Investigation of the Effect of Peptide p5 Targeting CDK5-p25 Hyperactivity on Munc18-1 (P67) Regulating Neuronal Exocytosis Using Molecular Simulations.

Munc18-1 is an SM (sec1/munc-like) family protein involved in vesicle fusion and neuronal exocytosis. Munc18-1 is known to regulate the exocytosis process by binding with closed- and open-state conformations of Syntaxin1, a protein belonging to the SNARE family established to be central to the exocytosis process. Our previous work studied peptide p5 as a promising drug candidate for CDK5-p25 complex, an Alzheimer's disease (AD) pathological target. Experimental in vivo and in vitro studies suggest that Munc18-1 promotes p5 to selectively inhibit the CDK5-p25 complex without affecting the endogenous CDK5 activity, a characteristic of remarkable therapeutic implications. In this paper, we identify several binding modes of p5 with Munc18-1 that could potentially affect the Munc18-1 binding with SNARE proteins and lead to off-target effects on neuronal communication using molecular dynamics simulations. Recent studies indicate that disruption of Munc18-1 function not only disrupts neurotransmitter release but also results in neurodegeneration, exhibiting clinical resemblance to other neurodegenerative conditions such as AD, causing diagnostic and treatment challenges. We characterize such interactions between p5 and Munc18-1, define the corresponding pharmacophores, and provide guidance for the in vitro validation of our findings to improve therapeutic efficacy and safety of p5.

Modeling, validation and verification of three-dimensional cell-scaffold contacts from terabyte-sized images.

BACKGROUND: Cell-scaffold contact measurements are derived from pairs of co-registered volumetric fluorescent confocal laser scanning microscopy (CLSM) images (z-stacks) of stained cells and three types of scaffolds (i.e., spun coat, large microfiber, and medium microfiber). Our analysis of the acquired terabyte-sized collection is motivated by the need to understand the nature of the shape dimensionality (1D vs 2D vs 3D) of cell-scaffold interactions relevant to tissue engineers that grow cells on biomaterial scaffolds. RESULTS: We designed five statistical and three geometrical contact models, and then down-selected them to one from each category using a validation approach based on physically orthogonal measurements to CLSM. The two selected models were applied to 414 z-stacks with three scaffold types and all contact results were visually verified. A planar geometrical model for the spun coat scaffold type was validated from atomic force microscopy images by computing surface roughness of 52.35 nm ±31.76 nm which was 2 to 8 times smaller than the CLSM resolution. A cylindrical model for fiber scaffolds was validated from multi-view 2D scanning electron microscopy (SEM) images. The fiber scaffold segmentation error was assessed by comparing fiber diameters from SEM and CLSM to be between 0.46% to 3.8% of the SEM reference values. For contact verification, we constructed a web-based visual verification system with 414 pairs of images with cells and their segmentation results, and with 4968 movies with animated cell, scaffold, and contact overlays. Based on visual verification by three experts, we report the accuracy of cell segmentation to be 96.4% with 94.3% precision, and the accuracy of cell-scaffold contact for a statistical model to be 62.6% with 76.7% precision and for a geometrical model to be 93.5% with 87.6% precision. CONCLUSIONS: The novelty of our approach lies in (1) representing cell-scaffold contact sites with statistical intensity and geometrical shape models, (2) designing a methodology for validating 3D geometrical contact models and (3) devising a mechanism for visual verification of hundreds of 3D measurements. The raw and processed data are publicly available from https://isg.nist.gov/deepzoomweb/data/ together with the web -based verification system.

Detection and characterization of nonspecific, sparsely populated binding modes in the early stages of complexation.

A method is proposed to study protein-ligand binding in a system governed by specific and nonspecific interactions. Strong associations lead to narrow distributions in the proteins configuration space; weak and ultraweak associations lead instead to broader distributions, a manifestation of nonspecific, sparsely populated binding modes with multiple interfaces. The method is based on the notion that a discrete set of preferential first-encounter modes are metastable states from which stable (prerelaxation) complexes at equilibrium evolve. The method can be used to explore alternative pathways of complexation with statistical significance and can be integrated into a general algorithm to study protein interaction networks. The method is applied to a peptide-protein complex. The peptide adopts several low-population conformers and binds in a variety of modes with a broad range of affinities. The system is thus well suited to analyze general features of binding, including conformational selection, multiplicity of binding modes, and nonspecific interactions, and to illustrate how the method can be applied to study these problems systematically. The equilibrium distributions can be used to generate biasing functions for simulations of multiprotein systems from which bulk thermodynamic quantities can be calculated.

