The effect of adsorbent textural and functional properties on model naphthenic acid adsorption.

Naphthenic acids, NAs, are a major contaminant of concern and a focus of much research around remediation of oil sand process affected waters, OSPW. Using activated carbon adsorbents are an attractive option given their low cost of fabrication and implementation. A deeper evaluation of the effect NA structural differences have on uptake affinity is warranted. Here we provide an in-depth exploration of NA adsorption including many more model NA species than have been assessed previously with evaluation of adsorption kinetics and isotherms at the relevant alkaline pH of OSPW using several different carbon adsorbents with pH buffering to simulate the behaviour of real OSPW. Uptake for the NA varied considerably regardless of the activated carbon used, ranging from 350 mg/g to near zero highlighting recalcitrant NAs. The equilibrium data was explored to identify structural features of these species and key physiochemical properties that influence adsorption. We found that certain NA will be resistant to adsorption when hydrophobic adsorbents are used. Adsorption isotherm modelling helped explore interactions occurring at the interface between NA and adsorbent surfaces. We identified the importance of NA hydrophobicity for activated carbon uptake. Evidence is also presented that indicates favorable hydrogen bonding between certain NA and surface site hydroxyl groups, demonstrating the importance of adsorbent surface functionality for NA uptake. This research highlights the challenges associated with removing NAs from OSPW through adsorption and also identifies how adsorbent surface chemistry modification can be used to increase the removal efficiency of recalcitrant NA species.

Intima media thickness of the carotid artery in primary antiphospholipid syndrome: A systematic review and meta-analysis.

BACKGROUND: Primary antiphospholipid syndrome (PAPS) has been associated with an increase in clinical events associated with atherosclerotic vascular disease. Intima media thickness (IMT) of carotid arteries is a surrogate marker of atherosclerotic vascular disease. OBJECTIVES: To conduct a systematic review and meta-analysis of studies evaluating IMT and their clinical correlates in PAPS. METHODS: Systematic search of EMBASE and PubMed databases from January 2000 to December 2023; we employed random effect meta-analyses for continuous outcomes and Peto's odds ratio for rare events. RESULTS: The meta-analysis included 21 studies (20 case control and 1 cohort) showing that PAPS patients (n = 1103) had thicker IM than controls (n = 832) (p < 0.0001) with wide heterogeneity (I2 = 86.9 %); PAPS patients (n = 782) also had a greater pooled prevalence of carotid plaques than controls (n = 537) (13.1 % vs 2.97 %, p < 0.0001). A sensitivity analysis by meta-regression indicated that mean age, gender, disease duration, lipid profile, blood pressures, smoking and statin use all explained the heterogeneity variance; a sensitivity analysis by subgroups confirmed smoking status and statin use as explanatory variables with the addition of ethnicity. CONCLUSION: Atherosclerosis of the carotid artery represents a clinical feature of PAPS in relation to the traditional risk factors and to statin use. Minimising the atherogenic risk with statins could reduce the late arterial atherothrombotic risks of PAPS.

Physicochemical and biocompatibility characterisation of a 3D lyophilised platelet-rich fibrin scaffold for cleft lip and palate repair.

Craniofacial bone defects result from various disorders such as trauma, congenital malformations and infections. Cleft lip and palate are the most prevalent congenital craniofacial birth defect in humans. Growth factors (GFs) are soluble proteins secreted by cells that regulate various cellular processes and tissue regeneration. At present, developing three-dimensional scaffolds for delivering GFs to the site of injury has become an important aspect in craniofacial bone regeneration. This study aims to develop a novel 3D bone substitute using lyophilized-platelet-rich fibrin (LyPRF) biocomposite scaffolds for potential application for CLP repair. Collagen (C), bioglass (BG), and LyPRF were used to fabricate a biocomposite (C-BG-LyPRF) scaffold. The physical, chemical, and biocompatibility properties of the scaffold were evaluated. The C-BG-LyPRF scaffold demonstrated a mean pore diameter of 146 µm within a porosity of 87.26%. The FTIR spectra verified the presence of am-ide I, II, and III functional groups. The inorganic phase of the C-BG-LyPRF scaffold was composed of sodium, calcium, silicon, and phosphorus, as determined by EDX analysis. Furthermore, C-BG-LyPRF scaffold was biocompatible with MC3T3-E1 cells in both the Live/Dead and prolif-eration assays. Data demonstrate the developed C-BG-LyPRF scaffold exhibits biomimetic and biocompatibility properties, establishing it as a promising biomaterial for craniofacial regeneration.

