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Abstract: Functional medicine is a patient-centered approach that seeks to address the underlying causes of disease rather than focusing on managing the symptoms. This article explains the core principles of functional medicine and explores the potential for nurses to learn and incorporate functional medicine into their practice. By adopting a functional medicine approach, nurses can promote a more personalized and collaborative health care environment that can improve patient outcomes and empower patients to take an active role in their own health journey., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Lithium is a promising anode material for advanced batteries because of its high capacity and low redox potential. However, its practical use is hindered by nonuniform Li deposition and dendrite formation, leading to safety concerns in Li metal batteries. Our study shows that Ag-based materials enhance the uniformity of Li deposition on Ag-modified Li (AgLi) surfaces, thereby addressing these key challenges. This improvement is due to the strong affinity of Ag for Li, which promotes uniform deposition and dissolution. Additionally, the AgLi surface demonstrated an improved cycling stability, which is crucial for long-term battery reliability. Emphasizing our analytical approach, we utilized comprehensive techniques such as Kelvin probe force microscopy (KPFM) and electrochemical atomic force microscopy (EC-AFM) to locally analyze the electrical properties and unravel the Li deposition/dissolution mechanisms. KPFM analysis provided crucial insights into surface potential variations, while EC-AFM highlighted topographical changes during the Li deposition and dissolution processes, contributing significantly to the development of safer and more efficient Li metal batteries.

Recent studies on reservoir computing essentially involve a high-dimensional dynamical system as the reservoir, which transforms and stores the input as a higher-dimensional state for temporal and nontemporal data processing. We demonstrate here a method to predict temporal and nontemporal tasks by constructing virtual nodes as constituting a reservoir in reservoir computing using a nonlinear map, namely, the logistic map, and a simple finite trigonometric series. We predict three nonlinear systems, namely, Lorenz, Rössler, and Hindmarsh-Rose, for temporal tasks and a seventh-order polynomial for nontemporal tasks with great accuracy. Also, the prediction is made in the presence of noise and found to closely agree with the target. Remarkably, the logistic map performs well and predicts close to the actual or target values. The low values of the root mean square error confirm the accuracy of this method in terms of efficiency. Our approach removes the necessity of continuous dynamical systems for constructing the reservoir in reservoir computing. Moreover, the accurate prediction for the three different nonlinear systems suggests that this method can be considered a general one and can be applied to predict many systems. Finally, we show that the method also accurately anticipates the time series of the all the three variable of Rössler system for the future (self-prediction).

Background: Recurrent Takotsubo syndrome (TS) is not uncommon but experience with TS recurrence is inherently limited by the infrequency of the condition itself and incomplete long-term follow-up. There is limited published data on the clinical features and outcomes of patients with recurrent TS. We aimed to describe the clinical characteristics and outcomes of patients with recurrent TS in a large Auckland cohort., Method: The clinical profile, in-hospital, and long-term outcomes were prospectively assessed in consecutive patients with recurrent TS presenting to Auckland's three major hospitals between January 2006 and January 2023., Results: During the study period, 472 TS patients were identified. Of the 467 patients discharged alive after the index event, 45 (9.6%) patients (mean age 62.3±11.0 years), all women, experienced recurrent TS. Median time interval from index event to the first recurrence was 3.14 years (range 27 days to 13.8 years). In 27 (60%) of the 45 patients, the subsequent events involved a stressor (physical triggers, n=8; emotional triggers, n=19). The stressor type differed between the index and recurrent event in 18 (40%) of the 45 patients. Thirteen (28.9%) had a different echocardiographic variant of TS at first recurrence. All patients with recurrent TS were discharged alive. Four patients died late after discharge from the first recurrence, all but one from a non-cardiac cause., Conclusions: One in 10 patients with TS experience recurrent events. These may occur many years later, and both the stressor type and the echocardiographic variant may be different at the recurrent event., Competing Interests: Conflicts of Interest There are no conflicts of interest to disclose., (Copyright © 2024 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Lithium metal is promising for high-capacity batteries because of its high theoretical specific capacity of 3860 mAh g -1 and low redox potential of -3.04 V versus the standard hydrogen electrode. However, it encounters challenges, such as dendrite formation, which poses risks of short circuits and safety hazards. This study examines Li deposition using electrochemical atomic force microscopy (EC-AFM) and Kelvin probe force microscopy (KPFM). KPFM provides insights into local surface potential, while EC-AFM captures the surface response evolution to electrochemical reactions. We selectively removed metallic coatings from current collectors to compare lithium deposition on coated and exposed copper surfaces. Observations from the Ag-coated Cu (Ag/Cu), Pt-coated Cu (Pt/Cu), and Au-coated Cu (Au/Cu) samples revealed variations in lithium deposition. Ag/Cu and Au/Cu exhibited two-dimensional growth, whereas Pt/Cu exhibited three-dimensional growth, highlighting the impact of electrode materials on morphology. These insights advance the development of safer lithium metal batteries.

The blacklegged tick, Ixodes scapularis, is an ectoparasitic arachnid and vector for infectious diseases, including Lyme borreliosis. Here, we investigate the diurnal activity and respiration of wild-caught and lab-reared adult ticks with long-term video recording, multi-animal tracking and high-resolution respirometry. We find male and female ticks are in a more active, more arousable state during circadian night. We find respiration is augmented by light, with dark onset triggering more frequent bouts of discontinuous gas exchange and a higher overall volume of CO 2 respired. Observed inactivity during the day meets the criteria of sleep: homeostatic in nature, rapidly reversible, a characteristic pose, and reduced arousal threshold. Our findings indicate that blacklegged ticks are in a distinct, heightened state of activity and arousability during night and in dark, suggesting this period may carry higher risk for tick bites and subsequent contraction of tick-borne diseases., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Transthoracic echocardiography (TTE) is the most widely available and utilised imaging modality for the screening, diagnosis, and serial monitoring of all abnormalities related to cardiac structure or function. The primary objectives of this document are to provide (1) a guiding framework for treating clinicians of the acceptable indications for the initial and serial TTE assessments of the commonly encountered cardiovascular conditions in adults, and (2) the minimum required standard for TTE examinations and reporting for imaging service providers. The main areas covered within this Position Statement pertain to the TTE assessment of the left and right ventricles, valvular heart diseases, pericardial diseases, aortic diseases, infective endocarditis, cardiac masses, pulmonary hypertension, and cardiovascular diseases associated with cancer treatments or cardio-oncology. Facilitating the optimal use and performance of high quality TTEs will prevent the over or under-utilisation of this resource and unnecessary downstream testing due to suboptimal or incomplete studies., (Copyright © 2024. Published by Elsevier B.V.)

