Comparative vaccine effectiveness against severe COVID-19 over time in US hospital administrative data: a case-control study.

BACKGROUND: Research suggests the protection offered by COVID-19 vaccines might wane over time, prompting consideration of booster vaccinations. Data on which vaccines offer the most robust protection over time, and which patients are most vulnerable to attenuating protection, could help inform potential booster programmes. In this study, we used comprehensive hospitalisation data to estimate vaccine effectiveness over time. METHODS: In this case-control study, we used data from a large US health-care system to estimate vaccine effectiveness against severe SARS-CoV-2 infection and examined variation based on time since vaccination, vaccine type, and patients' demographic and clinical characteristics. We compared trends in attenuation of protection across vaccines and used a multivariable model to identify key factors associated with risk for severe breakthrough infection. Patients were considered to have severe COVID-19 if they were admitted to the hospital, had a final coded diagnosis of COVID-19 (according to International Classification of Diseases Tenth Revision code U07.1) or a positive nucleic acid amplification test for symptomatic SARS-CoV-2 during their hospitalisation, and were treated with remdesivir or dexamethasone during hospitalisation. FINDINGS: Between April 1, 2021, and Oct 26, 2021, we observed 9667 admissions for severe COVID-19 (ie, cases). Overall, 1293 (13·4%) of 9667 cases were fully vaccinated at the time of admission, compared with 22 308 (57·7%) of 38 668 controls, who were admitted to hospital for other reasons. The median time between vaccination and hospital admission among cases was 162 days (IQR 118-198). Overall vaccine effectiveness declined mostly over the course of the summer, from 94·5% (95% CI 91·4-96·5) in April, 2021 (pre-delta), to 84·0% (81·6-86·1) by October, 2021. Notably, vaccine effectiveness declined over time, from 94·0% (95% CI 92·8-95·0) at days 50-100 after vaccination to 80·4% (77·8-82·7) by days 200-250 after vaccination. After 250 days, vaccine effectiveness declines were even more notable. Among those who received the BNT162b2 (Pfizer-BioNTech) vaccine, vaccine effectiveness fell from an initial peak of 94·9% (93·2-96·2) to 74·1% (69·6-77·9) by days 200-250 after vaccination. Protection from the mRNA-1273 (Moderna) and Ad26.COV2 (Janssen) vaccines declined less over time, although the latter offered lower overall protection. Holding other factors constant, the risk of severe breakthrough infection was most strongly associated with age older than 80 years (adjusted odds ratio 1·76, 95% CI 1·43-2·15), vaccine type (Pfizer 1·39, 0·98-1·97; Janssen 14·53, 8·43-25·03; both relative to Moderna), time since vaccination (1·05, 1·03-1·07; per week after week 8 when protection peaks, technically), and comorbidities including organ transplantation (3·44, 95% CI 2·12-5·57), cancer (1·93, 1·60-2·33), and immunodeficiency (1·49, 1·13-1·96). INTERPRETATION: Vaccination remains highly effective against hospitalisation, but vaccine effectiveness declined after 200 days, particularly for older patients or those with specific comorbidities. Additional protection (eg, a booster vaccination) might be warranted for everyone, but especially for these populations. In addition to promoting general vaccine uptake, clinicians and policy makers should consider prioritising booster vaccinations in those most at risk of severe COVID-19. FUNDING: None.

Remdesivir and Mortality in Patients With Coronavirus Disease 2019.

