Mapping the differential impact of spontaneous and conversational laughter on brain and mind: an fMRI study in autism.

Spontaneous and conversational laughter are important socio-emotional communicative signals. Neuroimaging findings suggest that non-autistic people engage in mentalizing to understand the meaning behind conversational laughter. Autistic people may thus face specific challenges in processing conversational laughter, due to their mentalizing difficulties. Using fMRI, we explored neural differences during implicit processing of these two types of laughter. Autistic and non-autistic adults passively listened to funny words, followed by spontaneous laughter, conversational laughter, or noise-vocoded vocalizations. Behaviourally, words plus spontaneous laughter were rated as funnier than words plus conversational laughter, and the groups did not differ. However, neuroimaging results showed that non-autistic adults exhibited greater medial prefrontal cortex activation while listening to words plus conversational laughter, than words plus genuine laughter, while autistic adults showed no difference in medial prefrontal cortex activity between these two laughter types. Our findings suggest a crucial role for the medial prefrontal cortex in understanding socio-emotionally ambiguous laughter via mentalizing. Our study also highlights the possibility that autistic people may face challenges in understanding the essence of the laughter we frequently encounter in everyday life, especially in processing conversational laughter that carries complex meaning and social ambiguity, potentially leading to social vulnerability. Therefore, we advocate for clearer communication with autistic people.

Differential modulation of allergic rhinitis nasal transcriptome by dupilumab and allergy immunotherapy.

BACKGROUND: Nasal epithelial cells are important regulators of barrier function and immune signaling; however, in allergic rhinitis (AR) these functions can be disrupted by inflammatory mediators. We aimed to better discern AR disease mechanisms using transcriptome data from nasal brushing samples from individuals with and without AR. METHODS: Data were drawn from a feasibility study of individuals with and without AR to Timothy grass and from a clinical trial evaluating 16 weeks of treatment with the following: dupilumab, a monoclonal antibody that binds interleukin (IL)-4Rα and inhibits type 2 inflammation by blocking signaling of both IL-4/IL-13; subcutaneous immunotherapy with Timothy grass (SCIT), which inhibits allergic responses through pleiotropic effects; SCIT + dupilumab; or placebo. Using nasal brushing samples from these studies, we defined distinct gene signatures in nasal tissue of AR disease and after nasal allergen challenge (NAC) and assessed how these signatures were modulated by study drug(s). RESULTS: Treatment with dupilumab (normalized enrichment score [NES] = -1.73, p = .002) or SCIT + dupilumab (NES = -2.55, p < .001), but not SCIT alone (NES = +1.16, p = .107), significantly repressed the AR disease signature. Dupilumab (NES = -2.55, p < .001), SCIT (NES = -2.99, p < .001), and SCIT + dupilumab (NES = -3.15, p < .001) all repressed the NAC gene signature. CONCLUSION: These results demonstrate type 2 inflammation is an important contributor to the pathophysiology of AR disease and that inhibition of the type 2 pathway with dupilumab may normalize nasal tissue gene expression.

A qualitative exploration of 40 Hz sound and music for older adults with mild cognitive impairment.

Emerging evidence suggests that 40 Hz auditory stimulation may benefit cognition. Nested within a randomized crossover trial, this qualitative study evaluates the acceptability and experience of three auditory interventions-self-selected music, 40 Hz sound, and a novel combination, termed 40 Hz music-in individuals with Mild Cognitive Impairment (MCI). Semi-structured interviews were conducted with individuals with MCI post-intervention exposure. Findings indicated a preference for self-selected music due to its memory-boosting and emotional benefits, while responses to 40 Hz sound were mixed, with several participants reporting discomfort. The composite 40 Hz music intervention showed promise, striking a balance by enhancing user experience and mitigating the 40 Hz sound's negative aspects. Engagement was influenced by personal music interests, listening routines, and support networks. This study highlights the potential of integrating 40 Hz sound with personalized music to offer a more acceptable 40 Hz auditory intervention for cognition in older adults with MCI.

Novel Human Parechovirus 3 Diversity, Recombination, and Clinical Impact Across 7 Years: An Australian Story.