Background: Busulfan is widely used in conditioning regimens to prepare patients for hematopoietic stem cell transplantation. Therapeutic drug monitoring (TDM) is critical due to large inter- and intra-individual variability in busulfan pharmacokinetics, and the risk of adverse consequences of toxicity including hepatic veno-occlusive disease. Busulfan is most commonly measured by liquid chromatography-mass spectrometry (LC-MS/MS), which is not as widely available in clinical laboratories as automated routine clinical chemistry analyzers. The objective was to perform analytical verification of a busulfan immunoassay on the Abbott Alinity c platform., Methods: The MyCare Oncology busulfan immunoassay was configured as a third-party reagent on the Abbott Alinity c. Imprecision, linearity, sample carryover, and onboard stability of reagent studies were evaluated. The performance of the busulfan immunoassay using the Abbott Alinity c was compared to the Beckman Coulter AU480 using sodium heparinized plasma, as well as to LC-MS/MS using lithium heparinized plasma., Results: The imprecision goal of 8% was met, and linearity within the analytical measurement range of 240 to 1700 ng/mL was verified. Sample carryover was negligible, and the reagents were stable onboard for at least 84 days. The busulfan immunoassay correlated well with LC-MS/MS (slope = 0.949, y-intercept = -7.8 ng/mL, r2 = 0.9935) and the Beckman Coulter AU480 (slope = 1.090, y-intercept = -34.5 ng/mL, r2 = 0.9988)., Conclusions: This study demonstrated successful analytical verification of a busulfan third-party immunoassay on the Abbott Alinity c platform. The ability to perform TDM of busulfan on a routine clinical chemistry analyzer will positively impact turnaround times to improve patient outcomes., (© Association for Diagnostics & Laboratory Medicine 2024. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Due to low compliance by bedside nursing with a central line-associated bloodstream infection (CLABSI) prevention bundle and increased CLABSI rates, a mandatory re-education initiative at a 1200-bed university-affiliated hospital was undertaken. Despite this, 2 units, housing high-risk immunocompromised patients, continued to experience increased CLABSI rates. A quality improvement before-after project design in these units replaced bedside nursing staff with 2 nurses from the vascular access team (VAT) to perform central vascular access device (CVAD) dressing changes routinely every 7 days or earlier if needed. The VAT consistently followed the bundled components, including use of chlorhexidine gluconate (CHG)-impregnated dressings on all patients unless an allergy was identified. In this case, a non-CHG transparent semipermeable membrane dressing was used. There were 884 patients with 14 211 CVAD days in the preimplementation period and 1136 patients with 14 225 CVAD days during the postimplementation period. The VAT saw 602 (53.0%) of the 1136 patients, performing at least 1 dressing change in 98% of the patients (n = 589). The combined CLABSI rate for the 2 units decreased from 2.53 per 1000 CVAD days preintervention to 1.62 per 1000 CVAD days postintervention. The estimated incidence rate ratio (IRR) for the intervention was 0.639, a 36.1% reduction in monthly CLABSI rates during the postimplementation period., Competing Interests: Conflict of Interest: The authors declare that they have no conflict of interest., (Copyright © 2024 Infusion Nurses Society.)

SARS-CoV-2 provokes devastating tissue damage by cytokine release syndrome and leads to multi-organ failure. Modeling the process of immune cell activation and subsequent tissue damage is a significant task. Organoids from human tissues advanced our understanding of SARS-CoV-2 infection mechanisms though, they are missing crucial components: immune cells and endothelial cells. This study aims to generate organoids with these components. We established vascular immune organoids from human pluripotent stem cells and examined the effect of SARS-CoV-2 infection. We demonstrated that infections activated inflammatory macrophages. Notably, the upregulation of interferon signaling supports macrophages' role in cytokine release syndrome. We propose vascular immune organoids are a useful platform to model and discover factors that ameliorate SARS-CoV-2-mediated cytokine release syndrome., (© 2024. The Author(s).)

Zika virus (ZIKV) is an emerging flavivirus associated with several neurological diseases such as Guillain-Barré syndrome in adults and microcephaly in newborn children. Its distribution and mode of transmission (via Aedes aegypti and Aedes albopictus mosquitoes) collectively cause ZIKV to be a serious concern for global health. High genetic homology of flaviviruses and shared ecology is a hurdle for accurate detection. Distinguishing infections caused by different viruses based on serological recognition can be misleading as many anti-flavivirus monoclonal antibodies (mAbs) discovered to date are highly cross-reactive, especially those against the envelope (E) protein. To provide more specific research tools, we produced ZIKV E directed hybridoma cell lines and characterized two highly ZIKV-specific mAb clones (mAbs A11 and A42) against several members of the Flavivirus genus. Epitope mapping of mAb A11 revealed glycan loop specificity in Domain I of the ZIKV E protein. The development of two highly specific mAbs targeting the surface fusion protein of ZIKV presents a significant advancement in research capabilities as these can be employed as essential tools to enhance our understanding of ZIKV identification on infected cells ex vivo or in culture.

Purpose: Surface electromyography (sEMG) is a non-invasive technique to characterize muscle electrical activity. The analysis of sEMG signals under muscle fatigue play a crucial part in the branch of neurorehabilitation, sports medicine, biomechanics, and monitoring neuromuscular pathologies. In this work, a method to transform sEMG signals to complex networks under muscle fatigue conditions using Markov transition field (MTF) is proposed. The importance of normalization to a constant Maximum voluntary contraction (MVC) is also considered., Methods: For this, dynamic signals are recorded using two different experimental protocols one under constant load and another referenced to 50% MVC from Biceps brachii of 50 and 45 healthy subjects respectively. MTF is generated and network graph is constructed from preprocesses signals. Features such as average self-transition probability, average clustering coefficient and modularity are extracted., Results: All the extracted features showed statistical significance for the recorded signals. It is found that during the transition from non-fatigue to fatigue, average clustering coefficient decreases while average self-transition probability and modularity increases., Conclusion: The results indicate higher degree of signal complexity during non-fatigue condition. Thus, the MTF approach may be used to indicate the complexity of sEMG signals. Although both datasets showed same trend in results, sEMG signals under 50% MVC exhibited higher separability for the features. The inter individual variations of the MTF features is found to be more for the signals recorded using constant load. The proposed study can be adopted to study the complex nature of muscles under various neuromuscular conditions., Competing Interests: Conflict of interestThe authors have no relevant financial or non-financial interests to disclose., (© Korean Society of Medical and Biological Engineering 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

The SARS-CoV-2 pandemic ignited global efforts to rapidly develop testing, therapeutics, and vaccines. However, the rewards of these efforts were slow to reach many low- to middle-income countries (LMIC) across the African continent and globally. Therefore, two bead-based multiplexed serological assays were developed to determine SARS-CoV-2 exposure across four counties in Liberia. This study was conducted during the summer of 2021 on 189 samples collected throughout Grand Bassa, Bong, Margibi, and Montserrado counties. Our multiplexed immunoassay (MIA) detected elevated exposure to SARS-CoV-2 and multiple variant antigens. Additionally, we detected evidence of exposure to Dengue virus serotype 2, Chikungunya virus, and the seasonal coronavirus NL63. Our multiplexed inhibition test (MINT) was developed from the MIA to observe antibody-mediated inhibition of SARS-CoV-2 spike protein binding to its cognate cellular receptor ACE-2. We detected inhibitory antibodies in the tested Liberian samples, which were collectively consistent with a convalescent serological profile. These complementary assays serve to supplement existing serological testing needs and may enhance the technical capacity of scientifically underrepresented regions globally., Competing Interests: Conflicts of Interest: The authors declare no conflicts of interest.

