Prospective cohort study of long-term neurological outcomes in retired elite athletes: the Advanced BiomaRker, Advanced Imaging and Neurocognitive (BRAIN) Health Study protocol.

INTRODUCTION: Although limited, recent research suggests that contact sport participation might have an adverse long-term effect on brain health. Further work is required to determine whether this includes an increased risk of neurodegenerative disease and/or subsequent changes in cognition and behaviour. The Advanced BiomaRker, Advanced Imaging and Neurocognitive Health Study will prospectively examine the neurological, psychiatric, psychological and general health of retired elite-level rugby union and association football/soccer players. METHODS AND ANALYSIS: 400 retired athletes will be recruited (200 rugby union and 200 association football players, male and female). Athletes will undergo a detailed clinical assessment, advanced neuroimaging, blood testing for a range of brain health outcomes and neuropsychological assessment longitudinally. Follow-up assessments will be completed at 2 and 4 years after baseline visit. 60 healthy volunteers will be recruited and undergo an aligned assessment protocol including advanced neuroimaging, blood testing and neuropsychological assessment. We will describe the previous exposure to head injuries across the cohort and investigate relationships between biomarkers of brain injury and clinical outcomes including cognitive performance, clinical diagnoses and psychiatric symptom burden. ETHICS AND DISSEMINATION: Relevant ethical approvals have been granted by the Camberwell St Giles Research Ethics Committee (Ref: 17/LO/2066). The study findings will be disseminated through manuscripts in clinical/academic journals, presentations at professional conferences and through participant and stakeholder communications.

Application of Laser-Induced Acoustic Desorption for Molecular Rotational Resonance Spectroscopy.

Molecular Rotational Resonance (MRR) spectroscopy is a uniquely precise tool for the determination of molecular structures of volatile compounds in mixtures, as the characteristic rotational transition frequencies of a molecule are extremely sensitive to its 3D structure through the moments of inertia in a three-dimensional coordinate system. This enables identification of the compounds based on just a few parameters that can be calculated, as opposed to, for example, mass spectrometric data, which often require expert analysis of 10-20 different signals and the use of many standards/model compounds. This paper introduces a new sampling technique for MRR, laser-induced acoustic desorption (LIAD), to allow the vaporization of nonvolatile and thermally labile analytes without the need for excessive heating or derivatization. In this proof-of-concept study, LIAD was successfully coupled to an MRR instrument to conduct measurements on seven compounds with differing polarities, molecular weights, and melting and boiling points. Identification of three isomers in a mixture was also successfully performed using LIAD/MRR. Based on these results, LIAD/MRR is demonstrated to provide a powerful approach for the identification of nonvolatile and/or thermally labile analytes with molecular weights up to 600 Da in simple mixtures, which does not require the use of reference compounds. In the future, applications to more complex mixtures, such as those relevant to pharmaceutical research, and quantitative aspects of LIAD/MRR will be reported.

Honokiol Suppresses Cell Proliferation and Tumor Migration through ROS in Human Anaplastic Thyroid Cancer Cells.

BACKGROUND: Honokiol is a natural polyphenolic compound extracted from Magnolia officinali, which is commonly used material in Chinese herbal medicine, has a variety of biological functions, including anti-tumor, anti-oxidant, anti-inflammation, anti-microbial and anti-allergy. Although honokiol has numerous beneficial effects on human diseases, the underlying mechanisms of tumor metastasis are still unclear. Previously, we reported that honokiol suppresses thyroid cancer cell proliferation with cytotoxicity through cell cycle arrest, apoptosis, and dysregulation of intracellular hemostasis. Herein, we hypothesized that the antioxidant effect of honokiol might play a critical role in thyroid cancer cell proliferation and migration. METHODS: The cell viability assays, cellular reactive oxygen species (ROS) activity, cell migration, and immunoblotting were performed after cells were treated with honokiol. RESULTS: Based on this hypothesis, we first demonstrated that honokiol suppresses cell proliferation in two human anaplastic thyroid carcinoma (ATC) cell lines, KMH-2 and ASH-3, within a dosage- and time-dependent manner by cell counting kit-8 (CCK-8) assay. Next, we examined that honokiol induced ROS activation and could be suppressed by pre-treated with an antioxidant agent, N-acetyl-l-cysteine (NAC). Furthermore, the honokiol suppressed cell proliferation can be rescued by pre-treated with NAC. Finally, we demonstrated that honokiol inhibited ATC cell migration by modulating epithelial-mesenchymal transition (EMT)-related markers by Western blotting. CONCLUSION: Taken together, we provided the potential mechanism for treating ATC cells with honokiol, which significantly suppresses tumor proliferation and inhibits tumor metastasis in vitro through reactive oxygen species (ROS) induction.

