INTRODUCTION:Traveller's diarrhoea is a common complaint among deployed military personnel. Maintaining sample integrity prior to diagnostic testing is a key challenge in resource-limited environments. We report the comparison of three long-term ambient temperature stool sample stabilisation matrices for the detection of Cryptosporidium hominis from samples collected during an outbreak among British military personnel stationed in Kenya. METHODS:A retrospective cohort of stool samples, each stabilised for more than 12 months at ambient temperatures using Flinders Technical Associate (FTA) cards, OMNIgene GUT tubes and DNA Shield faecal collection tubes, were analysed by Nanopore-based clinical metagenomic (CMgs) DNA sequencing and quantitative real-time PCR (qPCR) in the UK. The results were compared with BioFire FilmArray Gastrointestinal Panel testing carried out at the point of sampling in Kenya. RESULTS:Cryptosporidium DNA was detected in 13/24 (54.2%) OMNIgene GUT samples by CMg following long-term storage, compared with 9/24 (37.5%) of DNA Shield samples. Samples stored on FTA cards did not identify Cryptosporidium DNA by CMg in any sample. OMNIgene GUT samples also had the highest rate of detection of C. hominis DNA by qPCR, with 23/24 samples testing positive, compared with 21/24 and 17/20 of DNA Shield and FTA samples, respectively. CONCLUSIONS:Samples stored in OMNIgene GUT tubes retained detectable levels of Cryptosporidium DNA in a higher proportion of samples following long-term storage. This study demonstrates the importance of selecting the optimal sample collection and stabilisation matrix for CMg and qPCR based diagnostic testing in austere environments.

BackgroundGastrointestinal illnesses are common during military training and operational deployments. We compared the incidence and burden of travellers’ diarrhoea (TD) reported by British service personnel (SP) during recent training exercises in Kenya and Oman.MethodsSP completed a validated anonymous questionnaire regarding clinical features of any diarrhoeal illness, associated risk factors and impact on work capability after 6-week training exercises in 2018 in Kenya and 2018–2019 in Oman. Responses were tabulated for descriptive comparisons.ResultsQuestionnaires were received from 388 (32%) SP in Kenya and 627 (52%) in Oman. The cumulative incidence of reported diarrhoea over 6-weeks was 14.2% (95% CI 8.02% to 22.61%) in Kenya compared with 3.9% (95% CI 1.10% to 9.91%) in Oman (OR 3.56, 95% CI 2.18 to 5.8; p<0.0001). Attack rates were 9.45 SP/100 exposure-months in Kenya and 2.66/100 in Oman. The number of workdays lost was greater in Kenya (6.26 per 1000 days) compared with Oman (4.13 per 1000 days) (p<0.01). In Kenya, 52.3% of those experiencing diarrhoea became ill during the first 14 days of deployment, but in Oman, 50% were ill in the last deployment week. The strongest risk factor associated with TD at both locations was contact with a colleague experiencing diarrhoea, followed in Kenya by eating locally sourced food and swimming in local water, which had weaker protective associations in Oman.ConclusionsThe epidemiology, risk factors and burden of TD in Kenya were similar to previous descriptions, where overall incidence continues to decline. Incidence and burden were significantly lower in Oman, where both were much lower than historical descriptions. Peak timing of illness and associated risk factors differed between Kenya and Oman. Continued documentation and review of TD during training exercises at different geographical locations is essential to inform the chain of command about risks to operational effectiveness.