Feeding is an essential biological process for an organism's growth, reproduction, and survival. This assay aims to measure the food intake of Caenorhabditis elegans (C. elegans), an important parameter when studying the genetics of aging or metabolism. In most species, feeding is determined by measuring the difference between the amount of food provided and the amount left after a given time interval. The method presented here uses the same strategy to determine the feeding of C. elegans. It measures the amount of bacteria, the food source of C. elegans, cleared within 72 h. This method uses 96-well microtiter plates and has allowed the screening of hundreds of drugs for their ability to modulate food intake at a speed and depth not possible in other animal models. The strength of this assay is that it allows to measure feeding and lifespan simultaneously and directly measures the disappearance of food and, thus, is based on the same principles used for other organisms, facilitating species-to-species comparison.

Although two vaccines for Zaire ebolavirus (EBOV) have been licensed and deployed successfully to combat recurring outbreaks of Ebolavirus Disease in West Africa, there are no vaccines for two other highly pathogenic members of the Filoviridae, Sudan ebolavirus (SUDV) and Marburg marburgvirus (MARV). The results described herein document the immunogenicity and protective efficacy in cynomolgus macaques of a single-vial, thermostabilized (lyophilized) monovalent (SUDV) and bivalent (SUDV & MARV) protein vaccines consisting of recombinant glycoproteins (GP) formulated with a clinical-grade oil-in-water nanoemulsion adjuvant (CoVaccine HT™). Lyophilized formulations of the vaccines were reconstituted with Water for Injection and used to immunize groups of cynomolgus macaques before challenge with a lethal dose of a human SUDV or MARV isolate. Sera collected after each of the three immunizations showed near maximal GP-binding IgG concentrations starting as early as the second dose. Most importantly, the vaccine candidates (monovalent or bivalent) provided 100% protection against severe and lethal filovirus disease after either SUDV or MARV infection. Although mild, subclinical infection was observed in a few macaques, all vaccinated animals remained healthy and survived the filovirus challenge. These results demonstrate the value that thermostabilized protein vaccines could provide for addressing an important gap in preparedness for future filovirus outbreaks., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Axel T. Lehrer and Oreola Donini are named inventors on a patent covering multivalent filovirus subunit vaccines (U.S. Patent 11,433,129B2). Jake Yalley-Ogunro, Mehtap Cabus, Sara Nezami, Fabian Paz, Hanne Andersen Elyard are current employees of BIOQUAL, Inc. Oreola Donini is a current employee of Soligenix Inc. All other authors declare no competing interests., (Copyright © 2023. Published by Elsevier Ltd.)

Through an ambitious change management initiative titled "No One Waits (NOW)," Bluewater Health leaders enlisted staff to take ownership of reducing wait times by identifying barriers to transitions within the hospital and to the community. The approach shifted the hospital's culture to overcome those impediments and succeed in reducing wait times dramatically, including compared with peers. Meanwhile, overall patient experience ratings improved and staff trust increased. These changes have been maintained over several years and have resulted in better management of patient volumes during the COVID-19 pandemic and the current health human resources crisis., (Copyright © 2024 Longwoods Publishing.)

In order to capture the drought impacts on seed quality acquisition in Brassica napus and its potential interaction with early biotic stress, seeds of the 'Express' genotype of oilseed rape were characterized from late embryogenesis to full maturity from plants submitted to reduced watering (WS) with or without pre-occurring inoculation by the telluric pathogen Plasmodiophora brassicae (Pb + WS or Pb, respectively), and compared to control conditions (C). Drought as a single constraint led to significantly lower accumulation of lipids, higher protein content and reduced longevity of the WS-treated seeds. In contrast, when water shortage was preceded by clubroot infection, these phenotypic differences were completely abolished despite the upregulation of the drought sensor RD20. A weighted gene co-expression network of seed development in oilseed rape was generated using 72 transcriptomes from developing seeds from the four treatments and identified 33 modules. Module 29 was highly enriched in heat shock proteins and chaperones that showed a stronger upregulation in Pb + WS compared to the WS condition, pointing to a possible priming effect by the early P. brassicae infection on seed quality acquisition. Module 13 was enriched with genes encoding 12S and 2S seed storage proteins, with the latter being strongly upregulated under WS conditions. Cis-element promotor enrichment identified PEI1/TZF6, FUS3 and bZIP68 as putative regulators significantly upregulated upon WS compared to Pb + WS. Our results provide a temporal co-expression atlas of seed development in oilseed rape and will serve as a resource to characterize the plant response towards combinations of biotic and abiotic stresses., (© 2024 The Authors. Physiologia Plantarum published by John Wiley & Sons Ltd on behalf of Scandinavian Plant Physiology Society.)

Parents of children with medical complexities (CMCs) report significant challenges affecting their financial, emotional and social well-being in relation to caring for their child's medical needs. The Complex Care Navigator Program was designed to provide social, emotional and economic support to parents of CMCs. This paper describes the results and outcomes of the program and the challenges experienced during the evaluation process. Overall, results suggest that the program had a positive impact on the parents' psychosocial functioning and social connections. The results demonstrate the importance of providing early screening, psychosocial intervention and peer support., (Copyright © 2024 Longwoods Publishing.)