The Evaluation of Teleost-Derived Antimicrobial Peptides Against Neisseria gonorrhoeae.

Introduction Gonorrhea has become an emerging sexually transmitted infection worldwide. The multi-antibiotic resistance facilitates the transmission; thus, new antibiotics or alternatives are needed. Antimicrobial peptides (AMP) are antimicrobials naturally secreted by the host as a defense material. Teleost-derived AMP have gained attention over the past two decades due to their potent efficacy toward microorganisms. This study examines teleost-derived AMP against Neisseria gonorrhoeae (GC), the responsible bacteria for gonorrhea, to evaluate the antibiotic potential as a future alternative for preventing gonorrhea. Methods Minimal inhibitory concentration (MIC) and time-killed assay were conducted to evaluate the inhibition concentration of each AMP. Transmission electron microscopy was used to confirm the potential mode of action. The inhibition of microcolony formation and adherence to epithelial cells were examined to assess the infection inhibition. Results Pardaxin-based (flatfish pardaxin {PB2}) and piscidin-based (striped bass piscidin 1 {PIS} and tilapia piscidin {TP} 4) AMP were effective toward GC under or equal to 7.5 µg/mL as of minimal inhibitory concentration. Transmission electron microscopy images revealed that these AMP attack bacterial membranes as membrane blebbing and breakage were observed. These AMP also effectively reduced the GC biofilm formation, as well as their adherence to human endocervical epithelial cells. Conclusion Pardaxin-based (PB2) and piscidin-based (PIS and TP4) teleost-derived AMP can inhibit GC and potentially serve as the new antibiotic alternative for preventing GC colonization and infection. This study will shed some light on the future development of teleost-derived AMP in treating gonorrhea and maintaining reproductive health.

Clinical characteristics and treatment exposure of patients with marked treatment-resistant unipolar major depressive disorder: A RECOVER trial report.

BACKGROUND: RECOVER is a randomized sham-controlled trial of vagus nerve stimulation and the largest such trial conducted with a psychiatric neuromodulation intervention. OBJECTIVE: To describe pre-implantation baseline clinical characteristics and treatment history of patients with unipolar, major depressive disorder (MDD), overall and as a function of exposure to interventional psychiatric treatments (INTs), including electroconvulsive therapy, transcranial magnetic stimulation, and esketamine. METHODS: Medical, psychiatric, and treatment records were reviewed by study investigators and an independent Study Eligibility Committee prior to study qualification. Clinical characteristics and treatment history (using Antidepressant Treatment History [Short] Form) were compared in those qualified (N = 493) versus not qualified (N = 228) for RECOVER, and among the qualified group as a function of exposure to INTs during the current major depressive episode (MDE). RESULTS: Unipolar MDD patients who qualified for RECOVER had marked TRD (median of 11.0 lifetime failed antidepressant treatments), severe disability (median WHODAS score of 50.0), and high rate of baseline suicidality (77% suicidal ideation, 40% previous suicide attempts). Overall, 71% had received at least one INT. Compared to the no INT group, INT recipients were younger and more severely depressed (QIDS-C, QIDS-SR), had greater suicidal ideation, earlier diagnosis of MDD, and failed more antidepressant medication trials. CONCLUSIONS: RECOVER-qualified unipolar patients had marked TRD and marked treatment resistance with most failing one or more prior INTs. Treatment with ≥1 INTs in the current MDE was associated with earlier age of MDD onset, more severe clinical presentation, and greater treatment resistance relative to patients without a history of INT. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03887715.