BACKGROUND: The impact of remdesivir (RDV) on mortality rates in coronavirus disease 2019 (COVID-19) is controversial, and the mortality effect in subgroups of baseline disease severity has been incompletely explored. The purpose of this study was to assess the association of RDV with mortality rates in patients with COVID-19. METHODS: In this retrospective cohort study we compared persons receiving RDV with those receiving best supportive care (BSC). Patients hospitalized between 28 February and 28 May 2020 with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection were included with the development of COVID-19 pneumonia on chest radiography and hypoxia requiring supplemental oxygen or oxygen saturation ≤94% with room air. The primary outcome was overall survival, assessed with time-dependent Cox proportional hazards regression and multivariable adjustment, including calendar time, baseline patient characteristics, corticosteroid use, and random effects for hospital. RESULTS: A total of 1138 patients were enrolled, including 286 who received RDV and 852 treated with BSC, 400 of whom received hydroxychloroquine. Corticosteroids were used in 20.4% of the cohort (12.6% in RDV and 23% in BSC). Comparing persons receiving RDV with those receiving BSC, the hazard ratio (95% confidence interval) for death was 0.46 (.31-.69) in the univariate model (P < .001) and 0.60 (.40-.90) in the risk-adjusted model (P = .01). In the subgroup of persons with baseline use of low-flow oxygen, the hazard ratio (95% confidence interval) for death in RDV compared with BSC was 0.63 (.39-1.00; P = .049). CONCLUSION: Treatment with RDV was associated with lower mortality rates than BSC. These findings remain the same in the subgroup with baseline use of low-flow oxygen.

Anosmia impairs homing orientation but not foraging behaviour in free-ranging shearwaters.

Shearwaters deprived of their olfactory sense before being displaced to distant sites have impaired homing ability but it is unknown what the role of olfaction is when birds navigate freely without their sense of smell. Furthermore, treatments used to induce anosmia and to disrupt magneto-reception in displacement experiments might influence non-specific factors not directly related to navigation and, as a consequence, the results of displacement experiments can have multiple interpretations. To address this, we GPS-tracked the free-ranging foraging trips of incubating Scopoli's shearwaters within the Mediterranean Sea. As in previous experiments, shearwaters were either made anosmic with 4% zinc sulphate solution, magnetically impaired by attachment of a strong neodymium magnet or were controls. We found that birds from all three treatments embarked on foraging trips, had indistinguishable at-sea schedules of behaviour and returned to the colony having gained mass. However, we found that in the pelagic return stage of their foraging trips, anosmic birds were not oriented towards the colony though coastal navigation was unaffected. These results support the case for zinc sulphate having a specific effect on the navigational ability of shearwaters and thus the view that seabirds consult an olfactory map to guide them across seascapes.

Breeding phenology and winter activity predict subsequent breeding success in a trans-global migratory seabird.

Inter-seasonal events are believed to connect and affect reproductive performance (RP) in animals. However, much remains unknown about such carry-over effects (COEs), in particular how behaviour patterns during highly mobile life-history stages, such as migration, affect RP. To address this question, we measured at-sea behaviour in a long-lived migratory seabird, the Manx shearwater (Puffinus puffinus) and obtained data for individual migration cycles over 5 years, by tracking with geolocator/immersion loggers, along with 6 years of RP data. We found that individual breeding and non-breeding phenology correlated with subsequent RP, with birds hyperactive during winter more likely to fail to reproduce. Furthermore, parental investment during one year influenced breeding success during the next, a COE reflecting the trade-off between current and future RP. Our results suggest that different life-history stages interact to influence RP in the next breeding season, so that behaviour patterns during winter may be important determinants of variation in subsequent fitness among individuals.

Three-dimensional spatial cognition in a benthic fish, Corydoras aeneus.

The way animals move through space is likely to affect the way they learn and remember spatial information. For example, a pelagic fish, Astyanax fasciatus, moves freely in vertical and horizontal space and encodes information from both dimensions with similar accuracy. Benthic fish can also move with six degrees of freedom, but spend much of their time travelling over the substrate; hence they might be expected to prioritise the horizontal dimension. To understand how benthic fish encode and deploy three-dimensional spatial information we used a fully rotational Y-maze to test whether Corydoras aeneus (i) encode space as an integrated three-dimensional unit or as separate elements, by testing whether they can decompose a three-dimensional trajectory into its vertical and horizontal components, and (ii) whether they prioritise vertical or horizontal information when the two conflict. In contradiction to the expectation generated by our hypothesis, our results suggest that C. aeneus are better at extracting vertical information than horizontal information from a three-dimensional trajectory, suggesting that the vertical axis is learned and remembered robustly. Our results also showed that C. aeneus prioritise vertical information when it conflicts with horizontal information. From these results, we infer that benthic fish attend preferentially to a cue unique to the vertical axis, and we suggest that this cue is hydrostatic pressure.

