Activation of Mast-Cell-Expressed Mas-Related G-Protein-Coupled Receptors Drives Non-histaminergic Itch.

Classical itch studies have focused on immunoglobulin E (IgE)-mediated mast cell activation and histamine release. Recently, members of the Mas-related G-protein-coupled receptor (Mrgpr) family have been identified as mast cell receptors, but their role in itch is unclear. Here, we report that mast cell activation via Mrgprb2 evoked non-histaminergic itch in mice independently of the IgE-Fc epsilon RI (FcεRI)-histamine axis. Compared with IgE-FcεRI stimulation, Mrgprb2 activation of mast cells was distinct in both released substances (histamine, serotonin, and tryptase) and the pattern of activated itch-sensory neurons. Mrgprb2 deficiency decreased itch in multiple preclinical models of allergic contact dermatitis (ACD), a pruritic inflammatory skin disorder, and both mast cell number and PAMP1-20 concentrations (agonist of the human Mrgprb2 homolog, MRGPRX2) were increased in human ACD skin. These findings suggest that this pathway may represent a therapeutic target for treating ACD and mast-cell-associated itch disorders in which antihistamines are ineffective.

Clinical targeting of HIV capsid protein with a long-acting small molecule.

Oral antiretroviral agents provide life-saving treatments for millions of people living with HIV, and can prevent new infections via pre-exposure prophylaxis1-5. However, some people living with HIV who are heavily treatment-experienced have limited or no treatment options, owing to multidrug resistance6. In addition, suboptimal adherence to oral daily regimens can negatively affect the outcome of treatment-which contributes to virologic failure, resistance generation and viral transmission-as well as of pre-exposure prophylaxis, leading to new infections1,2,4,7-9. Long-acting agents from new antiretroviral classes can provide much-needed treatment options for people living with HIV who are heavily treatment-experienced, and additionally can improve adherence10. Here we describe GS-6207, a small molecule that disrupts the functions of HIV capsid protein and is amenable to long-acting therapy owing to its high potency, low in vivo systemic clearance and slow release kinetics from the subcutaneous injection site. Drawing on X-ray crystallographic information, we designed GS-6207 to bind tightly at a conserved interface between capsid protein monomers, where it interferes with capsid-protein-mediated interactions between proteins that are essential for multiple phases of the viral replication cycle. GS-6207 exhibits antiviral activity at picomolar concentrations against all subtypes of HIV-1 that we tested, and shows high synergy and no cross-resistance with approved antiretroviral drugs. In phase-1 clinical studies, monotherapy with a single subcutaneous dose of GS-6207 (450 mg) resulted in a mean log10-transformed reduction of plasma viral load of 2.2 after 9 days, and showed sustained plasma exposure at antivirally active concentrations for more than 6 months. These results provide clinical validation for therapies that target the functions of HIV capsid protein, and demonstrate the potential of GS-6207 as a long-acting agent to treat or prevent infection with HIV.

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.

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.

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.

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.

Comparison of CO2 Reduction Performance with NH3 and H2O between Cu/TiO2 and Pd/TiO2.

The aim of this study is to clarify the effect of doped metal type on CO2 reduction characteristics of TiO2 with NH3 and H2O. Cu and Pd have been selected as dopants for TiO2. In addition, the impact of molar ratio of CO2 to reductants NH3 and H2O has been investigated. A TiO2 photocatalyst was prepared by a sol-gel and dip-coating process, and then doped with Cu or Pd fine particles by using the pulse arc plasma gun method. The prepared Cu/TiO2 film and Pd/TiO2 film were characterized by SEM, EPMA, TEM, STEM, EDX, EDS and EELS. This study also has investigated the performance of CO2 reduction under the illumination condition of Xe lamp with or without ultraviolet (UV) light. As a result, it is revealed that the CO2 reduction performance with Cu/TiO2 under the illumination condition of Xe lamp with UV light is the highest when the molar ratio of CO2/NH3/H2O = 1:1:1 while that without UV light is the highest when the molar ratio of CO2/NH3/H2O = 1:0.5:0.5. It is revealed that the CO2 reduction performance of Pd/TiO2 is the highest for the molar ratio of CO2/NH3/H2O = 1:1:1 no matter the used Xe lamp was with or without UV light. The molar quantity of CO per unit weight of photocatalyst for Cu/TiO2 produced under the illumination condition of Xe lamp with UV light was 10.2 µmol/g, while that for Pd/TiO2 was 5.5 µmol/g. Meanwhile, the molar quantity of CO per unit weight of photocatalyst for Cu/TiO2 produced under the illumination condition of Xe lamp without UV light was 2.5 µmol/g, while that for Pd/TiO2 was 3.5 µmol/g. This study has concluded that Cu/TiO2 is superior to Pd/TiO2 from the viewpoint of the molar quantity of CO per unit weight of photocatalyst as well as the quantum efficiency.

