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Stackelberg evolutionary game (SEG) theory combines classical and evolutionary game theory to frame interactions between a rational leader and evolving followers. In some of these interactions, the leader wants to preserve the evolving system (e.g. fisheries management), while in others, they try to drive the system to extinction (e.g. pest control). Often the worst strategy for the leader is to adopt a constant aggressive strategy (e.g. overfishing in fisheries management or maximum tolerable dose in cancer treatment). Taking into account the ecological dynamics typically leads to better outcomes for the leader and corresponds to the Nash equilibria in game-theoretic terms. However, the leader's most profitable strategy is to anticipate and steer the eco-evolutionary dynamics, leading to the Stackelberg equilibrium of the game. We show how our results have the potential to help in fields where humans try to bring an evolutionary system into the desired outcome, such as, among others, fisheries management, pest management and cancer treatment. Finally, we discuss limitations and opportunities for applying SEGs to improve the management of evolving biological systems. This article is part of the theme issue 'Half a century of evolutionary games: a synthesis of theory, application and future directions'.

The endangered black-footed ferret (ferret; Mustela nigripes) is a North American carnivore that is actively managed to reestablish self-sustaining wild populations. Behavioral abnormalities have been reported in the breeding program and may be a limiting factor for the species' success. Our goal was to design and test an assay that examines the ferret's exploratory response to odor cues in the form of soiled bedding from opposite-sex conspecifics. Across two breeding seasons, males and females were tested using a T-maze that connected their home nest box to two novel nest boxes containing two different conspecific's soiled bedding. For a control, we provided two clean bedding samples. We ran linear mixed models to determine the effect of sex, type of odor cue (soiled, clean), and order of trial (first, second) on time exploring and proportion of that time spent in each behavior. Ferrets spent the majority of time in the novel nest boxes sniffing (44%), standing alert (27%) and scratching (14%). Males explored for longer than females; however, both displayed similar behaviors. Type of cue influenced behavior, with ferrets sniffing more among soiled cues than clean cues. Habituation to the assay was also observed, with less exploration and more standing alert during the second trial of the day. This study is the first step in characterizing the ferret's exploratory response and provides information regarding vital investigatory and vigilance behaviors. The continual development of this assay to further evaluate reproductive and mate choice behaviors will facilitate more successful breeding of the species., (© 2022 Wiley Periodicals LLC.)

PIWI-interacting RNAs (piRNAs) protect genome integrity by silencing transposon mRNAs and some endogenous mRNAs in various animals. However, C. elegans piRNAs only trigger gene silencing at select predicted targeting sites, suggesting additional cellular mechanisms regulate piRNA silencing. To gain insight into possible mechanisms, we compared the transcriptome-wide predicted piRNA targeting sites to the in vivo piRNA binding sites. Surprisingly, while sequence-based predicted piRNA targeting sites are enriched in 3' UTRs, we found that C. elegans piRNAs preferentially bind to coding regions (CDS) of target mRNAs, leading to preferential production of secondary silencing small RNAs in the CDS. However, our analyses suggest that this CDS binding preference cannot be explained by the action of antisilencing Argonaute CSR-1. Instead, our analyses imply that CSR-1 protects mRNAs from piRNA silencing through two distinct mechanisms-by inhibiting piRNA binding across the entire CSR-1 targeted transcript, and by inhibiting secondary silencing small RNA production locally at CSR-1 bound sites. Together, our work identifies the CDS as the critical region that is uniquely competent for piRNA binding in C. elegans. We speculate the CDS binding preference may have evolved to allow the piRNA pathway to maintain robust recognition of RNA targets in spite of genetic drift. Together, our analyses revealed that distinct mechanisms are responsible for restricting piRNA binding and silencing to achieve proper transcriptome surveillance., (© 2023 Wu et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.)

Background: The risk factors for recovery from COVID-19 dyspnoea are poorly understood. We investigated determinants of recovery from dyspnoea in adults with COVID-19 and compared these to determinants of recovery from non-COVID-19 dyspnoea., Methods: We used data from two prospective cohort studies: PHOSP-COVID (patients hospitalised between March 2020 and April 2021 with COVID-19) and COVIDENCE UK (community cohort studied over the same time period). PHOSP-COVID data were collected during hospitalisation and at 5-month and 1-year follow-up visits. COVIDENCE UK data were obtained through baseline and monthly online questionnaires. Dyspnoea was measured in both cohorts with the Medical Research Council Dyspnoea Scale. We used multivariable logistic regression to identify determinants associated with a reduction in dyspnoea between 5-month and 1-year follow-up., Findings: We included 990 PHOSP-COVID and 3309 COVIDENCE UK participants. We observed higher odds of improvement between 5-month and 1-year follow-up among PHOSP-COVID participants who were younger (odds ratio 1.02 per year, 95% CI 1.01-1.03), male (1.54, 1.16-2.04), neither obese nor severely obese (1.82, 1.06-3.13 and 4.19, 2.14-8.19, respectively), had no pre-existing anxiety or depression (1.56, 1.09-2.22) or cardiovascular disease (1.33, 1.00-1.79), and shorter hospital admission (1.01 per day, 1.00-1.02). Similar associations were found in those recovering from non-COVID-19 dyspnoea, excluding age (and length of hospital admission)., Interpretation: Factors associated with dyspnoea recovery at 1-year post-discharge among patients hospitalised with COVID-19 were similar to those among community controls without COVID-19., Funding: PHOSP-COVID is supported by a grant from the MRC-UK Research and Innovation and the Department of Health and Social Care through the National Institute for Health Research (NIHR) rapid response panel to tackle COVID-19. The views expressed in the publication are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR or the Department of Health and Social Care.COVIDENCE UK is supported by the UK Research and Innovation, the National Institute for Health Research, and Barts Charity. The views expressed are those of the authors and not necessarily those of the funders., Competing Interests: Aziz Sheikh received research grant to Institution from the National Institute of Health and Care Research (NIHR); participated in AstraZeneca's Thrombotic Thrombocytopenic TaskForce (unremunerated); served as an adviser to UK and Scottish Government COVID bodies (unremunerated). LGH received project grant funding to Institution from MedImmune, Novartis UK, Roche/Genentech and GlaxoSmithKline (GSK); payment for lectures from AstraZeneca, Novartis, Roche/Genentech, Sanofi, Circassia, GSK, Chiesi, Teva; travel funding from AstraZeneca, Chiesi, Novartis, Boehringer Ingelheim, Teva and GSK; attended advisory boards/lectures of Novartis, Roche/Genentech, GSK, Evelo Biosciences, Teva, Theravance and Vectura. ADS received grants unrelated to the current work from AstraZeneca, Bayer, GSK, Pfizer, Novartis; consulting fees from AstraZeneca, GSK, Insmed and Bayer; travel support from Chiesi, AstraZeneca and GSK; attended advisory board of Insmed. AH received funding from UK Research and Innovation, National Institute of Health Research, NIHR Manchester BRC; chair NIHR Translational Research Collaboration (unpaid). JDC received funding from AstraZeneca, Genentech, Gilead Sciences, GSK, Insmed, Grifols, Novartis, Boehringer Ingelheim; consulting fees from Astrazeneca, Chiesi, GSK, Insmed, Grifols, Novartis, Boehringer Ingelheim, Pfizer, Janssen, Antabio, Zambon. RAE received funding from NIHR, UKRI, Wolfson Foundation; consulting fees from AstraZeneca; payment for lecture from Boeringher; support for attending meetings from Chiesi; served as ERS Group 01.02 Pulmonary Rehabilitation Secretary (unpaid). AM received funding to Institution from Barts Charity, Pharma Nord, Fischer Family Foundation, DSM Nutritional Products, The Exilarch's Foundation, The Karl R Pfleger Foundation, The AIM Foundation, Synergy Biologics, Cytoplan Ltd, UK NIHR Clinical Research Network, Health Data Research UK BREATHE Hub, UK Research and Innovation Industrial Strategy Challenge Fund, Thornton & Ross, Warburtons, Matthew Isaacs (personal donation), Barbara Boucher (personal donation), Hyphens Pharma. Amisha Singapuri received funding to Institution from UKRI and NIHR. BR received funding from BHF Oxford CRE Transition Intermediate Clinical Research Fellowship; payment for lecture from Axcella Therapeutics. CEB received funding to Institution from MRC, NIHR, Leicester NIHR BRC, GSK, AstraZeneca, Sanofi, Regeneron, Roche, Genentech, BI, Novartis, Chiesi, 4Dpharma, Mologic; consulting fees to institution from GSK, AstraZeneca, Sanofi, Regeneron, Roche, Genentech, BI, Novartis, Chiesi, 4Dpharma, Mologic. MS received funding to Institution from UKRI-MRC and DHSC-NIHR. LVW received funding from UK Research and Innovation, GSK/Asthma + Lung UK, NIHR, Orion Pharma, GSK, Genentech, AstraZeneca; consulting fees to institution from Galapagos, Boehringer Ingelheim; travel support from Genentech; attended Advisory Board for Galapagos; served as Associate Editor for European Respiratory Journal. PEP received funding from NIHR. JKQ received funding to Institution from MRC, HDR UK, GSK, BI, asthma + lung UK, AstraZeneca; consulting fees from GSK, AstraZeneca, Insmed. MM received funding from the PHOSP Covid grant. Other authors declare no conflict of interests., (© 2023 The Author(s).)

