Baseline characteristics of patients with heart failure with mildly reduced or preserved ejection fraction: The FINEARTS-HF trial.

AIMS: To describe the baseline characteristics of participants in the FINEARTS-HF trial, contextualized with prior trials including patients with heart failure (HF) with mildly reduced and preserved ejection fraction (HFmrEF/HFpEF). The FINEARTS-HF trial is comparing the effects of the non-steroidal mineralocorticoid receptor antagonist finerenone with placebo in reducing cardiovascular death and total worsening HF events in patients with HFmrEF/HFpEF. METHODS AND RESULTS: Patients with symptomatic HF, left ventricular ejection fraction (LVEF) ≥40%, estimated glomerular filtration rate ≥ 25 ml/min/1.73 m2, elevated natriuretic peptide levels and evidence of structural heart disease were enrolled and randomized to finerenone titrated to a maximum of 40 mg once daily or matching placebo. We validly randomized 6001 patients to finerenone or placebo (mean age 72 ± 10 years, 46% women). The majority were New York Heart Association functional class II (69%). The baseline mean LVEF was 53 ± 8% (range 34-84%); 36% of participants had a LVEF <50% and 64% had a LVEF ≥50%. The median N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 1041 (interquartile range 449-1946) pg/ml. A total of 1219 (20%) patients were enrolled during or within 7 days of a worsening HF event, and 3247 (54%) patients were enrolled within 3 months of a worsening HF event. Compared with prior large-scale HFmrEF/HFpEF trials, FINEARTS-HF participants were more likely to have recent (within 6 months) HF hospitalization and greater symptoms and functional limitations. Further, concomitant medications included a larger percentage of sodium-glucose cotransporter 2 inhibitors and angiotensin receptor-neprilysin inhibitors than previous trials. CONCLUSIONS: FINEARTS-HF has enrolled a broad range of high-risk patients with HFmrEF and HFpEF. The trial will determine the safety and efficacy of finerenone in this population.

The Effect of Time-Equated Concurrent Training Programs in Resistance-Trained Men.

The purpose of this investigation was to compare the effects of three different concurrent training (CT) programs and a resistance training (RT) program. Twenty-three resistance trained men (age: 24 ± 3 years) were randomized into four groups: concurrent RT and high intensity interval cycling (CTH, n = 6), concurrent RT and moderate intensity continuous cycling (CTM, n = 5), RT and barbell circuit training (RTC, n = 6), or RT only (RT, n = 6). Back squat and bench press strength, quadriceps, and pectoralis muscle thickness, VO2peak, and maximum workload (Wmax, Watts) were assessed. Squat strength gains were meaningful in all groups and comparable among CTH (16.88 kg [95% CrI: 11.15, 22.63]), CTM (25.54 kg [95% CrI: 19.24, 31.96]), RTC (17.5 kg [95% CrI: 11.66, 23.39]), and RT (20.36 kg [95% CrI: 15.29, 25.33]) groups. Bench press strength gains were meaningful in all groups and comparable among CTH (11.86 kg [95% CrI: 8.28, 15.47]), CTM (10.3 kg [95% CrI: 6.49, 14.13]), RTC (4.84 kg [95% CrI: 1.31, 8.47]), and RT (10.16 kg [95% CrI: 7.02, 13.22]) groups. Quadriceps hypertrophy was meaningful in all groups and comparable among CTH (2.29 mm [95% CrI: 0.84, 3.76]), CTM (3.41 mm [95% CrI: 1.88, 4.91]), RTC (2.6 mm [95% CrI: 1.17, 4.05]), and RT (2.83 mm [95% CrI: 1.55, 4.12]) groups. Pectoralis hypertrophy was meaningful in CTH (2.29 mm [95% CrI: -0.52, 5.1]), CTM (5.14 mm [95% CrI: 2.1, 8.15]), and RTC (7.19 mm [95% CrI: 4.26, 10.02]) groups, but not in the RT group (1 mm [95% CrI: -1.59, 3.59]); further, between-group contrasts indicated less pectoralis growth in the RT compared to the RTC group. Regarding cardiovascular outcomes, only the RTH and RTM groups experienced meaningful improvements in either measure (VO2peak or Wmax). These data suggest that the interference effect on maximal strength and hypertrophy can be avoided when the aerobic training is moderate intensity cycling, high intensity cycling, or a novel barbell circuit for ~one hour per week and on non-RT days. However, the barbell circuit failed to elicit meaningful cardiovascular adaptations.

