Macintosh-style videolaryngoscope use for tracheal intubation in elective surgical patients revisited: a sub-analysis of the 2022 Cochrane review data.

The Cochrane systematic review and meta-analysis published in 2022 that compared videolaryngoscopy (VL) with direct laryngoscopy (DL) for facilitating tracheal intubation in adults found that all three types of VL device (Macintosh-style, hyper-angulated and channeled) reduced the risk of failed intubation and increased the likelihood of first-pass success. We report the findings of a subgroup re-analysis of the 2022 Cochrane meta-analysis data focusing on the Macintosh-style VL group. This was undertaken to establish whether sufficient evidence exists to guide airway managers in making purchasing decisions for their local institutions based upon individual device-specific performance. This re-analysis confirmed the superiority of Macintosh-style VL over Macintosh DL in elective surgical patients, with similar efficacy demonstrated between the Macintosh-style VL devices examined. Thus, when selecting which VL device(s) to purchase for their hospital, airway managers decisions are likely to remain focused upon issues such as financial costs, portability, cleaning schedules and previous device experience.

First-principles study of MXene properties with varying hydrofluoric acid concentration.

With varying hydrofluoric acid (HF) concentrations under three etching conditions, we presented a comparative study of the effects of both the ordered and randomly ternary mixed terminated Ti3C2Tx surfaces with a wide variation of O/OH/F stoichiometry on the thermodynamic stability and electronic properties. Regardless of the HF concentration, an OH-rich surface is found to be thermodynamically stable and the electrical conductivity of Ti3C2Tx is substantially affected by the OH concentration. The charge density difference and electron localization function demonstrated a significant electron localization at the hydroxyl group on the O/OH/F mixed terminated surface, which could yield a locally induced dipole on the surface that renders favorable reaction sites on the functionalized surface. In addition, a large tunability in the work function (ΔΦ âˆ¼ 3.5 eV) is predicted for Ti3C2Tx. These findings provide a pathway for strategically tuning the electronic and structural properties of Ti3C2 MXenes etched with HF.

Integration of Genetic Testing and Counseling in Patients With Breast Cancer in a Large, Multisite Community-Based Practice.

PURPOSE: Despite data-driven consensus recommendations, there remains significant nonadherence to genetic screening and testing. More than 300,000 patients are diagnosed with breast cancer annually, with one third of these estimated to be eligible for homologous recombination deficiency (HRD)/BRCA testing following National Comprehensive Cancer Network (NCCN) guidelines. Only 35% of eligible patients are referred for genetic counseling. METHODS: The goal of this project was to apply NCCN guidelines for germline genetic testing to all new patients with breast cancer within a large community oncology practice to improve HRD/BRCA testing. Plan-Do-Study-Act methodology was used, and cycles were built on a proven teaching infrastructure. In cycle 1, providers were educated and directed to use electronic health record (EHR) templates in the setting of an initial diagnosis visit and treatment planning. Discreet data fields were created in the EHR during cycle 2 to streamline and automate the process. Appropriate patients were referred to the genetics team for further evaluation, counseling, and testing. Adherence to the plan was maintained and measured using data analytic reports and chart audits. RESULTS: Of the 1,203 patients with breast cancer eligible for inclusion, 1,200 (99%) were screened according to NCCN guidelines. Of the screened patients, 631 (52.5%) met the referral/testing criteria. In total, 585 (92.7%) of the 631 were referred to a genetic specialist. Seven percent had previous referrals. A total of 449 (71%) patients were acceptable to genetics referral while 136 (21.5%) patients refused. CONCLUSION: The implemented methods of education, NCCN guidelines imbedded within provider notes, and discreet data fields in the EHR have proven to be highly effective in screening appropriate patients and ordering subsequent genetic referrals.

Eccentric Force-Velocity-Load Relationship in Trained Rugby Union Athletes.