Inhalation is a portal-of-entry for aerosols via the respiratory tract where particulate burden accumulates depending on sites of particle deposition, normal clearance mechanisms, and particle solubility. The time available for dissolution of particles is determined by the balance between the rate of particle clearance from a region and their solubility in respiratory solvents. Dissolution is a function of particle surface area divided by particle volume or mass (i.e., dissolution is inversely proportional to the physical diameter of particles). As a conservative approach, investigators commonly assume the complete and instantaneous dissolution of metals from particles depositing in the alveolar region of the respiratory tract. We derived first-order dissolution rate constants to facilitate biokinetic modeling of particle clearance, dissolution, and absorption into the blood. We then modeled pulmonary burden and total dissolution of particles over time as a function of particle size, density, and solubility. We show that assuming poorly soluble particle forms will enter the blood as quickly as highly soluble forms causes an overestimation of concentrations of the compound of interest in blood and other extrapulmonary tissues while also underestimating its pulmonary burden. We conclude that, in addition to modeling dose rates for particle deposition into the lung, physiologically based pharmacokinetic modeling of pulmonary and extrapulmonary tissues concentrations of moderately and poorly soluble materials can be improved by including estimates of lung burden and particle dissolution over time., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The impermeable outer membrane of Pseudomonas aeruginosa is bypassed by antibacterial proteins known as S-type pyocins. Because of their properties, pyocins are investigated as a potential new class of antimicrobials against Pseudomonas infections. Their production and modification, however, remain challenging. To address this limitation, we employed automated fast-flow peptide synthesis for the rapid production of a pyocin S2 import domain. The N-terminal domain sequence (PyS2 NTD ) was synthesized in under 10 h and purified to yield milligram quantities of the desired product. To our knowledge, the 214 amino acid sequence of PyS2 NTD is among the longest peptides produced from a "single-shot" synthesis, i.e., made in a single stepwise route without the use of ligation techniques. Biophysical characterization of the PyS2 NTD with circular dichroism was consistent with the literature reports. Fluorescently labeled PyS2 NTD binds to P. aeruginosa expressing the cognate ferripyoverdine receptor and is taken up into the periplasm. This selective uptake was validated with confocal and super resolution microscopy, flow cytometry, and fluorescence recovery after photobleaching. These modified, synthetic S-type pyocin domains can be used to probe import mechanisms of P. aeruginosa and leveraged to develop selective antimicrobial agents that bypass the outer membrane.

Chronic hepatitis B virus (HBV) infection can lead to substantial morbidity and mortality. Although treatment is not considered curative, antiviral treatment, monitoring, and liver cancer surveillance can reduce morbidity and mortality. Effective vaccines to prevent hepatitis B are available. This report updates and expands CDC's previously published Recommendations for Identification and Public Health Management of Persons with Chronic Hepatitis B Virus Infection (MMWR Recomm Rep 2008;57[No. RR-8]) regarding screening for HBV infection in the United States. New recommendations include hepatitis B screening using three laboratory tests at least once during a lifetime for adults aged ≥18 years. The report also expands risk-based testing recommendations to include the following populations, activities, exposures, or conditions associated with increased risk for HBV infection: persons incarcerated or formerly incarcerated in a jail, prison, or other detention setting; persons with a history of sexually transmitted infections or multiple sex partners; and persons with a history of hepatitis C virus infection. In addition, to provide increased access to testing, anyone who requests HBV testing should receive it, regardless of disclosure of risk, because many persons might be reluctant to disclose stigmatizing risks., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were reported.

Background: The Integrated Exposure Uptake Biokinetic Model for Lead in Children (IEUBK model) was developed by the U.S. Environmental Protection Agency to support assessments of health risks to children from exposures to lead (Pb)., Objective: This study evaluated performance of IEUBK model (v2.0) as it would be typically applied at Superfund sites to predict blood Pb levels (BLLs) in populations of children., Methods: The model was evaluated by comparing model predictions of BLLs to 1144 observed BLLs in a population of children at the Bunker Hill Superfund Site for which there were paired estimates of environmental Pb concentrations., Results: Predicted population geometric mean (GM) BLLs (GM: 3.4 µg/dL, 95% CI: 3.3, 3.5) were within 0.3 µg/dL of observed (GM: 3.6 µg/dL, 95% CI: 3.5, 3.8). The model predicted the observed age trend in GM BLLs and explained ~90% of the variance in the observed age-stratified GM BLLs. The mean predicted probability of exceeding 5 µg/dL (P 5 ) was 27% (95% CI: 24, 29) and observed P 5 was 32% (95% CI: 29, 35), a difference of 5%. Differences between geographic area stratified mean P 5 (predicted minus observed) ranged from -11 to 14% (mean difference: 2.3%)., Significance: Although the more general applicability of these findings to other populations remains to be determined in future studies, our results support applications of the IEUBK model (v2.0) for informing risk-based decisions regarding remediation of soils and mitigation of exposures at Superfund sites where the majority of the exposure unit GM BLLs are expected to be ≤5 µg/dL and where it is desired to limit the predicted probability of exceeding 5 µg/dL to <5%., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

In this didactic paper, we present a theoretical modeling framework, called the G-function, that integrates both the ecology and evolution of cancer to understand oncogenesis. The G-function has been used in evolutionary ecology, but has not been widely applied to problems in cancer. Here, we build the G-function framework from fundamental Darwinian principles and discuss how cancer can be seen through the lens of ecology, evolution, and game theory. We begin with a simple model of cancer growth and add on components of cancer cell competition and drug resistance. To aid in exploration of eco-evolutionary modeling with this approach, we also present a user-friendly software tool. By the end of this paper, we hope that readers will be able to construct basic G function models and grasp the usefulness of the framework to understand the games cancer plays in a biologically mechanistic fashion., (© 2023. The Author(s).)

