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Background: Retrieval analysis has long served the orthopaedic community as a tool for understanding implant failure modes; however, what retrieval studies can reveal about the nature of prosthetic joint infection (PJI) remains unknown. We hypothesize that records from a comprehensive joint retrieval program should corroborate clinically-reported temporal characteristics of prosthesis-related infection. Methods: We examined 2527 records documenting a decade of explanted hip and knee components to quantify the following: (1) the relative contribution of infection to revision arthroplasty; (2) the effects of joint type, revision status, and reason for retrieval on indwelling time; and (3) whether the temporal distribution of infected explants reflects clinical experience. Results: In this series, 20% (507/2527) of explants were performed for infection, with PJI being more commonly implicated in the retrieval of revision implants than of primaries. Infected prostheses were explanted 23.2 months sooner on average than those retrieved for other causes. Within the subset of infected devices, revision components were explanted 11.2 months sooner than primaries, with no appreciable difference observed between hips and knees. Retrieval-based temporal distributions were most similar to PJI studies with endpoint enrollment or long duration follow-up, suggesting a later average onset of infection than reported in comparable clinical studies with short (

Objectives: Maternal socioeconomic status (SES) is an important predictor of adverse birth outcomes and postnatal health across global populations. Chronic inflammation is implicated in cardiometabolic disease risk in high-income contexts and is a potential pathway linking maternal adversity to offspring health trajectories. To clarify how socioeconomic inequality shapes pregnancy inflammation in middle-income settings, we investigated SES as a predictor of inflammatory cytokines in late gestation in a sample from the Cebu Longitudinal Health Nutrition Survey in Cebu, Philippines., Methods: We used multiple regression to evaluate maternal SES, reflected in household assets, as a predictor of general inflammation (C-reactive protein), inflammatory cytokines (interleukin-6, interleukin-10), and inflammatory balance (n = 407). Inflammatory markers were measured at 29.9 weeks gestation in dried blood spots, and a measure reflecting relative balance of IL6 and IL10 was calculated to capture pro- versus anti-inflammatory skewed immune profiles., Results: Greater household assets significantly predicted lower IL6 concentration (p <  0.001), with a trend toward lower IL6 relative to IL10 (p = 0.084). C-reactive protein and IL10 were not individually related to SES., Conclusions: The inverse relationship between SES and pregnancy inflammation in Cebu is consistent with results from high-income settings. These findings further highlight the influence of socioeconomic conditions on immune regulation during pregnancy. Given the evidence that gestational inflammation impacts offspring fetal growth, our results suggest that social and economic effects on immune function may be an important pathway for the intergenerational transmission of health disparities., (© 2024 The Author(s). American Journal of Human Biology published by Wiley Periodicals LLC.)

Background: Though social determinants are the primary drivers of health, few studies of people living with HIV (PLWH) focus on non-clinical correlates of insecure and/or fragmented connections with the care system. Our team has used linked clinical and multisector non-clinical data to study how residential mobility and connection to social services influence the HIV care continuum. We engage a diverse group of invested patients and community members to guide and inform this research. Our objective is to generate stakeholder-informed, research-based interventions that are relevant to the community, and to share our engagement approach and findings so that other researchers can do the same., Methods: Our research team partnered with the Indiana Clinical and Translational Sciences Institute's Research Jam, to develop and implement a human-centered design research plan to engage with individuals with lived experience relevant to our research. We recruited a panel composed of PLWH as well as clinicians and individuals from agencies that provide medical and non-medical services to PLWH in Marion County, Indiana. We used a variety of human-centered design tools and activities to engage individuals during six sessions, with results informing our engagement and research activities., Results: Since the inception of the project, 48 individuals have joined the stakeholder panel. Thirty-five are actively engaged and have participated in one or more of the six sessions conducted to date. The panel helped guide and prioritize analyses, aided in identification of data missing from our ecosystem, helped interpret results, provided feedback on future interventions, and co-presented with us at a local health equity conference., Conclusions: We utilized community engagement to expand the scope of our research and found that the process provided value to both stakeholders and research team members. Human-centered design enhanced this partnership by keeping it person-centered, developing empathy and trust, increasing stakeholder retention, and empowering stakeholders to collaborate meaningfully with the research team. The use of these methods is essential to conducting relevant, impactful, and sustainable research. We anticipate that these methods will be important for academic and public health researchers wishing to engage with and integrate the ideas of community stakeholders., Competing Interests: Competing Interests Dr. Sarah Wiehe is a member of the United States Preventive Services Task Force (USPSTF). This article does not necessarily represent the views and policies of the USPSTF. There are no other competing interests to disclose.

There is a lack of new antibiotics to combat drug-resistant bacterial infections that increasingly threaten global health. The current pipeline of clinical-stage antimicrobials is primarily populated by "new and improved" versions of existing antibiotic classes, supplemented by several novel chemical scaffolds that act on traditional targets. The lack of fresh chemotypes acting on previously unexploited targets (the "holy grail" for new antimicrobials due to their scarcity) is particularly unfortunate as these offer the greatest opportunity for innovative breakthroughs to overcome existing resistance. In recognition of their potential, this review focuses on this subset of high value antibiotics, providing chemical structures where available. This review focuses on candidates that have progressed to clinical trials, as well as selected examples of promising pioneering approaches in advanced stages of development, in order to stimulate additional research aimed at combating drug-resistant infections.

