Characterising the blood-stage antimalarial activity of pyronaridine in healthy volunteers experimentally infected with Plasmodium falciparum.

With the spread of artemisinin resistance throughout Southeast Asia and now in Africa, the antimalarial drug pyronaridine is likely to become an increasingly important component of new antimalarial drug regimens. However, the antimalarial activity of pyronaridine in humans has not been completely characterised. This volunteer infection study aimed to determine the pharmacokinetic/pharmacodynamic (PK/PD) relationship of pyronaridine in malaria naïve adults. Volunteers were inoculated with Plasmodium falciparum-infected erythrocytes on day 0 and administered different single oral doses of pyronaridine on day 8. Parasitaemia and concentrations of pyronaridine were measured and standard safety assessments performed. Curative artemether-lumefantrine therapy was administered if parasite regrowth occurred, or on day 47 ± 2. Outcomes were parasite clearance kinetics, PK and PK/PD parameters from modelling. Ten participants were inoculated and administered 360 mg (n = 4), 540 mg (n = 4) or 720 mg (n = 1) pyronaridine. One participant was withdrawn without receiving pyronaridine. The time to maximum pyronaridine concentration was 1-2 h, the elimination half-life was 8-9 d, and the parasite clearance half-life was approximately 5 h. Parasite regrowth occurred with 360 mg (4/4 participants) and 540 mg (2/4 participants). Key efficacy parameters including the minimum inhibitory concentration (5.5 ng/mL) and minimum parasiticidal concentration leading to 90% of maximum effect (MPC90: 8 ng/mL) were derived from the PK/PD model. Adverse events considered related to pyronaridine were predominantly mild to moderate gastrointestinal symptoms. There were no serious adverse events. Data obtained in this study will support the use of pyronaridine in new antimalarial combination therapies by informing partner drug selection and dosing considerations.

Clinical effectiveness of drop-in mental health services at paediatric hospitals: A non-randomised multi-site study for children and young people and their families - study protocol.

BACKGROUND: Despite the high prevalence of mental health difficulties in children and young people with long-term health conditions (LTCs), these difficulties and experiences are often overlooked and untreated. Previous research demonstrated the effectiveness of psychological support provided via a drop-in mental health centre located in a paediatric hospital. The aim of this prospective non-randomised single-arm multi-centre interventional study is to determine the clinical effectiveness of drop-in mental health services when implemented at paediatric hospitals in England. METHODS: It is hypothesised that families who receive psychological interventions through the drop-in services will show improved emotional and behavioural symptoms. Outcomes will be measured at baseline and at 6-month follow-up. The primary outcome is the difference in the total difficulties score on the Strengths and Difficulties Questionnaire (SDQ) reported by parent or child at 6 months. Secondary outcomes include self and parent reported Paediatric Quality of Life Inventory (PedsQL), self-reported depression (PHQ-9) and anxiety measures (GAD-7) and family satisfaction (CSQ-8). DISCUSSION: This trial aims to determine the clinical effectiveness of providing psychological support in the context of LTCs through drop-in mental health services at paediatric hospitals in England. These findings will contribute to policies and practice addressing mental health needs in children and young people with other long-term health conditions. TRIAL REGISTRATION: ISRCTN15063954, Registered on 9 December 2022.

The effect of nocebo explanation and empathy on side-effect expectations of medication use following a fictional GP consultation.

The simple act of informing patients about side-effects increases the likelihood they will experience them (i.e. the nocebo effect). Explaining this psychological phenomenon could help to reduce side-effect experience, however, it is yet to be explored if this can be applied to clinical settings where new medication is prescribed. In addition, the degree to which a health-care provider empathetically communicates this to patients may have an impact. To investigate this, we carried out 2 × 2 factorial trial to assess the effect of nocebo explanation and empathy (plus their interaction) on side-effect expectations following a fictional GP consultation prescribing a new medication. Overall, 208 participants were randomised to watch one of the four fictive GP consultations and play the role of the patient. In all videos, participants received information about the reason for the consultation, the recommendation of a new fictive medicine, how to take it, benefits and side-effects. The videos differed in whether the GP provided an explanation of the nocebo effect (yes/no) and whether they communicated in an empathetic style (yes/no). After watching the video, participants were asked about their side-effect expectations and rated the quality of the GP's communication. Two-way ANOVAs revealed no main effect of nocebo explanation on expectation of side-effects warned or not warned about in the consultation. However, there was a main effect of empathy, with participants watching the empathetic consultations having significantly lower expectations of non-warned-about side-effects. There was no significant interaction. Findings suggest that explaining the nocebo effect and GP empathy did little to allay expectations of side-effects that were specifically mentioned in the consultation. However, GP empathy had an effect by helping to reduce additional side-effect expectations participants still had. Future work should extend these findings to real GP consultations where the full dimensions of empathy can be explored.