Background: Persistence of respiratory symptoms, particularly breathlessness, after acute coronavirus disease 2019 (COVID-19) infection has emerged as a significant clinical problem. We aimed to characterise and identify risk factors for patients with persistent breathlessness following COVID-19 hospitalisation., Methods: PHOSP-COVID is a multicentre prospective cohort study of UK adults hospitalised for COVID-19. Clinical data were collected during hospitalisation and at a follow-up visit. Breathlessness was measured by a numeric rating scale of 0-10. We defined post-COVID-19 breathlessness as an increase in score of ≥1 compared to the pre-COVID-19 level. Multivariable logistic regression was used to identify risk factors and to develop a prediction model for post-COVID-19 breathlessness., Results: We included 1226 participants (37% female, median age 59 years, 22% mechanically ventilated). At a median 5 months after discharge, 50% reported post-COVID-19 breathlessness. Risk factors for post-COVID-19 breathlessness were socioeconomic deprivation (adjusted OR 1.67, 95% CI 1.14-2.44), pre-existing depression/anxiety (adjusted OR 1.58, 95% CI 1.06-2.35), female sex (adjusted OR 1.56, 95% CI 1.21-2.00) and admission duration (adjusted OR 1.01, 95% CI 1.00-1.02). Black ethnicity (adjusted OR 0.56, 95% CI 0.35-0.89) and older age groups (adjusted OR 0.31, 95% CI 0.14-0.66) were less likely to report post-COVID-19 breathlessness. Post-COVID-19 breathlessness was associated with worse performance on the shuttle walk test and forced vital capacity, but not with obstructive airflow limitation. The prediction model had fair discrimination (concordance statistic 0.66, 95% CI 0.63-0.69) and good calibration (calibration slope 1.00, 95% CI 0.80-1.21)., Conclusions: Post-COVID-19 breathlessness was commonly reported in this national cohort of patients hospitalised for COVID-19 and is likely to be a multifactorial problem with physical and emotional components., Competing Interests: Conflict of interest: C.E. Brightling, A. Shikotra and M. Sereno report grants from UKRI–MRC/DHSC–NIHR during the conduct of the study. J.D. Chalmers reports grants and personal fees from AstraZeneca and BI, personal fees from Chiesi, grants from Gilead Sciences, grants and personal fees from GSK and Insmed, personal fees from Janssen, grants and personal fees from Novartis, and personal fees from Zambon outside the submitted work, and is an associate editor of this journal. A. De Soyza reports grants, personal fees and other support from AstraZeneca, Bayer, BI, Chiesi, Forest Labs, GSK, Grifols, Insmed, MedImmune, Novartis, Pfizer and 30T outside the submitted work. R.A. Evans reports grants from UKRI/MRC/NIHR during the conduct of the study and speaker fees from BI. A. Horsley reports funding from NIHR Manchester Biomedical Research Centre, grants from the Cystic Fibrosis Foundation, JP Moulton Trust and NIHR, and personal fees from Vertex Pharmaceuticals and Mylan Healthcare, all outside the submitted work. L.G. Heaney reports support from AstraZeneca, BI, Chiesi, GSK and Napp Pharmaceuticals, personal fees from Novartis, Hoffman la Roche/Genentech Inc., Sanofi, Evelo Biosciences, GSK, AstraZeneca, Teva, Theravance and Circassia, grants from Medimmune, Novartis UK, Roche/Genetech Inc and GSK, Amgen, Genetech/Hoffman la Roche, AZ, Medimmune, GSK, Aerocrine and Vitalograph, outside the submitted work. J.R. Hurst reports grants, personal fees and nonfinancial support from pharmaceutical companies that make medicines to treat respiratory disease, outside the submitted work. G. Jenkins reports grants from GSK, grants and personal fees from Pliant Therapeutics, and grants from Biogen, during the conduct of the study; personal fees from Galapagos, other support from Galecto, personal fees and other support from GSK and AstraZeneca, personal fees from Boehringer Ingelheim, Pliant, Bristol Myers Squibb, Chiesi and Roche/Promedior, personal fees and other support from RedX, other support from NuMedii and Nordic Biosciences, personal fees from Veracyte, PatientMPower, Resolution Therapeutics and Vicore, outside the submitted work; and is supported by a National Institute of Health Research Professorship (NIHR ref. RP-2017-08-ST2-014) and is trustee for Action for Pulmonary Fibrosis. P. Pfeffer reports grants from NIHR outside the submitted work. J.K. Quint reports grants and personal fees from AstraZeneca, grants from Bayer, grants and personal fees from BI, Chiesi and GSK, grants from MRC, The Health Foundation and AUK/BLF, outside the submitted work. B. Raman is supported by the British Heart Foundation Oxford Centre of Research Excellence (RE/18/3/34214). A. Sheikh reports grants from HDRUK, NIHR, MRC and ICSF, during the conduct of the study; and is a Member of the Scottish Government's CMO COVID-19 Advisory Group and Standing Committee on Pandemics. A. Singapuri reports grants from MRC during the conduct of the study. S. Siddiqui reports grants from NIHR Leicester Biomedical Research Centre and NIHR PHOSP COVID, personal fees from AstraZeneca, GSK, CSL Behring, Knopp Biosciences, Owlstone Medical and Chiesi, outside the submitted work; and has a patent pending for volatile breath biomarkers of breathlessness. M. Toshner reports personal fees from Actelion/J&J and GSK, and other support from Morphogen-IX, outside the submitted work. L.V. Wain reports grants from GSK and Orion, outside the submitted work. All other authors declare no competing interests., (Copyright ©The authors 2023.)

Many early-career neuroscientists with diverse identities may not have mentors who are more advanced in the neuroscience pipeline and have a congruent identity due to historic biases, laws, and policies impacting access to education. Cross-identity mentoring relationships pose challenges and power imbalances that impact the retention of diverse early career neuroscientists, but also hold the potential for a mutually enriching and collaborative relationship that fosters the mentee's success. Additionally, the barriers faced by diverse mentees and their mentorship needs may evolve with career progression and require developmental considerations. This article provides perspectives on factors that impact cross-identity mentorship from individuals participating in Diversifying the Community of Neuroscience (CNS)-a longitudinal, National Institute of Neurological Disorders and Stroke (NINDS) R25 neuroscience mentorship program developed to increase diversity in the neurosciences. Participants in Diversifying CNS were comprised of 14 graduate students, postdoctoral fellows, and early career faculty who completed an online qualitative survey on cross-identity mentorship practices that impact their experience in neuroscience fields. Qualitative survey data were analyzed using inductive thematic analysis and resulted in four themes across career levels: (1) approach to mentorship and interpersonal dynamics, (2) allyship and management of power imbalance, (3) academic sponsorship, and (4) institutional barriers impacting navigation of academia. These themes, along with identified mentorship needs by developmental stage, provide insights mentors can use to better support the success of their mentees with diverse intersectional identities. As highlighted in our discussion, a mentor's awareness of systemic barriers along with active allyship are foundational for their role., 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 Hill-Jarrett, Ng, Cardenas-Iniguez, Akinsanya, Blanco, Borland, Brown, Clemons, Cushnie, Garcia, George, Hassinan, Hines, Landayan, McCorkle, Meckel, Metcalfe, Montoya, Rose and Warren.)

Streptococcus pneumoniae (SPN) is a globally significant cause of meningitis, the pathophysiology of which involves damage to the brain by both bacterial virulence factors and the host inflammatory response. In most cases of SPN meningitis bacteria translocate from the blood into the central nervous system (CNS). The principal site of SPN translocation into the CNS is not known, with possible portals of entry proposed to be the cerebral or meningeal blood vessels or the choroid plexus. All require SPN to bind to and translocate across the vascular endothelial barrier, and subsequently the basement membrane and perivascular structures, including an additional epithelial barrier in the case of the blood-CSF barrier. The presence of SPN in the CNS is highly inflammatory resulting in marked neutrophilic infiltration. The secretion of toxic inflammatory mediators by activated neutrophils within the CNS damages pathogen and host alike, including the non-replicative neurons which drives morbidity and mortality. As with the translocation of SPN, the recruitment of neutrophils into the CNS in SPN meningitis necessitates the translocation of neutrophils from the circulation across the vascular barrier, a process that is tightly regulated under basal conditions - a feature of the 'immune specialization' of the CNS. The brain barriers are therefore central to SPN meningitis, both through a failure to exclude bacteria and maintain CNS sterility, and subsequently through the active recruitment and/or failure to exclude circulating leukocytes. The interactions of SPN with these barriers, barrier inflammatory responses, along with their therapeutic implications, are explored in this review., 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 Gil, Wall, Noursadeghi and Brown.)

The aim of this systematic review is not only to analyse the accuracy of clinical examination and radiological preoperative assessment of mandibular invasion reported in isolation, but to highlight those reports that have combined them. A total of 1636 titles and abstracts published between 1995 - 2000 were screened following a literature search in PubMed. Keywords were "mandible" and "squamous cell carcinoma". A total of 90 full manuscripts were reviewed with 24 meeting defined inclusion/exclusion criteria and yielding the data reported. The most sensitive test was single photon emission tomography with eight out of the 10 studies reporting sensitivity higher than 95%. Magnetic resonance imaging (MRI) demonstrated superior sensitivity but was less specific than computed tomography (CT). A single report attempted to report the combined CT and MRI scans with a separate expert reporting but did not result in more reliable detection. Periosteal stripping was not reported, and there was insufficient data to establish the value of new technologies. This review confirms that, to our knowledge, there are no reliable data on the results of combining imaging techniques with or without clinical examination. It emphasises the lack of data for the combination of preoperative techniques to enhance safe oncological resection of the mandible. Based on the evidence gathered in this review an algorithm of assessment of possible mandibular invasion is proposed. With new technologies available and 3-dimensional models to help plan the mandibular resection and reconstruction, the potential of combining preoperative investigations should be fully realised through prospective research., (Crown Copyright © 2022. Published by Elsevier Ltd. All rights reserved.)