Bone Marrow and Peripheral Blood Mononuclear Cell Phenotype Changes after Cultivation and Autologous Infusion in Patients with Primary Biliary Cholangitis.

Background: Primary biliary cholangitis (PBC) is a condition affecting the liver and immune system. In this study, the impact of autologous bone marrow-derived mononuclear cell (BM-MNC) transplantation on PBC patients was investigated. Methods: Sixteen eligible PBC patients participated at the National Scientific Medical Center in Astana, Kazakhstan, between 2017 and 2022, and BM-MNCs were harvested from their anterior iliac crest. After isolating and cultivating the BM-MNCs, they were infused back into the patient's peripheral veins. Changes in BM-MNC and peripheral blood mononuclear cell (PB-MNC) phenotypes were assessed before and after a 24-hour cultivation period and 72 hours post-transplantation. We monitored liver function parameters over 6-month intervals and conducted flow cytometry analysis to assess CD markers on BM-MNCs before and after cultivation and PB-MNCs before and after transplantation. Statistical analysis included the Friedman test for liver parameters and the Wilcoxon signed-rank test for BM-MNC and PB-MNC comparisons. Results: Our findings revealed significant reductions in liver function tests after multiple transplantations. Flow cytometry analysis before and after a 24-hour culture and autologous BM-MNC infusion revealed the expansion of specific cell populations, with significant increases in CD3+, CD4+, CD16+, CD20+, CD25+, CD34+, CD105+, CD73+, СD117+, and CD34+populations, while CD4+25+, CD34+105+, and CD4+FOXP3+ populations decreased. Interestingly, a contradictory finding was observed with a decrease in bone marrow CD34+105+ cell lines (P=0.03) alongside an increase in peripheral CD34+105+ population (P=0.03). Conclusion: In summary, our study shows that BM-MNC transplantation in PBC patients leads to changes in immune cell populations and liver function. These findings suggest potential therapeutic applications of BM-MNC transplantation in managing PBC and offer insights into the dynamics of immune cells associated with this treatment approach.

A multiple x-ray-source array (MXA) system with a planar two-dimensional source distribution for digital breast tomosynthesis.

BACKGROUND: Digital breast tomosynthesis (DBT) has outpaced digital mammography in clinical adoption in the United States; however, substantial technological limitations remain to image quality in DBT, including undersampling from a one-dimensional (1D) scan geometry, x-ray source motion during acquisition, and patient motion artifacts from long exam times. PURPOSE: A thermionic cathode x-ray system employing two-dimensional (2D, planar) multiple x-ray-source arrays (MXA) is proposed to improve DBT image quality. METHODS: A 1D MXA, consisting of a linear array of thermionic cathodes was used to simulate a 2D MXA. The 1D MXA included 11 focal spots separated by a distance of Δ d ${{\Delta}}d$  = 23 mm. The 11 cathodes were paired with 11 molybdenum 50 mm diameter anode disks, mounted on a rotating shaft within a single vacuum enclosure. Image quality was investigated as a function of MXA configuration by integrating the 1D MXA with a 200 × 250 mm2 flat panel detector at a source-to-detector distance of 630 mm, resulting in a 20° tomographic arc. To simulate a 2D MXA, the detector (with phantom) was translated orthogonally to the linear array by a distance ( δ $\delta $ ) ranging from δ $\delta $  = 0 mm (conventional 1D) to δ $\delta $  = 57 mm. All sources operated at 30 kV with 80 mA and 4.5 mAs/pulse, yielding ∼100 mAs per DBT dataset. DBT reconstructions involved 22 projections and used filtered backprojection with a ramp and Hann apodization filter. Volumetric reconstructions for each source were weighted by sampling differences between sources, and averaged. Image quality was assessed in terms of contrast-to-noise ratio (CNR), background clutter noise and power spectrum, and slice sensitivity profile (SSP) using a set of physical phantoms, including: (i) contrast-detail signals coupled to spherical clutter (PMMA in air); (ii) an SSP phantom; (iii) a commercial "breast" phantom (CIRS BR3D, Sun Nuclear, Norfolk, VA); and (iv) bovine muscle. RESULTS: Background clutter noise amplitude reduced monotonically from the 1D MXA (σclutter = 5.9 A.U., δ $\delta $  = 0 mm) and 2D MXA arrays with increasing δ $\delta $ , with statistical significance between the 1D MXA and 2D MXA with δ $\delta $  = 57 mm (σclutter = 5.0 A.U., p < 0.001). The contrast-detail/clutter phantom demonstrated CNR from the 2D MXA (δ  = 57 mm) outperforming the 1D MXA in all combinations of contrast and detail. 2D power spectrum analysis of clutter demonstrated a pronounced Fourier domain null cone for the 1D MXA in the anterior field-of-view (away from the 1D MXA position), whereas the 2D MXA geometry (δ = 57 mm) did not exhibit the null cone. The SSP was 15%-50% narrower (FWHM) for the 2D versus the 1D geometry, across all reconstruction setups. CONCLUSIONS: The advantages of a 2D source geometry for DBT imaging were demonstrated quantitatively compared to a conventional 1D line of x-ray sources. The improvement in the 2D geometry was attributed both to improved Fourier domain sampling and reduced SSP. We conclude that 2D MXA sources have the potential to substantially improve DBT imaging in comparison to existing commercial DBT systems.