Why do children attend school, engage in other activities or socialise when they have symptoms of an infectious illness? A cross-sectional survey.

OBJECTIVES: To prevent the spread of infectious disease, children are typically asked not to attend school, clubs or other activities, or socialise with others while they have specific symptoms. Despite this, many children continue to participate in these activities while symptomatic. DESIGN AND SETTING: We commissioned a national cross-sectional survey with data collected between 19 November and 18 December 2021. PARTICIPANTS: Eligible parents (n=941) were between 18 and 75 years of age, lived in the UK and had at least one child aged between 4 and 17 years. Parents were recruited from a pre-existing pool of potential respondents who had already expressed an interest in receiving market research surveys. OUTCOME MEASURES: Parents were asked whether their children had exhibited either recent vomiting, diarrhoea, high temperature/fever, a new continuous cough, a loss or change to their sense of taste or smell in the absence of a negative (PCR) COVID-19 test ('stay-at-home symptoms') since September 2021 and whether they attended school, engaged in other activities outside the home or socialised with members of another household while symptomatic ('non-adherent'). We also measured parent's demographics and attitudes about illness. RESULTS: One-third (33%, n=84/251, 95% CI: 28% to 39%) of children were 'non-adherent' in that they had attended activities outside the home or socialised when they had stay-at-home symptoms. Children were significantly more likely to be non-adherent when parents were aged 45 and younger; they allowed their children to make their own decisions about school attendance; they agreed that their child should go to school if they took over-the-counter medication; or they believed that children should go to school if they have mild symptoms of illness. CONCLUSION: To reduce the risk of spreading disease, parents and teenagers need guidance to help them make informed decisions about engaging in activities and socialising with others while unwell.

Parent-reported child's close contact with non-household family members and their well-being during the COVID-19 pandemic: A cross-sectional survey.

In England (UK), at the start of the COVID-19 pandemic the public were required to reduce their physical contacts to slow the spread of COVID-19. We investigated the factors associated with children having: 1) close contact with family members from outside their household ('non-adherent behaviour'); and 2) low well-being (Revised Child Anxiety and Depression Scale). We conducted an online cross-sectional survey, completed at any location of the participant's choice between 8 and 11 June 2020 in parents (n = 2,010) who were aged eighteen years or over and had a school-aged child (4-18 years old). Parents reported that 15% (n = 309) of children had non-adherent contact and that 26% (n = 519) had low well-being. We used a series of binary logistic regressions to investigate associations between outcomes and child and parent characteristics. Children had higher odds of having non-household contact when they had special educational needs [adjusted odds ratio, 2.19 (95% CI, 1.47 to 3.27)], lower well-being [2.65 (95% CI, 2.03 to 3.46)], were vulnerable to COVID-19 [2.17 (95% CI, 1.45 to 3.25)], lived with someone who was over 70 years old [2.56 (95% CI, 1.55 to 4.24)] and their parent had low well-being [1.94 (95% CI, 1.45 to 2.58)]. Children had higher odds of lower well-being when they had special educational needs [4.13 (95% CI, 2.90 to 5.87)], were vulnerable to COVID-19 [3.06 (95% CI, 2.15 to 4.36)], lived with someone else who was vulnerable to COVID-19 [2.08 (95% CI, 1.64 to 2.64)], or lived with someone who was over 70 years old [2.41 (95% CI, 1.51 to 3.83)]. Many children came into contact with non-household family members, mainly for childcare. Factors relating to COVID-19, children's well-being and education were also important. If school closures are needed in future, addressing these issues may help reduce contact.

