Two Randomized Trials of Neutralizing Antibodies to Prevent HIV-1 Acquisition.

BACKGROUND: Whether a broadly neutralizing antibody (bnAb) can be used to prevent human immunodeficiency virus type 1 (HIV-1) acquisition is unclear. METHODS: We enrolled at-risk cisgender men and transgender persons in the Americas and Europe in the HVTN 704/HPTN 085 trial and at-risk women in sub-Saharan Africa in the HVTN 703/HPTN 081 trial. Participants were randomly assigned to receive, every 8 weeks, infusions of a bnAb (VRC01) at a dose of either 10 or 30 mg per kilogram (low-dose group and high-dose group, respectively) or placebo, for 10 infusions in total. HIV-1 testing was performed every 4 weeks. The VRC01 80% inhibitory concentration (IC80) of acquired isolates was measured with the TZM-bl assay. RESULTS: Adverse events were similar in number and severity among the treatment groups within each trial. Among the 2699 participants in HVTN 704/HPTN 085, HIV-1 infection occurred in 32 in the low-dose group, 28 in the high-dose group, and 38 in the placebo group. Among the 1924 participants in HVTN 703/HPTN 081, infection occurred in 28 in the low-dose group, 19 in the high-dose group, and 29 in the placebo group. The incidence of HIV-1 infection per 100 person-years in HVTN 704/HPTN 085 was 2.35 in the pooled VRC01 groups and 2.98 in the placebo group (estimated prevention efficacy, 26.6%; 95% confidence interval [CI], -11.7 to 51.8; P = 0.15), and the incidence per 100 person-years in HVTN 703/HPTN 081 was 2.49 in the pooled VRC01 groups and 3.10 in the placebo group (estimated prevention efficacy, 8.8%; 95% CI, -45.1 to 42.6; P = 0.70). In prespecified analyses pooling data across the trials, the incidence of infection with VRC01-sensitive isolates (IC80 <1 µg per milliliter) per 100 person-years was 0.20 among VRC01 recipients and 0.86 among placebo recipients (estimated prevention efficacy, 75.4%; 95% CI, 45.5 to 88.9). The prevention efficacy against sensitive isolates was similar for each VRC01 dose and trial; VRC01 did not prevent acquisition of other HIV-1 isolates. CONCLUSIONS: VRC01 did not prevent overall HIV-1 acquisition more effectively than placebo, but analyses of VRC01-sensitive HIV-1 isolates provided proof-of-concept that bnAb prophylaxis can be effective. (Supported by the National Institute of Allergy and Infectious Diseases; HVTN 704/HPTN 085 and HVTN 703/HPTN 081 ClinicalTrials.gov numbers, NCT02716675 and NCT02568215.).

The Clinical Utility of Genetic Testing in the Diagnosis and Management of Adults with Chronic Kidney Disease.

SIGNIFICANCE STATEMENT: Accurate diagnosis of a patient's underlying cause of CKD can influence management and ultimately overall health. The single-arm, interventional, prospective Renasight Clinical Application, Review, and Evaluation study assessed the utility of genetic testing with a 385 gene kidney disease panel on the diagnosis and management of 1623 patients with CKD. Among 20.8% of patients who had positive genetic findings, half resulted in a new or reclassified diagnosis. In addition, a change in management because of genetic testing was reported for 90.7% of patients with positive findings, including treatment changes in 32.9%. These findings demonstrate that genetic testing has a significant effect on both CKD diagnosis and management. BACKGROUND: Genetic testing in CKD has recently been shown to have diagnostic utility with many predicted implications for clinical management, but its effect on management has not been prospectively evaluated. METHODS: Renasight Clinical Application, Review, and Evaluation RenaCARE (ClinicalTrials.gov NCT05846113 ) is a single-arm, interventional, prospective, multicenter study that evaluated the utility of genetic testing with a broad, 385 gene panel (the Renasight TM test) on the diagnosis and management of adult patients with CKD recruited from 31 US-based community and academic medical centers. Patient medical history and clinical CKD diagnosis were collected at enrollment. Physician responses to questionnaires regarding patient disease categorization and management were collected before genetic testing and 1 month after the return of test results. Changes in CKD diagnosis and management after genetic testing were assessed. RESULTS: Of 1623 patients with CKD in 13 predefined clinical disease categories (ages, 18-96; median, 55 years), 20.8% ( n =338) had positive genetic findings spanning 54 genes. Positive genetic findings provided a new diagnosis or reclassified a prior diagnosis in 48.8% of those patients. Physicians reported that genetic results altered the management of 90.7% of patients with a positive genetic finding, including changes in treatment plan, which were reported in 32.9% of these patients. CONCLUSIONS: Genetic testing with a CKD-focused 385 gene panel substantially refined clinical diagnoses and had widespread implications for clinical management, including appropriate treatment strategies. These data support the utility of broader integration of panels of genetic tests into the clinical care paradigm for patients with CKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ClinicalTrials.gov, NCT05846113 .