Experiences of Participation in a Study Investigating Feasibility of the Implantable Doppler Probe in Kidney Transplantation: An Embedded Qualitative Study.

OBJECTIVES: Kidney transplant survival can be improved with better graft surveillance postoperatively. In the quest to explore new technologies, we explored the feasibility of an implantable Doppler probe as a blood flow monitoring device in kidney transplant patients. This qualitative study was embeddedin a feasibility trial and aimed to test the device's clinical acceptability and obtain suggestions for the development of the intervention. Objectives included exploring the experiences of feasibility study participants and identifying barriers to the implementation of implantable Doppler probes in clinical practice. MATERIALS AND METHODS: We conducted semi-structured interviews containing open-ended questions with 12 feasibility study participants recruited by purposive sampling. All interviews were audio-recorded with verbatim transcription. Thematic data analysis was performed at the latent level by using an inductive approach with a previously published 6-phase guide. RESULTS: Three key themes emerged: (1) perceived value of the intervention in clinical practice, (2) challenges and barriers to implementation of the intervention, and (3) suggestions forthe development of the intervention. Due to functional limitations and lack of research, medical professional participants revealed clinical equipoise regarding the utility of implantable Doppler probes. However,the device was well received by patient participants. Challenges included device training needs for medical professionals and educational sessions for patients. Innovative ideas for development included the insertion of a display screen, adopting disposable units to reduce overall cost, online access allowing remote monitoring, decreasing external monitoring unit size, and integrating a wireless connection with the probe to reduce signal errors and increase patient safety. CONCLUSIONS: The clinical need for blood flow sensing technology in kidney transplants has been widely acknowledged. Implantable Doppler probes may be a beneficial adjunct in the early postoperative surveillance of kidney transplant patients. However, the device's technical limitations are the main challenges to its acceptance in clinical practice.

Principles for optimizing anterior cruciate ligament reconstruction outcomes in elite athletes: a review of current techniques.

Anterior cruciate ligament (ACL) tears are one of the most common sport-related injuries and occur in greater than 3% of athletes in a four-year window of sports participation. Non-contact injuries are the most common mechanism for ACL injury in elite-level athletes, especially with increased valgus and external rotation of the knee when loading eccentrically in flexion. Because of the immense toll these injuries and their recovery take on athletes especially, optimal treatment has been a subject of great interest for some time. Many ACL reconstruction (ACLR) and repair techniques have been implemented and improved in the last two decades, leading to many surgical options for this type of injury. The surgical approach to high-level athletes in particular requires additional attention that may not be necessary in the general population. Important considerations for optimizing ACL treatment in high-level athletes include choosing repair vs. reconstruction, surgical techniques, choice of auto- or allograft, and associated concomitant procedures including other injuries or reinforcing techniques as well as attention to rehabilitation. Here, we discuss a range of surgical techniques from repair to reconstruction, and compare and contrast various reconstructive and reinforcing techniques as well as associated surgical pearls and pitfalls. Good outcomes for athletes suffering from ACL injury are attainable with proper treatment including the principles discussed herein.

Reliability and Validity of Muscle Size and Quality Analysis Techniques.