ABSTRACT: McNeill, C, Beaven, CM, McMaster, DT, Ward, P, and Gill, N. Eccentric force-velocity-load relationship in trained rugby union athletes. J Strength Cond Res 38(3): 549-555, 2024-The force-velocity relationship is traditionally believed to resemble a hyperbolic shape, known as the "force-velocity curve." However, there is less evidence regarding this relationship during eccentric muscle action in multijoint isotonic exercise, especially in applied settings. The purpose of this study was to investigate the force-velocity-load relationship in an incremental eccentric back squat test. In addition, 37 professional male rugby union athletes were recruited to participate. Separate generalized linear mixed models were used to analyze the effect of barbell load on relative eccentric peak force (REPF), relative eccentric mean force (REMF), eccentric peak velocity (EPV), and eccentric mean velocity (EMV). A significant effect of load ( p < 0.05) was observed for each of the eccentric variables tested. Each increase in barbell load tended to result in a linear increase in REMF and a decrease in EMV and EPV; however, we observed a plateauing effect for REPF as load increased. These results show that for "peak" variables lighter loads produced similar magnitudes of force, but generally moved at higher velocities than heavier loads. These observations suggest that the eccentric force-velocity-load relationship may vary depending on the parameters used. Quantifying rapid, multijoint eccentric performance is justified as it seems to provide valuable insight into individual athletic capability and training program design. Further research may investigate the responsiveness of the qualities to training and the causal nature of eccentric characteristics and athletic performance.

Xaluritamig, a STEAP1 × CD3 XmAb 2+1 Immune Therapy for Metastatic Castration-Resistant Prostate Cancer: Results from Dose Exploration in a First-in-Human Study.

Xaluritamig (AMG 509) is a six-transmembrane epithelial antigen of the prostate 1 (STEAP1)-targeted T-cell engager designed to facilitate lysis of STEAP1-expressing cancer cells, such as those in advanced prostate cancer. This first-in-human study reports monotherapy dose exploration for patients with metastatic castration-resistant prostate cancer (mCRPC), primarily taxane pretreated. Ninety-seven patients received ≥1 intravenous dose ranging from 0.001 to 2.0 mg weekly or every 2 weeks. MTD was identified as 1.5 mg i.v. weekly via a 3-step dose. The most common treatment-related adverse events were cytokine release syndrome (CRS; 72%), fatigue (45%), and myalgia (34%). CRS occurred primarily during cycle 1 and improved with premedication and step dosing. Prostate-specific antigen (PSA) and RECIST responses across cohorts were encouraging [49% PSA50; 24% objective response rate (ORR)], with greater frequency at target doses ≥0.75 mg (59% PSA50; 41% ORR). Xaluritamig is a novel immunotherapy for prostate cancer that has shown encouraging results supporting further development. SIGNIFICANCE: Xaluritamig demonstrated encouraging responses (PSA and RECIST) compared with historical established treatments for patients with late-line mCRPC. This study provides proof of concept for T-cell engagers as a potential treatment for prostate cancer, validates STEAP1 as a target, and supports further clinical investigation of xaluritamig in prostate cancer. See related commentary by Hage Chehade et al., p. 20. See related article by Nolan-Stevaux et al., p. 90. This article is featured in Selected Articles from This Issue, p. 5.

Up Front and Open? Shrouded in Secrecy? Or Somewhere in Between? A Meta-Research Systematic Review of Open Science Practices in Sport Medicine Research.

OBJECTIVE: To investigate open science practices in research published in the top 5 sports medicine journals from May 1, 2022, and October 1, 2022. DESIGN: A meta-research systematic review. LITERATURE SEARCH: Open science practices were searched in MEDLINE. STUDY SELECTION CRITERIA: We included original scientific research published in one of the identified top 5 sports medicine journals in 2022 as ranked by Clarivate: (1) British Journal of Sports Medicine, (2) Journal of Sport and Health Science, (3) American Journal of Sports Medicine, (4) Medicine and Science in Sports and Exercise, and (5) Sports Medicine-Open. Studies were excluded if they were systematic reviews, qualitative research, gray literature, or animal or cadaver models. DATA SYNTHESIS: Open science practices were extracted in accordance with the Transparency and Openness Promotion guidelines and patient and public involvement. RESULTS: Two hundred forty-three studies were included. The median number of open science practices in each study was 2, out of a maximum of 12 (range: 0-8; interquartile range: 2). Two hundred thirty-four studies (96%, 95% confidence interval [CI]: 94%-99%) provided an author conflict-of-interest statement and 163 (67%, 95% CI: 62%-73%) reported funding. Twenty-one studies (9%, 95% CI: 5%-12%) provided open-access data. Fifty-four studies (22%, 95% CI: 17%-27%) included a data availability statement and 3 (1%, 95% CI: 0%-3%) made code available. Seventy-six studies (32%, 95% CI: 25%-37%) had transparent materials and 30 (12%, 95% CI: 8%-16%) used a reporting guideline. Twenty-eight studies (12%, 95% CI: 8%-16%) were preregistered. Six studies (3%, 95% CI: 1%-4%) published a protocol. Four studies (2%, 95% CI: 0%-3%) reported an analysis plan a priori. Seven studies (3%, 95% CI: 1%-5%) reported patient and public involvement. CONCLUSION: Open science practices in the sports medicine field are extremely limited. The least followed practices were sharing code, data, and analysis plans. J Orthop Sports Phys Ther 2023;53(12):1-13. Epub 20 October 2023. doi:10.2519/jospt.2023.12016.