BACKGROUND: A novel human parechovirus 3 Australian recombinant (HPeV3-AR) strain emerged in 2013 and coincided with biennial outbreaks of sepsis-like illnesses in infants. We evaluated the molecular evolution of the HPeV3-AR strain and its association with severe HPeV infections. METHODS: HPeV3-positive samples collected from hospitalized infants aged 5-252 days in 2 Australian states (2013-2020) and from a community-based birth cohort (2010-2014) were sequenced. Coding regions were used to conduct phylogenetic and evolutionary analyses. A recombinant-specific polymerase chain reaction was designed and utilized to screen all clinical and community HPeV3-positive samples. RESULTS: Complete coding regions of 54 cases were obtained, which showed the HPeV3-AR strain progressively evolving, particularly in the 3' end of the nonstructural genes. The HPeV3-AR strain was not detected in the community birth cohort until the initial outbreak in late 2013. High-throughput screening showed that most (>75%) hospitalized HPeV3 cases involved the AR strain in the first 3 clinical outbreaks, with declining prevalence in the 2019-2020 season. The AR strain was not statistically associated with increased clinical severity among hospitalized infants. CONCLUSIONS: HPeV3-AR was the dominant strain during the study period. Increased hospital admissions may have been from a temporary fitness advantage and/or increased virulence.

REGN1908/1909 prevented cat allergen-induced early asthmatic responses in an environmental exposure unit.

BACKGROUND: The dominant allergen in cat dander, Felis domesticus allergen 1 (Fel d 1), is a persistent trigger for allergic rhinitis and asthma symptoms. OBJECTIVE: We evaluated the efficacy of Fel d 1 monoclonal antibodies (REGN1908/1909) in preventing cat allergen-induced early asthmatic responses (EARs) in cat-allergic patients with mild asthma. METHODS: Patients were randomized to single-dose REGN1908/1909 600 mg (n = 29) or placebo (n = 27). The FEV1 was measured for up to 4 hours in a cat allergen environmental exposure unit up to 85 days after dosing. Assessments included between-group differences in change from baseline in FEV1 area under the curve (AUC; 0-2 hours) and incidence of EAR (FEV1 reduction ≥20%). TRIAL REGISTRATION: NCT03838731. RESULTS: Single-dose REGN1908/1909 significantly prevented reductions in FEV1 on days 8, 29, 57, and 85. Most REGN1908/1909 patients did not have an EAR by 4 hours (the last time point tested). In contrast, placebo-treated patients experienced a ≥20% mean FEV1 reduction on days 8, 29, 57, and 85 after dosing, with most experiencing an EAR within 1 hour. REGN1908/1909-treated patients tolerated 3-fold higher allergen quantities (P < .05 at all time points) versus placebo. REGN1908/1909 substantially reduced skin test reactivity to cat allergen versus placebo at all time points tested (nominal P < .001). REGN1908/1909 was generally well tolerated; no serious adverse events or deaths were reported. CONCLUSION: Single-dose REGN1908/1909 significantly prevented reductions in FEV1 in cat-allergic patients with mild asthma on cat allergen environmental exposure unit exposure at 8 days and up to 85 days after dose.

Novel antibody cocktail targeting Bet v 1 rapidly and sustainably treats birch allergy symptoms in a phase 1 study.

BACKGROUND: The efficacy of an allergen-specific IgG cocktail to treat cat allergy suggests that allergen-specific IgG may be a major protective mechanism elicited by allergen immunotherapy. OBJECTIVES: Extending these findings, we tested a Bet v 1-specific antibody cocktail in birch-allergic subjects. METHODS: This was a phase 1, randomized, double-blind, study with 2 parts. Part A administered ascending doses of the Bet v 1-specific antibody cocktail REGN5713/14/15 (150-900 mg) in 32 healthy adults. Part B administered a single subcutaneous 900-mg dose or placebo in 64 birch-allergic subjects. Total nasal symptom score response to titrated birch extract nasal allergen challenge and skin prick test (SPT) with birch and alder allergen were assessed at screening and days 8, 29, 57, and 113 (SPT only); basophil activation tests (n = 26) were conducted. RESULTS: Single-dose REGN5713/14/15 significantly reduced total nasal symptom score following birch nasal allergen challenge relative to baseline. Differences in total nasal symptom score areas under the curve (0-1 hour) for subjects treated with REGN5713/14/15 versus those given placebo (day 8: -1.17, P = .001; day 29: -1.18, P = .001; day 57: -0.85, P = .024) and titration SPT with birch difference in area under the curve of mean wheal diameters for subjects treated with REGN5713/14/15 versus placebo (all P < .001) were sustained for ≥2 months; similar results were observed with alder SPT. REGN5713/14/15 was well tolerated. Basophil responsiveness to birch-related allergens was significantly decreased in subjects treated with REGN5713/14/15 versus those given placebo on days 8, 57, and 113 (all P < .01). CONCLUSIONS: Single-dose REGN5713/14/15 was well tolerated and provided a rapid (1 week) and durable (2 months) reduction in allergic symptoms after birch allergen nasal allergen challenge, potentially offering a new paradigm for the treatment of birch allergy symptoms.