Nurses are a critical part of the health care system. Yet the nursing profession continually faces shortages in all specialties. Several causes and issues of concern related to the nursing shortage in nephrology are discussed, including the prevalence of kidney disease and its increasing number of associated comorbidities, which has also heightened the urgent need for nephrology nurses. Data have shown that the lack of nephrology nurses caring for patients with kidney disease impacts patient outcomes and nephrology nurse burnout. Strategies must be implemented to manage these growing needs that affect both patient outcomes and nurse staffing. This article aims to identify methods to combat the nursing shortage, promote recruitment and retention strategies for nephrology nurses, and discuss leadership issues related to the topic., Competing Interests: The authors reported no actual or potential conflict of interest in relation to this nursing continuing professional development (NCPD) activity., (Copyright© by the American Nephrology Nurses Association.)

Infections by Acinetobacter species are recognized as a serious global threat due to causing severe disease and their high levels of antibiotic resistance. Acinetobacter baumannii is the most prevalent pathogen in the genus, but infection by Acinetobacter nosocomialis has been reported widely. Diagnosis of patients with A. baumannii infection is often misdiagnosed with other Acinetobacter species, especially A. nosocomialis. This study investigated whether there were significant differences in clinical outcomes between patients infected with A. baumannii versus A. nosocomialis in Northeast Thailand, and to characterize serological responses to infection with these pathogens. The results show that A. baumannii had higher levels of multidrug resistance. Despite this, clinical outcomes for infection with A. baumannii or A. nosocomialis were similar with mortalities of 33% and 36%, respectively. Both pathogens caused community-acquired infections (A. baumannii 35% and A. nosocomialis 29% of cases). Plasma from uninfected healthy controls contained IgG antibody that recognized both organisms, and infected patients did not show a significantly enhanced antibody response from the first week versus 2 weeks later. Finally, the patterns of antigen recognition for plasma IgG were similar for patients infected with A. baumannii or A. nosocomialis infection, and distinct to the pattern for patients infected with non-Acinetobacter. In conclusion, our data revealed that infection with A. nosocomialis was associated with a similarly high level of mortality as infection with A. baumannii, the high rate of community-acquired infection and antibodies in uninfected individuals suggesting that there is significant community exposure to both pathogens. IMPORTANCE Bacterial infections by Acinetobacter species are global threats due to their severity and high levels of antibiotic resistance. A. baumannii is the most common pathogen in the genus; however, infection by A. nosocomialis has also been widely reported but is thought to be less severe. In this study, we have prospectively investigated 48 reported cases of A. baumannii infection in Northeast Thailand, and characterized the serological responses to infection. We found that 14 (29%) of these infections were actually caused by A. nosocomialis. Furthermore, the incidence of antibiotic resistance among A. nosocomialis strains, APACHE II scores, and mortality for patients infected with A. nosocomialis were much higher than published data. Both A. baumannii and A. nosocomialis had unexpectedly mortality rates of over 30%, and both pathogens caused a high rate of community-acquired infections. Importantly, background antibodies in uninfected individuals suggest significant community exposure to both pathogens in the environment.

We identify critical conserved and mutated genes through a theoretical model linking a gene’s fitness contribution to its observed mutational frequency in a clinical cohort. “Passenger” gene mutations do not alter fitness and have mutational frequencies determined by gene size and the mutation rate. Driver mutations, which increase fitness (and proliferation), are observed more frequently than expected. Non-synonymous mutations in essential genes reduce fitness and are eliminated by natural selection resulting in lower prevalence than expected. We apply this “evolutionary triage” principle to TCGA data from EGFR-mutant, KRAS-mutant, and NEK (non-EGFR/KRAS) lung adenocarcinomas. We find frequent overlap of evolutionarily selected non-synonymous gene mutations among the subtypes suggesting enrichment for adaptations to common local tissue selection forces. Overlap of conserved genes in the LUAD subtypes is rare suggesting negative evolutionary selection is strongly dependent on initiating mutational events during carcinogenesis. Highly expressed genes are more likely to be conserved and significant changes in expression (>20% increased/decreased) are common in genes with evolutionarily selected mutations but not in conserved genes. EGFR-mut cancers have fewer average mutations (89) than KRAS-mut (228) and NEK (313). Subtype-specific variation in conserved and mutated genes identify critical molecular components in cell signaling, extracellular matrix remodeling, and membrane transporters. These findings demonstrate subtype-specific patterns of co-adaptations between the defining driver mutation and somatically conserved genes as well as novel insights into epigenetic versus genetic contributions to cancer evolution.

Introduction: This study aimed to assess data relevancy and data quality of the Innovation in Medical Evidence Development and Surveillance System Distributed Database (IMEDS-DD) for diabetes research and to evaluate comparability of its type 2 diabetes cohort to the general type 2 diabetes population., Research Design and Methods: A retrospective study was conducted using the IMEDS-DD. Eligible members were adults with a medical encounter between April 1, 2018 and March 31, 2019 (index period). Type 2 diabetes and co-existing conditions were determined using all data available from April 1, 2016 to the most recent encounter within the index period. Type 2 diabetes patient characteristics, comorbidities and hemoglobin A 1c (HbA 1c ) values were summarized and compared with those reported in national benchmarks and literature., Results: Type 2 diabetes prevalence was 12.6% in the IMEDS-DD. Of 4 14 672 patients with type 2 diabetes, 52.8% were male, and the mean age was 65.0 (SD 13.3) years. Common comorbidities included hypertension (84.5%), hyperlipidemia (82.8%), obesity (45.3%), and cardiovascular disease (44.7%). Moderate-to-severe chronic kidney disease was observed in 20.2% patients. The most commonly used antihyperglycemic agents included metformin (35.7%), sulfonylureas (14.8%), and insulin (9.9%). Less than one-half (48.9%) had an HbA 1c value recorded. These findings demonstrated the notable similarity in patient characteristics between type 2 diabetes populations identified within the IMEDS-DD and other large databases., Conclusions: Despite the limitations related to HbA 1c data, our findings indicate that the IMEDS-DD contains robust information on key data elements to conduct pharmacoepidemiological studies in diabetes, including member demographic and clinical characteristics and health services utilization., Competing Interests: Competing interests: TW and SRC are employees of Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc, Rahway, New Jersey, USA, who may own stock and/or stock options in Merck & Co, Inc, Rahway, New Jersey, USA., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The US Food and Drug Administration (FDA) created the Sentinel System in response to a requirement in the FDA Amendments Act of 2007 that the agency establish a system for monitoring risks associated with drug and biologic products using data from disparate sources. The Sentinel System has completed hundreds of analyses, including many that have directly informed regulatory decisions. The Sentinel System also was designed to support a national infrastructure for a learning health system. Sentinel governance and guiding principles were designed to facilitate Sentinel's role as a national resource. The Sentinel System infrastructure now supports multiple non-FDA projects for stakeholders ranging from regulated industry to other federal agencies, international regulators, and academics. The Sentinel System is a working example of a learning health system that is expanding with the potential to create a global learning health system that can support medical product safety assessments and other research., (Published by Oxford University Press on behalf of the American Medical Informatics Association 2022.)

This paper develops and analyzes a Markov chain model for the treatment of cancer. Cancer therapy is modeled as the patient's Markov Decision Problem, with the objective of maximizing the patient's discounted expected quality of life years. Patients make decisions on the duration of therapy based on the progression of the disease as well as their own preferences. We obtain a powerful analytic decision tool through which patients may select their preferred treatment strategy. We illustrate the tradeoffs patients in a numerical example and calculate the value lost to a cohort in suboptimal strategies. In a second model patients may make choices to include drug holidays. By delaying therapy, the patient temporarily forgoes the gains of therapy in order to delay its side effects. We obtain an analytic tool that allows numerical approximations of the optimal times of delay., 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 © 2022 Elsevier Ltd. All rights reserved.)