The visual experience dataset: Over 200 recorded hours of integrated eye movement, odometry, and egocentric video.

We introduce the Visual Experience Dataset (VEDB), a compilation of more than 240 hours of egocentric video combined with gaze- and head-tracking data that offer an unprecedented view of the visual world as experienced by human observers. The dataset consists of 717 sessions, recorded by 56 observers ranging from 7 to 46 years of age. This article outlines the data collection, processing, and labeling protocols undertaken to ensure a representative sample and discusses the potential sources of error or bias within the dataset. The VEDB's potential applications are vast, including improving gaze-tracking methodologies, assessing spatiotemporal image statistics, and refining deep neural networks for scene and activity recognition. The VEDB is accessible through established open science platforms and is intended to be a living dataset with plans for expansion and community contributions. It is released with an emphasis on ethical considerations, such as participant privacy and the mitigation of potential biases. By providing a dataset grounded in real-world experiences and accompanied by extensive metadata and supporting code, the authors invite the research community to use and contribute to the VEDB, facilitating a richer understanding of visual perception and behavior in naturalistic settings.

A Standard Approach to Project-Based Learning in a Clinical Informatics Fellowship.

BACKGROUND: The Accreditation Council for Graduate Medical Education suggests that Clinical Informatics (CI) fellowship programs foster broad skills, which include collaboration and project management. However, they do not dictate how to best accomplish these learning objectives. OBJECTIVES: This study aimed to describe a standard approach to project-based learning for CI, to share its implementation, and to discuss lessons learned. METHODS: We created a standard approach to project-based learning based on concepts from adult learning theory, the project life cycle framework, the Toyota Production System, and Improvement Science. RESULTS: With this standard approach in place, we learned how best to support fellows in its use. In addition to this approach to supporting needs assessment, risk/change management, implementation, and evaluation/improvement skills, we found the need to develop fellow skills in collaboration, leadership, and time management/managing up. Supported by project-based learning using this standard approach, and with targeted project selection to meet topic-based learning objectives, fellows reached the ability to practice independently in 15 to 21 months. DISCUSSION: Fellows are uniquely positioned to ensure the success of projects due to their increased availability and protected time compared with attendings. They are readily available for project teams to draw upon their expertise with clinical workflows and understanding of technological solutions. Project-based learning addressing organizational priorities complements fellow project management coursework and improves fellows' ability to function successfully in large, complex, and dynamic organizations. Exposing fellows to contemporary problems, then addressing them through projects, provides fellows with up-to-date applied informatics knowledge. CONCLUSION: Project-based learning can ensure that many general CI learning objectives are supported inherently. It reinforces project management teachings, while providing fellows with a marketable project portfolio to aid with future job applications. Having projects tightly aligned with organizational priorities supports ongoing investment in fellowship programs.

Upregulation of keratin 15 is required for varicella-zoster virus replication in keratinocytes and is attenuated in the live attenuated vOka vaccine strain.

