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Background: The development of an effective human immunodeficiency virus (HIV) vaccine is a high global priority. Here, we report the safety, tolerability, and immunogenicity of a replication-defective recombinant adenovirus serotype 5 (rAd5) vector HIV-1 candidate vaccine.Methods: The vaccine is a mixture of 4 rAd5 vectors that express HIV-1 subtype B Gag-Pol fusion protein and envelope (Env) from subtypes A, B, and C. Healthy, uninfected adults were randomized to receive 1 intramuscular injection of placebo (n=6) or vaccine at dose levels of 10(9) (n=10), 10(10) (n=10), or 10(11) (n=10) particle units and were followed for 24 weeks to assess immunogenicity and safety.Results: The vaccine was well tolerated but was associated with more reactogenicity at the highest dose. At week 4, vaccine antigen-specific T cell responses were detected in 28 (93.3%) and 18 (60%) of 30 vaccine recipients for CD4(+) and CD8(+) T cells, respectively, by intracellular cytokine staining assay and in 22 (73%) of 30 vaccine recipients by enzyme-linked immunospot assay. Env-specific antibody responses were detected in 15 (50%) of 30 vaccine recipients by enzyme-linked immunosorbant assay and in 28 (93.3%) of 30 vaccine recipients by immunoprecipitation followed by Western blotting. No neutralizing antibody was detected.Conclusions: A single injection induced HIV-1 antigen-specific CD4(+) T cell, CD8(+) T cell, and antibody responses in the majority of vaccine recipients. This multiclade rAd5 HIV-1 vaccine is now being evaluated in combination with a multiclade HIV-1 DNA plasmid vaccine. [ABSTRACT FROM AUTHOR]

Circulating sexual stages of Plasmodium falciparum (Pf ) can be transmitted from humans to mosquitoes, thereby furthering the spread of malaria in the population. It is well established that antibodies can efficiently block parasite transmission. In search for naturally acquired antibodies targets on sexual stages, we established an efficient method for target-agnostic single B cell activation followed by high-throughput selection of human monoclonal antibodies (mAbs) reactive to sexual stages of Pf in the form of gametes and gametocyte extracts. We isolated mAbs reactive against a range of Pf proteins including well-established targets Pfs48/45 and Pfs230. One mAb, B1E11K, was cross-reactive to various proteins containing glutamate-rich repetitive elements expressed at different stages of the parasite life cycle. A crystal structure of two B1E11K Fab domains in complex with its main antigen, RESA, expressed on asexual blood stages, showed binding of B1E11K to a repeating epitope motif in a head-to-head conformation engaging in affinity-matured homotypic interactions. Thus, this mode of recognition of Pf proteins, previously described only for Pf circumsporozoite protein (PfCSP), extends to other repeats expressed across various stages. The findings augment our understanding of immune-pathogen interactions to repeating elements of the Plasmodium parasite proteome and underscore the potential of the novel mAb identification method used to provide new insights into the natural humoral immune response against Pf ., Competing Interests: AA, RY, AF, JB, WS, IB, SD, IK, Rd, Md, TB, CK, RM, RS, JJ, PP, MJ No competing interests declared, (© 2024, Amen, Yoo, Fabra-García et al.)

We introduce a novel model of nonsegmented negative-strand RNA virus (NNSV) transcription. Previous models have relied on polymerase behavioral differences in the highly conserved intergenic sequences. Our model hypothesizes the transcriptional gradient in NNSVs is explained through a simple model with two parameters associated with the viral polymerase. Most differences in expression can be attributed to the processivity of the polymerase while additional attenuation occurs in the presence of overlapping genes. This model reveals a correlation between polymerase processivity and genome length, which is consistent with the universal entry of polymerases through the 3' end of the genome. Using this model, it is now possible to predict the transcriptional behavior of NNSVs from genotype alone, revolutionizing the design of novel NNSV variants for biomedical applications.

BACKGROUNDThe mechanism(s) responsible for the efficacy of WHO-recommended malaria vaccine RTS,S/AS01 are not completely understood. We previously identified RTS,S vaccine-induced Plasmodium falciparum circumsporozoite protein-specific (PfCSP-specific) antibody measures associated with protection from controlled human malaria infection (CHMI). Here, we tested the protection-predicting capability of these measures in independent CHMI studies.METHODSVaccine-induced total serum antibody (immunoglobulins, Igs) and subclass antibody (IgG1 and IgG3) responses were measured by biolayer interferometry and the binding antibody multiplex assay, respectively. Immune responses were compared between protected and nonprotected vaccinees using univariate and multivariate logistic regression.RESULTSBlinded prediction analysis showed that 5 antibody binding measures, including magnitude-avidity composite of serum Ig specific for PfCSP, major NANP repeats and N-terminal junction, and PfCSP- and NANP-specific IgG1 subclass magnitude, had good prediction accuracy (area under the receiver operating characteristic curves [ROC AUC] > 0.7) in at least 1 trial. Furthermore, univariate analysis showed a significant association between these antibody measures and protection (odds ratios 2.6-3.1). Multivariate modeling of combined data from 3 RTS,S CHMI trials identified the combination of IgG1 NANP binding magnitude plus serum NANP and N-junction Ig binding magnitude-avidity composite as the best predictor of protection (95% confidence interval for ROC AUC 0.693-0.834).CONCLUSIONThese results reinforce our previous findings and provide a tool for predicting protection in future trials.TRIAL REGISTRATIONClinicalTrials.gov NCT03162614, NCT03824236, NCT01366534, and NCT01857869.FUNDINGThis study was supported by Bill & Melinda Gates Foundation's Global Health-Discovery Collaboratory grants (INV-008612 and INV-043419) to GDT.