Persistent breathlessness >28 days after acute COVID-19 infection has been identified as a highly debilitating post-COVID symptom. However, the prevalence, risk factors, mechanisms and treatments for post-COVID breathlessness remain poorly understood. We systematically searched PubMed and Embase for relevant studies published from 1 January 2020 to 1 November 2021 (PROSPERO registration number: CRD42021285733) and included 119 eligible papers. Random-effects meta-analysis of 42 872 patients with COVID-19 reported in 102 papers found an overall prevalence of post-COVID breathlessness of 26% (95% CI 23-29) when measuring the presence/absence of the symptom, and 41% (95% CI 34-48) when using Medical Research Council (MRC)/modified MRC dyspnoea scale. The pooled prevalence decreased significantly from 1-6 months to 7-12 months post-infection. Post-COVID breathlessness was more common in those with severe/critical acute infection, those who were hospitalised and females, and was less likely to be reported by patients in Asia than those in Europe or North America. Multiple pathophysiological mechanisms have been proposed (including deconditioning, restrictive/obstructive airflow limitation, systemic inflammation, impaired mental health), but the body of evidence remains inconclusive. Seven cohort studies and one randomised controlled trial suggested rehabilitation exercises may reduce post-COVID breathlessness. There is an urgent need for mechanistic research and development of interventions for the prevention and treatment of post-COVID breathlessness., Competing Interests: Conflict of interest: A. Sheikh is a member of the Scottish Government Chief Medical Officer's COVID-19 Advisory Group and its Standing Committee on Pandemics, and a member of the UK Government's Risk Stratification Subgroup and AstraZeneca's Thrombotic Thrombocytopenic Taskforce; all roles are unremunerated. P. Pfeffer reports grants from NIHR, outside the submitted work. M. Shankar-Hari reports grants from National Institute for Health Research, outside the submitted work. C.E. Brightling reports grants from UKRI-MRC/DHSC-NIHR. R.A. Evans reports a grant from NIHR Clinician Scientist Fellowship, outside the submitted work. L.V. Wain reports grants from GSK, grants from Orion, outside the submitted work. L.G. Heaney reports personal fees from Novartis, Hoffman la Roche/Genentech Inc, Sanofi, Evelo Biosciences, GlaxoSmithKline, AstraZeneca, Teva, Theravance and Circassia; grants from Medimmune, Novartis UK, Roche/Genentech Inc, GlaxoSmithKline, Amgen, Genentech/Hoffman la Roche, AstraZeneca, Medimmune, Aerocrine and Vitalograph; and other support from Boehringer Ingelheim, Chiesi and Napp Pharmaceuticals, outside the submitted work. All other authors declare no competing interests., (Copyright ©The authors 2022.)

Background and Objective: Lyme disease (LD) is the fifth most commonly reported notifiable infectious disease in the United States (US) with approximately 35,000 cases reported in 2019 via public health surveillance. However, healthcare claims-based studies estimate that the number of LD cases is >10 times larger than reported through surveillance. To assess the burden of LD using healthcare claims data and the effectiveness of interventions for LD prevention and treatment, it is important to use validated well-performing LD case-finding algorithms ("LD algorithms"). We conducted a systematic literature review to identify LD algorithms used with US healthcare claims data and their validation status., Methods: We searched PubMed and Embase for articles published in English since January 1, 2000 (search date: February 20, 2021), using the following search terms: (1) "Lyme disease"; and (2) "claim*" or "administrative* data"; and (3) "United States" or "the US*". We then reviewed the titles, abstracts, full texts, and bibliographies of the articles to select eligible articles, i.e., those describing LD algorithms used with US healthcare claims data., Results: We identified 15 eligible articles. Of these, seven studies used LD algorithms with LD diagnosis codes only, four studies used LD diagnosis codes and antibiotic dispensing records, and the remaining four studies used serologic test order codes in combination with LD diagnosis codes and antibiotics records. Only one of the studies that provided data on algorithm performance: sensitivity 50% and positive predictive value 5%, and this was based on Lyme disease diagnosis code only., Conclusions: US claims-based LD case-finding algorithms have used diverse strategies. Only one algorithm was validated, and its performance was poor. Further studies are warranted to assess performance for different algorithm designs and inform efforts to better assess the true burden of LD., Competing Interests: BDG, JS, and SP are employees of and recipients of the financial support from Pfizer, Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors (YHN, SW, ABM, SF, and JSB) have declared that no competing interests exist.

Streptococcus pneumoniae (Spn) remains a major cause of global mortality, with extensive antigenic diversity between capsular serotypes that poses an ongoing challenge for vaccine development. Widespread use of pneumococcal conjugate vaccines (PCVs) targeting Spn capsules has greatly reduced infections by vaccine-included serotypes but has led to increased infections by nonincluded serotypes. To date, high cost of PCVs has also limited their usefulness in low-income regions where disease burdens are highest. To overcome these limitations, serotype-independent vaccines are being actively researched. We have developed a whole-cell gamma-irradiated Spn vaccine (termed Gamma-PN) providing serotype-independent protection. We demonstrate that Gamma-PN immunization of mice or rabbits via the clinically relevant intramuscular route induces protein-specific antibodies able to bind numerous nonvaccine encapsulated serotypes, which mediate opsonophagocytic killing and protection against lethal challenges. Gamma-PN induced comparable or superior opsonophagocytic killing assay (OPKA) responses in rabbits to the licensed Prevnar 13 vaccine (PCV13) for vaccine-included serotypes, and a superior response to nonincluded serotypes, including emergent 22F and 35B. Additionally, despite a lower observed reactogenicity, administration of Gamma-PN without adjuvant resulted in higher OPKA responses and improved protection compared to adjuvanted Gamma-PN. To our knowledge, this has not been demonstrated previously for a whole-inactivated Spn vaccine. Eliminating the requirement for adjuvant comes with numerous benefits for clinical applications of this vaccine and poses interesting questions for the inclusion of adjuvant in similar vaccines in development. IMPORTANCE The target pathogen of this study, Streptococcus pneumoniae, kills over 300,000 children <5 years of age every single year, and is the leading cause of pneumonia-associated mortality globally. While the capsular polysaccharide (CPS)-based vaccine Prevnar13 prevents serious illness caused by 13 serotypes, ongoing Prevnar13 use has driven the emergence of nonincluded serotypes as major causes of infection and disease. To overcome this issue, we have developed a next-generation pneumococcal vaccine conferring serotype-independent protection. This vaccine shows equivalent or superior efficacy to Prevnar13, and performance was heightened when our vaccine was administered with no adjuvant. These findings should be considered for similar vaccines in development, as the benefit of adjuvant is often assumed and its automatic inclusion may be limiting product efficacy, resulting in potential abandonment of viable vaccine candidates, or prolonging their time to clinic.

Background: We hypothesize that cancer survival can be improved through adapting treatment strategies to cancer evolutionary dynamics and conducted a phase 1b study in metastatic castration sensitive prostate cancer (mCSPC). Methods: Men with asymptomatic mCSPC were enrolled and proceeded with a treatment break after achieving > 75% PSA decline with LHRH analog plus an NHA. ADT was restarted at the time of PSA or radiographic progression and held again after achieving >50% PSA decline. This on-off cycling of ADT continued until on treatment imaging progression. Results: At data cut off in August 2022, only 2 of the 16 evaluable patients were off study due to imaging progression at 28 months from first dose of LHRH analog for mCSPC. Two additional patients showed PSA progression at 12.4 and 20.5 months and remain on trial. Since none of the 16 patients developed imaging progression at 12 months, the study succeeded in its primary objective of feasibility. The secondary endpoints of median time to PSA progression and median time to radiographic progression have not been reached at a median follow up of 26 months. Conclusions: It is feasible to use an individual’s PSA response and testosterone levels to guide intermittent ADT in mCSPC.

