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

The Responses of the Bed Bug (Cimex Lectularius L.) to Heat Exposure at the Population, Behavioral, and Physiological Levels

Elimination of bed bug infestations remains a challenge for the pest management industry as these insects continue to resurge on a global scale. However, the use of integrated pest management (IPM) to control bed bugs has been effective. A key part of an IPM program is the combined use of chemical and non-chemical techniques, and one effective non-chemical technique is the use of lethal heat. When properly done, heat treatments can eliminate all bed bug life stages. However, household items with variable thermal conductivities can lead to uneven temperatures within the structures being treated. Uneven heating of bed bug harborage areas may allow bed bugs to behaviorally respond to heat exposure by escaping to cooler zones or be exposed to sub-lethal heat when within hiding places. Survival of bed bugs immediately following heat treatments could mainly occur due to two reasons: (1) the ability of bed bugs to develop physiological heat resistance; and (2) their ability to chemically (through release of alarm pheromones) and behaviorally respond to lethal heat exposure by escaping to cooler spots or areas that have been sub-lethally heated, which has not been investigated. Therefore, the main objectives of this study are: 1) Evaluate ability of bed bugs to develop heat resistance or thermo-tolerance at the population level in relation to their history of previous heat exposure, insecticide resistance status, and geographic origin using two different exposure techniques. 2) Determine the temperatures that will stimulate bed bugs to move in search for cooler areas. 3) Identify which HSP genes are expressed by bed bugs after heat exposure. 4) Determine if alarm pheromones (APs) are released by bed bugs that are heat exposed and how conspecifics that are not exposed to heat will react to these APs. For the first objective, selection experiments found an initial increase in bed bug survivorship over the first 2–3 generations; however, survivorship did not increase past the fourth generation. The step-function exposure technique revealed non-significant variation in heat tolerance between populations and the ramp-function exposure technique provided similar results. Based on this objective 1 findings, the ability of bed bugs to develop heat resistance within a few generations appears to be limited. Behavioral experiments (objective 2) found that at specific temperatures, different bed bug populations had similar probabilities to flee and their ability to locate unheated areas or survive heat exposure in the arena was not different. Also, if bed bugs are exposed to temperatures of 47–48°C in their harborage while exterior temperatures approach 53–54°C, they will be forced into the open. The RT-qPCR experiments (objective 3) revealed that the expression of the HSP70.1, HSP70.3, and Putative SmallHSP genes were significantly upregulated after heat exposure in all tested populations and are likely critical in their recovery process after heat exposure. For the fourth objective, analysis of head space volatiles, using a SIFT-MS (soft ion flow tube mass spectrometer), revealed that bed bugs responded to lethal and sub-lethal heat exposure by emitting their APs. In separate behavioral experiments, it was shown that conspecifics from both tested populations reacted to APs emitted by heated bed bugs and synthetic APs by frantically moving

Comparative Efficacy of a Fungal Entomopathogen with a Broad Host Range against Two Human-Associated Pests

The ability of a fungal entomopathogen to infect an insect depends on a variety of factors, including strain, host, and environmental conditions. Similarly, an insect’s ability to prevent fungal infection is dependent on its biology, environment, and evolutionary history. Synanthropic pests have adapted to thrive in the indoor environment, yet they arose from divergent evolutionary lineages and occupy different feeding guilds. The hematophagous bed bug (Cimex lectularius) and omnivorous German cockroach (Blattella germanica) are highly successful indoors, but have evolved different physiological and behavioral adaptations to cope with the human-built environment, some of which also reduce the efficacy of fungal biopesticides. In order to gain greater insight into the host barriers that prevent or constrain fungal infection in bed bugs and German cockroaches, we tested different doses of Beauveria bassiana GHA through surface contact, topical application, feeding, and injection. Bed bugs were generally more susceptible to infection by B. bassiana with the mode of delivery having a significant impact on infectivity. The German cockroach was highly resilient to infection, requiring high doses of fungal conidia (>8.8 × 104) delivered by injection into the hemocoel to cause mortality. Mortality occurred much faster in both insect species after exposure to surfaces dusted with dry conidia than surfaces treated with conidia suspended in water or oil. These findings highlight the importance of developing innovative delivery techniques to enhance fungal entomopathogens against bed bugs and cockroaches

Bed bugs (Cimex lectularius L.) exhibit limited ability to develop heat resistance.