Chronic stimulation can cause T cell dysfunction and limit the efficacy of cellular immunotherapies. Improved methods are required to compare large numbers of synthetic knockin (KI) sequences to reprogram cell functions. Here, we developed modular pooled KI screening (ModPoKI), an adaptable platform for modular construction of DNA KI libraries using barcoded multicistronic adaptors. We built two ModPoKI libraries of 100 transcription factors (TFs) and 129 natural and synthetic surface receptors (SRs). Over 30 ModPoKI screens across human TCR- and CAR-T cells in diverse conditions identified a transcription factor AP4 (TFAP4) construct that enhanced fitness of chronically stimulated CAR-T cells and anti-cancer function in vitro and in vivo. ModPoKI's modularity allowed us to generate an ∼10,000-member library of TF combinations. Non-viral KI of a combined BATF-TFAP4 polycistronic construct enhanced fitness. Overexpressed BATF and TFAP4 co-occupy and regulate key gene targets to reprogram T cell function. ModPoKI facilitates the discovery of complex gene constructs to program cellular functions., Competing Interests: Declaration of interests F.B. received research awards (Gilead and Kite and Bristol Myers Squibb Foundation Immunonkologie). E.S. was an advisor for Arsenal Biosciences. J.E. is a compensated co-founder at Mnemo Therapeutics and compensated scientific advisor to Cytovia Therapeutics. J.E. owns stocks in Mnemo Therapeutics and Cytovia Therapeutics. J.E. has received a consulting fee from Casdin Capital. The Eyquem lab has received research support from Cytovia Therapeutics and Takeda. T.L.R. is a compensated co-founder, member of the scientific advisory board, and previously worked as the CSO of Arsenal Biosciences. A.T.S. is a founder of Immunai and Cartography Biosciences and receives research funding from Allogene Therapeutics and Merck Research Laboratories. C.T.M. is a compensated Bio+Health Venture Fellow at Andreessen Horowitz. C.J.Y. is founder for and holds equity in DropPrint Genomics (now ImmunAI) and Survey Genomics, a scientific advisory board member for and holds equity in Related Sciences and ImmunAI, a consultant for and holds equity in Maze Therapeutics, and a consultant for TReX Bio, HiBio, ImYoo, and Santa Ana. C.J.Y. has received research support from Chan Zuckerberg Initiative, Chan Zuckerberg Biohub, Genentech, BioLegend, ScaleBio, and Illumina. A.M. is a co-founder of Arsenal Biosciences, Spotlight Therapeutics, and Survey Genomics, serves on the boards of directors at Spotlight Therapeutics and Survey Genomics, is a board observer (and former member of the board of directors) at Arsenal Biosciences, is a member of the scientific advisory boards of Arsenal Biosciences, Spotlight Therapeutics, Survey Genomics, NewLimit, Amgen, Tenaya, and Lightcast, owns stock in Arsenal Biosciences, Spotlight Therapeutics, NewLimit, Survey Genomics, PACT Pharma, Tenaya, and Lightcast and has received fees from Arsenal Biosciences, Spotlight Therapeutics, Survey Genomics, NewLimit, 23andMe, PACT Pharma, Juno Therapeutics, Tenaya, Lightcast, GLG, Gilead, Trizell, Vertex, Merck, Amgen, Genentech, AlphaSights, Rupert Case Management, Bernstein, and ALDA. A.M. is an investor in and informal advisor to Offline Ventures and a client of EPIQ. The Marson laboratory received research support from Juno Therapeutics, Epinomics, Sanofi, GlaxoSmithKline, Gilead, and Anthem. T.L.R., F.B., A.M., R.A., Y.Y.C., C.T.M., and E.S. are listed on patent applications related to this work., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Clinical presentation of Takotsubo Syndrome (TS) mimics acute coronary syndrome (ACS). A score to differentiate TS from ACS would be helpful to facilitate appropriate investigation and management. We have previously developed a clinical score (NSTE-Takotsubo Score) to distinguish women with non-ST-segment elevation myocardial infarction (NSTEMI) from TS with non-ST-segment elevation (NSTE-TS). This study sought to assess the diagnostic validity of this score in an external validation cohort., Methods: The external cohort consisted of women with NSTE-TS (n=110) and NSTEMI (n=113) from two major tertiary hospitals in New Zealand. The five variables in the arithmetic score (range -6 to +5) and their relative weights are: T-wave inversion (TWI) in ≥6 leads (3 points), recent stress (2 points), diabetes mellitus (DM) (-1 point), prior cardiovascular disease (CVD) (-2 points) and presence of ST depression (-3 points). Two clinicians blinded to the diagnoses calculated the score using clinical and electrocardiogram (ECG) data on day 1 post-admission., Results: The NSTE-Takotsubo Score discriminated well between NSTE-TS and NSTEMI. The sensitivity and specificity of a score ≥1 to distinguish NSTE-TS from NSTEMI were 78% and 85%, respectively. The area under the receiver operator curve was 0.78 (95% CI 0.72 to 0.84)., Conclusion: In an external validation cohort, the NSTE-Takotsubo Score was easy to apply and useful to identify women likely to have NSTE-TS on day 1 post-admission., (Copyright © 2023 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

The research review, "Three Decades of Research: The Case for Comprehensive Sex Education," by Goldfarb and Lieberman (2021), purports to show "strong support" for the effectiveness of school-based comprehensive sex education (CSE) at producing many benefits beyond its original goals of preventing teen pregnancy and STDs. We reviewed the evidence the study cites in support of these claims, item by item, and found that 1) 80% of the sources cited as supporting evidence for CSE are not studies of CSE programs and 2) of the few cited studies of actual CSE programs, roughly 90% do not meet recommended scientific standards for evidence of program effectiveness. Important to note, contrary to its claims, the study does not show scientific evidence that comprehensive sex education helps prevent child sex abuse, reduces dating/intimate partner violence or homophobic bullying, or that it should be taught to young children in the early grades. Rather than making "the case for CSE," Goldfarb and Lieberman's review gives the appearance of scientific support to a new CSE agenda that the authors articulate and endorse, which includes early sex education, gender ideology, and social justice theory. However, they do not present scientifically reliable confirmatory evidence for that agenda., (Copyright © 2023 by the National Legal Center for the Medically Dependent & Disabled, Inc.)

Often patients adapt to a decline in their oral condition over time and choose to live in discomfort, and sometimes pain, until it becomes intolerable. Ongoing parafunctional habits and other disease conditions may contribute to and exacerbate the problems. This case report illustrates an innovative approach to a full-mouth rehabilitation by staging complex treatment planning in the restoration of teeth severely damaged by the effects of gastroesophageal reflux disease compounded by clenching. Occlusal landmarks were identified and maintained, which allowed for both case completion and accommodation of the patient's travel commitments. The successful outcome resulted in a grateful patient who could chew comfortably with a stable occlusion and a pleasing, confident smile.

