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1.
Immunity ; 50(5): 1163-1171.e5, 2019 05 21.
Artículo en Inglés | MEDLINE | ID: mdl-31027996

RESUMEN

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.


Asunto(s)
Mastocitos/inmunología , Proteínas del Tejido Nervioso/metabolismo , Prurito/patología , Receptores Acoplados a Proteínas G/metabolismo , Receptores de IgE/metabolismo , Receptores de Neuropéptido/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Femenino , Histamina/metabolismo , Antagonistas de los Receptores Histamínicos/uso terapéutico , Humanos , Inmunoglobulina E/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Fragmentos de Péptidos/metabolismo , Receptores Acoplados a Proteínas G/genética , Serotonina/metabolismo , Piel/metabolismo , Triptasas/metabolismo , Adulto Joven
2.
Nature ; 584(7822): 614-618, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32612233

RESUMEN

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.


Asunto(s)
Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Proteínas de la Cápside/antagonistas & inhibidores , VIH-1/efectos de los fármacos , Adolescente , Adulto , Fármacos Anti-VIH/química , Proteínas de la Cápside/genética , Proteínas de la Cápside/metabolismo , Línea Celular , Células Cultivadas , Farmacorresistencia Viral/genética , Femenino , VIH-1/crecimiento & desarrollo , Humanos , Masculino , Persona de Mediana Edad , Modelos Moleculares , Replicación Viral/efectos de los fármacos , Adulto Joven
3.
Radiology ; 311(1): e232191, 2024 04.
Artículo en Inglés | MEDLINE | ID: mdl-38591980

RESUMEN

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.


Asunto(s)
Endometriosis , Humanos , Femenino , Endometriosis/diagnóstico por imagen , Consenso , Diagnóstico Tardío , Ultrasonografía , Radiólogos
4.
Arthroscopy ; 2024 Jul 20.
Artículo en Inglés | MEDLINE | ID: mdl-39038502

RESUMEN

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.

5.
Gen Dent ; 72(6): 38-45, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39451088

RESUMEN

The purpose of this study was to compare the flexural strength, Weibull modulus (reliability), marginal gap, and internal fit (internal gap) of 4 materials for milling or 3-dimensional (3D) printing of definitive and provisional crowns: IPS e.max CAD (IEC), Paradigm MZ100 Block (PMB), Permanent Crown Resin (PCR), and Temporary CB Resin (TCR). Flexural strength was tested by subjecting sectioned milling blocks (IEC and PMB) or 3D-printed bars (PCR and TCR) to a 3-point bending test in a universal testing machine (n = 15 per material). Crowns were milled or 3D printed, and the marginal gap and internal fit were measured using microcomputed tomography (n = 5 per material). The data were analyzed with a t test and compared using analysis of variance (ANOVA) with Tukey post hoc comparisons (α = 0.05). The groups demonstrated the following mean (SD) flexural strength values: IEC, 335.50 (28.97) MPa; PMB, 154.34 (21.03) MPa; PCR, 128.09 (7.30) MPa; and TCR, 126.29 (9.23) MPa. A 1-way ANOVA revealed significant differences in the flexural strengths of sectioned and 3D-printed bars (P < 0.001). The PMB group showed the lowest Weibull modulus (8.77), indicating its poor reliability. The IEC group showed the smallest marginal gap, 53.42 (31.99) µm; this value was significantly smaller than the gap in the TCR group (P < 0.001) but not the PCR or PMB group. The PMB group had the smallest internal fit discrepancy (87.44 [37.60] µm) but was not significantly different from PCR, while TCR had a significantly greater internal fit discrepancy (130.61 [65.16] µm) than IEC, PMB, and PCR (P < 0.001). The occlusal internal fit discrepancies of 3D-printed crowns were significantly greater than those of milled crowns (P < 0.001). There was no statistically significant difference in flexural strength between the 3D-printed definitive (PCR) and provisional (TCR) materials. When the data were combined according to manufacturing method, the marginal gap and internal fit of crowns fabricated with 3D printing were comparable to those of milled crowns, and all mean marginal gaps were within a clinically acceptable limit of less than 120 µm.


Asunto(s)
Coronas , Adaptación Marginal Dental , Resistencia Flexional , Impresión Tridimensional , Humanos , Ensayo de Materiales , Análisis del Estrés Dental , Diseño de Prótesis Dental/métodos , Materiales Dentales/química , Microtomografía por Rayos X , Diseño Asistido por Computadora
6.
J Neurosci ; 42(31): 6121-6130, 2022 08 03.
Artículo en Inglés | MEDLINE | ID: mdl-35764380

RESUMEN

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.


Asunto(s)
Esfuerzo Físico , Corteza Sensoriomotora , Actividades Cotidianas , Mapeo Encefálico , Femenino , Humanos , Masculino , Esfuerzo Físico/fisiología , Corteza Sensoriomotora/fisiología , Ácido gamma-Aminobutírico
7.
J Pediatr ; 253: 297-303.e6, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36152688

RESUMEN

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.


Asunto(s)
Etnicidad , Accesibilidad a los Servicios de Salud , Niño , Humanos , Adolescente , Estados Unidos , Estudios Transversales , Renta , Atención Dirigida al Paciente , Disparidades en Atención de Salud
8.
Int J Mol Sci ; 24(3)2023 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-36768310

RESUMEN

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.