Circular Upcycling of Bottlebrush Thermosets.

The inability to re-process thermosets hinders their utility and sustainability. An ideal material should combine closed-loop recycling and upcycling capabilities. This trait is realized in polydimethylsiloxane bottlebrush networks using thermoreversible Diels-Alder cycloadditions to enable both reversible disassembly into a polymer melt and on-demand reconfiguration to an elastomer of either lower or higher stiffness. The crosslink density was tuned by loading the functionalized networks with a controlled fraction of dormant crosslinkers and crosslinker scavengers, such as furan-capped bis-maleimide and anthracene, respectively. The resulting modulus variations precisely followed the stoichiometry of activated furan and maleimide moieties, demonstrating the lack of side reactions during reprocessing. The presented circularity concept is independent from the backbone or side chain chemistry, making it potentially applicable to a wide range of brush-like polymers.

Cat allergen exposure in a naturalistic exposure chamber: A prospective observational study in cat-allergic subjects.

BACKGROUND: To determine the proportion and reproducibility of cat-allergic mild asthmatics with early asthmatic response (EAR) during cat allergen exposure in a naturalistic exposure chamber (NEC). METHODS: This was a prospective, observational study in 30 cat-allergic mild asthmatics who received two 180-min cat-allergen (Felis domesticus allergen 1 [Fel d 1]) challenges 27 days apart in an NEC. RESULTS: An EAR (≥20% reduction from baseline in forced expiratory volume in 1 s [FEV1]) was observed in 67% and 52% of subjects at first and second NEC exposure, respectively, with similar median time to EAR; 44% of subjects had an EAR on days 1 and 28. Late asthmatic response (≥15% reduction in FEV1 within 24 h of NEC exit) was observed in 33% of subjects following either exposure. Average FEV1 and total nasal symptom score during NEC exposure were highly correlated within subjects between NEC exposures (r = 0.91, p < 0.0001; r = 0.73, p < 0.001), but total ocular symptom score was not. Time to EAR, but not average FEV1, was significantly associated with NEC Fel d 1 concentration, which was variable. There were no serious adverse events; 12/30 subjects experienced 20 adverse events (including asthma, 10%; headache, 10%). CONCLUSIONS: The NEC model demonstrates that average FEV1 change is highly reproducible and has a low correlation with cat allergen levels. However, time to EAR and incidence of EAR are less reproducible and are highly correlated with NEC allergen levels. Average FEV1, rather than incidence of EAR or time to EAR, could be considered as an endpoint for interventional trials testing cat-specific anti-allergy therapies using an NEC.

The Long Noncoding RNA RP11-728F11.4 Promotes Atherosclerosis.

OBJECTIVE: Noncoding RNAs are emerging as important players in gene regulation and cardiovascular diseases. Their roles in the pathogenesis of atherosclerosis are not fully understood. The purpose of this study was to determine the role played by a previously uncharacterized long noncoding RNA, RP11-728F11.4, in the development of atherosclerosis and the mechanisms by which it acts. Approach and Results: Expression microarray analysis revealed that atherosclerotic plaques had increased expression of RP11-728F11.4 as well as the cognate gene FXYD6 (FXYD domain containing ion transport regulator 6), which encodes a modulator of Na+/K+-ATPase. In vitro experiments showed that RP11-728F11.4 interacted with the RNA-binding protein EWSR1 (Ewings sarcoma RNA binding protein-1) and upregulated FXYD6 expression. Lentivirus-induced overexpression of RP11-728F11.4 in cultured monocytes-derived macrophages resulted in higher Na+/K+-ATPase activity, intracellular cholesterol accumulation, and increased proinflammatory cytokine production. The effects of RP11-728F11.4 were enhanced by siRNA-mediated knockdown of EWSR1 and reduced by downregulation of FXYD domain containing ion transport regulator 6. In vivo experiments in apoE knockout mice fed a Western diet demonstrated that RP11-728F11.4 increased proinflammatory cytokine production and augmented atherosclerotic lesions. CONCLUSIONS: RP11-728F11.4 promotes atherosclerosis, with an influence on cholesterol homeostasis and proinflammatory molecule production, thus representing a potential therapeutic target. Graphic Abstract: A graphic abstract is available for this article.

