Merging Natural Product Structures with Pharmaceutical Leads: Unnatural Enantiomers of Estranes as Glucocorticoid Receptor Modulators That Suppress TNF-α and IL-6 Release.

Natural products are widely recognized as valuable starting points for the development of therapeutics, with synthetic tetracyclic triterpenoids (e.g., steroids) being the most well represented among the drugs approved by the Food and Drug Administration. Here, recently developed synthetic tools for concise, asymmetric, and convergent construction of steroidal systems are leveraged to drive a program aimed at identifying novel glucocorticoid receptor (GR) modulators. While glucocorticoids have been extensively used as anti-inflammatory agents, they are plagued by severe side effects that include bone loss, muscle wasting, and metabolic disease. Ultimately, a program targeting the unnatural enantiomers of estranes (ent-estranes) that are practically inaccessible from natural product derivatization (semisynthesis) has resulted in the identification of a new class of potent dissociated GR modulators. We identify several leads with >99% efficacy as antagonists of GR trans-activation (potency within 10-fold of that of mifepristone) and further characterize examples that also inhibit release of pro-inflammatory cytokines IL-6 and TNF-α.

Drug Repurposing using consilience of Knowledge Graph Completion methods.

While link prediction methods in knowledge graphs have been increasingly utilized to locate potential associations between compounds and diseases, they suffer from lack of sufficient evidence to explain why a drug and a disease may be indicated. This is especially true for knowledge graph embedding (KGE) based methods where a drug-disease indication is linked only by information gleaned from a vector representation. Complementary pathwalking algorithms can increase the confidence of drug repurposing candidates by traversing a knowledge graph. However, these methods heavily weigh the relatedness of drugs, through their targets, pharmacology or shared diseases. Furthermore, these methods can rely on arbitrarily extracted paths as evidence of a compound to disease indication and lack the ability to make predictions on rare diseases. In this paper, we evaluate seven link prediction methods on a vast biomedical knowledge graph for drug repurposing. We follow the principle of consilience, and combine the reasoning paths and predictions provided by path-based reasoning approaches with those of KGE methods to identify putative drug repurposing indications. Finally, we highlight the utility of our approach through a potential repurposing indication.

Editorial Commentary: Decreased Hip Ligament Thickness in Patients With Dysplasia May Contribute to Hip Instability, Above and Beyond Associated Acetabular Under-coverage.

Hip dysplasia is a pathomorphologic deformity that leads to decreased acetabular coverage and hip instability. Many different radiographic measurements have been explored to characterize hip dysplasia, including the lateral center-edge angle, femoral-epiphyseal acetabular roof index, and Tönnis angle. Magnetic resonance imaging offers 3-dimensional characterization of the hip pathomorphology that may be more detailed than 2-dimensional radiographs, as well as a modality that is free of radiation. Recent research has shown that dysplastic hips are associated with significantly thinner ligament thickness compared with non-dysplastic hips. The iliofemoral ligament is the most important hip capsular structure and helps to stabilize the hip joint, particularly in hip extension and external rotation. Differences in iliofemoral ligament thickness may help to explain why patients with dysplasia are more prone to hip instability, above and beyond their acetabular under-coverage. This reiterates the need for routine capsular closure and/or plication in patients with femoroacetabular impingement syndrome to prevent further instability.

Artificial intelligence coronary computed tomography, coronary computed tomography angiography using fractional flow reserve, and physician visual interpretation in the per-vessel prediction of abnormal invasive adenosine fractional flow reserve.