Sustainable Integration of US Food and Drug Administration-Approved Biosimilars: Pharmacy- Versus Physician-Driven Change.

PURPOSE: Biosimilars are clinically equivalent to branded products yet cost significantly less. Interchangeability is a US Food and Drug Administration (FDA) designation that allows generic drugs to be substituted for reference drugs at the pharmacy, without a physician's consent. Currently, no oncologic biosimilar has FDA approval for interchangeability. METHODS: Building on pharmacy auto-substitution processes with therapeutic interchange, Plan-Do-Study-Act methodology was used to automate conversions from reference biological products to Pharmacy and Therapeutics-/Physician-approved biosimilars. After establishing the baseline metrics, cycle 1 focused on full staff education (completed July 2020) with systematic pharmacy-driven biosimilar conversion initiated in September 2020 for rituximab, trastuzumab, and bevacizumab. Physician-initiated conversion of Neulasta biosimilar products was encouraged but not mandated. During cycle 2 (May 1, 2021-November 30, 2021), pharmacy-driven Neulasta biosimilar conversion was mandated. In cycle 3 (December 1, 2021-April 30, 2023), stakeholder education was reinforced and the sustainability of conversions was confirmed. RESULTS: Systematic pharmacy-driven conversion to biosimilar products improved over cycles 1 and 2 from baseline: 1.8% to 90.3% for rituximab, 9.2% to 89.7% for trastuzumab, and 20.5% to 96.1% for bevacizumab. Physician-driven biosimilar conversion for Neulasta was lower at 12.7% through April 2021. Pharmacy-driven Neulasta biosimilar conversion was initiated during cycle 2, resulting in a conversion rate of 39.7%. The conversion rates remained sustainable through April 2023. CONCLUSION: Pharmacy-driven auto-substitution of biosimilar products results in rapid and statistically significant biosimilar adoption. The pharmacy-based substitution approach was found to be far more effective than physician-driven substitution. Rapid conversion from branded products to FDA-approved biosimilar is feasible, measurable, and sustainable and can be scaled. Barriers to Neulasta conversion warrant further investigation.

Airway Management: The Current Role of Videolaryngoscopy.

Airway management is usually an uncomplicated and safe intervention; however, when problems arise with the primary airway technique, the clinical situation can rapidly deteriorate, resulting in significant patient harm. Videolaryngoscopy has been shown to improve patient outcomes when compared with direct laryngoscopy, including improved first-pass success at tracheal intubation, reduced difficult laryngeal views, reduced oxygen desaturation, reduced airway trauma, and improved recognition of oesophageal intubation. The shared view that videolaryngoscopy affords may also facilitate superior teaching, training, and multidisciplinary team performance. As such, its recommended role in airway management has evolved from occasional use as a rescue device (when direct laryngoscopy fails) to a first-intention technique that should be incorporated into routine clinical practice, and this is reflected in recently updated guidelines from a number of international airway societies. However, currently, overall videolaryngoscopy usage is not commensurate with its now widespread availability. A number of factors exist that may be preventing its full adoption, including perceived financial costs, inadequacy of education and training, challenges in achieving deliverable decontamination processes, concerns over sustainability, fears over "de-skilling" at direct laryngoscopy, and perceived limitations of videolaryngoscopes. This article reviews the most up-to-date evidence supporting videolaryngoscopy, explores its current scope of utilisation (including specialist techniques), the potential barriers preventing its full adoption, and areas for future advancement and research.

Simple steps towards improving safety in obstetric airway management: A quality improvement project.

