Physiological and Morphological Aspects of Aedes aegypti Developing Larvae: Effects of the Chitin Synthesis Inhibitor Novaluron

Population control of the dengue vector mosquito, Aedes aegypti, is difficult due to many reasons, one being the development of resistance to neurotoxic insecticides employed. The biosynthesis of chitin, a major constituent of insect cuticle, is a novel target for population control. Novaluron is a benzoylphenylurea (BPU) that acts as a chitin synthesis inhibitor, already used against mosquitoes. However, information regarding BPU effects on immature mosquito stages and physiological parameters related with mosquito larval development are scarce. A set of physiological parameters were recorded in control developing larvae and novaluron was administered continuously to Ae. aegypti larvae, since early third instar. Larval instar period duration was recorded from third instar until pupation. Chitin content was measured during third and fourth instars. Fourth instars were processed histochemically at the mesothorax region, stained with hematoxylin and eosin (HE) for assessment of internal tissues, and labeled with WGA-FITC to reveal chitinized structures. In control larvae: i) there is a chitin content increase during both third and fourth instars where late third instars contain more chitin than early fourth instars; ii) thoracic organs and a continuous cuticle, closely associated with the underlying epidermis were observed; iii) chitin was continuously present throughout integument cuticle. Novaluron treatment inhibited adult emergence, induced immature mortality, altered adult sex ratio and caused delay in larval development. Moreover, novaluron: i) significantly affected chitin content during larval development; ii) induced a discontinuous and altered cuticle in some regions while epidermis was often thinner or missing; iii) rendered chitin cuticle presence discontinuous and less evident. In both control and novaluron larvae, chitin was present in the peritrophic matrix. This study showed quantitatively and qualitatively evidences of novaluron effects on Ae. aegypti larval development. To our knowledge, this is the first report describing histological alterations produced by a BPU in immature vector mosquitoes

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

The mental health of mothers of unsettled infants: Is there value in routine psychosocial assessment in this context?

This study aims to investigate the (1) pattern of psychosocial risk factors among mothers of unsettled infants, (2) the relationship between these risk factors and current mental health status and (3) acceptability of psychosocial risk assessment in the parentcraft setting. Women with unsettled infants aged up to 12 months were assessed using the Edinburgh Postnatal Depression Scale, a diagnostic interview (Mini-International Neuropsychiatric Interview (MINI)) and a psychosocial assessment tool, the Postnatal Risk Questionnaire (PNRQ). Of the women, 27.5 % met the MINI diagnostic criteria for a current (predominantly) anxiety disorder, and 43.1 %, for a past psychiatric diagnosis. On the Edinburgh Postnatal Depression Scale, 29.9 % of women scored above 12 (mean 9.8; SD 5.1). The most common psychosocial risk factors were high trait anxiety (40.9 %), past mental health problems (40.7 %), perfectionistic traits (38.1 %) and 'abuse trauma' of any kind (31.6 %). The likelihood of meeting diagnostic criteria for a current mental illness was significantly increased for women who experienced emotional abuse during childhood (adj. odds ratio (OR) 3.386; p = 0.006), had high trait anxiety (adj. OR = 2.63, p = 0.003) or had a negative birth experience (adj. OR 2.78; p = 0.015). The majority of women (78 %) felt moderately to very comfortable completing the PNRQ. The results showed high rates of current anxiety disorders (almost twice that of the general postnatal population) and multiple significant psychosocial risk factors among mothers with unsettled infants. Identification of specific psychosocial risk factors in mothers of unsettled infants can help to address issues beyond infant settling difficulties such as mother-infant interaction, especially for mothers with unresolved issues around their own parenting or trauma history. © 2013 Springer-Verlag Wien

Sterilising effects of pyriproxyfen on Anopheles arabiensis and its potential use in malaria control.

BACKGROUND: Insecticide resistance poses a major threat to current vector control campaigns. Insecticides with novel modes of action are therefore in high demand. Pyriproxyfen (PPF), a conventional mosquito pupacide, has a unique mode of action that also sterilises adult mosquitoes (unable to produce viable offspring) upon direct contact. However, the timing of PPF exposure in relation to when mosquitoes take a blood meal has an important impact on that sterilisation. This study investigated the relationship between different blood feeding and PPF exposure timings to determine the potential of PPF sterilisation in controlling Anopheles arabiensis. METHODS: Four treatment regimens were investigated: blood fed three days before PPF exposure (A), blood fed one day before PPF exposure (B), blood fed one day after PPF exposure (C) and blood fed three days after PPF exposure (D) for their impact on egg laying (fecundity) and the production of viable offspring (fertility), while the impact of PPF exposure on mosquito survival was investigated in the absence of a blood meal. All regimens and the survival study exposed mosquitoes to PPF via the bottle assay at 3 mg AI/m(2) for 30 minutes. RESULTS: Female mosquitoes that blood-fed one day prior to PPF exposure (regimen B), produced no viable offspring during that gonotrophic cycle (100% reduction in fertility). All other treatments had no significant effect. The observed reductions in fecundity and fertility were caused by the retention of eggs (97% of eggs retained, i.e. produced in the ovaries but not laid, in regimen B, p = 0.0004). Some of these retained eggs were deformed in shape. PPF exposure on mosquito survival in the absence of a blood meal was found to have no effect. CONCLUSIONS: The results presented here suggest that sterilising adult malaria vectors using PPF could form part of a malaria control strategy, taking advantage of the lack of reported resistance to PPF in mosquitoes and its unique mode of action. We propose that targeting resting mosquitoes, which are highly susceptible to PPF at low doses, is the optimal direction for developing this control tool