Foundation metrics for evaluating effectiveness of healthcare conversations powered by generative AI.

Generative Artificial Intelligence is set to revolutionize healthcare delivery by transforming traditional patient care into a more personalized, efficient, and proactive process. Chatbots, serving as interactive conversational models, will probably drive this patient-centered transformation in healthcare. Through the provision of various services, including diagnosis, personalized lifestyle recommendations, dynamic scheduling of follow-ups, and mental health support, the objective is to substantially augment patient health outcomes, all the while mitigating the workload burden on healthcare providers. The life-critical nature of healthcare applications necessitates establishing a unified and comprehensive set of evaluation metrics for conversational models. Existing evaluation metrics proposed for various generic large language models (LLMs) demonstrate a lack of comprehension regarding medical and health concepts and their significance in promoting patients' well-being. Moreover, these metrics neglect pivotal user-centered aspects, including trust-building, ethics, personalization, empathy, user comprehension, and emotional support. The purpose of this paper is to explore state-of-the-art LLM-based evaluation metrics that are specifically applicable to the assessment of interactive conversational models in healthcare. Subsequently, we present a comprehensive set of evaluation metrics designed to thoroughly assess the performance of healthcare chatbots from an end-user perspective. These metrics encompass an evaluation of language processing abilities, impact on real-world clinical tasks, and effectiveness in user-interactive conversations. Finally, we engage in a discussion concerning the challenges associated with defining and implementing these metrics, with particular emphasis on confounding factors such as the target audience, evaluation methods, and prompt techniques involved in the evaluation process.

Computational Study of the Allosteric Effects of p5 on CDK5-p25 Hyperactivity as Alternative Inhibitory Mechanisms in Neurodegeneration.

The cyclin-dependent kinase (CDK5) forms a stable complex with its activator p25, leading to the hyperphosphorylation of tau proteins and to the formation of plaques and tangles that are considered to be one of the typical causes of Alzheimer's disease (AD). Hence, the pathological CDK5-p25 complex is a promising therapeutic target for AD. Small peptides, obtained from the truncation of CDK5 physiological activator p35, have shown promise in inhibiting the pathological complex effectively while also crossing the blood-brain barrier. One such small 24-residue peptide, p5, has shown selective inhibition toward the pathological complex in vivo. Our previous research focused on the characterization of a computationally predicted CDK5-p5 binding mode and of its pharmacophore, which was consistent with competitive inhibition. In continuation of our previous work, herein, we investigate four additional binding modes to explore other possible mechanisms of interaction between CDK5 and p5. The quantitative description of the pharmacophore is consistent with both competitive and allosteric p5-induced inhibition mechanisms of CDK5-p25 pathology. The gained insights can direct further in vivo/in vitro tests and help design small peptides, linear or cyclic, or peptidomimetic compounds as adjuvants of orthosteric inhibitors or as part of a cocktail of drugs with enhanced effectiveness and lower side effects.

Effect of COVID-19 on Orthopaedic Trauma Admissions and Operating in a London District General Hospital.