New Coding Guidelines Reduce Emergency Department Note Bloat But More Work Is Needed.

STUDY OBJECTIVE: The length and redundancy of notes authored by clinicians has significantly increased, giving rise to the term "note bloat." We analyzed the impact of new coding guidelines and documentation best practices on the length of emergency department (ED) notes and the amount of time clinicians spent documenting. METHODS: In a large, multisite health care delivery organization, we retrospectively evaluated the length of all ED provider notes and the amount of time clinicians spent documenting between February 2018 and June 2023. In January 2023, we implemented changes to the standardized note template to align with the new coding guidelines from the American Medical Association and the Centers for Medicare & Medicaid Services. The primary outcomes were the length of provider notes and the amount of time spent documenting. RESULTS: Our study sample consisted of 1,679,762 ED provider notes. Six months after the intervention, the average note length decreased by 872 words (95% confidence interval 867 to 877 words), whereas the amount of time clinicians spent documenting did not change. CONCLUSIONS: Embracing new guidelines and practices, we reduced the length of ED provider notes by 872 words. Despite this, the time clinicians spent documenting did not change significantly. We provide an early report of success in reducing note bloat in the ED to help guide future efforts to reduce overall documentation burden.

De Novo Design of Molecules with Low Hole Reorganization Energy Based on a Quarter-Million Molecule DFT Screen: Part 2.

Organic semiconductors have many desirable properties including improved manufacturing and flexible mechanical properties. Due to the vastness of chemical space, it is essential to efficiently explore chemical space when designing new materials, including through the use of generative techniques. New generative machine learning methods for molecular design continue to be published in the literature at a significant rate but successfully adapting methods to new chemistry and problem domains remains difficult. These challenges necessitate continual method evaluation to probe method viability for use in alternative applications not covered in the original works. In continuation of our previous work, we evaluate four additional machine-learning-based de novo methods for generating molecules with high predicted hole mobility for use in semiconductor applications. The four generative methods evaluated here are (1) Molecule Deep Q-Networks (MolDQN), which utilizes Deep-Q learning to directly optimize molecular structure graphs for desired properties instead of generating SMILES, (2) Graph-based Genetic Algorithm (GraphGA), which uses a genetic algorithm for optimization where crossovers and mutations are defined in terms of RDKit's reaction SMILES, (3) Generative Tensorial Reinforcement Learning (GENTRL), which is a variational autoencoder (VAE) with a learned prior distribution and optimized using reinforcement learning, and (4) Monte Carlo tree search exploration of chemical space in conjunction with a recurrent neural network (RNN) decoder (ChemTS). The generated molecules were evaluated using density functional theory (DFT) and we discovered better performing molecules with the GraphGA method compared to the other approaches.

Phase 1 Human Immunodeficiency Virus (HIV) Vaccine Trial to Evaluate the Safety and Immunogenicity of HIV Subtype C DNA and MF59-Adjuvanted Subtype C Envelope Protein.