OBJECTIVE: This study investigated reliability and validity of muscle cross-sectional area and echo intensity using an automatic image analysis program. METHODS: Twenty-two participants completed two data collection trials consisting of ultrasound imaging of the vastus lateralis (VL) at 10 and 12 MHz. Images were analyzed manually and with Deep Anatomical Cross-Sectional Area (DeepACSA). Reliability statistics (i.e., intraclass correlation coefficient [ICC] model 2,1, standard error of measure expressed as a percentage of the mean [SEM%], minimal differences [MD] values needed to be considered real) and validity statistics (i.e., constant error [CE], total error [TE], standard error of the estimate [SEE]) were calculated. RESULTS: Automatic analyses of ACSA and EI demonstrated good reliability (10 MHz: ICC2,1 = 0.83 - 0.90; 12 MHz: ICC2,1 = 0.87-0.88), while manual analyses demonstrated moderate to excellent reliability (10 MHz: ICC2,1 = 0.82-0.99; 12 MHz: ICC2,1 = 0.73-0.99). Automatic analyses of ACSA presented greater error at 10 (CE = -0.76 cm2, TE = 4.94 cm2, SEE = 3.65 cm2) than 12 MHz (CE = 0.17 cm2, TE = 3.44 cm2, SEE = 3.11 cm2). Analyses of EI presented greater error at 10 (CE = 3.35 a.u., TE = 2.70 a.u., SEE = 2.58 a.u.) than at 12 MHz (CE = 3.21 a.u., TE = 2.61 a.u., SEE = 2.34 a.u.). CONCLUSION: The results suggest the DeepACSA program may be less reliable compared to manual analysis for VL ACSA but displayed similar reliability for EI. In addition, the results demonstrated the automatic program had low error for 10 and 12 MHz.

Does Nesting Material Affect Wood Duck (Aix sponsa) Nest Box Selection, Reproduction, and Eggshell Bacteria?

Wood Ducks (Aix sponsa) are secondary cavity nesters that use natural cavities and artificial nest boxes, the latter of which has been attributed to the recovery of populations across the southeastern US. Continual use of these boxes results in a buildup of bacteria, parasites, and other pathogens. To avoid the accumulation of these deleterious organisms, best management practices include the occasional removal of old nesting material (i.e., wood shavings) and replacement with fresh wood shavings. No studies have been performed on the effects of shaving material on nest box selection, nest success, and bacterial growth. We monitored 142 and 111 nest boxes in Florida and Georgia, USA, respectively, and filled a random sample with aspen or cedar shavings. We then swabbed the surface of 144 and 150 eggs during 2020 and 2021, respectively, to screen for culturable bacteria. We detected no effect of shaving type on nest box selection, nest success, or egg surface bacterial growth. We found 3-8 bacterial colony types (1-123 colony-forming units [CFU]/box) and 1-8 bacterial colony types (3-382 CFU/box) among the Georgia and Florida samples, respectively. We detected no effect from shaving type on Wood Duck reproduction or bacterial growth in the sampled nest boxes. We concluded that both shaving types are suitable nesting materials for box-nesting Wood Duck populations and the continued use of either would be a reasonable decision for managers.

Polygenic risk-stratified screening for nasopharyngeal carcinoma in high-risk endemic areas of China: a cost-effectiveness study.