INTRODUCTION:Travel to resource-limited settings is a known risk for acquisition of extended-spectrum β-lactamase-producing Enterobacterales (ESBL-PE) and carbapenem-resistant Enterobacterales (CRE), which are both associated with increased morbidity and mortality. We investigated the ESBL-PE and CRE baseline prevalence in British service personnel (SP). METHODS:SP provided faecal samples for research projects in several different settings, between September 2021 and April 2022. Bacterial colonies from faecal isolates were recovered from incubated ChromID ESBL plates (bioMérieux, Marcy-l'Étoile, France) and DNA extracted using Qiagen DNeasy extraction kits (Qiagen, UK). PCR to identify β-lactamase and CRE encoding genes was performed using the Rotor-Gene Q (RGQ) (Qiagen, UK), with positivity detected by RGQ software. Phenotypic assessment of antimicrobial susceptibility was not performed. RESULTS:Out of 250 personnel approached, 239 (85.5% men, median (IQR) age 31 (26-37) years) provided faecal samples suitable for analysis. The ESBL prevalence was 40/239 (16.7%), with ESBL-producing Escherichia coli detected in 39 (16.3%) samples and ESBL-producing Klebsiella pneumoniae in 1 (0.4%) sample. Combinations including Temoniera, sulfhydryl reagent variable (SHV), cefotaxime hydrolysing β-lactamase (Munich) (CTX-M) 1 and CTX-M 9 genes were detected in 18 (7.5%), 33 (13.8%) 16 (6.7%) and 8 (3.3%) samples, respectively. E. coli samples had mixtures of all four genotypes with SHV predominating. One (0.4%) sample carried all four gene types and the only K. pneumoniae sample carried a single SHV gene. No CRE were detected. CONCLUSIONS:The prevalence of ESBL-PE in cohorts of SP closely matches that of civilian populations in England; however, we noted differences in ESBL genotype distribution. Potential exposure risks for SP from international travel and occupational trauma emphasise the need for repeated surveillance to characterise and detect changes in acquisition epidemiology and carriage of ESBL. Such prospective data have important antimicrobial stewardship implications in optimising clinical outcomes, controlling resistance and guiding empirical antibiotic formulary policy recommendations.

Introduction. Immediate identification of travellers’ diarrhoea-causing pathogens may not be possible in remote settings, but samples can be stored for epidemiological and related research. We collected pilot data to evaluate the utility of three different preservation media for testing stored faecal samples compared to immediate testing of fresh samples using the BioFire ® FilmArray ® multiplex PCR gastrointestinal panel (bioMérieux). Gap statement. No previous studies have demonstrated the utility of testing faecal samples directly by PCR BioFire ® FilmArray ® following prolonged storage and transportation in OMNIgene ® , DNA ™ shield and FTA ™ cards. Aims. To evaluate the reliability of OMNIgene ® , DNA shield ™ and FTA ™ card faecal storage and transport media in parallel, compared to initial testing of fresh faeces obtained from the same individuals at the time of presentation with diarrhoea in the field compare the results of faecal samples stored and transported at ambient temperature in OMNIgene ® , DNA shield ™ and FTA ™ cards then tested using PCR BioFire ® FilmArray ® 6–18 months later with those obtained from fresh faecal samples during a diarrhoea outbreak. Methodology. Fresh faecal samples were obtained from British military personnel who developed diarrhoea during deployment to Kenya between February-April 2022. Unpreserved fresh samples were tested onsite using PCR BioFire ® FilmArray ® and corresponding samples were stored at ambient temperature in OMNIgene ® 200 (DNAgenotek ® ), DNA/RNA shield DX ™ (Zymo Research) and Whatman FTA™ Elute cards (GE Healthcare) then repatriated to the UK for direct testing by PCR BioFire ® FilmArray ® , 6-18 months later. The most common enteropathogens evaluated were: Cryptosporidium spp., Enteroaggregative Escherichia coli ( E. coli ; EAEC), Enteropathogenic E. coli (EPEC), Shiga toxin-producing E. coli (STEC) and Campylobacter spp. Test results for the three storage modalities were compared to the fresh sample tests as a reference standard. Results. Samples from 60 individuals [80% male; median (interquartile range) age 24 (22–28) years] were analysed. Test sensitivity for Campylobacter spp. and EAEC was high across all three storage modalities (86.4–100%). OMNIgene ® 200 and DNA/RNA shield ™ showed significant concordance with the reference standard test for other pathogens, but FTA ™ Elute card tests had low sensitivity for STEC and poor specificity for Campylobacter spp. Agreement between FTA ™ Elute cards and the reference standard test was low-moderate (kappa coefficient ≤0–0.49) for all enteropathogens. Conclusions. This study demonstrates successful PCR BioFire ® FilmArray ® utility in testing samples stored in different media and is the first to compare the use of OMNIgene ® 200, DNA/RNA shield ™ and FTA ™ Elute cards simultaneously with the results of clinical samples. Stored samples were tested up to 18 months later with significant concordance observed in OMNIgene ® 200 and DNA/RNA shield ™ compared to reference standard testing. The distorted performance of FTA ™ Elute card testing requires further optimisation. Testing of samples stored in these media is suitable for research studies, but their applicability with other molecular diagnostic platforms, or clinical diagnostics, requires confirmation.

