Exploring the ability of the MD+FoldX method to predict SARS-CoV-2 antibody escape mutations using large-scale data.

Antibody escape mutations pose a significant challenge to the effectiveness of vaccines and antibody-based therapies. The ability to predict these escape mutations with computer simulations would allow us to detect threats early and develop effective countermeasures, but a lack of large-scale experimental data has hampered the validation of these calculations. In this study, we evaluate the ability of the MD+FoldX molecular modeling method to predict escape mutations by leveraging a large deep mutational scanning dataset, focusing on the SARS-CoV-2 receptor binding domain. Our results show a positive correlation between predicted and experimental data, indicating that mutations with reduced predicted binding affinity correlate moderately with higher experimental escape fractions. We also demonstrate that better performance can be achieved using affinity cutoffs tailored to distinct antibody-antigen interactions rather than a one-size-fits-all approach. We find that 70% of the systems surpass the 50% precision mark, and demonstrate success in identifying mutations present in significant variants of concern and variants of interest. Despite promising results for some systems, our study highlights the challenges in comparing predicted and experimental values. It also emphasizes the need for new binding affinity methods with improved accuracy that are fast enough to estimate hundreds to thousands of antibody-antigen binding affinities.

Inspired anatomy education: Might God be relevant?

Anatomy education is essential for developing healthcare professionals, and discussion continues about factors that impact and improve the anatomy learning environment. Neglected in this discussion is a consideration of the diverse religious assumptions and beliefs that college students bring to anatomy learning. Surveys of religion among United States college students indicate that many identify as religious and Christian. This viewpoint commentary summarizes main elements of Christian theology and anthropology, discusses the holistic and positive view of the body presented in Christian scripture, and outlines how these Christian beliefs inform and impact student preparation for anatomy education and human body dissection, address ethical issues in body donation, and support professionalism for future career practice.

Saltwater-Induced Rapid Gelation of Photoredox-Responsive Mucomimetic Hydrogels.

Shear-thinning hydrogels represent an important class of injectable soft materials that are often used in a wide range of biomedical applications. Creation of new shear-thinning materials often requires that factors such as viscosity, injection rate/force, and needle gauge be evaluated to achieve efficient delivery, while simultaneously protecting potentially sensitive cargo. Here, a new approach to establishing shear-thinning hydrogels is reported where a host-guest cross-linked network initially remains soluble in deionized water but is kinetically trapped as a viscous hydrogel once exposed to saltwater. The shear-thinning properties of the hydrogel is then "switched on" in response to heating or exposure to visible light. These hydrogels consist of polynorbornene-based bottlebrush copolymers with porphyrin- and oligoviologen-containing side chains that are cross-linked through the reversible formation of ß-cyclodextrin-adamantane inclusion complexes. The resultant viscous hydrogels display broad adhesive properties across polar and nonpolar substrates, mimicking that of natural mucous and thus making it easier to distribute onto a wide range of surfaces. Additional control over the hydrogel's mechanical properties (storage/loss moduli) and performance (adhesion) is achieved post-injection using a low-energy (blue light) photoinduced electron-transfer process. This work envisions these injectable copolymers and multimodal hydrogels can serve as versatile next-generation biomaterials capable of light-based mechanical manipulation post-injection.

Development of a High-Throughput Mass Spectrometry-Based SARS-CoV-2 Immunoassay.

The serious impact of the Covid-19 pandemic underscores the need for rapid, reliable, and high-throughput diagnosis methods for infection. Current analytical methods, either point-of-care or centralized detection, are not able to satisfy the requirements of patient-friendly testing, high demand, and reliability of results. Here, we propose a two-point separation on-demand diagnostic strategy that uses laser desorption/ionization time-of-flight mass spectrometry (LDI-TOF MS) and adopts a stable yet cleavable ionic probe as a mass reporter. The use of this reporter enables ultrasensitive, interruptible, storable, restorable, and high-throughput on-demand detection. We describe a demonstration of the concept whereby we (i) design and synthesize a laser-cleavable reporter (DTPA), (ii) conjugate the reporter onto an antibody and verify the function of the conjugate, (iii) detect with good turnaround and high sensitivity the conjugated reporter, (iv) analyze quantitatively by using a laser-cleavable internal standard, and (v) identify negative and positive samples containing the spike protein. The protocol has excellent sensitivity (amol for the SARS-CoV-2 Spike S1 subunit antibody) without any amplification. This strategy is also applicable for the detection of other disease antigens besides SARS-CoV-2.

