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Abstract Release of Aedes aegypti mosquitoes infected with Wolbachia pipientis (wMel strain) is a biocontrol approach against Ae. aegypti-transmitted arboviruses. The Applying Wolbachia to Eliminate Dengue (AWED) cluster-randomised trial was conducted in Yogyakarta, Indonesia in 2018–2020 and provided pivotal evidence for the efficacy of wMel-Ae. aegypti mosquito population replacement in significantly reducing the incidence of virologically-confirmed dengue (VCD) across all four dengue virus (DENV) serotypes. Here, we sequenced the DENV genomes from 318 dengue cases detected in the AWED trial, with the aim of characterising DENV genetic diversity, measuring genotype-specific intervention effects, and inferring DENV transmission dynamics in wMel-treated and untreated areas of Yogyakarta. Phylogenomic analysis of all DENV sequences revealed the co-circulation of five endemic DENV genotypes: DENV-1 genotype I (12.5%) and IV (4.7%), DENV-2 Cosmopolitan (47%), DENV-3 genotype I (8.5%), and DENV-4 genotype II (25.7%), and one recently imported genotype, DENV-4 genotype I (1.6%). The diversity of genotypes detected among AWED trial participants enabled estimation of the genotype-specific protective efficacies of wMel, which were similar (± 10%) to the point estimates of the respective serotype-specific efficacies reported previously. This indicates that wMel afforded protection to all of the six genotypes detected in Yogyakarta. We show that within this substantial overall viral diversity, there was a strong spatial and temporal structure to the DENV genomic relationships, consistent with highly focal DENV transmission around the home in wMel-untreated areas and a near-total disruption of transmission by wMel. These findings can inform long-term monitoring of DENV transmission dynamics in Wolbachia-treated areas including Yogyakarta.

Abstract Light availability (LAv) dictates a variety of biological and ecological processes across a range of spatiotemporal scales. Quantifying the spatial pattern of LAv in three‐dimensional (3D) space can promote the understanding of microclimates that are critical to fine‐scale species distribution. However, there is still a lack of tools that are robust to evaluate spatiotemporal heterogeneity of LAv in forests. Here, we propose the Forest Light Analyzer python package (FLApy), an open‐source computational tool designed for the analysis of intra‐forest LAv variation across multiple spatial scales. FLApy is freely invoked by Python, facilitating the processing of LiDAR point cloud data into a 3D data container constructed by voxels, as well as traversal calculations related to the LAv regime by high performance synthetic hemispherical algorithm. Furthermore, FLApy incorporates 37 indicators, enabling users to expediently export and visualize LAv patterns and the evaluation of heterogeneity of LAv at two scales (voxel scale and 3D‐cluster scale) for a range of fine‐scale ecological study purposes. To validate the efficacy of the FLApy, we employed a simulated point cloud dataset that simulates forests (varying in canopy closure). Furthermore, to evaluate real world forest, we executed the standard workflow of FLApy utilizing drone‐derived data from three subtropical evergreen broad‐leaved forest dynamics plots within the Ailao Mountain Reserve. Our findings underscore that a series of indices derived from FLApy provide a robust characterization of light availability heterogeneity within diverse forest settings. Additionally, when juxtaposed with conventional monitoring techniques, the metrics offered by FLApy demonstrated better generality in our field assessments. FLApy offers ecologists a solution for rapid quantification of understory light 3D‐regimes across multiple scales, addressing the disparity between traditional manual approaches and the precision required for contemporary ecological studies. Moreover, FLApy provides robust support for the establishment and expansion of heterogeneity indices based on 3D micro‐environments, enhancing our understanding of the largely uncharted 3D structural patterns. Anticipated outcomes suggest that FLApy will enhance our knowledge concerning the intra‐forest climatic conditions into a 3D context, proving pivotal in the delineation of microhabitats and the development of detailed 3D‐scale species distribution models.

Aim: To examine speed and accuracy of newborn heart rate measurement by various assessment methods employed at birth. Methods: A search of Medline, SCOPUS, CINAHL and Cochrane was conducted between January 1, 1946, to until August 16, 2023. (CRD 42021283364) Study selection was based on predetermined criteria. Reviewers independently extracted data, appraised risk of bias and assessed certainty of evidence. Results: Pulse oximetry is slower and less precise than ECG for heart rate assessment. Both auscultation and palpation are imprecise for heart rate assessment. Other devices such as digital stethoscope, Doppler ultrasound, an ECG device using dry electrodes incorporated in a belt, photoplethysmography and electromyography are studied in small numbers of newborns and data are not available for extremely preterm or bradycardic newborns receiving resuscitation. Digital stethoscope is fast and accurate. Doppler ultrasound and dry electrode ECG in a belt are fast, accurate and precise when compared to conventional ECG with gel adhesive electrodes. Limitations: Certainty of evidence was low or very low for most comparisons. Conclusion: If resources permit, ECG should be used for fast and accurate heart rate assessment at birth. Pulse oximetry and auscultation may be reasonable alternatives but have limitations. Digital stethoscope, doppler ultrasound and dry electrode ECG show promise but need further study.

Abstract The intention-to-treat (ITT) analysis of the Applying Wolbachia to Eliminate Dengue (AWED) trial estimated a protective efficacy of 77.1% for participants resident in areas randomised to receive releases of wMel-infected Aedes aegypti mosquitoes, an emerging dengue preventive intervention. The limiting assumptions of ITT analyses in cluster randomised trials and the mobility of mosquitoes and humans across cluster boundaries indicate the primary analysis is likely to underestimate the full public health benefit. Using spatiotemporally-resolved data on the distribution of Wolbachia mosquitoes and on the mobility of AWED participants (n = 6306), we perform complier-restricted and per-protocol re-examinations of the efficacy of the Wolbachia intervention. Increased intervention efficacy was estimated in all analyses by the refined exposure measures. The complier-restricted analysis returned an estimated efficacy of 80.7% (95% CI 65.9, 89.0) and the per-protocol analysis estimated 82.7% (71.7, 88.4) efficacy when comparing participants with an estimated wMel exposure of $$\ge$$ ≥ 80% compared to those with

Abstract Across the cell cycle, mitochondrial dynamics are regulated by a cycling wave of actin polymerization/depolymerization. In metaphase, this wave induces actin comet tails on mitochondria that propel these organelles to drive spatial mixing, resulting in their equitable inheritance by daughter cells. In contrast, during interphase the cycling actin wave promotes localized mitochondrial fission. Here, we identify the F-actin nucleator/elongator FMNL1 as a positive regulator of the wave. FMNL1-depleted cells exhibit decreased mitochondrial polarization, decreased mitochondrial oxygen consumption, and increased production of reactive oxygen species. Accompanying these changes is a loss of hetero-fusion of wave-fragmented mitochondria. Thus, we propose that the interphase actin wave maintains mitochondrial homeostasis by promoting mitochondrial content mixing. Finally, we investigate the mechanistic basis for the observation that the wave drives mitochondrial motility in metaphase but mitochondrial fission in interphase. Our data indicate that when the force of actin polymerization is resisted by mitochondrial tethering to microtubules, as in interphase, fission results.

Primary fibroblasts from six individuals with CLN3-related conditions were used to generate induced pluripotent stem cell (iPSC) lines CHDTRi001-B, CHDTRi002-B, CHDTRi003-A, CHDTRi004-B, CHDTRi005-A, and CHDTRi006-E through the expression of four reprogramming factors: human OCT3/4, KLF4, SOX2, and c-MYC. The iPSC lines were characterized to confirm their pluripotency via immunocytochemistry, flow cytometry, and teratoma formation. Genomic stability, cell line identity, and CLN3 genotype were confirmed. These iPSC lines may be used as participant-derived experimental models for further investigation of CLN3, a rare, fatal, pediatric, blindness and neurodegenerative lysosomal disorder with no cure.