Background:  The Clificol COVID-19 Support Project is an innovative international data collection project aimed at tackling some of the core questions in homeopathy. This paper reports on the further investigation of the genus epidemicus concept during the first wave of the pandemic in the Chinese population., Methods:  The design is an observational clinical case registry study of Chinese patients with confirmed or suspected coronavirus disease 2019 (COVID-19). The symptoms were prospectively collected via a 150-item questionnaire. The concept of genus epidemicus, including the role of treatment individualization, was investigated by analyzing whether presenting symptoms clustered into distinct groups. Two standard statistical analysis techniques were utilized: principal component analysis for extracting the most meaningful symptoms of the dataset; the k -means clustering algorithm for automatically assigning groups based on similarity between presenting symptoms., Results:  20 Chinese practitioners collected 359 cases in the first half of 2020 (766 consultations, 363 prescriptions). The cluster analysis found two to be the optimum number of clusters. These two symptomatic clusters had a high overlap with the two most commonly prescribed remedies in these sub-populations: in cluster 1 there were 297 prescriptions, 95.6% of which were Gelsemium sempervirens ; in cluster 2 there were 61 prescriptions, 95.1% of which were Bryonia alba ., Conclusion:  This is the first study to investigate the notion of genus epidemicus by using modern statistical techniques. These analyses identified at least two distinct symptom pictures. The notion of a single COVID-19 genus epidemicus did not apply in the studied population., Competing Interests: None declared., (The Faculty of Homeopathy. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Precise targeting of large transgenes to T cells using homology-directed repair has been transformative for adoptive cell therapies and T cell biology. Delivery of DNA templates via adeno-associated virus (AAV) has greatly improved knockin efficiencies, but the tropism of current AAV serotypes restricts their use to human T cells employed in immunodeficient mouse models. To enable targeted knockins in murine T cells, we evolved Ark313, a synthetic AAV that exhibits high transduction efficiency in murine T cells. We performed a genome-wide knockout screen and identified QA2 as an essential factor for Ark313 infection. We demonstrate that Ark313 can be used for nucleofection-free DNA delivery, CRISPR-Cas9-mediated knockouts, and targeted integration of large transgenes. Ark313 enables preclinical modeling of Trac-targeted CAR-T and transgenic TCR-T cells in immunocompetent models. Efficient gene targeting in murine T cells holds great potential for improved cell therapies and opens avenues in experimental T cell immunology., Competing Interests: Declaration of interests J.A., W.A.N., J.E., and A.A. are co-inventors on a patent application filed on the subject matter of this study. A.A. is a cofounder and board member at StrideBio and TorqueBio. J.E. is a compensated co-founder at Mnemo Therapeutics and a compensated scientific advisor to Cytovia Therapeutics. J.E. owns stocks in Mnemo Therapeutics and Cytovia Therapeutics. J.E. has received a consulting fee from Casdin Capital, Resolution Therapeutics and Treefrog Therapeutics. The J.E. lab has received research support from Cytovia Therapeutics, Mnemo Therapeutics, and Takeda Pharmaceutical Company., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Zaire ebolavirus, Sudan ebolavirus, and Marburg marburgvirus are the filoviruses most commonly associated with human disease. Previously, we administered a three-dose regimen of trivalent vaccines comprising glycoprotein antigens from each virus in mice and non-human primates (NHPs). The vaccines, which contained a polysorbate 80-stabilized squalane-in-water emulsion adjuvant and were lyophilized from a solution containing trehalose, produced high antibody levels against all three filovirus antigens. Subsequently, single-vial formulations containing a higher concentration of adjuvant were generated for testing in NHPs, but these vaccines elicited lower neutralizing antibody titers in NHPs than previously tested formulations. In order to explain these results, in the current work we measured the size of adjuvant emulsion droplets and the peroxide levels present in the vaccines after lyophilization and reconstitution and tested the effects of these variables on the immune response in mice. Increases in squalane droplet sizes were observed when the ratio of adjuvant to trehalose was increased beyond a critical value, but antibody and neutralizing antibody titers in mice were independent of the droplet size. Higher levels of peroxides in the vaccines correlated with higher concentrations of adjuvant in the formulations, and higher peroxide levels were associated with increased levels of oxidative damage to glycoprotein antigens. Neutralizing titers in mice were inversely correlated with peroxide levels in the vaccines, but peroxide levels could be reduced by adding free methionine, resulting in retention of high neutralizing antibody titers. Overall, the results suggest that oxidation of glycoprotein antigens by peroxides in the polysorbate 80-stabilized squalane-in-water emulsion adjuvant, but not lyophilization-induced increases in adjuvant emulsion droplet size may have been responsible for the decreased neutralizing titers seen in formulations containing higher amounts of adjuvant., Competing Interests: Declaration of Competing Interest The University of Colorado has licensed intellectual property related to thermostabilization of lyophilized vaccines to VitriVax, Inc., a company in which TWR holds equity. OD is an employee of Soligenix, Inc. ATL and OD are inventors on patents related to vaccine technology, including technology specific to filovirus vaccines., (Copyright © 2022 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

To compare the efficacy of the sublabial and modified Denker's procedure in clearance of fungal disease from the anterior wall of maxilla and the pre-maxillary area i.e. the difficult areas of maxillary sinus. A prospective observational study was conducted over a period of 2 months (April 21-June 21) in the ENT department of Sawai Man Singh hospital, Jaipur. All the patients with clinical involvement of the premaxilla or the cheek abutting the anterior wall of maxilla were included in the study population. Cases matched in both groups were subjected to debridement either by the sublabial or the modified denker's approach. Outcomes were measured by assessing the daily CRP values, post-operative DNE every 3 days after pack removal, and imaging at the end of 1 month. Repeat biopsies were performed in patients that still had persistent symptoms after getting operated on. 16 of the 60 patients (26.6%) operated on by the endoscopic approach showed evidence of residual disease on follow-up whereas only 5 patients (9.6%) in the other category had a similar outcome. Most of the recidivism was seen in the anterior maxilla. Lower rates of complications were found following debridement by the sublabial approach. Since the sublabial approach is the most direct approach for the key areas of fungal involvement of maxillary sinus, it is recommended over the modified Denker's procedure for disease clearance from pre maxilla and the anterior wall of maxillary sinus. This view is also supported by the lower rates of complications encountered following the former., Competing Interests: Conflict of interestAll Authors declare that they have no conflict of interest., (© Association of Otolaryngologists of India 2022.)