Talcarpones A (1) and B (2) are rare bisnaphthazarin derivatives produced by Talaromyces johnpittii (ex-type strain MST-FP2594), a newly discovered Australian fungus, which is formally described and named herein. The talcarpones were isolated along with the previously reported monomeric naphthoquinone, aureoquinone (3), suggesting a biosynthetic link between these metabolites. Talcarpone A is a lower homologue of hybocarpone (4), which was first isolated from a mycobiont of the lichen Lecanora hybocarpa. The structures of 1 and 2 were elucidated by detailed spectroscopic analysis, molecular modelling and comparison with literature data. Talcarpones 1 and 2 exhibited moderate antifungal activity (MIC 0.78-3.1 µg ml -1 ) and weak activity against Gram-positive bacteria (MIC 13-25 µg ml -1 ). The talcarpones also demonstrated noteworthy chemical reactivities, with 2 converting rapidly to 1, which in turn converted slowly to the highly coloured 3. These post-biosynthetic reactions point to a potential ecological role for the talcarpones in providing ongoing (slow-release) physicochemical protection for T. johnpittii against solar irradiation., (© 2023. The Author(s), under exclusive licence to the Japan Antibiotics Research Association.)

Probing the surface of proteins to predict the binding site and binding affinity for a given small molecule is a critical but challenging task in drug discovery. Blind docking addresses this issue by performing docking on binding regions randomly sampled from the entire protein surface. However, compared with local docking, blind docking is less accurate and reliable because the docking space is too largetly sampled. Cavity detection-guided blind docking methods improved the accuracy by using cavity detection (also known as binding site detection) tools to guide the docking procedure. However, it is worth noting that the performance of these methods heavily relies on the quality of the cavity detection tool. This constraint, namely the dependence on a single cavity detection tool, significantly impacts the overall performance of cavity detection-guided methods. To overcome this limitation, we proposed Consensus Blind Dock (CoBDock), a novel blind, parallel docking method that uses machine learning algorithms to integrate docking and cavity detection results to improve not only binding site identification but also pose prediction accuracy. Our experiments on several datasets, including PDBBind 2020, ADS, MTi, DUD-E, and CASF-2016, showed that CoBDock has better binding site and binding mode performance than other state-of-the-art cavity detector tools and blind docking methods., (© 2024. The Author(s).)

Covering literature to December 2022This review provides a comprehensive account of all natural products (500 compounds, including 17 semi-synthetic derivatives) described in the primary literature up to December 2022, reported to be capable of inhibiting the egg hatching, motility, larval development and/or the survival of helminths ( i.e. , nematodes, flukes and tapeworms). These parasitic worms infect and compromise the health and welfare, productivity and lives of commercial livestock ( i.e. , sheep, cattle, horses, pigs, poultry and fish), companion animals ( i.e. , dogs and cats) and other high value, endangered and/or exotic animals. Attention is given to chemical structures, as well as source organisms and anthelmintic properties, including the nature of bioassay target species, in vivo animal hosts, and measures of potency.

Background: As breastfeeding rates in the United States increase, barriers persist for Black, Latine, and low-socioeconomic status household dyads when compared to White and high-socioeconomic status household dyads. Previous breastfeeding disparities research has almost exclusively considered the influence of race, ethnicity, and socioeconomic status separately, although these attributes are not randomly distributed across the population., Research Aim: To identify breastfeeding duration patterns by race/ethnicity and educational attainment in a nationally representative U.S. National Immunization Survey sample., Method: We conducted a cross-sectional, secondary analysis of the U.S. Centers for Disease Control and Prevention's 2020 National Immunization Survey-Child public-use data. To examine breastfeeding and exclusive breastfeeding durations at the intersection of race/ethnicity and educational attainment, we created a 12-item, cross-classified variable using three educational attainment groups and four race/ethnicity groups. We used linear regressions to test these associations., Results: In all, 83% of the sample breastfed. Mean durations of breastfeeding were 7.5 ( SE  = 1.95) months and exclusive breastfeeding duration was 4.9 ( SE  = 0.87) months. In adjusted models, multi-race/other high-educational attainment participants had the longest breastfeeding duration by almost 3 weeks (β: 19.53, 95% CI [5.27, 33.79]), and Black low-educational attainment participants exclusively breastfed for 1 month less than White high-educational attainment participants (β:-30.23, 95% CI [-40.87, -19.58])., Conclusions: Examining race/ethnicity and educational attainment together provides an intersectional understanding of breastfeeding outcomes and can inform targeted, culturally appropriate interventions., Competing Interests: Disclosures and Conflicts of InterestThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: During the writing of this manuscript, Lauren S. Keenan-Devlin was on Margaret Butler’s dissertation committee.