Morphological, gene sequence, host tissue tropism, and life cycle characteristics were utilized to describe the myxozoan, Myxobolus rasmusseni n. sp. from fathead minnow, Pimephales promelas, collected from reservoirs in southern Alberta. Results from serial histological sections of whole heads showed that myxospores were contained within irregular-shaped and sized coelozoic capsules (=plasmodia). Clusters of membrane-bound, myxospore-filled plasmodia filled the head cavities of juvenile fathead minnows, leading to the development of large, white, disfiguring lesions in mid to late summer. Bilateral exopthalmia (pop-eye disease) was a common outcome of M. rasmusseni n. sp. development. BLASTn search of a 1974 bp sequence of the 18S rDNA gene isolated from myxospores indicated that M. rasmusseni n. sp. was distinct from other coelozoic and histozoic Myxobolus spp. cataloged in GenBank. 18S rDNA gene sequences from triactinomyxon spores released from the oligochaete Tubifex were 100% identical to sequences from myxospores collected from syntopic fathead minnows. Results from a longitudinal survey of the 2020 cohort of fathead minnows showed that young-of-the-year are exposed at 1–5 mo and that 60–90% of these had developed myxospore-filled lesions approximately one year later. Data regarding potential sources and timing of M. rasmusseni n. sp. emergence in fathead minnow populations are needed.

Objective:The worldwide spread of SARS-CoV-2 and the resulting COVID-19 pandemic has been driven by international travel. This has led to the desire to develop surveillance approaches which can estimate the rate of import of pathogenic organisms across international borders. The aim of this study was to investigate the use of wastewater-based approaches for the surveillance of viral pathogens on commercial short-haul (3.5 h transit time) roll-on/roll-off passenger/freight ferries operating between the UK and the Republic of Ireland.MethodsSamples of toilet-derived wastewater (blackwater) were collected from two commercial ships over a 4-week period and analysed for SARS-CoV-2, influenza, enterovirus, norovirus, the faecal-marker virus crAssphage and a range of physical and chemical indicators of wastewater quality.ResultsA small proportion of the wastewater samples were positive for SARS-CoV-2 (8% of the total), consistent with theoretical predictions of detection frequency (4%–15% of the total) based on the national COVID-19 Infection Survey and defecation behaviour. In addition, norovirus was detected in wastewater at low frequency. No influenza A/B viruses, enterovirus or enterovirus D68 were detected throughout the study period.ConclusionWe conclude that testing of wastewater from ships that cross international maritime boundaries may provide a cost-effective and relatively unbiased method to estimate the flow of infected individuals between countries. The approach is also readily applicable for the surveillance of other disease-causing agents.

Background: Viremia is a critical factor in understanding the pathogenesis of dengue infection, but limited data exist on viremia kinetics. This study aimed to investigate the kinetics of viremia and its effects on subsequent platelet count, severe dengue, and plasma leakage. Methods: We pooled data from three studies conducted in Vietnam between 2000 and 2016, involving 2340 dengue patients with daily viremia measurements and platelet counts after symptom onset. Viremia kinetics were assessed using a random effects model that accounted for left-censored data. The effects of viremia on subsequent platelet count and clinical outcomes were examined using a landmark approach with a random effects model and logistic regression model with generalized estimating equations, respectively. The rate of viremia decline was derived from the model of viremia kinetics. Its effect on the clinical outcomes was assessed by logistic regression models. Results: Viremia levels rapidly decreased following symptom onset, with variations observed depending on the infecting serotype. DENV-1 exhibited the highest mean viremia levels during the first 5–6 days, while DENV-4 demonstrated the shortest clearance time. Higher viremia levels were associated with decreased subsequent platelet counts from day 6 onwards. Elevated viremia levels on each illness day increased the risk of developing severe dengue and plasma leakage. However, the effect size decreased with later illness days. A more rapid decline in viremia is associated with a reduced risk of the clinical outcomes. Conclusions: This study provides comprehensive insights into viremia kinetics and its effect on subsequent platelet count and clinical outcomes in dengue patients. Our findings underscore the importance of measuring viremia levels during the early febrile phase for dengue studies and support the use of viremia kinetics as outcome for phase-2 dengue therapeutic trials. Funding: Wellcome Trust and European Union Seventh Framework Programme.

Background: Physical activity (PA) is important for cancer survivors. Trials of remotely delivered interventions are needed to assist in reaching under-served non-metropolitan cancer survivors. The objective of this study was to ascertain whether wearable technology, coupled with health coaching was effective in increasing PA in breast and colorectal cancer survivors living in regional and remote areas in Australia. Methods: Cancer survivors from 5 states were randomized to intervention and control arms. Intervention participants were given a Fitbit Charge 2TM and received up to 6 telephone health coaching sessions. Control participants received PA print materials. Accelerometer assessments at baseline and 12 weeks measured moderate-to-vigorous PA (MVPA), light PA, and sedentary behavior. Results: Eighty-seven participants were recruited (age = 63 ± 11 years; 74 (85%) female). There was a significant net improvement in MVPA of 49.8 min/week, favoring the intervention group (95% confidence interval (95%CI): 13.6–86.1, p = 0.007). There was also a net increase in MVPA bouts of 39.5 min/week (95%CI: 11.9–67.1, p = 0.005), favoring the intervention group. Both groups improved light PA and sedentary behavior, but there were no between-group differences. Conclusion: This is the first study to demonstrate that, when compared to standard practice (i.e., PA education), a wearable technology intervention coupled with distance-based health coaching, improves MVPA in non-metropolitan cancer survivors. The results display promise for the use of scalable interventions using smart wearable technology in conjunction with phone-based health coaching to foster increased PA in geographically disadvantaged cancer survivors.

Abstract Background People experiencing homelessness also experience poorer health and frequently attend acute care settings when primary health care would be better equipped to meet their needs. Existing scholarship identifies a complex mix of individual and structural‐level factors affecting primary health care engagement driving this pattern of health services utilisation. We build on this existing knowledge, by bringing the spatio‐temporal configurations of primary health care into focus. Specifically, we interrogate how space and time inflect situated practices and relations of care. Methods This study took an ethnographic approach and was conducted 2021–2022 at an inclusive health and wellness centre ("the Centre") in Southeast Queensland, Australia. The data consists of 46 interviews with 48 people with lived experience of homelessness, including participants who use the services offered at the Centre (n = 26) and participants who do not (n = 19). We also interviewed 20 clinical and non‐clinical service providers affiliated with the Centre and observed how service delivery took place. Interviews and observations were complemented by visual data, including participant‐produced photography. All data were analysed employing a narrative framework. Results We present three interrelated themes demonstrating how space and time affect care, that is ‘staying safe’, ‘feeling welcome’ and ‘being seen’. ‘Staying safe’ captures the perceptions and practices around safety, which sit in tension with making service users feel welcome. ‘Feeling welcome’ attends to the sense of being invited to use services free of judgment. ‘Being seen’ depicts capacities to see a health care provider as well as being understood in one's lived experience. Conclusion Spatio‐temporal configurations, such as attendance policies, consultation modalities and time allocated to care encounters afford differential opportunities to nurture reciprocal relations. We conclude that flexible service configurations can leverage a relational model of care. Patient or Public Contribution Service providers were consulted during the design stage of the project and had opportunities to inform data collection instruments. Two service providers contributed to the manuscript as co‐authors. People with lived experience of homelessness who use the services at the inclusive health centre contributed as research participants and provided input into the dissemination of findings. The photography they produced has been featured in an in‐person exhibition, to which some have contributed as consultants or curators. It is hoped that their insights into experiences of welcomeness, safety and being seen will inform flexible and relational primary health care design, delivery, and evaluation to better cater for people experiencing housing instability and poverty.

Background: Cell-based therapies for drug-resistant epilepsy using induced pluripotent stem cell-derived inhibitory interneurons are now in early-phase clinical trials, building on findings from trials in Parkinson’s disease (PD) and Huntington’s disease (HD). Graft rejection and the need for immunosuppressive therapy post-transplantation pose potential barriers to more epilepsy patients becoming potential candidates for inhibitory interneurons transplantation surgery. Objectives: The present literature review weighs the evidence for and against human leukocyte antigen (HLA)-mediated graft rejection in PD and HD and examines the potential advantages and drawbacks to five broad approaches to cell-based therapies, including autologous cell culture and transplantation, in vivo reprogramming of glial cells using viral vectors, allogeneic transplantation using off-the-shelf cell lines, transplantation using inhibitory interneurons cultured from HLA-matched cell lines, and the use of hypoimmunogenic-induced pluripotent stem cell-derived inhibitory interneurons. The impact of surgical technique and associated needle trauma on graft rejection is also discussed. Methods: Non-systematic literature review. Results: While cell-based therapies have enjoyed early successes in treating a host of central nervous system disorders, the immunologic reaction against surgical procedures and implanted materials has remained a major obstacle. Conclusions: Adapting cell-based therapies using iPSC-derived inhibitory interneurons for epilepsy surgery will similarly require surmounting the challenge of immunogenicity.