Over a century ago, the phenothiazine dye, methylene blue, was discovered to have both antipsychotic and anti-cancer effects. In the 20th-century, the first phenothiazine antipsychotic, chlorpromazine, was found to inhibit cancer. During the years of elucidating the pharmacology of the phenothiazines, reserpine, an antipsychotic with a long historical background, was likewise discovered to have anti-cancer properties. Research on the effects of antipsychotics on cancer continued slowly until the 21st century when efforts to repurpose antipsychotics for cancer treatment accelerated. This review examines the history of these developments, and identifies which antipsychotics might treat cancer, and which cancers might be treated by antipsychotics. The review also describes the molecular mechanisms through which antipsychotics may inhibit cancer. Although the overlap of molecular pathways between schizophrenia and cancer have been known or suspected for many years, no comprehensive review of the subject has appeared in the psychiatric literature to assess the significance of these similarities. This review fills that gap and discusses what, if any, significance the similarities have regarding the etiology of schizophrenia., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Currently available medications for chronic osteoarthritis pain are only moderately effective, and their use is limited in many patients because of serious adverse effects and contraindications. The primary surgical option for osteoarthritis is total joint replacement (TJR). The objectives of this study were to describe the treatment history of patients with osteoarthritis receiving prescription pain medications and/or intra-articular corticosteroid injections, and to estimate the incidence of TJR in these patients., Methods: This retrospective, multicenter, cohort study utilized health plan administrative claims data (January 1, 2013, through December 31, 2019) of adult patients with osteoarthritis in the Innovation in Medical Evidence Development and Surveillance Distributed Database, a subset of the US FDA Sentinel Distributed Database. Patients were analyzed in two cohorts: those with prevalent use of "any pain medication" (prescription non-steroidal anti-inflammatory drugs [NSAIDs], opioids, and/or intra-articular corticosteroid injections) using only the first qualifying dispensing (index date); and those with prevalent use of "each specific pain medication class" with all qualifying treatment episodes identified., Results: Among 1 992 670 prevalent users of "any pain medication", pain medications prescribed on the index date were NSAIDs (596 624 [29.9%] patients), opioids (1 161 806 [58.3%]), and intra-articular corticosteroids (323 459 [16.2%]). Further, 92 026 patients received multiple pain medications on the index date, including 71 632 (3.6%) receiving both NSAIDs and opioids. Altogether, 20.6% of patients used an NSAID at any time following an opioid index dispensing and 17.2% used an opioid following an NSAID index dispensing. The TJR incidence rates per 100 person-years (95% confidence interval [CI]) were 3.21 (95% CI: 3.20-3.23) in the "any pain medication" user cohort, and among those receiving "each specific pain medication class" were NSAIDs, 4.63 (95% CI: 4.58-4.67); opioids, 7.45 (95% CI: 7.40-7.49); and intra-articular corticosteroids, 8.05 (95% CI: 7.97-8.13)., Conclusions: In patients treated with prescription medications for osteoarthritis pain, opioids were more commonly prescribed at index than NSAIDs and intra-articular corticosteroid injections. Of the pain medication classes examined, the incidence of TJR was highest in patients receiving intra-articular corticosteroids and lowest in patients receiving NSAIDs., (© 2022. The Author(s).)

piRNAs function as guardians of the genome by silencing non-self nucleic acids and transposable elements in animals. Many piRNA factors are enriched in perinuclear germ granules, but whether their localization is required for piRNA biogenesis or function is not known. Here we show that GLH/VASA helicase mutants exhibit defects in forming perinuclear condensates containing PIWI and other small RNA cofactors. These mutant animals produce largely normal levels of piRNA but are defective in triggering piRNA silencing. Strikingly, while many piRNA targets are activated in GLH mutants, we observe that hundreds of endogenous genes are aberrantly silenced by piRNAs. This defect in self versus non-self recognition is also observed in other mutants where perinuclear germ granules are disrupted. Together, our results argue that perinuclear germ granules function critically to promote the fidelity of piRNA-based transcriptome surveillance in C. elegans and preserve self versus non-self distinction., (© 2022. The Author(s).)

Preparation for post-hurricane mosquito control is essential for an effective emergency response to protect public health and promote recovery efforts. Effective pre-hurricane planning includes laying the groundwork for a successful reimbursement application to the Federal Emergency Management Agency. The critical and overlapping need to sustain funding for mosquito control programs is highlighted here in the context of both normal and emergency responses. Community support is an integral component of an effective integrated pest management program and is established over time with appropriate communication and engagement. Experienced mosquito control operators who are familiar with treatment areas are an essential component of successful operations. Here, practical advice is provided to plan, prepare, and implement a successful ground- and aerial-based mosquito control response.

Therapeutic resistance is one of the main reasons for treatment failure in cancer patients. The polyaneuploid cancer cell (PACC) state has been shown to promote resistance by providing a refuge for cancer cells from the effects of therapy and by helping them adapt to a variety of environmental stressors. This state is the result of aneuploid cancer cells undergoing whole genome doubling and skipping mitosis, cytokinesis, or both. In this paper, we create a novel mathematical framework for modeling the eco-evolutionary dynamics of state-structured populations and use this framework to construct a model of cancer populations with an aneuploid and a PACC state. Using in silico simulations, we explore how the PACC state allows cancer cells to (1) survive extreme environmental conditions by exiting the cell cycle after S phase and protecting genomic material and (2) aid in adaptation to environmental stressors by increasing the cancer cell's ability to generate heritable variation (evolvability) through the increase in genomic content that accompanies polyploidization. In doing so, we demonstrate the ability of the PACC state to allow cancer cells to persist under therapy and evolve therapeutic resistance. By eliminating cells in the PACC state through appropriately-timed PACC-targeted therapies, we show how we can prevent the emergence of resistance and promote cancer eradication., (© 2022. The Author(s).)

Recent evidence suggests that a polyaneuploid cancer cell (PACC) state may play a key role in the adaptation of cancer cells to stressful environments and in promoting therapeutic resistance. The PACC state allows cancer cells to pause cell division and to avoid DNA damage and programmed cell death. Transition to the PACC state may also lead to an increase in the cancer cell's ability to generate heritable variation (evolvability). One way this can occur is through evolutionary triage. Under this framework, cells gradually gain resistance by scaling hills on a fitness landscape through a process of mutation and selection. Another way this can happen is through self-genetic modification whereby cells in the PACC state find a viable solution to the stressor and then undergo depolyploidization, passing it on to their heritably resistant progeny. Here, we develop a stochastic model to simulate both of these evolutionary frameworks. We examine the impact of treatment dosage and extent of self-genetic modification on eco-evolutionary dynamics of cancer cells with aneuploid and PACC states. We find that under low doses of therapy, evolutionary triage performs better whereas under high doses of therapy, self-genetic modification is favored. This study generates predictions for teasing apart these biological hypotheses, examines the implications of each in the context of cancer, and provides a modeling framework to compare Mendelian and non-traditional forms of inheritance., (© 2022. The Author(s).)

Host innate and adaptive immunity to infection with Streptococcus pneumoniae is critically dependent on the complement system, demonstrated by the high incidence of invasive S. pneumoniae infection in people with inherited deficiency of complement components. The complement system is activated by S. pneumoniae through multiple mechanisms. The classical complement pathway is activated by recognition of S. pneumoniae by C-reactive protein, serum amyloid P, C1q, SIGN-R1, or natural or acquired antibody. Some S. pneumoniae strains are also recognised by ficolins to activate the mannose binding lectin (MBL) activation pathway. Complement activation is then amplified by the alternative complement pathway, which can also be activated by S. pneumoniae directly. Complement activation results in covalent linkage of the opsonic complement factors C3b and iC3b to the S. pneumoniae surface which promote phagocytic clearance, along with complement-mediated immune adherence to erythrocytes, thereby protecting against septicaemia. The role of complement for mucosal immunity to S. pneumoniae is less clear. Given the major role of complement in controlling infection with S. pneumoniae , it is perhaps unsurprising that S. pneumoniae has evolved multiple mechanisms of complement evasion, including the capsule, multiple surface proteins, and the toxin pneumolysin. There is considerable variation between S. pneumoniae capsular serotypes and genotypes with regards to sensitivity to complement which correlates with ability to cause invasive infections. However, at present we only have a limited understanding of the main mechanisms causing variations in complement sensitivity between S. pneumoniae strains and to non-pathogenic streptococci., 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 © 2022 Gil, Noursadeghi and Brown.)

Excessive neutrophil extravasation can drive immunopathology, exemplified in pyogenic meningitis caused by Streptococcus pneumoniae infection. Insufficient knowledge of the mechanisms that amplify neutrophil extravasation has limited innovation in therapeutic targeting of neutrophil mediated pathology. Attention has focussed on neutrophil interactions with endothelia, but data from mouse models also point to a role for the underlying pericyte layer, as well as perivascular macrophages, the only other cell type found within the perivascular space in the cerebral microvasculature. We tested the hypothesis that human brain vascular pericytes (HBVP) contribute to neutrophil extravasation in a transwell model of the cerebral post-capillary venule. We show that pericytes augment endothelial barrier formation. In response to inflammatory cues, they significantly enhance neutrophil transmigration across the endothelial barrier, without increasing the permeability to small molecules. In our model, neither pericytes nor endothelia responded directly to bacterial stimulation. Instead, we show that paracrine signalling by multiple cytokines from monocyte derived macrophages drives transcriptional upregulation of multiple neutrophil chemokines by pericytes. Pericyte mediated amplification of neutrophil transmigration was independent of transcriptional responses by endothelia, but could be mediated by direct chemokine translocation across the endothelial barrier. Our data support a model in which microbial sensing by perivascular macrophages generates an inflammatory cascade where pericytes serve to amplify production of neutrophil chemokines that are translocated across the endothelial barrier to act directly on circulating neutrophils. In view of the striking redundancy in inflammatory cytokines that stimulate pericytes and in the neutrophil chemokines they produce, we propose that the mechanism of chemokine translocation may offer the most effective therapeutic target to reduce neutrophil mediated pathology in pyogenic meningitis., 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 © 2022 Gil, Venturini, Stirling, Turner, Tezera, Ercoli, Baker, Best, Brown and Noursadeghi.)