Right ventricular scalloping index as cardiac magnetic resonance-derived marker for diagnosis of arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: The cardiac magnetic resonance (CMR) evaluation of right ventricular (RV) morphologic abnormalities in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) is subjective. Here, we aimed to use a quantitative index, the right ventricular scalloping index (RVSI), to standardize the measurement of RV free wall scalloping and aid in the imaging diagnosis. METHODS: We retrospectively included 15 patients with definite ARVC and 45 age- and sex-matched patients with idiopathic right ventricular outflow tract ventricular arrhythmia (RVOT-VA) as controls. The RVSI was measured from cine images on four-chamber view to evaluate its ability to distinguish between ARVC and RVOT-VA patients. Other cardiac functional parameters including strain analysis were also performed. RESULTS: The RVSI was significantly higher in the ARVC than RVOT-VA group (1.56 ± 0.23 vs 1.30 ± 0.08, p < 0.001). The diagnostic performance of the RVSI was superior to the RV global longitudinal, circumferential, and radial strains, RV ejection fraction, and RV end-diastolic volume index. The RVSI demonstrated high intraobserver and interobserver reliability (intraclass correlation coefficient, 0.94 and 0.96, respectively). RVSI was a strong discriminator between ARVC and RVOT-VA patients (area under curve [AUC], 0.91; 95% CI, 0.82-0.99). A cutoff value of RVSI ≥1.49 provided an accuracy of 90.0%, specificity of 97.8%, sensitivity of 66.7%, positive predictive value (PPV) of 90.9%, and a negative predictive value (NPV) of 89.8%. In a multivariable analysis, a family history of ARVC or sudden cardiac death (odds ratio, 38.71; 95% CI, 1.48-1011.05; p = 0.028) and an RVSI ≥1.49 (odds ratio, 64.72; 95% CI, 4.58-914.63; p = 0.002) remained predictive of definite ARVC. CONCLUSION: RVSI is a quantitative method with good performance for the diagnosis of definite ARVC.

Real-world evaluation of access-driven Canadian treatment sequences in progressive prostate cancer (REACTIVATE).

INTRODUCTION: The results of the phase 3 ALSYMPCA trial showed that Radium-223 (Ra-223) improves overall survival (OS) and delays onset of first symptomatic skeletal event vs. placebo in patients with metastatic castration-resistant prostate cancer (mCRPC). The purpose of the REACTIVATE study was to inform the optimal placement of Ra-233 in the treatment sequence by evaluating clinical outcomes and healthcare resource utilization using real-world data from multiple Canadian provinces. METHODS: This retrospective cohort study analyzed patient outcomes according to Ra-223 placement using administrative databases of four Canadian provinces, encompassing 4301 patients with mCRPC who received at least two lines of life-prolonging therapy (LPT) for mCRPC. Outcomes included OS, event-free survival (EFS), and healthcare resource utilization. Each province was analyzed separately. RESULTS: OS, measured from the start of second-line LPT, differed between provinces: those in Ontario receiving second-line Ra-223 had a longer OS vs. those receiving it in third-line or later (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.66-0.95). There was no difference between lines of therapy in patients in British Columbia (HR 1.165, 95% CI, 0.894-1.518, p=0.2576), and OS was numerically worse but not statistically significant in patients receiving Ra-223 in second-line in Quebec (HR 1.44, 95% CI, 0.93-2.24). Other outcomes also varied across provinces, with second-line use of Ra-223 being associated with longer EFS and reduced healthcare utilization vs. third-line use in Ontario but not in Quebec. CONCLUSIONS: Significant heterogeneity exists in the management and outcomes of mCRPC between provinces, particularly regarding the placement of Ra-223 in the treatment sequence.