Pharmacological and non-pharmacological interventions to prevent delirium after cardiac surgery: a protocol for a systematic review and meta-analysis.

INTRODUCTION: Delirium is a syndrome characterised by a disturbance in attention, awareness and cognition as a result of another physical condition. It occurs in up to 50% of patients after cardiac surgery and is associated with increased mortality, prolonged intensive care and hospital stay and long-term cognitive dysfunction. Identifying effective preventive interventions is important. We will therefore conduct a systematic review to identify all randomised controlled studies that have tested a pharmacological or non-pharmacological intervention to prevent delirium. METHODS AND ANALYSIS: We will search electronic databases (CDSR (Reviews), CENTRAL (Trials), MEDLINE Ovid, Embase Ovid, PsycINFO Ovid) as well as trial registers (clinicaltrials.gov and ISCRTN) for randomised controlled trials of both pharmacological and non-pharmacological interventions designed to prevent delirium after cardiac surgery in adults. Screening of search results and data extraction from included articles will be performed by two independent reviewers using Rayyan. The primary outcome will be the incidence of delirium. Secondary outcomes include: duration of postoperative delirium, all-cause mortality, length of postoperative hospital and intensive care stay, postoperative neurological complications other than delirium, health-related quality of life and intervention-specific adverse events. Studies will be assessed for risk of bias using the Cochrane RoB2 tool. A narrative synthesis of all included studies will be presented and meta-analysis (if appropriate network meta-analysis) will be undertaken where there are sufficient studies (three or more) for pooling results. Results will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. ETHICS AND DISSEMINATION: No ethical approval is required. This review will be disseminated via peer-reviewed manuscript and conferences. PROSPERO REGISTRATION NUMBER: CRD42022369068.

Comparison of Magnetic Deflection among Neutral Sodium-Doped Clusters: Na(H2O)n, Na(NH3)n, Na(MeOH)n, and Na(DME)n.

Using a pulsed Stern-Gerlach deflection experiment, we present the results of a comparative study on the magnetic properties of neutral sodium-doped solvent clusters Na(Sol)n with n = 1-4 (Sol: H2O, NH3, CH3OH, CH3OCH3). Experimental deflection ratios are compared with values calculated from molecular dynamics simulations. NaNH3 and NaH2O are deflected as a spin 1/2 system, consistent with spin transitions occurring on a time scale significantly longer than 100 µs. For all other clusters, reduced deflection is observed. The observed magnetic deflection behavior is correlated to the number of thermally populated rotational states in the clusters. We discuss that spin-rotational couplings allow for avoided crossings and a reduction in the effective magnetic moment of the cluster. This work attempts to understand the evolution of magnetic properties in isolated weakly bound clusters and is relevant to diamagnetic and paramagnetic species expected to exist in solvated electron systems.

Protocol for a systematic review and meta-analysis of tobacco-cessation interventions delivered perioperatively.

INTRODUCTION: Tobacco smoking is associated with a substantially increased risk of perioperative complications. The perioperative period is an opportunity to introduce tobacco-cessation strategies. A previous systematic review provided evidence that perioperative interventions increase short-term abstinence and may reduce postoperative complications. The evidence base has since expanded, with the subsequent publication of numerous randomised studies. This protocol outlines a systematic review examining the impact of perioperative tobacco-cessation interventions on successful abstinence from tobacco smoking, and on the incidence of perioperative complications. METHODS AND ANALYSIS: A systematic search of the literature will be run across EMBASE (Ovid), MEDLINE (Ovid), CINAHL (Ebsco) and PsycInfo (ProQuest), from inception to present, using text words and subject headings. Randomised controlled trials published in English, examining adults in the perioperative period and reporting the outcomes from tobacco-cessation interventions will be included.Abstract screening and data extraction will be performed by five reviewers. Each abstract will be screened by two blinded reviewers, with discrepancies resolved by group consensus. The primary outcome will be point prevalence abstinence from tobacco-use at the time of surgery. Secondary outcomes are prolonged abstinence from tobacco use at 6 months and 12 months, and postoperative complications. Any other reported outcomes will be documented in the descriptive analysis. The review will also describe details of the investigated perioperative tobacco-cessation interventions. If sufficient studies report relevant data, meta-analysis of the primary and secondary outcomes will be undertaken. Results will be reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement. ETHICS AND DISSEMINATION: No ethical approval is required. Results will be disseminated by open-access, peer-reviewed journal publication and conference presentations. Results will underpin future work to modify perioperative tobacco-cessation interventions to enhance engagement and accessibility, and to develop trials aiming to facilitate abstinence from tobacco-use in patients presenting for surgery.