KAT6A, and its paralog KAT6B, are histone lysine acetyltransferases (HAT) that acetylate histone H3K23 and exert an oncogenic role in several tumor types including breast cancer where KAT6A is frequently amplified/overexpressed. However, pharmacologic targeting of KAT6A to achieve therapeutic benefit has been a challenge. Here we describe identification of a highly potent, selective, and orally bioavailable KAT6A/KAT6B inhibitor CTx-648 (PF-9363), derived from a benzisoxazole series, which demonstrates anti-tumor activity in correlation with H3K23Ac inhibition in KAT6A over-expressing breast cancer. Transcriptional and epigenetic profiling studies show reduced RNA Pol II binding and downregulation of genes involved in estrogen signaling, cell cycle, Myc and stem cell pathways associated with CTx-648 anti-tumor activity in ER-positive (ER+) breast cancer. CTx-648 treatment leads to potent tumor growth inhibition in ER+ breast cancer in vivo models, including models refractory to endocrine therapy, highlighting the potential for targeting KAT6A in ER+ breast cancer., Competing Interests: Declaration of interests S.S., T.A.P., C.Y.C., S.U., J.P., J.C., A.R., N.N., S.G., E.J., O.B., S.K., H.W., Z.W., Y.Z., K.T., L.C., A.M., J.L., P.P.K., S.S., P.F.R., E.C.G., S.Y., R.J., K.A.M., P.B., and H.L. are/were employees of Pfizer and some of the authors are shareholders in Pfizer Inc. L.C. and A.M. are co-inventors on patent WO2022013369. P.S., H.R.L., B.J.M., R.F., C.H., M.C., Y.B., and S.W. are inventors on patent WO2019243491 and have received payments from Monash University derived from distribution of licensing income received from Pfizer. P.P.K., S.S., P.F.R., Y.B., and P.S. are inventors on patent WO2020254946. P.S. is an inventor on patent WO2022013369. T.T., H.R.L and A.K.V. are inventors on patent WO2016198507 A1. The Thomas and Voss laboratories received research funding from the Cooperative Research Centre (CRC) for Cancer Therapeutics (CTx), Australia. T.T. and A.K.V. have received payments from a distribution of the licensing income from Pfizer for serving on an advisory board meeting for Pfizer. M.A.D. has been a member of advisory boards for CTX CRC, GSK, Storm Therapeutics, Celgene and Cambridge Epigenetix. S.-J.D. has been a member of advisory boards for Adela. M.A.D. and S.-J.D. receive research funding from CTx CRC and from the Pfizer Emerging Science Fund. Ian Street is a member of the Scientific Advisory Board of Oncology One Pty Ltd and has received payments from distribution of licensing income from Pfizer. J.N. is currently an adjunct professor at the University of New South Wales, Kensington, NSW, Australia. M.J.D and D.D.B. are currently working at South Australian immunoGENomics Cancer Institute (SAiGENCI), Faculty of Health and Medical Sciences, The University of Adelaide. J.C. is a current employee of oNKo-innate Pty Ltd. J.L. is currently an employee and shareholder of Belharra Therapeutics., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Turonicin A ( 1 ) was isolated from Streptomyces sp. MST-123921, which was recovered from soil collected on the banks of the Turon River in New South Wales, Australia. Turonicin A ( 1 ) is an amphoteric linear polyene polyketide featuring independent pentaene and tetraenone chromophores and is structurally related to linearmycins A-C ( 2 - 4 ). The structure of 1 was determined by detailed spectroscopic analysis and comparison to literature data. Bioinformatic analysis of the linearmycin biosynthetic gene cluster also allowed the previously unresolved absolute stereostructures of 2 - 4 to be elucidated. Turonicin A ( 1 ) exhibited very potent activity against the fungi Candida albicans (MIC 0.0031 μg/mL, 2.7 nM) and Saccharomyces cerevisiae (MIC 0.0008 μg/mL, 0.7 nM), moderate activity against the bacteria Bacillus subtilis (MIC 0.097 μg/mL, 85 nM) and Staphylococcus aureus (MIC 0.39 μg/mL, 340 nM), and no cytotoxicity against human fibroblasts, making it an attractive candidate for further development as a potential next-generation antibiotic scaffold.

Antimicrobial resistance has emerged as a global public health threat, and development of novel therapeutics for treating infections caused by multi-drug resistant bacteria is urgent. Staphylococcus aureus is a major human and animal pathogen, responsible for high levels of morbidity and mortality worldwide. The intracellular survival of S. aureus in macrophages contributes to immune evasion, dissemination, and resilience to antibiotic treatment. Here, we present a confocal fluorescence imaging assay for monitoring macrophage infection by green fluorescent protein (GFP)-tagged S. aureus as a front-line tool to identify antibiotic leads. The assay was employed in combination with nanoscaled chemical analyses to facilitate the discovery of a new, active rifamycin analogue. Our findings indicate a promising new approach for the identification of antimicrobial compounds with macrophage intracellular activity. The antibiotic identified here may represent a useful addition to our armory in tackling the silent pandemic of antimicrobial resistance.

The need for new antibacterial drugs to treat the increasing global prevalence of drug-resistant bacterial infections has clearly attracted global attention, with a range of existing and upcoming funding, policy, and legislative initiatives designed to revive antibacterial R&D. It is essential to assess whether these programs are having any real-world impact and this review continues our systematic analyses that began in 2011. Direct-acting antibacterials (47), non-traditional small molecule antibacterials (5), and β-lactam/β-lactamase inhibitor combinations (10) under clinical development as of December 2022 are described, as are the three antibacterial drugs launched since 2020. Encouragingly, the increased number of early-stage clinical candidates observed in the 2019 review increased in 2022, although the number of first-time drug approvals from 2020 to 2022 was disappointingly low. It will be critical to monitor how many Phase-I and -II candidates move into Phase-III and beyond in the next few years. There was also an enhanced presence of novel antibacterial pharmacophores in early-stage trials, and at least 18 of the 26 phase-I candidates were targeted to treat Gram-negative bacteria infections. Despite the promising early-stage antibacterial pipeline, it is essential to maintain funding for antibacterial R&D and to ensure that plans to address late-stage pipeline issues succeed., (© 2023. The Author(s).)