Plasmodium falciparum reticulocyte-binding protein homolog 5 (RH5) is a leading blood-stage malaria vaccine antigen target, currently in a phase 2b clinical trial as a full-length soluble protein/adjuvant vaccine candidate called RH5.1/Matrix-M. We identify that disordered regions of the full-length RH5 molecule induce non-growth inhibitory antibodies in human vaccinees and that a re-engineered and stabilized immunogen (including just the alpha-helical core of RH5) induces a qualitatively superior growth inhibitory antibody response in rats vaccinated with this protein formulated in Matrix-M adjuvant. In parallel, bioconjugation of this immunogen, termed "RH5.2," to hepatitis B surface antigen virus-like particles (VLPs) using the "plug-and-display" SpyTag-SpyCatcher platform technology also enables superior quantitative antibody immunogenicity over soluble protein/adjuvant in vaccinated mice and rats. These studies identify a blood-stage malaria vaccine candidate that may improve upon the current leading soluble protein vaccine candidate RH5.1/Matrix-M. The RH5.2-VLP/Matrix-M vaccine candidate is now under evaluation in phase 1a/b clinical trials., Competing Interests: Declaration of interests S.J.D. is an inventor on patent applications relating to RH5 malaria vaccines and antibodies, is a co-founder of and shareholder in SpyBiotech, and has been a consultant to GSK on malaria vaccines. A.M.M. has been a consultant to GSK on malaria vaccines, has an immediate family member who is an inventor on patent applications relating to RH5 malaria vaccines and antibodies, and is a co-founder of and shareholder in SpyBiotech. M.R.H. is an inventor on patents relating to peptide targeting via spontaneous amide bond formation and is a co-founder of and shareholder in SpyBiotech. S.B. is an inventor on patent applications relating to vaccines made using spontaneous amide bond formation and is a co-founder of, shareholder in, and employee of SpyBiotech. J.J. is an inventor on patent applications relating to vaccines made using spontaneous amide bond formation and is a co-founder of and shareholder in SpyBiotech. R.A.D. is an inventor on patent applications relating to vaccines made using spontaneous amide bond formation and shareholder in SpyBiotech. L.D.W.K., J.R.B., D.Q., A.M.L., S.E.S., B.G.W., K. McHugh, I.C., S.J.F., and D.P. are inventors on patent applications relating to RH5 malaria vaccines and/or antibodies., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Post-operative complications present a challenge to the healthcare system due to the high unpredictability of their incidence. Socioeconomic conditions have been established as social determinants of health. However, their contribution relating to postoperative complications is still unclear as it can be heterogeneous based on community, type of surgical services, and sex and gender. Uncovering these relations can enable improved public health policy to reduce such complications., Methods: In this study, we conducted a large population cross-sectional analysis of social vulnerability and the odds of various post-surgical complications. We collected electronic health records data from over 50,000 surgeries that happened between 2012 and 2018 at a quaternary health center in St. Louis, Missouri, United States and the corresponding zip code of the patients. We built statistical logistic regression models of postsurgical complications with the social vulnerability index of the tract consisting of the zip codes of the patient as the independent variable along with sex and race interaction., Results: Our sample from the St. Louis area exhibited high variance in social vulnerability with notable rapid increase in vulnerability from the south west to the north of the Mississippi river indicating high levels of inequality. Our sample had more females than males, and females had slightly higher social vulnerability index. Postoperative complication incidence ranged from 0.75% to 41% with lower incidence rate among females. We found that social vulnerability was associated with abnormal heart rhythm with socioeconomic status and housing status being the main association factors. We also found associations of the interaction of social vulnerability and female sex with an increase in odds of heart attack and surgical wound infection. Those associations disappeared when controlling for general health and comorbidities., Conclusions: Our results indicate that social vulnerability measures such as socioeconomic status and housing conditions could affect postsurgical outcomes through preoperative health. This suggests that the domains of preventive medicine and public health should place social vulnerability as a priority to achieve better health outcomes of surgical interventions., (© 2024. The Author(s).)

Reticulocyte-binding protein homologue 5 (RH5), a leading blood-stage Plasmodium falciparum malaria vaccine target, interacts with cysteine-rich protective antigen (CyRPA) and RH5-interacting protein (RIPR) to form an essential heterotrimeric "RCR-complex". We investigate whether RCR-complex vaccination can improve upon RH5 alone. Using monoclonal antibodies (mAbs) we show that parasite growth-inhibitory epitopes on each antigen are surface-exposed on the RCR-complex and that mAb pairs targeting different antigens can function additively or synergistically. However, immunisation of female rats with the RCR-complex fails to outperform RH5 alone due to immuno-dominance of RIPR coupled with inferior potency of anti-RIPR polyclonal IgG. We identify that all growth-inhibitory antibody epitopes of RIPR cluster within the C-terminal EGF-like domains and that a fusion of these domains to CyRPA, called "R78C", combined with RH5, improves the level of in vitro parasite growth inhibition compared to RH5 alone. These preclinical data justify the advancement of the RH5.1 + R78C/Matrix-M™ vaccine candidate to Phase 1 clinical trial., (© 2024. The Author(s).)

To streamline standard virological assays, we developed a suite of nine fluorescent or bioluminescent replication competent human species C5 adenovirus reporter viruses that mimic their parental wild-type counterpart. These reporter viruses provide a rapid and quantitative readout of various aspects of viral infection and replication based on EGFP, mCherry, or NanoLuc measurement. Moreover, they permit real-time non-invasive measures of viral load, replication dynamics, and infection kinetics over the entire course of infection, allowing measurements that were not previously possible. This suite of replication competent reporter viruses increases the ease, speed, and adaptability of standard assays and has the potential to accelerate multiple areas of human adenovirus research.IMPORTANCEIn this work, we developed a versatile toolbox of nine HAdV-C5 reporter viruses and validated their functions in cell culture. These reporter viruses provide a rapid and quantitative readout of various aspects of viral infection and replication based on EGFP, mCherry, or NanoLuc measurement. The utility of these reporter viruses could also be extended for use in 3D cell culture, organoids, live cell imaging, or animal models, and provides a conceptual framework for the development of new reporter viruses representing other clinically relevant HAdV species., Competing Interests: The authors declare no conflict of interest.

The rapidly evolving coaching profession has permeated the health care industry and is gaining ground as a viable solution for addressing physician burnout, turnover, and leadership crises that plague the industry. Although various coach credentialing bodies are established, the profession has no standardized competencies for physician coaching as a specialty practice area, creating a market of aspiring coaches with varying degrees of expertise. To address this gap, we employed a modified Delphi approach to arrive at expert consensus on competencies necessary for coaching physicians and physician leaders. Informed by the National Board of Medical Examiners' practice of rapid blueprinting, a group of 11 expert physician coaches generated an initial list of key thematic areas and specific competencies within them. The competency document was then distributed for agreement rating and comment to over 100 stakeholders involved in physician coaching. Our consensus threshold was defined at 70% agreement, and actual responses ranged from 80.5% to 95.6% agreement. Comments were discussed and addressed by 3 members of the original group, resulting in a final model of 129 specific competencies in the following areas: (1) physician-specific coaching, (2) understanding physician and health care context, culture, and career span, (3) coaching theory and science, (4) diversity, equity, inclusion, and other social dynamics, (5) well-being and burnout, and (6) physician leadership. This consensus on physician coaching competencies represents a critical step toward establishing standards that inform coach education, training, and certification programs, as well as guide the selection of coaches and evaluation of coaching in health care settings., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

New strategies are needed to reduce the incidence of malaria, and promising approaches include vaccines targeting the circumsporozoite protein (CSP). To improve upon the malaria vaccine, RTS,S/AS01, it is essential to standardize preclinical assays to measure the potency of next-generation vaccines against this benchmark. We focus on RTS,S/AS01-induced antibody responses and functional activity in conjunction with robust statistical analyses. Transgenic Plasmodium berghei sporozoites containing full-length P. falciparum CSP (tgPb-PfCSP) allow two assessments of efficacy: quantitative reduction in liver infection following intravenous challenge, and sterile protection from mosquito bite challenge. Two or three doses of RTS,S/AS01 were given intramuscularly at 3-week intervals, with challenge 2-weeks after the last vaccination. Minimal inter- and intra-assay variability indicates the reproducibility of the methods. Importantly, the range of this model is suitable for screening more potent vaccines. Levels of induced anti-CSP antibody 2A10 equivalency were also associated with activity: 105 μg/mL (95% CI: 68.8, 141) reduced liver infection by 50%, whereas 285 μg/mL (95% CI: 166, 404) is required for 50% sterile protection from mosquito bite challenge. Additionally, the liver burden model was able to differentiate between protected and non-protected human plasma samples from a controlled human malaria infection study, supporting these models' relevance and predictive capability. Comparison in animal models of CSP-based vaccine candidates to RTS,S/AS01 is now possible under well controlled conditions. Assessment of the quality of induced antibodies, likely a determinant of durability of protection in humans, should be possible using these methods., (© 2024. The Author(s).)