Worldwide, obesity rates have doubled since the 1980s and in the USA alone, almost 40% of adults are obese, which is closely associated with a myriad of metabolic diseases such as type 2 diabetes and arteriosclerosis. Obesity is derived from an imbalance between energy intake and consumption, therefore balancing energy homeostasis is an attractive target for metabolic diseases. One therapeutic approach consists of increasing the number of brown-like adipocytes in the white adipose tissue (WAT). Whereas WAT stores excess energy, brown adipose tissue (BAT) can dissipate this energy overload in the form of heat, increasing energy expenditure and thus inhibiting metabolic diseases. To facilitate BAT production a high-throughput screening approach was developed on previously known drugs using human Simpson-Golabi-Behmel Syndrome (SGBS) preadipocytes. The screening allowed us to discover that zafirlukast, an FDA-approved small molecule drug commonly used to treat asthma, was able to differentiate adipocyte precursors and white-biased adipocytes into functional brown adipocytes. However, zafirlukast is toxic to human cells at higher dosages. Drug-Initiated Activity Metabolomics (DIAM) was used to investigate zafirlukast as a BAT inducer, and the endogenous metabolite myristoylglycine was then discovered to mimic the browning properties of zafirlukast without impacting cell viability. Myristoylglycine was found to be bio-synthesized upon zafirlukast treatment and was unique in inducing brown adipocyte differentiation, raising the possibility of using endogenous metabolites and bypassing the exogenous drugs to potentially alleviate disease, in this case, obesity and other related metabolic diseases.

Methods: Patients with SCAD on invasive coronary angiography who underwent a follow-up CTCA between 2010 and 2018 at our institute were included. CTCA was reported by two cardiologists-one with knowledge of the SCAD location, and a second blinded. Assessment of dissection healing were made and optimal timing of CTCA was also calculated., Results: A total of 32 patients with 38 non-contiguous SCAD lesions were included (mean age 50.5 ± 8.8 years, 65.6% women). The left circumflex artery was the most commonly affected vessel (34.2%), and 71.1% of lesions occurred in distal or branch vessels. Median time that CTCA was performed was 40.5 days from the index event, and 25 of 38 lesions had healed (65.8%). On blinded reporting, the sensitivity and specificity of CTCA for assessment of dissection healing was 72% and 53.8%, respectively. The optimal timing of CTCA to assess healing was 80 days (AUC 0.774, p=0.006; sensitivity 76.9%, specificity 84.0%). When early CTCA was performed (<80 days), 21 of 24 lesions (87.5%) were unhealed, whereas late CTCA (≥80 days) showed healing in 10 of 14 lesions (71.4%)., Conclusion: The usefulness of CTCA in diagnosing SCAD remains challenging due to limitations in spatial and temporal resolution, particularly in distal vessels. The optimal timing of CTCA to assess dissection healing was 80 days., Competing Interests: Nil

There is considerable interest in developing effective tools to detect Alzheimer's Disease (AD) early in its course, prior to clinical progression [...].

FDA-approved and emergency use-authorized vaccines using new mRNA and viral-vector technology are highly effective in preventing moderate to severe disease; however, information on their long-term efficacy and protective breadth against severe acute respiratory syndrome coronavirus 2 variants of concern (VOCs) is currently scarce. Here, we describe the durability and broad-spectrum VOC immunity of a prefusion-stabilized spike (S) protein adjuvanted with liquid or lyophilized CoVaccine HT in cynomolgus macaques. This recombinant subunit vaccine is highly immunogenic and induces robust spike-specific and broadly neutralizing antibody responses effective against circulating VOCs (B.1.351 [Beta], P.1 [Gamma], and B.1.617 [Delta]) for at least three months after the final boost. Protective efficacy and postexposure immunity were evaluated using a heterologous P.1 challenge nearly three months after the last immunization. Our results indicate that while immunization with both high and low S doses shorten and reduce viral loads in the upper and lower respiratory tract, a higher antigen dose is required to provide durable protection against disease as vaccine immunity wanes. Histologically, P.1 infection causes similar COVID-19-like lung pathology as seen with early pandemic isolates. Postchallenge IgG concentrations were restored to peak immunity levels, and vaccine-matched and cross-variant neutralizing antibodies were significantly elevated in immunized macaques indicating an efficient anamnestic response. Only low levels of P.1-specific neutralizing antibodies with limited breadth were observed in control (nonvaccinated but challenged) macaques, suggesting that natural infection may not prevent reinfection by other VOCs. Overall, these results demonstrate that a properly dosed and adjuvanted recombinant subunit vaccine can provide protective immunity against circulating VOCs for at least three months.

Background: Takotsubo syndrome (TS) is often triggered by an acute physical or emotional stressor. We hypothesised that medium-term prognosis may be better for TS patients with an associated emotional stressor than for those with an acute physical illness., Methods: We identified consecutive TS patients presenting in New Zealand (2006-2018). The clinical presentation and outcomes of TS patients according to types of stressor (physical, emotional or no stressor) were assessed. Post-discharge survival after TS was compared with age- and gender-matched patients after myocardial infarction (MI) and people in the community without known cardiovascular disease (CVD)., Results: Of 632 TS patients (95.9% women, mean age 65.0±11.1 years), 27.4% had an associated acute physical stressor, 46.4% an emotional stressor and 26.2% no evident stressor. In-hospital mortality was similar for each group (1.7%, 1.2%, 0.3% respectively, p=0.29). In a median 4.4 years post-discharge there were 54 deaths (53 non-cardiac). Compared with patients without known CVD, TS patients with physical stress and those with MI were less likely to survive (HR 4.46, 95%CI 3.10-6.42; HR 4.23, 95%CI 3.81-4.70 respectively) but survival for TS patients associated with emotional stress or no stressor was similar (HR 1.11, 95%CI 0.66-1.85; HR 1.08, 95%CI 0.54-2.18, respectively). Recurrence was similar among the three groups (p=0.14)., Conclusion: Takotsubo syndrome associated with physical stressor has a post-discharge mortality risk as high as after MI. In contrast, prognosis for TS triggered by an emotional stressor is excellent, and similar to that of those without known CVD., (Copyright © 2021 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Lassa Fever (LF) is an acute viral hemorrhagic fever caused by Lassa virus (LASV) that is primarily transmitted through contact with wild rodents in West Africa. Although several advanced vaccine candidates are progressing through clinical trials, some effective vaccines are virally vectored and thus require a stringent cold-chain, making distribution to rural and resource-poor areas difficult. Recombinant subunit vaccines are advantageous in this aspect as they can be thermostabilized and deployed with minimal storage and transportation requirements. However, antigen dose and adjuvant formulation must be carefully selected to ensure both the appropriate humoral and cell-mediated immune responses are elicited. In this study, we examine the immunogenicity of a two-step immunoaffinity-purified recombinant LASV glycoprotein (GP) with five clinical- and preclinical-grade adjuvants. Swiss Webster mice immunized intramuscularly with 2 or 3 doses of each vaccine formulation showed complete seroconversion and maximal GP-specific antibody response after two immunizations. Formulations with GPI-0100, LiteVax, Montanide™ ISA 51, and Montanide™ ISA 720 induced both IgG1 and IgG2 antibodies suggesting a balanced Th1/Th2 response, whereas formulation of LASV GP with Alhydrogel elicited a IgG1-dominant response. Splenocytes secreting both Th1 and Th2 cytokines i.e., IFN-γ, TNF-α, IL-2, IL-4 and IL-5, were observed from mice receiving both antigen doses formulated with ISA 720, LiteVax and GPI-0100. However, robust, multifunctional T-cells were only detected in mice receiving a higher dose of LASV GP formulated with GPI-0100. Our results emphasize the importance of careful adjuvant selection and lay the immunological basis for a recombinant subunit protein LF vaccine formulation., Competing Interests: Conflict of Interest: 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.