Motivation: To predict drug targets, graph-based machine-learning methods have been widely used to capture the relationships between drug, target and disease entities in drug-disease-target (DDT) networks. However, many methods cannot explicitly consider disease types at inference time and so will predict the same target for a given drug under any disease condition. Meanwhile, DDT networks are usually organized hierarchically carrying interactive relationships between involved entities, but these methods, especially those based on Euclidean embedding cannot fully utilize such topological information, which might lead to sub-optimal results. We hypothesized that, by importing hyperbolic embedding specifically for modeling hierarchical DDT networks, graph-based algorithms could better capture relationships between aforementioned entities, which ultimately improves target prediction performance., Results: We formulated the target prediction problem as a knowledge graph completion task explicitly considering disease types. We proposed FLONE, a hyperbolic embedding-based method based on capturing hierarchical topological information in DDT networks. The experimental results on two DDT networks showed that by introducing hyperbolic space, FLONE generates more accurate target predictions than its Euclidean counterparts, which supports our hypothesis. We also devised hyperbolic encoders to fuse external domain knowledge, to make FLONE enable handling samples corresponding to previously unseen drugs and targets for more practical scenarios., Availability and Implementation: Source code and dataset information are at: https://github.com/arantir123/DDT&#95;triple&#95;prediction., Supplementary Information: Supplementary data are available at Bioinformatics Advances online., (© The Author(s) 2023. Published by Oxford University Press.)

Antimicrobial resistance is an urgent threat to human health, and new antibacterial drugs are desperately needed, as are research tools to aid in their discovery and development. Vancomycin is a glycopeptide antibiotic that is widely used for the treatment of Gram-positive infections, such as life-threatening systemic diseases caused by methicillin-resistant Staphylococcus aureus (MRSA). Here we demonstrate that modification of vancomycin by introduction of an azide substituent provides a versatile intermediate that can undergo copper-catalysed azide-alkyne cycloaddition (CuAAC) reaction with various alkynes to readily prepare vancomycin fluorescent probes. We describe the facile synthesis of three probes that retain similar antibacterial profiles to the parent vancomycin antibiotic. We demonstrate the versatility of these probes for the detection and visualisation of Gram-positive bacteria by a range of methods, including plate reader quantification, flow cytometry analysis, high-resolution microscopy imaging, and single cell microfluidics analysis. In parallel, we demonstrate their utility in measuring outer-membrane permeabilisation of Gram-negative bacteria. The probes are useful tools that may facilitate detection of infections and development of new antibiotics., (© 2023. The Author(s).)

The myxomycete Fuligo septica , colloquially referred to as "dog vomit fungus", forms vibrant yellow fruiting bodies (aethalia) on wood chips during warm and humid conditions in spring. In 2018, ideal climatic conditions in Sydney, Australia, provided a rare opportunity to access abundant quantities of F. septica aethalia, which enabled the isolation, purification, structure elucidation, and biological screening of two avenalumamide pyrones, fuligopyrone ( 1 ) and fuligopyrone B ( 2 ). While 1 and 2 did not exhibit any appreciable biological activity, their significant UV absorption at 325 nm suggested they may be acting as transient sunscreens to help protect the fruiting mass from exposure to sunlight. In support of this hypothesis, exposing a solution of 2 to direct sunlight for 5 min resulted in rapid equilibration with a mixture of 2 E ,4 Z -fuligopyrone B ( 10 ) and 2 Z ,4 E -fuligopyrone B ( 11 ) photoisomers.

Drug-resistant Gram-positive bacterial infections are still a substantial burden on the public health system, with two bacteria ( Staphylococcus aureus and Streptococcus pneumoniae ) accounting for over 1.5 million drug-resistant infections in the United States alone in 2017. In 2019, 250,000 deaths were attributed to these pathogens globally. We have developed a preclinical glycopeptide antibiotic, MCC5145, that has excellent potency (MIC 90 ≤ 0.06 μg/ml) against hundreds of isolates of methicillin-resistant S. aureus (MRSA) and other Gram-positive bacteria, with a greater than 1000-fold margin over mammalian cell cytotoxicity values. The antibiotic has therapeutic in vivo efficacy when dosed subcutaneously in multiple murine models of established bacterial infections, including thigh infection with MRSA and blood septicemia with S. pneumoniae , as well as when dosed orally in an antibiotic-induced Clostridioides difficile infection model. MCC5145 exhibited reduced nephrotoxicity at microbiologically active doses in mice compared to vancomycin. MCC5145 also showed improved activity against biofilms compared to vancomycin, both in vitro and in vivo, and a low propensity to select for drug resistance. Characterization of drug action using a transposon library bioinformatic platform showed a mechanistic distinction from other glycopeptide antibiotics.

