast-growing sibships were not characterized by lower host survival or more predation-risky host behavior. Parental investment also had little effect on larval growth rates. The commonly assumed constraints on larval growth and development were not observed in this system, so it remains unclear what prevents worms from exploiting their intermediate hosts more aggressively

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

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

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

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

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

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Data from: Parental effects on the larval performance of a tapeworm in its copepod first host

Parents can influence the phenotype of their offspring through various mechanisms, besides the direct effect of heredity. Such parental effects are little explored in parasitic organisms, perhaps because in many parasites per capita investment into offspring is low. I investigated whether parental identity, beyond direct genetic effects, could explain variation in the performance of the tapeworm Schistocephalus solidus in its first intermediate host, a copepod. I first determined that two breeding worms could be separated from one another after ~48 hrs of in vitro incubation and that the isolated worms continued producing outcrossed eggs, i.e. rates self-fertilization did not increase after separation. Thus, from a breeding pair, two sets of genetically comparable eggs can be collected that have unambiguous parental identities. In an infection experiment, I found that the development of larval worms tended to vary between the two parental worms within breeding pairs, but infection success and growth rate in copepods did not. Accounting for this parental effect decreased the estimated heritability for development by nearly half. These results suggest that larval performance is not simply a function of a worm’s genotype; who mothered or fathered an offspring can also affect offspring fitness, contradicting the perhaps naïve idea that parasites simply produce large quantities of uniformly low-quality offspring

Developmental inflexibility of larval tapeworms in response to resource variation

The timing of habitat switching in organisms with complex life cycles is an important life history characteristic that is often influenced by the larval growth environment. Under starvation, longer developmental times are frequently observed, probably as a consequence of developmental thresholds, but prolonged ontogeny sometimes also occurs under good conditions, as organisms may take advantage of the large potential gains in body size. I investigated whether variation in growth conditions affects the larval development time of a complex life cycle tapeworm (Schistocephalus solidus) in its copepod first host. Moreover, I reviewed patterns of developmental plasticity in larval tapeworms to assess the generality of my findings. Copepod starvation weakly retarded parasite growth but did not affect development. Worms grew bigger in larger copepods, but they developed at a similar rate in large and small hosts. Thus, S. solidus does not delay ontogeny under good conditions nor does it fail to reach a developmental threshold under poor conditions. Although unusual in comparison to free-living organisms, such inflexibility is common in tapeworms. Plasticity, namely prolonged ontogeny, has been mainly observed at high infection intensities. For S. solidus, there were large cross-environment genetic correlations for development, suggesting there may be genetic constraints on the evolution of developmental plasticity

Sep_dryad

Data from breeding protocol experimen

Inf_exp_dryad

Data from infection experiment

Data from: Copulation order, density cues and variance in fertilization success in a cestode

Simultaneous hermaphrodites maximize their fitness by optimizing their investment into male or female functions. Allocation of resources to male function (tissues, traits, and/or behaviours increasing paternity) is predicted to increase as density, and the associated level of sperm competition, increases. We tested whether the simultaneous hermaphroditic cestode Schistocephalus solidus uses cues of potential partner densities in its fish intermediate host to improve its male reproductive success in the final host. We had two worms, one originating from a multiple infection in the fish intermediate host and one from a single infection, sequentially compete to fertilize the eggs of a third worm. The fertilization rates of the two competitors nearly always differed from the 50-50 null expectation, sometimes considerably, implying there was a 'winner' in each experimental competition. However, we did not find a significant effect of density in the fish host (single vs multiple) or mating order on paternity. Additional work will be needed to identify the traits and environmental conditions that explain the high variance in male reproductive success observed in this experiment