Novel viruses of the family Partitiviridae discovered in Saccharomyces cerevisiae.

It has been 49 years since the last discovery of a new virus family in the model yeast Saccharomyces cerevisiae. A large-scale screen to determine the diversity of double-stranded RNA (dsRNA) viruses in S. cerevisiae has identified multiple novel viruses from the family Partitiviridae that have been previously shown to infect plants, fungi, protozoans, and insects. Most S. cerevisiae partitiviruses (ScPVs) are associated with strains of yeasts isolated from coffee and cacao beans. The presence of partitiviruses was confirmed by sequencing the viral dsRNAs and purifying and visualizing isometric, non-enveloped viral particles. ScPVs have a typical bipartite genome encoding an RNA-dependent RNA polymerase (RdRP) and a coat protein (CP). Phylogenetic analysis of ScPVs identified three species of ScPV, which are most closely related to viruses of the genus Cryspovirus from the mammalian pathogenic protozoan Cryptosporidium parvum. Molecular modeling of the ScPV RdRP revealed a conserved tertiary structure and catalytic site organization when compared to the RdRPs of the Picornaviridae. The ScPV CP is the smallest so far identified in the Partitiviridae and has structural homology with the CP of other partitiviruses but likely lacks a protrusion domain that is a conspicuous feature of other partitivirus particles. ScPVs were stably maintained during laboratory growth and were successfully transferred to haploid progeny after sporulation, which provides future opportunities to study partitivirus-host interactions using the powerful genetic tools available for the model organism S. cerevisiae.

Solvated dielectrons from optical excitation: An effective source of low-energy electrons.

Low-energy electrons dissolved in liquid ammonia or aqueous media are powerful reducing agents that promote challenging reduction reactions but can also cause radiation damage to biological tissue. Knowledge of the underlying mechanistic processes remains incomplete, particularly with respect to the details and energetics of the electron transfer steps. In this work, we show how ultraviolet (UV) photoexcitation of metal-ammonia clusters could be used to generate tunable low-energy electrons in situ. Specifically, we identified UV light-induced generation of spin-paired solvated dielectrons and their subsequent relaxation by an unconventional electron transfer-mediated decay as an efficient, low-energy electron source. The process is robust and straightforward to induce with the prospect of improving our understanding of radiation damage and fostering mechanistic studies of solvated electron reduction reactions.

Does melatonin administration reduce the incidence of postoperative delirium in adults? Systematic review and meta-analysis.

Postoperative delirium (POD) is common. It is associated with increased morbidity and mortality. Many cases may be preventable and melatonin offers promise as a preventative agent. OBJECTIVE: This systematic review provides an up-to-date synthesis of the evidence on the effect of melatonin in preventing POD. DESIGN: A systematic search of randomised controlled trials of melatonin in POD was run across multiple databases (EMBASE, MEDLINE, CINAHL, PsycINFO) and a clinical trials registry (ClinicalTrials.org) (1 January 1990 to 5 April 2022). Studies examining the effects of melatonin on POD incidence in adults are included. Risk of bias was assessed using the Cochrane risk of bias 2 tool. OUTCOME MEASURES: The primary outcome is POD incidence. Secondary outcomes are POD duration and length of hospital stay. Data synthesis was undertaken using a random-effects meta-analysis and presented using forest plots. A summary of methodology and outcome measures in included studies is also presented. RESULTS: Eleven studies, with 1244 patients from a range of surgical specialties were included. Seven studies used melatonin, in variable doses, and four used ramelteon. Eight different diagnostic tools were used to diagnose POD. Time points for assessment also varied. Six studies were assessed as low risk of bias and five as some concern. The combined OR of developing POD in the melatonin groups versus control was 0.41 (95% CI 0.21 to 0.80, p=0.01). CONCLUSION: This review found that melatonin may reduce the incidence of POD in adults undergoing surgery. However, included studies displayed inconsistency in their methodology and outcome reporting. Further work to determine the optimum regime for melatonin administration, along with consensus of how best to evaluate results, would be beneficial. PROSPERO REGISTRATION NUMBER: CRD42021285019.