We present the first complete stochastic model of vesicular stomatitis virus (VSV) intracellular replication. Previous models developed to capture VSV's intracellular replication have either been ODE-based or have not represented the complete replicative cycle, limiting our ability to understand the impact of the stochastic nature of early cellular infections on virion production between cells and how these dynamics change in response to mutations. Our model accurately predicts changes in mean virion production in gene-shuffled VSV variants and can capture the distribution of the number of viruses produced. This model has allowed us to enhance our understanding of intercellular variability in virion production, which appears to be influenced by the duration of the early phase of infection, and variation between variants, arising from balancing the time the genome spends in the active state, the speed of incorporating new genomes into virions, and the production of viral components. Being a stochastic model, we can also assess other effects of mutations beyond just the mean number of virions produced, including the probability of aborted infections and the standard deviation of the number of virions produced. Our model provides a biologically interpretable framework for studying the stochastic nature of VSV replication, shedding light on the mechanisms underlying variation in virion production. In the future, this model could enable the design of more complex viral phenotypes when attenuating VSV, moving beyond solely considering the mean number of virions produced., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 King et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Over 75% of malaria-attributable deaths occur in children under the age of 5 years. However, the first malaria vaccine recommended by the World Health Organization (WHO) for pediatric use, RTS,S/AS01 (Mosquirix), has modest efficacy. Complementary strategies, including monoclonal antibodies, will be important in efforts to eradicate malaria. Here we characterize the circulating B cell repertoires of 45 RTS,S/AS01 vaccinees and discover monoclonal antibodies for development as potential therapeutics. We generated >28,000 antibody sequences and tested 481 antibodies for binding activity and 125 antibodies for antimalaria activity in vivo. Through these analyses we identified correlations suggesting that sequences in Plasmodium falciparum circumsporozoite protein, the target antigen in RTS,S/AS01, may induce immunodominant antibody responses that limit more protective, but subdominant, responses. Using binding studies, mouse malaria models, biomanufacturing assessments and protein stability assays, we selected AB-000224 and AB-007088 for advancement as a clinical lead and backup. We engineered the variable domains (Fv) of both antibodies to enable low-cost manufacturing at scale for distribution to pediatric populations, in alignment with WHO's preferred product guidelines. The engineered clone with the optimal manufacturing and drug property profile, MAM01, was advanced into clinical development., (© 2024. The Author(s).)

Malaria transmission-blocking vaccines (TBVs) aim to induce antibodies that block Plasmodium parasite development in the mosquito midgut, thus preventing mosquitoes from becoming infectious. While the Pro-domain and first of fourteen 6-Cysteine domains (Pro-D1) of the Plasmodium gamete surface protein Pfs230 are known targets of transmission-blocking antibodies, no studies to date have discovered other Pfs230 domains that are functional targets. Here, we show that a murine monoclonal antibody (mAb), 18F25.1, targets Pfs230 Domain 7. We generated a subclass-switched complement-fixing variant, mAb 18F25.2a, using a CRISPR/Cas9-based hybridoma engineering method. This subclass-switched mAb 18F25.2a induced lysis of female gametes in vitro. Importantly, mAb 18F25.2a potently reduced P. falciparum infection of Anopheles stephensi mosquitoes in a complement-dependent manner, as assessed by standard membrane feeding assays. Together, our data identify Pfs230 Domain 7 as target for transmission-blocking antibodies and provide a strong incentive to study domains outside Pfs230Pro-D1 as TBV candidates., (© 2023. The Author(s).)