Background: Nasopharyngeal carcinoma (NPC) has an extremely high incidence rate in Southern China, resulting in a severe disease burden for the local population. Current EBV serologic screening is limited by false positives, and there is opportunity to integrate polygenic risk scores for personalized screening which may enhance cost-effectiveness and resource utilization. Methods: A Markov model was developed based on epidemiological and genetic data specific to endemic areas of China, and further compared polygenic risk-stratified screening [subjects with a 10-year absolute risk (AR) greater than a threshold risk underwent EBV serological screening] to age-based screening (EBV serological screening for all subjects). For each initial screening age (30-34, 35-39, 40-44, 45-49, 50-54, 55-59, 60-64, and 65-69 years), a modeled cohort of 100,000 participants was screened until age 69, and then followed until age 79. Results: Among subjects aged 30 to 54 years, polygenic risk-stratified screening strategies were more cost-effective than age-based screening strategies, and almost comprised the cost-effectiveness efficiency frontier. For men, screening strategies with a 1-year frequency and a 10-year absolute risk (AR) threshold of 0.7% or higher were cost-effective, with an incremental cost-effectiveness ratio (ICER) below the willingness to pay (¥203,810, twice the local per capita GDP). Specifically, the strategies with a 10-year AR threshold of 0.7% or 0.8% are the most cost-effective strategies, with an ICER ranging from ¥159,752 to ¥201,738 compared to lower-cost non-dominated strategies on the cost-effectiveness frontiers. The optimal strategies have a higher probability (29.4-35.8%) of being cost-effective compared to other strategies on the frontier. Additionally, they reduce the need for nasopharyngoscopies by 5.1-27.7% compared to optimal age-based strategies. Likewise, for women aged 30-54 years, the optimal strategy with a 0.3% threshold showed similar results. Among subjects aged 55 to 69 years, age-based screening strategies were more cost-effective for men, while no screening may be preferred for women. Conclusion: Our economic evaluation found that the polygenic risk-stratified screening could improve the cost-effectiveness among individuals aged 30-54, providing valuable guidance for NPC prevention and control policies in endemic areas of China.

Case Volumes and Outcomes Among Early-Career Interventional Cardiologists in the United States.

BACKGROUND: Little is known about the procedural characteristics, case volumes, and mortality rates for early- vs non-early-career interventional cardiologists in the United States. OBJECTIVES: This study examined operator-level data for patients who underwent percutaneous coronary intervention (PCI) between April 2018 and June 2022. METHODS: Data were collected from the National Cardiovascular Data Registry CathPCI Registry, American Board of Internal Medicine certification database, and National Plan and Provider Enumeration System database. Early-career operators were within 5 years of the end of training. Annual case volume, expected mortality and bleeding risk, and observed/predicted mortality and bleeding outcomes were evaluated. RESULTS: A total of 1,451 operators were early career; 1,011 changed their career status during the study; and 6,251 were non-early career. Overall, 514,540 patients were treated by early-career and 2,296,576 patients by non-early-career operators. The median annual case volume per operator was 59 (Q1-Q3: 31-97) for early-career and 57 (Q1-Q3: 28-100) for non-early-career operators. Early-career operators were more likely to treat patients presenting with ST-segment elevation myocardial infarction and urgent indications for PCI (both P < 0.001). The median predicted mortality risk was 2.0% (Q1-Q3: 1.5%-2.7%) for early-career and 1.8% (Q1-Q3: 1.2%-2.4%) for non-early-career operators. The median predicted bleeding risk was 4.9% (Q1-Q3: 4.2%-5.7%) for early-career and 4.4% (Q1-Q3: 3.7%-5.3%) for non-early-career operators. After adjustment, an increased risk of mortality (OR: 1.08; 95% CI: 1.05-1.17; P < 0.0001) and bleeding (OR: 1.08; 95% CI: 1.05-1.12; P < 0.0001) were associated with early-career status. CONCLUSIONS: Early-career operators are caring for patients with more acute presentations and higher predicted risk of mortality and bleeding compared with more experienced colleagues, with modestly worse outcomes. These data should inform institutional practices to support the development of early-career proceduralists.

Evaluation of GPT-4 ability to identify and generate patient instructions for actionable incidental radiology findings.