The emergence of multidrug-resistant bacteria and fungi requires the development of antibiotics and antifungal agents. This review identified natural products isolated from Asian angiosperms with antibacterial and/or antifungal activities and analyzed their distribution, molecular weights, solubility, and modes of action. All data in this review were compiled from Google Scholar, PubMed, Science Direct, Web of Science, ChemSpider, PubChem, and a library search from 1979 to 2022. One hundred and forty-one antibacterial and/or antifungal alkaloids were identified during this period, mainly from basal angiosperms. The most active alkaloids are mainly planar, amphiphilic, with a molecular mass between 200 and 400 g/mol, and a polar surface area of about 50 Å 2 , and target DNA and/or topoisomerase as well as the cytoplasmic membrane. 8-Acetylnorchelerythrine, cryptolepine, 8-hydroxydihydrochelerythrine, 6-methoxydihydrosanguinarine, 2'-nortiliacorinine, pendulamine A and B, rhetsisine, sampangine, tiliacorine, tryptanthrin, tylophorinine, vallesamine, and viroallosecurinine yielded MIC ≤ 1 µg/mL and are candidates for the development of lead molecules.

Background: Older age and frailty are risk factors for poor clinical outcomes following SARS-CoV-2 infection. As such, COVID-19 vaccination has been prioritised for individuals with these factors, but there is concern that immune responses might be impaired due to age-related immune dysregulation and comorbidity. We aimed to study humoral and cellular responses to COVID-19 vaccines in residents of long-term care facilities (LTCFs)., Methods: In this observational cohort study, we assessed antibody and cellular immune responses following COVID-19 vaccination in members of staff and residents at 74 LTCFs across the UK. Staff and residents were eligible for inclusion if it was possible to link them to a pseudo-identifier in the COVID-19 datastore, if they had received two vaccine doses, and if they had given a blood sample 6 days after vaccination at the earliest. There were no comorbidity exclusion criteria. Participants were stratified by age (<65 years or ≥65 years) and infection status (previous SARS-CoV-2 infection [infection-primed group] or SARS-CoV-2 naive [infection-naive group]). Anticoagulated edetic acid (EDTA) blood samples were assessed and humoral and cellular responses were quantified., Findings: Between Dec 11, 2020, and June 27, 2021, blood samples were taken from 220 people younger than 65 years (median age 51 years [IQR 39-61]; 103 [47%] had previously had a SARS-CoV-2 infection) and 268 people aged 65 years or older of LTCFs (median age 87 years [80-92]; 144 [43%] had a previous SARS-CoV-2 infection). Samples were taken a median of 82 days (IQR 72-100) after the second vaccination. Antibody responses following dual vaccination were strong and equivalent between participants younger then 65 years and those aged 65 years and older in the infection-primed group (median 125 285 Au/mL [1128 BAU/mL] for <65 year olds vs 157 979 Au/mL [1423 BAU/mL] for ≥65 year olds; p=0·47). The antibody response was reduced by 2·4-times (467 BAU/mL; p≤0·0001) in infection-naive people younger than 65 years and 8·1-times (174 BAU/mL; p≤0·0001) in infection-naive residents compared with their infection-primed counterparts. Antibody response was 2·6-times lower in infection-naive residents than in infection-naive people younger than 65 years (p=0·0006). Impaired neutralisation of delta (1.617.2) variant spike binding was also apparent in infection-naive people younger than 65 years and in those aged 65 years and older. Spike-specific T-cell responses were also significantly enhanced in the infection-primed group. Infection-naive people aged 65 years and older (203 SFU per million [IQR 89-374]) had a 52% lower T-cell response compared with infection-naive people younger than 65 years (85 SFU per million [30-206]; p≤0·0001). Post-vaccine spike-specific CD4 T-cell responses displayed single or dual production of IFN-γ and IL-2 were similar across infection status groups, whereas the infection-primed group had an extended functional profile with TNFα and CXCL10 production., Interpretation: These data reveal suboptimal post-vaccine immune responses within infection-naive residents of LTCFs, and they suggest the need for optimisation of immune protection through the use of booster vaccination., Funding: UK Government Department of Health and Social Care., Competing Interests: LS reports grants from the Department of Health and Social Care during the study and is a member of the Social Care Working Group, which reports to the Scientific Advisory Group for Emergencies. AH is a member of the New and Emerging Respiratory Virus Threats Advisory Group at the Department of Health. All other authors declare no competing interests., (© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.)

We studied humoral and cellular immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 152 long-term care facility staff and 124 residents over a prospective 4-month period shortly after the first wave of infection in England. We show that residents of long-term care facilities developed high and stable levels of antibodies against spike protein and receptor-binding domain. Nucleocapsid-specific responses were also elevated but waned over time. Antibodies showed stable and equivalent levels of functional inhibition against spike-angiotensin-converting enzyme 2 binding in all age groups with comparable activity against viral variants of concern. SARS-CoV-2 seropositive donors showed high levels of antibodies to other beta-coronaviruses but serostatus did not impact humoral immunity to influenza or other respiratory syncytial viruses. SARS-CoV-2-specific cellular responses were similar across all ages but virus-specific populations showed elevated levels of activation in older donors. Thus, survivors of SARS-CoV-2 infection show a robust and stable immunity against the virus that does not negatively impact responses to other seasonal viruses., (© 2022. The Author(s).)

The brevijanazines are novel p -nitrobenzoylated piperazines isolated from Aspergillus brevijanus . Their structures were elucidated by spectroscopic analysis, X-ray crystallography and total synthesis. Heterologous biosynthesis, precursor feeding and in vitro microsomal assays unveiled the biosynthetic pathway to the brevijanazines, featuring a cytochrome P450 oxygenase that converts p -aminobenzoic acid to p -nitrobenzoic acid.