The effect of mutations on binding interactions between the SARS-CoV-2 receptor binding domain and neutralizing antibodies B38 and CB6.

SARS-CoV-2 is the pathogen responsible for COVID-19 that has claimed over six million lives as of July 2022. The severity of COVID-19 motivates a need to understand how it could evolve to escape potential treatments and to find ways to strengthen existing treatments. Here, we used the molecular modeling methods MD + FoldX and PyRosetta to study the SARS-CoV-2 spike receptor binding domain (S-RBD) bound to two neutralizing antibodies, B38 and CB6 and generated lists of antibody escape and antibody strengthening mutations. Our resulting watchlist contains potential antibody escape mutations against B38/CB6 and consists of 211/186 mutations across 35/22 S-RBD sites. Some of these mutations have been identified in previous studies as being significant in human populations (e.g., N501Y). The list of potential antibody strengthening mutations that are predicted to improve binding of B38/CB6 to S-RBD consists of 116/45 mutations across 29/13 sites. These mutations could be used to improve the therapeutic value of these antibodies.

Using a cohort study of diabetes and peripheral artery disease to compare logistic regression and machine learning via random forest modeling.

BACKGROUND: This study illustrates the use of logistic regression and machine learning methods, specifically random forest models, in health services research by analyzing outcomes for a cohort of patients with concomitant peripheral artery disease and diabetes mellitus. METHODS: Cohort study using fee-for-service Medicare beneficiaries in 2015 who were newly diagnosed with peripheral artery disease and diabetes mellitus. Exposure variables include whether patients received preventive measures in the 6 months following their index date: HbA1c test, foot exam, or vascular imaging study. Outcomes include any reintervention, lower extremity amputation, and death. We fit both logistic regression models as well as random forest models. RESULTS: There were 88,898 fee-for-service Medicare beneficiaries diagnosed with peripheral artery disease and diabetes mellitus in our cohort. The rate of preventative treatments in the first six months following diagnosis were 52% (n = 45,971) with foot exams, 43% (n = 38,393) had vascular imaging, and 50% (n = 44,181) had an HbA1c test. The directionality of the influence for all covariates considered matched those results found with the random forest and logistic regression models. The most predictive covariate in each approach differs as determined by the t-statistics from logistic regression and variable importance (VI) in the random forest model. For amputation we see age 85 + (t = 53.17) urban-residing (VI = 83.42), and for death (t = 65.84, VI = 88.76) and reintervention (t = 34.40, VI = 81.22) both models indicate age is most predictive. CONCLUSIONS: The use of random forest models to analyze data and provide predictions for patients holds great potential in identifying modifiable patient-level and health-system factors and cohorts for increased surveillance and intervention to improve outcomes for patients. Random forests are incredibly high performing models with difficult interpretation most ideally suited for times when accurate prediction is most desirable and can be used in tandem with more common approaches to provide a more thorough analysis of observational data.

Comprehensive geriatric assessment (CGA) in perioperative care: a systematic review of a complex intervention.

OBJECTIVES: Comprehensive geriatric assessment (CGA) is a complex intervention applied to older people with evidence of benefit in medical populations. The aim of this systematic review was to describe how CGA is applied to surgical populations in randomised controlled trials. This will provide a basis for design of future studies focused on optimising CGA as a complex intervention. SETTING: A systematic review of randomised controlled trials. PARTICIPANTS: A systematic search was performed for studies of CGA in the perioperative period across Ovid MEDLINE, Ovid EMBASE, CINAHL and Cochrane CENTRAL, from inception to March 2021. INTERVENTIONS: Any randomised controlled trials of perioperative CGA versus 'standard care' were included. OUTCOME MEASURES: Qualitative description of CGA. RESULTS: 12 121 titles and abstracts were screened, 68 full-text articles were assessed for eligibility and 22 articles included, reporting on 13 trials. 10 trials focused on inpatients with hip fracture, with 7 of these delivering CGA on a geriatric medicine ward, 3 on a surgical ward. The remaining three trials were in elective general surgery all delivering CGA on a surgical ward. CGA components, duration of intervention and personnel delivering the intervention were highly variable across the different studies. Trials favoured postoperative delivery of CGA (11/13). Only four trials reported data on adherence to the CGA intervention. CONCLUSIONS: CGA as an intervention is variably described and delivered in randomised controlled trials in the perioperative setting. The reporting of both the intervention and standard care is often poor with little focus on adherence. Future research should focus on clearly defining and standardising the intervention as well as measuring adherence within trials. PROSPERO REGISTRATION NUMBER: CRD42020221797.

