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The development of highly effective malaria vaccines and improvement of drug- treatment protocols to boost antiparasitic immunity are critical for malaria elimination. However, the rapid establishment of parasite-specific immune regulatory networks following exposure to malaria parasites hampers these efforts. Here, we identified stimulator of interferon genes (STING) as a critical mediator of type I interferon production by [CD4.sup.+] T cells during blood-stage Plasmodium falciparum infection. The activation of STING in [CD4.sup.+] T cells by cyclic guanosine monophosphate- adenosine monophosphate (cGAMP) stimulated IFNB gene transcription, which promoted development of IL-10- and IFN- [gamma]-coproducing [CD4.sup.+] T (type I regulatory [Tr1]) cells. The critical role for type I IFN signaling for Tr1 cell development was confirmed in vivo using a preclinical malaria model. [CD4.sup.+] T cell sensitivity to STING phosphorylation was increased in healthy volunteers following P. falciparum infection, particularly in Tr1 cells. These findings identified STING expressed by [CD4.sup.+] T cells as an important mediator of type I IFN production and Tr1 cell development and activation during malaria., Introduction Malaria is a devastating human disease of global importance. It not only caused an estimated 247 million cases and 619,000 deaths in 2021, but also promoted poverty by imposing [...]

Maintaining high-affinity antibodies after vaccination may be important for long-lasting immunity to malaria, but data on induction and kinetics of affinity is lacking. In a phase 1 malaria vaccine trial, antibody affinity increased following a second vaccination but declined substantially over 12 months, suggesting poor maintenance of high-affinity antibodies. Clinical Trials Registration Australian New Zealand Clinical Trials Registry ACTRN12607000552482. [ABSTRACT FROM AUTHOR]

Background: The human peripheral nervous system embodies anatomical, physiologic, and diagnostic perplexities that remain unexplained. Yet in the course of human history, there are no mechanisms, such as computed tomography (CT) or radiography, by which to image the peripheral nervous system in vivo using a contrast agent that is identified by ionizing radiation, which would aid in surgical navigation, diagnostic radiology, and basic science thereof. Methods: A novel class of contrast was created by linking iodine to lidocaine. The radiodensity of 0.5% experimental contrast molecule was compared with a control of 1% lidocaine by placing 1.5-mL aliquots of each liquid into centrifuge tubes and performing micro–computed tomography (micro-CT) synchronously under identical settings. Physiologic binding to the sciatic nerve was evaluated by injecting 10 mg of the experimental contrast and 10 mg of the control into the contralateral sciatic nerve, and documenting loss of hindlimb function and recovery. In vivo visualization of the sciatic nerve was evaluated by injecting 10 mg of experimental contrast or control into either sciatic nerve and imaging the hindlimbs under identical conditions using micro-CT. Results: The mean Hounsfield unit of the contrast was 56.09 compared with −0.48 for control (116-fold increase, P =.0001). Hindlimb paresis revealed similar degree of paresis, baseline recovery, and time to recovery. In vivo enhancement between the contralateral sciatic nerves was similar. Conclusion: Iodinated lidocaine offers a viable mechanism for in vivo peripheral nerve imaging using CT; however, it requires modification to improve in vivo radiodensity. [ABSTRACT FROM AUTHOR]

Background: Infections with soil-transmitted helminths (STH) and schistosomiasis (SCH) result in a significant global health burden, particularly in rural communities in low and middle-income countries. While microscopy remains the primary diagnostic method for STH and SCH in resource-limited settings, nucleic acid amplification tests (NAATs) are gaining prominence as tools for evaluation of public health control programs in endemic countries, and individual diagnosis in high-income countries. Despite the high sensitivity and specificity of NAATs, previous research has highlighted inter-laboratory variations, both in technical and clinical performance, justifying the need for continuous proficiency testing. Methodology: Results from 5 rounds over a 5-year period of the so far only longitudinal international Helminth External Molecular Quality Assessment Scheme (HEMQAS), coordinated by the Dutch Foundation for Quality Assessment in Medical Laboratories (SKML), were examined in order to (i) assess the diagnostic proficiency of laboratories in detecting helminths in stool and (ii) identify potential factors contributing to variations in performance. Outcome and conclusions: Thirty-six laboratories, from 18 countries and 5 continents, participated in HEMQAS. The overall diagnostic performances were satisfying, with remarkably low numbers (<2%) of false-positive results. False-negative results were more often reported for stool (15%) than for DNA (5%) samples. False-negative results varied largely between targets (the highest number (29%) for Trichuris trichiura). Twenty-five laboratories provided a sufficient number of results for a robust comparison between participating laboratories, which confirmed substantial inter-laboratory variability in quantitative NAAT results (Cq-values). This variability likely arises from differences in pre-treatment, DNA isolation and DNA-target amplification procedures. This study emphasizes the complexity of molecular diagnosis for STH and SCH, highlighting the critical role of proper stool preparation and DNA isolation methods. The results underscore the necessity for laboratory professionals and public health decision-makers to recognize these complexities and continuously undertake external quality assessment schemes to ensure accurate and reliable performance in molecular diagnosis. Author summary: Parasitic worms cause significant global health challenges, particularly in rural communities in low and middle-income countries. Laboratory tests that detect parasite DNA in human stool are increasingly being used for the diagnosis of parasitic worm infections. While parasite DNA detection can be an excellent diagnostic tool, its performance in clinical practice varies considerably, as demonstrated by previous research. To ensure the quality in diagnostic testing of these parasitic worms, it is important that laboratories evaluate the diagnostic performance of their DNA-based tests by participating in a so-called external quality assessment scheme (EQAS). This study, focusing on the first five-yearly rounds of the so far only longitudinal international EQAS to date, reveals that quantitative DNA detection results are not directly comparable across laboratories due to substantial inter-laboratory variability. This variability mainly stems from differences in pre-treatment and DNA isolation protocols, and to a lesser extent from differences in DNA target amplification procedures. Furthermore, the study underscores the complexity of molecular diagnosis for parasitic worms in clinical practice and the necessity for laboratories to engage in EQAs to guarantee the proper functioning of these diagnostic tests. [ABSTRACT FROM AUTHOR]