BACKGROUND: The Pox-Protein Public-Private Partnership is performing a suite of trials to evaluate the bivalent subtype C envelope protein (TV1.C and 1086.C glycoprotein 120) vaccine in the context of different adjuvants and priming agents for human immunodeficiency virus (HIV) type 1 (HIV-1) prevention. METHODS: In the HIV Vaccine Trials Network 111 trial, we compared the safety and immunogenicity of DNA prime followed by DNA/protein boost with DNA/protein coadministration injected intramuscularly via either needle/syringe or a needle-free injection device (Biojector). One hundred thirty-two healthy, HIV-1-uninfected adults were enrolled from Zambia, South Africa, and Tanzania and were randomized to 1 of 6 arms: DNA prime, protein boost by needle/syringe; DNA and protein coadministration by needle/syringe; placebo by needle/syringe; DNA prime, protein boost with DNA given by Biojector; DNA and protein coadministration with DNA given by Biojector; and placebo by Biojector. RESULTS: All vaccinations were safe and well tolerated. DNA and protein coadministration was associated with increased HIV-1 V1/V2 antibody response rate, a known correlate of decreased HIV-1 infection risk. DNA administration by Biojector elicited significantly higher CD4+ T-cell response rates to HIV envelope protein than administration by needle/syringe in the prime/boost regimen (85.7% vs 55.6%; P = .02), but not in the coadministration regimen (43.3% vs 48.3%; P = .61). CONCLUSIONS: Both the prime/boost and coadministration regimens are safe and may be promising for advancement into efficacy trials depending on whether cellular or humoral responses are desired. CLINICAL TRIALS REGISTRATION: South African National Clinical Trials Registry (application 3947; Department of Health [DoH] no. DOH-27-0715-4917) and ClinicalTrials.gov (NCT02997969).

De Novo Design of Molecules with Low Hole Reorganization Energy Based on a Quarter-Million Molecule DFT Screen.

Materials exhibiting higher mobilities than conventional organic semiconducting materials such as fullerenes and fused thiophenes are in high demand for applications in printed electronics. To discover new molecules in the heteroacene family that might show improved hole mobility, three de novo design methods were applied. Machine learning (ML) models were generated based on previously calculated hole reorganization energies of a quarter million examples of heteroacenes, where the energies were calculated by applying density functional theory (DFT) and a massive cloud computing environment. The three generative methods applied were (1) the continuous space method, where molecular structures are converted into continuous variables by applying the variational autoencoder/decoder technique; (2) the method based on reinforcement learning of SMILES strings (the REINVENT method); and (3) the junction tree variational autoencoder method that directly generates molecular graphs. Among the three methods, the second and third methods succeeded in obtaining chemical structures whose DFT-calculated hole reorganization energy was lower than the lowest energy in the training dataset. This suggests that an extrapolative materials design protocol can be developed by applying generative modeling to a quantitative structure-property relationship (QSPR) utility function.

Combining Cloud-Based Free-Energy Calculations, Synthetically Aware Enumerations, and Goal-Directed Generative Machine Learning for Rapid Large-Scale Chemical Exploration and Optimization.

The hit identification process usually involves the profiling of millions to more recently billions of compounds either via traditional experimental high-throughput screens (HTS) or computational virtual high-throughput screens (vHTS). We have previously demonstrated that, by coupling reaction-based enumeration, active learning, and free energy calculations, a similarly large-scale exploration of chemical space can be extended to the hit-to-lead process. In this work, we augment that approach by coupling large scale enumeration and cloud-based free energy perturbation (FEP) profiling with goal-directed generative machine learning, which results in a higher enrichment of potent ideas compared to large scale enumeration alone, while simultaneously staying within the bounds of predefined drug-like property space. We can achieve this by building the molecular distribution for generative machine learning from the PathFinder rules-based enumeration and optimizing for a weighted sum QSAR-based multiparameter optimization function. We examine the utility of this combined approach by designing potent inhibitors of cyclin-dependent kinase 2 (CDK2) and demonstrate a coupled workflow that can (1) provide a 6.4-fold enrichment improvement in identifying <10 nM compounds over random selection and a 1.5-fold enrichment in identifying <10 nM compounds over our previous method, (2) rapidly explore relevant chemical space outside the bounds of commercial reagents, (3) use generative ML approaches to "learn" the SAR from large scale in silico enumerations and generate novel idea molecules for a flexible receptor site that are both potent and within relevant physicochemical space, and (4) produce over 3 000 000 idea molecules and run 1935 FEP simulations, identifying 69 ideas with a predicted IC50 < 10 nM and 358 ideas with a predicted IC50 < 100 nM. The reported data suggest combining both reaction-based and generative machine learning for ideation results in a higher enrichment of potent compounds over previously described approaches and has the potential to rapidly accelerate the discovery of novel chemical matter within a predefined potency and property space.