Information is the cornerstone of research, from experimental (meta)data and computational processes to complex inventories of reagents and equipment. These 10 simple rules discuss best practices for leveraging laboratory information management systems to transform this large information load into useful scientific findings., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests:J.P., S.P., and K.M. have a financial interest in GenoFAB, Inc., M.K. is an employee of LanzaTech. N.J.H. has a financial interest in TeselaGen Biotechnology, Inc. and Ansa Biotechnologies, Inc. GenoFAB Inc. and TeselaGen Biotechnology, Inc. provide research information management systems. These companies may benefit or be perceived as benefiting from this publication., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Context and Background: The prevalence of uterine fibroids is estimated to be approximately 80%. Fibroids can be associated with abnormal uterine bleeding, pressure symptoms, and infertility. Given this high prevalence, approximately 30,000 myomectomies are performed in the United States per year. Minimally invasive approaches are preferred, if feasible. The minimally invasive techniques include laparoscopic, robot-assisted, hysteroscopic, and mini-laparotomy., Objective: To discuss the multiple techniques for optimizing the use of mini-laparotomy in minimally invasive myomectomy., Design: We use intraoperative surgical video to demonstrate techniques that optimize the use of the mini-laparotomy for myomectomy., Setting: Cleveland Clinic., Patient(s): Patient's undergoing fertility preserving, minimally invasive myomectomy at the Cleveland Clinic. The patient(s) included in this video gave consent for publication of the video and posting of the video online, including social media, the journal website, scientific literature websites (such as PubMed, ScienceDirect, and Scopus), and other applicable sites., Intervention(s): After the surgeon has selected to proceed with mini-laparotomy myomectomy, different techniques can be employed to optimize management. We demonstrate and discuss these techniques to ensure that surgeons have a set of tools to tackle a fibroid uterus. These techniques include direct palpation of the fibroids, use of a uterine manipulator to visualize the endometrial cavity, use of the uterine manipulator to aid in repair of the cavity if entered, suturing technique that avoids the endometrial cavity and therefore limits foreign body exposure and decreases intrauterine adhesion formation, utilization of barbed suture in a layered fashion, in-situ debulking to avoid injury to fallopian tubes and other critical uterine structures, easy identification of the optimal enucleation plane, use of single hysterotomy for multiple fibroids, visualization of the "Tortuga" sign, and evaluation of the abdominal cavity using the mini-laparotomy site as a port site. To limit postoperative adhesion formation, the investigators place cellulose-based adhesion barriers with peritoneum closure. Although the need for prolonged postoperative observation can be made on a case-by-case basis, we consider this as an outpatient surgery and anticipate same-day discharge for our patients., Main Outcome Measure(s): In this video, we perform a mini-laparotomy myomectomy optimally and describe the techniques employed., Result(s): Specific techniques employed in mini-laparotomy myomectomy make the case safe, effective, and can lead to same-day discharge., Conclusion(s): Mini-laparotomy myomectomy is a technique used to perform minimally invasive myomectomy. Following the discussed steps, surgeons can be more confident in performing this method of myomectomy., Competing Interests: Declaration of interests C.R.K. reports travel supports from AAGL 2022, AUGS 2022 Clinical course, SGS 2022, Creighton residency graduation speech, Society of Robotic Surgery conference, and SGS Strategic planning meeting outside the submitted work. M.L.D. has nothing to disclose. T.G. has nothing to disclose., (Copyright © 2023 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Peptide-domain interactions mediated by short linear motifs (SLiMs) play crucial roles in cellular biology. The simplicity of SLiMs poses challenges in their computational identification. Existing high-throughput methods for discovering SLiMs lack cellular context as they are typically performed in vitro. We developed a functional selection method using yeast to identify peptides that interact with the endogenous yeast nuclear proteome. Remarkably, peptides selected for in yeast also mediated nuclear import in human cells. Notably, the identified peptides did not resemble classical nuclear localization sequences. This platform has the potential to identify and investigate motifs that interact with the nuclear proteome of yeast and human and to aid in the identification and understanding of alternative protein nuclear import mechanisms., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Reducing brain levels of both soluble and insoluble forms of amyloid beta (Aβ) remains the primary goal of most therapies that target Alzheimer's disease (AD). However, no treatment has so far resulted in patient benefit, and clinical trials of the most promising drug candidates have generally failed due to significant adverse effects. This highlights the need for safer and more selective ways to target and modulate Aβ biogenesis., Methods: Peptide technology has advanced to allow reliable synthesis, purification, and delivery of once-challenging hydrophobic sequences. This is opening up new routes to target membrane processes associated with disease. Here we deploy a combination of atomic detail molecular dynamics (MD) simulations, living-cell Förster resonance energy transfer (FRET), and in vitro assays to elucidate the atomic-detail dynamics, molecular mechanisms, and cellular activity and selectivity of a membrane-active peptide that targets the Aβ precursor protein (APP)., Results: We demonstrate that Aβ biogenesis can be downregulated selectively using an APP occlusion peptide (APPOP). APPOP inhibits Aβ production in a dose-dependent manner, with a mean inhibitory concentration (IC 50 ) of 450 nM toward exogenous APP and 50 nM toward endogenous APP in primary rat cortical neuronal cultures. APPOP does not impact the γ-secretase cleavage of Notch-1, or exhibit toxicity toward cultured primary rat neurons, suggesting that it selectively shields APP from proteolysis., Discussion: Drugs targeting AD need to be given early and for very long periods to prevent the onset of clinical symptoms. This necessitates being able to target Aβ production precisely and without affecting the activity of key cellular enzymes such as γ-secretase for other substrates. Peptides offer a powerful way for targeting key pathways precisely, thereby reducing the risk of adverse effects. Here we show that protecting APP from proteolytic processing offers a promising route to safely and specifically lower Aβ burden. In particular, we show that the amyloid pathway can be targeted directly and specificically. This reduces the risk of off-target effects and paves the way for a safe prophylactic treatment., Competing Interests: The authors declare no conflicts of interest. Author disclosures are available in the supporting information., (© 2023 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Host:pathogen interactions dictate the outcome of infection, yet the limitations of current approaches leave large regions of this interface unexplored. Here, we develop a novel fitness-based screen that queries factors important during the middle to late stages of infection. This is achieved by engineering influenza virus to direct the screen by programming dCas9 to modulate host gene expression. Our genome-wide screen for pro-viral factors identifies the cytoplasmic DNA exonuclease TREX1. TREX1 degrades cytoplasmic DNA to prevent inappropriate innate immune activation by self-DNA. We reveal that this same process aids influenza virus replication. Infection triggers release of mitochondrial DNA into the cytoplasm, activating antiviral signaling via cGAS and STING. TREX1 metabolizes the DNA, preventing its sensing. Collectively, these data show that self-DNA is deployed to amplify innate immunity, a process tempered by TREX1. Moreover, they demonstrate the power and generality of pathogen-driven fitness-based screens to pinpoint key host regulators of infection., Competing Interests: Declaration of interests C.R.K. and A.M. are inventors on a provisional patent related to this work., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Importance: Telemedicine for clinical decision support has been adopted in many health care settings, but its utility in improving intraoperative care has not been assessed., Objective: To pilot the implementation of a real-time intraoperative telemedicine decision support program and evaluate whether it reduces postoperative hypothermia and hyperglycemia as well as other quality of care measures., Design, Setting, and Participants: This single-center pilot randomized clinical trial (Anesthesiology Control Tower-Feedback Alerts to Supplement Treatments [ACTFAST-3]) was conducted from April 3, 2017, to June 30, 2019, at a large academic medical center in the US. A total of 26 254 adult surgical patients were randomized to receive either usual intraoperative care (control group; n = 12 980) or usual care augmented by telemedicine decision support (intervention group; n = 13 274). Data were initially analyzed from April 22 to May 19, 2021, with updates in November 2022 and February 2023., Intervention: Patients received either usual care (medical direction from the anesthesia care team) or intraoperative anesthesia care monitored and augmented by decision support from the Anesthesiology Control Tower (ACT), a real-time, live telemedicine intervention. The ACT incorporated remote monitoring of operating rooms by a team of anesthesia clinicians with customized analysis software. The ACT reviewed alerts and electronic health record data to inform recommendations to operating room clinicians., Main Outcomes and Measures: The primary outcomes were avoidance of postoperative hypothermia (defined as the proportion of patients with a final recorded intraoperative core temperature >36 °C) and hyperglycemia (defined as the proportion of patients with diabetes who had a blood glucose level ≤180 mg/dL on arrival to the postanesthesia recovery area). Secondary outcomes included intraoperative hypotension, temperature monitoring, timely antibiotic redosing, intraoperative glucose evaluation and management, neuromuscular blockade documentation, ventilator management, and volatile anesthetic overuse., Results: Among 26 254 participants, 13 393 (51.0%) were female and 20 169 (76.8%) were White, with a median (IQR) age of 60 (47-69) years. There was no treatment effect on avoidance of hyperglycemia (7445 of 8676 patients [85.8%] in the intervention group vs 7559 of 8815 [85.8%] in the control group; rate ratio [RR], 1.00; 95% CI, 0.99-1.01) or hypothermia (7602 of 11 447 patients [66.4%] in the intervention group vs 7783 of 11 672 [66.7.%] in the control group; RR, 1.00; 95% CI, 0.97-1.02). Intraoperative glucose measurement was more common among patients with diabetes in the intervention group (RR, 1.07; 95% CI, 1.01-1.15), but other secondary outcomes were not significantly different., Conclusions and Relevance: In this randomized clinical trial, anesthesia care quality measures did not differ between groups, with high confidence in the findings. These results suggest that the intervention did not affect the targeted care practices. Further streamlining of clinical decision support and workflows may help the intraoperative telemedicine program achieve improvement in targeted clinical measures., Trial Registration: ClinicalTrials.gov Identifier: NCT02830126.

In this narrative review, we describe historical and contemporary influences that prevent patients with fibroids from getting appropriate medical care. Using patient stories as examples, we highlight how misogyny on all levels hurts patients and prevents medical teams from doing their best. Importantly, inequity and disparities result in massive gaps in care delivery. We suggest that we, as gynecologists and surgeons, must join public discourse on this topic to highlight the inadequacies of care delivery and the reasons behind it, suggest potential solutions, and join patients and communities in formulating and implementing remedies., Competing Interests: V.T.L.: consultant for Applied Medical. N.D.: none. M.S.: Applied Medical, Caldera Medical, Eximis Surgical, Hologic. M.T.: Cooper Surgical. C.K.: none., (© Veronica T. Lerner et al., 2023; Published by Mary Ann Liebert, Inc.)

The generation of high-quality antibody responses to Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP), the primary surface antigen of Pf sporozoites, is paramount to the development of an effective malaria vaccine. Here we present an in-depth structural and functional analysis of a panel of potent antibodies encoded by the immunoglobulin heavy chain variable (IGHV) gene IGHV3-33, which is among the most prevalent and potent antibody families induced in the anti-PfCSP immune response and targets the Asn-Ala-Asn-Pro (NANP) repeat region. Cryo-electron microscopy (cryo-EM) reveals a remarkable spectrum of helical antibody-PfCSP structures stabilized by homotypic interactions between tightly packed fragments antigen binding (Fabs), many of which correlate with somatic hypermutation. We demonstrate a key role of these mutated homotypic contacts for high avidity binding to PfCSP and in protection from Pf malaria infection. Together, these data emphasize the importance of anti-homotypic affinity maturation in the frequent selection of IGHV3-33 antibodies and highlight key features underlying the potent protection of this antibody family., (© 2023. The Author(s).)