Migration and stopover in a small pelagic seabird, the Manx shearwater Puffinus puffinus: insights from machine learning.

The migratory movements of seabirds (especially smaller species) remain poorly understood, despite their role as harvesters of marine ecosystems on a global scale and their potential as indicators of ocean health. Here we report a successful attempt, using miniature archival light loggers (geolocators), to elucidate the migratory behaviour of the Manx shearwater Puffinus puffinus, a small (400 g) Northern Hemisphere breeding procellariform that undertakes a trans-equatorial, trans-Atlantic migration. We provide details of over-wintering areas, of previously unobserved marine stopover behaviour, and the long-distance movements of females during their pre-laying exodus. Using salt-water immersion data from a subset of loggers, we introduce a method of behaviour classification based on Bayesian machine learning techniques. We used both supervised and unsupervised machine learning to classify each bird's daily activity based on simple properties of the immersion data. We show that robust activity states emerge, characteristic of summer feeding, winter feeding and active migration. These can be used to classify probable behaviour throughout the annual cycle, highlighting the likely functional significance of stopovers as refuelling stages.

Pyrazine odour makes visually conspicuous prey aversive.

Unpalatable insects frequently adopt multimodal signals to ward off predators, incorporating sounds and odours into their colourful displays. Pyrazine is an odour commonly used in insect warning displays, and has previously been shown to elicit unlearned biases against common warning colours, e.g. yellow and red in naive predators. We designed two experiments to test for similar effects of pyrazine on the conspicuousness of prey, perhaps the most ubiquitous aspect of aposematic coloration. In the first experiment, we offered predators (Gallus gallus domesticus) a choice between conspicuous crumbs and cryptic crumbs in the presence or absence of pyrazine. In the second experiment, we manipulated the birds' experience of conspicuous prey during an initial training phase. Only in the presence of pyrazine did birds show a bias against conspicuously coloured food, and this occurred whether or not they had previously experienced food that contrasted with the background. This emergent behaviour relied upon the visual and odorous signal components being presented together. These unlearned, yet hidden, responses against conspicuousness demonstrate that there are initial benefits to prey being conspicuous when the multimodal nature of warning signals is accounted for.

Accurate route demonstration by experienced homing pigeons does not improve subsequent homing performance in naive conspecifics.

We describe an experiment that uses the grouping tendencies and navigational abilities of the homing pigeon (Columba livia) to investigate the possibility of socially mediated information transfer in a field setting. By varying the composition of paired-release types, we allowed some naive birds to receive an accurate demonstration of the home route whilst others were paired with similarly naive conspecifics. After this 'paired phase', we predicted that if any learning of spatial information occurred then naive members of the former pairs would outperform their untutored conspecifics when re-released individually during the subsequent 'single phase' of the experiment. This prediction was not confirmed. Neither homing speed nor initial orientation was superior in individually released tutored versus untutored birds, despite the fact that both performance measures were better in the earlier 'paired phase' with experienced demonstrators. Our results suggest that although naive homing pigeons clearly interact with their experienced partners, they are unable to transfer any individually useful spatial information to subsequent homing flights.

Tracking clock-shifted homing pigeons from familiar release sites.

Clock-shifted homing pigeons were tracked from familiar sites 17.1 km and 23.5 km from the home loft in Pisa, Italy, using an on-board route recorder. At the first release site, north of home, the majority of clock-shifted birds had relatively straight tracks comparable with those of control birds. At the second release site, south of home, the clock-shifted birds deflected in the direction predicted for the degree of clock shift, with many birds travelling some distance in the wrong direction before correcting their course. The possible role of large-scale terrain features in homing pigeon navigation is discussed.