Impact of Pd Loading on CO2 Reduction Performance over Pd/TiO2 with H2 and H2O.

This study investigated the impact of molar ratio of CO2 to reductants H2O and H2, as well as Pd loading weight on CO2 reduction performance with Pd/TiO2 as the photocatalyst. The Pd/TiO2 film photocatalyst is prepared by the sol-gel and dip-coating process to prepare TiO2 film and the pulse arc plasma method is used to dope Pd on TiO2 film. The prepared Pd/TiO2 film was characterized by SEM, EPMA, STEM, EDS, and EELS. This study also investigated the performance of CO2 reduction under the illumination condition of Xe lamp with or without ultraviolet (UV) light. As a result, it is revealed that when the molar ratio of CO2/H2/H2O is set at 1:0.5:0.5, the best CO2 reduction performance has been obtained under the illumination condition of Xe lamp with and without UV light. In addition, it is found that the optimum Pd loading weight is 3.90 wt%. The maximum molar quantities of CO and CH4 produced per unit weight of photocatalyst are 30.3 µmol/g and 22.1 µmol/g, respectively, for the molar ratio of CO2/H2/H2O = 1:0.5:0.5 under the condition of Xe lamp illumination with UV light. With UV light, C2H4 and C2H6, as well as CO and CH4 are also produced by the Pd/TiO2 film photocatalyst prepared in this study.

Advanced Quality Training in Radiology: Inaugural Report of a 2-Year Program.

OBJECTIVE. The purpose of this study is to describe and analyze the outcomes of a 2-year advanced quality training program for radiology residents. MATERIALS AND METHODS. In 2016, the radiology quality committee of a quaternary health system created a hands-on 2-year advanced quality training curriculum for diagnostic and interventional radiology residents. Internal candidates with the following prerequisites submitted competitive applications: registration for a 2-day lean health care management course, completion of four or more Radiological Society of North America (RSNA) quality essentials certificates, identification of faculty mentor(s), selection of one quality improvement project to champion, and completion of a two-page essay summarizing interest in quality improvement, the proposed project, and its potential impact. Residents were required to attend monthly quality meetings, pursue their project and its derivatives, submit completed work for consideration to a national meeting and for publication, and present at departmental grand rounds. Outcomes were summarized using descriptive statistics. RESULTS. Five residents submitted four projects for consideration, and all five were selected. In addition to the four submitted projects, seven additional projects were pursued. Participants worked on nine local and three multicenter process improvements, gave one to two grand rounds each, presented three oral and five poster presentations, generated eight publications, received three awards, formed 14 mentor-mentee relationships, and influenced local and multisite practice patterns. Participants reported gaining firsthand experience in quality improvement principles and developing real-world leadership skills. CONCLUSION. A targeted 2-year curriculum emphasizing hands-on quality improvement experience with rich mentor-mentee relationships can produce meaningful results.

Effect of Screw Channel Angulation on Reverse Torque Values of Dental Implant Abutment Screws.