OBJECTIVES: To evaluate the proficiency of a HIPAA-compliant version of GPT-4 in identifying actionable, incidental findings from unstructured radiology reports of Emergency Department patients. To assess appropriateness of artificial intelligence (AI)-generated, patient-facing summaries of these findings. MATERIALS AND METHODS: Radiology reports extracted from the electronic health record of a large academic medical center were manually reviewed to identify non-emergent, incidental findings with high likelihood of requiring follow-up, further sub-stratified as "definitely actionable" (DA) or "possibly actionable-clinical correlation" (PA-CC). Instruction prompts to GPT-4 were developed and iteratively optimized using a validation set of 50 reports. The optimized prompt was then applied to a test set of 430 unseen reports. GPT-4 performance was primarily graded on accuracy identifying either DA or PA-CC findings, then secondarily for DA findings alone. Outputs were reviewed for hallucinations. AI-generated patient-facing summaries were assessed for appropriateness via Likert scale. RESULTS: For the primary outcome (DA or PA-CC), GPT-4 achieved 99.3% recall, 73.6% precision, and 84.5% F-1. For the secondary outcome (DA only), GPT-4 demonstrated 95.2% recall, 77.3% precision, and 85.3% F-1. No findings were "hallucinated" outright. However, 2.8% of cases included generated text about recommendations that were inferred without specific reference. The majority of True Positive AI-generated summaries required no or minor revision. CONCLUSION: GPT-4 demonstrates proficiency in detecting actionable, incidental findings after refined instruction prompting. AI-generated patient instructions were most often appropriate, but rarely included inferred recommendations. While this technology shows promise to augment diagnostics, active clinician oversight via "human-in-the-loop" workflows remains critical for clinical implementation.

Laser interstitial thermal therapy for first-line treatment of insular glioma.

OBJECTIVE: Insular gliomas pose a significant surgical challenge due to the complex surrounding functional and vascular anatomy. The authors report their experience using a novel framework for the treatment of insular gliomas with laser interstitial thermal therapy (LITT) and provide representative case examples emphasizing indications, rationale, and technical pearls. METHODS: A prospectively gathered institutional database was used to identify patients with newly diagnosed insular gliomas who underwent LITT between 2015 and 2023. The proposed framework of insular glioma management is guided by tumor size and extent of extra-insular tumor involvement. Patients with tumors localized to the insula (insula-only) were treated with single-session or staged LITT. Patients with insular tumors with frontotemporal involvement (insular+) were treated with insular LITT and standard frontotemporal resection of extra-insular tumor. Clinical and volumetric lesional characteristics were analyzed, with particular emphasis on extent of cytoreductive treatment and safety. RESULTS: Of the 261 patients treated at the authors' institution with LITT between 2015 and 2023, 33 LITT procedures were identified involving 22 unique patients with treatment-naive insular gliomas. Of the 22 patients, 12 had insular-only tumors and were treated with LITT alone, while 10 patients had insular+ lesions and were treated with LITT and resection. The median tumor volume for insular-only tumors was 13.4 cm3 (IQR 10.6, 26.3 cm3), with a median extent of treatment of 100% (IQR 92.1%, 100%). Insular+ lesions were significantly larger, with a median volume of 81.2 cm3 (IQR 51.9, 97 cm3) and median extent of treatment of 96.6% (IQR 93.7%, 100%). All patients with insular-only tumors were discharged the day after ablation, while insular+ patients had significantly longer hospital stays, with 50% staying more than 3 days. Overall, 8% of insular-only patients had permanent neurological deficits compared with 33% of insular+ patients. Two patients' tumors progressed during follow-up: one patient with WHO grade 4 astrocytoma and the other with diffuse glioma not otherwise specified. Patients with grade 4 tumors had the highest rate of permanent neurological deficit (43%) and a larger decline in postoperative Karnofsky Performance Status score (p = 0.046). CONCLUSIONS: The authors present their experience using a novel insular glioma treatment paradigm that incorporates LITT into the broader framework of insular glioma surgery. Their findings suggest that insular LITT is feasible and may allow for high rates of cytoreduction while potentially ameliorating the risks of conventional insular glioma surgery.

Involvement of ArlI, ArlJ, and CirA in archaeal type IV pilin-mediated motility regulation.