The secondary metabolites of endemic plants from the Rutaceae family, such as Burkillanthusmalaccensis (Ridl.) Swingle from the rainforest of Malaysia, has not been studied. Burkillanthusmalaccensis (Ridl.) Swingle may produce antibacterial and antibiotic-potentiating secondary metabolites. Hexane, chloroform, and methanol extracts of leaves, bark, wood, pericarps, and endocarps were tested against bacteria by broth microdilution assay and their antibiotic-potentiating activities. Chromatographic separations of hexane extracts of seeds were conducted to investigate effective phytochemicals and their antibacterial activities. Molecular docking studies of werneria chromene and dihydroxyacidissiminol against SARS-CoV-2 virus infection were conducted using AutoDock Vina. The methanol extract of bark inhibited the growth of Staphylococcusaureus, Escherichiacoli, and Pseudomonasaeruginosa with the minimum inhibitory concentration of 250, 500, and 250 µg/mL, respectively. The chloroform extract of endocarps potentiated the activity of imipenem against imipenem-resistant Acinetobacterbaumannii. The hexane extract of seeds increased the sensitivity of P. aeruginosa against ciprofloxacin and levofloxacin. The hexane extract of seeds and chloroform extract of endocarps were chromatographed, yielding werneria chromene and dihydroxyacidissiminol. Werneria chromene was bacteriostatic for P.aeruginosa and P.putida, with MIC/MBC values of 1000 > 1000 µg/mL. Dihydroxyacidissiminol showed the predicted binding energies of −8.1, −7.6, −7.0, and −7.5 kcal/mol with cathepsin L, nsp13 helicase, SARS-CoV-2 main protease, and SARS-CoV-2 spike protein receptor-binding domain S-RBD. Burkillanthusmalaccensis (Ridl.) Swingle can be a potential source of natural products with antibiotic-potentiating activity and that are anti-SARS-CoV-2.

N -benzyl-cinchonidinium bromide, C 26 H 29 N 2 O + ·Br - , with the systematic name ( R )-[(2 S ,4 S ,5 R )-1-benzyl-5-ethenyl-1-azoniabi-cyclo-[2.2.2]octan-2-yl](quinolin-4-yl)-methanol bromide, is a quaternary ammonium salt of the cinchona alkaloid cinchonidine. This salt is widely used as a chiral phase-transfer catalyst and chiral resolution agent. Both classical and non-classical hydrogen-bonding inter-actions, as well as anion effects have been shown to play key mechanistic roles in the catalysis of cinchona alkaloids. In an effort to understand the effects of water on these inter-molecular inter-actions, the structures of anhydrous N -benzyl-cinchonidinium bromide, (I), and the sesquihydrate, C 26 H 29 N 2 O + ·Br - ·1.5H 2 O, (II), were determined., (© Janzen et al. 2022.)

There is an urgent global need for new strategies and drugs to control and treat multidrug-resistant bacterial infections. In 2017, the World Health Organization (WHO) released a list of 12 antibiotic-resistant priority pathogens and began to critically analyze the antibacterial clinical pipeline. This review analyzes "traditional" and "nontraditional" antibacterial agents and modulators in clinical development current on 30 June 2021 with activity against the WHO priority pathogens mycobacteria and Clostridioides difficile. Since 2017, 12 new antibacterial drugs have been approved globally, but only vaborbactam belongs to a new antibacterial class. Also innovative is the cephalosporin derivative cefiderocol, which incorporates an iron-chelating siderophore that facilitates Gram-negative bacteria cell entry. Overall, there were 76 antibacterial agents in clinical development (45 traditional and 31 nontraditional), with 28 in phase 1, 32 in phase 2, 12 in phase 3, and 4 under regulatory evaluation. Forty-one out of 76 (54%) targeted WHO priority pathogens, 16 (21%) were against mycobacteria, 15 (20%) were against C. difficile, and 4 (5%) were nontraditional agents with broad-spectrum effects. Nineteen of the 76 antibacterial agents have new pharmacophores, and 4 of these have new modes of actions not previously exploited by marketed antibacterial drugs. Despite there being 76 antibacterial clinical candidates, this analysis indicated that there were still relatively few clinically differentiated antibacterial agents in late-stage clinical development, especially against critical-priority pathogens. We believe that future antibacterial research and development (R&D) should focus on the development of innovative and clinically differentiated candidates that have clear and feasible progression pathways to the market.

SARS-CoV-2 infection is generally mild or asymptomatic in children but a biological basis for this outcome is unclear. Here we compare antibody and cellular immunity in children (aged 3-11 years) and adults. Antibody responses against spike protein were high in children and seroconversion boosted responses against seasonal Beta-coronaviruses through cross-recognition of the S2 domain. Neutralization of viral variants was comparable between children and adults. Spike-specific T cell responses were more than twice as high in children and were also detected in many seronegative children, indicating pre-existing cross-reactive responses to seasonal coronaviruses. Importantly, children retained antibody and cellular responses 6 months after infection, whereas relative waning occurred in adults. Spike-specific responses were also broadly stable beyond 12 months. Therefore, children generate robust, cross-reactive and sustained immune responses to SARS-CoV-2 with focused specificity for the spike protein. These findings provide insight into the relative clinical protection that occurs in most children and might help to guide the design of pediatric vaccination regimens., (© 2021. The Author(s).)