Aims: A comparison of diagnostic performance comparing AI-QCTISCHEMIA, coronary computed tomography angiography using fractional flow reserve (CT-FFR), and physician visual interpretation on the prediction of invasive adenosine FFR have not been evaluated. Furthermore, the coronary plaque characteristics impacting these tests have not been assessed. Methods and results: In a single centre, 43-month retrospective review of 442 patients referred for coronary computed tomography angiography and CT-FFR, 44 patients with CT-FFR had 54 vessels assessed using intracoronary adenosine FFR within 60 days. A comparison of the diagnostic performance among these three techniques for the prediction of FFR ≤ 0.80 was reported. The mean age of the study population was 65 years, 76.9% were male, and the median coronary artery calcium was 654. When analysing the per-vessel ischaemia prediction, AI-QCTISCHEMIA had greater specificity, positive predictive value (PPV), diagnostic accuracy, and area under the curve (AUC) vs. CT-FFR and physician visual interpretation CAD-RADS. The AUC for AI-QCTISCHEMIA was 0.91 vs. 0.76 for CT-FFR and 0.62 for CAD-RADS ≥ 3. Plaque characteristics that were different in false positive vs. true positive cases for AI-QCTISCHEMIA were max stenosis diameter % (54% vs. 67%, P < 0.01); for CT-FFR were maximum stenosis diameter % (40% vs. 65%, P < 0.001), total non-calcified plaque (9% vs. 13%, P < 0.01); and for physician visual interpretation CAD-RADS ≥ 3 were total non-calcified plaque (8% vs. 12%, P < 0.01), lumen volume (681 vs. 510 mm3, P = 0.02), maximum stenosis diameter % (40% vs. 62%, P < 0.001), total plaque (19% vs. 33%, P = 0.002), and total calcified plaque (11% vs. 22%, P = 0.003). Conclusion: Regarding per-vessel prediction of FFR ≤ 0.8, AI-QCTISCHEMIA revealed greater specificity, PPV, accuracy, and AUC vs. CT-FFR and physician visual interpretation CAD-RADS ≥ 3.

Efficient Digital Workflow to Replace a Missing Denture Tooth for Complete Denture Repair.

Debonded denture teeth is a common complication on a fixed or removable dental prosthesis when denture teeth are fabricated separately from the denture base and bonded together. Missing denture teeth can alter a person's appearance, speech, or ability to eat. Traditionally, denture teeth repair can be a challenge for clinicians or dental laboratory technicians to find the identical tooth mould to meet esthetic and functional demands. This case report describes a digital workflow to scan, design, and mill a well-fitting and esthetic denture tooth to expedite treatment, improve patient satisfaction, and increase troop readiness when traditional methods may not be feasible.

Society of Radiologists in Ultrasound Consensus on Routine Pelvic US for Endometriosis.

Endometriosis is a prevalent and potentially debilitating condition that mostly affects individuals of reproductive age, and often has a substantial diagnostic delay. US is usually the first-line imaging modality used when patients report chronic pelvic pain or have issues of infertility, both common symptoms of endometriosis. Other than the visualization of an endometrioma, sonologists frequently do not appreciate endometriosis on routine transvaginal US images. Given a substantial body of literature describing techniques to depict endometriosis at US, the Society of Radiologists in Ultrasound convened a multidisciplinary panel of experts to make recommendations aimed at improving the screening process for endometriosis. The panel was composed of experts in the imaging and management of endometriosis, including radiologists, sonographers, gynecologists, reproductive endocrinologists, and minimally invasive gynecologic surgeons. A comprehensive literature review combined with a modified Delphi technique achieved a consensus. This statement defines the targeted screening population, describes techniques for augmenting pelvic US, establishes direct and indirect observations for endometriosis at US, creates an observational grading and reporting system, and makes recommendations for additional imaging and patient management. The panel recommends transvaginal US of the posterior compartment, observation of the relative positioning of the uterus and ovaries, and the uterine sliding sign maneuver to improve the detection of endometriosis. These additional techniques can be performed in 5 minutes or less and could ultimately decrease the delay of an endometriosis diagnosis in at-risk patients.

Deep learning automation of radiographic patterns for hallux valgus diagnosis.