Passive Prophylactic Administration with a Single Dose of Anti-Fel d 1 Monoclonal Antibodies REGN1908-1909 in Cat Allergen-induced Allergic Rhinitis: A Randomized, Double-Blind, Placebo-controlled Clinical Trial.

Rationale: Sensitization to Fel d 1 (Felis domesticus allergen 1) contributes to persistent allergic rhinitis and asthma. Existing treatment options for cat allergy, including allergen immunotherapy, are only moderately effective, and allergen immunotherapy has limited use because of safety concerns. Objectives: To explore the relationship among the pharmacokinetic, clinical, and immunological effects of anti-Fel d 1 monoclonal antibodies (REGN1908-1909) in patients after treatment. Methods: Patients received REGN1908-1909 (n = 36) or a placebo (n = 37) in a phase 1b study. Fel d 1-induced basophil and IgE-facilitated allergen binding responses were evaluated at baseline and Days 8, 29, and 85. Cytokine and chemokine concentrations in nasal fluids were measured, and REGN1908-1909 inhibition of allergen-IgE binding in patient serum was evaluated. Measurements and Main Results: Peak serum drug concentrations were concordant with maximal observed clinical response. The anti-Fel d 1 IgE/cat dander IgE ratio in pretreatment serum correlated with Total Nasal Symptom Score improvement. The allergen-neutralizing capacity of REGN1908-1909 was observed in serum and nasal fluid and was detected in an inhibition assay. Type 2 cytokines (IL-4, IL-5, and IL-13) and chemokines (CCL17/TARC, CCL5/RANTES [regulated upon activation, normal T-cell expressed and secreted]) in nasal fluid were inhibited in REGN1908-1909-treated patients compared with placebo (P < 0.05 for all); IL-13 and IL-5 concentrations correlated with Total Nasal Symptom Score improvement. Ex vivo assays demonstrated that REGN1908 and REGN1909 combined were more potent than each alone for inhibiting FcεRI- and FcεRII (CD23)-mediated allergic responses and subsequent T-cell activation. Conclusions: A single, passive-dose administration of Fel d 1-neutralizing IgG antibodies improved nasal symptoms in cat-allergic patients and was underscored by suppression of FcεRI-, FcεRII-, and T-helper cell type 2-mediated allergic responses. Clinical trial registered with www.clinicaltrials.gov (NCT02127801).

The role of the histone H3 variant CENPA in prostate cancer.

Overexpression of centromeric proteins has been identified in a number of human malignancies, but the functional and mechanistic contributions of these proteins to disease progression have not been characterized. The centromeric histone H3 variant centromere protein A (CENPA) is an epigenetic mark that determines centromere identity. Here, using an array of approaches, including RNA-sequencing and ChIP-sequencing analyses, immunohistochemistry-based tissue microarrays, and various cell biology assays, we demonstrate that CENPA is highly overexpressed in prostate cancer in both tissue and cell lines and that the level of CENPA expression correlates with the disease stage in a large cohort of patients. Gain-of-function and loss-of-function experiments confirmed that CENPA promotes prostate cancer cell line growth. The results from the integrated sequencing experiments suggested a previously unidentified function of CENPA as a transcriptional regulator that modulates expression of critical proliferation, cell-cycle, and centromere/kinetochore genes. Taken together, our findings show that CENPA overexpression is crucial to prostate cancer growth.

Sex difference in kidney electrolyte transport III: Impact of low K intake on thiazide-sensitive cation excretion in male and female mice.