The opioid epidemic is a significant public health crisis that has caused extensive harm and devastation in the United States. This literature review aimed to identify the contributing factors and negative consequences of the epidemic, as well as best practices for healthcare providers in managing the epidemic. Overprescribing opiates and opioids, lack of education and opportunity, and being unmarried or divorced were some of the identified contributing factors to dependence on opioids. The epidemic's negative consequences are substantial, leading to increased access to opioids for vulnerable populations, which consequently cause accidental death among men and the degradation of rural community health services. As part of the literature review, we also analyzed the best practices for healthcare providers, including implementing prescription drug monitoring programs (PDMPs). However, we found that while PDMPs resulted in a decrease in opioid overprescription and an increase in provider confidence when prescribing medication, the evidence for their effectiveness in improving rural community health services or reducing opioid overdoses and opioid-related deaths was inconclusive. Our review highlights that the greatest challenge to overcome is a lack of legal mandates and proper education for healthcare providers on best practices for addressing the epidemic. To regulate and control opioids effectively, tracking and standardizing prescription models by federal agencies and medical institutions is necessary but not enough. Legal action is vital for the successful containment of the opioid crisis., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Judd et al.)

Objective: Situational awareness and anticipatory guidance for nurses receiving a patient after surgery are keys to patient safety. Little work has defined the role of artificial intelligence (AI) to support these functions during nursing handoff communication or patient assessment. We used interviews to better understand how AI could work in this context., Materials and Methods: Eleven nurses participated in semistructured interviews. Mixed inductive-deductive thematic analysis was used to extract major themes and subthemes around roles for AI supporting postoperative nursing., Results: Five themes were generated from the interviews: (1) nurse understanding of patient condition guides care decisions, (2) handoffs are important to nurse situational awareness, but multiple barriers reduce their effectiveness, (3) AI may address barriers to handoff effectiveness, (4) AI may augment nurse care decision making and team communication outside of handoff, and (5) user experience in the electronic health record and information overload are likely barriers to using AI. Important subthemes included that AI-identified problems would be discussed at handoff and team communications, that AI-estimated elevated risks would trigger patient re-evaluation, and that AI-identified important data may be a valuable addition to nursing assessment., Discussion and Conclusion: Most research on postoperative handoff communication relies on structured checklists. Our results suggest that properly designed AI tools might facilitate postoperative handoff communication for nurses by identifying specific elevated risks faced by a patient, triggering discussion on those topics. Limitations include a single center, many participants lacking of applied experience with AI, and limited participation rate., Competing Interests: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Malaria transmission-blocking vaccines (TBVs) aim to induce antibodies that interrupt malaria parasite development in the mosquito, thereby blocking onward transmission, and provide a much-needed tool for malaria control and elimination. The parasite surface protein Pfs48/45 is a leading TBV candidate. Here, we isolated and characterized a panel of 81 human Pfs48/45-specific monoclonal antibodies (mAbs) from donors naturally exposed to Plasmodium parasites. Genetically diverse mAbs against each of the three domains (D1-D3) of Pfs48/45 were identified. The most potent mAbs targeted D1 and D3 and achieved >80% transmission-reducing activity in standard membrane-feeding assays, at 10 and 2 μg/mL, respectively. Co-crystal structures of D3 in complex with four different mAbs delineated two conserved protective epitopes. Altogether, these Pfs48/45-specific human mAbs provide important insight into protective and non-protective epitopes that can further our understanding of transmission and inform the design of refined malaria transmission-blocking vaccine candidates., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To review causes of pelvic pain among adolescents and discuss surgical techniques for safe and effective resection of juvenile cystic adenomyomas., Design: Case report., Setting: Academic medical center., Patients: We present a 16-year-old patient with chronic pelvic pain and ultrasound evidence of a 2.4 cm adenomyoma. The lesion was thought specifically to represent a juvenile cystic adenomyoma, defined as a cystic lesion >1 cm occurring in women younger than 30 years with severe dysmenorrhea that is distinct from the uterine cavity and surrounded by hypertrophic myometrium., Intervention: Given minimal relief from medical therapy and high suspicion for coexistent endometriosis, our patient elected to undergo laparoscopic resection of adenomyoma and excision of pelvic lesions., Main Outcome Measures: Preoperative considerations discussed in this video include imaging to identify the location of the lesion and adjacent structures, such as the uterine vessels, discontinuation of gonadotropin-releasing hormone agonist for adequate intraoperative visualization, and the high likelihood of encountering endometriosis at operation., Results: We review the following surgical techniques: maximize visualization with the use of a uterine manipulator and temporary oophoropexy, optimize hemostasis via temporary uterine artery ligation and control of collateral blood vessels, complete ureterolysis, meticulous enucleation of adenomyoma, and excision of coexistent endometriotic lesions. Surgical findings demonstrated a 2 cm lesion along the left lower uterine segment and red-brown lesions along bilateral ovarian fossa, pathologically confirmed as adenomyoma and superficial endometriosis, respectively., Conclusion: This video presents strategies for safe and effective adenomyoma resection and treatment of refractory chronic pelvic pain in an adolescent., (Copyright © 2022 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Malaria transmission-blocking vaccines (TBVs) aim to elicit human antibodies that inhibit sporogonic development of Plasmodium falciparum in mosquitoes, thereby preventing onward transmission. Pfs48/45 is a leading clinical TBV candidate antigen and is recognized by the most potent transmission-blocking monoclonal antibody (mAb) yet described; still, clinical development of Pfs48/45 antigens has been hindered, largely by its poor biochemical characteristics. Here, we used structure-based computational approaches to design Pfs48/45 antigens stabilized in the conformation recognized by the most potently inhibitory mAb, achieving >25°C higher thermostability compared with the wild-type protein. Antibodies elicited in mice immunized with these engineered antigens displayed on liposome-based or protein nanoparticle-based vaccine platforms exhibited 1-2 orders of magnitude superior transmission-reducing activity, compared with immunogens bearing the wild-type antigen, driven by improved antibody quality. Our data provide the founding principles for using molecular stabilization solely from antibody structure-function information to drive improved immune responses against a parasitic vaccine target., Competing Interests: Declaration of interests The authors declare no competing interests. A patent application has been filed that relates to this work., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

A vaccine targeting multiple stages of the Plasmodium falciparum parasite life cycle is desirable. The sporozoite surface Circumsporozoite Protein (CSP) is the target of leading anti-infective P. falciparum pre-erythrocytic vaccines. Pfs230, a sexual-stage P. falciparum surface protein, is currently in trials as the basis for a transmission-blocking vaccine, which inhibits parasite development in the mosquito vector. Here, recombinant full-length CSP and a Pfs230 fragment (Pfs230D1+) are co-displayed on immunogenic liposomes to induce immunity against both infection and transmission. Liposomes contain cobalt-porphyrin phospholipid (CoPoP), monophosphoryl lipid A and QS-21, and rapidly bind His-tagged CSP and Pfs230D1+ upon admixture to form bivalent particles that maintain reactivity with conformational monoclonal antibodies. Use of multicolor fluorophore-labeled antigens reveals liposome binding upon admixture, stability in serum and enhanced uptake in murine macrophages in vitro. Bivalent liposomes induce humoral and cellular responses against both CSP and Pfs230D1+. Vaccine-induced antibodies reduce parasite numbers in mosquito midguts in a standard membrane feeding assay. Mice immunized with liposome-displayed antigens or that passively receive antibodies from immunized rabbits have reduced parasite liver burden following challenge with transgenic sporozoites expressing P. falciparum CSP., (© 2022. The Author(s).)