Artificial intelligence (AI) and deep learning are becoming increasingly powerful tools in diagnostic and radiographic medicine. Deep learning has already been utilized for automated detection of pneumonia from chest radiographs, diabetic retinopathy, breast cancer, skin carcinoma classification, and metastatic lymphadenopathy detection, with diagnostic reliability akin to medical experts. In the World Journal of Orthopedics article, the authors apply an automated and AI-assisted technique to determine the hallux valgus angle (HVA) for assessing HV foot deformity. With the U-net neural network, the authors constructed an algorithm for pattern recognition of HV foot deformity from anteroposterior high-resolution radiographs. The performance of the deep learning algorithm was compared to expert clinician manual performance and assessed alongside clinician-clinician variability. The authors found that the AI tool was sufficient in assessing HVA and proposed the system as an instrument to augment clinical efficiency. Though further sophistication is needed to establish automated algorithms for more complicated foot pathologies, this work adds to the growing evidence supporting AI as a powerful diagnostic tool.

Vital signs among emergency department trauma patients in the setting of alcohol or drug use.

INTRODUCTION: The incidence of alcohol use among trauma patients has been estimated at 19-55%. This study was undertaken to identify any relationship between vital signs and alcohol and drug use among Emergency Department (ED) patients with trauma. METHODS: In this retrospective case control study, eligible subjects included trauma patients ages 18 and over, with trauma and drug or alcohol use, between 2018 and 2022. The control group was comprised of trauma patients ages 18 and over, with trauma and no drug or alcohol use, who were matched by Injury Severity Score (ISS). Vital signs on ED arrival were compared among patients with and without alcohol use, and with and without recreational drug use. RESULTS: Among 16,159 eligible trauma subjects, 5,323 had tests available for drugs and alcohol of whom 2,750 had complete ISS and vital signs data. 684 subjects were identified with alcohol intoxication, 707 subjects were identified with recreational drug use. Patients with alcohol use had lower mean systolic blood pressure (Mean=133, SD=26.7), compared to patients without alcohol use (Mean=143, SD=29.4) (p < 0.001). Patients with alcohol use had higher mean heart rate (Mean=93, SD=19.9) compared to patients without alcohol use (Mean=91, SD=19.7) (p = 0.01). Patients with recreational drug use had lower mean systolic blood pressure (Mean=137, SD=28.5) compared to patients without drug use (Mean=143, SD=29.6) (p < 0.001). Patients with drug use had higher mean heart rate (Mean=94, SD=22.8), compared to patients without drug use (Mean=91, SD=20.0) (p = 0.002). Cannabinoids were associated with lower SBP (Case Mean=136 (25.4) vs. Control Mean=141 (31.0), p = 0.009). Opioids were associated with lower SBP (Case Mean=138 (28.0) vs. Control Mean=145 (29.4), p = 0.01). Benzodiazepines were associated with increased HR and decreased SBP and RR. CONCLUSIONS: There appear to be no clinically relevant differences in vital signs among trauma patients with drug use and/or alcohol use, compared to patients without drug or alcohol use. Abnormal vital signs should not be prematurely attributed solely to acute substance intoxication before fully evaluating for associated traumatic injuries.

Sociodemographic disparities in ADHD diagnosis and treatment among U.S. elementary schoolchildren.

We examined whether some groups of U.S. elementary schoolchildren are less likely to be diagnosed and treated for ADHD in analyses of a population-based cohort (N = 10,920). We predicted ADHD diagnosis using measures of race and ethnicity, age, socioeconomic status, birthweight, individually assessed academic, behavioral, and executive functioning, family language use, mental health, health insurance coverage, marital status, school composition, and geographic region. We predicted prescription medication use among those diagnosed with ADHD. We stratified additional analyses by biological sex. Black children (aOR, 0.60), girls (aOR, 0.55), and emergent bilinguals (aOR, 0.29) were less likely to have an ADHD diagnosis than observationally similar White children, boys, or those from English-speaking households. Black children's under-diagnosis occurred among boys. Emergent bilingual children's under-diagnosis occurred among both boys and girls. Girls (aOR, 0.52) and emergent bilinguals (aOR, 0.24) with ADHD were less likely to use prescription medication. Sociodemographic disparities in ADHD diagnosis and treatment occur among U.S. elementary schoolchildren. Measured confounds including independently assessed ADHD symptomatology and impairment do not explain the disparities. The findings empirically support cultural, linguistic, and biological sensitivity in the ADHD diagnostic and treatment procedures in use for the U.S. pediatric population.