We compared the regulation of the NaCl cotransporter (NCC) in adaptation to a low-K (LK) diet in male and female mice. We measured hydrochlorothiazide (HCTZ)-induced changes in urine volume (UV), glomerular filtration rate (GFR), absolute (ENa, EK), and fractional (FENa, FEK) excretion in male and female mice on control-K (CK, 1% KCl) and LK (0.1% KCl) diets for 7 days. With CK, NCC-dependent ENa and FENa were larger in females than males as observed previously. However, with LK, HCTZ-induced ENa and FENa increased in males but not in females, abolishing the sex differences in NCC function as observed in CK group. Despite large diuretic and natriuretic responses to HCTZ, EK was only slightly increased in response to the drug when animals were on LK. This suggests that the K-secretory apparatus in the distal nephron is strongly suppressed under these conditions. We also examined LK-induced changes in Na transport protein expression by Western blotting. Under CK conditions females expressed more NCC protein, as previously reported. LK doubled both total (tNCC) and phosphorylated NCC (pNCC) abundance in males but had more modest effects in females. The larger effect in males abolished the sex-dependence of NCC expression, consistent with the measurements of function by renal clearance. LK intake did not change NHE3, NHE2, or NKCC2 expression, but reduced the amount of the cleaved (presumably active) form of γENaC. LK reduced plasma K to lower levels in females than males. These results indicated that males had a stronger NCC-mediated adaptation to LK intake than females.

Clinical and immunological evaluation of cat-allergic asthmatics living with or without a cat.

BACKGROUND: Characterising the clinical and immunological impact of daily cat exposure in cat-allergic subjects with asthma who live with cats (WC) and those who do not (WoC) may provide understanding of the drivers of the allergic response. METHODS: Clinical and immunological characteristics (skin prick test, spirometry, symptom assessments, immunological markers) were compared between asthmatic subjects WC (n = 10) and WoC (n = 9). RESULTS: WC subjects had greater use of long-acting beta agonists (p < .05) and high-potency corticosteroids. No differences were observed in lung function, nasal and ocular symptoms, or asthma control between the groups. Cat dander- and Fel d 1-specific IgG4 concentrations were higher in WC than WoC subjects (both p < .05). Total IgE and cat dander-, Fel d 1- and Fel d 7-specific IgE concentrations were similar, but Fel d 4-sIgE was higher in WC subjects (p < .05) versus WoC. Basophil sensitivity to cat dander extract and Fel d 1 was lower in WC versus WoC subjects (p < .05) and correlated with higher IgG4 concentrations (r = 0.63; p = .009). Fel d 1-specific CD4+ T-cell responses polarised toward Th2A responses in WC versus WoC subjects; Fel d 1-specific IgE correlated with surface expression of CRTH2 and CD200R (both p ≤ .05). CONCLUSION: Immunological differences observed in WC versus WoC did not reflect clinical tolerance with natural cat exposure. The ability to live with a cat despite allergy could be driven by higher preventative medication use. This study may support design of novel therapeutics for allergy management.

Analytical validation of a real-time hydrolysis probe PCR assay for quantifying Plasmodium falciparum parasites in experimentally infected human adults.

BACKGROUND: Volunteer infection studies have become a standard model for evaluating drug efficacy against Plasmodium infections. Molecular techniques such as qPCR are used in these studies due to their ability to provide robust and accurate estimates of parasitaemia at increased sensitivity compared to microscopy. The validity and reliability of assays need to be ensured when used to evaluate the efficacy of candidate drugs in clinical trials. METHODS: A previously described 18S rRNA gene qPCR assay for quantifying Plasmodium falciparum in blood samples was evaluated. Assay performance characteristics including analytical sensitivity, reportable range, precision, accuracy and specificity were assessed using experimental data and data compiled from phase 1 volunteer infection studies conducted between 2013 and 2019. Guidelines for validation of laboratory-developed molecular assays were followed. RESULTS: The reportable range was 1.50 to 6.50 log10 parasites/mL with a limit of detection of 2.045 log10 parasites/mL of whole blood based on a parasite diluted standard series over this range. The assay was highly reproducible with minimal intra-assay (SD = 0.456 quantification cycle (Cq) units [0.137 log10 parasites/mL] over 21 replicates) and inter-assay (SD = 0.604 Cq units [0.182 log10 parasites/mL] over 786 qPCR runs) variability. Through an external quality assurance program, the QIMR assay was shown to generate accurate results (quantitative bias + 0.019 log10 parasites/mL against nominal values). Specificity was 100% after assessing 164 parasite-free human blood samples. CONCLUSIONS: The 18S rRNA gene qPCR assay is specific and highly reproducible and can provide reliable and accurate parasite quantification. The assay is considered fit for use in evaluating drug efficacy in malaria clinical trials.

