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There is a shortage of rapid, accurate, and low-cost assays for diagnosing enteric fever. The dual-path platform for typhoid (DPPT) assay had high accuracy in retrospective studies with banked plasma samples. We aimed to evaluate the diagnostic accuracy of the DPPT assay in a prospective study using fingerstick capillary blood. For this prospective diagnostic accuracy study, we enrolled children younger than 18years, who presented at the Bangladesh Shishu Hospital and Institute (Dhaka, Bangladesh) with at least 3days of fever. We collected blood and nasal swabs, and did the following assays to assess the accuracy of DPPT: blood culture, serological assays for typhoid fever (DPPT assay, Widal, and Test-it), and molecular assays to identify alternative aetiologies (eg, respiratory syncytial virus [RSV], influenza, dengue virus, and Rickettsia spp). The primary outcomes of the study were the sensitivity and specificity of the DPPT assay for diagnosis of enteric fever. We evaluated the accuracy of combined anti-haemolysin Eand anti-lipopolysaccharide IgA readings using the DPPT assay in distinguishing culture-confirmed enteric fever from alternative aetiologies using receiver operating characteristic area under the curve (AUC). Given the imperfect reference standard diagnostics for enteric fever, we used Bayesian latent class models, incorporating results from the typhoid and alternative aetiology diagnostics, to estimate the sensitivity and specificity of the DPPT assay. We also did subgroup analyses for the assay across multiple biological variables. Between Aug 17, 2021, and July 16, 2022, we enrolled 501participants who presented with at least 3days of fever. 223 (45%) of 501participants were female and 278 (55%) were male. 77participants had culture-confirmed enteric fever (62 Salmonella entericaserotype Typhi and 15 Salmonella entericaserotype Paratyphi A) and 70were culture-negative with PCR-confirmed alternative aetiology (34 influenza Aor B, 22dengue virus, seven Rickettsia spp, six RSV, and one participant co-infected with RSV and dengue virus). The AUC for DPPT on fingerstick capillary blood in distinguishing typhoid from alternative aetiologies was 0·969 (95% CI 0·943-0·994). In latent class analysis, the sensitivity of DPPT was 93%(95% credible interval [CrI] 87-97) and specificity was 89% (85-93). The balanced accuracy was higher for DPPT (91%, 95% CrI 87-94) than blood culture (81%, 78-85), Test-it (77%,74-79), or Widal (70%, 67-73). Assay performance did not vary by sex, age, duration of fever at presentation, antibiotic use before presentation, Salmonella serotype, or sample type. The point-of-care DPPT assay achieved high diagnostic accuracy for enteric fever in a highly endemic community. This assay has the potential to improve clinical outcomes for enteric fever, allowing rapid diagnosis and treatment, and could facilitate more appropriate antimicrobial use. National Institute of Health, Bill & Melinda Gates Foundation, and Child Health Research Foundation.

SummaryBackgroundThe population structure of the malaria parasite Plasmodium falciparum can reveal underlying adaptive evolutionary processes. Selective pressures to maintain complex genetic backgrounds can encourage inbreeding, producing distinct parasite clusters identifiable by population structure analyses.MethodsWe analysed population structure in 3783 P falciparum genomes from 21 countries across Africa, provided by the MalariaGEN Pf7 dataset. We used Principal Coordinate Analysis to cluster parasites, identity by descent (IBD) methods to identify genomic regions shared by cluster members, and linkage analyses to establish their co-inheritance patterns. Structural variants were reconstructed by de novo assembly and verified by long-read sequencing.FindingsWe identified a strongly differentiated cluster of parasites, named AF1, comprising 47 (1·2%) of 3783 samples analysed, distributed over 13 countries across Africa, at locations over 7000 km apart. Members of this cluster share a complex genetic background, consisting of up to 23 loci harbouring many highly differentiated variants, rarely observed outside the cluster. IBD analyses revealed common ancestry at these loci, irrespective of sampling location. Outside the shared loci, however, AF1 members appear to outbreed with sympatric parasites. The AF1 differentiated variants comprise structural variations, including a gene conversion involving the dblmsp and dblmsp2 genes, and numerous single nucleotide polymorphisms. Several of the genes harbouring these mutations are functionally related, often involved in interactions with red blood cells including invasion, egress, and erythrocyte antigen export.InterpretationWe propose that AF1 parasites have adapted to some unidentified evolutionary niche, probably involving interactions with host erythrocytes. This adaptation involves a complex compendium of interacting variants that are rarely observed in Africa, which remains mostly intact despite recombination events. The term cryptotype was used to describe a common background interspersed with genomic regions of local origin.FundingBill & Melinda Gates Foundation.