Pacific Island countries have experienced periodic dengue, chikungunya and Zika outbreaks for decades. The prevention and control of these mosquito-borne diseases rely heavily on control of Aedes aegypti mosquitoes, which in most settings are the primary vector. Introgression of the intracellular bacterium Wolbachia pipientis (wMel strain) into Ae. aegypti populations reduces their vector competence and consequently lowers dengue incidence in the human population. Here we describe successful area-wide deployments of wMel-infected Ae. aegypti in Suva, Lautoka, Nadi (Fiji), Port Vila (Vanuatu) and South Tarawa (Kiribati). With community support, weekly releases of wMel-infected Ae. aegypti mosquitoes for between 2 to 5 months resulted in wMel introgression in nearly all locations. Long term monitoring confirmed a high, self-sustaining prevalence of wMel infecting mosquitoes in almost all deployment areas. Measurement of public health outcomes were disrupted by the Covid19 pandemic but are expected to emerge in the coming years.

Transition metal supported N-doped carbon (M-N-C) catalysts for oxygen reduction reaction (ORR) are viewed as the promising candidate to replace Pt-group metal (PGM) for proton exchange membrane fuel cells (PEMFCs). However, the stability of M-N-C is extremely challenging due to the demetalation, H2O2 attack, etc. in the strongly oxidative conditions of PEMFCs. In this study, we demonstrate the universal effect of Zn on promoting the stability of atomically dispersed M-Nx/C (M = Co, Fe, Mn) catalysts and the enhancement mechanism is unveiled for the first time. The best-performing dual-metal-site Zn-Co-N-C catalyst exhibits a high half-wave potential (E1/2) value of 0.81 V vs. reversible hydrogen electrode (RHE) in acid and outstanding durability with no activity decay after 15,000 accelerated degradation test (ADT) cycles at 60 °C, surpassing most reported Co-based PGM-free catalysts in acid media. For comparison, the Co-N-C in the absence of Zn suffers from a rapid degradation after ADT due to the demetalation and higher H2O2 yield. X-ray adsorption spectroscopy (XAS) and density functional theory (DFT) calculations suggest the more negative formation energy (by 1.2 eV) and increased charge transfer of Zn-Co dual-site structure compared to Co-N-C could strength the Co-N bonds against the demetalation and the optimized d-band center accounts for the improved ORR kinetics.

Individual hosts are often co-infected with multiple parasite species. Evidence from theoretical and empirical studies supports the idea that co-occurring parasites can impact each other and their hosts via synergistic or antagonistic interactions. The fundamental aim of understanding the consequences of co-infection to hosts and parasites requires an understanding of patterns of species co-occurrence within samples of hosts. We censused parasite assemblages in 755 adult, male fathead minnows collected from 7 lakes/ponds in southern Alberta, Canada between 2018 and 2020. Fifteen species of endoparasites infected fathead minnows, 98% of which were co-infected with between 2 and 9 parasite species (mean species richness: 4.4 ± 1.4). Non-random pairwise associations were detected within the overall parasite community. There were particularly strong, positive associations in the occurrences and intensities of the 2 congeneric larval trematodes Ornithodiplostomum sp. and Ornithodiplostomum ptychocheilus that comprised >96% of the 100 000+ parasites counted in the total sample of minnows. Furthermore, the occurrence of Ornithodiplostomum sp. was a strong predictor of the occurrence of O. ptychocheilus, and vice versa. Positive covariation in the intensities of these 2 dominants likely arises from their shared use of physid snails as first intermediate hosts in these waterbodies. These 2 species represent a predictable and non-random component within the complex assemblage of parasites of fathead minnows in this region.

pH-responsive hydrogels have numerous applications in tissue engineering, drug delivery systems, and diagnostics. Gelatin methacryloyl (GelMA) is a biocompatible, semi-synthetic polymer prepared from gelatin. When combined with aqueous solvents, GelMA forms hydrogels that have extensive applications in biomedical engineering. GelMA can be produced with different degrees of methacryloyl substitution; however, the synthesis of this polymer has not been tuned towards producing selectively modified materials for single-component pH-responsive hydrogels. In this work, we have explored two different synthetic routes targeting different gelatin functional groups (amine, hydroxyl, and/or carboxyl) to produce two GelMA analogs: gelatin A methacryloyl glycerylester (polymer A) and gelatin B methacrylamide (polymer B). Polymers A and B were used to fabricate pH-responsive hydrogel microspheres in a flow-focusing microfluidic device. At neutral pH, polymer A and B microspheres displayed an average diameter of ~40 µm. At pH 6, microspheres from polymer A showed a swelling ratio of 159.1 ± 11.5%, while at pH 10, a 288.6 ± 11.6% swelling ratio was recorded for polymer B particles.

Controls on Arctic vegetation physiology have been linked to microscale (1–100 m) topography and landscape position, yet drivers may change under future climates as temperature, active-layer thickness, and nutrient limitations are removed or altered. Focusing on the cosmopolitan dwarf birch (Betula glandusa), physiological metrics were measured over two field campaigns at Trail Valley Creek, NWT, Canada, and linked to tasked and archived multispectral imagery to investigate drivers. Relative humidity was ~31.1% on 25 June 2023, and increased to 45.6% on 29 June 2023, which corresponded to heightened physiological activity of stomatal conductance and light-adapted fluorescence (gsm: 0.118 vs. 0.165 μmol m−2 s−1, Fs: 129.29 vs. 178.42). Normalized difference vegetation index of AVIRIS, Sentinel 2, and SkySat were negligibly correlated to dwarf birch physiological activity, but moderately correlated to dwarf birch height and active-layer thickness. Random forest variable importance revealed that environmental factors and field-measured active-layer thickness ranked higher than remote sensing metrics in explaining physiological activity regardless of the field campaign. Overall, these findings suggest that microscale variation can influence dwarf birch physiological activity, yet microscale effects are overwritten by environmental conditions that may hinder fine-scale space-based monitoring of Arctic vegetation physiological dynamics.

Abstract Background Dengue virus serotypes (DENV-1 to -4) can be transmitted vertically in Aedes aegpti mosquitoes. Whether infection with the wMel strain of the endosymbiont Wolbachia can reduce the incidence of vertical transmission of DENV from infected females to their offspring is not well understood. Methods A laboratory colony of Vietnamese Ae. aegypti, both with and without wMel infection, were infected with DENV-1 by intrathoracic injection (IT) to estimate the rate of vertical transmission (VT) of the virus. VT in the DENV-infected mosquitoes was calculated via the infection rate estimation from mosquito pool data using maximum likelihood estimation (MLE). Results In 6047 F1 Vietnamese wild-type Ae. aegypti, the MLE of DENV-1 infection was 1.49 per 1000 mosquitoes (95% confidence interval [CI] 0.73–2.74). In 5500 wMel-infected Ae. aegypti, the MLE infection rate was 0 (95% CI 0–0.69). The VT rates between mosquito lines showed a statistically significant difference. Conclusions The results reinforce the view that VT is a rare event in wild-type mosquitoes and that infection with wMel is effective in reducing VT. Graphical Abstract

Abstract Background Lung cancer screening in high-risk populations with low-dose computed tomography is supported by international associations and recommendations. Overdiagnosis is considered a risk of screening with associated harms. The aim of this paper is to determine the prevalence of subclinical lung cancer diagnosed post-mortem to better understand the reservoir of subclinical lung cancer. Methods We searched EMBASE, PubMed, and MEDLINE databases from inception until March 2022 with no language restrictions. We considered all studies with ≥100 autopsies in adults. Two reviewers independently assessed eligibility of studies, extracted data, and assessed risk of bias of included studies. We performed a meta-analysis using a random-effects model for prevalence of subclinical lung cancer diagnosed post-mortem with sensitivity and subgroup analyses. Results A total of 13 studies with 16 730 autopsies were included. Pooled prevalence was 0.4% (95% CI 0.20 to 0.82%, I2 = 84%, tau2 = 1.19, low certainty evidence,16 730 autopsies). We performed a sensitivity analysis excluding studies which did not specify exclusion of children in their cohort, with a pooled prevalence of subclinical lung cancer of 0.87% (95% CI 0.48 to 1.57%, I2 = 71%, tau2 = 0.38, 6998 autopsies, 8 studies). Conclusions This is the first published systematic review to evaluate the prevalence of post-mortem subclinical lung cancer. Compared to autopsy systematic reviews in breast, prostate and thyroid cancers, the pooled prevalence is lower in lung cancer for subclinical cancer. This result should be interpreted with caution due to the included studies risk of bias and heterogeneity, with further high-quality studies required in target screening populations.