Relationship between workplace violence and mental/physical health of security guards during the COVID-19 pandemic in Taiwan.

Objectives: To investigate the relationship between workplace violence (WPV) and mental and physical health (MPH) of security guards during the COVID-19 pandemic in Taiwan. Methods: A cross-sectional survey was conducted in 15 representative security companies across northern, central, and southern Taiwan, and outlying islands from July 2021 to June 2022 during the COVID-19 pandemic. 1,200 questionnaires were distributed. A total of 1,032 valid questionnaires were collected. Results: 13.18% of the participants reported that they had experienced WPV during the COVID-19 pandemic, including physical violence (PhV), psychological violence (PsV), verbal violence (VV), and sexual harassment (SH). The most common violence was VV (54.19%), followed by PsV (20.69%). Community residents and property owners were the primary perpetrators, followed by strangers. The study showed that the security guards who had experienced WPV had higher scores on the 12-item Chinese Health Questionnaire (Taiwan version) (CHQ-12), indicating poorer MPH than those who had never experienced WPV. The result showed that VV had strong correlations with the lack of effective communication, dissatisfaction with treatment and service attitude, and work stress. PsV was strongly associated with excessive waiting times. Conclusion: There were correlations among PhV, VV, and PsV and they had adverse impacts on MPH, except for SH. The study found that the primary perpetrators of WPV against security guards were community residents and property owners. The causes were the lack of effective communication, dissatisfaction with treatment and service attitude, excessive waiting times, and work stress, which further led to turnover intention and poor MPH. The findings of this study have useful implications and it is recommended to enhance the understanding of workplace violence against security guards and to formulate appropriate local and international strategies to address it.

Technological Challenges and Solutions in Emergency Remote Teaching for Nursing: An International Cross-Sectional Survey.

OBJECTIVES: With the sudden global shift to online learning modalities, this study aimed to understand the unique challenges and experiences of emergency remote teaching (ERT) in nursing education. METHODS: We conducted a comprehensive online international cross-sectional survey to capture the current state and firsthand experiences of ERT in the nursing discipline. Our analytical methods included a combination of traditional statistical analysis, advanced natural language processing techniques, latent Dirichlet allocation using Python, and a thorough qualitative assessment of feedback from open-ended questions. RESULTS: We received responses from 328 nursing educators from 18 different countries. The data revealed generally positive satisfaction levels, strong technological self-efficacy, and significant support from their institutions. Notably, the characteristics of professors, such as age (p = 0.02) and position (p = 0.03), influenced satisfaction levels. The ERT experience varied significantly by country, as evidenced by satisfaction (p = 0.05), delivery (p = 0.001), teacher-student interaction (p = 0.04), and willingness to use ERT in the future (p = 0.04). However, concerns were raised about the depth of content, the transition to online delivery, teacher-student interaction, and the technology gap. CONCLUSIONS: Our findings can help advance nursing education. Nevertheless, collaborative efforts from all stakeholders are essential to address current challenges, achieve digital equity, and develop a standardized curriculum for nursing education.

Understanding ADC variation by fat content effect using a dual-function MRI phantom.