Rapid detection of NDM and VIM carbapenemase encoding genes by recombinase polymerase amplification and lateral flow-based detection.

Carbapenemase-producing organisms (CPOs) pose a serious clinical threat and rapid detection tools are essential to aid in patient management. We developed rapid and simple molecular tests to detect blaNDM-type and blaVIM-type carbapenemase genes using recombinase polymerase amplification (RPA) combined with a lateral flow detection. The tests could provide results in approximately 15 min when using DNA extracts, with limits of detection of 9.2 copies/µl for the blaNDM-type assay and 7.5 copies/µl for blaVIM-type assay, and successfully detected all isolates harbouring the carbapenemase encoding genes in a panel of 57 isolates. These RPA tests may be suitable for use in low-resource settings to tailor rapid implementation of infection control precautions and antibiotic stewardship.

Voice Assistants and Cancer Screening: A Comparison of Alexa, Siri, Google Assistant, and Cortana.

Despite increasing interest in how voice assistants like Siri or Alexa might improve health care delivery and information dissemination, there is limited research assessing the quality of health information provided by these technologies. Voice assistants present both opportunities and risks when facilitating searches for or answering health-related questions, especially now as fewer patients are seeing their physicians for preventive care due to the ongoing pandemic. In our study, we compared the 4 most widely used voice assistants (Amazon Alexa, Apple Siri, Google Assistant, and Microsoft Cortana) and their ability to understand and respond accurately to questions about cancer screening. We show that there are clear differences among the 4 voice assistants and that there is room for improvement across all assistants, particularly in their ability to provide accurate information verbally. In order to ensure that voice assistants provide accurate information about cancer screening and support, rather than undermine efforts to improve preventive care delivery and population health, we suggest that technology providers prioritize partnership with health professionals and organizations.

Environmental exposure unit simulates natural seasonal birch pollen exposures while maximizing change in allergic symptoms.

BACKGROUND: Birch pollen is a prevalent aeroallergen during the springtime allergy season. In field studies, variable allergen exposure and environmental factors can affect data quality while environmental exposure units (EEUs) deliver controlled, standardized, and reproducible allergen exposures. OBJECTIVE: To inform study design for EEU trials evaluating antiallergic therapies. METHODS: In this prospective study, 76 participants with birch allergy experienced 3 exposures to birch pollen: (1) an out-of-season EEU challenge (two 3-hour sessions on consecutive days); (2) a natural seasonal exposure; and (3) an in-season EEU challenge (3-hour exposure for 2 weeks after birch pollen season initiation). RESULTS: The total nasal symptom score, total ocular symptom score, and total symptom score (TSS = total nasal symptom score plus total ocular symptom score) were assessed every 30 minutes and daily during EEU and natural exposures. A high association between TSSs and day 2 of the out-of-season and in-season EEU challenges was noted, with a good association between the maximum TSS during the natural and in-season EEU challenges, and natural season and day 2 of the out-of-season EEU challenge (P < .001 for all). Participants had higher maximum change from the baseline TSS during day 2 of the out-of-season EEU challenge (12.4) vs the following: (1) first day (9.8); (2) in-season EEU challenge (8.4); and (3) natural seasonal exposure (7.6) (P < .001 for all). CONCLUSION: A strong association was seen between the presence of allergy symptoms and exposure to birch pollen in the EEU (maximum change in symptom scores during day 2) and in the field. A hybrid trial design may be useful to demonstrate the clinical efficacy of novel antiallergic therapies requiring fewer participants and shorter timelines and expediting treatment availability.

An Experimental Human Blood-Stage Model for Studying Plasmodium malariae Infection.

BACKGROUND: Plasmodium malariae is considered a minor malaria parasite, although its global disease burden is underappreciated. The aim of this study was to develop an induced blood-stage malaria (IBSM) model of P. malariae to study parasite biology, diagnostic assays, and treatment. METHODS: This clinical trial involved 2 healthy subjects who were intravenously inoculated with cryopreserved P. malariae-infected erythrocytes. Subjects were treated with artemether-lumefantrine after development of clinical symptoms. Prior to antimalarial therapy, mosquito-feeding assays were performed to investigate transmission, and blood samples were collected for rapid diagnostic testing and parasite transcription profiling. Serial blood samples were collected for biomarker analysis. RESULTS: Both subjects experienced symptoms and signs typical of early malaria. Parasitemia was detected 7 days after inoculation, and parasite concentrations increased until antimalarial treatment was initiated 25 and 21 days after inoculation for subjects 1 and 2 respectively (peak parasitemia levels, 174 182 and 50 291 parasites/mL, respectively). The parasite clearance half-life following artemether-lumefantrine treatment was 6.7 hours. Mosquito transmission was observed for 1 subject, while in vivo parasite transcription and biomarkers were successfully profiled. CONCLUSIONS: An IBSM model of P. malariae has been successfully developed and may be used to study the biology of, diagnostic testing for, and treatment of this neglected malaria species. CLINICAL TRIALS REGISTRATION: ACTRN12617000048381.

