Search

In this paper, we investigate the influence of cementitious matrix cracking on the electrochemical polarization and impedance behaviors of corroding reinforced concrete and crack-resistant reinforced hybrid fiber-reinforced concrete (HyFRC). Samples were exposed to a chloride environment for 2.5 years while in either a continuous tensile stress state or in a nonloaded condition, and were periodically monitored for Tafel polarization responses. Electrochemical impedance spectroscopy (EIS) was additionally performed at the conclusion of the test program. Greater severity of corrosion-induced matrix splitting cracks along the length of embedded steel reinforcing bars and subsequent formation of anodic surfaces were found to affect several electrochemical parameters, including increase of the corrosion current and decrease of the ohmic resistance of concrete. Cathodic and anodic Tafel coefficients and Stern-Geary coefficients for passive and active samples are also reported, highlighted by a Stern-Geary coefficient of B = 28.1 mV for active corrosion.

With the expected replacement of deteriorated reinforced concrete bridges to occur in the next several decades, an opportunity exists to design more economic bridge columns in seismically active regions which are rapidly constructed while having enhanced crack resistance for extended service life. A precast hybrid fiber-reinforced concrete (HyFRC) tube, which contains a column's steel reinforcement, is proposed for accelerating construction and is to be filled with plain concrete at the construction site. An experimental column was subjected to static, uni-directional, cyclic loading and utilized a base-rocking design for further ductility enhancement. At the conclusion of the test, the column reached a peak drift ratio of 13.1% and showed minor damage, including elimination of cover spalling. The HyFRC tube column design contributed effective resistance against longitudinal reinforcing bar buckling, allowing the column to maintain 93% of its peak load capacity at 9.5% drift. Compared to a monolithic HyFRC column, the precast HyFRC tube column was constructed with less HyFRC volume while having similar seismic performance, making it a more sustainable alternative.

Background: Streptococcus suis is an emerging zoonotic pathogen and is the leading cause of bacterial meningitis in adults in Vietnam. Systematic data on the antimicrobial susceptibility profiles of S. suis strains isolated from human cases are lacking. We studied antimicrobial resistance and associated resistance determinants in S. suis isolated from patients with meningitis in southern Vietnam. Methods: S. suis strains isolated between 1997 and 2008 were investigated for their susceptibility to six antimicrobial agents. Strains were screened for the presence and expression of tetracycline and erythromycin resistance determinants and the association of tet(M) genes with Tn916- like transposons. The localization of tetracycline resistance gene tet(L) was determined by pulse field gel electrophoresis and Southern blotting. Results: We observed a significant increase in resistance to tetracycline and chloramphenicol, which was concurrent with an increase in multi-drug resistance. In tetracycline resistance strains, we identified tet(M), tet(O), tet (W) and tet(L) and confirmed their expression. All tet(M) genes were associated with a Tn916-like transposon. The co-expression of tet(L) and other tetracycline resistance gene(s) encoding for ribosomal protection protein(s) was only detected in strains with a minimum inhibitory concentration (MIC) of tetracycline of ≥ 64 mg/L Conclusions: We demonstrated that multi-drug resistance in S. suis causing disease in humans in southern Vietnam has increased over the 11-year period studied. We report the presence and expression of tet(L) in S. suis strains and our data suggest that co-expression of multiple genes encoding distinct mechanism is required for an MIC ≥ 64 mg/L to tetracycline. [ABSTRACT FROM AUTHOR]