BACKGROUND: Guidelines from the Obstetric Anaesthetists' Association and Difficult Airway Society state that 'a videolaryngoscope should be immediately available for all obstetric general anaesthetics'. OBJECTIVE: To report the incidence of videolaryngoscopy use, and other airway management safety interventions, in an obstetric population before and after various quality improvement interventions. DESIGN: Prospective data collection was undertaken over 18 months, divided into three separate 6-month periods: June to November 2019; March to August 2021; January to June 2022. These periods relate to evaluation of specific quality improvement interventions. SETTING: The project was carried out in a large tertiary referral obstetric unit. PATIENTS: We identified 401 pregnant women (> 20 weeks' gestation) and postnatal women (up to 48 h post delivery) undergoing an obstetric surgical procedure under general anaesthesia. INTERVENTIONS: To standardise practice, an intubation checklist was introduced in December 2020 and multidisciplinary staff training in August 2021. MAIN OUTCOME MEASURES: Primary outcome measures were use of a Macintosh-style videolaryngoscope and tracheal intubation success. Secondary outcome measures were use of an intubation checklist; low flow nasal oxygen; and ramped patient positioning. RESULTS: Data from 334 tracheal intubations (83.3% of cases) were recorded. Videolaryngoscope use increased from 60% in 2019, to 88% in 2021, to 94% in 2022. Tracheal intubation was successful in all patients, with 94% first pass success overall and only 0.9% requiring three attempts. Use of secondary outcome measures also increased: low flow nasal oxygen from 48% in 2019 to 90% in 2022; ramped positioning from 95% in 2021 to 97% in 2022; and checklist use from 63% in 2021 to 92% in 2022. CONCLUSIONS: We describe the successful adoption of simple safety measures introduced into routine practice. These comprised videolaryngoscopy, ramped positioning and low flow nasal oxygen. Their introduction was supported by the implementation of an intubation checklist and multidisciplinary team training.

The mitochondrial calcium uniporter transports Ca 2+ via a ligand-relay mechanism.

The mitochondrial calcium uniporter (mtCU) is a multicomponent Ca 2+ -specific channel that imparts mitochondria with the capacity to sense the cytosolic calcium signals. The metazoan mtCU comprises the pore-forming subunit MCU and the essential regulator EMRE, arranged in a tetrameric channel complex, and the Ca 2+ sensing peripheral proteins MICU1-3. The mechanism of mitochondrial Ca 2+ uptake by mtCU and its regulation is poorly understood. Our analysis of MCU structure and sequence conservation, combined with molecular dynamics simulations, mutagenesis, and functional studies, led us to conclude that the Ca 2+ conductance of MCU is driven by a ligand-relay mechanism, which depends on stochastic structural fluctuations in the conserved DxxE sequence. In the tetrameric structure of MCU, the four glutamate side chains of DxxE (the E-ring) chelate Ca 2+ directly in a high-affinity complex (site 1), which blocks the channel. The four glutamates can also switch to a hydrogen bond-mediated interaction with an incoming hydrated Ca 2+ transiently sequestered within the D-ring of DxxE (site 2), thus releasing the Ca 2+ bound at site 1. This process depends critically on the structural flexibility of DxxE imparted by the adjacent invariant Pro residue. Our results suggest that the activity of the uniporter can be regulated through the modulation of local structural dynamics. A preliminary account of this work was presented at the 67 th Annual Meeting of the Biophysical Society in San Diego, CA, February 18-22, 2023.

Dose escalation and expansion cohorts in patients with advanced breast cancer in a Phase I study of the CDK7-inhibitor samuraciclib.

Samuraciclib is a selective oral CDK7-inhibitor. A multi-modular, open-label Phase I study to evaluate safety and tolerability of samuraciclib in patients with advanced malignancies was designed (ClinicalTrials.gov: NCT03363893). Here we report results from dose escalation and 2 expansion cohorts: Module 1A dose escalation with paired biopsy cohort in advanced solid tumor patients, Module 1B-1 triple negative breast cancer (TNBC) monotherapy expansion, and Module 2A fulvestrant combination in HR+/HER2- breast cancer patients post-CDK4/6-inhibitor. Core study primary endpoints are safety and tolerability, and secondary endpoints are pharmacokinetics (PK), pharmacodynamic (PD) activity, and anti-tumor activity. Common adverse events are low grade nausea, vomiting, and diarrhea. Maximum tolerated dose is 360 mg once daily. PK demonstrates dose proportionality (120 mg-480 mg), a half-life of approximately 75 hours, and no fulvestrant interaction. In dose escalation, one partial response (PR) is identified with disease control rate of 53% (19/36) and reduction of phosphorylated RNA polymerase II, a substrate of CDK7, in circulating lymphocytes and tumor tissue. In TNBC expansion, one PR (duration 337 days) and clinical benefit rate at 24 weeks (CBR) of 20.0% (4/20) is achieved. In combination with fulvestrant, 3 patients achieve PR with CBR 36.0% (9/25); in patients without detectable TP53-mutation CBR is 47.4% (9/19). In this study, samuraciclib exhibits tolerable safety and PK is supportive of once-daily oral administration. Clinical activity in TNBC and HR+/HER2-breast cancer post-CDK4/6-inhibitor settings warrants further evaluation.