Potent and durable vaccine responses will be required for control of malaria caused by Plasmodium falciparum (Pf). RTS,S/AS01 is the first, and to date, the only vaccine that has demonstrated significant reduction of clinical and severe malaria in endemic cohorts in Phase 3 trials. Although the vaccine is protective, efficacy declines over time with kinetics paralleling the decline in antibody responses to the Pf circumsporozoite protein (PfCSP). Although most attention has focused on antibodies to repeat motifs on PfCSP, antibodies to other regions may play a role in protection. Here, we expressed and characterized seven monoclonal antibodies to the C-terminal domain of CSP (ctCSP) from volunteers immunized with RTS,S/AS01. Competition and crystal structure studies indicated that the antibodies target two different sites on opposite faces of ctCSP. One site contains a polymorphic region (denoted α-ctCSP) and has been previously characterized, whereas the second is a previously undescribed site on the conserved β-sheet face of the ctCSP (denoted β-ctCSP). Antibodies to the β-ctCSP site exhibited broad reactivity with a diverse panel of ctCSP peptides whose sequences were derived from field isolates of P. falciparum whereas antibodies to the α-ctCSP site showed very limited cross reactivity. Importantly, an antibody to the β-site demonstrated inhibition activity against malaria infection in a murine model. This study identifies a previously unidentified conserved epitope on CSP that could be targeted by prophylactic antibodies and exploited in structure-based vaccine design., Competing Interests: We have read the journal’s policy and the authors of this manuscript have the following competing interests. The authors N.B., T.P., D.O., Y.F.G., R.S.M., E.G., J.C., M.P., L.Y., E.L., J.A.R., S.D., A.M.E., D.E.N., E.W., C.R.K., F.Z., D.R.B., I.A.W., and T.F.R. declare that they have no competing interests. W.V., D.E. were or are employees of Atreca, Inc. and own equity in Atreca, Inc.

Importance: Falls after elective inpatient surgical procedures are common and have physical, emotional, and financial consequences. Close interactions between patients and health care teams before and after surgical procedures may offer opportunities to address modifiable risk factors associated with falls., Objective: To assess whether a multicomponent intervention that incorporates education, home medication review, and home safety assessment is associated with reductions in the incidence of falls after elective inpatient surgical procedures., Design, Setting, and Participants: This prospective propensity score-matched cohort study was a prespecified secondary analysis of data from the Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) randomized clinical trial, which was conducted at a single academic medical center between January 16, 2015, and May 7, 2018. Patients in the intervention group of the present study were enrolled in either arm of the ENGAGES clinical trial. Patients in the control group were selected from the Systematic Assessment and Targeted Improvement of Services Following Yearly Surgical Outcomes Surveys prospective observational cohort study, which created a registry of patient-reported postoperative outcomes at the same single center. The propensity score-matched cohort in the present study included 1396 patients (698 pairs) selected from a pool of 2013 eligible patients. All patients underwent elective surgical procedures with general anesthesia and had a hospital stay of 2 or more days. Data were analyzed from January 2, 2020, to January 11, 2022., Interventions: The multicomponent safety intervention (offered to all patients in the ENGAGES clinical trial) included patient education on fall prevention techniques, home medication review by a geriatric psychiatrist (with communication of recommended changes to the surgeon), a self-administered home safety assessment, and targeted occupational therapy home visits with home hazard removal (offered to patients with a preoperative history of falls)., Main Outcomes and Measures: The primary outcome was patient-reported falls within 1 year after an elective inpatient surgical procedure. The secondary outcome was quality of life 1 year after an elective surgical procedure, which was measured using the physical and mental composite summary scores on the Veterans RAND 12-item health survey (score range, 0-100 points, with 0 indicating lowest quality of life and 100 indicating highest quality of life)., Results: Among 1396 patients, the median age was 69 years (IQR, 64-75 years), and 739 patients (52.9%) were male. With regard to race, 5 patients (0.4%) were Asian, 97 (6.9%) were Black or African American, 2 (0.1%) were Native Hawaiian or Pacific Islander, 1237 (88.6%) were White, 3 (0.2%) were of other race, and 52 (3.7%) were of unknown race; with regard to ethnicity, 12 patients (0.9%) were Hispanic or Latino, 1335 (95.6%) were non-Hispanic or non-Latino, and 49 (3.5%) were of unknown ethnicity. Adherence to individual intervention components was modest (from 22.9% for completion of the self-administered home safety assessment to 28.2% for implementation of the geriatric psychiatrist's recommended medication changes). Falls within 1 year after surgical procedures were reported by 228 of 698 patients (32.7%) in the intervention group and 225 of 698 patients (32.2%) in the control group. No significant difference was found in falls between the 2 groups (standardized risk difference, 0.4%; 95% CI, -4.5% to 5.3%). After adjusting for preoperative quality of life, patients in the intervention group had higher physical composite summary scores (3.8 points; 95% CI, 2.4-5.1 points) and higher mental composite summary scores (5.7 points; 95% CI, 4.7-6.7 points) at 1 year compared with patients in the control group., Conclusions and Relevance: In this cohort study, a multicomponent safety intervention was not associated with reductions in falls within the first year after an elective surgical procedure; however, an increase in quality of life at 1 year was observed. These results suggest a need for other interventions, such as those designed to increase adherence, to lower the incidence of falls after surgical procedures.

Background: Intraoperative EEG suppression duration has been associated with postoperative delirium and mortality. In a clinical trial testing anaesthesia titration to avoid EEG suppression, the intervention did not decrease the incidence of postoperative delirium, but was associated with reduced 30-day mortality. The present study evaluated whether the EEG-guided anaesthesia intervention was also associated with reduced 1-yr mortality., Methods: This manuscript reports 1 yr follow-up of subjects from a single-centre RCT, including a post hoc secondary outcome (1-yr mortality) in addition to pre-specified secondary outcomes. The trial included subjects aged 60 yr or older undergoing surgery with general anaesthesia between January 2015 and May 2018. Patients were randomised to receive EEG-guided anaesthesia or usual care. The previously reported primary outcome was postoperative delirium. The outcome of the current study was all-cause 1-yr mortality., Results: Of the 1232 subjects enrolled, 614 subjects were randomised to EEG-guided anaesthesia and 618 subjects to usual care. One-year mortality was 57/591 (9.6%) in the guided group and 62/601 (10.3%) in the usual-care group. No significant difference in mortality was observed (adjusted absolute risk difference, -0.7%; 99.5% confidence interval, -5.8% to 4.3%; P=0.68)., Conclusions: An EEG-guided anaesthesia intervention aiming to decrease duration of EEG suppression during surgery did not significantly decrease 1-yr mortality. These findings, in the context of other studies, do not provide supportive evidence for EEG-guided anaesthesia to prevent intermediate term postoperative death., Clinical Trial Registration: NCT02241655., (Copyright © 2021 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Current approaches to understanding medication ordering errors rely on relatively small manually captured error samples. These approaches are resource-intensive, do not scale for computerized provider order entry (CPOE) systems, and are likely to miss important risk factors associated with medication ordering errors. Previously, we described a dataset of CPOE-based medication voiding accompanied by univariable and multivariable regression analyses. However, these traditional techniques require expert guidance and may perform poorly compared to newer approaches. In this paper, we update that analysis using machine learning (ML) models to predict erroneous medication orders and identify its contributing factors. We retrieved patient demographics (race/ethnicity, sex, age), clinician characteristics, type of medication order (inpatient, prescription, home medication by history), and order content. We compared logistic regression, random forest, boosted decision trees, and artificial neural network models. Model performance was evaluated using area under the receiver operating characteristic curve (AUROC) and the area under the precision-recall curve (AUPRC). The dataset included 5,804,192 medication orders, of which 28,695 (0.5%) were voided. ML correctly classified voids at reasonable accuracy; with a positive predictive value of 10%, ~20% of errors were included. Gradient boosted decision trees achieved the highest AUROC (0.7968) and AUPRC (0.0647) among all models. Logistic regression had the poorest performance. Models identified predictive factors with high face validity (e.g., student orders), and a decision tree revealed interacting contexts with high rates of errors not identified by previous regression models. Prediction models using order-entry information offers promise for error surveillance, patient safety improvements, and targeted clinical review. The improved performance of models with complex interactions points to the importance of contextual medication ordering information for understanding contributors to medication errors., Competing Interests: The authors have declared that no competing interests exist.