Abstract The phylum Apicomplexa comprises important eukaryotic parasites that invade host tissues and cells using a unique mechanism of gliding motility. Gliding is powered by actomyosin motors that translocate host-attached surface adhesins along the parasite cell body. Actin filaments (F-actin) generated by Formin1 play a central role in this critical parasitic activity. However, their subcellular origin, path and ultrastructural arrangement are poorly understood. Here we used cryo-electron tomography to image motile Cryptosporidium parvum sporozoites and reveal the cellular architecture of F-actin at nanometer-scale resolution. We demonstrate that F-actin nucleates at the apically positioned preconoidal rings and is channeled into the pellicular space between the parasite plasma membrane and the inner membrane complex in a conoid extrusion-dependent manner. Within the pellicular space, filaments on the inner membrane complex surface appear to guide the apico-basal flux of F-actin. F-actin concordantly accumulates at the basal end of the parasite. Finally, analyzing a Formin1-depleted Toxoplasma gondii mutant pinpoints the upper preconoidal ring as the conserved nucleation hub for F-actin in Cryptosporidium and Toxoplasma. Together, we provide an ultrastructural model for the life cycle of F-actin for apicomplexan gliding motility.

Abstract Background Snacking is nearly universal and contributes significant energy to U.S. children’s diets. Little is known, however, about where and when snacking intake occurs and if such patterns change with age. This research evaluated age-related differences in eating location, food source location, and timing of snacking among U.S. children aged 1–19 years (y). Methods A cross-sectional analysis of snacking among 14,666 children in the 2007–2018 U.S. National Health and Nutrition Examination Survey was conducted using a single 24-hour dietary recall. Snacking was participant-defined and included all eating occasions outside of meals. Linear regression and analysis of covariance were used to examine the effects of age (toddler 1–2 y, preschooler 3–5 y, school-age 6–11 y, adolescent 12–19 y) on the percentage of daily snack energy consumed by eating location (at home vs. away from home), food source location (grocery store, convenience store, school/childcare, restaurant, from someone else (i.e. “socially”), and other), and time of day (morning, 6am-12pm; early afternoon, 12pm-3pm; late afternoon/afterschool 3pm-6pm; evening 6pm-9pm, late-night 9pm-12am, and overnight 12am-6am). Results On average, U.S. children consumed most of their daily snacking energy at home (71%), from foods and beverages obtained from grocery stores (75%), and in the late afternoon/afterschool (31%). Toddlers and preschoolers consumed a greater percentage of their daily snack energy during the morning hours compared to school-age children and adolescents (both p

Abstract In this study, we compared 12 mm cell culture inserts with permeable polyester membranes (0.4 μm pores) from two different manufacturers: CELLTREAT® and Corning®. Physical dimensions and masses of the inserts were found to be very similar between the two brands, with CELLTREAT® inserts having a slightly smaller diameter and growth area (11.91 mm; 1.11 cm2) compared to Corning® Transwells® (12 mm; 1.13 cm2). We compared cell differentiation outcomes of human nasal epithelial cells (HNECs) at air–liquid interface grown on inserts from the two different manufacturers, including trans‐epithelial electrical resistance, ciliary beat frequency, ciliated area, and gene expression. HNECs from three male donors were used for all endpoints. No statistically significant differences were observed between paired cultures grown on different brands of insert. In conclusion, these inserts are comparable for use with airway epithelial cell model systems and likely do not impact cellular differentiation or cell culture quality.

ABSTRACT Wolbachia are a genus of insect endosymbiotic bacteria which includes strains wMel and wAlbB that are being utilized as a biocontrol tool to reduce the incidence of Aedes aegypti-transmitted viral diseases like dengue. However, the precise mechanisms underpinning the antiviral activity of these Wolbachia strains are not well defined. Here, we generated a panel of Ae. aegypti-derived cell lines infected with antiviral strains wMel and wAlbB or the non-antiviral Wolbachia strain wPip to understand host cell morphological changes specifically induced by antiviral strains. Antiviral strains were frequently found to be entirely wrapped by the host endoplasmic reticulum (ER) membrane, while wPip bacteria clustered separately in the host cell cytoplasm. ER-derived lipid droplets (LDs) increased in volume in wMel- and wAlbB-infected cell lines and mosquito tissues compared to cells infected with wPip or Wolbachia-free controls. Inhibition of fatty acid synthase (required for triacylglycerol biosynthesis) reduced LD formation and significantly restored ER-associated dengue virus replication in cells occupied by wMel. Together, this suggests that antiviral Wolbachia strains may specifically alter the lipid composition of the ER to preclude the establishment of dengue virus (DENV) replication complexes. Defining Wolbachia’s antiviral mechanisms will support the application and longevity of this effective biocontrol tool that is already being used at scale.IMPORTANCEAedes aegypti transmits a range of important human pathogenic viruses like dengue. However, infection of Ae. aegypti with the insect endosymbiotic bacterium, Wolbachia, reduces the risk of mosquito to human viral transmission. Wolbachia is being utilized at field sites across more than 13 countries to reduce the incidence of viruses like dengue, but it is not well understood how Wolbachia induces its antiviral effects. To examine this at the subcellular level, we compared how different strains of Wolbachia with varying antiviral strengths associate with and modify host cell structures. Strongly antiviral strains were found to specifically associate with the host endoplasmic reticulum and induce striking impacts on host cell lipid droplets. Inhibiting Wolbachia-induced lipid redistribution partially restored dengue virus replication demonstrating this is a contributing role for Wolbachia's antiviral activity. These findings provide new insights into how antiviral Wolbachia strains associate with and modify Ae. aegypti host cells.

Inflammatory bowel diseases (IBD) result from uncontrolled inflammation in the intestinal mucosa leading to damage and loss of function. Both innate and adaptive immunity contribute to the inflammation of IBD and innate and adaptive immune cells reciprocally activate each other in a forward feedback loop. In order to better understand innate immune contributions to IBD, we developed a model of spontaneous 100% penetrant, early onset colitis that occurs in the absence of adaptive immunity by crossing villin-TNFAIP3 mice to RAG1-/- mice (TRAG mice). This model is driven by microbes and features increased levels of innate lymphoid cells in the intestinal mucosa. To investigate the role of type 3 innate lymphoid cells (ILC3) in the innate colitis of TRAG mice, we crossed them to retinoid orphan receptor gamma t deficient (Rorγt-/-) mice. Rorγt-/- x TRAG mice exhibited markedly reduced eosinophilia in the colonic mucosa, but colitis persisted in these mice. Colitis in Rorγt-/- x TRAG mice was characterized by increased infiltration of the intestinal mucosa by neutrophils, inflammatory monocytes, macrophages and other innate cells. RNA and cellular profiles of Rorγt-/- x TRAG mice were consistent with a lack of ILC3 and ILC3 derived cytokines, reduced antimicrobial factors, increased activation oof epithelial repair processes and reduced activation of epithelial cell STAT3. The colitis in Rorγt-/- x TRAG mice was ameliorated by antibiotic treatment indicating that microbes contribute to the ILC3-independent colitis of these mice. Together, these gene expression and cell signaling signatures reflect the double-edged sword of ILC3 in the intestine, inducing both proinflammatory and antimicrobial protective responses. Thus, Rorγt promotes eosinophilia but Rorγt and Rorγt-dependent ILC3 are dispensable for the innate colitis in TRAG mice.