Asunto(s)
Osteomielitis , Infecciones Estafilocócicas , Humanos , Staphylococcus aureus , Difosfonatos/uso terapéutico , Moxifloxacino , Ácido Etidrónico/uso terapéutico , Impedancia Eléctrica , Antibacterianos/química , Infecciones Estafilocócicas/tratamiento farmacológico , Osteomielitis/tratamiento farmacológico , Ciprofloxacina/farmacología , Ciprofloxacina/uso terapéutico , Biopelículas , Durapatita/química , Pruebas de Sensibilidad Microbiana
9.
Early Child Res Q ; 63: 98-112, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36643857

RESUMEN

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.

10.
Molecules ; 26(10)2021 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-34068414

RESUMEN

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.

11.
Molecules ; 25(6)2020 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-32214030

RESUMEN

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.


Asunto(s)
Dióxido de Carbono/química , Hidrógeno/química , Plomo/química , Titanio/química , Fotoquímica/métodos , Rayos Ultravioleta
12.
AJR Am J Roentgenol ; 212(5): 1082-1090, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30835516

RESUMEN

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.

14.
J Prosthodont ; 28(9): 969-972, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31560132

RESUMEN

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.


Asunto(s)
Implantes Dentales , Pilares Dentales , Fracaso de la Restauración Dental , Análisis del Estrés Dental , Torque
15.
Prehosp Emerg Care ; 20(5): 609-14, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26985695

RESUMEN

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.


Asunto(s)
Transfusión Sanguínea/estadística & datos numéricos , Servicios Médicos de Urgencia/métodos , Mortalidad Hospitalaria , Signos Vitales , Heridas y Lesiones/terapia , Adulto , Simulación por Computador , Femenino , Frecuencia Cardíaca , Humanos , Unidades de Cuidados Intensivos , Tiempo de Internación/estadística & datos numéricos , Masculino , Estudios Retrospectivos , Triaje , Heridas y Lesiones/mortalidad
16.
Biochemistry ; 54(13): 2240-8, 2015 Apr 07.
Artículo en Inglés | MEDLINE | ID: mdl-25774576

RESUMEN

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.


Asunto(s)
Fármacos Anti-VIH/farmacología , Técnicas Biosensibles/métodos , Cápside/metabolismo , Evaluación Preclínica de Medicamentos/métodos , Factores de Escisión y Poliadenilación de ARNm/metabolismo , Secuencia de Aminoácidos , Fármacos Anti-VIH/química , Fármacos Anti-VIH/metabolismo , Bencimidazoles/farmacología , Cápside/química , VIH-1 , Interacciones Huésped-Patógeno/efectos de los fármacos , Indoles/química , Indoles/metabolismo , Indoles/farmacología , Datos de Secuencia Molecular , Fenilalanina/análogos & derivados , Fenilalanina/química , Fenilalanina/metabolismo , Fenilalanina/farmacología , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Factores de Escisión y Poliadenilación de ARNm/genética
17.
Mil Med ; 2024 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-38954460

RESUMEN

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.

18.
World J Orthop ; 15(2): 105-109, 2024 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-38464350

RESUMEN

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.

19.
Mil Med ; 2024 Oct 14.
Artículo en Inglés | MEDLINE | ID: mdl-39401150

RESUMEN

INTRODUCTION: Dental impressions and casts play a critical role in dental care, facilitating diagnoses and the fabrication of prostheses. Traditional methods of fabrication involve elastomeric materials that are more prone to errors and patient discomfort. Digital advancements offer promising alternatives, yet their accuracy and applicability to military dentistry remain under-explored. This study evaluates the accuracy of digital casts produced with material available in the Military Health System compared to conventional methods. MATERIALS AND METHODS: Using a digital (n = 10) and analog (n = 10) methodology casts were fabricated from a reference cast (n = 1). The reference and cast samples were scanned with a reference scanner to generate stereolithography files. These files were used to generate full arch, single crown, fixed dental prosthesis, and inlay digital casts which were then compared using a three-dimensional (3D) comparison software to evaluate accuracy. Root mean square values were obtained, giving a quantitative evaluation of the deviation of each sample from the reference cast. Statistical analysis consisted of a Shapiro-Wilk and Levene test to account for homogeneity of variances in each group. An ANOVA and Tukey post-hoc test were used to determine differences in accuracy among the full arch and a two-way ANOVA and Tukey post-hoc test evaluated differences in trueness among the casts of the individual preparations. RESULTS: Analog full arch casts had an average root mean square of 106 ±19.18 µm when examining trueness and 12 ±2.58 µm for precision. Digital full arch casts had an average root mean square of 51.9 ±5.39 µm when examining trueness and 4.2 ±1.57 µm for precision. Overall digital casts surpassed analog counterparts in accuracy. Fixed dental prostheses were found to be the only group, which showed no statistically significant difference between digital and analog. CONCLUSION: These findings validate the potential of digital workflows in enhancing the speed and accuracy of dental care in the Military Health System, while underscoring the need for further exploration and refinement in specific clinical contexts.

20.
Injury ; 55(1): 111024, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37709640

RESUMEN

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.


Asunto(s)
Signos Vitales , Heridas y Lesiones , Humanos , Estudios Retrospectivos , Estudios de Casos y Controles , Servicio de Urgencia en Hospital , Presión Sanguínea , Heridas y Lesiones/epidemiología , Heridas y Lesiones/terapia
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