Risk factors for school-based presenteeism in children: a systematic review.

INTRODUCTION: Children attending school whilst unwell, known as school-based presenteeism, results in negative impacts on education and mental and physical health. We aimed to identify the risk factors for this behaviour. METHOD: We conducted a systematic search of five databases (11 July 2022) using words associated with school (e.g., school and childcare) and presenteeism (e.g., presenteeism and sick leave). The studies are synthesised according to the risk factors associated with school-based presenteeism and are grouped into themes by related topics. RESULTS: Our review included 18 studies, with quantitative, qualitative, and mixed-method study designs. Children, parents, and school staff reported past incidents and intentions for future presenteeism. We identified five themes from these reports: perceptions about the illness / signs and symptom(s); children's characteristics; children's and parents' motivations and attitudes towards school; organisational factors; and school sickness policy. Increased risk of school-based presenteeism was commonly linked to symptoms that were perceived low in severity and unidentifiable, children with a high school absence record, disbelief in children's illness, unsupportive employers, vague school policies and financial consequences. CONCLUSIONS: School-based presenteeism is complex due to the competing interests of the multiple individuals involved, such as children, parents, and school staff. Sickness policies need to include clear and specific guidance about illness and the signs and symptoms of diseases and should be communicated to all relevant individuals to mitigate against discrepancies in how the policy is interpreted. Furthermore, parents and school staff need support, such as financial and childcare, to be able to manage children when they are unwell.

Characterizing the Blood-Stage Antimalarial Activity of Tafenoquine in Healthy Volunteers Experimentally Infected With Plasmodium falciparum.

BACKGROUND: The long-acting 8-aminoquinoline tafenoquine may be a good candidate for mass drug administration if it exhibits sufficient blood-stage antimalarial activity at doses low enough to be tolerated by glucose 6-phosphate dehydrogenase (G6PD)-deficient individuals. METHODS: Healthy adults with normal levels of G6PD were inoculated with Plasmodium falciparum 3D7-infected erythrocytes on day 0. Different single oral doses of tafenoquine were administered on day 8. Parasitemia and concentrations of tafenoquine and the 5,6-orthoquinone metabolite in plasma/whole blood/urine were measured and standard safety assessments performed. Curative artemether-lumefantrine therapy was administered if parasite regrowth occurred, or on day 48 ± 2. Outcomes were parasite clearance kinetics, pharmacokinetic and pharmacokinetic/pharmacodynamic (PK/PD) parameters from modelling, and dose simulations in a theoretical endemic population. RESULTS: Twelve participants were inoculated and administered 200 mg (n = 3), 300 mg (n = 4), 400 mg (n = 2), or 600 mg (n = 3) tafenoquine. The parasite clearance half-life with 400 mg or 600 mg (5.4 hours and 4.2 hours, respectively) was faster than with 200 mg or 300 mg (11.8 hours and 9.6 hours, respectively). Parasite regrowth occurred after dosing with 200 mg (3/3 participants) and 300 mg (3/4 participants) but not after 400 mg or 600 mg. Simulations using the PK/PD model predicted that 460 mg and 540 mg would clear parasitaemia by a factor of 106 and 109, respectively, in a 60-kg adult. CONCLUSIONS: Although a single dose of tafenoquine exhibits potent P. falciparum blood-stage antimalarial activity, the estimated doses to effectively clear asexual parasitemia will require prior screening to exclude G6PD deficiency. Clinical Trials Registration. Australian and New Zealand Clinical Trials Registry (ACTRN12620000995976).

Social communication pathways to COVID-19 vaccine side-effect expectations and experience.