BackgroundThe interaction between iron status and malaria is incompletely understood. We evaluated longitudinal changes in iron homeostasis in volunteers enrolled in malaria volunteer infection studies (VIS) and in Malaysian patients with falciparum and vivax malaria.MethodsWe retrieved data and samples from 55 participants (19 female) enrolled in malaria VIS, and 171 patients (45 female) with malaria and 30 healthy controls (13 female) enrolled in clinical studies in Malaysia. Ferritin, hepcidin, erythropoietin, and soluble transferrin receptor (sTfR) were measured by ELISA.FindingsIn the VIS, participants’ parasitaemia was correlated with baseline mean corpuscular volume (MCV), but not iron status (ferritin, hepcidin or sTfR). Ferritin, hepcidin and sTfR all increased during the VIS. Ferritin and hepcidin normalised by day 28, while sTfR remained elevated. In VIS participants, baseline ferritin was associated with post-treatment increases in liver transaminase levels. In Malaysian patients with malaria, hepcidin and ferritin were elevated on admission compared to healthy controls, while sTfR increased following admission. By day 28, hepcidin had normalised; however, ferritin and sTfR both remained elevated.InterpretationOur findings demonstrate that parasitaemia is associated with an individual's MCV rather than iron status. The persistent elevation in sTfR 4 weeks post-infection in both malaria VIS and clinical malaria may reflect a causal link between malaria and iron deficiency.FundingNational Health and Medical Research Council (Program Grant 1037304, Project Grants 1045156 and 1156809; Investigator Grants 2016792 to BEB, 2016396 to JCM, 2017436 to MJG); US National Institute of Health (R01-AI116472-03); Malaysian Ministry of Health (BP00500420).

Background We report clinical, epidemiological, and laboratory features of a large diarrhea outbreak caused by a novel Cryptosporidium hominis subtype during British military training in Kenya between February and April 2022.Methods Data were collated from diarrhea cases, and fecal samples were analyzed on site using the multiplex polymerase chain reaction (PCR) BioFire FilmArray. Water was tested using Colilert kits (IDEXX, UK). DNA was extracted from feces for molecular characterization of Cryptosporidium A135, Lib13, ssu rRNA, and gp60 genes.Results One hundred seventy-two of 1200 (14.3%) personnel at risk developed diarrhea over 69 days. One hundred six primary fecal samples were tested, and 63/106 (59.4%; 95% CI, 0.49%-0.69%) were positive for Cryptosporidium spp. Thirty-eight had Cryptosporidium spp. alone, and 25 had Cryptosporidium spp. with >= 1 other pathogen. A further 27/106 (25.5%; 95% CI, 0.18%-0.35%) had non-Cryptosporidium pathogens only, and 16/106 (15.1%; 95% CI, 0.09%-0.23%) were negative. C. hominis was detected in 58/63 (92.1%) Cryptosporidium spp.-positive primary samples, but the others were not genotypable. Twenty-seven C. hominis specimens were subtypable; 1 was gp60 subtype IeA11G3T3, and 26 were an unusual subtype, ImA13G1 (GenBank accession OP699729), supporting epidemiological evidence suggesting a point source outbreak from contaminated swimming water. Diarrhea persisted for a mean (SD) of 7.6 (4.6) days in Cryptosporidium spp. cases compared with 2.3 (0.9) days in non-Cryptosporidium cases (P = .001).Conclusions Real-time multiplex PCR fecal testing was vital in managing this large cryptosporidiosis outbreak. The etiology of a rare C. hominis gp60 subtype emphasizes the need for more genotypic surveillance to identify widening host and geographic ranges of novel C. hominis subtypes.