Background The coronavirus disease 2019 (COVID-19) has presented orthopaedic departments around the world with unprecedented challenges across all aspects of health care service delivery. This study explores the effect of the COVID-19 lockdown on trauma admissions and trauma theater utilization at a London District General Hospital. Methods Data was collected retrospectively from electronic patient records for 4 weeks from the initiation of two lockdown periods beginning March 16, 2020 and December 23, 2020. Results were compared with a comparable time period in 2019. Patient age, date of admission, time of admission, date of operation, length of stay, length of operation, type of operation, and length of anesthesia were analyzed. Results Fewer patients were admitted during the COVID-19 period for trauma (108 in 2019 vs. 65 in March 2020 and 77 in December 2020). In addition, there was a significant shift in patient demographics, with the mean age of patients being 55.6 years in 2019 and 64.1 years in March 2020 and December 2020 ( p = 0.038). The most common mechanism of injury in both years was due to falls; however, the proportion of injuries due to falls fell from 75% in 2019 to 62% March 2020, but not significant change from pre-COVID baseline in December 2020 (77% falls). The duration of anesthesia was significantly longer in March 2020 (136 minutes) compared with in 2019 (83 minutes) ( p < 0.00001). There was no statistically significant difference in operation length for each operation type, but there was an overall increase in median operation length of 13.6% in March 2020 from the previous year. Finally, although overall length of stay was roughly constant, the time between admission and operation was significantly reduced in March 2020 (1.22 vs. 4.74 days, p < 0.0000001). Conclusion Orthopaedic trauma remains an essential service which has always had to overcome the challenges of capacity and resources in busy cities like London. Despite the reduction in trauma volume during the COVID-19 lockdown there have still been significant pressures on the health care system due to new challenges in the face of this new disease. By understanding the effects of the lifestyle restrictions brought about by the lockdown on trauma services as well as the impact of COVID-19 on service delivery measures such as length of surgery and stay, health care managers can plan for service delivery in the future as we attempt to return to nonemergency orthopaedic services and move lockdown restrictions are eased.

PIE: an online prediction system for protein-protein interactions from text.

Protein-protein interaction (PPI) extraction has been an important research topic in bio-text mining area, since the PPI information is critical for understanding biological processes. However, there are very few open systems available on the Web and most of the systems focus on keyword searching based on predefined PPIs. PIE (Protein Interaction information Extraction system) is a configurable Web service to extract PPIs from literature, including user-provided papers as well as PubMed articles. After providing abstracts or papers, the prediction results are displayed in an easily readable form with essential, yet compact features. The PIE interface supports more features such as PDF file extraction, PubMed search tool and network communication, which are useful for biologists and bio-system developers. The PIE system utilizes natural language processing techniques and machine learning methodologies to predict PPI sentences, which results in high precision performance for Web users. PIE is freely available at http://bi.snu.ac.kr/pie/.

Transforming Health Care through Digital Revolutions.

The Internet, which has spanned several networks in a broad range of domains, is having a significant impact on every aspect of our lives. The next generation of networks will utilize a wide variety of resources with significant sensing capabilities. Such networks will extend beyond physically linked computers to include multimodal-information from biological, cognitive, semantic, and social networks. This paradigm shift will involve symbiotic networks of smart medical devices, and smart phones or mobile personal computing and communication devices. These devices-and the network-will be constantly sensing, monitoring, and interpreting the environment; this is sometimes referred to as the Internet of Things (IoT). We are also witnessing considerable interest in the "Omics" paradigm, which can be viewed as the study of a domain in a massive scale, at different levels of abstraction, in an integrative manner. The IoT revolution, combined with the Omics revolution (genomics and socio-omics or social networks) and artificial intelligence resurgence, will have significant implications for the way health care is delivered in the United States. After discussing a vision for health care in the future, we introduce the P9 health care concept, followed by a discussion of a framework for smart health care. Then, we present a case study and research directions, followed by examples of ongoing work at the National Institute of Standards and Technology (NIST).

Artificial Intelligence and Digital Tools: Future of Diabetes Care.

Diabetes mellitus has become a global threat, especially in the emerging economies. In the United States, there are about 24 million people with diabetes mellitus. Diabetes represents a trove of physiologic and sociologic data that are only superficially understood by the health care system. Artificial intelligence can address many problems posed by the prevalence of diabetes mellitus and the impact of diabetes on individual and societal health. We provide a brief overview of artificial intelligence and discuss case studies that illustrate how artificial intelligence can enhance diabetes care.

A Web Resource for Exploring the CORD-19 Dataset Using Root- and Rule-Based Phrases.

This short paper describes a web resource-the NIST CORD-19 Web Resource-for community explorations of the COVID-19 Open Research Dataset (CORD-19). The tools for exploration in the web resource make use of the NIST-developed Root- and Rule-based method, which exploits underlying linguistic structures to create terms that represent phrases in a corpus. The method allows for auto-suggesting-related terms to discover terms to refine the search of a COVID-19 heterogenous document base. The method also produces taxonomic structures in the target domain as well as providing semantic information about the relationships between terms. This term structure can serve as a basis for creating topic modeling and trend analysis tools. In this paper, we describe use of a novel search engine to demonstrate some of the capabilities above.

Use of a distal radius endoprosthesis following resection of a bone tumour: a case report.

Limited literature is available on the reconstruction of the distal radius using prosthetic replacement following resection of a bone tumour. We present the first reported case, in the English literature, of the use of an entirely metal endoprosthesis for the reconstruction of the distal radius. This case involves a 66-year-old male who was treated for giant cell tumour of the distal radius with surgical excision of the lesion and replacement of the defect using a predominantly titanium endoprosthesis. He was followed-up for 56 months following surgery and had a good functional outcome with no associated pain or complications. We propose that the use of a primarily titanium endoprosthesis for the reconstruction of a bone defect of the distal radius is a suitable alternative, providing good function of the forearm with satisfactory range of movement at the wrist and adequate pain relief.

Imaging as a Biomarker: Standards for Change Measurements in Therapy workshop summary.

Biomarkers are biological indicators of disease or therapeutic effects that can be measured by in vivo biomedical/molecular imaging, as well as other in vitro or laboratory methods. Recent work has shown that biomedical imaging can provide an early indication of drug response by use of x-ray, computed tomography (CT), positron-emission tomography/CT (PET/CT), or magnetic resonance imaging (MRI). There are three primary sources of uncertainty in using imaging as a biomarker: 1) the biological variability, 2) the variability associated with the clinicians interpreting the images, and 3) the physical measurement variability associated with image data collection and analysis across the same or different imaging platforms. Although biological variability is a large source of error, the physical uncertainty often significantly reduces the robustness of the imaging methods and the clinical decision tools required for quantitative measurement of therapy response over time. Physical and biological measurement uncertainties may be addressed prior to designing a clinical trial and thus help in reducing the case size and cost of a clinical trial associated with a drug submission to the U.S. Food and Drug Administration (FDA). The National Institute of Standards and Technology (NIST) has been approached over the last few years by several industry and medical stakeholders to address the physical sources of measurement uncertainty. NIST's initial research discovered that the characterization of measurement uncertainty poses many complex metrology and standardization problems on a scale that appears to need significant collaboration across the different medical imaging stakeholders. Many of the issues are similar to other scientific domains that NIST has addressed as part of its mission to provide metrology standards to enhance the competitiveness of U.S. industries. To better assess the measurement and standards needs for using imaging as a biomarker, NIST engaged leading representatives from many of the different imaging societies, the imaging, pharmaceutical and e-health and other health care stakeholders, as well as other key federal agencies (the National Institutes of Health Institutes and Centers [NIH ICs], and FDA) to organize and conduct a United States Measurement System (USMS) workshop: http://usms.nist.gov/workshops. The workshop entitled Imaging as a Biomarker: Standards for Change Measurements in Therapy, was thus held on September 14-15, 2006, at NIST in Gaithersburg, Maryland. (Workshop agenda, presentations. and final workshop report will be available at http://usms.nist.gov/workshops/bioimaging.htm.)

Generating Domain Terminologies using Root- and Rule-Based Terms.

Motivated by the need for flexible, intuitive, reusable, and normalized terminology for guiding search and building ontologies, we present a general approach for generating sets of such terminologies from natural language documents. The terms that this approach generates are root- and rule-based terms, generated by a series of rules designed to be flexible, to evolve, and, perhaps most important, to protect against ambiguity and standardize semantically similar but syntactically distinct phrases to a normal form. This approach combines several linguistic and computational methods that can be automated with the help of training sets to quickly and consistently extract normalized terms. We discuss how this can be extended as natural language technologies improve and how the strategy applies to common use-cases such as search, document entry and archiving, and identifying, tracking, and predicting scientific and technological trends.

Corrigendum: Incorrect Spelling of Author's Name: US Preventive Services Task Force prostate-specific antigen screening guidelines result in higher Gleason score diagnoses.

[This corrects the article on p. 423 in vol. 58.].

Carpal tunnel syndrome in lysosomal storage disorders: simple decompression or external neurolysis?

Thirty-two patients (61 limbs) with lysosomal storage disorders underwent surgery for 'carpal tunnel syndrome'. Twenty-two limbs underwent a simple decompression whereas 39 limbs underwent additional neurolysis and tenosynovectomy. Data were incomplete for six patients (12 limbs). The mean age at operation for the decompression group (11 patients) was 10.5 years and for the neurolysis group (15 patients), 6.9 years. Overall, using a neurophysiological rating system, 39% of limbs demonstrated sensory improvement and 47% motor improvement with no significant difference between the groups. Only in the neurolysis group was a decline in motor conduction (2/29 limbs) or sensory conduction (four limbs) noted. Using neurophysiological criteria, no added benefit from external neurolysis was identified.

US Preventive Services Task Force prostate-specific antigen screening guidelines result in higher Gleason score diagnoses.

Purpose: To evaluate the impact that the 2012 US Preventive Services Task Force (USPSTF) prostate-specific antigen (PSA) screening guidelines have had on the diagnosis of prostate cancer, we compared the incidence and distribution of new cases diagnosed in 2011-before the USPSTF PSA screening recommendations versus 2014 at which time the guidelines were widely adopted. Materials and Methods: We identified all prostate biopsies performed by a large urology group practice utilizing a centralized pathology lab. We examined total biopsies performed, percentage of positive biopsies, and for those with positive biopsies examined for differences in patient age, PSA, and Gleason score. Results: A total of 4,178 biopsies were identified - 2,513 in 2011 and 1,665 in 2014. The percentage of positive biopsies was 27% in 2011 versus 34% in 2014 (p<0.0001). Among patients with positive biopsies, we found statistically significant differences between the 2 cohorts in the median ages and Gleason scores. Patients were about 1 year younger in 2014 compared to 2011 (t-test; p=0.043). High Gleason scores (8-10) were diagnosed in 19% of the 2014 positive biopsies versus 9% in the 2011 positive biopsies (chi square; p<0.0001). Conclusions: After the widespread implementation of the 2011 USPTF PSA screening guidelines, 34% fewer biopsies were performed with a 29% increase in positive biopsy rates. We found a significantly higher incidence of high grade disease in 2014 compared with 2011. The percentage of patients with positive biopsies having Gleason scores 8-10 more than doubled in 2014. The higher incidence of these more aggressive cancers must be part of the discussion regarding PSA screening.

Variation of the distal metatarsal articular angle with axial rotation and inclination of the first metatarsal.

BACKGROUND: The distal metatarsal articular angle (DMAA) is a radiographic measure of the orientation of the first metatarsal articular surface. There is debate with regards to the accuracy, reproducibility, and validity of measurement of the DMAA in the literature. This study aimed to test the validity of the measurement of the DMAA from standard radiographs, to explore the trigonometric relationship of the first metatarsal rotation and the DMAA, and to assess interobserver reliability. METHODS: Thirty-four separate dry cadaver first metatarsal bones were mounted onto a customized light-box-protractor, allowing controlled incremental changes in rotation and inclination. A series of 39 digital photographs were taken of each metatarsal in 5-degree increments of rotation between 30 degrees supination and 30 degrees pronation at 10, 20 and 30 degrees of inclination. Three reviewers performed blinded DMAA measurements from each photographic image; the data were collated for statistical analysis. The data were analysed using a mixed effects linear model comparing the DMAA with rotation of the first metatarsal. RESULTS: A strong statistically significant trend of increasing score with increasing pronation of the metatarsal was observed, the relationship was approximately linear. There was a strong effect of inclination, but the strength of this varied with rotation and was amplified at higher inclinations. Interobserver error was noted in line with other studies, but even allowing for this interobserver error, the linear relationship was maintained. CONCLUSIONS: This study showed that the DMAA varies significantly in a linear pattern with axial rotation of the first metatarsal. Inclination of the first metatarsal also affects the magnitude of the angle. This study does not refute the DMAA as an entity but does confirm the inaccuracy of extrapolating the DMAA from plain anteroposterior radiographs.