Many prokaryotes use swimming motility to move toward favorable conditions and escape adverse surroundings. Regulatory mechanisms governing bacterial flagella-driven motility are well-established; however, little is yet known about the regulation underlying swimming motility propelled by the archaeal cell surface structure, the archaella. Previous research showed that the deletion of the adhesion pilins (PilA1-6), subunits of the type IV pili cell surface structure, renders the model archaeon Haloferax volcanii non-motile. In this study, we used ethyl methanesulfonate mutagenesis and a motility assay to identify motile suppressors of the ∆pilA[1-6] strain. Of the eight suppressors identified, six contain missense mutations in archaella biosynthesis genes, arlI and arlJ. In trans expression of arlI and arlJ mutant constructs in the respective multi-deletion strains ∆pilA[1-6]∆arlI and ∆pilA[1-6]∆arlJ confirmed their role in suppressing the ∆pilA[1-6] motility defect. Additionally, three suppressors harbor co-occurring disruptive missense and nonsense mutations in cirA, a gene encoding a proposed regulatory protein. A deletion of cirA resulted in hypermotility, while cirA expression in trans in wild-type cells led to decreased motility. Moreover, quantitative real-time PCR analysis revealed that in wild-type cells, higher expression levels of arlI, arlJ, and the archaellin gene arlA1 were observed in motile early-log phase rod-shaped cells compared to non-motile mid-log phase disk-shaped cells. Conversely, ∆cirA cells, which form rods during both early- and mid-log phases, exhibited similar expression levels of arl genes in both growth phases. Our findings contribute to a deeper understanding of the mechanisms governing archaeal motility, highlighting the involvement of ArlI, ArlJ, and CirA in pilin-mediated motility regulation.IMPORTANCEArchaea are close relatives of eukaryotes and play crucial ecological roles. Certain behaviors, such as swimming motility, are thought to be important for archaeal environmental adaptation. Archaella, the archaeal motility appendages, are evolutionarily distinct from bacterial flagella, and the regulatory mechanisms driving archaeal motility are largely unknown. Previous research has linked the loss of type IV pili subunits to archaeal motility suppression. This study reveals three Haloferax volcanii proteins involved in pilin-mediated motility regulation, offering a deeper understanding of motility regulation in this understudied domain while also paving the way for uncovering novel mechanisms that govern archaeal motility. Understanding archaeal cellular processes will help elucidate the ecological roles of archaea as well as the evolution of these processes across domains.

ß-Phase Crystallinity, Printability, and Piezoelectric Characteristics of Polyvinylidene Fluoride (PVDF)/Poly(methyl methacrylate) (PMMA)/Cyclopentyl-Polyhedral Oligomeric Silsesquioxane (Cp-POSS) Melt-Compounded Blends.

Poly(vinylidene fluoride) (PVDF) is a semicrystalline polymer that exhibits unique piezoelectric characteristics along with good chemical resistance and high thermal stability. Layer-based material extrusion (MEX) 3D printing of PVDF is desired to create complex structures with piezoelectric properties; however, the melt processing of PVDF typically directs the formation of the α crystalline allomorph, which does not contribute to the piezoelectric response. In this work, PVDF was compounded with poly(methyl methacrylate) (PMMA) and cyclopentyl-polyhedral oligomeric silsesquioxane (Cp-POSS) nanostructured additives in binary and ternary blends to improve MEX printability while maintaining piezoelectric performance. Overall crystallinity and ß phase content were evaluated and quantified using a combination of attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) and differential scanning calorimetry (DSC). Enhancement of MEX printability was measured by quantifying the interlayer adhesion and warpage of printed parts. All blends studied contained a significant percentage of ß allomorph, but it could be detected by ATR-FTIR only after the removal of a thin surface layer. Inclusion of 1% Cp-POSS and up to 10% PMMA in blends with PVDF improved interlayer adhesion (2.3-3.6x) and lowered warpage of MEX printed parts compared to neat PVDF. The blend of 1% Cp-POSS/1% PMMA/PVDF was demonstrated to significantly improve the quality of MEX printed parts while showing similar piezoelectric performance to that of neat PVDF (average piezoelectric coefficient 24 pC/N). MEX printing of PVDF blends directly into usable parts with significant piezoelectric performance while reducing the challenges of printing the semicrystalline polymer opens the potential for application in a number of high value sectors.

eIF4A controls translation of estrogen receptor alpha and is a therapeutic target in advanced breast cancer.