Varicella-zoster virus (VZV) is the etiological agent of chickenpox and shingles, diseases characterised by epidermal virus replication in skin and mucosa and the formation of blisters. We have previously shown that VZV infection has a profound effect on keratinocyte differentiation, altering the normal pattern of epidermal gene expression. In particular, VZV infection reduces expression of suprabasal keratins 1 and 10 and desmosomal proteins, disrupting epidermal structure to promote expression of a blistering phenotype. Here, we extend these findings to show that VZV infection upregulates the expression of keratin 15 (KRT15), a marker expressed by basal epidermal keratinocytes and hair follicles stem cells. We demonstrate that KRT15 is essential for VZV replication in the skin, since downregulation of KRT15 inhibits VZV replication in keratinocytes, while KRT15 exogenous overexpression supports viral replication. Importantly, our data show that VZV upregulation of KRT15 depends on the expression of the VZV immediate early gene ORF62. ORF62 is the only regulatory gene that is mutated in the live attenuated VZV vaccine and contains four of the five fixed mutations present in the VZV Oka vaccine. Our data indicate that the mutated vaccine ORF62 is not capable of upregulating KRT15, suggesting that this may contribute to the vaccine attenuation in skin. Taken together our data present a novel association between VZV and KRT15, which may open a new therapeutic window for a topical targeting of VZV replication in the skin via modulation of KRT15.

Home Health Care and Place of Death in Medicare Beneficiaries With and Without Dementia.

BACKGROUND AND OBJECTIVES: Home health care supports patient goals for aging in place. Our objective was to determine if home health care use in the last 3 years of life reduces the risk of inpatient death without hospice. RESEARCH DESIGN AND METHODS: We analyzed the characteristics of 2,065,300 Medicare beneficiaries who died in 2019 and conducted multinomial logistic regression analyses to evaluate the association between the use and timing of home health care, dementia diagnosis, and place of death. RESULTS: Receiving any home health care in the last 3 years of life was associated with a lower probability of inpatient death without hospice (Pr 23.3% vs 31.5%, p < .001), and this effect was stronger when home health care began prior to versus during the last year of life (Pr 22.5% vs 24.3%, p < .001). Among all decedents, the probability of death at home with hospice compared to inpatient death with hospice was greater when any home health care was used (Pr 46.0% vs 36.5%, p < .001), and this association was strongest among beneficiaries with dementia who started home health care at least 1 year prior to death (Pr 55.6%, p < .001). DISCUSSION AND IMPLICATIONS: Use of home health care during the last 3 years of life was associated with reduced rates of inpatient death without hospice, and increased rates of home death with hospice. Increasing affordable access to home health care can positively affect end-of-life care outcomes for older Americans and their family caregivers, especially those with dementia.

SEC31a-ATG9a Interaction Mediates the Recruitment of COPII Vesicles for Autophagosome Formation.

Autophagy plays an important role in determining stem-cell differentiation. During the osteogenic differentiation of mesenchymal stem cells (MSCs), autophagosome formation is upregulated but the reason is unknown. A long-standing quest in the autophagy field is to find the membrane origin of autophagosomes. In this study, cytoplasmic coat protein complex II (COPII) vesicles, endoplasmic reticulum-derived vesicles responsible for the transport of storage proteins to the Golgi, are demonstrated to be a critical source of osteoblastic autophagosomal membrane. A significant correlation between the number of COPII vesicle and the autophagy level is identified in the rat bone tissues. Disruption of COPII vesicles restrained osteogenesis and decreased the number and size of autophagosomes. SEC31a (an outer coat protein of COPII vesicle) is found to be vital to regulate COPII vesicle-dependent autophagosome formation via interacting with ATG9a of autophagosomal seed vesicles. The interference of Sec31a inhibited autophagosome formation and osteogenesis in vitro and in vivo. These results identified a novel mechanism of autophagosome formation in osteogenic differentiation of stem cells and identified SEC31a as a critical protein that mediates the interplay between COPII and ATG9a vesicles. These findings broaden the understanding of the regulatory mechanism in the osteogenic differentiation of MSCs.

Ethical dimensions of clinical data sharing by US healthcare organizations for purposes beyond direct patient care: Interviews with healthcare leaders.