The challenges faced by science, engineering, and society are increasingly complex, requiring broad, cross-disciplinary teams to contribute to collective knowledge, cooperation, and sensemaking efforts. However, existing approaches to collaboration and knowledge sharing are largely manual, inadequate to meet the needs of teams that are not closely connected through personal ties or which lack the time to respond to dynamic requests for contextual information sharing. Nonetheless, in the current remote-first, complexity-driven, time-constrained workplace, such teams are both more common and more necessary. For example, the NASA Center for HelioAnalytics (CfHA) is a growing and cross-disciplinary community that is dedicated to aiding the application of emerging data science techniques and technologies, including AI/ML, to increase the speed, rigor, and depth of space physics scientific discovery. The members of that community possess innumerable skills and competencies and are involved in hundreds of projects, including proposals, committees, papers, presentations, conferences, groups, and missions. Traditional structures for information and knowledge representation do not permit the community to search and discover activities that are ongoing across the Center, nor to understand where skills and knowledge exist. The approaches that do exist are burdensome and result in inefficient use of resources, reinvention of solutions, and missed important connections. The challenge faced by the CfHA is a common one across modern groups and one that must be solved if we are to respond to the grand challenges that face our society, such as complex scientific phenomena, global pandemics and climate change. We present a solution to the problem: a community knowledge graph (KG) that aids an organization to better understand the resources (people, capabilities, affiliations, assets, content, data, models) available across its membership base, and thus supports a more cohesive community and more capable teams, enables robust and responsible application of new technologies, and provides the foundation for all members of the community to co-evolve the shared information space. We call this the Community Action and Understanding via Semantic Enrichment (CAUSE) ontology. We demonstrate the efficacy of KGs that can be instantiated from the ontology together with data from a given community (shown here for the CfHA). Finally, we discuss the implications, including the importance of the community KG for open science.

Background: Long COVID has affected 13.5% of Veterans Affairs (VA) Healthcare System users during the first pandemic year. With 700,000+ United States Veterans diagnosed with COVID-19, addressing the impact of Long COVID on this population is crucial. Since empirically-based mental health interventions for Long COVID are lacking, a vital need exists for a tailored recovery-oriented intervention for this population. This study intends to assess the feasibility and acceptability of a novel recovery-oriented intervention, Long COVID Coping and Recovery (LCCR), for Veterans with Long COVID, aiming to support symptom management and quality of life. LCCR is an adaptation of Continuous Identity Cognitive Therapy (CI-CT), a suicide recovery-oriented treatment for Veterans. Methods: In a two-year open-label pilot, three single-arm treatment trials will be conducted with 18 Veterans suffering from Long COVID. Each trial includes 16 weekly 60-min sessions delivered via VA Video Connect (VVC) and/or VA WebEx. Primary objectives include optimizing LCCR for Veterans with Long COVID and assessing the acceptability and feasibility of the intervention, using attendance and retention rates, drop-out statistics, and client satisfaction levels. Additionally, potential benefits of LCCR will be explored by evaluating alterations in quality of life, resilience, mental health status (anxiety, depression, suicide risk/behavior), and personal identity. The protocol has been tailored based on Veterans' needs assessment interviews and stakeholder feedback. Conclusion: If the LCCR intervention proves feasible and acceptable, a manualized version will be created and a randomized controlled trial planned to examine its efficacy in the broader Veteran population.

Background Releases of Wolbachia (wMel)-infected Aedes aegypti mosquitoes significantly reduced the incidence of virologically confirmed dengue in a previous cluster randomised trial in Yogyakarta City, Indonesia. Following the trial, wMel releases were extended to the untreated control areas, to achieve city-wide coverage of Wolbachia. Objective In this predefined analysis, we evaluated the impact of the wMel deployments in Yogyakarta on dengue hemorrhagic fever (DHF) case notifications and on the frequency of perifocal insecticide spraying by public health teams. Methods Monthly counts of DHF cases notified to the Yogyakarta District Health Office between January 2006 and May 2022 were modelled as a function of time-varying local wMel treatment status (fully- and partially-treated vs untreated, and by quintile of wMel prevalence). The frequency of insecticide fogging in wMel-treated and untreated areas was analysed using negative binomial regression. Results Notified DHF incidence was 83% lower in fully treated vs untreated periods (IRR 0.17 [95% CI 0.14, 0.20]), and 78% lower in areas with 80–100% wMel prevalence compared to areas with 0–20% wMel (IRR 0.23 [0.17, 0.30]). A similar intervention effect was observed at 60–80% wMel prevalence as at 80–100% prevalence (76% vs 78% efficacy, respectively). Pre-intervention, insecticide fogging occurred at similar frequencies in areas later randomised to wMel-treated and untreated arms of the trial. After wMel deployment, fogging occurred significantly less frequently in treated areas (IRR 0.17 [0.10, 0.30]). Conclusions Deployments of wMel-infected Aedes aegypti mosquitoes resulted in an 83% reduction in the application of perifocal insecticide spraying, consistent with lower dengue case notifications in wMel-treated areas. These results show that the Wolbachia intervention effect demonstrated previously in a cluster randomised trial was also measurable from routine surveillance data.

Abstract Long-read single-cell RNA sequencing (scRNA-seq) enables the quantification of RNA isoforms in individual cells. However, long-read scRNA-seq using the Oxford Nanopore platform has largely relied upon matched short-read data to identify cell barcodes. We introduce BLAZE, which accurately and efficiently identifies 10x cell barcodes using only nanopore long-read scRNA-seq data. BLAZE outperforms the existing tools and provides an accurate representation of the cells present in long-read scRNA-seq when compared to matched short reads. BLAZE simplifies long-read scRNA-seq while improving the results, is compatible with downstream tools accepting a cell barcode file, and is available at https://github.com/shimlab/BLAZE .

Abstract Background Introgression of the bacterial endosymbiont Wolbachia into Aedes aegypti populations is a biocontrol approach being used to reduce arbovirus transmission. This requires mass release of Wolbachia-infected mosquitoes. While releases have been conducted using a variety of techniques, egg releases, using water-soluble capsules containing mosquito eggs and larval food, offer an attractive method due to its potential to reduce onsite resource requirements. However, optimisation of this approach is required to ensure there is no detrimental impact on mosquito fitness and to promote successful Wolbachia introgression. Methods We determined the impact of storage time and temperature on wild-type (WT) and Wolbachia-infected (wMel or wAlbB strains) Ae. aegypti eggs. Eggs were stored inside capsules over 8 weeks at 18 °C or 22 °C and hatch rate, emergence rate and Wolbachia density were determined. We next examined egg quality and Wolbachia density after exposing eggs to 4–40 °C to determine how eggs may be impacted if exposed to extreme temperatures during shipment. Results Encapsulating eggs for 8 weeks did not negatively impact egg viability or resulting adult emergence and Wolbachia density compared to controls. When eggs were exposed to temperatures within 4–36 °C for 48 h, their viability and resulting adult Wolbachia density were maintained; however, both were significantly reduced when exposed to 40 °C. Conclusions We describe the time and temperature limits for maintaining viability of Wolbachia-infected Ae. aegypti eggs when encapsulated or exposed to extreme temperatures. These findings could improve the efficiency of mass releases by providing transport and storage constraints to ensure only high-quality material is utilised during field releases. Graphical Abstract

Abstract In this work, a multi-resonant metasurface that can be tailored to absorb microwaves at one or more frequencies is explored. Surface shapes based on an ‘anchor’ motif, incorporating hexagonal, square and triangular-shaped resonant elements, are shown to be readily tailorable to provide a targeted range of microwave responses. A metasurface consisting of an etched copper layer, spaced above a ground plane by a thin (

BackgroundThe introduction of Wolbachia (wMel strain) into Aedes aegypti mosquitoes reduces their capacity to transmit dengue and other arboviruses. Randomised and non-randomised studies in multiple countries have shown significant reductions in dengue incidence following field releases of wMel-infected Ae. aegypti. We report the public health outcomes from phased, large-scale releases of wMel-Ae. aegypti mosquitoes throughout three contiguous cities in the Aburrá Valley, Colombia.Methodology/principal findingsFollowing pilot releases in 2015-2016, staged city-wide wMel-Ae. aegypti deployments were undertaken in the cities of Bello, Medellín and Itagüí (3.3 million people) between October 2016 and April 2022. The impact of the Wolbachia intervention on dengue incidence was evaluated in two parallel studies. A quasi-experimental study using interrupted time series analysis showed notified dengue case incidence was reduced by 95% in Bello and Medellín and 97% in Itagüí, following establishment of wMel at ≥60% prevalence, compared to the pre-intervention period and after adjusting for seasonal trends. A concurrent clinic-based case-control study with a test-negative design was unable to attain the target sample size of 63 enrolled virologically-confirmed dengue (VCD) cases between May 2019 and December 2021, consistent with low dengue incidence throughout the Aburrá Valley following wMel deployments. Nevertheless, VCD incidence was 45% lower (OR 0.55 [95% CI 0.25, 1.17]) and combined VCD/presumptive dengue incidence was 47% lower (OR 0.53 [95% CI 0.30, 0.93]) among participants resident in wMel-treated versus untreated neighbourhoods.Conclusions/significanceStable introduction of wMel into local Ae. aegypti populations was associated with a significant and sustained reduction in dengue incidence across three Colombian cities. These results from the largest contiguous Wolbachia releases to-date demonstrate the real-world effectiveness of the method across large urban populations and, alongside previously published results, support the reproducibility of this effectiveness across different ecological settings.Trial registrationNCT03631719.

Introduction Field trials and modelling studies suggest that elimination of dengue transmission may be possible through widespread release of Aedes aegypti mosquitoes infected with the insect bacterium Wolbachia pipientis (wMel strain), in conjunction with routine dengue control activities. This study aimed to develop a modelling framework to guide planning for the potential elimination of locally acquired dengue in Yogyakarta, a city of almost 400 000 people in Java, Indonesia.Methods A scenario-tree modelling approach was used to estimate the sensitivity of the dengue surveillance system (including routine hospital-based reporting and primary-care-based enhanced surveillance), and time required to demonstrate elimination of locally acquired dengue in Yogyakarta city, assuming the detected incidence of dengue decreases to zero in the future. Age and gender were included as risk factors for dengue, and detection nodes included the probability of seeking care, probability of sample collection and testing, diagnostic test sensitivity and probability of case notification. Parameter distributions were derived from health system data or estimated by expert opinion. Alternative simulations were defined based on changes to key parameter values, separately and in combination.Results For the default simulation, median surveillance system sensitivity was 0.131 (95% PI 0.111 to 0.152) per month. Median confidence in dengue elimination reached 80% after a minimum of 13 months of zero detected dengue cases and 90% confidence after 25 months, across different scenarios. The alternative simulations investigated produced relatively small changes in median system sensitivity and time to elimination.Conclusion This study suggests that with a combination of hospital-based surveillance and enhanced clinic-based surveillance for dengue, an acceptable level of confidence (80% probability) in the elimination of locally acquired dengue can be reached within 2 years. Increasing the surveillance system sensitivity could shorten the time to first ascertainment of elimination of dengue and increase the level of confidence in elimination.

Large-scale dam removals provide opportunities to restore river function in the long-term and are massive disturbances to riverine ecosystems in the short-term. The removal of two dams on the Elwha River (WA, USA) between 2011 and 2014 was the largest dam removal project to be completed by that time and has since resulted in major changes to channel dynamics, river substrates, in-stream communities, and the size and shape of the river delta. To assess ecosystem function across the restored Elwha watershed, we compared leaf litter decomposition at twenty sites: 1) four tributary sites not influenced by restoration activities; 2) four river sites downstream of the upper dam (Glines Canyon Dam); 3) four river sites within the footprint of the former Aldwell Reservoir upstream of the lower dam (Elwha Dam); 4) four river sites downstream of the lower dam; and 5) four lentic sites in the newly developing Elwha delta. Three major findings emerged: 1) decomposition rates differed among sections of the Elwha watershed, with slowest decomposition rates at the delta sites and fastest decomposition rates just downstream of the upper dam; 2) aquatic macroinvertebrate communities establishing in leaf litterbags differed significantly among sections of the Elwha watershed; and 3) aquatic fungal communities growing on leaf litter differed significantly among sections. Aquatic macroinvertebrate and fungal diversity were sensitive to differences in canopy cover, water chemistry, and river bottom sediments across sites, with a stronger relationship to elevation for aquatic macroinvertebrates. As the Elwha River undergoes recovery following the massive sediment flows associated with dam removal, we expect to see changes in leaf litter processing dynamics and shifts in litter-dependent decomposer communities (both fungal and invertebrate) involved in this key ecosystem process.

ABSTRACT Lysyl-diacylglycerol (Lys-DAG) was identified three decades ago in Mycobacterium phlei, but the biosynthetic pathway and function of this aminoacylated lipid have since remained uncharacterized. Combining genetic methods, mass spectrometry, and biochemical approaches, we show that the multiple peptide resistance factor (MprF) homolog LysX from Corynebacterium pseudotuberculosis and two mycobacterial species is responsible for Lys-DAG synthesis. LysX is conserved in most Actinobacteria and was previously implicated in the synthesis of another modified lipid, lysyl-phosphatidylglycerol (Lys-PG), in Mycobacterium tuberculosis. Although we detected low levels of Lys-PG in the membrane of C. pseudotuberculosis, our data suggest that Lys-PG is not directly synthesized by LysX and may require an additional downstream pathway, which is as yet undefined. Our results show that LysX in C. pseudotuberculosis is a major factor of resistance against a variety of positively charged antibacterial agents, including cationic antimicrobial peptides (e.g., human peptide LL-37 and polymyxin B) and aminoglycosides (e.g., gentamycin and apramycin). Deletion of lysX caused an increase in cellular membrane permeability without dissipation of the membrane potential, suggesting that loss of the protein does not result in mechanical damage to the cell membrane. Furthermore, lysX-deficient cells exhibited an attenuated virulence phenotype in a Galleria mellonella infection model, supporting a role for LysX during infection. Altogether, Lys-DAG represents a novel molecular determinant for antimicrobial resistance and virulence that may be widespread in Actinobacteria and points to a richer landscape than previously realized of lipid components contributing to overall membrane physiology in this important bacterial phylum. IMPORTANCE In the past two decades, tRNA-dependent modification of membrane phosphatidylglycerol has been implicated in altering the biochemical properties of the cell surface, thereby enhancing the antimicrobial resistance and virulence of various bacterial pathogens. Here, we show that in several Actinobacteria, the multifunctional protein LysX attaches lysine to diacylglycerol instead of phosphatidylglycerol. We found that lysyl-diacylglycerol (Lys-DAG) confers high levels of resistance against various cationic antimicrobial peptides and aminoglycosides and also enhances virulence. Our data show that Lys-DAG is a lipid commonly found in important actinobacterial pathogens, including Mycobacterium and Corynebacterium species.

Dengue virus (DENV) transmission from humans to mosquitoes is a poorly documented, but critical component of DENV epidemiology. Magnitude of viremia is the primary determinant of successful human-to-mosquito DENV transmission. People with the same level of viremia, however, can vary in their infectiousness to mosquitoes as a function of other factors that remain to be elucidated. Here, we report on a field-based study in the city of Iquitos, Peru, where we conducted direct mosquito feedings on people naturally infected with DENV and that experienced mild illness. We also enrolled people naturally infected with Zika virus (ZIKV) after the introduction of ZIKV in Iquitos during the study period. Of the 54 study participants involved in direct mosquito feedings, 43 were infected with DENV-2, two with DENV-3, and nine with ZIKV. Our analysis excluded participants whose viremia was detectable at enrollment but undetectable at the time of mosquito feeding, which was the case for all participants with DENV-3 and ZIKV infections. We analyzed the probability of onward transmission during 50 feeding events involving 27 participants infected with DENV-2 based on the presence of infectious virus in mosquito saliva 7-16 days post blood meal. Transmission probability was positively associated with the level of viremia and duration of extrinsic incubation in the mosquito. In addition, transmission probability was influenced by the day of illness in a non-monotonic fashion; i.e., transmission probability increased until 2 days after symptom onset and decreased thereafter. We conclude that mildly ill DENV-infected humans with similar levels of viremia during the first two days after symptom onset will be most infectious to mosquitoes on the second day of their illness. Quantifying variation within and between people in their contribution to DENV transmission is essential to better understand the biological determinants of human infectiousness, parametrize epidemiological models, and improve disease surveillance and prevention strategies.