A predictive analytics model for differentiating between transient ischemic attacks (TIA) and its mimics.

BACKGROUND: Transient ischemic attack (TIA) is a brief episode of neurological dysfunction resulting from cerebral ischemia not associated with permanent cerebral infarction. TIA is associated with high diagnostic errors because of the subjective nature of findings and the lack of clinical and imaging biomarkers. The goal of this study was to design and evaluate a novel multinomial classification model, based on a combination of feature selection mechanisms coupled with logistic regression, to predict the likelihood of TIA, TIA mimics, and minor stroke. METHODS: We conducted our modeling on consecutive patients who were evaluated in our health system with an initial diagnosis of TIA in a 9-month period. We established the final diagnoses after the clinical evaluation by independent verification from two stroke neurologists. We used Recursive Feature Elimination (RFE) and Least Absolute Shrinkage and Selection Operator (LASSO) for prediction modeling. RESULTS: The RFE-based classifier correctly predicts 78% of the overall observations. In particular, the classifier correctly identifies 68% of the cases labeled as "TIA mimic" and 83% of the "TIA" discharge diagnosis. The LASSO classifier had an overall accuracy of 74%. Both the RFE and LASSO-based classifiers tied or outperformed the ABCD2 score and the Diagnosis of TIA (DOT) score. With respect to predicting TIA, the RFE-based classifier has 61.1% accuracy, the LASSO-based classifier has 79.5% accuracy, whereas the DOT score applied to the dataset yields an accuracy of 63.1%. CONCLUSION: The results of this pilot study indicate that a multinomial classification model, based on a combination of feature selection mechanisms coupled with logistic regression, can be used to effectively differentiate between TIA, TIA mimics, and minor stroke.

Molecular Structure Extraction from Documents Using Deep Learning.

Chemical structure extraction from documents remains a hard problem because of both false positive identification of structures during segmentation and errors in the predicted structures. Current approaches rely on handcrafted rules and subroutines that perform reasonably well generally but still routinely encounter situations where recognition rates are not yet satisfactory and systematic improvement is challenging. Complications impacting the performance of current approaches include the diversity in visual styles used by various software to render structures, the frequent use of ad hoc annotations, and other challenges related to image quality, including resolution and noise. We present end-to-end deep learning solutions for both segmenting molecular structures from documents and predicting chemical structures from the segmented images. This deep-learning-based approach does not require any handcrafted features, is learned directly from data, and is robust against variations in image quality and style. Using the deep learning approach described herein, we show that it is possible to perform well on both segmentation and prediction of low-resolution images containing moderately sized molecules found in journal articles and patents.

Transitioning from intrathecal bupivacaine to mepivacaine for same-day discharge total joint arthroplasty: a quality improvement study.

INTRODUCTION: Same-day discharge total knee and hip arthroplasty is becoming more common. Anesthetic approaches that optimize readiness for discharge are important. Based on an institutional change from low-dose bupivacaine to mepivacaine, we aimed to assess the impact on postanesthesia care unit (PACU) recovery in a quaternary care, academic medical center. METHODS: In this quality improvement retrospective study, a single surgeon performed 96 combined total knee and hip arthroplasties booked as same-day discharge from September 20, 2021 to December 20, 2021. Starting on November 15, 2021 the subarachnoid block was performed with isobaric mepivacaine 37.5-45 mg instead of hyperbaric bupivacaine 9-10.5 mg. We compare these cohorts for time to discharge from PACU, perioperative oral morphine milligram equivalent (OMME) administration, PACU pain scores, conversion to general anesthesia (GA), and overnight admission. RESULTS: We found the use of isobaric mepivacaine as compared with hyperbaric bupivacaine for intrathecal block in same-day discharge total joint arthroplasty was associated with decreased length of PACU stay at our academic center (median 4.03 vs 5.33 hours; p=0.008), increased perioperative OMME (mean 22.5 vs 11.4 mg; p<0.001), increased PACU pain scores (mean 6.29 vs 3.41; p<0.01) and no difference in conversion to GA or overnight admission. CONCLUSIONS: Intrathecal mepivacaine was associated with increased perioperative OMME consumption and PACU pain scores, but still realized a decreased PACU length of stay.