OBJECTIVES: Empirically investigate current practices and analyze ethical dimensions of clinical data sharing by healthcare organizations for uses other than treatment, payment, and operations. Make recommendations to inform research and policy for healthcare organizations to protect patients' privacy and autonomy when sharing data with unrelated third parties. METHODS: Semi-structured interviews and surveys involving 24 informatics leaders from 22 US healthcare organizations, accompanied by thematic and ethical analyses. RESULTS: We found considerable heterogeneity across organizations in policies and practices. Respondents understood "data sharing" and "research" in very different ways. Their interpretations of these terms ranged from making data available for academic and public health uses, and to HIEs; to selling data for corporate research, to contracting with aggregators for future resale or use. The nine interview themes were that healthcare organizations: (1) share clinical data with many types of organizations, (2) have a variety of motivations for sharing data, (3) do not make data sharing policies readily available, (4) have widely varying data sharing approval processes, (5) most commonly rely on HIPAA de-identification to protect privacy, (6) were concerned about clinical data use by electronic health record vendors, (7) lacked data sharing transparency to the general public, (8) allowed individual patients little control over sharing of their data, and (9) had not yet changed data sharing practices within the year following the US Supreme Court 2022 decision denying rights to abortion. CONCLUSIONS: Our analysis identified gaps between ethical principles and healthcare organizations' data sharing policies and practices. To better align clinical data sharing practices with patient expectations and biomedical ethical principles, we recommend: updating HIPAA, including re-identification and upstream sharing restrictions in data sharing contracts, better coordination across data sharing approval processes, fuller transparency and opt-out options for patients, and accountability for data sharing and consequent harms.

Sentiment analysis of letters of recommendation for a U.S. pain medicine fellowship from 2020 to 2023.

OBJECTIVES: Letters of recommendation (LORs) are an important part of pain medicine fellowship applications that may be subject to implicit bias by the letter's author. This study evaluated letters of recommendation for applications to pain medicine fellowships in the United States to characterize biases and differences among applicants over four application cycles. METHODS: This was a retrospective single-site cohort study. De-identified LORs were collected from 2020 to 2023 from one institution. The Valence Aware Dictionary and sEntiment Reasoner (VADER) natural language processing package scored positive LOR sentiment. In addition, the deep learning tool, Empath, scored LORs for 15 sentiments. Wilcoxon rank-sum and one-way ANOVA tests compared scores between applicant demographics: gender, race, medical school type, residency specialty, and chief resident status, as well as letter writers' academic position. RESULTS: Nine hundred and sixty-four applications were studied over four application cycles. Program directors wrote fewer words (p = 0.020) and less positively (p < 0.001) compared to department chairs and letter writers with neither position. Department chairs wrote with less "negative emotion" compared to both program directors and writers with neither position (p < 0.001). Anesthesiologist applicants received more letters highlighting "achievement" (p < 0.001) while PM&R applicants submitted letters with less "negative emotion" (p < 0.001) compared to other specialties. Chief residents' letters scored higher in "leader" sentiment (p < 0.001) and lower in "negative emotion" (p < 0.001). DISCUSSION: Linguistic content did not favor certain genders or races over others. However, disparities in LORs do exist depending on an applicant's specialty and chief resident status, as well as the academic status of the letter writer.

Out-of-Hospital Cardiac Arrest Outcomes After Ventricular Fibrillation.

INTRODUCTION:  This study is a retrospective review of patients who sustained out-of-hospital cardiac arrest due to ventricular fibrillation. The data were analyzed to decipher predictors of good outcomes as the overall survival rate in the county is significantly higher than the national average. METHODS: The inclusion criteria for the study comprised all patients over the age of 18 for whom a call was made for unresponsiveness. Data for this project included all cardiac arrests due to ventricular fibrillation in the calendar year 2022.  Results: A total of 80 patients sustained cardiac arrest due to ventricular fibrillation. The age range was 27-80 years old. The study has 71% White, 19% African American, 8.7% Hispanic, and 1% other populations. Ninety-five percent received epinephrine, 89% utilized an advanced airway, 60% underwent hypothermia protocol, 24% utilized an AED device, and 14% used a mechanical CPR device. Seventy-six percent were pronounced dead in the ER or the hospital, and 19% survived to discharge. In the survivor population, CPR was initiated in 13 minutes or less and defibrillation occurred in 23 minutes or less. While none of the variables achieved statistical significance, epinephrine use showed a trend toward statistical significance for the outcome of sustained return of spontaneous circulation (ROSC) with a p-value of 0.05346. CONCLUSION: Nineteen percent of patients survived out-of-hospital cardiac arrests in the Polk County hospital system. This is significantly higher than the national average. This likely reflects the emphasis on high-quality CPR and active on-scene management, as no individual variable was statistically significant.