We assessed predominantly pediatric patients in Vietnam with dengue and other febrile illness 3 months after acute illness. Among dengue patients, 47% reported >1 postacute symptom. Most resolved by 3 months, but alopecia and vision problems often persisted. Our findings provide additional evidence on postacute dengue burden and confirm children are affected.

The circumstances associated with high levels of achievement in undergraduate studies has not been thoroughly explored in the Australian context. This study investigated factors predicting high academic achievement, defined as maintaining a Distinction average, at undergraduate level. Findings revealed several factors that predicted achievement after two semesters of study. These factors included essay writing skills, with students having satisfactory writing 5.16 times more likely to maintain a Distinction average compared to those with below satisfactory writing; faculty, with students enrolled in Health Sciences 4.63 times more likely compared to students from other faculties; language background, with English-speaking background students 1.67 times more likely compared to English as an additional language or dialect (EAL/D) students; gender, with females 1.45 more likely compared to males; and age, with older students 1.03 times more likely to achieve high performance compared to younger students. Creating a profile of students likely to excel academically assists decision makers in allocating resources to students less likely to achieve. This research opens the door to further studies investigating whether these factors play a role in predicting student achievement at university.

Abstract Atomically dispersed and nitrogen coordinated single metal site (MNx, M = Fe, Co, or Mn) moieties embedded in partially graphitized carbon (denoted as M–N–C) are recognized as the most promising platinum group metal‐free catalysts for the oxygen reduction reaction (ORR) in proton exchange membrane fuel cells. However, simply regulating their coordination environments and local structures of single metal sites cannot fundamentally change active site structure, which leads to insufficient activity and stability. A second transition metal can be incorporated to design dual‐metal sites, offering a new opportunity to modulate the electronic and geometric structures of M–N–C catalysts. Therefore, exploring optimal atomically dispersed dual‐metal‐site is essential to designing new active sites with enhanced ORR activity, and stability, especially breaking the activity‐stability trade‐off. This review provides a comprehensive analysis of the advances in developing atomically dispersed dual‐metal site catalysts for the ORR, including innovative synthesis methods, primary structural configurations, and the mechanisms to promote catalytic performance. We aim to elucidate the crucial structure–property correlation, emphasizing the inherent electronic and geometric effects of dual metal sites. Finally, we discuss the current challenges of dual‐metal site catalysts concerning rational design, precise synthesis, and high‐fidelity structural characterization.

Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic cause of adult T-cell leukemia/lymphoma (ATL) and encodes a viral oncoprotein (Hbz) that is consistently expressed in asymptomatic carriers and ATL patients, suggesting its importance in the development and maintenance of HTLV-1 leukemic cells. Our previous work found Hbz protein is dispensable for virus-mediated T-cell immortalization but enhances viral persistence. We and others have also shown that hbz mRNA promotes T-cell proliferation. In our current studies, we evaluated the role of hbz mRNA on HTLV-1-mediated immortalization in vitro as well as in vivo persistence and disease development. We generated mutant proviral clones to examine the individual contributions of hbz mRNA, hbz mRNA secondary structure (stem-loop), and Hbz protein. Wild-type (WT) and all mutant viruses produced virions and immortalized T-cells in vitro. Viral persistence and disease development were also evaluated in vivo by infection of a rabbit model and humanized immune system (HIS) mice, respectively. Proviral load and sense and antisense viral gene expression were significantly lower in rabbits infected with mutant viruses lacking Hbz protein compared to WT or virus with an altered hbz mRNA stem-loop (M3 mutant). HIS mice infected with Hbz protein-deficient viruses showed significantly increased survival times compared to animals infected with WT or M3 mutant virus. Altered hbz mRNA secondary structure, or loss of hbz mRNA or protein, has no significant effect on T-cell immortalization induced by HTLV-1 in vitro; however, the Hbz protein plays a critical role in establishing viral persistence and leukemogenesis in vivo.

Spatiotemporal monitoring of reactive nitrogen atmospheric deposition is essential for understanding its impact on sensitive ecosystems and quantifying cumulative effects. However, the sparsity of direct surface flux measurements combined with barriers in dissemination are major limiting factors in providing this information to decision makers and non-experts in a timely manner. This work addresses both aspects of this information gap by, 1) utilizing satellite-derived reactive nitrogen dry deposition data products that can be used by decision-makers to supplement the sparse direct surface flux measurements and 2) fill in measurement gaps. Therefore, we have developed a Reactive Nitrogen Flux Mapper (RNFM) component of the interactive Cloud-based Data Mapper (CDM) for providing easy access of satellite-derived reactive nitrogen (defined here as nitrogen dioxide (NO2) and ammonia (NH3)) dry deposition flux spatial maps/data to decision-makers/stakeholders over North America. The RNFM component of CDM has a Graphical User Interface (GUI) that allows users to specify the geographical regions and time periods for computing the average fluxes on the fly using an integrated cloud-based computing platform. The CDM architecture is flexible and can be upgraded in the future to take advantage of upstream satellite data directly on cloud platforms to provide results in near real-time.

A toddler presented with hematemesis a few weeks after ingesting a penny. Workup revealed an esophageal lesion communicating with an aortic pseudoaneurysm in the setting of Actinomyces odontolyticus bacteremia. A. odontolytica is an oropharyngeal bacteria known to cause fistulas when introduced into tissue planes. (Level of Difficulty: Intermediate.)

The Miniature Radio Frequency instrument (Mini-RF) on the Lunar Reconnaissance Orbiter obtained widespread synthetic aperture radar observations of the Moon in the S band (12.6 cm), including nearly complete coverage at both lunar poles. The currently archived monostatic data have spatial offsets from the lunar reference frame, making them more difficult to compare to other data sets. To address this issue, we have developed a new algorithm for spatially controlling the Mini-RF S-band monostatic data set and orthorectifying these data onto lunar topography. Additionally, as the influence of incidence angle changes on radar observations is well known, we describe an empirical approach to account for variations in observation geometry and surface topography. Individual radar swaths and mosaics produced using this method more clearly show the variability in scattering behavior due to changes in lunar regolith properties and suppress some of the behavior arising from these topographic effects alone. Once these terrain effects are taken into account, we find that areas of permanent shadow at both poles have a higher median radar reflectivity than nonpermanently shadowed regions, but the polarization behavior of shadowed versus unshadowed areas is largely similar. The higher radar reflectivity in permanent shadow is likely the result of physical or compositional differences in these unique environments, though the precise cause remains uncertain. The results here illustrate how reducing the influence of topography and geometry effects in Mini-RF radar data may enable better characterization of lunar geologic units, regolith structure, and potential areas hosting volatile deposits at the lunar poles.