SummaryBackgroundDoxycycline post-exposure prophylaxis (PEP) has been shown to be efficacious for the prevention of bacterial sexually transmitted infections, but resistance implications for Neisseria gonorrhoeae remain unknown. We aimed to use a mathematical model to investigate the anticipated impact of doxycycline PEP on the burden of gonorrhoea and antimicrobial resistance dynamics in men who have sex with men (MSM) in the USA.MethodsUsing a deterministic compartmental model, characterising gonorrhoea transmission in a US MSM population comprising three sexual activity groups defined by annual partner turnover rates, we introduced doxycycline PEP at various uptake levels (10–90%) among those with high sexual activity. Infections were stratified by symptom status and resistance profile (ie, susceptible, ceftriaxone-resistant, tetracycline-resistant, or dual-resistant), with ceftriaxone the treatment for active infection. As resistance to tetracycline, not doxycycline, is monitored and reported nationally, we used this as a proxy for doxycycline PEP resistance. We compared the 20-year prevalence, incidence rates, and cumulative incidence of gonococcal infection, resistance dynamics (time to 5% prevalence of ceftriaxone resistance, 5% prevalence of dual resistance, and 84% prevalence of tetracycline resistance), and antibiotic consumption with baseline (ie, no doxycycline PEP).FindingsUptake of doxycycline PEP resulted in substantial reductions in the prevalence and incidence of gonorrhoea, but accelerated the spread of tetracycline resistance. The maximum reduction in prevalence over 20 years compared with no uptake ranged from 40·3% (IQR 15·3–83·4) with 10% doxycycline PEP uptake to 77·4% (68·4–84·9) with 90% uptake. Similarly, the maximum reduction in the incidence rate ranged from 38·6% (14·1–83·6) with 10% uptake to 77·6% (68·1–84·7) with 90% uptake. Cumulative gonococcal infections were reduced by a median of 14·5% (IQR 8·4–21·6) with 10% uptake and up to 46·2% (26·5–59·9) with 90% uptake after 5 years, and by 6·5% (3·4-13·0) with 10% uptake and 8·7% (4·3–36·2) with 90% uptake by 20 years. In almost all scenarios explored, doxycycline PEP lost clinical effectiveness (defined as 84% prevalence of tetracycline resistance) within the 20-year period, but its lifespan ranged from a median of 12·1 years (IQR 9·9–15·7) with 10% uptake to 1·6 years (1·3–1·9) with 90% uptake. Doxycycline PEP implementation had minimal impact on extending the clinical lifespan of ceftriaxone monotherapy (5·0 years [IQR 4·0–6·2]), with the median time to 5% prevalence of resistance ranging from 4·8 years (3·9–6·0) for 90% uptake to 5·0 years (4·1–6·2) for 10% uptake. Similarly, the median time to 5% prevalence of dual resistance to ceftriaxone and tetracycline ranged from 4·8 years (3·9–6·0) for 90% uptake to 5·8 years (4·8–7·4) for 10% uptake. Median decrease in ceftriaxone consumption for high doxycycline PEP uptake levels compared with baseline ranged from 41·7% (27·0–54·3) for 50% uptake to 50·2% (29·3–62·7) for 90% uptake at 5 years, but dropped to 11·8% (6·9–32·0) for 50% uptake and 12·1% (7·0–41·6) for 90% uptake after 20 years.InterpretationNotwithstanding the clear benefits of doxycycline PEP for other sexually transmitted infections, for N gonorrhoeae, model findings suggest that doxycycline PEP is an effective but impermanent solution for reducing infection burden, given eventual selection for resistant strains. This finding presents a challenge for policy makers considering strategies for doxycycline PEP implementation and oversight: the need to balance the clear, short-term clinical benefits with the risk of harm via antimicrobial resistance.FundingUS Centers for Disease Control and Prevention, National Institute of Allergy and Infectious Diseases.