OBJECTIVE: Negative beliefs about medication and vaccine side-effects can spread rapidly through social communication. This has been recently documented with the potential side-effects from the COVID-19 vaccines. We tested if pre-vaccination social communications about side-effects from personal acquaintances, news reports, and social media predict post-vaccination side-effect experiences. Further, as previous research suggests that side-effects can be exacerbated by negative expectations, we assessed if personal expectations mediate the relationships between social communication and side-effect experience. METHOD: In a prospective longitudinal survey (N = 551), COVID-19 vaccine side-effect information from three sources-social media posts, news reports, and first-hand accounts from personal acquaintances-as well as side-effect expectations, were self-reported pre-vaccination. Vaccination side-effect experience was assessed post-vaccination. RESULTS: In multivariate regression analyses, the number of pre-vaccination social media post views (ß = 0.17) and impressions of severity conveyed from personal acquaintances (ß = 0.42) significantly predicted an increase in pre-vaccination side-effect expectations, and the same variables (ßs = 0.11, 0.14, respectively) predicted post-vaccination side-effect experiences. Moreover, pre-vaccination side-effect expectations mediated the relationship between both sources of social communication and experienced side-effects from a COVID-19 vaccination. CONCLUSIONS: This study identifies links between personal acquaintance and social media communications and vaccine side-effect experiences and provides evidence that pre-vaccination expectations account for these relationships. The results suggest that modifying side-effect expectations through these channels may change the side-effects following a COVID-19 vaccination as well as other publicly discussed vaccinations and medications.

Transmission Blocking Activity of Low-dose Tafenoquine in Healthy Volunteers Experimentally Infected With Plasmodium falciparum.

BACKGROUND: Blocking the transmission of parasites from humans to mosquitoes is a key component of malaria control. Tafenoquine exhibits activity against all stages of the malaria parasite and may have utility as a transmission blocking agent. We aimed to characterize the transmission blocking activity of low-dose tafenoquine. METHODS: Healthy adults were inoculated with Plasmodium falciparum 3D7-infected erythrocytes on day 0. Piperaquine was administered on days 9 and 11 to clear asexual parasitemia while allowing gametocyte development. A single 50-mg oral dose of tafenoquine was administered on day 25. Transmission was determined by enriched membrane feeding assays predose and at 1, 4, and 7 days postdose. Artemether-lumefantrine was administered following the final assay. Outcomes were the reduction in mosquito infection and gametocytemia after tafenoquine and safety parameters. RESULTS: Six participants were enrolled, and all were infective to mosquitoes before tafenoquine, with a median 86% (range, 22-98) of mosquitoes positive for oocysts and 57% (range, 4-92) positive for sporozoites. By day 4 after tafenoquine, the oocyst and sporozoite positivity rate had reduced by a median 35% (interquartile range [IQR]: 16-46) and 52% (IQR: 40-62), respectively, and by day 7, 81% (IQR 36-92) and 77% (IQR 52-98), respectively. The decline in gametocyte density after tafenoquine was not significant. No significant participant safety concerns were identified. CONCLUSIONS: Low-dose tafenoquine (50 mg) reduces P. falciparum transmission to mosquitoes, with a delay in effect.

A qualitative study about how families coped with managing their well-being, children's physical activity and education during the COVID-19 school closures in England.

In 2020, schools in England closed for six months due to COVID-19, resulting in children being home-schooled. There is limited understanding about the impacts of this on children's mental and physical health and their education. Therefore, we explored how families coped with managing these issues during the school closures. We conducted 30 qualitative interviews with parents of children aged 18 years and under (who would usually be in school) between 16 and 21 April 2020. We identified three themes and eight sub-themes that impacted how families coped whilst schools were closed. We found that family dynamics, circumstances, and resources (Theme 1), changes in entertainment activities and physical movement (Theme 2) and worries about the COVID-19 pandemic (Theme 3) impacted how well families were able to cope. A key barrier to coping was struggles with home-schooling (e.g., lack of resources and support from the school). However, parents being more involved in their children's personal development and education were considered a benefit to home-schooling. Managing the lack of entertainment activities and in-person interactions, and additional health worries about loved ones catching COVID-19 were challenges for families. Parents reported adverse behaviour changes in their children, although overall, they reported they were coping well. However, pre-existing social and educational inequalities are at risk of exacerbation. Families with more resources (e.g., parental supervision, access to green space, technology to facilitate home-schooling and no special educational needs) were better able to cope when schools were closed. On balance, however, families appeared to be able to adapt to the schools being closed. We suggest that policy should focus on supporting families to mitigate the widening health and educational gap between families with more and less resources.

Quantification of Tafenoquine and 5,6-Orthoquinone Tafenoquine by UHPLC-MS/MS in Blood, Plasma, and Urine, and Application to a Pharmacokinetic Study.

Analytical methods for the quantification of the new 8-aminoquinoline antimalarial tafenoquine (TQ) in human blood, plasma and urine, and the 5,6-orthoquinone tafenoquine metabolite (5,6-OQTQ) in human plasma and urine have been validated. The procedure involved acetonitrile extraction of samples followed by ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). Chromatography was performed using a Waters Atlantis T3 column with a gradient of 0.1% formic acid and acetonitrile at a flow rate of 0.5 mL per minute for blood and plasma. Urine analysis was the same but with methanol containing 0.1% formic acid replacing acetonitrile mobile phase. The calibration range for TQ and 5,6-OQTQ in plasma was 1 to 1200 ng/mL, and in urine was 10 to 1000 ng/mL. Blood calibration range for TQ was 1 to 1200 ng/mL. Blood could not be validated for 5,6-OQTQ due to significant signal suppression. The inter-assay precision (coefficient of variation %) was 9.9% for TQ at 1 ng/mL in blood (n = 14) and 8.2% for TQ and 7.1% for 5,6-OQTQ at 1 ng/mL in plasma (n = 14). For urine, the inter-assay precision was 8.2% for TQ and 6.4% for 5,6-OQTQ at 10 ng/mL (n = 14). TQ and 5,6-OQTQ are stable in blood, plasma and urine for at least three months at both -80 °C and -20 °C. Once validated, the analytical methods were applied to samples collected from healthy volunteers who were experimentally infected with Plasmodium falciparum to evaluate the blood stage antimalarial activity of TQ and to determine the therapeutic dose estimates for TQ, the full details of which will be published elsewhere. In this study, the measurement of TQ and 5,6-OQTQ concentrations in samples from one of the four cohorts of participants is reported. Interestingly, TQ urine concentrations were proportional to parasite recrudescence times post dosing To our knowledge, this is the first description of a fully validated method for the measurement of TQ and 5,6-OQTQ quantification in urine.

A Qualitative Study Evaluating the Factors Affecting Families' Adherence to the First COVID-19 Lockdown in England Using the COM-B Model and TDF.

The ability of families to adhere to public health guidance is critical to controlling a pandemic. We conducted qualitative interviews with 30 parents of children aged 18 and under, between 16 and 21 April 2020 when schools in England were closed due to the COVID-19 pandemic. Using the Theoretical Domains Framework, we classified the factors that influenced adherence to seven non-pharmaceutical interventions. We found 40 factors that influenced a family's ability to adhere. Parents generally indicated they could adhere and reported how their family had changed their behaviour to comply with the guidance. Parents primarily reported they were motivated to adhere out of concern for the health consequences of COVID-19, and because the guidance was delivered by the government. However, we found that reduced access to resources (e.g., technology, transport, and outside space) and social influences that encouraged non-adherent behaviour, decreased adherence. Furthermore, we suggest that families with low psychological and physical ability may face additional challenges to adherence and need to be supported. During future school closures, public health agencies should account for these factors when developing guidance.

Do Side Effects to the Primary COVID-19 Vaccine Reduce Intentions for a COVID-19 Vaccine Booster?

BACKGROUND: Vaccines are being administered worldwide to combat the COVID-19 pandemic. Vaccine boosters are essential for maintaining immunity and protecting against virus variants. The side effects of the primary COVID-19 vaccine (e.g., headache, nausea), however, could reduce intentions to repeat the vaccination experience, thereby hindering global inoculation efforts. PURPOSE: The aim of this research was to test whether side effects of a primary COVID-19 vaccine relate to reduced intentions to receive a COVID-19 booster. The secondary aim was to test whether psychological and demographic factors predict booster intentions. METHODS: Secondary data analyses were conducted on a U.S. national sample of 551 individuals recruited through the online platform Prolific. Key measures in the dataset were side effects reported from a primary COVID-19 vaccination and subsequent intentions to receive a booster vaccine. Psychological and demographic variables that predicted primary vaccination intentions in prior studies were also measured. RESULTS: Booster intentions were high. COVID-19 booster vaccine intentions were uncorrelated with the number of side effects, intensity of side effects, or occurrence of an intense side effect from the primary COVID-19 vaccine. Correlational and regression analyses indicated intentions for a booster vaccination increased with positive vaccination attitudes, trust in vaccine development, worry about the COVID-19 pandemic, low concern over vaccine side effects, and democratic political party affiliation. CONCLUSIONS: Side effects of a primary COVID-19 vaccine were not directly associated with lower intentions to receive a booster of the COVID-19 vaccine early in the pandemic. However, many variables that predict primary vaccination intentions also predict booster intentions.

What influences whether parents recognise COVID-19 symptoms, request a test and self-isolate: A qualitative study.

BACKGROUND: Using test, trace and isolate systems can help reduce the spread of COVID-19. Parents have the additional responsibility of using these systems for themselves and acting on behalf of their children to help control COVID-19. We explored factors associated with the use of England's NHS Test and Trace service among parents of school-aged children. METHODS: One-to-one telephone interviews with parents (n = 18) of school-aged (4 to 18 years) children living in England between 30 November to 11 December 2020. Data were explored using thematic analysis. RESULTS: Three themes and eight sub-themes emerged. In terms of recognising symptoms of COVID-19, parents needed prompting before recalling the main symptoms described by the NHS. Parents suggested several factors relating to the nature of the symptom(s) and contextual information that might lead to or prevent them from seeking a test. Although parents supported symptomatic testing and described trusting official sources of information (e.g., Government and NHS websites). However, some concerns were raised regarding the accuracy of test results, safety at testing centres and logistics of testing but none of the concerns appeared to prevent engagement with testing. Parents perceived adherence to testing and self-isolation as pro-social behaviour, although family resources and circumstances impacted their ability to adhere fully. CONCLUSIONS: Our study identified several barriers to parents using NHS Test and Trace as needed. Information about the eligibility of testing (main symptoms of COVID-19 and the age of eligibility) needs to be more precise and resources provided to enable families to adhere to self-isolation if the efficiency of test, trace and isolate systems is to be optimised.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Coadministered Ruxolitinib and Artemether-Lumefantrine in Healthy Adults.

Despite repeated malaria infection, individuals living in areas where malaria is endemic remain vulnerable to reinfection. The Janus kinase (JAK1/2) inhibitor ruxolitinib could potentially disrupt the parasite-induced dysfunctional immune response when administered with antimalarial therapy. This randomized, single-blind, placebo-controlled, single-center phase 1 trial investigated the safety, tolerability, and pharmacokinetic and pharmacodynamic profile of ruxolitinib and the approved antimalarial artemether-lumefantrine in combination. Ruxolitinib pharmacodynamics were assessed by inhibition of phosphorylation of signal transducer and activator of transcription 3 (pSTAT3). Eight healthy male and female participants ages 18 to 55 years were randomized to either ruxolitinib (20 mg) (n = 6) or placebo (n = 2) administered 2 h after artemether-lumefantrine (80/480 mg) twice daily for 3 days. Mild adverse events occurred in six participants (four ruxolitinib; two placebo). The combination of artemether-lumefantrine and ruxolitinib was well tolerated, with adverse events and pharmacokinetics consistent with the known profiles of both drugs. The incidence of adverse events and artemether, dihydroartemisinin (the major active metabolite of artemether), and lumefantrine exposure were not affected by ruxolitinib coadministration. Ruxolitinib coadministration resulted in a 3-fold-greater pSTAT3 inhibition compared to placebo (geometric mean ratio = 3.01 [90% confidence interval = 2.14 to 4.24]), with a direct and predictable relationship between ruxolitinib plasma concentrations and %pSTAT3 inhibition. This study supports the investigation of the combination of artemether-lumefantrine and ruxolitinib in healthy volunteers infected with Plasmodium falciparum malaria. (This study has been registered at ClinicalTrials.gov under registration no. NCT04456634.).

Safety, infectivity and immunogenicity of a genetically attenuated blood-stage malaria vaccine.

BACKGROUND: There is a clear need for novel approaches to malaria vaccine development. We aimed to develop a genetically attenuated blood-stage vaccine and test its safety, infectivity, and immunogenicity in healthy volunteers. Our approach was to target the gene encoding the knob-associated histidine-rich protein (KAHRP), which is responsible for the assembly of knob structures at the infected erythrocyte surface. Knobs are required for correct display of the polymorphic adhesion ligand P. falciparum erythrocyte membrane protein 1 (PfEMP1), a key virulence determinant encoded by a repertoire of var genes. METHODS: The gene encoding KAHRP was deleted from P. falciparum 3D7 and a master cell bank was produced in accordance with Good Manufacturing Practice. Eight malaria naïve males were intravenously inoculated (day 0) with 1800 (2 subjects), 1.8 × 105 (2 subjects), or 3 × 106 viable parasites (4 subjects). Parasitemia was measured using qPCR; immunogenicity was determined using standard assays. Parasites were rescued into culture for in vitro analyses (genome sequencing, cytoadhesion assays, scanning electron microscopy, var gene expression). RESULTS: None of the subjects who were administered with 1800 or 1.8 × 105 parasites developed parasitemia; 3/4 subjects administered 3× 106 parasites developed significant parasitemia, first detected on days 13, 18, and 22. One of these three subjects developed symptoms of malaria simultaneously with influenza B (day 17; 14,022 parasites/mL); one subject developed mild symptoms on day 28 (19,956 parasites/mL); and one subject remained asymptomatic up to day 35 (5046 parasites/mL). Parasitemia rapidly cleared with artemether/lumefantrine. Parasitemia induced a parasite-specific antibody and cell-mediated immune response. Parasites cultured ex vivo exhibited genotypic and phenotypic properties similar to inoculated parasites, although the var gene expression profile changed during growth in vivo. CONCLUSIONS: This study represents the first clinical investigation of a genetically attenuated blood-stage human malaria vaccine. A P. falciparum 3D7 kahrp- strain was tested in vivo and found to be immunogenic but can lead to patent parasitemia at high doses. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (number: ACTRN12617000824369 ; date: 06 June 2017).

Why did some parents not send their children back to school following school closures during the COVID-19 pandemic: a cross-sectional survey.

Background: On 23 March 2020, schools closed to most children in England in response to COVID-19 until September 2020. Schools were kept open to children of key workers and vulnerable children on a voluntary basis. Starting 1 June 2020, children in reception (4-5 years old), year 1 (5-6 years old) and year 6 (10-11 years old) also became eligible to attend school. Methods: 1373 parents or guardians of children eligible to attend school completed a cross-sectional survey between 8 and 11 June 2020. We investigated factors associated with whether children attended school or not. Results: 46% (n=370/803) of children in year groups eligible to attend school and 13% (n=72/570) of children of key workers had attended school in the past 7 days. The most common reasons for sending children to school were that the child's education would benefit, the child wanted to go to school and the parent needed to work. A child was significantly more likely to attend if the parent believed the child had already had COVID-19, they had special educational needs or a person in the household had COVID-19 symptoms. Conclusions: Following any future school closure, helping parents to feel comfortable returning their child to school will require policy makers and school leaders to communicate about the adequacy of their policies to: (A) ensure that the risk to children in school is minimised; (B) ensure that the educational potential within schools is maximised; and (C) ensure that the benefits of school for the psychological well-being of children are prioritised.

Safety, pharmacokinetics, and antimalarial activity of the novel plasmodium eukaryotic translation elongation factor 2 inhibitor M5717: a first-in-human, randomised, placebo-controlled, double-blind, single ascending dose study and volunteer infection study.