The roles of the sun and the landscape in pigeon homing.

It seems reasonable to assume that pigeons use visual features in the landscape for orientation when they are homing over familiar terrain. Experimental evidence to prove or disprove this possibility is, however, difficult to obtain. Here, we link the problem with the observation that deflections of initial orientation caused by clock-shift are often smaller than predicted on a pure sun compass basis. We substantiate the hypothesis that consistently reduced deflections and increased angular scatter occur only when pigeons are released in familiar areas where a remembered pattern of landscape features can conflict with the position of the sun. Repeated releases of the same individuals under clock-shift, or elimination of non-visual navigational clues (odours), appear to strengthen the conflicting influence of familiar visual landmarks. Accelerated returns of birds allowed to preview the surrounding familiar scenery before release also support the conclusion that the visual environment is included in the homing system of pigeons. The landscape, however, not only helps home-finding, if it is familiar, but may also have a distracting influence that contributes to the great variability of initial orientation patterns.

Novelty effects in a multimodal warning signal.

The warning signals of toxic insects are often 'multimodal', combining bright coloration with sounds or odours (or both). Pyrazine (a common insect warning odour) can elicit an intrinsic avoidance in domestic chicks Gallus gallus domesticus, both against novel coloured food, and also against food colours that are specifically associated with aposematism, namely yellow and red. In three experiments, we investigated the role of novelty in this innate bias against yellow coloured food in the presence of pyrazine. Naive chicks were familiarized either to pyrazine odour or to coloured food before being tested for a bias against yellow (warningly coloured) food as opposed to green (nonwarningly coloured) food. In experiment 1, pyrazine novelty was shown to be vital for eliciting a bias against yellow food. However, experiment 2 suggested that colour novelty was not important: chicks familiarized with coloured crumbs still avoided yellow crumbs when pyrazine was presented. In a third experiment that gave chicks an even greater degree of pre-exposure to coloured crumbs, the bias against yellow food eventually waned, although pyrazine continued to elicit an aversion to yellow even after birds had had experience of up to 24 palatable yellow crumbs. Pyrazine novelty has been an important pressure in the evolution of multimodal warning signals, and can continue to promote the avoidance of warningly coloured food, even when it is relatively familiar. The implications for warning signals are discussed. Copyright 1999 The Association for the Study of Animal Behaviour.

The social transmission of spatial information in homing pigeons.

We adapted a technique to explore the social transmission of spatial information in homing pigeons Columba livia. Five demonstrator pigeons were first trained to find a food goal within an indoor arena. This arena consisted of nine lidded cups laid out within a 12x12 grid on the floor. The task was to find the goal cup and flip the lid to obtain the food hidden within. Once the demonstrators had reached criterion the experiment proper began. During stage 1 of the experiment, 10 target birds, which had not previously been trained to find the goal, were introduced to the spatial task either in isolation or paired with a demonstrator. We measured how long they took to complete the task, the number of squares crossed on the grid, and the number of incorrect lids flipped. In stage 2, the target birds were introduced to the arena a second time, by themselves, and we compared the performance of the birds in the two treatments. The pigeons that had been introduced to the task with a demonstrator in stage 1 walked further and made more incorrect choices when searching for the food goal in stage 2 than the pigeons that were introduced to the task alone. This indicates that pigeons learn a spatial, food-finding task more effectively when performing the task alone than when accompanied by a knowledgeable conspecific. We discuss possible reasons for this in the light of previous experiments. Copyright 1999 The Association for the Study of Animal Behaviour.