BACKGROUND: A dual-function phantom designed to quantify the apparent diffusion coefficient (ADC) in different fat contents (FCs) and glass bead densities (GBDs) to simulate the human tissues has not been documented yet. We propose a dual-function phantom to quantify the FC and to measure the ADC at different FCs and different GBDs. METHODS: A fat-containing diffusion phantom comprised by 30 glass-bead-containing fat-water emulsions consisting of six different FCs (0, 10, 20, 30, 40, and 50%) multiplied by five different GBDs (0, 0.1, 0.25, 0.5, and 1.0 g/50 mL). The FC and ADC were measured by the "iterative decomposition of water and fat with echo asymmetry and least squares estimation-IQ," IDEAL-IQ, and single-shot echo-planar diffusion-weighted imaging, SS-EP-DWI, sequences, respectively. Linear regression analysis was used to evaluate the relationship among the fat fraction (FF) measured by IDEAL-IQ, GBD, and ADC. RESULTS: The ADC was significantly, negatively, and linearly associated with the FF (the linear slope ranged from -0.005 to -0.017, R2 = 0.925 to 0.986, all p < 0.001). The slope of the linear relationship between the ADC and the FF, however, varied among different GBDs (the higher the GBD, the lower the slope). ADCs among emulsions across different GBDs and FFs were overlapped. Emulsions with low GBDs plus high FFs shared a same lower ADC range with those with median or high GBDs plus median or lower FFs. CONCLUSIONS: A novel dual-function phantom simulating the human tissues allowed to quantify the influence of FC and GBD on ADC. RELEVANCE STATEMENT: The study developed an innovative dual-function MRI phantom to explore the impact of FC on ADC variation that can affect clinical results. The results revealed the superimposed effect on FF and GBD density on ADC measurements. KEY POINTS: • A dual-function phantom made of glass bead density (GBD) and fat fraction (FF) emulsion has been developed. • Apparent diffusion coefficient (ADC) values are determined by GBD and FF. • The dual-function phantom showed the mutual ADC addition between FF and GBD.

The Evolution of the Reconstructive Strategy for Elbow Flexion for Acute C5, C6 Brachial Plexus Injuries over Two Decades.

BACKGROUND: Over the course of the past two decades, improved outcomes following brachial plexus reconstruction have been attributed to newer nerve transfer techniques. However, key factors aside from surgical techniques have brought improved consistency to elbow flexion techniques in the latter decade. METHODS: One-hundred seventeen patients who underwent brachial plexus reconstruction from 1996 to 2006 were compared with 120 patients from 2007 to 2017. All patients were evaluated preoperatively and postoperatively to assess the recovery time and of elbow flexion strength. RESULTS: In the first decade, nerve reconstruction methods included proximal nerve grafting, intercostal nerve transfer, and Oberlin-I transfer. In the second decade, newer methods such as double fascicular transfer and ipsilateral C7 division transfer to the anterior division of upper trunk were introduced. About 78.6% of the first decade group versus 87.5% of the second decade group were able to reach M3 flexion strength (p = 0.04), with shorter time recovery to reach M3 in the 2nd decade. About 59.8% of the first decade group versus 65.0% of the second decade group were able to reach M4 (p = 0.28), but no significant difference in time of recovery. In both groups, the double fascicular nerve transfer had the highest impact when introduced in the second decade. More precise magnetic resonance imaging (MRI) techniques helped to diagnose the level of injury, the roots involved and evaluate the health of the donor nerves in preparation for intraplexus transfer. CONCLUSION: In addition to modified techniques in nerve transfers, (1) MRI-assisted evaluation and surgical exploration of the roots with (2) more judicious choice of donor nerves for primary nerve transfer were factors that ensured reliable and outcomes in the second decade.

Delayed nerve reconstruction for brachial plexus injuries: is the risk worth the reward?