BACKGROUND:We evaluated the results of examining a single faecal sample for gastrointestinal parasites (GIP) using a combination of traditional methods with multiplex qPCR for helminths and protozoa, compared to a reference standard of examining three faecal samples from each person using traditional diagnostic methods alone. METHODS:Three faecal samples were collected at weekly intervals from 596 healthy Nepalese men. Each sample underwent formalin-ethyl acetate (FEA) concentration and light microscopy, and charcoal culture. The combined results of these investigations for all three stool samples were designated the reference standard. The first sample was also analysed using a multiplex TaqMan™ qPCR assay, screening for five helminths and three protozoa. We compared sensitivity and specificity of analysing the first faecal sample with qPCR alone, or a hybrid approach combining qPCR with traditional methods, to the reference standard. Additionally, a serum sample was taken from each participant for Strongyloides stercoralis IgG ELISA. RESULTS:The reference standard identified 139 GIP infections in 133 (22.3%) participants. Use of qPCR alone in one stool identified 176 infections in 147 (24.8%) participants, rising to 187 infections in 156 (26.3%) when combined with FEA microscopy and charcoal culture. The sensitivity of this latter hybrid approach was 100% for Strongyloides spp., 90.9% for Trichuris trichiura, 86.8% for hookworm species and 75% for Giardia duodenalis compared to the reference standard. The hybrid approach increased the detected prevalence of G. duodenalis by 4.5% (27 cases) overall, T. trichiura by 2.9% (17 cases), Strongyloides spp. by 1% (6 cases), and hookworm by 0.5% (3 cases), compared to the reference standard. CONCLUSION:Examination of a single faecal sample using qPCR alone showed superior or equivalent sensitivity to traditional methods for most GIP infections when both were compared to the reference standard. Combining molecular and traditional methods to analyse a single stool improved the detection rate for most studied parasites. This approach has value in settings where repeated sampling and/or faecal culture for helminths is impractical, but molecular diagnostics are available.

The World Health Organization (WHO)’s list of neglected tropical diseases (NTDs) highlights conditions that are responsible for devastating health, social and economic consequences, and yet, they are overlooked and poorly resourced. The NTD list does not include conditions caused by Gram-negative bacilli (GNB). Infections due to GNB cause significant morbidity and mortality and are prevalent worldwide. Southeast Asia is a WHO region of low- and middle-income countries carrying the largest burden of NTDs. Two significant health threats in Southeast Asia are Burkholderia pseudomallei (causing melioidosis) and hypervirulent Klebsiella pneumoniae (HvKp). Both diseases have high mortality and increasing prevalence, yet both suffer from a lack of awareness, significant under-resourcing, incomplete epidemiological data, limited diagnostics, and a lack of evidence-based treatment. Emerging evidence shows that both melioidosis and HvKp are spreading globally, including in high-income countries, highlighting the potential future global threat they pose. In this article, we review both conditions, identifying current trends and challenges in Southeast Asia and areas for future research. We also argue that melioidosis and HvKp merit inclusion as NTDs, and that mandatory global surveillance and reporting systems should be established, and we make an urgent call for research to better understand, detect, and treat these neglected diseases.