The majority of human breast cancers are dependent on hormone-stimulated estrogen receptor alpha (ER) and are sensitive to its inhibition. Treatment resistance arises in most advanced cancers due to genetic alterations that promote ligand independent activation of ER itself or ER target genes. Whereas re-targeting of the ER ligand binding domain (LBD) with newer ER antagonists can work in some cases, these drugs are largely ineffective in many genetic backgrounds including ER fusions that lose the LBD or in cancers that hyperactivate ER targets. By identifying the mechanism of ER translation, we herein present an alternative strategy to target ER and difficult to treat ER variants. We find that ER translation is cap-independent and mTOR inhibitor insensitive, but dependent on 5' UTR elements and sensitive to pharmacologic inhibition of the translation initiation factor eIF4A, an mRNA helicase. EIF4A inhibition rapidly reduces expression of ER and short-lived targets of ER such as cyclin D1 and other components of the cyclin D-CDK complex in breast cancer cells. These effects translate into suppression of growth of a variety of ligand-independent breast cancer models including those driven by ER fusion proteins that lack the ligand binding site. The efficacy of eIF4A inhibition is enhanced when it is combined with fulvestrant-an ER degrader. Concomitant inhibition of ER synthesis and induction of its degradation causes synergistic and durable inhibition of ER expression and tumor growth. The clinical importance of these findings is confirmed by results of an early clinical trial (NCT04092673) of the selective eIF4A inhibitor zotatifin in patients with estrogen receptor positive metastatic breast cancer. Multiple clinical responses have been observed on combination therapy including durable regressions. These data suggest that eIF4A inhibition could be a useful new strategy for treating advanced ER+ breast cancer.

Solvent-Assisted Control of Metal-Organic Nanotube Size and Morphology.

While intensive studies have focused on the synthesis and characterization of new metal-organic nanotube (MONT) structures, the lack of size and morphology control remains an obstacle in broadening applications for this class of materials. Herein, we demonstrate control of MONT crystallite size and morphology by tuning polarity and the protic/aprotic nature of solvents, including dimethylformamide, N-methyl-2-pyrrolidone, ethanol, and 2-methyltetrahydrofuran, for the isostructural syntheses of two MONTs. Through a combination of transmission electron microscopy, powder X-ray diffraction, and selected area electron diffraction, we find that MONT crystallite sizes can be tuned while maintaining control over the relative dispersity without significantly altering the underlying crystal structure.

Adjuvant-dependent impact of inactivated SARS-CoV-2 vaccines during heterologous infection by a SARS-related coronavirus.

Whole virus-based inactivated SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide have been critical to the COVID-19 pandemic response. Although these vaccines are protective against homologous coronavirus infection, the emergence of novel variants and the presence of large zoonotic reservoirs harboring novel heterologous coronaviruses provide significant opportunities for vaccine breakthrough, which raises the risk of adverse outcomes like vaccine-associated enhanced respiratory disease. Here, we use a female mouse model of coronavirus disease to evaluate inactivated vaccine performance against either homologous challenge with SARS-CoV-2 or heterologous challenge with a bat-derived coronavirus that represents a potential emerging disease threat. We show that inactivated SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide can cause enhanced respiratory disease during heterologous infection, while use of an alternative adjuvant does not drive disease and promotes heterologous viral clearance. In this work, we highlight the impact of adjuvant selection on inactivated vaccine safety and efficacy against heterologous coronavirus infection.

Validity and Impact of Methods for Collecting Training Data for Myoelectric Prosthetic Control Algorithms.