Homing pigeons use olfactory cues for navigation in england

Although the use of olfactory cues in pigeon navigation is well established, the generality of olfactory navigation remains uncertain because of apparent variability in results gained by different researchers in different regions. We report the results of the first experiments investigating the effect of anosmia on homing pigeons reared in a previously uninvestigated region, southern England. In series 1, experienced birds showed little effect of anosmia induced with zinc sulphate at unfamiliar sites 30 km and 39 km from the loft, but treated birds were significantly poorer than controls at homing from an unfamiliar site 66 km distant (and in pooled results). In series 2, naive (untrained) birds, both control and zinc-sulphate-treated, showed poor homing abilities and initial orientation from sites 25 km, 36 km and 39 km from the loft. Nevertheless, in pooled results, controls showed significantly better homeward orientation than anosmic birds and were significantly more likely to home on the day of release. The most likely explanation for our results is that pigeons are able to use olfactory navigation in southern England, but that for some reason the olfactory map is relatively weak.

Further evidence for visual landmark involvement in the pigeon's familiar area map

In previous experiments suggesting that previewing visual landscapes speeds homing from familiar release sites, restricted access to olfactory cues may have artefactually encouraged homing pigeons, Columba liviato resort to visual landmark orientation. Since evidence for the role of visual landmarks in wide-ranging avian orientation is still equivocal, Braithwaite & Guilford's (1991, Proc. R. Soc. Lond. Ser. B245, 183-186) 'previewing' experiments were replicated: birds were allowed or denied visual access to a familiar site prior to release, but allowed ample access to olfactory cues. In experiment 1, allowing birds to preview familiar sites for 5 min prior to release enhanced homing speeds by about 12%. In experiment 2, modified to reduce between-day effects on variation, previewing enhanced homing speeds by about 16%. These experiments support the conclusion that visual landmarks remote from sight of the loft are an important component of the familiar area map, although the nature of the landmarks and how they are encoded remain to be determined.

Discrimination and recognition of photographs of places by homing pigeons.

Operant studies on pigeons using slide-projected images suggest that photographs of geographical locations might be used as a research tool to study the importance of visual landmarks in homing. Before using this method, however, it is necessary to show that pigeons do see photographic slides as representing real world locations. After reviewing the evidence for picture-to-object correspondence for geographical locations in pigeons, we report the results of an experiment designed to test whether outdoor experience at a location affected homing pigeons' ability to categorise slides of that versus another location displayed in an operant set-up. Four birds visited one location immediately before each experimental session; four birds visited an irrelevant location. No effect of outdoor experience was found on acquisition, or transfer to novel stimuli. The possible reasons for limitations on picture-to-object correspondence are discussed.

An exaggerated preference for simple neural network models of signal evolution?

Recently, simple neural network models have been used to explain the evolution of important phenomena in animal signalling, such as extravagant ornamentation and symmetrical signals, as responses to inevitable 'hidden preferences' of recognition systems. We argue that these very simple models may be misleading because they may not behave in important ways like the recognition systems of real animals and so cannot justify their claim to demonstrate general principles of perception in a signalling context. We show that the way in which these simple models respond to exaggerated signals may not be, as is claimed, a close parallel to the phenomena of peak shift or supernormal responses. We also argue that the preference for symmetrical patterns shown by the models is unlikely to reflect the way computationally that real animals solve problems of pattern invariance and may be an artefact of the particular way the models have been set up. Whereas more sophisticated neural net models do capture known properties of real visual systems and are consequently of great use in understanding perception, the same cannot be said of very simple one-dimensional models with small numbers of units and connections. Given the far reaching explanatory claims made of these simpler models their limitations should be more widely recognized.

Receiver psychology and the design of animal signals.

Animal communication is studied both by neurobiologists and by evolutionary biologists, but in very different ways. The purpose of this article is to show how both groups could benefit from a greater appreciation of each other's approach. Evolutionary biologists should take more account of the role played by the sensory systems and brains of receivers in constraining the design of animal signals. Neurobiologists should be more aware of recent advances in the understanding of signal-receiver co-evolution and the evolutionary origins of animal signals. A series of recent examples are cited that illustrate how pre-existing neurophysiological or psychological properties of receiver organisms are essential to our understanding of the design characteristics of animal signals and of their origins. Also discussed are a number of other areas of signalling in which the study of 'receiver psychology' is likely to be fruitful.