Severe burns are a major component of conflict-related injuries and can result in high rates of mortality. Conflict and disaster-related severe burn injuries present unique challenges in logistic, diagnostic and treatment options, while wider conflict is associated with driving local antimicrobial resistance. We present a targeted review of available literature over the last 10 years on the use of systemic antimicrobial antibiotics in this setting and, given limited available data, provide an expert consensus discussion. While international guidelines do not tend to recommend routine use of prophylactic systemic antibiotics, the challenges of conflict settings and potential for polytrauma are likely to have ongoing impacts on antimicrobial decision-making and use. Efforts must be made to develop a suitable evidence base in this unique setting. In the interim, a pragmatic approach to balancing selective pressures of antimicrobial use with realistic access is possible.

Introduction. Strongyloides stercoralis, the human threadworm, is a parasitic nematode with global distribution, estimated to infect over 600 million people. Chronic infection is often asymptomatic, but hyperinfection and dissemination syndromes can occur in the immunosuppressed with high case fatality rates. Whilst strongyloidiasis is endemic in Fiji, its prevalence in Fijian migrant groups in the UK is unknown. Gap Statement. No previous studies have been conducted on the prevalence of Strongyloides and other gastrointestinal parasites (GIPs) in Fijian migrants to the UK. Aim. We conducted a cross-sectional study of the prevalence of GIPs in a Fijian migrant population. Methodology. Participants completed a questionnaire on residence, travel and clinical symptoms and were asked to provide a serum sample for S. stercoralis IgG ELISA, venous blood samples for eosinophil count and a faecal sample for charcoal culture, multiplex real-time PCR (rtPCR) and microscopy after formalin-ethyl acetate concentration. Sequencing was performed on pooled Strongyloides larvae for nuclear 18S rRNA hyper-variable regions (HVRs) I and IV. Results. A total of 250 participants (94% male) with median (range) age 37 (20-51) years entered the study, 15 (1-24) years since leaving Fiji. S. stercoralis IgG ELISA was positive in 87/248 (35.1 %) and 14/ 74 (18.9%) had a GIP detected in faeces. This included 7/ 74 (9.5 %) with Strongyloides and 5/74 (6.8%) with hookworms. Dermatological symptoms were more common in those with Strongyloides, and eosinophilia (> 0.5x109 cells per litre) was present in 55.6% of those with positive S. stercoralis IgG. rtPCR was the most sensitive faecal diagnostic test for Strongyloides and hookworms in faeces. Sequences of nuclear 18S rRNA for HVRs I and IV confirmed the presence of S. stercoralis. Conclusion. This first cross-sectional study in Fijian migrants found a high rate of chronic infection with GIPs, particularly S. stercoralis. Faecal microscopy was insensitive compared to charcoal culture, rtPCR or serology, demonstrating the importance of specialist parasitological tests when investigating people with a suspected chronic infection. Our study highlights an overlooked burden of strongyloidiasis in the UK and has implications for screening and treatment programmes in Fiji and for migrants from Fiji.