Purpose: Contrast-enhanced magnetic resonance imaging (MRI) is the preeminent diagnostic test for brain metastases (BM). BM detection for stereotactic radiosurgery (SRS) planning may improve with a time delay following administration of a high-relaxivity agent for 1.5T and 3T imaging systems. Metastasis detection with time-delayed MRI was evaluated in this study. Methods: 53 volumetric MRI studies from 38 patients undergoing SRS for BM were evaluated. All studies used 0.1 mmol/kg Gadobenate dimeglumin (MultiHance®), immediately after injection, followed by two more axial T1 sequences after 5 minute intervals (final image acquisition commenced 15 minutes after contrast injection). Two studies were motion-limited and excluded. 287 BM were identified. The studies were randomized and examined separately by 3 radiologists, who were blinded to the temporal sequence. Each recorded the number of BM detected per scan. A Friedman test compared BM numbers between scans. One radiologist determined the scan on which BM were best defined. Results: The interclass correlations for Scans 1, 2, and 3 were 0.7392, 0.7951 and 0.7290, respectively, demonstrating excellent inter-rater reliability. At least one new lesion was detected in the 2nd scan as compared to the 1st in 35.3% of subjects (95% CI: 22.4%-49.9%). The increase in BM numbers between scans 1 and 2 ranged from 1 to 10. At least 1 new lesion was detected in the 3rd scan as compared to the 2nd in 21.6% of subjects (95% CI: 11.3%-35.3%). The increase in BM numbers between scans 2 and 3 ranged from 1 to 9. Between scans 1 and 3 additional tumors were seen on 41.2% of scans (increase range 1 to 14). The median increase in tumor number for all comparisons was 1. There was a trend towards significance in the increased numbers of BM detected, in each group, between earlier and later scans (p=0.098). In 34 of the 51 studies (66.7%), the radiologist selected the 3rd scan as providing the clearest tumor definition. Conclusion: In patients who are being prepared for SRS of brain metastases, delayed MRI after contrast injection may reveal an increased number of targets that need treatment. To avoid missing tumors that could be treated at the time of planned SRS, and resulting "treatment failures", we recommend that post-contrast MRI be acquired 15 minutes after injection in patients undergoing SRS for treatment of metastatic brain tumors. Disclosure: No significant relationships. [ABSTRACT FROM AUTHOR]

A transition from traditional problem-based clinics to the Sports Medicine and Reconditioning Team (SMART) clinic model was completed by January 2009 at Marine Corps Base Camp Lejeune. The SMART clinic model allows for more patients to be seen and enhances coordinated care between providers. The objective of this research is to show the advantages of implementing a training room team approach for the care of musculoskeletal injuries in active duty members by comparing the number of patients seen, the number of limited duty (LIMDU) periods, the number of physical evaluation boards (PEBs), and the percentage of orthopedic referrals. Electronic medical records for patients seen at sports medicine clinics between January 1, 2007 and December 31, 2010 were reviewed. Naval Hospital Camp Lejeune provided a database of patients placed on LIMDU and PEB from 2007 through 2010. Fifty-eight and twenty-four percent more encounters occurred in 2009 and 2010, respectively, than that in 2007. The percentage of LIMDU referred for PEB in 2010 was reduced to 9% compared to that in 2007. In conclusion, the SMART clinic model allows for more patients to be seen and a reduction in the percentage of patients recommended for PEB from LIMDU. [ABSTRACT FROM AUTHOR]

Drug resistance against antimalarials is rendering them increasingly ineffective and so there is a need for the development of new antimalarials. To discover new antimalarial chemotypes a phenotypic screen of the Janssen Jumpstarter library against the P. falciparum asexual stage was undertaken, uncovering the cyclopropyl carboxamide structural hit class. Structure-activity analysis revealed that each structural moiety was largely resistant to change, although small changes led to the frontrunner compound, WJM280, which has potent asexual stage activity (EC 50 40 nM) and no human cell cytotoxicity. Forward genetics uncovered that cyclopropyl carboxamide resistant parasites have mutations and an amplification in the cytochrome b gene. Cytochrome b was then verified as the target with profiling against cytochrome b drug-resistant parasites and a mitochondrial oxygen consumption assay. Accordingly, the cyclopropyl carboxamide class was shown to have slow-acting asexual stage activity and activity against male gametes and exoerythrocytic forms. Enhancing metabolic stability to attain efficacy in malaria mouse models remains a challenge in the future development of this antimalarial chemotype., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Angiotensin-converting enzyme 2 (ACE2) is the primary entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but ACE2-independent entry has been observed in vitro for strains with the spike-E484D substitution. Here, we conduct a whole-genome CRISPR-Cas9 knockout screen using SARS-CoV-2 mouse adapted 1 (SARS-CoV-2 MA1 ), which carries spike-E484D, to identify the ACE2-independent entry mechanisms. SARS-CoV-2 MA1 infection in HEK293T cells relies on heparan sulfate and endocytic pathways, with TMEM106B, a transmembrane lysosomal protein, the most significant contributor. While SARS-CoV-2 MA1 productively infects human brain organoids and K18-hACE2 mouse brains, it does not infect C57BL/6J or Ifnar -/- mouse brains. This suggests that ACE2-independent entry via TMEM106B, which is predominantly expressed in the brain, does not overtly increase the risk of SARS-CoV-2 neuroinvasiveness in mice with endogenous Ace2 expression. Importantly, SARS-CoV-2 MA1 does not replicate in the Ace2 -/- mouse respiratory tract. Overall, this suggests that robust ACE2-independent infection by SARS-CoV-2 MA1 is likely an in vitro phenomenon with no apparent implications for infection in vivo., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Getah virus (GETV) is an emerging mosquito-borne virus with economic impact on the livestock industry in East Asia. In this study, we successfully produced GETV virus-like particles (VLPs) in insect cells using the baculovirus expression vector system. We show that the GETV envelope glycoproteins were successfully expressed at the surface of the insect cell and were glycosylated. VLPs were isolated from the culture fluid as enveloped particles of 60-80 nm in diameter. Two 1 µg vaccinations with this GETV VLP vaccine, without adjuvant, generated neutralizing antibody responses and protected wild-type C57/BL6 mice against GETV viremia and arthritic disease. The GETV VLP vaccine may find application as a horse and/or pig vaccine in the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 2019 (COVID-19), which can result in severe disease, often characterised by a 'cytokine storm' and the associated acute respiratory distress syndrome. However, many infections with SARS-CoV-2 are mild or asymptomatic throughout the course of infection. Although blood biomarkers of severe disease are well studied, less well understood are the inflammatory signatures in lung tissues associated with mild disease or silent infections, wherein infection and inflammation are rapidly resolved leading to sequelae-free recovery. Herein we described RNA-Seq and histological analyses of lungs over time in an omicron BA.1/K18-hACE2 mouse infection model, which displays these latter features. Although robust infection was evident at 2 days post infection (dpi), viral RNA was largely cleared by 10 dpi. Acute inflammatory signatures showed a slightly different pattern of cytokine signatures compared with severe infection models, and where much diminished 30 dpi and absent by 66 dpi. Cellular deconvolution identified significantly increased abundance scores for a number of anti-inflammatory pro-resolution cell types at 5/10 dpi. These included type II innate lymphoid cells, T regulatory cells, and interstitial macrophages. Genes whose expression trended downwards over 2-66 dpi included biomarkers of severe disease and were associated with 'cytokine storm' pathways. Genes whose expression trended upward during this period were associated with recovery of ciliated cells, AT2 to AT1 transition, reticular fibroblasts and innate lymphoid cells, indicating a return to homeostasis. Very few differentially expressed host genes were identified at 66 dpi, suggesting near complete recovery. The parallels between mild or subclinical infections in humans and those observed in this BA.1/K18-hACE2 mouse model are discussed with reference to the concept of "protective inflammation"., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Carolin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: The severity of Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is often dictated by a range of comorbidities. A considerable literature suggests iron deficiency and iron overload may contribute to increased infection, inflammation and disease severity, although direct causal relationships have been difficult to establish., Methods: Here we generate iron deficient and iron loaded C57BL/6 J mice by feeding standard low and high iron diets, with mice on a normal iron diet representing controls. All mice were infected with a primary SARS-CoV-2 omicron XBB isolate and lung inflammatory responses were analyzed by histology, immunohistochemistry and RNA-Seq., Results: Compared with controls, iron deficient mice showed no significant changes in lung viral loads or histopathology, whereas, iron loaded mice showed slightly, but significantly, reduced lung viral loads and histopathology. Transcriptional changes were modest, but illustrated widespread dysregulation of inflammation signatures for both iron deficient vs. controls, and iron loaded vs. controls. Some of these changes could be associated with detrimental outcomes, whereas others would be viewed as beneficial., Discussion: Diet-associated iron deficiency or overload thus induced modest modulations of inflammatory signatures, but no significant histopathologically detectable disease exacerbations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Carolin, Frazer, Yan, Bishop, Tang, Nguyen, Helman, Horvat, Larcher, Rawle and Suhrbier.)

Previous studies along the banks of the tidal Meghna River of the Ganges-Brahmaputra-Meghna Delta demonstrated the active sequestration of dissolved arsenic (As) on newly formed iron oxide minerals (Fe(III)-oxides) within riverbank sands. The sand with high solid-phase As (>500 mg/kg) was located within the intertidal zone where robust mixing occurs with oxygen-rich river water. Here we present new evidence that upwelling groundwater through a buried silt layer generates the dissolved products of reductive dissolution of Fe(III)-oxides, including As, while mobilization of DOC by upwelling groundwater prevents their reconstitution in the intertidal zone by lowering the redox state. A three end-member conservative mixing model demonstrated mixing between riverbank groundwater above the silt layer, upwelling groundwater through the silt layer, and river water. An electrochemical mass balance model confirmed that Fe(III)-oxides were the primary electron acceptor driving the oxidation of DOC sourced from sediment organic carbon in the silt. Thus, the presence of an intercalating silt layer in the riverbanks of tidal rivers can represent a biogeochemical hotspot of As release while preventing its retention in the hyporheic zone.

Self-amplifying mRNA (SAM) vaccines can be rapidly deployed in the event of disease outbreaks. A legitimate safety concern is the potential for recombination between alphavirus-based SAM vaccines and circulating viruses. This theoretical risk needs to be assessed in the regulatory process for SAM vaccine approval. Herein, we undertake extensive in vitro and in vivo assessments to explore recombination between SAM vaccine and a wide selection of alphaviruses and a coronavirus. SAM vaccines were found to effectively limit alphavirus co-infection through superinfection exclusion, although some co-replication was still possible. Using sensitive cell-based assays, replication-competent alphavirus chimeras were generated in vitro as a result of rare, but reproducible, RNA recombination events. The chimeras displayed no increased fitness in cell culture. Viable alphavirus chimeras were not detected in vivo in C57BL/6J, Rag1 -/- and Ifnar -/- mice, in which high levels of SAM vaccine and alphavirus co-replicated in the same tissue. Furthermore, recombination between a SAM-spike vaccine and a swine coronavirus was not observed. In conclusion we state that although the ability of SAM vaccines to recombine with alphaviruses might be viewed as an environmental safety concern, several key factors substantially mitigate against in vivo emergence of chimeric viruses from SAM vaccine recipients., Competing Interests: Declaration of interests The user committee for the RepliSAFE project included members from MSD Animal Health. MSD Animal Health provided TC-83 replicons and antibodies but otherwise provided no other resources or funding, had no input into the manuscript nor the decision to publish., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Mixed-Reality (XR) technologies promise a user experience (UX) that rivals the interactive experience with the real-world. The key facilitators in the design of such a natural UX are that the interaction has zero lag and that users experience no excess mental load. This is difficult to achieve due to technical constraints such as motion-to-photon latency as well as false-positives during gesture-based interaction., Methods: In this paper, we explored the use of physiological features to model the user's intent to interact with a virtual reality (VR) environment. Accurate predictions about when users want to express an interaction intent could overcome the limitations of an interactive device that lags behind the intention of a user. We computed time-domain features from electroencephalography (EEG) and electromyography (EMG) recordings during a grab-and-drop task in VR and cross-validated a Linear Discriminant Analysis (LDA) for three different combinations of (1) EEG, (2) EMG and (3) EEG-EMG features., Results & Conclusion: We found the classifiers to detect the presence of a pre-movement state from background idle activity reflecting the users' intent to interact with the virtual objects (EEG: 62 % ± 10 %, EMG: 72 % ± 9 %, EEG-EMG: 69 % ± 10 %) above simulated chance level. The features leveraged in our classification scheme have a low computational cost and are especially useful for fast decoding of users' mental states. Our work is a further step towards a useful classification of users' intent to interact, as a high temporal resolution and speed of detection is crucial. This facilitates natural experiences through zero-lag adaptive interfaces.

In 2022, a genotype IV (GIV) strain of Japanese encephalitis virus (JEV) caused an unprecedented and widespread outbreak of disease in pigs and humans in Australia. As no veterinary vaccines against JEV are approved in Australia and all current approved human and veterinary vaccines are derived from genotype (G) III JEV strains, we used the recently described insect-specific Binjari virus (BinJV) chimeric flavivirus vaccine technology to produce a JEV GIV vaccine candidate. Herein we describe the production of a chimeric virus displaying the structural prM and E proteins of a JEV GIV isolate obtained from a stillborn piglet (JEV NSW/22 ) in the genomic backbone of BinJV (BinJ/JEV NSW/22- prME). BinJ/JEV NSW/22- prME was shown to be antigenically indistinguishable from the JEV NSW/22 parental virus by K D analysis and a panel of JEV-reactive monoclonal antibodies in ELISA. BinJ/JEV NSW/22- prME replicated efficiently in C6/36 cells, reaching titres of >10 7 infectious units/mL - an important attribute for vaccine manufacture. As expected, BinJ/JEV NSW/22- prME failed to replicate in a variety of vertebrate cells lines. When used to immunise mice, the vaccine induced a potent virus neutralising response against JEV NSW/22 and to GII and GIII JEV strains. The BinJ/JEV NSW/22- prME vaccine provided complete protection against lethal challenge with JEV NSW/22 , whilst also providing partial protection against viraemia and disease for the related Murray Valley encephalitis virus. Our results demonstrate that BinJ/JEV NSW/22- prME is a promising vaccine candidate against JEV., (© 2024. The Author(s).)

With resistance to most antimalarials increasing, it is imperative that new drugs are developed. We previously identified an aryl acetamide compound, MMV006833 (M-833), that inhibited the ring-stage development of newly invaded merozoites. Here, we select parasites resistant to M-833 and identify mutations in the START lipid transfer protein (PF3D7_0104200, PfSTART1). Introducing PfSTART1 mutations into wildtype parasites reproduces resistance to M-833 as well as to more potent analogues. PfSTART1 binding to the analogues is validated using organic solvent-based Proteome Integral Solubility Alteration (Solvent PISA) assays. Imaging of invading merozoites shows the inhibitors prevent the development of ring-stage parasites potentially by inhibiting the expansion of the encasing parasitophorous vacuole membrane. The PfSTART1-targeting compounds also block transmission to mosquitoes and with multiple stages of the parasite's lifecycle being affected, PfSTART1 represents a drug target with a new mechanism of action., (© 2024. The Author(s).)

Introduction: Global microplastic (MP) pollution is now well recognized, with humans and animals consuming and inhaling MPs on a daily basis, with a growing body of concern surrounding the potential impacts on human health., Methods: Using a mouse model of mild COVID-19, we describe herein the effects of azide-free 1 μm polystyrene MP beads, co-delivered into lungs with a SARS-CoV-2 omicron BA.5 inoculum. The effect of MPs on the host response to SARS-CoV-2 infection was analysed using histopathology and RNA-Seq at 2 and 6 days post-infection (dpi)., Results: Although infection reduced clearance of MPs from the lung, virus titres and viral RNA levels were not significantly affected by MPs, and overt MP-associated clinical or histopathological changes were not observed. However, RNA-Seq of infected lungs revealed that MP exposure suppressed innate immune responses at 2 dpi and increased pro-inflammatory signatures at 6 dpi. The cytokine profile at 6 dpi showed a significant correlation with the 'cytokine release syndrome' signature observed in some COVID-19 patients., Discussion: The findings are consistent with the recent finding that MPs can inhibit phagocytosis of apoptotic cells via binding of Tim4. They also add to a growing body of literature suggesting that MPs can dysregulate inflammatory processes in specific disease settings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Bishop, Yan, Nguyen, Rawle, Tang, Larcher and Suhrbier.)