Predictors of death without prior appropriate therapy in ICD recipients: the comorbidities, frailty and functional status (COMFFORT study).

OBJECTIVE: Most patients who have an implantable cardioverter-defibrillator (ICD) implant do not receive life-prolonging therapy from it. Little research has been undertaken to determine which patients benefit the least from ICD therapy. As patients age and accumulate comorbidities, the risk of death increases and the benefit of ICDs diminishes. We sought to evaluate the impact of comorbidity, frailty, functional status on death with no prior appropriate ICD therapy. METHODS: A prospective, multicentre, observational study involving 12 English hospitals was undertaken. Patients were eligible for inclusion for the study if they were scheduled to have a de novo, upgrade to or replacement of a transvenous or subcutaneous ICD or cardiac resynchronisation therapy device and defibrillator (CRT-D). Baseline characteristics were collected. Participants were asked to complete a frailty assessment (Fried score) and a functional status questionnaire (EuroQol 5-Dimension 5-Level (EQ-5D-5L)). The Charlson Comorbidity Index was calculated. Patients were prospectively followed up for 2.5 years. The primary outcome was death with no prior appropriate therapy. RESULTS: In total, 675 patients were enrolled, mean age 65.7 (IQR 65-75) years. A total of 63 patients (9.5%) died during follow-up, 58 without receiving appropriate ICD therapy. Frailty was present in 86/675 (12.7%) and severe comorbidity in 69/675 (10.2%). Multivariate predictors of death with no appropriate therapy were identified and a risk score comprising frailty, comorbidity, increasing age, estimated glomerular filtration rate and EQ-5D-5L was developed. CONCLUSION: Comorbidities, frailty and the EQ-5D-5L score are powerful, independent predictors of death with no prior appropriate therapy in ICD/CRT-D recipients.

Institution-Wide Moral Distress Among Nurses.

BACKGROUND: Moral distress is the inability to do the right thing due to imposed constraints. OBJECTIVE: Explore the presence of moral distress among nurses. METHODS: A quantitative, exploratory, cross-sectional study at a level 1 trauma center using the Measure of Moral Distress for Healthcare Professionals (MMD-HP). RESULTS: Ninety-seven nurses completed the MMD-HP. The top 3 items contributing to moral distress included inadequate staffing, inadequate resources, and lack of administrative support. Nurses who considered leaving had more moral distress. Moral distress explained 28.5% of the variance associated with nurses' "intent to leave" and "primary unit" (P < 0.001). Moral distress for nurses 40 to 49 years of age was higher compared with nurses 50 years or older. CONCLUSIONS: Moral distress involved deficiencies in staffing, resources, and administrative support. Research should explore interventions to mitigate moral distress among nurses by promoting safe staffing levels, the provision of adequate resources, and increased administrative support.

OQuPy: A Python package to efficiently simulate non-Markovian open quantum systems with process tensors.

Non-Markovian dynamics arising from the strong coupling of a system to a structured environment is essential in many applications of quantum mechanics and emerging technologies. Deriving an accurate description of general quantum dynamics including memory effects is, however, a demanding task, prohibitive to standard analytical or direct numerical approaches. We present a major release of our open source software package, OQuPy (Open Quantum System in Python), which provides several recently developed numerical methods that address this challenging task. It utilizes the process tensor approach to open quantum systems (OQS) in which a single map, the process tensor, captures all possible effects of an environment on the system. The representation of the process tensor in a tensor network form allows for an exact yet highly efficient description of non-Markovian OQS (NM-OQS). The OQuPy package provides methods to (1) compute the dynamics and multi-time correlations of quantum systems coupled to single and multiple environments, (2) optimize control protocols for NM-OQS, (3) simulate interacting chains of NM-OQS, and (4) compute the mean-field dynamics of an ensemble of NM-OQS coupled to a common central system. Our aim is to provide an easily accessible and extensible tool for researchers of OQS in fields such as quantum chemistry, quantum sensing, and quantum information.