BACKGROUND:Gastrointestinal parasite (GIP) infections are a major cause of global morbidity, infecting hundreds of millions of people each year and potentially leading to lifelong infection and serious complications. Few data exist on screening for GIP infections in migrants entering the UK or on the current performance of different traditional diagnostic approaches. This study aimed to describe the prevalence of GIP infections in Nepalese Gurkha recruits screened on arrival in the UK. METHODOLOGY/PRINCIPAL FINDINGS:We present a retrospective analysis of data from screening male adults (18-21 years) who arrived in the UK from Nepal between 2012 and 2020. Three separate faecal samples were obtained from participants at weekly intervals and processed for formalin-ethyl acetate (FEA) concentration/light microscopy and charcoal culture. Serum samples were analysed for IgG antibodies to Strongyloides stercoralis by ELISA. Results were available from 2,263 participants, of whom 463 (20.5%, 95% CI 18.8%-22.2%) had a positive diagnostic test for at least one GIP infection. A total of 525 potential infections were identified. Giardia duodenalis was most common (231/2263, 10.2%), followed by S. stercoralis (102/2263, 4.5%), and hookworm species (86/2263, 3.8%). Analysis (microscopy and culture) of the initial stool sample diagnosed only 244/427 (57.1%) faecally identified pathogens, including 41/86 (47.7%) hookworm infections. The proportion of participants infected with any GIP showed a downward trend over the study period. Log-binomial regression showed risk of infection decreasing by 6.1% year-on-year (95% CI 3.2% - 9.0%). This was driven predominantly by a fall in hookworm, S. stercoralis and Trichuris trichiura prevalence. CONCLUSIONS/SIGNIFICANCE:The level of potentially pathogenic GIP infection in young Nepalese men migrating to the UK is high (20.5%) and requires a combined diagnostic approach including serology and analysis of multiple stool samples incorporating specialised parasitological methods. Advances in molecular approaches may optimise and simplify the intensive screening strategy required.

Abstract Background The combination antimalarial artefenomel-piperaquine failed to achieve target efficacy in a phase 2b study in Africa and Vietnam. We retrospectively evaluated whether characterizing the pharmacological interaction of this antimalarial combination in a volunteer infection study (VIS) would have enabled prediction of the phase 2b study results. Methods Twenty-four healthy adults enrolled over three consecutive cohorts were inoculated with Plasmodium falciparum-infected erythrocytes on day 0. Participants were randomized within each cohort to one of seven dose combination groups and administered a single oral dose of artefenomel-piperaquine on day 8. Participants received definitive antimalarial treatment with artemether-lumefantrine upon parasite regrowth or on day 42 ± 2. The general pharmacodynamic interaction (GPDI) model implemented in the Bliss Independence additivity criterion was developed to characterize the pharmacological interaction between artefenomel and piperaquine. Simulations based on the model were performed to predict the outcomes of the phase 2b combination study. Results For a dose of 800 mg artefenomel administered with 640 mg, 960 mg, or 1440 mg piperaquine, the simulated adequate parasitological response at day 28 (APR28), incorporating actual patient pharmacokinetic (PK) data from the phase 2b trial, was 69.4%, 63.9%, and 74.8%, respectively. These results closely matched the observed APR28 in the phase 2b trial of 67.0%, 65.5%, and 75.4%, respectively. Conclusions These results indicate that VIS offer an efficient means for informing antimalarial combination trials conducted in the field, potentially expediting clinical development. Trial registration This study was registered on ClinicalTrials.gov on 11 May 2018 with registration number NCT03542149.

IntroductionOutbreaks of SARS-CoV-2 onboard maritime platforms spread rapidly and have high attack rates. The aim of the COVID-19 Risk, Attitudes and Behaviour (CRAB) study was to investigate the knowledge, attitudes, and practises in the Royal Navy in relation to COVID-19 prevention.MethodsThe CRAB study was a cross-sectional survey, using a census sampling method, conducted in May and June 2021. An online questionnaire was distributed to all serving Royal Navy regular personnel using either the MyNavy application or via a QR code through email for a continuous 14 day period. The questionnaire was based on an existing validated questionnaire used for avian influenza epidemics. Questions investigated individual perceptions of COVID-19 seriousness, compliance with prevention methods, explored vaccination intention and vaccine hesitancy (unvaccinated individuals who declined or were unsure about receiving a COVID-19 vaccine). The chi-squared test of best fit was used to compare the demographic responses against the whole organisation, with p-value < 0.05 deemed significant. Odds ratios were used to investigate associations between demographic groups and responses to questions, with an odds ratio crossing 1.0 deemed non-significant.ResultsThe response rate was 6% (2,080/33,200), with 315 responses collated in the pilot phase and 1,765 in the main study phase. Male participants were less likely to rate COVID-19 as serious (OR 0.34; 95% CI: 0.23–0.49). BAME ethnicity (OR 2.41; 95% CI: 1.12–5.17) rated it as more serious. At the time of the study 62% of respondents had received one dose of a COVID-19 vaccine. In the 797 unvaccinated personnel, vaccine hesitancy accounted for 24.2% (193/797), of whom 136 were white males. Those who had a higher COVID-19 serious rating, the most significant factor for non-adherence to COVID-19 prevention measures in both vaccinated (OR 1.61 [95%CI: 1.20–2.17]) and vaccine-hesitant (OR 3.24 [95%CI: 1.63–6.41]) individuals was colleagues' non-adherence. The most trusted source of information on vaccines was provided by the Defence Medical Services (77.2% [1,606/2,080]).ConclusionThis study has identified reasons for COVID-19 protective measure adherence, sources of information trusted by respondents and vaccine hesitancy, in the Royal Navy. The questionnaire can be used to investigate attitudes and behaviours in future emerging infectious diseases.

With the emergence of SARS-CoV-2 and now monkeypox, the UK Defence Medical Services have been required to provide rapid advice in the management of patients with airborne high consequence infectious diseases (A-HCID). The Defence Public Health Network (DPHN) cadre, consisting of closely aligned uniformed and civilian public health specialists have worked at pace to provide evidence-based recommendations on the clinical management, public health response and policy for monkeypox, with military medicine and pathology clinicians (primarily infectious disease physicians and medical microbiologists). Military environments can be complicated and nuanced requiring specialist input and advice to non-specialists as well as unit commanders both in the UK and overseas. DPHN and military infection clinicians have close links with the UK National Health Service (NHS) and the UK Health Security Agency (UKHSA), allowing for a dynamic two-way relationship that encompasses patient management, public health response, research and development of both UK military and national guidelines. This is further demonstrated with the Royal Air Force (RAF) Air Transport Isolator (ATI) capability, provided by Defence to support the UK Government and UKHSA. Military infectious disease clinicians are also embedded within NHS A-HCID units. In this manuscript we provide examples of the close interdisciplinary working of the DPHN and Defence clinicians in managing military monkeypox patients, co-ordinating the public health response, advising the Command and developing monkeypox policy for Defence through cross-government partnership. We also highlight the co-operation between civilian and military medical authorities in managing the current outbreak.

As of Dec 5, 2022, there were 3730 mpox (formerly known as monkeypox) cases in the UK,1 with clade IIb B.1 being the predominant lineage. Cases of mpox associated with travel or proven not to be B.1 lineage on whole genome sequencing were managed in airborne high consequence infectious disease (A-HCID) units, following the derogation of mpox associated with men who have sex with men (MSM) by the Advisory Committee on Dangerous Pathogens.2 To date, successfully sequenced non-B.1 lineage imported mpox cases to the UK have been within clade IIb A.2.

Infections caused by Plasmodium falciparum, P. vivax, and P. malariae have decreased globally following the successful roll-out of malaria elimination strategies. However, there have been increasing reports of human P. knowlesi infections across Southeast Asia; in some areas, it is now the only malaria species reported in humans. This is driven by land use change, forcing the simian macaque hosts and the Anopheles mosquito vectors into closer contact with humans, coupled with the potential loss of cross-protective immunity in countries approaching the elimination of human malaria species. P. knowlesi usually causes asymptomatic or mild disease in children, but adults may experience disease resembling severe falciparum malaria. It remains a public health burden on the local health systems, especially the need for rapid diagnosis and treatment to prevent severe disease. Following the introduction of polymerase chain reaction-based diagnostic technologies, other simian malarias such as P. coatneyi, P. cynomolgi, P. inui, P. inui-like and P. simiovale have also been found to cause natural human disease that had not previously been recognised. Furthermore, the discovery of P. brasilianum and P. simium as causes of naturally acquired malaria in South America has highlighted the need to incorporate a One Health approach to malaria control. This article reviews the clinical and epidemiological features of these malarias.