Malaria is a devastating disease that causes significant morbidity worldwide. The development of new antimalarial chemotypes is urgently needed because of the emergence of resistance to frontline therapies. Independent phenotypic screening campaigns against the Plasmodium asexual parasite, including our own, identified the aryl amino acetamide hit scaffold. In a prior study, we identified the STAR-related lipid transfer protein (PfSTART1) as the molecular target of this antimalarial chemotype. In this study, we combined structural elements from the different aryl acetamide hit subtypes and explored the structure-activity relationship. It was shown that the inclusion of an endocyclic nitrogen, to generate the tool compound WJM-715, improved aqueous solubility and modestly improved metabolic stability in rat hepatocytes. Metabolic stability in human liver microsomes remains a challenge for future development of the aryl acetamide class, which was underscored by modest systemic exposure and a short half-life in mice. The optimized aryl acetamide analogs were cross resistant to parasites with mutations in PfSTART1, but not to other drug-resistant mutations, and showed potent binding to recombinant PfSTART1 by biophysical analysis, further supporting PfSTART1 as the likely molecular target. The optimized aryl acetamide analogue, WJM-715 will be a useful tool for further investigating the druggability of PfSTART1 across the lifecycle of the malaria parasite., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Brad Sleebs reports financial support was provided by National Health and Medical Research Council. Susan Charman reports financial support was provided by National Health and Medical Research Council. Paul Gilson reports financial support was provided by National Health and Medical Research Council. Alan Cowman reports financial support was provided by National Health and Medical Research Council. William Nguyen reports financial support was provided by National Health and Medical Research Council. Tania de Koning Ward reports financial support was provided by National Health and Medical Research Council. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

To reach World Health Organization elimination targets for hepatitis C, different strategies are needed to reach people who have not yet been diagnosed and treated. In the context of declining treatment initiation rates, innovation in service design and delivery is necessary: testing and treatment needs to be offered to people in non-traditional settings. The community corrections (probation and parole) population is larger than the prison population, which has high prevalence of hepatitis C and-in some countries-established diagnosis and treatment programs. In this Viewpoint we identify a gap in hepatitis C care for people under community correctional supervision, a group who have either never been imprisoned or need continuity of healthcare provided in prison. We propose that offering hepatitis C screening and treatment would benefit this population, and accelerate progress to hepatitis C elimination., Competing Interests: RW has received investigator-initiated funding from Gilead Sciences. YS is a co-investigator on investigator-initiated research grants from Gilead Sciences and AbbVie. MS has received investigator-initiated research grants from Abbvie and Gilead and consultancy from Gilead. AL has received investigator-initiated research grant support from Gilead Sciences and AbbVie. AJT has received consulting fees from Gilead, Abbvie, Roche Diagnostics, Assembly Biosciences, speaker fees from Gilead Sciences, Roche Diagnostics and investigator-initiated grants from Gilead Sciences. All other authors have no conflicts to declare., (© 2024 The Author(s).)

The reduced pathogenicity of the omicron BA.1 sub-lineage compared to earlier variants is well described, although whether such attenuation is retained for later variants like BA.5 and XBB remains controversial. We show that BA.5 and XBB isolates were significantly more pathogenic in K18-hACE2 mice than a BA.1 isolate, showing increased neurotropic potential, resulting in fulminant brain infection and mortality, similar to that seen for original ancestral isolates. BA.5 also infected human cortical brain organoids to a greater extent than the BA.1 and original ancestral isolates. In the brains of mice, neurons were the main target of infection, and in human organoids neuronal progenitor cells and immature neurons were infected. The results herein suggest that evolving omicron variants may have increasing neurotropic potential., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Stewart, Yan, Ellis, Bishop, Dumenil, Tang, Nguyen, Larcher, Parry, Sng, Khromykh, Sullivan, Lor, Meunier, Rawle and Suhrbier.)