A framework for translating tauopathy therapeutics: Drug discovery to clinical trials.

The tauopathies are defined by pathological tau protein aggregates within a spectrum of clinically heterogeneous neurodegenerative diseases. The primary tauopathies meet the definition of rare diseases in the United States. There is no approved treatment for primary tauopathies. In this context, designing the most efficient development programs to translate promising targets and treatments from preclinical studies to early-phase clinical trials is vital. In September 2022, the Rainwater Charitable Foundation convened an international expert workshop focused on the translation of tauopathy therapeutics through early-phase trials. Our report on the workshop recommends a framework for principled drug development and a companion lexicon to facilitate communication focusing on reproducibility and achieving common elements. Topics include the selection of targets, drugs, biomarkers, participants, and study designs. The maturation of pharmacodynamic biomarkers to demonstrate target engagement and surrogate disease biomarkers is a crucial unmet need. HIGHLIGHTS: Experts provided a framework to translate therapeutics (discovery to clinical trials). Experts focused on the "5 Rights" (target, drug, biomarker, participants, trial). Current research on frontotemporal degeneration, progressive supranuclear palsy, and corticobasal syndrome therapeutics includes 32 trials (37% on biologics) Tau therapeutics are being tested in Alzheimer's disease; primary tauopathies have a large unmet need.

Invariance of Mitochondria and Synapses in the Primary Visual Cortex of Mammals Provides Insight Into Energetics and Function.

The cerebral cortex accounts for substantial energy expenditure, primarily driven by the metabolic demands of synaptic signaling. Mitochondria, the organelles responsible for generating cellular energy, play a crucial role in this process. We investigated ultrastructural characteristics of the primary visual cortex in 18 phylogenetically diverse mammals, spanning a broad range of brain sizes from mouse to elephant. Our findings reveal remarkable uniformity in synapse density, postsynaptic density (PSD) length, and mitochondria density, indicating functional and metabolic constraints that maintain these fundamental features. Notably, we observed an average of 1.9 mitochondria per synapse across mammalian species. When considered together with the trend of decreasing neuron density with larger brain size, we find that brain enlargement in mammals is characterized by increasing proportions of synapses and mitochondria per cortical neuron. These results shed light on the adaptive mechanisms and metabolic dynamics that govern cortical ultrastructure across mammals.

The Use of Artificial Intelligence for Orthopedic Surgical Backlogs Such as the One Following the COVID-19 Pandemic: A Narrative Review.

➤ The COVID-19 pandemic created a persistent surgical backlog in elective orthopedic surgeries. ➤ Artificial intelligence (AI) uses computer algorithms to solve problems and has potential as a powerful tool in health care. ➤ AI can help improve current and future orthopedic backlogs through enhancing surgical schedules, optimizing preoperative planning, and predicting postsurgical outcomes. ➤ AI may help manage existing waitlists and increase efficiency in orthopedic workflows.

All-reflective tethered capsule endoscope for multimodal optical coherence tomography in the esophagus.

Significance: Esophageal cancer is becoming increasingly prevalent in Western countries. Early detection is crucial for effective treatment. Multimodal imaging combining optical coherence tomography (OCT) with complementary optical imaging techniques may provide enhanced diagnostic capabilities by simultaneously assessing tissue morphology and biochemical content. Aim: We aim to develop a tethered capsule endoscope (TCE) that can accommodate a variety of point-scanning techniques in addition to OCT without requiring design iterations on the optical or mechanical design. Approach: We propose a TCE utilizing exclusively reflective optics to focus and steer light from and to a double-clad fiber. Specifically, we use an ellipsoidal mirror to achieve finite conjugation between the fiber tip and the imaging plane. Results: We demonstrate a functional all-reflective TCE. We first detail the design, fabrication, and assembly steps required to obtain such a device. We then characterize its performance and demonstrate combined OCT at 1300 nm and visible spectroscopic imaging in the 500- to 700-nm range. Finally, we discuss the advantages and limitations of the proposed design. Conclusions: An all-reflective TCE is feasible and allows for achromatic high-quality imaging. Such a device could be utilized as a platform for testing various combinations of modalities to identify the optimal candidates without requiring design iterations.