Elevation of Donor-derived Cell-free DNA Before Biopsy-proven Rejection in Kidney Transplant.

BACKGROUND: Standard-of-care biomarkers for renal allograft rejection are lagging indicators, signaling existing organ injury. This precludes early intervention, when immunological cascades leading to rejection are most susceptible. Donor-derived cell-free DNA (dd-cfDNA) shows promise as an early indicator of rejection, allowing earlier and possibly more effective treatment. This analysis was designed to assess this promise using real-world dd-cfDNA testing evidence. METHODS: This retrospective analysis of the prospective, observational ProActive registry study (NCT04091984) assessed dd-cfDNA and serum creatinine levels before biopsy in 424 patients with ≥1 dd-cfDNA test (n = 1013) in the 6 mo before biopsy. RESULTS: Of 4667 enrolled patients, 1631 patients had ≥18 mo of follow-up data, of which 424 had a biopsy and were included in this analysis. Twenty-six biopsies showed antibody-mediated rejection (ABMR), 62 showed T cell-mediated rejection, and 336 showed nonrejection; each from a unique patient. dd-cfDNA fractions were significantly elevated 5 mo before ABMR biopsies, and 2 mo before T cell-mediated rejection biopsies, compared with nonrejection biopsies. In contrast, serum creatinine did not discriminate between rejection and nonrejection in advance, or concurrent with biopsy. Among patients with nonrejection biopsies, estimated glomerular filtration rate was significantly lower in cases with ≥2 increased dd-cfDNA results (≥1%), compared with those with 0 or 1 increased dd-cfDNA result. CONCLUSIONS: These data indicate that dd-cfDNA is an early indicator of biopsy-proven rejection, especially ABMR, suggesting a greater role for dd-cfDNA in surveillance to identify patients at high risk of ongoing or future rejection, thus requiring closer monitoring, biopsy, or other management changes.

Toward Alleviating Clinician Documentation Burden: A Scoping Review of Burden Reduction Efforts.

BACKGROUND: Studies have shown that documentation burden experienced by clinicians may lead to less direct patient care, increased errors, and job dissatisfaction. Implementing effective strategies within health care systems to mitigate documentation burden can result in improved clinician satisfaction and more time spent with patients. However, there is a gap in the literature regarding evidence-based interventions to reduce documentation burden. OBJECTIVES: The objective of this review was to identify and comprehensively summarize the state of the science related to documentation burden reduction efforts. METHODS: Following Joanna Briggs Institute Manual for Evidence Synthesis and Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines, we conducted a comprehensive search of multiple databases, including PubMed, Medline, Embase, CINAHL Complete, Scopus, and Web of Science. Additionally, we searched gray literature and used Google Scholar to ensure a thorough review. Two reviewers independently screened titles and abstracts, followed by full-text review, with a third reviewer resolving any discrepancies. Data extraction was performed and a table of evidence was created. RESULTS: A total of 34 articles were included in the review, published between 2016 and 2022, with a majority focusing on the United States. The efforts described can be categorized into medical scribes, workflow improvements, educational interventions, user-driven approaches, technology-based solutions, combination approaches, and other strategies. The outcomes of these efforts often resulted in improvements in documentation time, workflow efficiency, provider satisfaction, and patient interactions. CONCLUSION: This scoping review provides a comprehensive summary of health system documentation burden reduction efforts. The positive outcomes reported in the literature emphasize the potential effectiveness of these efforts. However, more research is needed to identify universally applicable best practices, and considerations should be given to the transfer of burden among members of the health care team, quality of education, clinician involvement, and evaluation methods.

Understanding the perceived role of electronic health records and workflow fragmentation on clinician documentation burden in emergency departments.