Although disturbance is considered a major driver of plant invasions across many systems, our understanding of the mechanisms by which disturbance mediates understorey invasions in natural forests is limited.We used a national natural forest inventory dataset spanning New Zealand's wide climatic and soil fertility gradients to disentangle disturbance‐mediated community characteristics driving abundance, species richness and functional composition of understorey plant invasions.Disturbance‐mediated declines in canopy tree abundance and increases in soil fertility and pH increased non‐native plant richness and cover relative to co‐occurring native plant assemblages. Cover of non‐native species also increased with proximity to anthropogenic land cover.Non‐native plant assemblages had higher community‐weighted mean (CWM) values for specific leaf area (SLA) but lower CWM values for height and woodiness relative to native assemblages irrespective of disturbance. However, greater nearby anthropogenic land cover drove increased woodiness in non‐native assemblages but decreased woodiness in co‐occurring native assemblages.Synthesis: Our study provides the first national‐scale evidence that canopy disturbance effects on soil properties increase both richness and abundance of non‐native plants in natural forest understories. We also revealed functional trait differences between native and non‐native assemblages (SLA in particular), which could alter fundamental forest ecosystem processes like litter decomposition and nutrient cycling. Finally, landscape‐scale anthropogenic impacts may exacerbate forest invasions by increasing non‐native abundance and favouring woody invaders, which may achieve dominance in future forest communities over the longer‐term. [ABSTRACT FROM AUTHOR]

Interactions between and within abiotic and biotic processes generate nonadditive density-dependent effects on species performance that can vary in strength or direction across environments. If ignored, nonadditivities can lead to inaccurate predictions of species responses to environmental and compositional changes. While there are increasing empirical efforts to test the constancy of pairwise biotic interactions along environmental and compositional gradients, few assess both simultaneously. Using a nationwide forest inventory that spans broad ambient temperature and moisture gradients throughout New Zealand, we address this gap by analyzing the diameter growth of six focal tree species as a function of neighbor densities and climate, as well as neighbor × climate and neighbor × neighbor statistical interactions. The most complex model featuring all interaction terms had the highest predictive accuracy. Compared with climate variables, biotic interactions typically had stronger effects on diameter growth, especially when subjected to nonadditivities from local climatic conditions and the density of intermediary species. Furthermore, statistically strong (or weak) nonadditivities could be biologically irrelevant (or significant) depending on whether a species pair typically interacted under average or more extreme conditions. Our study highlights the importance of considering both the statistical potential and the biological relevance of nonadditive biotic interactions when assessing species performance under global change. [ABSTRACT FROM AUTHOR]

Background: There is no study to date that has examined the association between history of abuse and adaptive functioning deficits in youth with co-occurring and psychotic disorders or mood disorders. Method: This study used a retrospective chart review of 98 youth under the age of 18 (Mean age = 16.06 years) with co-occurring intellectual impairment (Mean IQ = 63.9) and psychotic disorders, mood disorders, or other psychiatric disorders. Using multimediation models in the path analytic framework, this study examined the relationships between psychiatric diagnosis (based on DSM-IV criteria), cognitive functioning (Full Scale IQ Scores), adaptive functioning (Socialization, Communication, Motor Skills, Daily Living Skills), and the presence of the history of physical, sexual, and/or emotional abuse/neglect. Results: A very high incidence of all three forms of abuse was present in the study sample, with more than three-quarters of the youth having experienced at least one form of abuse and more than half having experienced two or the three forms of abuse. A history of sexual abuse was significantly and directly associated with an increased incidence of mood disorders. Mood disorders were the strongest predictors of adaptive functioning deficits. Youth with schizophrenia spectrum disorder scored significantly lower in communication skills than those with bipolar disorder. Conclusion: Results are discussed in terms of the need for treatment studies and further investigations of the relationship between childhood maltreatment and adaptive functioning in youth with intellectual impairment and psychiatric disorders.