OBJECTIVE: Nerve reconstruction after 6 months of denervation time in brachial plexus injuries (BPIs) can be inconsistent. A dilemma exists when the use of critical donor nerves for nerve transfers may lead to unreliable outcomes that would waste the donor nerve. The purpose of this study was to evaluate the long-term outcomes of elbow and shoulder function in patients with BPIs receiving nerve reconstruction in the delayed setting (i.e., 6-12 months after injury). METHODS: Data from patients with delayed BPIs who received a nerve transfer (including proximal and distal nerve transfer/grafting) at a tertiary medical center were retrospectively collected from January 1999 to March 2020. Demographics, extent of injury, mechanism of injury, and reconstructive methods were collected. Patients were categorized into two groups: non-pan-plexus BPI (C5-6, C5-7, and C5-8) and pan-plexus BPI (C5-T1). Acceptable outcome was defined as elbow flexion ≥ M3 status or shoulder abduction ≥ 60°. RESULTS: Sixty-four patients were included in the study. The average time from injury to nerve reconstruction was 236 (range 180-441) days, and the average follow-up time was 66 months. In the non-pan-plexus BPI group (n = 43 patients), 74.4% of patients demonstrated M3 elbow flexion, and 48.8% of patients demonstrated M4 elbow flexion. Double fascicular transfer yielded better results and faster recovery than a single fascicular transfer. In the pan-plexus BPI group (n = 21 patients), 38.1% of patients reached M3 elbow flexion and 23.8% attained M4 elbow flexion. In the non-pan-plexus BPI group, the recovery rate of acceptable shoulder abduction was 53.5%, but only 23.5% of pan-plexus patients with BPI achieved acceptable shoulder abduction. CONCLUSIONS: Nerve reconstruction can effectively restore functional elbow flexion and acceptable shoulder abduction in non-pan-plexus patients with BPI in the delayed setting. However, neither acceptable elbow flexion nor shoulder abduction could be consistently achieved in pan-plexus BPI. Judicious use of the donor nerves in pan-plexus injuries is required, in addition to preserving a donor nerve for a backup plan such as free-functioning muscle transplantation or tendon transfers.

Management of aggressive variants of papillary thyroid cancer.

PURPOSE OF REVIEW: The aim of this study was to provide a timely and relevant review of the latest findings and explore appropriate management of aggressive variants of papillary thyroid cancer (AVPTC). RECENT FINDINGS: In general, AVPTCs tend to exhibit more invasive characteristics, a lack of responsiveness to radioiodine, increased occurrences of regional spreading, distant metastases and higher mortality rates. Meanwhile, each variant showcases unique clinical and molecular profiles. SUMMARY: Given the elevated risk of recurrence postsurgery, a more aggressive strategy may be necessary when suspected preoperatively, particularly for those presenting with invasive features. Decision on the extent of surgical treatment and adjuvant therapy is individualized and made by experienced clinicians and multidisciplinary teams based on the clinical presentation, presence of aggressive features and molecular profile. Future studies on development of personalized medicine and molecular target therapy may offer tailored treatment options.

Examining the functional space of gut microbiome-derived peptides.

The human gut microbiome contains thousands of small, novel peptides that could play a role in microbe-microbe and host-microbe interactions, contributing to human health and disease. Although these peptides have not yet been systematically characterized, computational tools can be used to elucidate the bioactivities they may have. This article proposes probing the functional space of gut microbiome-derived peptides (MDPs) using in silico approaches for three bioactivities: antimicrobial, anticancer, and nucleomodulins. Machine learning programs that support peptide and protein queries are provided for each bioactivity. Considering the biases of an activity-centric approach, activity-agnostic tools using structural and chemical similarity and target prediction are also described. Gut MDPs represent a vast functional space that can not only contribute to our understanding of microbiome interactions but potentially even serve as a source of life-changing therapeutics.

Ice Cores as a Source for Antimicrobials: From Bioprospecting to Biodesign.

The golden age has passed for antibiotic discovery, and while some antibiotics are currently in various phases of clinical trials in the United States, many pharmaceutical companies have abandoned antibiotic research. With the need for antibiotics, we should expand our horizon for therapeutic mining and can look toward understudied sources such as ice cores. Ice cores contain microorganisms and genetic material that have been frozen in time for thousands of years. The antibiotics used by these organisms are encoded in their genomes, which can be unlocked, identified, and characterized with modern advances in molecular biology, genetic sequencing, various computational approaches, and established natural product discovery pipelines. While synthetic biology can be used in natural product discovery approaches, synthetic biology and bioengineering efforts can also be leveraged in the selection and biodesign of increased compound yields, potency, and stability. Here, we provide the perspective that ice cores can be a source of novel antibiotic compounds and that the tools of synthetic biology can be used to design better antimicrobials.

From Hype To Reality: A Narrative Review on the Promising Role of Artificial Intelligence in Larynx Cancer Detection and Transoral Microsurgery.