Profiling of serological responses to establish the landscape of antibody specificities in individuals exposed to pathogens or vaccines is crucial for (a) revealing humoral immune correlates of protection; (b) uncovering markers of pathogen exposure; and (c) identifying antigens and epitopes associated with disease vs. protection. Establishing the antigenic profile of serological responses requires either expensive microarrays or labor- and time-intensive ELISA assays. Multiplex assay platforms are increasingly being evaluated for their usefulness for high-throughput testing of sera or plasma. The methodology described here utilizes a plate-based assay that allows the simultaneous detection of up to ten antigens per well in a 96 well format using an electrochemiluminescence immunoassay (ECLIA).•The newly developed protocol outlines high-throughput profiling of serological responses using a multiplex testing platform with subsequent computational analysis.•The protocol is a modification of the basic assay development manual from the manufacturer of the MESO QuickPlex SQ 120 instrument (MSD, Gaithersburg, MD) and can be used for synthetic peptides as well as full length proteins.•The protocol can be applied to map serological responses to pathogens or pathogen-derived antigens to establish serological profiles in search for biomarkers or immune correlates., Competing Interests: The authors declare that they have no conflict of interest.

Importance: Postoperative complications can significantly impact perioperative care management and planning., Objectives: To assess machine learning (ML) models for predicting postoperative complications using independent and combined preoperative and intraoperative data and their clinically meaningful model-agnostic interpretations., Design, Setting, and Participants: This retrospective cohort study assessed 111 888 operations performed on adults at a single academic medical center from June 1, 2012, to August 31, 2016, with a mean duration of follow-up based on the length of postoperative hospital stay less than 7 days. Data analysis was performed from February 1 to September 31, 2020., Main Outcomes and Measures: Outcomes included 5 postoperative complications: acute kidney injury (AKI), delirium, deep vein thrombosis (DVT), pulmonary embolism (PE), and pneumonia. Patient and clinical characteristics available preoperatively, intraoperatively, and a combination of both were used as inputs for 5 candidate ML models: logistic regression, support vector machine, random forest, gradient boosting tree (GBT), and deep neural network (DNN). Model performance was compared using the area under the receiver operating characteristic curve (AUROC). Model interpretations were generated using Shapley Additive Explanations by transforming model features into clinical variables and representing them as patient-specific visualizations., Results: A total of 111 888 patients (mean [SD] age, 54.4 [16.8] years; 56 915 [50.9%] female; 82 533 [73.8%] White) were included in this study. The best-performing model for each complication combined the preoperative and intraoperative data with the following AUROCs: pneumonia (GBT), 0.905 (95% CI, 0.903-0.907); AKI (GBT), 0.848 (95% CI, 0.846-0.851); DVT (GBT), 0.881 (95% CI, 0.878-0.884); PE (DNN), 0.831 (95% CI, 0.824-0.839); and delirium (GBT), 0.762 (95% CI, 0.759-0.765). Performance of models that used only preoperative data or only intraoperative data was marginally lower than that of models that used combined data. When adding variables with missing data as input, AUROCs increased from 0.588 to 0.905 for pneumonia, 0.579 to 0.848 for AKI, 0.574 to 0.881 for DVT, 0.5 to 0.831 for PE, and 0.6 to 0.762 for delirium. The Shapley Additive Explanations analysis generated model-agnostic interpretation that illustrated significant clinical contributors associated with risks of postoperative complications., Conclusions and Relevance: The ML models for predicting postoperative complications with model-agnostic interpretation offer opportunities for integrating risk predictions for clinical decision support. Such real-time clinical decision support can mitigate patient risks and help in anticipatory management for perioperative contingency planning.

Background: Handoffs or care transitions from the operating room (OR) to intensive care unit (ICU) are fragmented and vulnerable to communication errors. Although protocols and checklists for standardization help reduce errors, such interventions suffer from limited sustainability. An unexplored aspect is the potential role of developing personalized postoperative transition interventions using artificial intelligence (AI)-generated risks., Objectives: This study was aimed to (1) identify factors affecting sustainability of handoff standardization, (2) utilize a human-centered approach to develop design ideas and prototyping requirements for a sustainable handoff intervention, and (3) explore the potential role for AI risk assessment during handoffs., Methods: We conducted four design workshops with 24 participants representing OR and ICU teams at a large medical academic center. Data collection phases were (1) open-ended questions, (2) closed card sorting of handoff information elements, and (3) scenario-based design ideation and prototyping for a handoff intervention. Data were analyzed using thematic analysis. Card sorts were further tallied to characterize handoff information elements as core, flexible, or unnecessary., Results: Limited protocol awareness among clinicians and lack of an interdisciplinary electronic health record (EHR)-integrated handoff intervention prevented long-term sustainability of handoff standardization. Clinicians argued for a handoff intervention comprised of core elements (included for all patients) and flexible elements (tailored by patient condition and risks). They also identified unnecessary elements that could be omitted during handoffs. Similarities and differences in handoff intervention requirements among physicians and nurses were noted; in particular, clinicians expressed divergent views on the role of AI-generated postoperative risks., Conclusion: Current postoperative handoff interventions focus largely on standardization of information transfer and handoff processes. Our design approach allowed us to visualize accurate models of user expectations for effective interdisciplinary communication. Insights from this study point toward EHR-integrated, "flexibly standardized" care transition interventions that can automatically generate a patient-centered summary and risk-based report., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Preoperative cognitive dysfunction has been associated with adverse postoperative outcomes. There are limited data characterising the epidemiology of preoperative cognitive dysfunction in older surgical patients., Methods: This retrospective cohort included all patients ≥65 yr old seen at the Washington University preoperative clinic between January 2013 and June 2018. Cognitive screening was performed using the Short-Blessed Test (SBT) and Eight-Item Interview to Differentiate Aging and Dementia (AD8) screen. The primary outcome of abnormal cognitive screening was defined as SBT score ≥5 or AD8 score ≥2. Multivariable logistic regression was used to identify associated factors., Results: Overall, 21 666 patients ≥65 yr old completed screening during the study period; 23.5% (n=5099) of cognitive screens were abnormal. Abnormal cognitive screening was associated with increasing age, decreasing BMI, male sex, non-Caucasian race, decreased functional independence, and decreased metabolic functional capacity. Patients with a history of stroke or transient ischaemic attack, chronic obstructive pulmonary disease, diabetes mellitus, hepatic cirrhosis, and heavy alcohol use were also more likely to have an abnormal cognitive screen. Predictive modelling showed no combination of patient factors was able to reliably identify patients who had a <10% probability of abnormal cognitive screening., Conclusions: Routine preoperative cognitive screening of unselected aged surgical patients often revealed deficits consistent with cognitive impairment or dementia. Such deficits were associated with increased age, decreased function, decreased BMI, and several common medical comorbidities. Further research is necessary to characterise the clinical implications of preoperative cognitive dysfunction and identify interventions that may reduce related postoperative complications., (Copyright © 2020 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Plasma antimalarial Ab can mediate antiparasite immunity but has not previously been characterized at the molecular level. Here, we develop an innovative strategy to characterize humoral responses by integrating profiles of plasma immunoglobulins (IGs) or Abs with those expressed on B cells as part of the B cell receptor. We applied this strategy to define plasma IG and to determine variable (V) gene usage after vaccination with the Plasmodium falciparum zygote antigen Pfs25. Using proteomic tools coupled with bulk immunosequencing data, we determined human antigen-binding fragment [F(ab')2] peptide sequences from plasma IG of adults who received 4 doses of Pfs25-EPA/Alhydrogel. Specifically, Pfs25 antigen-specific F(ab')2 peptides (Pfs25-IG) were aligned to cDNA sequences of IG heavy (IGH) chain complementarity determining region 3 from a data set generated by total peripheral B cell immunosequencing of the entire vaccinated population. IGHV4 was the most commonly identified IGHV subgroup of Pfs25-IG, a pattern that was corroborated by V heavy/V light chain sequencing of Pfs25-specific single B cells from 5 vaccinees and by matching plasma Pfs25-IG peptides and V-(D)-J sequences of Pfs25-specific single B cells from the same donor. Among 13 recombinant human mAbs generated from IG sequences of Pfs25-specific single B cells, a single IGHV4 mAb displayed strong neutralizing activity, reducing the number of P. falciparum oocysts in infected mosquitoes by more than 80% at 100 μg/mL. Our approach characterizes the human plasma Ab repertoire in response to the Pfs25-EPA/Alhydrogel vaccine and will be useful for studying circulating Abs in response to other vaccines as well as those induced during infections or autoimmune disorders.