The speed at which several COVID-19 vaccines went from conception to receiving FDA and EMA approval for emergency use is an achievement unrivaled in the history of vaccine development. Mass vaccination efforts using the highly effective vaccines are currently underway to generate sufficient herd immunity and reduce transmission of the SARS-CoV-2 virus. Despite the most advanced vaccine technology, global recipient coverage, especially in resource-poor areas remains a challenge as genetic drift in naïve population pockets threatens overall vaccine efficacy. In this study, we described the production of insect-cell expressed SARS-CoV-2 spike protein ectodomain constructs and examined their immunogenicity in mice. We demonstrated that, when formulated with CoVaccine HT TM adjuvant, an oil-in-water nanoemulsion compatible with lyophilization, our vaccine candidates elicit a broad-spectrum IgG response, high neutralizing antibody (NtAb) titers against SARS-CoV-2 prototype and variants of concern, specifically B.1.351 (Beta) and P.1. (Gamma), and an antigen-specific IFN-γ secreting response in outbred mice. Of note, different ectodomain constructs yielded variations in NtAb titers against the prototype strain and some VOC. Dose response experiments indicated that NtAb titers increased with antigen dose, but not adjuvant dose, and may be higher with a lower adjuvant dose. Our findings lay the immunological foundation for the development of a dry-thermostabilized vaccine that is deployable without refrigeration., 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., (© 2021 Published by Elsevier Ltd.)

Leaves and flowers are colonized by diverse bacteria that impact plant fitness and evolution. Although the structure of these microbial communities is becoming well-characterized, various aspects of their environmental origin and selection by plants remain uncertain, such as the relative proportion of soilborne bacteria in phyllosphere communities. Here, to address this issue and to provide experimental support for bacteria being filtered by flowers, we conducted common-garden experiments outside and under gnotobiotic conditions. We grew Arabidopsis thaliana in a soil substitute and added two microbial communities from natural soils. We estimated that at least 25% of the phyllosphere bacteria collected from the plants grown in the open environment were also detected in the controlled conditions, in which bacteria could reach leaves and flowers only from the soil. These taxa represented more than 40% of the communities based on amplicon sequencing. Unsupervised hierarchical clustering approaches supported the convergence of all floral microbiota, and 24 of the 28 bacteria responsible for this pattern belonged to the Burkholderiaceae family, which includes known plant pathogens and plant growth-promoting members. We anticipate that our study will foster future investigations regarding the routes used by soil microbes to reach leaves and flowers, the ubiquity of the environmental filtering of Burkholderiaceae across plant species and environments, and the potential functional effects of the accumulation of these bacteria in the reproductive organs of flowering plants., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

Zaire ebolavirus (EBOV), Sudan ebolavirus (SUDV), and Marburg marburgvirus (MARV) are the most prevalent and pathogenic species of filovirus. Previously, we showed that glycoprotein antigens from each virus could be lyophilized to create thermostable monovalent subunit vaccines. However, cross-protection is not expected from the monovalent vaccines and therefore developing a trivalent filovirus vaccine would be desirable. Subunit protein vaccines often require the addition of an adjuvant to sufficiently boost the immunogenicity. Typically, liquid suspensions or emulsions of adjuvants and lyophilized antigens are stored in separate vials to avoid destabilizing interactions and are only mixed immediately before administration. Herein, we describe the development and characterization of monovalent and trivalent filovirus vaccines that are co-lyophilized with a squalane-in-water emulsion adjuvant. We found that the single-vial presentation retained adjuvant particle diameter and zeta potential after lyophilization and reconstitution. Furthermore, the trivalent vaccines elicited high antibody levels against all three antigens in mice and non-human primates. These results advance the prospect of developing a single-vial trivalent filovirus vaccine, which would enable easier distribution and administration of the vaccine to resource-poor areas., Competing Interests: Declaration of Competing Interest The University of Colorado has licensed intellectual property related to thermostabilization of lyophilized vaccines to VitriVax, Inc., a company in which TWR holds equity. ATL and OD are inventors on patents related to vaccine technology, including technology specific to filovirus vaccines., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The EXIT-CJS (N = 1005) multisite open-label randomized controlled trial will compare retention and effectiveness of extended-release buprenorphine (XR-B) vs. extended-release naltrexone (XR-NTX) to treat opioid use disorder (OUD) among criminal justice system (CJS)-involved adults in six U.S. locales (New Jersey, New York City, Delaware, Oregon, Connecticut, and New Hampshire). With a pragmatic, noninferiority design, this study hypothesizes that XR-B (n = 335) will be noninferior to XR-NTX (n = 335) in retention-in-study-medication treatment (the primary outcome), self-reported opioid use, opioid-positive urine samples, opioid overdose events, and CJS recidivism. In addition, persons with OUD not eligible or interested in the RCT will be recruited into an enhanced treatment as usual arm (n = 335) to examine usual care outcomes in a quasi-experimental observational cohort., (Copyright © 2021. Published by Elsevier Inc.)

Low levels of estradiol in women have been associated with impaired fear extinction recall, with suggestions this may promote the return of fear and heighten the female vulnerability for anxiety disorders. A particularly important measure for the return of fear is reinstatement, but no human studies to date have examined the impact of estradiol on fear reinstatement. Forty-two healthy females completed a differential fear conditioning, extinction and reinstatement task with skin conductance response (SCR) amplitude indexing level of conditioned fear. Saliva samples were taken to measure estradiol and progesterone. To examine fear reinstatement, SCR amplitude was compared between the last trial of the late extinction phase to the first re-extinction trial following the unsignaled presentation of two aversive electric shocks. No significant effects of estradiol were found for acquisition of fear conditioning or fear extinction learning. Lower estradiol predicted a significantly larger generalized SCR amplitude at re-extinction (post-reinstatement) in women. This provides novel evidence suggesting a protective role of estradiol in potentially reducing the relapse of fear following re-exposure to aversive stimuli, although further research is necessary in clinical populations to clarify this effect., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Families of children with medical complexity (CMC) face significant challenges beyond those related to caring for their child's medical condition. Parents of CMC report a variety of concerns impacting their social, emotional and financial well-being. This paper details how CHEO, community organizations and parents co-designed and evaluated the Navigator Program. Through system navigation, peer support and knowledge navigation, the program offers emotional, social and economic support for parents struggling to keep up with the demands of having CMC. A best practices toolkit also provides resources to help others better support these unique families locally, provincially and nationally., (Copyright © 2021 Longwoods Publishing.)