OBJECTIVE: Understand the perceived role of electronic health records (EHR) and workflow fragmentation on clinician documentation burden in the emergency department (ED). METHODS: From February to June 2022, we conducted semistructured interviews among a national sample of US prescribing providers and registered nurses who actively practice in the adult ED setting and use Epic Systems' EHR. We recruited participants through professional listservs, social media, and email invitations sent to healthcare professionals. We analyzed interview transcripts using inductive thematic analysis and interviewed participants until we achieved thematic saturation. We finalized themes through a consensus-building process. RESULTS: We conducted interviews with 12 prescribing providers and 12 registered nurses. Six themes were identified related to EHR factors perceived to contribute to documentation burden including lack of advanced EHR capabilities, absence of EHR optimization for clinicians, poor user interface design, hindered communication, increased manual work, and added workflow blockages, and five themes associated with cognitive load. Two themes emerged in the relationship between workflow fragmentation and EHR documentation burden: underlying sources and adverse consequences. DISCUSSION: Obtaining further stakeholder input and consensus is essential to determine whether these perceived burdensome EHR factors could be extended to broader contexts and addressed through optimizing existing EHR systems alone or through a broad overhaul of the EHR's architecture and primary purpose. CONCLUSION: While most clinicians perceived that the EHR added value to patient care and care quality, our findings underscore the importance of designing EHRs that are in harmony with ED clinical workflows to alleviate the clinician documentation burden.

Investigating the kinetic mechanism of inhibition of elongation factor 2 kinase by NH125: evidence of a common in vitro artifact.

Evidence that elongation factor 2 kinase (eEF-2K) has potential as a target for anticancer therapy and possibly for the treatment of depression is emerging. Here the steady-state kinetic mechanism of eEF-2K is presented using a peptide substrate and is shown to conform to an ordered sequential mechanism with ATP binding first. Substrate inhibition by the peptide was observed and revealed to be competitive with ATP, explaining the observed ordered mechanism. Several small molecules are reported to inhibit eEF-2K activity with the most notable being the histidine kinase inhibitor NH125, which has been used in a number of studies to characterize eEF-2K activity in cells. While NH125 was previously reported to inhibit eEF-2K in vitro with an IC(50) of 60 nM, its mechanism of action was not established. Using the same kinetic assay, the ability of an authentic sample of NH125 to inhibit eEF-2K was assessed over a range of substrate and inhibitor concentrations. A typical dose-response curve for the inhibition of eEF-2K by NH125 is best fit to an IC(50) of 18 ± 0.25 µM and a Hill coefficient of 3.7 ± 0.14, suggesting that NH125 is a weak inhibitor of eEF-2K under the experimental conditions of a standard in vitro kinase assay. To test the possibility that NH125 is a potent inhibitor of eEF2 phosphorylation, we assessed its ability to inhibit the phosphorylation of eEF2. Under standard kinase assay conditions, NH125 exhibits a similar weak ability to inhibit the phosphorylation of eEF2 by eEF-2K. Notably, the activity of NH125 is severely abrogated by the addition of 0.1% Triton to the kinase assay through a process that can be reversed upon dilution. These studies suggest that NH125 is a nonspecific colloidal aggregator in vitro, a notion further supported by the observation that NH125 inhibits other protein kinases, such as ERK2 and TRPM7 in a manner similar to that of eEF-2K. As NH125 is reported to inhibit eEF-2K in a cellular environment, its ability to inhibit eEF2 phosphorylation was assessed in MDA-MB-231 breast cancer, A549 lung cancer, and HEK-293T cell lines using a Western blot approach. No sign of a decrease in the level of eEF2 phosphorylation was observed up to 12 h following addition of NH125 to the media. Furthermore, contrary to the previously reported literatures, NH125 induced the phosphorylation of eEF-2.

Calcium/calmodulin stimulates the autophosphorylation of elongation factor 2 kinase on Thr-348 and Ser-500 to regulate its activity and calcium dependence.

Eukaryotic elongation factor 2 kinase (eEF-2K) is an atypical protein kinase regulated by Ca(2+) and calmodulin (CaM). Its only known substrate is eukaryotic elongation factor 2 (eEF-2), whose phosphorylation by eEF-2K impedes global protein synthesis. To date, the mechanism of eEF-2K autophosphorylation has not been fully elucidated. To investigate the mechanism of autophosphorylation, human eEF-2K was coexpressed with λ-phosphatase and purified from bacteria in a three-step protocol using a CaM affinity column. Purified eEF-2K was induced to autophosphorylate by incubation with Ca(2+)/CaM in the presence of MgATP. Analyzing tryptic or chymotryptic peptides by mass spectrometry monitored the autophosphorylation over 0-180 min. The following five major autophosphorylation sites were identified: Thr-348, Thr-353, Ser-445, Ser-474, and Ser-500. In the presence of Ca(2+)/CaM, robust phosphorylation of Thr-348 occurs within seconds of addition of MgATP. Mutagenesis studies suggest that phosphorylation of Thr-348 is required for substrate (eEF-2 or a peptide substrate) phosphorylation, but not self-phosphorylation. Phosphorylation of Ser-500 lags behind the phosphorylation of Thr-348 and is associated with the Ca(2+)-independent activity of eEF-2K. Mutation of Ser-500 to Asp, but not Ala, renders eEF-2K Ca(2+)-independent. Surprisingly, this Ca(2+)-independent activity requires the presence of CaM.