Electrostatic loading and photoredox-based release of molecular cargo from oligoviologen-crosslinked microparticles.

Although on-demand cargo release has been demonstrated in a wide range of microparticle platforms, many existing methods lack specific loading interactions and/or undergo permanent damage to the microparticle to release the cargo. Here, we report a novel method for electrostatically loading negatively charged molecular cargo in oligoviologen-crosslinked microparticles, wherein the cargo can be released upon activation by visible light. A water-in-oil (W/O) emulsion polymerization method was used to fabricate narrowly dispersed microparticles crosslinked by a dicationic viologen-based dimer and a poly(ethylene glycol) diacrylate. A zinc-tetraphenyl porphyrin photocatalyst was also polymerized into the microparticle and used to photochemically reduce the viologen subunits to their monoradical cations through a visible-light-mediated photoredox mechanism with triethanolamine (TEOA) as a sacrificial reductant. The microparticles were characterized by microscopy methods revealing uniform, spherical microparticles 481 ± 20.9 nm in diameter. Negatively charged molecular cargo (methyl orange, MO) was electrostatically loaded into the microparticles through counteranion metathesis. Upon irradiation with blue (450 nm) light, the photo-reduced viologen crosslinker subunits lose positive charges, resulting in release of the anionic MO cargo. Controlled release of the dye, as tracked by absorption spectroscopy, was observed over time, yielding release of up to 40% of the cargo in 48 h and 60% in 120 h in single dynamic dialysis experiment. However, full release of cargo was achieved upon transferring the microparticles to a fresh TEOA solution after the initial 120 h period.

Melatonin for the prevention of postoperative delirium in older adults: a protocol for a systematic review and meta-analysis.

INTRODUCTION: Postoperative delirium (POD) is a major cause of morbidity, particularly in elderly patients. Melatonin has been suggested as a low-risk pharmacological intervention to help prevent POD. A previous systematic review found limited high-quality evidence to support the use of melatonin in the prevention of POD. Several further randomised studies have since been published. This systematic review aims to synthesise the evidence from randomised controlled trials (RCTs) examining the effect of melatonin on the prevention of POD in older adults. METHODS AND ANALYSIS: A systematic search of RCTs of melatonin (any dose and formulation) in POD will be run across Embase, Medline, CINAHL and PsychInfo. RCTs published from January 1990 until the end of February 2022 and reporting outcomes for melatonin use to prevent POD in patients will be included. Screening of search results and data extraction from included articles will be performed by two independent reviewers. The primary outcome will be incidence of POD in older adults undergoing surgery. Secondary outcomes are delirium duration and length of hospital stay. The review will also describe the dosage, timing and administration regimes of melatonin therapy and as well as the scales and definitions used to describe POD. A registry review of ongoing trials will be also be performed. For the meta-analysis, data will be pooled using a random effects model to generate a forest plot and obtain an odds ratio (OR) for the incidence of POD. Results will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. ETHICS AND DISSEMINATION: No ethical approval is required. This review will be disseminated via peer-reviewed manuscript and conferences. The results will be used as the basis of work to optimise this intervention for future trials in surgical populations. PROSPERO REGISTRATION NUMBER: This review is registered with PROSPERO (CRD42021285019).

Use of real-world data and clinical registries to identify new uses of existing vascular endografts: combined use of GORE EXCLUDER Iliac Branch Endoprosthesis and GORE VIABAHN VBX Balloon Expandable Endoprosthesis.

Objective: To assess the feasibility of collecting, examining and reporting observational, real-world evidence regarding the novel use of the GORE EXCLUDER Iliac Branch Endoprosthesis (IBE) in conjunction with the GORE VIABAHN VBX Balloon Expandable Endoprosthesis (IBE+VBX stent graft). Design: Multicentre retrospective cohort study. Setting: Four real-world data sources were used: a national quality improvement registry, a statewide clinical research network, a regional quaternary health system and two tertiary academic medical centres. Participants: In total, 30 patients with 37 IBE+VBX stent graft were identified. Of those, the mean age was 72±10.2 years and 90% were male. The cohort was 77% white, 10% black, 3% Hispanic and 10% other. Main outcome measures: Outcome measures included: proportion of percutaneous vs open surgical access, intensive care admission, intensive care unit (ICU) length-of-stay (LOS), total LOS, postoperative complications, discharge disposition and 30-day mortality. Results: The majority (89%) of cases were performed percutaneously, 5% required surgical exposure following failed percutaneous access and 6% required open surgical exposure outright. Nearly half (43%) required intensive care admission with a median ICU LOS of 1 day (range: 1-2). Median total LOS was 1 day (IQR: 1-2). There were zero postoperative myocardial infarctions, zero reported leg embolisations and no reported reinterventions. Access site complications were described in 1 of 28 patients, manifesting as a haematoma or pseudoaneurysm. Ultimately, 97% were discharged to home and one patient was discharged to a nursing home or rehabilitation facility. There were no 30-day perioperative deaths. Conclusions: This project demonstrates the feasibility of identifying and integrating real-world evidence, as it pertains to an unapproved combination of endovascular devices (IBE+VBX stent graft), for short-term outcomes analysis. This new paradigm of evidence has potential to be used for device monitoring, submission to regulatory agencies, or consideration in indication expansions and approvals with further efforts to systematise data collection and transmission mechanisms.

An EvoDevo Study of Salmonid Visual Opsin Dynamics and Photopigment Spectral Sensitivity.

Salmonids are ideal models as many species follow a distinct developmental program from demersal eggs and a large yolk sac to hatching at an advanced developmental stage. Further, these economically important teleosts inhabit both marine- and freshwaters and experience diverse light environments during their life histories. At a genome level, salmonids have undergone a salmonid-specific fourth whole genome duplication event (Ss4R) compared to other teleosts that are already more genetically diverse compared to many non-teleost vertebrates. Thus, salmonids display phenotypically plastic visual systems that appear to be closely related to their anadromous migration patterns. This is most likely due to a complex interplay between their larger, more gene-rich genomes and broad spectrally enriched habitats; however, the molecular basis and functional consequences for such diversity is not fully understood. This study used advances in genome sequencing to identify the repertoire and genome organization of visual opsin genes (those primarily expressed in retinal photoreceptors) from six different salmonids [Atlantic salmon (Salmo salar), brown trout (Salmo trutta), Chinook salmon (Oncorhynchus tshawytcha), coho salmon (Oncorhynchus kisutch), rainbow trout (Oncorhynchus mykiss), and sockeye salmon (Oncorhynchus nerka)] compared to the northern pike (Esox lucius), a closely related non-salmonid species. Results identified multiple orthologues for all five visual opsin classes, except for presence of a single short-wavelength-sensitive-2 opsin gene. Several visual opsin genes were not retained after the Ss4R duplication event, which is consistent with the concept of salmonid rediploidization. Developmentally, transcriptomic analyzes of Atlantic salmon revealed differential expression within each opsin class, with two of the long-wavelength-sensitive opsins not being expressed before first feeding. Also, early opsin expression in the retina was located centrally, expanding dorsally and ventrally as eye development progressed, with rod opsin being the dominant visual opsin post-hatching. Modeling by spectral tuning analysis and atomistic molecular simulation, predicted the greatest variation in the spectral peak of absorbance to be within the Rh2 class, with a ∼40 nm difference in λ max values between the four medium-wavelength-sensitive photopigments. Overall, it appears that opsin duplication and expression, and their respective spectral tuning profiles, evolved to maximize specialist color vision throughout an anadromous lifecycle, with some visual opsin genes being lost to tailor marine-based vision.

Factors associated with preference of choice of aortic aneurysm repair in the PReference for Open Versus Endovascular repair of AAA (PROVE-AAA) study.