Objective: Hemarthrosis after knee trauma often indicates serious joint injury. Few studies have evaluated agreement between clinical examination and findings from magnetic resonance imaging (MRI). We aimed to describe the agreement between acute clinical examination and subacute MRI findings after acute knee trauma with hemarthrosis and the importance of the subspecialty of the examiner., Design: Longitudinal cohort study. Agreement with MRI findings was evaluated by logistic regression., Setting: Helsingborg hospital., Patients: Thousand one hundred forty-five consecutive patients with hemarthrosis after knee trauma., Interventions: Clinical examination and MRI., Main Outcome Measures: agreement between clinical examination and findings from MRI. We considered the radiologist's report as the gold standard., Results: Median time (25th, 75th percentile) from injury to clinical examination was 2 (1, 7) days, and from injury to imaging was 8 (5, 15) days. The overall sensitivity and specificity of clinical examination versus MRI for major ligament injury or lateral patella dislocation (LPD) were 70% [95% confidence interval 67-73) and 66% (61-72), respectively. Orthopedic subspecialist knee had the highest agreement with anterior cruciate ligament rupture (adjusted odds ratios were 1.7 (95% confidence interval 1.2-2.3), 1.9 (1.2-3.0) and 5.9 (3.7-9.5) for orthopedic trainees, orthopedic subspecialists other, and orthopedic subspecialist knee, respectively]. For other ligament injuries and LPD, we did not find statistically significant differences., Conclusions: Clinical diagnosis after acute knee injury is relatively unreliable versus MRI findings even when performed by orthopedic specialists. However, the agreement is improved when the examination is performed by an orthopedic knee subspecialist., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Non-medical factors can have a positive or negative effect on health outcomes and equity. These social determinants of health can play a role in patients' risk of developing kidney failure, as well as their access to kidney transplantation and long-term allograft survival. Nephrology nurses have the opportunity to identify and address negative social determinants of health factors in their patients because they are often patients' first contact in the nephrology setting. The purpose of this article is to promote nephrology nurses' and other nephrology health care providers' understanding of social determinants of health factors, and the fundamental practices for addressing them among kidney transplant candidates and kidney transplant recipients., Competing Interests: The authors reported no actual or potential conflict of interest in relation to this nursing continuing professional development (NCPD) activity., (Copyright© by the American Nephrology Nurses Association.)

The tragedy of the commons occurs when competition among individual members of a group leads to overexploitation of a shared resource to the detriment of the overall population. We hypothesize that cancer cells may engage in a tragedy of the commons when competing for a shared resource such as glucose. To formalize this notion, we create a game theoretic model of glucose uptake based on a cell's investment in transporters relative to that of its neighboring cells. We show that production of transporters per cell increases as the number of competing cells in a microenvironment increases and nutrient uptake per cell decreases. Furthermore, the greater the resource availability, the more intense the tragedy of the commons at the ESS. Based on our simulations, cancer cells produce 2.2-2.7 times more glucose transporters than would produce optimal fitness for all group members. A tragedy of the commons affords novel therapeutic strategies. By simulating GLUT1 inhibitor and glucose deprivation treatments, we demonstrate a synergistic combination with standard-of-care therapies, while also displaying the existence of a trade-off between competition among cancer cells and depression of their gain function. Assuming cancer cell transporter production is heritable, we then show the potential for a sucker's gambit therapy by exploiting this trade-off. By strategically changing environmental conditions, we can take advantage of cellular competition and gain function depression., (© 2022. The Author(s).)

The complement system is required for innate immunity against Acinetobacter baumannii , an important cause of antibiotic resistant systemic infections. A. baumannii strains differ in their susceptibility to the membrane attack complex (MAC) formed from terminal complement pathway proteins, but the reasons for this variation remain poorly understood. We have characterized in detail the complement sensitivity phenotypes of nine A. baumannii clinical strains and some of the factors that might influence differences between strains. Using A. baumannii laboratory strains and flow cytometry assays, we first reconfirmed that both opsonization with the complement proteins C3b/iC3b and MAC formation were inhibited by the capsule. There were marked differences in C3b/iC3b and MAC binding between the nine clinical A. baumannii strains, but this variation was partially independent of capsule composition or size. Opsonization with C3b/iC3b improved neutrophil phagocytosis of most strains. Importantly, although C3b/iC3b binding and MAC formation on the bacterial surface correlated closely, MAC formation did not correlate with variations between A. baumannii strains in their levels of serum resistance. Genomic analysis identified only limited differences between strains in the distribution of genes required for serum resistance, but RNAseq data identified three complement-resistance genes that were differentially regulated between a MAC resistant and two MAC intermediate resistant strains when cultured in serum. These data demonstrate that clinical A. baumannii strains vary in their sensitivity to different aspects of the complement system, and that the serum resistance phenotype was influenced by factors in addition to the amount of MAC forming on the bacterial surface., 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 © 2022 Kamuyu, Ercoli, Ramos-Sevillano, Willcocks, Kewcharoenwong, Kiratisin, Taylor, Wren, Lertmemongkolchai, Stabler and Brown.)

Enhanced recovery after surgery (ERAS) pathway is a multimodal perioperative care pathway designed to achieve early recovery after surgery. ERAS protocols have not yet been well recognized in kidney transplantation. The aim of this study was to investigate the impact of ERAS pathway on early recovery and short-term clinical outcomes of kidney transplant., Methods: This is a single-center retrospective analysis comparing the outcomes of 20 adult kidney transplant recipients subjected to ERAS pathway with 20 adult recipients operated before ERAS with traditional standard of care., Results: There were no significant differences between both groups regarding age, gender, race, dialysis status, living donor percentage, cold ischemia time, and warm ischemia time. Median hospital stay for ERAS patients was 2 d. Overall median pain scores were significantly lower in the ERAS group versus non-ERAS group (morning after surgery pain score 2 versus 5; peak pain score 4.5 versus 10; lowest pain score 0 versus 2; P  = 0.0001). ERAS patients had earlier ambulation (walking) and oral nutrition (regular diet) (first versus second day postoperatively in traditional group). Earlier bowel movement was observed in ERAS patients. There were no significant differences in graft function or 30-d readmission rates between both groups., Conclusions: Implementation of ERAS pathway in kidney transplantation is feasible. Using ERAS is associated with less pain, earlier ambulation and advancement of oral nutrition, and short hospital stay., (Copyright © 2022 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Objectives: The purpose of this study was to examine correlates of taking a COVID-19 test among late middle-aged and older adults using nationally representative data., Methods: Data were obtained from the 2020 Health and Retirement Study midway release COVID-19 module. Our sample was representative of community residing adults aged 51 and over in the United States ( n  = 2,870)., Measurements: We regressed taking a COVID-19 test on demographic characteristics, medical comorbidities, and measures related to the health belief model (i.e., perceived severity, perceived susceptibility, cues to action, and perceived barriers) using logistic regression, stratifying the model by 10-year age categories., Results: Concern about the pandemic was associated with an increase in the likelihood of taking a test among late middle-aged adults. Knowing someone who was diagnosed with COVID-19 was associated with taking a test in most age categories. Financial barriers and knowing someone who died of COVID-19 were not associated with taking a test., Conclusions: How late middle-aged and older adults perceive the COVID-19 pandemic may significantly influence their likelihood of taking a COVID-19 test., Competing Interests: 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., (© 2022 The Authors.)