Recent evidence indicates mass azithromycin distribution reduces under-5 mortality. This intervention is being considered for child survival programs in high mortality sub-Saharan African settings. The delivery approach used in prior studies required a full-time census and distribution team, which is not feasible for most programs. To determine the optimal programmatic approach to delivery, this study aimed to compare treatment coverage, costs, and acceptability of different delivery approaches with existing community health workers (CHWs). This cluster-randomized trial included rural and peri-urban communities in Dosso, Niger (clinicaltrials.gov, NCT04774991). A random sample of 80 eligible communities was randomized 1:1 to biannual door-to-door or fixed-point delivery of oral azithromycin to children 1-59 months old over 1 year. Data analysts alone were masked given the nature of the intervention. The primary outcome was community-level treatment coverage defined as the number of children treated recorded by CHWs divided by the number of eligible children determined using a post-distribution census. Costs were monitored through routine administrative data collection and micro-costing. The census included survey questions on intervention acceptability among caregivers, community leaders, and CHWs. After randomization, 1 community was excluded due to inaccuracies in available administrative data, resulting in 39 communities receiving door-to-door delivery. At the second distribution, community-level mean treatment coverage was 105% (SD 44%) in the door-to-door arm and 92% (SD 20%) in the fixed-point arm (Mean difference 13%, 95% CI -2% to 28%, P-value = 0.08). The total cost per dose delivered was $1.91 in the door-to-door arm and $2.51 in the fixed-point arm. Indicators of acceptability were similar across stakeholder groups in both arms, with most respondents in each group indicating a preference for door-to-door. Overall, door-to-door delivery is the preferred approach to azithromycin distribution in this setting and might reach more children at a lower cost per dose delivered than fixed-point. Trial Registration: clinicaltrials.gov NCT04774991., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Arzika et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Although carbon monoxide (CO)-based treatments have demonstrated the high cancer efficacy by promoting mitochondrial damage and core-region penetrating ability, the efficiency was often compromised by protective autophagy (mitophagy). Herein, cannabidiol (CBD) is integrated into biomimetic carbon monoxide nanocomplexes (HMPOC@M) to address this issue by inducing excessive autophagy. The biomimetic membrane not only prevents premature drugs leakage, but also prolongs blood circulation for tumor enrichment. After entering the acidic tumor microenvironment, carbon monoxide (CO) donors are stimulated by hydrogen oxide (H 2 O 2 ) to disintegrate into CO and Mn 2+ . The comprehensive effect of CO/Mn 2+ and CBD can induce ROS-mediated cell apoptosis. In addition, HMPOC@M-mediated excessive autophagy can promote cancer cell death by increasing autophagic flux via class III PI3K/BECN1 complex activation and blocking autolysosome degradation via LAMP1 downregulation. Furthermore, in vivo experiments showed that HMPOC@M+ laser strongly inhibited tumor growth and attenuated liver and lung metastases by downregulating VEGF and MMP9 proteins. This strategy may highlight the pro-death role of excessive autophagy in TNBC treatment, providing a novel yet versatile avenue to enhance the efficacy of CO treatments. Importantly, this work also indicated the applicability of CBD for triple-negative breast cancer (TNBC) therapy through excessive autophagy., Competing Interests: The authors have no conflicts of interest to declare., (© 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Humans have lived in tenuous battle with malaria over millennia. Today, while much of the world is free of the disease, areas of South America, Asia, and Africa still wage this war with substantial impacts on their social and economic development. The threat of widespread resistance to all currently available antimalarial therapies continues to raise concern. Therefore, it is imperative that novel antimalarial chemotypes be developed to populate the pipeline going forward. Phenotypic screening has been responsible for the majority of the new chemotypes emerging in the past few decades. However, this can result in limited information on the molecular target of these compounds which may serve as an unknown variable complicating their progression into clinical development. Target identification and validation is a process that incorporates techniques from a range of different disciplines. Chemical biology and more specifically chemo-proteomics have been heavily utilized for this purpose. This review provides an in-depth summary of the application of chemo-proteomics in antimalarial development. Here we focus particularly on the methodology, practicalities, merits, and limitations of designing these experiments. Together this provides learnings on the future use of chemo-proteomics in antimalarial development., (© 2023 The Authors. Medicinal Research Reviews published by Wiley Periodicals LLC.)