The global population growth of the bed bug, Cimex lectularius (L.), is attributed to their cryptic behavior, diverse insecticide resistance mechanisms, and lack of public awareness. Bed bug control can be challenging and typically requires chemical and non-chemical treatments. One common non-chemical method for bed bug management is thermal remediation. However, in certain instances, bed bugs are known to survive heat treatments. Bed bugs may be present after a heat treatment due to (i) abiotic factors associated with the inability to achieve lethal temperatures in harborage areas for a sufficient time period, (ii) re-infestation from insects that escaped to cooler areas during a heat treatment or (iii) development of physiological resistance that allows them to survive heat exposure. Previous research has investigated the optimal temperature and exposure time required for either achieving complete mortality or sublethally affecting their growth and development. However, no research has examined bed bug populations for their ability to develop resistance to heat exposure and variation in thermo-tolerance between different bed bug strains. The goals of this study were: i) to determine if bed bugs could be selected for heat resistance under a laboratory selection regime, and ii) to determine if bed bug populations with various heat exposure histories, insecticide resistance profiles, and geographic origins have differential temperature tolerances using two heat exposure techniques (step-function and ramp-function). Selection experiments found an initial increase in bed bug survivorship; however, survivorship did not increase past the fourth generation. Sublethal exposure to heat significantly reduced bed bug feeding and, in some cases, inhibited development. The step-function exposure technique revealed non-significant variation in heat tolerance between populations and the ramp-function exposure technique provided similar results. Based on these study outcomes, the ability of bed bugs to develop heat resistance appears to be limited

Lethal and sublethal heat-exposure of bed bugs (Cimex lectularius L.) causes alarm pheromone emission and elicits a movement response in nearby recipients

Abstract Many gregarious insect species use aggregation and alarm pheromones. The bed bug, Cimex lectularius L., emits an alarm pheromone (AP), a 70/30 blend of (E)-2-hexenal and (E)-2-octenal, when threatened. Bed bugs avoid temperatures above 43 °C, which are lethal to bugs and used commercially as spatial heat treatments to manage infestations. However, the interaction of bed bug AP in heat avoidance has not been investigated. The goal of this research was to: 1) determine if bed bugs emit AP as an alarm response to heat exposure, and 2) quantify the behavioral responses of conspecifics to AP emitted by heat-exposed bed bugs. Using a selected ion flow tube mass spectrometer, we found that bed bugs responded to lethal and sublethal heat exposure by emitting AP. The Harlan laboratory population emitted more pheromone than a laboratory adapted field population from Florida (McCall). Harlan females emitted the most AP, followed by Harlan males, McCall females and males. In separate behavioral experiments, we showed that conspecifics (i.e., recipients) reacted to AP released by heat exposed bed bugs (i.e., emitters) by frantically moving within 50 mm and 100 mm test arenas. The Harlan recipients reacted to AP in 100 mm areas, whereas the McCall strain did not, indicating a short area of effectiveness of the AP. Synthetic AP components tested in behavioral experiments caused identical effects as the natural AP blend released by heat-exposed bed bugs

Common genetic variants influence human subcortical brain structures

The highly complex structure of the human brain is strongly shaped by genetic influences1. Subcortical brain regions form circuits with cortical areas to coordinate movement2, learning, memory3 and motivation4, and altered circuits can lead to abnormal behaviour and disease2. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume5 and intracranial volume6. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10−33; 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction