Quantitative assessment of spicule length in Heligmosomoides spp. (Nematoda, Heligmosomidae): distinction between H. bakeri, H. polygyrus and H. glareoli.

Nematode spicules play a vital role in the reproductive activity of species that possess them. Our primary objective was to compare the lengths of spicules of the laboratory mouse (Mus musculus) ­ maintained isolate H. bakeri ­ with those of H. polygyrus from naturally infected wood mice (Apodemus sylvaticus). On a more limited scale, we also included H. glareoli from bank voles (Myodes glareolus), a species reputed to possess longer spicules than either of the 2 former species. In total, we measured 1264 spicules (H. bakeri, n = 614; H. polygyrus n = 582; and H. glareoli, n = 68). There was a highly significant difference between the spicule lengths of the Nottingham-maintained H. bakeri (mean = 0.518 mm) and H. polygyrus (0.598 mm) from 11 different localities across the British Isles. A comparison of the spicules of H. bakeri maintained in 4 different laboratories in 3 continents revealed a range in the mean values from 0.518 to 0.540 mm, while those of worms from Australian wild house mice were shorter (0.480 mm). Mean values for H. polygyrus from wood mice from the British Isles ranged from 0.564 to 0.635 mm, although isolates of this species from Norway had longer spicules (0.670 mm). In agreement with the literature, the spicules of H. glareoli were considerably longer (1.098 mm). Since spicules play a vital role in the reproduction of nematode species that possess them, the difference in spicule lengths between H. bakeri and H. polygyrus adds to the growing evidence that these 2 are quite distinct species and likely reproductively isolated.

Evaluating the scaling up of an effective implementation intervention (PACE) to increase the delivery of a mandatory physical activity policy in primary schools.

BACKGROUND: Physically Active Children in Education (PACE) is an effective implementation intervention for increasing the number of minutes classroom teachers schedule physical activity each week. To date, evaluations of PACE have included a smaller number of schools from only one region in New South Wales Australia. If PACE is to have population-wide benefits we must be able to deliver this support to a larger number of schools across multiple regions. This study aimed to evaluate the scale-up of PACE. METHODS: An uncontrolled before and after study, with 100 schools from three regions was conducted. Participating schools received PACE for approximately 12 months. We assessed the following outcomes: delivery of the evidence-based intervention (EBI) (i.e. minutes of physical activity scheduled by classroom teachers per week); delivery of the implementation strategies (i.e. reach, dose delivered, adherence and indicators of sustainability); and key determinants of implementation (i.e. acceptability of strategies and cost). Data were collected via project officer records, and principal and teacher surveys. Linear mixed models were used to assess EBI delivery by evaluating the difference in the mean minutes teachers scheduled physical activity per week from baseline to follow-up. Descriptive data were used to assess delivery of the implementation strategies and their perceived acceptability (i.e. PACE). A prospective, trial-based economic evaluation was used to assess cost. RESULTS: Delivery of the EBI was successful: teachers increas their average minutes of total physical activity scheduled across the school week by 26.8 min (95% CI: 21.2, 32.4, p < 0.001) after receiving PACE. Indicators for delivery of implementation strategies were high: 90% of consenting schools received all strategies and components (reach); 100% of strategies were delivered by the provider (dose); >50% of schools adhered to the majority of strategies (11 of the 14 components); and acceptability was > 50% agreement for all strategies. The incremental cost per additional minute of physical activity scheduled per week was $27 per school (Uncertainty Interval $24, $31). CONCLUSIONS: PACE can be successfully delivered across multiple regions and to a large number of schools. Given the ongoing and scalable benefits of PACE, it is important that we continue to extend and improve this program while considering ways to reduce the associated cost.

A Scoping Review of Economic Evaluations to Inform the Reorientation of Preventive Health Services in Australia.

The Australian National Preventive Health Strategy 2021-2030 recommended the establishment of evidence-based frameworks to enable local public health services to identify strategies and interventions that deliver value for money. This study aimed to review the cost-effectiveness of preventive health strategies to inform the reorientation of local public health services towards preventive health interventions that are financially sustainable. Four electronic databases were searched for reviews published between 2005 and February 2022. Reviews that met the following criteria were included: population: human studies, any age or sex; concept 1: primary and/or secondary prevention interventions; concept 2: full economic evaluation; context: local public health services as the provider of concept 1. The search identified 472 articles; 26 were included. Focus health areas included mental health (n = 3 reviews), obesity (n = 1), type 2 diabetes (n = 3), dental caries (n = 2), public health (n = 4), chronic disease (n = 5), sexual health (n = 1), immunisation (n = 1), smoking cessation (n = 3), reducing alcohol (n = 1), and fractures (n = 2). Interventions that targeted obesity, type 2 diabetes, smoking cessation, and fractures were deemed cost-effective, however, more studies are needed, especially those that consider equity in priority populations.

Start small and let it build; a mixed-method evaluation of a school-based physical activity program, Kilometre Club.

BACKGROUND: Despite the benefits of physical activity, there is minimal research focusing on factors that influence real-world school-based physical activity programs. Kilometre (KM) Club is an Australian grassroots program which aims to increase physical activity in students through the completion of an outside walk or run at school. This small-scale pilot evaluation aimed to examine families, teachers and principals' perceptions of the benefits, enablers and barriers of KM Club. It also aimed to examine the effects of KM Club on student's physical activity levels during the school day. METHODS: Four regional New South Wales (NSW) primary schools participated in this study. 26 families, four teachers, and two principals from School A, C, B and D completed semi-structured interviews to understand their perceptions of KM Club. 21 students completed emotional state-scales to understand their emotions when participating in KM Club. 141 students from Schools B, C and D participated in step-count measures using accelerometers. RESULTS: Families, teachers and principals reported a range of benefits such as improved social connectedness, wellbeing, home and classroom behaviours, participation in sport and fitness levels. Enablers consisted of champion engagement, incentives, versatile facilities and integration with other school activities. Identified barriers included the weather and environment, program timing and health issues. Most students reported that participating in KM Club made them feel proud, confident and fantastic. School B reported a significant increase in students' daily step counts on KM Club days compared to non-KM Club days (+ 15%; p = 0.001), while School C reported no significant changes (-5%; p = 0.26). School D reported a significant increase in the number of daily steps taken by KM Club participants compared with non-KM club participants (+ 10%; p = 0.024). CONCLUSION: There is no one-size-fits-all approach to implementing school-based physical activity initiatives. However, it appears that flexible and adaptable factors are important to the successful implementation of school-based programs, such as KM Club. This study revealed a variety of self-reported health, wellbeing and educational benefits for students, as well as an increase in student's physical activity levels at 2 of the 3 schools participating in the quantitative data collection. This pilot evaluation may help to inform future design, implementation and scale-up of KM Club and school-based health promotion programs, potentially improving child health, wellbeing and educational outcomes. TRIAL REGISTRATION: (LNR223 - LNR/19/NCC/45).

A Multicomponent mHealth-Based Intervention (SWAP IT) to Decrease the Consumption of Discretionary Foods Packed in School Lunchboxes: Type I Effectiveness-Implementation Hybrid Cluster Randomized Controlled Trial.

BACKGROUND: There is significant opportunity to improve the nutritional quality of foods packed in children's school lunchboxes. Interventions that are effective and scalable targeting the school and home environment are therefore warranted. OBJECTIVE: This study aimed to assess the effectiveness of a multicomponent, mobile health-based intervention, SWAP IT, in reducing the energy contribution of discretionary (ie, less healthy) foods and drinks packed for children to consume at school. METHODS: A type I effectiveness-implementation hybrid cluster randomized controlled trial was conducted in 32 primary schools located across 3 local health districts in New South Wales, Australia, to compare the effects of a 6-month intervention targeting foods packed in children's lunchboxes with those of a usual care control. Primary schools were eligible if they were not participating in other nutrition studies and used the required school communication app. The Behaviour Change Wheel was used to co-design the multicomponent SWAP IT intervention, which consisted of the following: school lunchbox nutrition guidelines, curriculum lessons, information pushed to parents digitally via an existing school communication app, and additional parent resources to address common barriers to packing healthy lunchboxes. The primary outcome, mean energy (kilojoules) content of discretionary lunchbox foods and drinks packed in lunchboxes, was measured via observation using a validated school food checklist at baseline (May 2019) and at 6-month follow-up (October 2019). Additional secondary outcomes included mean lunchbox energy from discretionary foods consumed, mean total lunchbox energy packed and consumed, mean energy content of core lunchbox foods packed and consumed, and percentage of lunchbox energy from discretionary and core foods, all of which were also measured via observation using a validated school food checklist. Measures of school engagement, consumption of discretionary foods outside of school hours, and lunchbox cost were also collected at baseline and at 6-month follow-up. Data were analyzed via hierarchical linear regression models, with controlling for clustering, socioeconomic status, and remoteness. RESULTS: A total of 3022 (3022/7212, 41.90%) students consented to participate in the evaluation (mean age 7.8 years; 1487/3022, 49.22% girls). There were significant reductions between the intervention and control groups in the primary trial outcome, mean energy (kilojoules) content of discretionary foods packed in lunchboxes (-117.26 kJ; 95% CI -195.59 to -39.83; P=.003). Relative to the control, the intervention also significantly reduced secondary outcomes regarding the mean total lunchbox energy (kilojoules) packed (-88.38 kJ; 95% CI -172.84 to -3.92; P=.04) and consumed (-117.17 kJ; 95% CI -233.72 to -0.62; P=.05). There was no significant difference between groups in measures of student engagement, consumption of discretionary foods outside of school hours, or cost of foods packed in children's lunchboxes. CONCLUSIONS: The SWAP IT intervention was effective in reducing the energy content of foods packed for and consumed by primary school-aged children at school. Dissemination of the SWAP IT program at a population level has the potential to influence a significant proportion of primary school-aged children, impacting weight status and associated health care costs. TRIAL REGISTRATION: Australian Clinical Trials Registry ACTRN12618001731280; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376191&isReview=true. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s12889-019-7725-x.

Antimalarial activity of single-dose DSM265, a novel plasmodium dihydroorotate dehydrogenase inhibitor, in patients with uncomplicated Plasmodium falciparum or Plasmodium vivax malaria infection: a proof-of-concept, open-label, phase 2a study.

BACKGROUND: DSM265 is a novel, long-duration inhibitor of plasmodium dihydroorotate dehydrogenase (DHODH) with excellent selectivity over human DHODH and activity against blood and liver stages of Plasmodium falciparum. This study aimed to assess the efficacy of DSM265 in patients with P falciparum or Plasmodium vivax malaria infection. METHODS: This proof-of-concept, open-label, phase 2a study was conducted at the Asociación Civil Selva Amazónica in Iquitos, Peru. Patients aged 18-70 years, weighing 45-90 kg, who had clinical malaria (P falciparum or P vivax monoinfection) and fever within the previous 24 h were eligible. Exclusion criteria were clinical or laboratory signs of severe malaria, inability to take oral medicine, and use of other antimalarial treatment in the preceding 14 days. Patients were divided into cohorts of those with P falciparum (cohort a) or P vivax (cohort b) infection. Two initial cohorts received single oral doses of 400 mg DSM265. Patients were followed up for efficacy for 28 days and safety for 35 days. Further cohorts received escalated or de-escalated doses of DSM265, after safety and efficacy assessment of the initial dose. The primary endpoints were the proportion of patients achieving PCR-adjusted adequate clinical and parasitological response (ACPR) by day 14 for patients infected with P falciparum and the proportion of patients achieving a crude cure by day 14 for those infected with P vivax. Cohort success, the criteria for dose escalation, was defined as ACPR (P falciparum) or crude cure (P vivax) in at least 80% of patients in the cohort. The primary analysis was done in the intention-to-treat population (ITT) and the per-protocol population, and safety analyses were done in all patients who received the study drug. This study is registered at ClinicalTrials.gov (NCT02123290). FINDINGS: Between Jan 12, 2015, and Dec 2, 2015, 45 Peruvian patients (24 with P falciparum [cohort a] and 21 with P vivax [cohort b] infection) were sequentially enrolled. For patients with P falciparum malaria in the per-protocol population, all 11 (100%) in the 400 mg group and eight (80%) of ten in the 250 mg group achieved ACPR on day 14. In the ITT analysis, 11 (85%) of 13 in the 400 mg group and eight (73%) of 11 in the 250 mg group achieved ACPR at day 14. For the patients with P vivax malaria, the primary endpoint was not met. In the per-protocol analysis, none of four patients who had 400 mg, three (50%) of six who had 600 mg, and one (25%) of four who had 800 mg DSM265 achieved crude cure at day 14. In the ITT analysis, none of five in the 400 mg group, three (33%) of nine in the 600 mg group, and one (14%) of seven in the 800 mg group achieved crude cure at day 14. During the 28-day extended observation of P falciparum patients, a resistance-associated mutation in the gene encoding the DSM265 target DHODH was observed in two of four recurring patients. DSM265 was well tolerated. The most common adverse events were pyrexia (20 [44%] of 45) and headache (18 [40%] of 45), which are both common symptoms of malaria, and no patients had any treatment-related serious adverse events or adverse events leading to study discontinuation. INTERPRETATION: After a single dose of DSM265, P falciparum parasitaemia was rapidly cleared, whereas against P vivax, DSM265 showed less effective clearance kinetics. Its long duration of action provides the potential to prevent recurrence of P falciparum after treatment with a single dose, which should be further assessed in future combination studies. FUNDING: The Global Health Innovative Technology Fund, the Bill & Melinda Gates Foundation, the National Institutes of Health (R01 AI103058), the Wellcome Trust, and the UK Department of International Development.

A Randomized Trial Evaluating the Prophylactic Activity of DSM265 Against Preerythrocytic Plasmodium falciparum Infection During Controlled Human Malarial Infection by Mosquito Bites and Direct Venous Inoculation.

Background: DSM265 is a selective inhibitor of Plasmodium dihydroorotate dehydrogenase that fully protected against controlled human malarial infection (CHMI) by direct venous inoculation of Plasmodium falciparum sporozoites when administered 1 day before challenge and provided partial protection when administered 7 days before challenge. Methods: A double-blinded, randomized, placebo-controlled trial was performed to assess safety, tolerability, pharmacokinetics, and efficacy of 1 oral dose of 400 mg of DSM265 before CHMI. Three cohorts were studied, with DSM265 administered 3 or 7 days before direct venous inoculation of sporozoites or 7 days before 5 bites from infected mosquitoes. Results: DSM265-related adverse events consisted of mild-to-moderate headache and gastrointestinal symptoms. DSM265 concentrations were consistent with pharmacokinetic models (mean area under the curve extrapolated to infinity, 1707 µg*h/mL). Placebo-treated participants became positive by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and were treated 7-10 days after CHMI. Among DSM265-treated subjects, 2 of 6 in each cohort were sterilely protected. DSM265-treated recipients had longer times to development of parasitemia than placebo-treated participants (P < .004). Conclusions: This was the first CHMI study of a novel antimalarial compound to compare direct venous inoculation of sporozoites and mosquito bites. Times to qRT-PCR positivity and treatment were comparable for both routes. DSM265 given 3 or 7 days before CHMI was safe and well tolerated but sterilely protected only one third of participants.

DSM265 for Plasmodium falciparum chemoprophylaxis: a randomised, double blinded, phase 1 trial with controlled human malaria infection.

BACKGROUND: A drug for causal (ie, pre-erythrocytic) prophylaxis of Plasmodium falciparum malaria with prolonged activity would substantially advance malaria control. DSM265 is an experimental antimalarial that selectively inhibits the parasite dihydroorotate dehydrogenase. DSM265 shows in vitro activity against liver and blood stages of P falciparum. We assessed the prophylactic activity of DSM265 against controlled human malaria infection (CHMI). METHODS: At the Institute of Tropical Medicine, Eberhard Karls University (Tübingen, Germany), healthy, malaria-naive adults were allocated to receive 400 mg DSM265 or placebo either 1 day (cohort 1A) or 7 days (cohort 2) before CHMI by direct venous inoculation (DVI) of 3200 aseptic, purified, cryopreserved P falciparum sporozoites (PfSPZ Challenge; Sanaria Inc, Rockville, MD, USA). An additional group received daily atovaquone-proguanil (250-100 mg) for 9 days, starting 1 day before CHMI (cohort 1B). Allocation to DSM265, atovaquone-proguanil, or placebo was randomised by an interactive web response system. Allocation to cohort 1A and 1B was open-label, within cohorts 1A and 2, allocation to DSM265 and placebo was double-blinded. All treatments were given orally. Volunteers were treated with an antimalarial on day 28, or when parasitaemic, as detected by thick blood smear (TBS) microscopy. The primary efficacy endpoint was time-to-parasitaemia, assessed by TBS. All participants receiving at least one dose of chemoprophylaxis or placebo were considered for safety, those receiving PfSPZ Challenge for efficacy analyses. Log-rank test was used to compare time-to-parasitemia between interventions. The trial was registered with ClinicalTrials.gov, number NCT02450578. FINDINGS: 22 participants were enrolled between Oct 23, 2015, and Jan 18, 2016. Five participants received 400 mg DSM265 and two participants received placebo 1 day before CHMI (cohort 1A), six participants received daily atovaquone-proguanil 1 day before CHMI (cohort 1B), and six participants received 400 mg DSM265 and two participants received placebo 7 days before CHMI (cohort 2). Five of five participants receiving DSM265 1 day before CHMI and six of six in the atovaquone-proguanil cohort were protected, whereas placebo recipients (two of two) developed malaria on days 11 and 14. When given 7 days before CHMI, three of six volunteers receiving DSM265 became TBS positive on days 11, 13, and 24. The remaining three DSM265-treated, TBS-negative participants of cohort 2 developed transient submicroscopic parasitaemia. Both participants receiving placebo 7 days before CHMI became TBS positive on day 11. The only possible DSM265-related adverse event was a moderate transient elevation in serum bilirubin in one participant. INTERPRETATION: A single dose of 400 mg DSM265 was well tolerated and had causal prophylactic activity when given 1 day before CHMI. Future trials are needed to investigate further the use of DSM265 for the prophylaxis of malaria. FUNDING: Global Health Innovative Technology Fund, Wellcome Trust, Bill & Melinda Gates Foundation through Medicines for Malaria Venture, and the German Center for Infection Research.