PURPOSE: To compare the reverse torque values (RTVs) of abutment screws tightened from three different angles. MATERIALS AND METHODS: Implant abutment screws (n = 48), abutments (3), and regular platform implant analogs (3) were divided into three angulation groups (n = 16/group). Custom guides of 0°, 10°, and 20° were fabricated to verify driver angulation. The implant components for each group were assembled and all screws torqued to 35 Ncm using a universal screwdriver in a manual torque wrench at the appropriate angle. Torque was reapplied 10 minutes after initial torque. A digital gauge was then used to measure reverse torque at a position parallel (0°) to the implant analog. RTVs were recorded and compared using one-way ANOVA and Tukey HSD post-hoc comparisons (α = 0.05). RESULTS: All mean RTVs fell below the targeted torque value of 35Ncm, with some values in each angulation group 10% below of the target value. Mean RTVs in descending order from targeted torque value were: 10° group = 32.07 ± 0.97 Ncm, 0° group = 31.16 ± 1.12 Ncm, and 20° group = 30.08 ± 0.88 Ncm. One-way ANOVA revealed significant differences between angulation groups (F = 15.954, p < 0.001). Tukey HSD post hoc comparisons revealed that the mean RTVs of the three angulation groups were significantly different from each other (0° vs. 10°: p = 0.033; 0° vs. 20°: p = 0.011; 10° vs. 20°: p < 0.001). CONCLUSIONS: All RTVs did not reach the targeted torque value of 35 Ncm. Mean screw RTVs were significantly influenced by screwdriver insertion angulation.

Computer Modelling Using Prehospital Vitals Predicts Transfusion and Mortality.

OBJECTIVE: Test computer-assisted modeling techniques using prehospital vital signs of injured patients to predict emergency transfusion requirements, number of intensive care days, and mortality, compared to vital signs alone. METHODS: This single-center retrospective analysis of 17,988 trauma patients used vital signs data collected between 2006 and 2012 to predict which patients would receive transfusion, require 3 or more days of intensive care, or die. Standard transmitted prehospital vital signs (heart rate, blood pressure, shock index, and respiratory rate) were used to create a regression model (PH-VS) that was internally validated and evaluated using area under the receiver operating curve (AUROC). Transfusion records were matched with blood bank records. Documentation of death and duration of intensive care were obtained from the trauma registry. RESULTS: During the course of their hospital stay, 720 of the 17,988 patients in the study population died (4%), 2,266 (12.6%) required at least a 3-day stay in the intensive care unit (ICU), 1,171 (6.5%) required transfusions, and 210 (1.2%) received massive transfusions. The PH-VS model significantly outperformed any individual vital sign across all outcomes (average AUROC = 0.82), The PH-VS model correctly predicted that 512 of 777 (65.9%) and 580 of 931 (62.3%) patients in the study population would receive transfusions within the first 2 and 6 hours of admission, respectively. CONCLUSIONS: The predictive ability of individual vital signs to predict outcomes is significantly enhanced with the model. This could support prehospital triage by enhancing decision makers' ability to match critically injured patients with appropriate resources with minimal delays.

Functional label-free assays for characterizing the in vitro mechanism of action of small molecule modulators of capsid assembly.

HIV capsid protein is an important target for antiviral drug design. High-throughput screening campaigns have identified two classes of compounds (PF74 and BI64) that directly target HIV capsid, resulting in antiviral activity against HIV-1 and HIV-2 laboratory strains. Using recombinant proteins, we developed a suite of label-free assays to mechanistically understand how these compounds modulate capsid activity. PF74 preferentially binds to the preassembled hexameric capsid form and prevents disruption of higher-order capsid structures by stabilizing capsid intersubunit interactions. BI64 binds only the monomeric capsid and locks the protein in the assembly incompetent monomeric form by disrupting capsid intersubunit interactions. We also used these assays to characterize the interaction between capsid and the host protein cleavage and polyadenylation specific factor 6 (CPSF6). Consistent with recently published results, our assays revealed CPSF6 activates capsid polymerization and preferentially binds to the preassembled hexameric capsid form similar to the small molecule compound, PF74. Furthermore, these label-free assays provide a robust method for facilitating the identification of a different class of small molecule modulators of capsid function.

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.

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.

Full of sound and fury, signifying nothing: burden of transient noncritical monitor alarms in a trauma resuscitation unit.

We examined the types of patient monitor alarms encountered in the trauma resuscitation unit of a major level 1 trauma center. Over a 1-year period, 316688 alarms were recorded for 6701 trauma patients (47 alarms/patient). Alarms were more frequent among patients with a Glasgow Coma Scale of 8 or less. Only 2.4% of all alarms were classified as "patient crisis," with the rest in the presumably less critical categories "patient advisory," "patient warning," and "system warning." Nearly half of alarms were ≤5 seconds in duration. In this patient population, a 2-second delay would reduce alarms by 25%, and a delay of 5 seconds would reduce all alarms by 49%.

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.