Association study between drug prescriptions and Alzheimer's disease claims in a commercial insurance database.

In the ongoing effort to discover treatments for Alzheimer's disease (AD), there has been considerable focus on investigating the use of repurposed drug candidates. Mining of electronic health record data has the potential to identify novel correlated effects between commonly used drugs and AD. In this study, claims from members with commercial health insurance coverage were analyzed to determine the correlation between the use of various drugs on AD incidence and claim frequency. We found that, within the insured population, several medications for psychotic and mental illnesses were associated with higher disease incidence and frequency, while, to a lesser extent, antibiotics and anti-inflammatory drugs were associated with lower AD incidence rates. The observations thus provide a general overview of the prescription and claim relationships between various drug types and Alzheimer's disease, with insights into which drugs have possible implications on resulting AD diagnosis.

Real-Time Impedance-Based Monitoring of the Growth and Inhibition of Osteomyelitis Biofilm Pathogen Staphylococcus aureus Treated with Novel Bisphosphonate-Fluoroquinolone Antimicrobial Conjugates.

Osteomyelitis is a limb- and life-threatening orthopedic infection predominantly caused by Staphylococcus aureus biofilms. Bone infections are extremely challenging to treat clinically. Therefore, we have been designing, synthesizing, and testing novel antibiotic conjugates to target bone infections. This class of conjugates comprises bone-binding bisphosphonates as biochemical vectors for the delivery of antibiotic agents to bone minerals (hydroxyapatite). In the present study, we utilized a real-time impedance-based assay to study the growth of Staphylococcus aureus biofilms over time and to test the antimicrobial efficacy of our novel conjugates on the inhibition of biofilm growth in the presence and absence of hydroxyapatite. We tested early and newer generation quinolone antibiotics (ciprofloxacin, moxifloxacin, sitafloxacin, and nemonoxacin) and several bisphosphonate-conjugated versions of these antibiotics (bisphosphonate-carbamate-sitafloxacin (BCS), bisphosphonate-carbamate-nemonoxacin (BCN), etidronate-carbamate-ciprofloxacin (ECC), and etidronate-carbamate-moxifloxacin (ECX)) and found that they were able to inhibit Staphylococcus aureus biofilms in a dose-dependent manner. Among the conjugates, the greatest antimicrobial efficacy was observed for BCN with an MIC of 1.48 µg/mL. The conjugates demonstrated varying antimicrobial activity depending on the specific antibiotic used for conjugation, the type of bisphosphonate moiety, the chemical conjugation scheme, and the presence or absence of hydroxyapatite. The conjugates designed and tested in this study retained the bone-binding properties of the parent bisphosphonate moiety as confirmed using high-performance liquid chromatography. They also retained the antimicrobial activity of the parent antibiotic in the presence or absence of hydroxyapatite, albeit at lower levels due to the nature of their chemical modification. These findings will aid in the optimization and testing of this novel class of drugs for future applications to pharmacotherapy in osteomyelitis.

Fixed Effect Estimates of Student-Teacher Racial or Ethnic Matching in U.S. Elementary Schools.