Eutrophication is a persistent threat to aquatic ecosystems worldwide. Foundation species, namely those that play a central role in the structuring of communities and functioning of ecosystems, are likely important for the resilience of aquatic ecosystems in the face of disturbance. However, little is known about how interactions among such species influence ecosystem responses to nutrient perturbation. Here, using an array (N = 20) of outdoor experimental pond ecosystems (15,000 L), we manipulated the presence of two foundation species, the macrophyte Myriophyllum spicatum and the mussel Dreissena polymorpha, and quantified ecosystem responses to multiple nutrient disturbances, spread over two years. In the first year, we added five nutrient pulses, ramping up from 10 to 50 μg P/L over a 10-week period from mid-July to mid-October, and in the second year, we added a single large pulse of 50 μg P/L in mid-October. We used automated sondes to measure multiple ecosystems properties at high frequency (15-minute intervals), including phytoplankton and dissolved organic matter fluorescence, and to model whole-ecosystem metabolism. Overall, both foundation species strongly affected the ecosystem responses to nutrient perturbation, and, as expected, initially suppressed the increase in phytoplankton abundance following nutrient additions. However, when both species were present, phytoplankton biomass increased substantially relative to other treatment combinations: non-additivity was evident for multiple ecosystem metrics following the nutrient perturbations in both years but was diminished in the intervening months between our perturbations. Overall, these results demonstrate how interactions between foundation species can cause surprisingly strong deviations from the expected responses of aquatic ecosystems to perturbations such as nutrient additions., (© 2021 by the Ecological Society of America.)

Targeting tumor-associated macrophages (TAMs) is a promising strategy to modify the immunosuppressive tumor microenvironment and improve cancer immunotherapy. Monoamine oxidase A (MAO-A) is an enzyme best known for its function in the brain; small molecule MAO inhibitors (MAOIs) are clinically used for treating neurological disorders. Here we observe MAO-A induction in mouse and human TAMs. MAO-A-deficient mice exhibit decreased TAM immunosuppressive functions corresponding with enhanced antitumor immunity. MAOI treatment induces TAM reprogramming and suppresses tumor growth in preclinical mouse syngeneic and human xenograft tumor models. Combining MAOI and anti-PD-1 treatments results in synergistic tumor suppression. Clinical data correlation studies associate high intratumoral MAOA expression with poor patient survival in a broad range of cancers. We further demonstrate that MAO-A promotes TAM immunosuppressive polarization via upregulating oxidative stress. Together, these data identify MAO-A as a critical regulator of TAMs and support repurposing MAOIs for TAM reprogramming to improve cancer immunotherapy.

Faecal proteomics studies have focussed on identification of microbial proteins, however; stool represents a valuable resource to interrogate the host interactions with the microbiota without the need for invasive intestinal biopsies. As the widely used enrichment method (differential centrifugation, DC) enriches for microbial proteins, we compared two other methods for enrichment of host proteins, termed 'host enriched' (HE) and ALL (all proteins). The HE and ALL protocols identified 1.8-fold more host proteins than DC while detecting a similar number of microbial proteins, but the methods had limited overlap in the specific microbial proteins detected. To maximize identification of both host and microbial proteins, samples were subjected to HE and the remaining material was used to perform DC. These two fractions displayed large differences in relative taxonomic abundance and cellular compartmentalization, with proteins from Bacteroidales and extracellular vesicles were enriched in the soluble HE component. The combination of data generated from these two fractions may allow identification of more distinct proteins than simply performing samples in duplicate or more complex fractionation techniques, or a single fraction could be chosen to suit the experimental hypothesis. SIGNIFICANCE: We compared how different stool protein preparation methods influenced the taxonomic and functional characteristics of microbial and host proteins identified. Surprisingly, a method designed to enrich for host proteins recovered a similar number of microbial protein groups to the method that specifically enriched intact bacterial cells. However, the taxonomic and subcellular origin of the microbial proteins differed considerably between the methods. By implementing a two-step method, we could maximize recovery of both host and microbial proteins derived from different cellular compartments and taxa., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Monoamine oxidase A (MAO-A) is an enzyme best known for its function in the brain, where it breaks down neurotransmitters and thereby influences mood and behavior. Small-molecule MAO inhibitors (MAOIs) have been developed and are clinically used for treating depression and other neurological disorders. However, the involvement of MAO-A in antitumor immunity has not been reported. Here, we observed induction of the Maoa gene in tumor-infiltrating immune cells. Maoa knockout mice exhibited enhanced antitumor T cell immunity and suppressed tumor growth. MAOI treatment significantly suppressed tumor growth in preclinical mouse syngeneic and human xenograft tumor models in a T cell-dependent manner. Combining MAOI and anti-PD-1 treatments generated synergistic tumor suppression effects. Clinical data correlation studies associated intratumoral MAOA expression with T cell dysfunction and decreased patient survival in a broad range of cancers. We further demonstrated that MAO-A restrains antitumor T cell immunity through controlling intratumoral T cell autocrine serotonin signaling. Together, these data identify MAO-A as an immune checkpoint and support repurposing MAOI antidepressants for cancer immunotherapy., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Fast diagnosis and treatment of pneumothorax, a collapsed or dropped lung, is crucial to avoid fatalities. Pneumothorax is typically detected on a chest X-ray image through visual inspection by experienced radiologists. However, the detection rate is quite low due to the complexity of visual inspection for small lung collapses. Therefore, there is an urgent need for automated detection systems to assist radiologists. Although deep learning classifiers generally deliver high accuracy levels in many applications, they may not be useful in clinical practice due to the lack of high-quality and representative labeled image sets. Alternatively, searching in the archive of past cases to find matching images may serve as a "virtual second opinion" through accessing the metadata of matched evidently diagnosed cases. To use image search as a triaging or diagnosis assistant, we must first tag all chest X-ray images with expressive identifiers, i.e., deep features. Then, given a query chest X-ray image, the majority vote among the top k retrieved images can provide a more explainable output. In this study, we searched in a repository with more than 550,000 chest X-ray images. We developed the Autoencoding Thorax Net (short AutoThorax -Net) for image search in chest radiographs. Experimental results show that image search based on AutoThorax -Net features can achieve high identification performance providing a path towards real-world deployment. We achieved 92% AUC accuracy for a semi-automated search in 194,608 images (pneumothorax and normal) and 82% AUC accuracy for fully automated search in 551,383 images (normal, pneumothorax and many other chest diseases).