The Trade Secret Taboo: Open Science Methods are Required to Improve Prediction Models in Sports Medicine and Performance.

Clinical prediction models in sports medicine that utilize regression or machine learning techniques have become more widely published, used, and disseminated. However, these models are typically characterized by poor methodology and incomplete reporting, and an inadequate evaluation of performance, leading to unreliable predictions and weak clinical utility within their intended sport population. Before implementation in practice, models require a thorough evaluation. Strong replicable methods and transparency reporting allow practitioners and researchers to make independent judgments as to the model's validity, performance, clinical usefulness, and confidence it will do no harm. However, this is not reflected in the sports medicine literature. As shown in a recent systematic review of models for predicting sports injury models, most were typically characterized by poor methodology, incomplete reporting, and inadequate performance evaluation. Because of constraints imposed by data from individual teams, the development of accurate, reliable, and useful models is highly reliant on external validation. However, a barrier to collaboration is a desire to maintain a competitive advantage; a team's proprietary information is often perceived as high value, and so these 'trade secrets' are frequently guarded. These 'trade secrets' also apply to commercially available models, as developers are unwilling to share proprietary (and potentially profitable) development and validation information. In this Current Opinion, we: (1) argue that open science is essential for improving sport prediction models and (2) critically examine sport prediction models for open science practices.

Closing the Testing Gap: Standardization of Comprehensive Biomarker Testing for Metastatic Non-Small-Cell Lung Cancer in a Large Community Oncology Practice.

PURPOSE: Non-small-cell lung cancer (NSCLC), the leading cause of cancer death in the United States, accounts for 85% of all lung cancer cases. Biomarker testing is an integral part of the care of patients with NSCLC. Despite broad consensus recommendations that all patients with metastatic NSCLC (mNSCLC) undergo comprehensive biomarker testing (comprehensive genomic profiling and PD-L1), testing rates remain suboptimal. METHODS: The primary goal of this project was to apply National Comprehensive Cancer Network (NCCN) guidelines for comprehensive biomarker testing to all new patients with mNSCLC within a large community practice. Plan-Do-Study-Act methodology was used, with cycle 1 focused on provider education and the creation of a mNSCLC initial consult Note (electronic health record template/McKesson iKnowMed G2) and accompanying order set. Staging, template/order set utilization, and comprehensive biomarker testing rates were recorded while workflow processes were monitored. Cycle 2 centered on improved cancer staging, data analytic reporting, auditing, and reeducation. RESULTS: The comprehensive biomarker testing rates increased from a historic rate of 68% to 92.7% during the 1-year intervention period. The template utilization rate was 71% with complete staging (TNM stage and relevant biomarkers) documented in 40%. CONCLUSION: Implementation and standardization of comprehensive biomarker testing of patients with mNSCLC in a large multisite community-based oncology practice is feasible and results in significant improvement in comprehensive biomarker testing and reporting. Establishing reliable and measurable tracking metrics to ensure that these new processes are used and maintained can assist in scaling these processes. Efforts to scale this best practice are planned across the US Oncology Network.

Using Randomized Controlled Trials in the Sports Medicine and Performance Environment: Is It Time to Reconsider and Think Outside the Methodological Box?

SYNOPSIS: Randomized controlled trials (RCTs) are ubiquitous in medicine and have facilitated great strides in clinical care. However, when applied in sport, RCTs have limitations that hinder implementing effective interventions in the real-world clinical setting. Pragmatic clinical trials offer some solutions. Yet due to the competitive, high-pressure nature of sport at the individual, team, and governing body level, RCTs are likely infeasible in certain sport settings. The small number of athletes at the elite team level, along with the potential financial consequences of randomizing at the individual athlete and team level, also restricts study power and feasibility, limiting conclusions. Consequently, researchers may need to "think outside the box" and consider other research methodology, to help improve athlete care. In this Viewpoint, we detail alternative study designs that can help solve real-world problems in sports medicine and performance, while maintaining robust research standards and accounting for the challenges that RCTs pose. We also provide practical examples of alternative designs. J Orthop Sports Phys Ther 2023;53(6):1-4. Epub: 18 April 2023. doi:10.2519/jospt.2023.11824.