Intuitive regression control of prostheses relies on training algorithms to correlate biological recordings to motor intent. The quality of the training dataset is critical to run-time regression performance, but accurately labeling intended hand kinematics after hand amputation is challenging. In this study, we quantified the accuracy and precision of labeling hand kinematics using two common training paradigms: 1) mimic training, where participants mimic predetermined motions of a prosthesis, and 2) mirror training, where participants mirror their contralateral intact hand during synchronized bilateral movements. We first explored this question in healthy non-amputee individuals where the ground-truth kinematics could be readily determined using motion capture. Kinematic data showed that mimic training fails to account for biomechanical coupling and temporal changes in hand posture. Additionally, mirror training exhibited significantly higher accuracy and precision in labeling hand kinematics. These findings suggest that the mirror training approach generates a more faithful, albeit more complex, dataset. Accordingly, mirror training resulted in significantly better offline regression performance when using a large amount of training data and a non-linear neural network. Next, we explored these different training paradigms online, with a cohort of unilateral transradial amputees actively controlling a prosthesis in real-time to complete a functional task. Overall, we found that mirror training resulted in significantly faster task completion speeds and similar subjective workload. These results demonstrate that mirror training can potentially provide more dexterous control through the utilization of task-specific, user-selected training data. Consequently, these findings serve as a valuable guide for the next generation of myoelectric and neuroprostheses leveraging machine learning to provide more dexterous and intuitive control.

Perceptions of HPV-Linked Oropharyngeal Cancer Risk Messages Among a Sample of Young Adult Men in the US: A Pilot Study.

Awareness of risk for oropharyngeal cancer from oral human papillomavirus (HPV) infection is low among men in the United States. This pilot study tested messages communicating oral HPV and oropharyngeal cancer risk among a sample of U.S. young adult men (aged 18-26). Six oral HPV and cancer risk messages were tested in an online survey. Participants (N = 68) were randomly assigned to one of two message sets, each containing three unique text-based messages. Participants evaluated messages separately based on various measures (e.g., perceived message effectiveness [PME], novelty). One-way repeated measures ANOVAs were used to assess evaluation differences within message sets. Participants provided open-ended feedback about each message, which were synthesized into overarching themes. Participants were receptive to the risk messages, rating them high on PME (mean range = 3.72-4.25 out of 5) and other measures. Analyses identified three high-performing messages. For example, participants rated a message about HPV-linked oropharyngeal cancer risk rates in men versus women higher on attention and novelty than two other messages in the same set (both ps < .05). Participants were shown three messages (instead of all six) in each message set to minimize survey fatigue. Common themes from open-ended feedback were that participants liked the short-form structure of the messages and that the messages used gender-tailored language. In conclusion, oral HPV and oropharyngeal cancer risk messages may be useful for increasing risk awareness among men in the U.S. Further work should test such messages in rigorous experimental contexts to assess their efficacy in modifying other health outcomes, such as HPV vaccination behaviors.

FBXO42 activity is required to prevent mitotic arrest, spindle assembly checkpoint activation and lethality in glioblastoma and other cancers.

Glioblastoma (GBM) is the most common and aggressive brain tumor in adults. To identify genes differentially required for the viability of GBM stem-like cells (GSCs), we performed functional genomic lethality screens comparing GSCs and control human neural stem cells. Among top-scoring hits in a subset of GBM cells was the F-box-containing gene FBXO42, which was also predicted to be essential in ∼15% of cell lines derived from a broad range of cancers. Mechanistic studies revealed that, in sensitive cells, FBXO42 activity prevents chromosome alignment defects, mitotic cell cycle arrest and cell death. The cell cycle arrest, but not the cell death, triggered by FBXO42 inactivation could be suppressed by brief exposure to a chemical inhibitor of Mps1, a key spindle assembly checkpoint (SAC) kinase. FBXO42's cancer-essential function requires its F-box and Kelch domains, which are necessary for FBXO42's substrate recognition and targeting by SCF (SKP1-CUL1-F-box protein) ubiquitin ligase complex. However, none of FBXO42's previously proposed targets, including ING4, p53 and RBPJ, were responsible for the observed phenotypes. Instead, our results suggest that FBOX42 alters the activity of one or more proteins that perturb chromosome-microtubule dynamics in cancer cells, which in turn leads to induction of the SAC and cell death.