Comparison of Ordering Tools on Adherence to Treatment Protocols in the Emergency Department.

OBJECTIVE: To assess adherence to clinical protocols in the emergency department after the implementation of embedded order panels in the electronic health record. MATERIALS AND METHODS: Due to infrequent use, a subset of order sets were redesigned as embedded order panels in a menu-style quick list. Usage was measured before and after implementation at seven departments. RESULTS: There were 2,247 applicable encounters during the pre-intervention period and 1,723 post-intervention. The use of order sets increased significantly after implementation (14% vs. 33% or encounters, p < 0.001). Traditional order sets required at least seven keystrokes or mouse clicks, while embedded order panels required only two. DISCUSSION AND CONCLUSION: Use of order sets increased after implementation of embedded order panels; however, they were still only used for about one-third of applicable encounters suggesting that more work is needed to increase treatment protocol adherence and electronic health record efficiency.

A Phase 2b Study to Evaluate the Safety and Efficacy of VRC01 Broadly Neutralizing Monoclonal Antibody in Reducing Acquisition of HIV-1 Infection in Women in Sub-Saharan Africa: Baseline Findings.

BACKGROUND: HIV Vaccine Trials Network 703/HIV Prevention Trials Network 081 is a phase 2b randomized, double-blind, placebo-controlled trial to assess the safety and efficacy of passively infused monoclonal antibody VRC01 in preventing HIV acquisition in heterosexual women between the ages of 18 and 50 years at risk of HIV. Participants were enrolled at 20 sites in Botswana, Kenya, Malawi, Mozambique, South Africa, Tanzania, and Zimbabwe. It is one of the 2 Antibody Mediated Prevention efficacy trials, with HIV Vaccine Trials Network 704/HIV Prevention Trials Network 085, evaluating VRC01 for HIV prevention. METHODS: Intense community engagement was used to optimize participant recruitment and retention. Participants were randomly assigned to receive intravenous VRC01 10 mg/kg, VRC01 30 mg/kg, or placebo in a 1:1:1 ratio. Infusions were given every 8 weeks with a total of 10 infusions and 104 weeks of follow-up after the first infusion. RESULTS: Between May 2016 and September 2018, 1924 women from sub-Saharan Africa were enrolled. The median age was 26 years (interquartile range: 22-30), and 98.9% were Black. Sexually transmitted infection prevalence at enrollment included chlamydia (16.9%), trichomonas (7.2%), gonorrhea (5.7%), and syphilis (2.2%). External condoms (83.2%) and injectable contraceptives (61.1%) were the methods of contraception most frequently used by participants. In total, through April 3, 2020, 38,490 clinic visits were completed with a retention rate of 96% and 16,807 infusions administered with an adherence rate of 98%. CONCLUSIONS: This proof-of-concept, large-scale monoclonal antibody study demonstrates the feasibility of conducting complex trials involving intravenous infusions in high incidence populations in sub-Saharan Africa.

Pain Management in Thoracic Surgery.

Thoracic surgery is considered one of the most painful surgical procedures performed. Pain is mediated via several mechanisms and is affected by the surgical approach as well as patient factors. Pain after thoracic surgery can be debilitating and lead to poor outcomes, such as respiratory complications, longer hospital stays, poor quality of life, and chronic post-thoracotomy pain syndrome. A multimodal approach to postoperative pain that combines systemic and regional anesthesia has been shown to be the most effective in optimizing analgesia in these patients.

Adjacent Segment Pathology After Treatment With Cervical Disc Arthroplasty or Anterior Cervical Discectomy and Fusion, Part 1: Radiographic Results at 7-Year Follow-Up.