Background New antimalarials with novel mechanisms of action are needed to combat the emergence of drug resistance. Triaminopyrimidines comprise a novel antimalarial class identified in a high-throughput screen against asexual blood-stage Plasmodium falciparum. This first-in-human study aimed to characterise the safety, pharmacokinetics, and antimalarial activity of the triaminopyrimidine ZY-19489 in healthy volunteers. Methods A three-part clinical trial was conducted in healthy adults (aged 18-55 years) in Brisbane, QLD, Australia. Part one was a double-blind, randomised, placebo-controlled, single ascending dose study in which participants enrolled into one of six dose groups (25,75,150,450,900, or 1500 mg) were randomly assigned (3:1) to ZY-19489 or placebo. Part two was an open-label, randomised, two-period cross-over, pilot food-effect study in which participants were randomly assigned (1:1) to a fasted-fed or a fed-fasted sequence. Part three was an open-label, randomised, volunteer infection study using the P falciparum induced blood-stage malaria model in which participants were enrolled into one of two cohorts, with participants in cohort one all receiving the same dose of ZY-19489 and participants in cohort two randomly assigned to receive one of two doses. The primary outcome for all three parts was the incidence, severity, and relationship to ZY-19489 of adverse events. Secondary outcomes were estimation of ZY-19489 pharmacokinetic parameters for all parts; how these parameters were affected by the fed state for part two only; and the parasite reduction ratio, parasite clearance half-life, recrudescent parasitaemia, and pharmacokinetic-pharmacodynamic modelling parameters for part three only. This trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12619000127101, ACTRN12619001466134, and ACTRN12619001215112). Findings 48 participants were enrolled in part one (eight per cohort for 25-1500 mg cohorts), eight in part two (four in each group, all dosed with 300 mg), and 15 in part three (five dosed with 200 mg, eight with 300 mg, and two with 900 mg). In part one, the incidence of drug-related adverse events was higher in the 1500 mg dose group (occurring in all six participants) than in lower-dose groups and the placebo group (occurring in one of six in the 25 mg group, two of six in the 75 mg group, three of six in the 150 mg group, two of six in the 450 mg group, four of six in the 900 mg group, and four of 12 in the placebo group), due to the occurrence of mild gastrointestinal symptoms. Maximum plasma concentrations occurred 5-9 h post-dosing, and the elimination half-life was 50-97 h across the dose range. In part two, three of seven participants had a treatment-related adverse event in the fed state and four of eight in the fasted state. Dosing in the fed state delayed absorption (maximum plasma concentration occurred a median of 12.0 h [range 7-5-16.0] after dosing in the fed state vs 6.0 h [4.5-9-1] in the fasted state) but had no effect on overall exposure (difference in area under the concentration-time curve from time 0 [dosing] extrapolated to infinity between fed and fasted states was -0.013 [90% CI -0.11 to 0.08]). In part three, drug-related adverse events occurred in four of five participants in the 200 mg group, seven of eight in the 300 mg group, and both participants in the 900 mg group. Rapid initial parasite clearance occurred in all participants following dosing (clearance half-life 6.6 h [95% CI 6.2-6.9] for 200 mg, 6.8 h 195% CI 6.5-7.11 for 300 mg, and 7.1 h [95% CI 6.6-7.6] for 900 mg). Recrudescence occurred in four of five participants in the 200 mg group, five of eight in the 300 mg group, and neither of the two participants in the 900 mg group. Simulations done using a pharmacokinetic-pharmacodynamic model predicted that a single dose of 1100 mg would clear baseline parasitaemia by a factor of 10(9). Interpretation The safety, pharmacokinetic profile, and antimalarial activity of ZY-19489 in humans support the further development of the compound as a novel antimalarial therapy. Copyright (C) 2022 Elsevier Ltd. All rights reserved.