Early larynx cancer detection plays a crucial role in improving treatment outcomes and recent studies have shown promising results in using artificial intelligence for larynx cancer detection. Artificial intelligence also has the potential to enhance transoral larynx microsurgery. This narrative review summarizes the current evidence regarding its use in larynx cancer detection and potential applications in transoral larynx microsurgery. The utilization of artificial intelligence in larynx cancer detection with white light endoscopy and narrow-band imaging helps improve diagnostic accuracy and efficiency. It can also potentially enhance transoral larynx microsurgery by aiding surgeons in real-time decision-making and minimizing the risk of complications. However, further prospective studies are warranted to validate the findings, and additional research is necessary to optimize the integration of artificial intelligence in our clinical practice.

The Need for Biosecurity Education in Biotechnology Curricula.

The growth of biotechnology in recent decades and the dual-use nature of most bioscience research are making their misuse, or accidental misuse or release, more likely and present as threats to biosecurity. A proactive approach is through educating the next generation of scientists to be more security conscious. However, current educational and professional programs in biosecurity are lacking. In this perspective, we recommend that biosecurity educational opportunities should be implemented and expanded for undergraduate and graduate students who will likely use one or more methods in the field of biotechnology. We then propose that biosecurity education is a key factor in a path toward sustainable and safe research. Finally, a set of 17 biosecurity competencies organized into 6 distinct themes is outlined.

Reduced-Dose Rivaroxaban Is Associated with Lower All-Cause Mortality in Older Patients with Nonvalvular Atrial Fibrillation.

BACKGROUND: Reduced-dose rivaroxaban (10 mg) was used in the J-ROCKET AF trial, demonstrating safety in the Asian population. It remains unclear whether treatment with reduced-dose versus full-dose rivaroxaban (20 mg/15 mg) is associated with all-cause mortality in older patients with nonvalvular atrial fibrillation. Proposed: To evaluate the effects of reduced-dose rivaroxaban on all-cause mortality in patients over 85. METHODS: We retrospectively enrolled medical records representing the period from October 2012 to November 2016. The 2 × 2 factorial design incorporated age (≥85 vs. <85) and rivaroxaban use (reduced vs. full dose). The primary study outcomes were all-cause and cardiac-related mortality. RESULTS: The study enrolled 2386 patients with a mean age of 76.6 ± 10.4 years; 51.8% were male. In the ≥85 group (n = 593), the reduced-dose subgroup had lower all-cause (5.3% vs. 10.6%, p = 0.02) and cardiac-related mortality (1.9% vs. 5.1%, p = 0.04), whereas the younger patients receiving reduced-dose rivaroxaban had higher all-cause mortality (3.7% vs. 1.8%, p = 0.01) but no difference in cardiac-related mortality (1.2% vs. 0.7%, p = 0.33). The rate of hospitalization for heart failure was significantly lower in the elderly group with reduced-dose rivaroxaban (7.2% vs. 15.7%, p < 0.01) but not in the younger group. After adjusting for confounders in the older group, treatment with reduced-dose rivaroxaban was associated with lower risk of all-cause mortality (adjusted HR (aHR): 0.40, 95% CI: 0.21-0.74, p < 0.01) and hospitalization for heart failure (aHR: 0.54, 95% CI: 0.29-0.99, p = 0.05). No associations were found between rivaroxaban dose and cardiac-related mortality in either group, nor between younger age and any outcome. CONCLUSIONS: Reduced-dose rivaroxaban was associated with lower risks of all-cause mortality and hospitalization for heart failure in older patients with nonvalvular atrial fibrillation. Future studies can investigate the effect of reduced-dose rivaroxaban on prognoses in elderly individuals ≥85 years in the west.

Measurement of renal congestion and compliance following intravenous fluid administration using shear wave elastography.