Unusually large cancer cells with abnormal nuclei have been documented in the cancer literature since 1858. For more than 100 years, they have been generally disregarded as irreversibly senescent or dying cells, too morphologically misshapen and chromatin too disorganized to be functional. Cell enlargement, accompanied by whole genome doubling or more, is observed across organisms, often associated with mitigation strategies against environmental change, severe stress, or the lack of nutrients. Our comparison of the mechanisms for polyploidization in other organisms and non-transformed tissues suggest that cancer cells draw from a conserved program for their survival, utilizing whole genome doubling and pausing proliferation to survive stress. These polyaneuploid cancer cells (PACCs) are the source of therapeutic resistance, responsible for cancer recurrence and, ultimately, cancer lethality., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Carboranes represent a class of compounds with increasing therapeutic potential. However, few general approaches to readily embed carboranes into small molecules, peptides, and proteins are available. We report a strategy based on palladium-mediated C-X (X = C, S, and N) bond formation for the installation of carborane-containing moieties onto small molecules and peptides. We demonstrate the ability of Pd-based reagents with appropriate ligands to overcome the high hydrophobicity of the carborane group and enable chemoselective conjugation of cysteine residues at room temperature in aqueous buffer. Accordingly, carboranes can be efficiently installed on proteins by employing a combination of a bis-sulfonated biarylphosphine-ligated Pd reagent in an aqueous histidine buffer. This method is successfully employed on nanobodies, a fully synthetic affibody, and the antibody therapeutics trastuzumab and cetuximab. The conjugates of the affibody Z HER2 and the trastuzumab antibody retained binding to their target antigens. Conjugated proteins maintain their activity in cell-based functional assays in HER2-positive BT-474 cell lines. This approach enables the rapid incorporation of carborane moieties into small molecules, peptides, and proteins for further exploration in boron neutron capture therapy, which requires the targeted delivery of boron-dense groups.

To investigate local tissue responses to infection we have developed a human model of killed Streptococcus pneumoniae challenge by intradermal injection into the forearm. S. pneumoniae intradermal challenge caused an initial local influx of granulocytes and increases in TNF, IL6 and CXCL8. However, by 48 h lymphocytes were the dominant cell population, mainly consisting of CD4 and CD8 T cells. Increases in local levels of IL17 and IL22 and the high proportion of CD4 cells that were CCR6 + suggested a significant Th17 response. Furthermore, at 48 h the CD4 population contained a surprisingly high proportion of likely memory Treg cells (CCR6 positive and CD45RA negative CD4 + CD25 high CD127 low cells) at 39%. These results demonstrate that the intradermal challenge model can provide novel insights into the human response to S. pneumoniae and that Tregs form a substantial contribution of the normal human lymphocyte response to infection with this important pathogen., (© 2022. The Author(s).)

Background: Lead exposures from legacy sources threaten children's health. Soil in Omaha, Nebraska, was contaminated by emissions from a lead smelter and refinery. The U.S. Environmental Protection Agency excavated and replaced contaminated soil at the Omaha Lead Superfund Site between 1999 and 2016., Objectives: The goal of this study was to assess the association of soil lead level (SLL) and soil remediation status with blood lead levels (BLLs) in children living near or on the site., Methods: We linked information on SLL at residential properties with children's BLLs and assigned remediation status to children's BLL measurements based on whether their measurements occurred during residence at remediated or unremediated properties. We examined the association of SLL and remediation status with elevated BLL (EBLL). We distinguished the roles of temporal trend and the intervention with time-by-intervention-status interaction contrasts. All analyses estimated odds ratios (ORs) with a generalized estimating equations approach to ensure robustness under the complex correlations among BLL measurements. All analyses controlled for relevant covariates including children's characteristics., Results: EBLL ( > 5 μ g / dL ) was associated with both residential SLL [e.g., OR = 2.00 ; 95% confidence interval (CI): 1.83, 2.19; > 400 - 800 vs. ≤ 200  ppm ] and neighborhood SLL [e.g., OR = 1.85 (95% CI: 1.62, 2.11; > 400 - 800 vs. ≤ 200  ppm )] before remediation but only with neighborhood SLL after remediation. The odds of EBLL were higher before remediation [OR 1.52 (95% CI: 1.34, 1.72)]. Similarly, EBLL was positively associated with preremediation status in our interaction analysis [interaction OR = 1.18 (95%CI: 1.02, 1.37)]., Discussion: Residential and neighborhood SLLs were important predictors of EBLLs in children residing near or on this Superfund site. Neighborhood SLL remained a strong predictor following remediation. Our data analyses showed the benefit of soil remediation. Results from the interaction analyses should be interpreted cautiously due to imperfect correspondence of remediation times between remediation and comparison groups. https://doi.org/10.1289/EHP8657.

The literature indicates that perceived neighborhood social cohesion is related to later life physical activity. However, there is no research that examines the role of childhood socioeconomic status (SES) in shaping this relationship. We use data from the Health and Retirement Study (2006-2016; N = 8,754) and a structural equation modeling approach to examine whether perceived neighborhood social cohesion and adulthood wealth mediate the relationship between childhood SES and physical activity. Perceived neighborhood social cohesion and adulthood wealth have small but statistically significant mediational effects in the relationship between childhood SES and physical activity. Research on the relationship between health and place should consider the potential impact of childhood circumstances on the neighborhood one lives in during adulthood.

Current vaccination against Streptococcus pneumoniae uses vaccines based on capsular polysaccharides from selected serotypes and has led to nonvaccine serotype replacement disease. We have investigated an alternative serotype-independent approach, using multiple-antigen vaccines (MAV) prepared from S. pneumoniae TIGR4 lysates enriched for surface proteins by a chromatography step after culture under conditions that induce expression of heat shock proteins (Hsp; thought to be immune adjuvants). Proteomics and immunoblot analyses demonstrated that, compared to standard bacterial lysates, MAV was enriched with Hsps and contained several recognized protective protein antigens, including pneumococcal surface protein A (PspA) and pneumolysin (Ply). Vaccination of rodents with MAV induced robust antibody responses to multiple serotypes, including nonpneumococcal conjugate vaccine serotypes. Homologous and heterologous strains of S. pneumoniae were opsonized after incubation in sera from vaccinated rodents. In mouse models, active vaccination with MAV significantly protected against pneumonia, while passive transfer of rabbit serum from MAV-vaccinated rabbits significantly protected against sepsis caused by both homologous and heterologous S. pneumoniae strains. Direct comparison of MAV preparations made with or without the heat shock step showed no clear differences in protein antigen content and antigenicity, suggesting that the chromatography step rather than Hsp induction improved MAV antigenicity. Overall, these data suggest that the MAV approach may provide serotype-independent protection against S. pneumoniae.

Correlates of protection for COVID-19 vaccines are urgently needed to license additional vaccines. We measured immune responses to four COVID-19 vaccines of proven efficacy using a single serological platform. IgG anti-Spike antibodies were highly correlated with ID50 neutralization in a validated pseudoviral assay and correlated significantly with efficacies for protection against infection with wild-type, alpha and delta variant SARS-CoV-2 virus. The protective threshold for each vaccine was calculated for IgG anti-Spike antibody. The mean protective threshold for all vaccine studies for WT virus was 154 BAU/ml (95 %CI 42-559), and for studies with antibody distributions that enabled precise estimation of thresholds (i.e. leaving out 2-dose mRNA regimens) was 60 BAU/ml (95 %CI 35-102). We propose that the proportion of individuals with responses above the appropriate protective threshold together with the geometric mean concentration can be used in comparative non-inferiority studies with licensed vaccines to ensure that new vaccines will be efficacious., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Dr. Plotkin consults for Janssen and Moderna; Dr. Siber reports personal fees and other from Clover Biopharmaceuticals, personal fees from AdVaccine, other from Vaxxinity personal fees from CanSino, personal fees from CureVac, personal fees from Valneva, personal fees from Vaxart, personal fees and other from Affinivax, outside the submitted work; Dr. Ambrosino reports personal fees from Vaxxinity, personal fees and other from Clover Biopharmaceuticals, outside the submitted work. Dr. Montefiori’s laboratory receives funding from Moderna for clinical sample testing]., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

We propose a model of cancer initiation and progression where tumor growth is modulated by an evolutionary coordination game. Evolutionary games of cancer are widely used to model frequency-dependent cell interactions with the most studied games being the Prisoner's Dilemma and public goods games. Coordination games, by their more obscure and less evocative nature, are left understudied, despite the fact that, as we argue, they offer great potential in understanding and treating cancer. In this paper we present the conditions under which coordination games between cancer cells evolve, we propose aspects of cancer that can be modeled as results of coordination games, and explore the ways through which coordination games of cancer can be exploited for therapy., Competing Interests: The authors have declared that no competing interests exist.