Parechovirus A Infections in Healthy Australian Children During the First 2 Years of Life: A Community-based Longitudinal Birth Cohort Study.

BACKGROUND: Hospital-based studies identify parechovirus (PeV), primarily PeV-A3, as an important cause of severe infections in young children. However, few community-based studies have been published and the true PeV infection burden is unknown. We investigated PeV epidemiology in healthy children participating in a community-based, longitudinal birth cohort study. METHODS: Australian children (n = 158) enrolled in the Observational Research in Childhood Infectious Diseases (ORChID) study were followed from birth until their second birthday. Weekly stool and nasal swabs and daily symptom diaries were collected. Swabs were tested for PeV by reverse-transcription polymerase chain reaction and genotypes determined by subgenomic sequencing. Incidence rate, infection characteristics, clinical associations, and virus codetections were investigated. RESULTS: PeV was detected in 1423 of 11 124 (12.8%) and 17 of 8100 (0.2%) stool and nasal swabs, respectively. Major genotypes among the 306 infection episodes identified were PeV-A1 (47.9%), PeV-A6 (20.1%), and PeV-A3 (18.3%). The incidence rate was 144 episodes (95% confidence interval, 128-160) per 100 child-years. First infections appeared at a median age of 8 (interquartile range, 6.0-11.7) months. Annual seasonal peaks changing from PeV-A1 to PeV-A3 were observed. Infection was positively associated with age ≥6 months, summer season, nonexclusive breastfeeding at age <3 months, and formal childcare attendance before age 12 months. Sole PeV infections were either asymptomatic (38.4%) or mild (32.7%), while codetection with other viruses in stool swabs was common (64.4%). CONCLUSIONS: In contrast with hospital-based studies, this study showed that diverse and dynamically changing PeV genotypes circulate in the community causing mild or subclinical infections in children.Parechovirus can cause severe illnesses in children. However, studies focus mainly on hospitalized populations. True disease burden in the community remains largely unknown. From our community-based cohort, we found diverse parechovirus genotypes in the community, causing mild or subclinical infections in children. CLINICAL TRIALS REGISTRATION: NCT01304914.

An Integrated Electrochemistry Approach to the Design and Synthesis of Polyhedral Noble Metal Nanoparticles.

The synthesis of shaped metal nanoparticles to meet the precise needs of emerging applications requires intentional synthetic design directed by fundamental chemical principles. We report an integrated electrochemistry approach to nanoparticle synthetic design that couples current-driven growth of metal nanoparticles on an electrode surface-in close analogy to standard colloidal synthesis-with electrochemical measurements of both electrochemical and colloidal nanoparticle growth. A simple chronopotentiometry method was used to translate an existing colloidal synthesis for corrugated palladium (Pd) nanoparticles to electrochemical growth on a glassy carbon electrode, with minimal modification to the growth solution. The electrochemical synthesis method was then utilized to produce large Pd icosahedra, a shape whose synthesis is challenging in a colloidal growth environment. This electrochemical synthesis for Pd icosahedra was used to develop a corresponding colloidal growth solution by tailoring a weak reducing agent to the measured potential profile of the electrochemical synthesis. Finally, measurements of colloidal syntheses were employed as guides for the directed design of electrochemical syntheses for Pd cubes and octahedra. Together, this work provides a cyclical approach to shaped nanoparticle design that allows for the optimization of nanoparticles grown via a colloidal approach with a chemical reducing agent or synthesized with an applied current on an electrode surface as well as subsequent bidirectional translation between the two methods. The enhanced chemical flexibility and direct tunability of this electrochemical method relative to combinatorial design of colloidal syntheses have the potential to accelerate the synthetic design process for noble metal nanoparticles with targeted morphologies.