Purpose: To review current literature on texting as a sustainable intervention of case management in the outpatient setting., Findings: Texting, as a case management intervention, provides the medically complex client with a pathway to achieve care plan goals. Texting increases adherence, communication, and self-management. It can increase client enrollment in disease management programs, while providing support, flexibility, convenience, cost savings, and increased participation., Implications for Case Management Practice: In current practice, such as management of the coronavirus (COVID-19), other pandemics, or natural/environmental disasters, texting is a solution-focused intervention that can deliver and retrieve real-time information to a medically complex population. It can link patients to resources and increase outreach, efficiency, quality, and coordination of care. Texting can promote adherence to appointments, increase medication compliance and disease management interventions, and provide motivational change messages. However, there are legal and regulatory concerns that carry potential consequences and implications that should be approached judiciously (Mellette, 2015). Texting is not one size fits all; it can cause HIPAA breeches, hinder communication with certain populations, confuse health messaging, and replace human communication, thereby reducing staffing in practice., Competing Interests: The author reports no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Residents of long-term care facilities (LTCFs) have been prioritised for COVID-19 vaccination because of the high COVID-19 mortality in this population. Several countries have implemented an extended interval of up to 12 weeks between the first and second vaccine doses to increase population coverage of single-dose vaccination. We aimed to assess the magnitude and quality of adaptive immune responses following a single dose of COVID-19 vaccine in LTCF residents and staff., Methods: From the LTCFs participating in the ongoing VIVALDI study (ISRCTN14447421), staff and residents who had received a first dose of COVID-19 vaccine (BNT162b2 [tozinameran] or ChAdOx1 nCoV-19), had pre-vaccination and post-vaccination blood samples (collected between Dec 11, 2020, and Feb 16, 2021), and could be linked to a pseudoidentifier in the COVID-19 Data Store were included in our cohort. Past infection with SARS-CoV-2 was defined on the basis of nucleocapsid-specific IgG antibodies being detected through a semiquantitative immunoassay, and participants who tested positive on this assay after but not before vaccination were excluded from the study. Processed blood samples were assessed for spike-specific immune responses, including spike-specific IgG antibody titres, T-cell responses to spike protein peptide mixes, and inhibition of ACE2 binding by spike protein from four variants of SARS-CoV-2 (the original strain as well as the B.1.1.7, B.1.351, and P.1 variants). Responses before and after vaccination were compared on the basis of age, previous infection status, role (staff or resident), and time since vaccination., Findings: Our cohort comprised 124 participants from 14 LTCFs: 89 (72%) staff (median age 48 years [IQR 35·5-56]) and 35 (28%) residents (87 years [77-90]). Blood samples were collected a median 40 days (IQR 25-47; range 6-52) after vaccination. 30 (24%) participants (18 [20%] staff and 12 [34%] residents) had serological evidence of previous SARS-CoV-2 infection. All participants with previous infection had high antibody titres following vaccination that were independent of age ( r s =0·076, p=0·70). In participants without evidence of previous infection, titres were negatively correlated with age ( r s =-0·434, p<0·0001) and were 8·2-times lower in residents than in staff. This effect appeared to result from a kinetic delay antibody generation in older infection-naive participants, with the negative age correlation disappearing only in samples taken more than 42 days post-vaccination ( r s =-0·207, p=0·20; n=40), in contrast to samples taken after 0-21 days ( r s =-0·774, p=0·0043; n=12) or 22-42 days ( r s =-0·437, p=0·0034; n=43). Spike-specific cellular responses were similar between older and younger participants. In infection-naive participants, antibody inhibition of ACE2 binding by spike protein from the original SARS-CoV-2 strain was negatively correlated with age ( r s =-0·439, p<0·0001), and was significantly lower against spike protein from the B.1.351 variant (median inhibition 31% [14-100], p=0·010) and the P.1 variant (23% [14-97], p<0·0001) than against the original strain (58% [27-100]). By contrast, a single dose of vaccine resulted in around 100% inhibition of the spike-ACE2 interaction against all variants in people with a history of infection., Interpretation: History of SARS-CoV-2 infection impacts the magnitude and quality of antibody response after a single dose of COVID-19 vaccine in LTCF residents. Residents who are infection-naive have delayed antibody responses to the first dose of vaccine and should be considered for an early second dose where possible., Funding: UK Government Department of Health and Social Care., Competing Interests: AI-S is an employee of the UK Department of Health and Social Care, which funded the study. AH is a member of the New and Emerging Respiratory Virus Threats Advisory Group at the Department of Health. AC reports grants from the UK Department of Health and Social Care during the conduct of the study. LS reports grants from the UK Department of Health and Social Care during the conduct of the study and is a member of the Social Care Working Group, which reports to the Scientific Advisory Group for Emergencies. All other authors declare no competing interests., (© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license.)