Objective: Ultrasound shear wave elastography (SWE) is a novel technique that may provide non-invasive measurements of renal compliance. We aimed to investigate the relationship between intravenous (IV) fluid administration and change in SWE measurements. We hypothesised that following IV fluid administration in healthy volunteers, global kidney stiffness would increase and that this increase in stiffness could be quantified using SWE. Our second hypothesis was that graduated doses of IV fluids would result in a dose-dependent increase in global kidney stiffness measured by SWE. Design: Randomised prospective study. Setting: Intensive Care Unit. Participants: Healthy volunteers aged 18-40 years. Interventions: Participants were randomised to receive 20 ml/kg, 30 ml/kg, or 40 ml/kg of normal saline. The volume of fluid infused was based on the actual body weight recorded. Main outcome measures: We recorded average SWE stiffness (kPa with standard deviation of the mean), median SWE stiffness (kPa), and the interquartile range. Results: Ninety-eight percent of participants (44/45) demonstrated an increase in global kidney stiffness following administration of IV fluids. The average SWE pre fluid administration was 7.572 kPa ± 2.38 versus 14.9 kPa ± 4.81 post fluid administration (p < 0.001). In subgroup analysis, there were significant changes in global kidney stiffness pre and post fluid administration with each volume (ml/kg) of fluid administered. Average percentage change in global kidney stiffness from baseline was compared between the three groups. There was no significant difference when comparing groups 1 and 2 (197.1% increase ± 49.5 vs 216.1% ± 72.0, p » 0.398), groups 2 and 3 (216.1% increase ± 72.0 vs 197.8% ± 59.9, p » 0.455), or groups 1 and 3 (197.1% increase ± 49.5 vs 197.8% ± 59.9, p » 0.972). Conclusions: Fluid administration results in immediately visible and quantifiable changes in global kidney stiffness across all infused volumes of fluid.

Conditional Knockout of N-WASP Enhanced the Formation of Keratinizing Squamous Cell Carcinoma Induced by KRasG12D.

Squamous cell carcinoma (SCC) is one of the most common forms of skin cancer in humans, and Neural Wiskott-Aldrich Syndrome Protein (N-WASP) plays a crucial role in epidermal homeostasis. To elucidate the role of N-WASP in skin cancer, we generated mice which expressed constitutively active KRas (KRasG12D) in keratinocytes with either homozygous (N-WASPKOG12D) or heterozygous (N-WASPHetG12D) N-WASP knockout upon Tamoxifen (TAM) injection. Both the N-WASPKOG12D and N-WASPHetG12D mice had similar body weights and no congenital malformations prior to the injection of TAM. Within 2 weeks of the injections, the N-WASPKOG12D mice exhibited significant reductions in weight coupled with visible tumors at numerous sites, unlike the N-WASPHetG12D mice, which had no visible tumors. We found that both sets of mice had oily, sticky skin and wet eyes 3 weeks after their exposure to TAM, indicating the overproduction of sebum/meibum. At 37 days post TAM injection, several notable observations were made. Tumors collected from the N-WASPKOG12D mice had small- to large-sized keratin pearls that were not observed in the N-WASPHetG12D mice. A Western blot and immunostaining analysis both highlighted significantly higher levels of expression of SCC markers, such as the cytokeratins 8, 17, 18, and 19 and TP63, in the tumors of the N-WASPKOG12D mice compared to those of the latter group. Furthermore, we noted increases in the expression levels of EGFR, P-ERK, GLUT1, P-mTOR, and P-4EBP in the N-WASPKOG12D mice, suggesting that the deletion of N-WASP in the keratinocytes enhanced KRas signaling and glucose uptake, resulting in aggressive tumor formation. Interestingly, a thickening of the epidermal layer within the esophagus and tongue was only observed in the N-WASPKOG12D mice. Immunostaining for PCNA emphasized a significantly higher number of PCNA-positive cells in the skin of the N-WASPKOG12D mice compared to their counterparts, implying that epidermal thickening and enhanced tumorigenesis are due to an increased proliferation of keratinocytes. Through our results, we have established that N-WASP plays a tumor-suppressive role in skin cancer.