OBJECTIVE: Patients can choose between open repair and endovascular repair (EVAR) of abdominal aortic aneurysm (AAA). However, the factors associated with patient preference for one repair type over another are not well-characterized. Here we assess the factors associated with preference of choice for open or endovascular AAA repair among veterans exposed to a decision aid to help with choosing surgical treatment. METHODS: Across 12 Veterans Affairs hospitals, veterans received a decision aid covering domains including patient information sources and understanding preference. Veterans were then given a series of surveys at different timepoints examining their preferences for open versus endovascular AAA repair. Questions from the preference survey were used in analyses of patient preference. Results were analyzed using χ2 tests. A logistic regression analysis was performed to assess factors associated with preference for open repair or preference for EVAR. RESULTS: A total of 126 veterans received a decision aid informing them of their treatment choices, after which 121 completed all preference survey questions; five veterans completed only part of the instruments. Overall, veterans who preferred open repair were typically younger (70 years vs 73 years; P = .02), with similar rates of common comorbidities (coronary disease 16% vs 28%; P = .21), and similar aneurysms compared with those who preferred EVAR (6.0 cm vs 5.7 cm; P = .50). Veterans in both preference categories (28% of veterans preferring EVAR, 48% of veterans preferring open repair) reported taking their doctor's advice as the top box response for the single most important factor influencing their decision. When comparing the tradeoff between less invasive surgery and higher risk of long-term complications, more than one-half of veterans preferring EVAR reported invasiveness as more important compared with approximately 1 in 10 of those preferring open repair (53% vs 12%; P < .001). Shorter recovery was an important factor for the EVAR group (74%) and not important in the open repair group (76%) (P = .5). In multivariable analyses, valuing a short hospital stay (odds ratio, 12.4; 95% confidence interval, 1.13-135.70) and valuing a shorter recovery (odds ratio, 15.72; 95% confidence interval, 1.03-240.20) were associated with a greater odds of preference for EVAR, whereas finding these characteristics not important was associated with a greater odds of preference for open repair. CONCLUSIONS: When faced with the decision of open repair versus EVAR, veterans who valued a shorter hospital stay and a shorter recovery were more likely to prefer EVAR, whereas those more concerned about long-term complications preferred an open repair. Veterans typically value the advice of their surgeon over their own beliefs and preferences. These findings need to be considered by surgeons as they guide their patients to a shared decision.

Sacubitril/valsartan vs ACEi/ARB at hospital discharge and 5-year survival in older patients with heart failure with reduced ejection fraction: A decision analysis approach.

BACKGROUND: In clinical trials, sacubitril/valsartan has demonstrated significant survival benefits compared to angiotensin converting enzyme inhibitors or angiotensin receptor blockers (ACEi/ARB). Whether older patients with heart failure with reduced ejection fraction (HFrEF) benefit as much, due to higher rates of comorbidities, frailty and drug discontinuation, is unknown. METHODS AND RESULTS: Using a cohort of Medicare beneficiaries hospitalized with HFrEF between 2016 and 2018, we determined all-cause mortality and HF-readmission rates among patients not given ACEi/ARB or sacubitril/valsartan at hospital discharge, by age. We then used risk reductions from the SOLVD, PARADIGM-HF and PIONEER-HF trials to estimate the benefits of ACEi/ARB and sacubitril/valsartan. We then incorporated age-specific estimates of drug discontinuation from Medicare. A Markov decision process model was used to simulate 5-year survival and estimate number needed to treat, comparing discharge on ACEi/ARB vs sacubitril/valsartan by age. After accounting for drug discontinuation rates, which were surprisingly slightly higher among those discharged on ACEi/ARB (2.3%/month vs 1.9%/month), there was a small but significant survival advantage to discharge on sacubitril/valsartan over 5 years (+0.81 months [95% CI 0.80, 0.81]). The benefit of sacubitril/valsartan over ACEi/ARB did not decrease with increasing age - the number needed to treat among 66 to 74-year-old patients was 84 and among 85+ year-old patients was 67. CONCLUSIONS: Even after accounting for "real world" rates of drug discontinuation, discharge on sacubitril/valsartan after conferred a small, but significant, survival advantage which does not appear to wane with increasing age.

Metalation/Demetalation as a Postgelation Strategy To Tune the Mechanical Properties of Catenane-Crosslinked Gels.

Mechanically interlocked molecules (MIMs) possess unique architectures and nontraditional degrees of freedom that arise from well-defined topologies that are achieved through precise mechanical bonding. Incorporation of MIMs into materials can thus provide an avenue to discover new and emergent macroscale properties. Here, the synthesis of a phenanthroline-based [2]catenane crosslinker and its incorporation into polyacrylate organogels are described. Specifically, Cu(I) metalation and demetalation was used as a postgelation strategy to tune the mechanical properties of a gel by controlling the conformational motions of integrated MIMs. The organogels were prepared via thermally initiated free radical polymerization, and Cu(I) metal was added in MeOH to the pretreated, swollen gels. Demetalation of the gels was achieved by adding lithium cyanide and washing the gels. Changes in Young's and shear moduli, as well as tensile strength, were quantified through oscillatory shear rheology and tensile testing. The reported approach provides a general method for postgelation tuning of mechanical properties using metals and well-defined catenane topologies as part of a gel network architecture.