BACKGROUND: Adjacent segment pathology (ASP) remains a concern following treatment with cervical disc arthroplasty (CDA) and anterior cervical discectomy and fusion (ACDF). Radiographic ASP (RASP) is ASP identified on imaging, which may or may not include clinical symptoms. The risk factors for development of RASP and its clinical effects remain controversial. In part 1 of a 2-part publication we evaluate the incidence and predictors of RASP as well as determine whether any association exists between RASP and patient-reported outcomes (PROs). METHODS: Data were prospectively collected during a US Food and Drug Administration randomized, multicenter, investigational device exemption trial comparing CDA (Mobi-C; Zimmer Biomet, Westminster, CO) with ACDF. Multiple post hoc analyses were conducted on RASP as it related to demographics and patient outcomes. Kaplan-Meier estimates of time to Kellgren-Lawrence (K-L) grade 3/4 were calculated separately for all groups. Multivariate Cox proportional hazard models were used analyze whether RASP was associated with patient preoperative demographic characteristics and preoperative and postoperative radiographic characteristics. The association of RASP with PROs was analyzed using generalized estimating equations and matched, retrospective cohort analysis. RESULTS: The incidence of grade 3/4 RASP was lower for patients treated with CDA when initial treatment was at 1 level (27% vs 47%, P < .0001) and at 2 levels (14% vs 49%, P < .0001). Kaplan-Meier estimates indicated significantly lower probability of grade 3/4 RASP over time for patients receiving CDA (P < .001). Treatment with ACDF, treatment of 1 level, higher age, body mass index, higher preoperative physical components score, and a lower Cobb angle were associated with elevated risk of grade 3/4 RASP. CDA was shown to be more effective than ACDF (64.4%; 95% CI = 50.9, 74.2; P < .0001) at preventing RASP. CONCLUSIONS: The incidence and risk of RASP is decreased when patients are treated with CDA compared with ACDF. Although the mechanism of CDA that generates this protective effect is not understood, PROs remain unaffected through 7 years despite changes in RASP.

Adjacent Segment Pathology After Treatment With Cervical Disc Arthroplasty or Anterior Cervical Discectomy and Fusion, Part 2: Clinical Results at 7-Year Follow-Up.

BACKGROUND: Adjacent segment pathology (ASP) following cervical disc arthroplasty (CDA) or anterior cervical discectomy and fusion (ACDF) is identified by imaging (RASP) or clinical symptoms (CASP). Clinical symptoms of CASP have been broadly defined, but subsequent adjacent-level surgeries are clear indicators of CASP. Current literature remains inconsistent in the incidence and potential predictors of CASP. Here, we will evaluate a robust data set for the incidence of CASP resulting in subsequent surgery, attempt to identify factors that might affect CASP, and analyze the association of CASP with patient-reported outcomes (PROS) and RASP. METHODS: Data were prospectively collected during a US Food and Drug Administration randomized, multicenter, investigational device exemption trial comparing CDA (Mobi-C, Zimmer Biomet, Westminster, CO) with ACDF. CASP was defined as any adjacent-level subsequent surgical intervention. Post hoc analyses were conducted on the incidence, time to CASP diagnosis, and relationship of CASP with patient demographics. Longitudinal retrospective case-control analysis was used to assess the correlation of CASP to PROs and radiographic adjacent segment pathology (RASP). RESULTS: Kaplan-Meier estimates indicated significantly lower probability of CASP over time for 1-level (P = .002) and 2-level (P = .008) CDA patients. Treatment with ACDF and younger age were associated with higher CASP risk. CDA was more effective than ACDF (70.5%; 95% CI = 45.1, 84.2; P < .0001) at preventing CASP. Case-control analysis indicated increased probability of CASP for patients with grade 3/4 RASP, but the difference was not statistically significant. When we pooled CASP patients, the median grade of RASP at the visit prior to surgery was 1, with only 6 patients presenting with grade 3/4 RASP. CONCLUSIONS: Patients treated with CDA have a lower incidence of CASP than do patients treated with ACDF, although the mechanism remains unclear. CASP and RASP remain uncorrelated in this large data set, but other predictive variables such as treatment, age, and number of levels should be further investigated.