Carbapenem-resistant Klebsiella pneumoniae has been classified as an Urgent Threat by the Centers for Disease Control and Prevention (CDC). The combination of two "old" antibiotics, polymyxin and chloramphenicol, displays synergistic killing against New Delhi metallo-β-lactamase (NDM)-producing K. pneumoniae . However, the mechanism(s) underpinning their synergistic killing are not well studied. We employed an in vitro pharmacokinetic/pharmacodynamic model to mimic the pharmacokinetics of the antibiotics in patients and examined bacterial killing against NDM-producing K. pneumoniae using a metabolomic approach. Metabolomic analysis was integrated with an isolate-specific genome-scale metabolic network (GSMN). Our results show that metabolic responses to polymyxin B and/or chloramphenicol against NDM-producing K. pneumoniae involved the inhibition of cell envelope biogenesis, metabolism of arginine and nucleotides, glycolysis, and pentose phosphate pathways. Our metabolomic and GSMN modeling results highlight the novel mechanisms of a synergistic antibiotic combination at the network level and may have a significant potential in developing precision antimicrobial chemotherapy in patients.

Background: Breastfeeding is recommended to improve maternal and infant health globally. Depression has been posited to negatively impact breastfeeding, although potential causal and bidirectional pathways between these two phenomena have not been sufficiently characterized. We therefore conducted a systematic review to critically evaluate available evidence on the relationship between perinatal depressive symptoms and breastfeeding behaviors; to identify knowledge gaps and propose a biosocial research agenda to advance our understanding of this topic., Methods: A systematic search strategy was applied across seven databases. Data were extracted and aggregated using the matrix method to provide a narrative synthesis of findings., Results: Thirty-eight studies from 20 countries spanning 1988 through 2018 fit the inclusion criteria. In general, methods across studies were heterogeneous. Fourteen different tools were used to measure perinatal depressive symptoms. Nearly half the studies did not provide breastfeeding definitions. No studies from low-income countries met inclusion criteria. More than half (63%) of studies demonstrated a negative association between depressive symptoms across the perinatal period and less exclusive breastfeeding and/or shorter breastfeeding durations., Limitations: Heterogeneity in study design, definitions, assessment tools, and measurement time points limited the comparability of study findings. Causality cannot be assessed., Conclusions: Available evidence suggests perinatal depressive symptoms negatively associated with breastfeeding exclusivity and duration, which can lead to suboptimal infant nutrition and detrimental impacts on maternal mental and physical health. To better understand this relationship, we propose including consistent operationalization and assessment of depression and breastfeeding globally and concurrent repeated measures of key biological and social factors., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Curcuma longa and Curcumin have been documented to have a wide spectrum of pharmacological effects, including anti-Acanthamoeba activity. Hence, this study sought to explore the anti-adhesion activity of C. longa extract and Curcumin against Acanthamoeba triangularis trophozoites and cysts in plastic and contact lenses. Our results showed that C. longa extract and Curcumin significantly inhibited the adhesion of A. triangularis trophozoites and cysts to the plastic surface, as investigated by the crystal violet assay (P < 0.05). Also, an 80-90% decrease in adhesion of trophozoites and cysts to the plastic surface was detected following the treatment with C. longa extract and Curcumin at 1/2 × MIC, compared to the control. In the contact lens model, approximately 1 log cells/mL of the trophozoites and cysts was reduced when the cells were treated with Curcumin, when compared to the control. Pre-treatment of the plastic surface with Curcumin at 1/2-MIC reduced 60% and 90% of the adhesion of trophozoites and cysts, respectively. The reduction in 1 Log cells/mL of the adhesion of A. triangularis trophozoites was observed when lenses were pre-treated with both the extract and Curcumin. Base on the results obtained from this study, A. triangularis trophozoites treated with C. longa extract and Curcumin have lost strong acanthopodia, thorn-like projection pseudopodia observed by scanning electron microscope. This study also revealed the therapeutic potentials of C. longa extract and Curcumin, as such, have promising anti-adhesive potential that can be used in the management/prevention of A. triangularis adhesion to contact lenses., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The combination of polymyxins and chloramphenicol possesses synergistic killing activity against New Delhi metallo-β-lactamase (NDM)-producing Klebsiella pneumoniae. This systems study examined the transcriptomic responses to the polymyxin/chloramphenicol combination in clinical NDM-producing K. pneumoniae isolate S01. Klebsiella pneumoniae S01 (initial inoculum ~10 8 CFU/mL) was treated with polymyxin B (1 mg/L, continuous infusion) or chloramphenicol [maximum concentration (C max ) = 8 mg/L, half-life (t 1/2 ) = 4 h], alone or in combination, using an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model to mimic their pharmacokinetics in patients. Transcriptomic profiles of bacterial samples collected at 0, 0.25, 1, 4 and 24 h were examined using RNA sequencing (RNA-Seq). Chloramphenicol monotherapy significantly increased the expression of genes involved in ribosomal synthesis across the entire 24-h treatment, reflective of chloramphenicol-mediated inhibition of protein synthesis. The effect of polymyxin B was rapid and no major pathways were perturbed at later time points (4 h and 24 h). Combination treatment yielded the highest number of differentially expressed genes, including a large number observed following chloramphenicol monotherapy, in particular carbohydrate, nucleotide, amino acid and cell wall metabolism. Notably, chloramphenicol alone and in combination with polymyxin B significantly inhibited the expression of the arn operon that is responsible for lipid A modification and polymyxin resistance. These results indicate that the polymyxin/chloramphenicol combination displayed persistent transcriptomic responses over 24 h mainly on cell envelope synthesis and metabolism of carbohydrates, nucleotides and amino acids., (Copyright © 2020 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.)