Control of intracellular parasites responsible for malaria requires host IFN-[[gamma].sup.+]T-[bet.sup.+][CD4.sup.+] T cells (Th1 cells) with IL-10 produced by Th1 cells to mitigate the pathology induced by this inflammatory response. However, these IL-10-producing Th1 (induced type I regulatory [Tr1]) cells can also promote parasite persistence or impair immunity to reinfection or vaccination. Here, we identified molecular and phenotypic signatures that distinguished IL-10Th1 cells from IL-[10.sup.+]Tr1 cells in Plasmodium falciparum-infected people who participated in controlled human malaria infection studies, as well as C57BL/6 mice with experimental malaria caused by P. berghei ANKA. We also identified a conserved Tr1 cell molecular signature shared between patients with malaria, dengue, and graft-versus-host disease. Genetic manipulation of primary human [CD4.sup.+] T cells showed that the transcription factor cMAF played an important role in the induction of IL-10, while BLIMP-1 promoted the development of human [CD4.sup.+] T cells expressing multiple coinhibitory receptors. We also describe heterogeneity of Tr1 cell coinhibitory receptor expression that has implications for targeting these molecules for clinical advantage during infection. Overall, this work provides insights into [CD4.sup.+] T cell development during malaria that offer opportunities for creation of strategies to modulate [CD4.sup.+] T cell functions and improve antiparasitic immunity., Introduction Under homeostatic conditions, inflammation is controlled by immunoregulatory networks that prevent disease (1). These networks comprise interactions among specialized immune cells, parenchymal cells, and tissue-specific microbiomes (2, 3). Following [...]

Stainless-steel screws are commonly used for fragment fixation during periacetabular osteotomy (PAO) at our institutions. Titanium is reserved for patients with documented nickel allergies. Titanium screws possess a significantly lower Young's modulus than stainless steel and, therefore, potentially less resistance to physiologic loading. Thus, we hypothesized that the use of titanium screws might be associated with changes in acetabular correction prior to healing. The aim of this study was to compare the maintenance of acetabular correction following PAO using stainless-steel or titanium screws. A documented nickel allergy was confirmed with an allergy specialist. Patients' age at surgery, gender and BMI were collected. The lateral center–edge angle of Wiberg (LCEA), medial center–edge angle (MCEA), anterior wall index (AWI), posterior wall index (PWI) and Tönnis angle were measured. The delta value for radiographic parameters was calculated as the difference between values immediately post-operation and at 6 months post-operation. Only age at surgery (P  < 0.001) and the pre-operative LCEA (P  = 0.013) were significantly different between groups (Tables I and II). The remaining pre- and post-operative radiological measurements were similar (Table II). Comparison of delta values at 6 months follow-up indicated no significant differences between screw types (Table III). No patients in the titanium group had a trans-iliac retrograde screw included in their construct (P  = 0.003). All patients healed from their osteotomies. The use of titanium screws in patients with an allergy to nickel was not associated with differences in acetabular correction or the rate of osseous union rates despite its lower inherent mechanical properties. [ABSTRACT FROM AUTHOR]

Critical scientific questions remain regarding infection with Mycobacterium ulcerans, the organism responsible for the neglected tropical disease, Buruli ulcer (BU). A controlled human infection model has the potential to accelerate our knowledge of the immunological correlates of disease, to test prophylactic interventions and novel therapeutics. Here we present microbiological evidence supporting M. ulcerans JKD8049 as a suitable human challenge strain. This non-genetically modified Australian isolate is susceptible to clinically relevant antibiotics, can be cultured in animal-free and surfactant-free media, can be enumerated for precise dosing, and has stable viability following cryopreservation. Infectious challenge of humans with JKD8049 is anticipated to imitate natural infection, as M. ulcerans JKD8049 is genetically stable following in vitro passage and produces the key virulence factor, mycolactone. Also reported are considerations for the manufacture, storage, and administration of M. ulcerans JKD8049 for controlled human infection. Non-technical author summary: In this paper, we progress our research towards establishing a controlled human infection model (CHIM) of Buruli ulcer, caused by Mycobacterium ulcerans. It is crucial that the challenge agent used for such experiments is thoroughly characterised; not only is this important to ensure standardisation between participants, but also to reinforce their safety. Using established criteria, we systematically demonstrate why the isolate M. ulcerans JKD8049 may be a suitable challenge strain. This strain is non-genetically modified, susceptible to antibiotics, can be cultured in relatively simple media, and can be filtered and preserved as individual bacteria to ensure accurate dosing of participants. Even after repeatedly culturing the organism for months, it remains genetically stable, so significant mutations are not expected to develop during manufacture. After preserving the isolate at -80°C, it can be revived and diluted for human inoculation at very low doses. Importantly, it produces the toxin mycolactone, so it is expected to recreate typical Buruli ulcer disease in participants, which will be important to properly test vaccines and other therapeutics. We also demonstrate a set of principles to ensure the produced batch is free from contamination. [ABSTRACT FROM AUTHOR]