Abstract Background Patients presenting for major surgery with low cardiorespiratory fitness (deconditioning) and other modifiable risk factors are at increased risk of postoperative complications. This study investigated the feasibility of delivering prehabilitation in high-risk patients scheduled for major abdominal cancer surgery. Methods Eligible patients in this single-center cohort study included patients with poor fitness (objectively assessed by cardiopulmonary exercise testing, CPET) scheduled for elective major abdominal cancer surgery. Patients were recruited to participate in a prehabilitation program that spanned up to 6 weeks pre-operatively and comprised aerobic and resistance exercise training, breathing exercise, and nutritional support. The primary outcome assessed pre-specified feasibility targets: recruitment >70%, retention >85%, and intervention adherence >70%. Secondary outcomes were assessed for improved pre-operative functional status and health-related quality of life and for postoperative complications. Results Eighty-two (34%) out of 238 patients screened between April 2018 and December 2019 were eligible for recruitment. Fifty (61%) patients (52% males) with a median age of 71 (IQR, 63–77) years participated in the study. Baseline oxygen consumption the at anaerobic threshold and at peak exercise (mean±SD: 9.8±1.8 and 14.0±2.9 mL/kg/min, respectively) confirmed the deconditioned state of the study cohort. The retention rate within the prehabilitation program was 84%, with 42 participants returning for repeat CPET testing. While >60% of participants preferred to do home-based prehabilitation, adherence to the intervention was low—with only 12 (28%) and 15 (35%) of patients having self-reported compliance >70% with their exercise prescriptions. Conclusion Our prehabilitation program in high-risk cancer surgery patients did not achieve pre-specified targets for recruitment, retention, and self-reported program adherence. These findings underpin the importance of implementation research and strategies for the prehabilitation programs in major surgery. Trial registration Australian New Zealand Clinical Trials Registry ( ACTRN12620000073909 ) retrospectively registered.

Abstract Dengue exhibits focal clustering in households and neighborhoods, driven by local mosquito population dynamics, human population immunity, and fine scale human and mosquito movement. We tested the hypothesis that spatiotemporal clustering of homotypic dengue cases is disrupted by introduction of the arbovirus-blocking bacterium Wolbachia (wMel-strain) into the Aedes aegypti mosquito population. We analysed 318 serotyped and geolocated dengue cases (and 5921 test-negative controls) from a randomized controlled trial in Yogyakarta, Indonesia of wMel deployments. We find evidence of spatial clustering up to 300 m among the 265 dengue cases (3083 controls) in the untreated trial arm. Participant pairs enrolled within 30 days and 50 m had a 4.7-fold increase (compared to 95% CI on permutation-based null distribution: 0.1, 1.2) in the odds of being homotypic (i.e. potentially transmission-related) as compared to pairs occurring at any distance. In contrast, we find no evidence of spatiotemporal clustering among the 53 dengue cases (2838 controls) resident in the wMel-treated arm. Introgression of wMel Wolbachia into Aedes aegypti mosquito populations interrupts focal dengue virus transmission leading to reduced case incidence; the true intervention effect may be greater than the 77% efficacy measured in the primary analysis of the Yogyakarta trial.

IntroductionDengue is a major public health challenge and a growing problem due to climate change. The release of Aedes aegypti mosquitoes infected with the intracellular bacterium Wolbachia is a novel form of vector control against dengue. However, there remains a need to evaluate the benefits of such an intervention at a large scale. In this paper, we evaluate the potential economic impact and cost-effectiveness of scaled Wolbachia deployments as a form of dengue control in Vietnam-targeted at the highest burden urban areas.MethodsTen settings within Vietnam were identified as priority locations for potential future Wolbachia deployments (using a population replacement strategy). The effectiveness of Wolbachia deployments in reducing the incidence of symptomatic dengue cases was assumed to be 75%. We assumed that the intervention would maintain this effectiveness for at least 20 years (but tested this assumption in the sensitivity analysis). A cost-utility analysis and cost-benefit analysis were conducted.ResultsFrom the health sector perspective, the Wolbachia intervention was projected to cost US$420 per disability-adjusted life year (DALY) averted. From the societal perspective, the overall cost-effectiveness ratio was negative, i.e. the economic benefits outweighed the costs. These results are contingent on the long-term effectiveness of Wolbachia releases being sustained for 20 years. However, the intervention was still classed as cost-effective across the majority of the settings when assuming only 10 years of benefits.ConclusionOverall, we found that targeting high burden cities with Wolbachia deployments would be a cost-effective intervention in Vietnam and generate notable broader benefits besides health gains.

Toxoplasma gondii is a widespread apicomplexan parasite that can cause severe disease in its human hosts. The ability of T. gondii and other apicomplexan parasites to invade into, egress from, and move between cells of the hosts they infect is critical to parasite virulence and disease progression. An unusual and highly conserved parasite myosin motor (TgMyoA) plays a central role in T. gondii motility. The goal of this work was to determine whether the parasite's motility and lytic cycle can be disrupted through pharmacological inhibition of TgMyoA, as an approach to altering disease progression in vivo. To this end, we first sought to identify inhibitors of TgMyoA by screening a collection of 50,000 structurally diverse small molecules for inhibitors of the recombinant motor's actin-activated ATPase activity. The top hit to emerge from the screen, KNX-002, inhibited TgMyoA with little to no effect on any of the vertebrate myosins tested. KNX-002 was also active against parasites, inhibiting parasite motility and growth in culture in a dose-dependent manner. We used chemical mutagenesis, selection in KNX-002, and targeted sequencing to identify a mutation in TgMyoA (T130A) that renders the recombinant motor less sensitive to compound. Compared to wild-type parasites, parasites expressing the T130A mutation showed reduced sensitivity to KNX-002 in motility and growth assays, confirming TgMyoA as a biologically relevant target of KNX-002. Finally, we present evidence that KNX-002 can slow disease progression in mice infected with wild-type parasites, but not parasites expressing the resistance-conferring TgMyoA T130A mutation. Taken together, these data demonstrate the specificity of KNX-002 for TgMyoA, both in vitro and in vivo, and validate TgMyoA as a druggable target in infections with T. gondii. Since TgMyoA is essential for virulence, conserved in apicomplexan parasites, and distinctly different from the myosins found in humans, pharmacological inhibition of MyoA offers a promising new approach to treating the devastating diseases caused by T. gondii and other apicomplexan parasites.

Summary: Background: Improvements in the early diagnosis of dengue are urgently needed, especially in resource-limited settings where the distinction between dengue and other febrile illnesses is crucial for patient management. Methods: In this prospective, observational study (IDAMS), we included patients aged 5 years and older with undifferentiated fever at presentation from 26 outpatient facilities in eight countries (Bangladesh, Brazil, Cambodia, El Salvador, Indonesia, Malaysia, Venezuela, and Viet Nam). We used multivariable logistic regression to investigate the association between clinical symptoms and laboratory tests with dengue versus other febrile illnesses between day 2 and day 5 after onset of fever (ie, illness days). We built a set of candidate regression models including clinical and laboratory variables to reflect the need of a comprehensive versus parsimonious approach. We assessed performance of these models via standard measures of diagnostic values. Findings: Between Oct 18, 2011, and Aug 4, 2016, we recruited 7428 patients, of whom 2694 (36%) were diagnosed with laboratory-confirmed dengue and 2495 (34%) with (non-dengue) other febrile illnesses and met inclusion criteria, and were included in the analysis. 2703 (52%) of 5189 included patients were younger than 15 years, 2486 (48%) were aged 15 years or older, 2179 (42%) were female and 3010 (58%) were male. Platelet count, white blood cell count, and the change in these variables from the previous day of illness had a strong association with dengue. Cough and rhinitis had strong associations with other febrile illnesses, whereas bleeding, anorexia, and skin flush were generally associated with dengue. Model performance increased between day 2 and 5 of illness. The comprehensive model (18 clinical and laboratory predictors) had sensitivities of 0·80 to 0·87 and specificities of 0·80 to 0·91, whereas the parsimonious model (eight clinical and laboratory predictors) had sensitivities of 0·80 to 0·88 and specificities of 0·81 to 0·89. A model that includes laboratory markers that are easy to measure (eg, platelet count or white blood cell count) outperformed the models based on clinical variables only. Interpretation: Our results confirm the important role of platelet and white blood cell counts in diagnosing dengue, and the importance of serial measurements over subsequent days. We successfully quantified the performance of clinical and laboratory markers covering the early period of dengue. Resulting algorithms performed better than published schemes for distinction of dengue from other febrile illnesses, and take into account the dynamic changes over time. Our results provide crucial information needed for the update of guidelines, including the Integrated Management of Childhood Illness handbook. Funding: EU's Seventh Framework Programme. Translations: For the Bangla, Bahasa Indonesia, Portuguese, Khmer, Spanish and Vietnamese translations of the abstract see Supplementary Materials section.