We used student fixed effects and statistical controls to investigate whether U.S. elementary students (N = 18,170) displayed greater academic achievement, social-emotional behavior, or executive functioning and were more likely to receive gifted or special education services when taught by teachers of the same race or ethnicity. We observed mostly null effects for student-teacher racial or ethnic matching across the study's 12 dependent measures in analyses adjusting for Type 1 error. For the full sample, matching resulted in lower science achievement (effect size [ES] = -.03 SD). For Black students, matching resulted in fewer internalizing problem behaviors (ES = 0.18 SD). We observed null effects for Hispanic students. Robustness checks including those stratified by race or ethnicity and biological sex or by prior levels of low or high level of achievement, behavior, or executive functioning largely supported the study's null findings. Exceptions were that matching resulted in fewer externalizing problem behaviors (ES = 0.22 SD) for Black girls and lower academic achievement (ES range = -0.04 to -0.14 SD) and fewer externalizing and internalizing problem behaviors (ES range = 0.24 to 0.33 SD) for students who had previously displayed low levels of academic, behavioral, or executive functioning. Collectively, the analyses provide limited support for student-teacher racial or ethnic matching as a school-based policy to address educational disparities in U.S. elementary schools.

Disparities in Family-Centered Care Among US Children and Youth with Special Healthcare Needs.

Cross-sectional analyses of 4 nationally representative samples indicate disparities in family-centered care occur among US children and youth with special healthcare needs by race and ethnicity, family income and composition, insurance coverage, and healthcare setting. Measured confounds including children's health and impairment severity do not explain the disparities.

Sensorimotor Cortex GABA Moderates the Relationship between Physical Exertion and Assessments of Effort.

Experiences of physical exertion guide our assessments of effort. While these assessments critically influence our decisions to engage in daily activities, little is known about how they are generated. We had female and male human participants exert grip force and assess how effortful these exertions felt; and used magnetic resonance spectroscopy to measure their brain GABA concentration. We found that variability in exertion (i.e., the coefficient of variation in their force exertion profile) was associated with increases in assessments of effort, making participants judge efforts as more costly. GABA levels in the sensorimotor cortex (SM1) moderated the influence of exertion variability on overassessments of effort. In individuals with higher sensorimotor GABA, exertion variability had a diminished influence on overassessments of effort. Essentially, sensorimotor GABA had a protective effect on the influence of exertion variability on inflations of effort assessment. Our findings provide a neurobiological account of how the brain's GABAergic system integrates features of physical exertion into judgments of effort, and how basic sensorimotor properties may influence higher-order judgments of effort.SIGNIFICANCE STATEMENT Feelings of effort critically shape our decisions to partake in activities of daily living. It remains unclear how the brain translates physical activity into judgments about effort (i.e., "How effortful did that activity feel?"). Using modeling of behavior and neuroimaging, we show how the nervous system uses information about physical exertion to generate assessments of effort. We found that higher variability in exertion was associated with increases in assessments of effort, making participants judge efforts as more costly. GABA, the brain's main inhibitory neurotransmitter, moderated the influence of exertion variability on overassessments of effort. These findings illustrate how low-level features of motor performance and sensorimotor neurochemistry influence higher-order cognitive processes related to feelings of effort.

Bisphosphonates: The role of chemistry in understanding their biological actions and structure-activity relationships, and new directions for their therapeutic use.

The bisphosphonates ((HO)2P(O)CR1R2P(O)(OH)2, BPs) were first shown to inhibit bone resorption in the 1960s, but it was not until 30 years later that a detailed molecular understanding of the relationship between their varied chemical structures and biological activity was elucidated. In the 1990s and 2000s, several potent bisphosphonates containing nitrogen in their R2 side chains (N-BPs) were approved for clinical use including alendronate, risedronate, ibandronate, and zoledronate. These are now mostly generic drugs and remain the leading therapies for several major bone-related diseases, including osteoporosis and skeletal-related events associated with bone metastases. The early development of chemistry in this area was largely empirical and only a few common structural features related to strong binding to calcium phosphate were clear. Attempts to further develop structure-activity relationships to explain more dramatic pharmacological differences in vivo at first appeared inconclusive, and evidence for mechanisms underlying cellular effects on osteoclasts and macrophages only emerged after many years of research. The breakthrough came when the intracellular actions on the osteoclast were first shown for the simpler bisphosphonates, via the in vivo formation of P-C-P derivatives of ATP. The synthesis and biological evaluation of a large number of nitrogen-containing bisphosphonates in the 1980s and 1990s led to the key discovery that the antiresorptive effects of these more complex analogs on osteoclasts result mostly from their potency as inhibitors of the enzyme farnesyl diphosphate synthase (FDPS/FPPS). This key branch-point enzyme in the mevalonate pathway of cholesterol biosynthesis is important for the generation of isoprenoid lipids that are utilized for the post-translational modification of small GTP-binding proteins essential for osteoclast function. Since then, it has become even more clear that the overall pharmacological effects of individual bisphosphonates on bone depend upon two key properties: the affinity for bone mineral and inhibitory effects on biochemical targets within bone cells, in particular FDPS. Detailed enzyme-ligand crystal structure analysis began in the early 2000s and advances in our understanding of the structure-activity relationships, based on interactions with this target within the mevalonate pathway and related enzymes in osteoclasts and other cells have continued to be the focus of research efforts to this day. In addition, while many members of the bisphosphonate drug class share common properties, now it is more clear that chemical modifications to create variations in these properties may allow customization of BPs for different uses. Thus, as the appreciation for new potential opportunities with this drug class grows, new chemistry to allow ready access to an ever-widening variety of bisphosphonates continues to be developed. Potential new uses of the calcium phosphate binding mechanism of bisphosphonates for the targeting of other drugs to the skeleton, and effects discovered on other cellular targets, even at non-skeletal sites, continue to intrigue scientists in this research field.

Toward Real-Time Muscle Force Inference and Device Control via Optical-Flow-Tracked Muscle Deformation.

Despite the utility of musculoskeletal dynamics modeling, there exists no safe, noninvasive method of measuring in vivo muscle output force in real time - limiting both biomechanical insight into dexterous motion and intuitive control of assistive devices. In this paper, we demonstrate that muscle deformation constitutes a promising, yet unexplored signal from which to 1) infer such forces and 2) build novel device control schemes. Through a case study of the elbow joint on a preliminary cohort of 10 subjects, we show that muscle deformation (specifically, thickness change of the brachioradialis, as measured via ultrasound and tracked via optical flow) correlates well with elbow output force to an extent comparable with standard surface electromyography (sEMG) activation during varied isometric elbow contraction. We then show that, given real-time visual feedback, subjects can readily perform a trajectory tracking task using this deformation signal, and that they largely prefer this method to a comparable sEMG-based control scheme and perform the tracking task with similar accuracy. Together, these contributions illustrate muscle deformation's potential utility for both biomechanical study of individual muscle dynamics and device control, in a manner that - thanks to, unlike sEMG, the localized nature of the signal and its tight mechanistic coupling to output force - is readily extensible to multiple muscles and device degrees of freedom. To enable such future extensions, all modeling, tracking, and visualization software described in this paper, as well as all raw and processed data, have been made available on SimTK as part of the Open-Arm project (https://simtk.org/projects/openarm) for general research use.

Prosthodontic and Endodontic Considerations for Treatment of Military Working Dogs.

Military Working Dogs (MWD) are highly trained in substance detection and various phases of controlled aggression to protect military assets and personnel. Dental health is essential to maintain their performance and mission readiness. MWD's dentition is often fractured or worn due to the physically demanding nature of their job. When non-surgical endodontic therapy or full coverage crowns are deemed necessary, good communication between veterinary and dental teams is necessary to provide quality and timely treatment. These two case reports describe important prosthodontic and endodontic procedural steps and treatment considerations for providing care to MWDs.