Introduction: The post-anesthesia care unit (PACU) is a clinical area designated for patients recovering from invasive procedures. There are typically several geographically dispersed PACUs within hospitals. Patients in the PACU can be unstable and at risk for complications. However, clinician coverage and patient monitoring in PACUs is not well regulated and might be sub-optimal. We hypothesize that a telemedicine center for the PACU can improve key PACU functions. Objectives: The objective of this study is to demonstrate the potential utility and acceptability of a telemedicine center to complement the key functions of the PACU. These include participation in hand-off activities to and from the PACU, detection of physiological derangements, identification of symptoms requiring treatment, recognition of situations requiring emergency medical intervention, and determination of patient readiness for PACU discharge. Methods and analysis: This will be a single center prospective before-and-after proof-of-concept study. Adults (18 years and older) undergoing elective surgery and recovering in two selected PACU bays will be enrolled. During the initial three-month observation phase, clinicians in the telemedicine center will not communicate with clinicians in the PACU, unless there is a specific patient safety concern. During the subsequent three-month interaction phase, clinicians in the telemedicine center will provide structured decision support to PACU clinicians. The primary outcome will be time to PACU discharge readiness determination in the two study phases. The attitudes of key stakeholders towards the telemedicine center will be assessed. Other outcomes will include detection of physiological derangements, complications, adverse symptoms requiring treatments, and emergencies requiring medical intervention. Registration: This trial is registered on clinicaltrials.gov, NCT04020887 (16 th July 2019)., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Budelier TP et al.)

Human adenoviruses (HAdV) are ubiquitous within the human population and comprise a significant burden of respiratory illnesses worldwide. Pediatric and immunocompromised individuals are at particular risk for developing severe disease; however, no approved antiviral therapies specific to HAdV exist. Ivermectin is an FDA-approved broad-spectrum antiparasitic drug that also exhibits antiviral properties against a diverse range of viruses. Its proposed function is inhibiting the classical protein nuclear import pathway mediated by importin-α (Imp-α) and -β1 (Imp-β1). Many viruses, including HAdV, rely on this host pathway for transport of viral proteins across the nuclear envelope. In this study, we show that ivermectin inhibits HAdV-C5 early gene transcription, early and late protein expression, genome replication, and production of infectious viral progeny. Similarly, ivermectin inhibits genome replication of HAdV-B3, a clinically important pathogen responsible for numerous recent outbreaks. Mechanistically, we show that ivermectin disrupts binding of the viral E1A protein to Imp-α without affecting the interaction between Imp-α and Imp-β1. Our results further extend ivermectin's broad antiviral activity and provide a mechanistic underpinning for its mode of action as an inhibitor of cellular Imp-α/β1-mediated nuclear import. IMPORTANCE Human adenoviruses (HAdVs) represent a ubiquitous and clinically important pathogen without an effective antiviral treatment. HAdV infections typically cause mild symptoms; however, individuals such as children, those with underlying conditions, and those with compromised immune systems can develop severe disseminated disease. Our results demonstrate that ivermectin, an FDA-approved antiparasitic agent, is effective at inhibiting replication of several HAdV types in vitro This is in agreement with the growing body of literature suggesting ivermectin has broad antiviral activity. This study expands our mechanistic knowledge of ivermectin by showing that ivermectin targets the ability of importin-α (Imp-α) to recognize nuclear localization sequences, without effecting the Imp-α/β1 interaction. These data also exemplify the applicability of targeting host factors upon which viruses rely as a viable antiviral strategy., (Copyright © 2020 American Society for Microbiology.)

Competing Interests: The authors have declared that no competing interests exist.

Mitochondrial and plastid genomes in land plants exhibit some of the slowest rates of sequence evolution observed in any eukaryotic genome, suggesting an exceptional ability to prevent or correct mutations. However, the mechanisms responsible for this extreme fidelity remain unclear. We tested seven candidate genes involved in cytoplasmic DNA replication, recombination, and repair ( POLIA , POLIB , MSH1 , RECA3 , UNG , FPG , and OGG1 ) for effects on mutation rates in the model angiosperm Arabidopsis thaliana by applying a highly accurate DNA sequencing technique (duplex sequencing) that can detect newly arisen mitochondrial and plastid mutations even at low heteroplasmic frequencies. We find that disrupting MSH1 (but not the other candidate genes) leads to massive increases in the frequency of point mutations and small indels and changes to the mutation spectrum in mitochondrial and plastid DNA. We also used droplet digital PCR to show transmission of de novo heteroplasmies across generations in msh1 mutants, confirming a contribution to heritable mutation rates. This dual-targeted gene is part of an enigmatic lineage within the mutS mismatch repair family that we find is also present outside of green plants in multiple eukaryotic groups (stramenopiles, alveolates, haptophytes, and cryptomonads), as well as certain bacteria and viruses. MSH1 has previously been shown to limit ectopic recombination in plant cytoplasmic genomes. Our results point to a broader role in recognition and correction of errors in plant mitochondrial and plastid DNA sequence, leading to greatly suppressed mutation rates perhaps via initiation of double-stranded breaks and repair pathways based on faithful homologous recombination., Competing Interests: The authors declare no competing interest.