Bioabsorbable Versus Titanium Screws in Anterior Cruciate Ligament Reconstruction Using Hamstring Autograft: A Prospective, Blinded, Randomized Controlled Trial With 5-Year Follow-up.

BACKGROUND: Longer-term results of bioabsorbable screws for anterior cruciate ligament reconstruction (ACLR) have been reported, but results are specific to the exact screw material and design. Titanium and poly-L-lactic acid with hydroxyapatite (PLLA-HA) screw outcomes have been compared only to 2 years. PURPOSE/HYPOTHESIS: The purpose of this study was to compare the clinical and radiologic outcomes of the PLLA-HA screw versus titanium screw for hamstring tendon ACLR over a 5-year follow-up period. The hypothesis was that there are no differences in clinical scores or tunnel widening between the PLLA-HA and the titanium screws and that the PLLA-HA screw as seen on magnetic resonance imaging (MRI) should show high-grade resorption and ossification response over 5 years. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A total of 40 patients undergoing ACLR were randomized to receive either a PLLA-HA screw (PLLA-HA group) or a titanium screw (titanium group) for ACL fixation. Blinded evaluation was performed at 2 and 5 years with the International Knee Documentation Committee and Lysholm knee score, KT-1000 arthrometer, single-legged hop test, and MRI to evaluate tunnel and screw volumes, periscrew ossification, graft integration, and cyst formation. RESULTS: There was no difference in any clinical outcome measure at 2- or 5-year follow-up between the 2 groups. At 2 years, the femoral tunnel in the PLLA-HA group was smaller than that in the titanium group (P = .02); at 5 years, there was no difference. At 2 years, the femoral PLLA-HA screw was a mean 76% of its original volume, and by 5 years, it was 36%. At 2 years, the tibial PLLA-HA screw mean volume was 68% of its original volume, and by 5 years, it was 46%. At 5 years in the PLLA-HA group, 88% of femoral tunnels and 56% of tibial tunnels demonstrated a significant ossification response. There was no increase in cyst formation in the PLLA-HA group and no screw breakages. CONCLUSION: There were equivalent clinical results between the PLLA-HA and titanium groups at 2- and 5-year follow-ups. The PLLA-HA screw was not associated with increased tunnel widening or cyst formation when compared with the titanium screw. The PLLA-HA screw demonstrated progressive screw resorption and gradual but incomplete ossification over 5 years.

Hypertension in African Americans with heart failure: progression from hypertrophy to dilatation; perhaps not.

AIM: Concentric hypertrophy is thought to transition to left ventricular (LV) dilatation and systolic failure in the presence of long standing hypertension (HTN). Whether or not this transition routinely occurs in humans is unknown. METHODS: We consecutively enrolled African American patients hospitalized for acute decompensated volume overload heart failure (HF) in this retrospective study. All patients had a history of HTN and absence of obstructive coronary disease. Patients were divided into those with normal left ventricular ejection fraction (LVEF) and reduced LVEF. LV dimensions were measured according to standard ASE recommendations. LV mass was calculated using the ASE formula with Devereux correction. RESULTS: Patients with normal LVEF HF were significantly older, female and had a longer duration of HTN with higher systolic blood pressure on admission. LV wall thickness was similarly elevated in both groups. LV mass was elevated in both groups however was significantly greater in the reduced LVEF HF group compared to the normal LVEF HF group. Furthermore, gender was an independent predictor for LV wall thickness in normal LVEF HF group. CONCLUSION: In African American patients with HF our study questions the paradigm that concentric hypertrophy transitions to LV dilatation and systolic failure in the presence of HTN. Genetics and gender likely play a role in an individual's response to long standing hypertension.

MitoMorphy: an alignment and annotation tool for human mitochondrial DNA polymorphisms.

MitoMorphy uses a number of publicly available human mitochondrial DNA (mtDNA) sequences from different ethnic groups to compare and annotate the associated polymorphic data. It provides an integrated display of mtDNA sequence comparison, sequence variation, and annotation for 695 different mtDNA sequences from many different ethnic groups around the world.