BACKGROUND: M5717 is the first plasmodium translation elongation factor 2 inhibitor to reach clinical development as an antimalarial. We aimed to characterise the safety, pharmacokinetics, and antimalarial activity of M5717 in healthy volunteers. METHODS: This first-in-human study was a two-part, single-centre clinical trial done in Brisbane, QLD, Australia. Part one was a double-blind, randomised, placebo-controlled, single ascending dose study in which participants were enrolled into one of nine dose cohorts (50, 100, 200, 400, 600, 1000, 1250, 1800, or 2100 mg) and randomly assigned (3:1) to M5717 or placebo. A sentinel dosing strategy was used for each dose cohort whereby two participants (one assigned to M5717 and one assigned to placebo) were initially randomised and dosed. Randomisation schedules were generated electronically by independent, unblinded statisticians. Part two was an open-label, non-randomised volunteer infection study using the Plasmodium falciparum induced blood-stage malaria model in which participants were enrolled into three dose cohorts. Healthy men and women of non-childbearing potential aged 18-55 years were eligible for inclusion; individuals in the volunteer infection study were required to be malaria naive. Safety and tolerability (primary outcome of the single ascending dose study and secondary outcome of the volunteer infection study) were assessed by frequency and severity of adverse events. The pharmacokinetic profile of M5717 was also characterised (primary outcome of the volunteer infection study and secondary outcome of the single ascending dose study). Parasite clearance kinetics (primary outcome of the volunteer infection study) were assessed by the parasite reduction ratio and the corresponding parasite clearance half-life; the incidence of recrudescence up to day 28 was determined (secondary outcome of the volunteer infection study). Recrudescent parasites were tested for genetic mutations (exploratory outcome). The trial is registered with ClinicalTrials.gov (NCT03261401). FINDINGS: Between Aug 28, 2017, and June 14, 2019, 221 individuals were assessed for eligibility, of whom 66 men were enrolled in the single ascending dose study (eight per cohort for 50-1800 mg cohorts, randomised three M5717 to one placebo, and two in the 2100 mg cohort, randomised one M5717 to one placebo) and 22 men were enrolled in the volunteer infection study (six in the 150 mg cohort and eight each in the 400 mg and 800 mg cohorts). No adverse event was serious; all M5717-related adverse events were mild or moderate in severity and transient, with increased frequency observed at doses above 1250 mg. In the single ascending dose study, treatment-related adverse events occurred in three of 17 individuals in the placebo group; no individual in the 50 mg, 100 mg, or 200 mg groups; one of six individuals in each of the 400 mg, 1000 mg, and 1250 mg groups; two of six individuals in the 600 mg group; and in all individuals in the 1800 mg and 2100 mg groups. In the volunteer infection study, M5717-related adverse events occurred in no participants in the 150 mg or 800 mg groups and in one of eight participants in the 400 mg group. Transient oral hypoesthesia (in three participants) and blurred vision (in four participants) were observed in the 1800 mg or 2100 mg groups and constituted an unknown risk; thus, further dosing was suspended after dosing of the two sentinel individuals in the 2100 mg cohort. Maximum blood concentrations occurred 1-7 h after dosing, and a long half-life was observed (146-193 h at doses ≥200 mg). Parasite clearance occurred in all participants and was biphasic, characterised by initial slow clearance lasting 35-55 h (half-life 231·1 h [95% CI 40·9 to not reached] for 150 mg, 60·4 h [38·6 to 138·6] for 400 mg, and 24·7 h [20·4 to 31·3] for 800 mg), followed by rapid clearance (half-life 3·5 h [3·1 to 4·0] for 150 mg, 3·9 h [3·3 to 4·8] for 400 mg, and 5·5 h [4·8 to 6·4] for 800 mg). Recrudescence occurred in three (50%) of six individuals dosed with 150 mg and two (25%) of eight individuals dosed with 400 mg. Genetic mutations associated with resistance were detected in four cases of parasite recrudescence (two individuals dosed with 150 mg and two dosed with 400 mg). INTERPRETATION: The safety, pharmacokinetics, and antimalarial activity of M5717 support its development as a component of a single-dose antimalarial combination therapy or for malaria prophylaxis. FUNDING: Wellcome Trust and the healthcare business of Merck KGaA, Darmstadt, Germany.