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PURPOSE: A decline in youth running was observed at the start of the COVID-19 pandemic. We investigated whether the resumption of organized running after social distancing restrictions changed running habits or injury frequency in adolescent runners. METHODS: Adolescents (age = 16.1 [2.1] y) who participated in long-distance running activities completed an online survey in the Spring and Fall of 2020. Participants self-reported average weekly running habits and whether they sustained an injury during the Fall 2020 season. Poisson regression models and 1-way analysis of variance compared running habits while Fisher exact test compared differences in frequencies of injuries during Fall 2020 among season statuses (full, delayed, and canceled). RESULTS: All runners, regardless of season status, increased weekly distance during Fall 2020. Only runners with a full Fall 2020 season ran more times per week and more high-intensity runs per week compared with their Spring 2020 running habits. There were no differences in running volume or running-related injury frequency among Fall 2020 season statuses. CONCLUSIONS: There were no significant differences in running-related injury (RRI) frequency among runners, regardless of season status, following the resumption of cross-country. Health care providers may need to prepare for runners to increase running volume and intensity following the resumption of organized team activities.
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COVID-19 , Carrera , Humanos , Adolescente , Pandemias , Estudios Prospectivos , Factores de Riesgo , HábitosRESUMEN
CONTEXT: High secondary injury rates after orthopedic surgeries have motivated concern toward the construct validity of return-to-sport test batteries, as it is evident that common strength and functional assessments fail to elicit pertinent behaviors like visual search and reactive decision making. This study aimed to establish the test-retest reliability of 2 reactive agility tasks and evaluate the impact of visual perturbation on physical performance. METHODS: Fourteen physically active individuals completed 2 agility tasks with reaction time (ie, 4 corner agility), working memory, and pathfinding (ie, color recall) components. Participants completed both tasks 4 times in 2 sessions scheduled 7 days apart. Outcomes included performance metrics of reaction time, time to target, number of targets, and total time assessed with reactive training timing gates. To assess test-retest reliability, we used intraclass correlation coefficients (ICCs), standard error of measurement (SEM), and minimal detectable change (MDC). Stroboscopic goggles induced visual perturbation during the fourth trial of each task. To assess the effect of visual perturbation, we used paired t tests and calculated performance costs. RESULTS: The 4-corner agility task demonstrated excellent reliability with respect to reaction time (ICC3,1 = .907, SEM = 0.13, MDC = 0.35 s); time to light (ICC3,1 = .935, SEM = 0.07, MDC = 0.18 s); and number of lights (ICC3,1 = .800, SEM = 0.24, MDC = 0.66 lights). The color recall task demonstrated good-to-excellent test-retest reliability for time to lights (ICC3,1 = .818-.953, SEM = 0.07-0.27, MDC = 0.19-0.74 s); test time (ICC3,1 = .969, SEM = 5.43, MDC = 15.04 s); and errors (ICC3,1 = .882, SEM = 0.19, MDC = 0.53 errors). Visual perturbation resulted in increased time to target (P = .022-.011), number of targets (P = .039), and total test time (P = .013) representing moderate magnitude degradation of performance (d = 0.55-0.87, performance costs = 5%-12%). CONCLUSIONS: Both tasks demonstrated acceptable test-retest reliability. Performance degraded on both tasks with the presence of visual perturbation. These results suggest standardized reactive agility tasks are reliable and could be developed as components of dynamic RTS testing.
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Tiempo de Reacción , Humanos , Reproducibilidad de los Resultados , Tiempo de Reacción/fisiología , Masculino , Femenino , Adulto Joven , Adulto , Memoria a Corto Plazo/fisiología , Rendimiento Atlético/fisiología , Volver al Deporte , Desempeño Psicomotor/fisiologíaRESUMEN
Runners and coaches are often interested in identifying the "ideal" running form to reduce the risk of injury and improve performance. While differences in pelvis and hip motion have been reported among adolescent female and male long-distance runners of different stages of physical maturation, the influence of sex and/or maturation on temporal-spatial parameters is unknown for adolescent runners. Adolescent runners of different stages of physical maturation (pre-, mid-, post-pubertal) completed an overground running analysis at a self-selected speed. We performed 2 × 3 ANCOVAs (covariate = running speed) to compare temporal-spatial parameters among sex and maturation groups. Pre-adolescents ran with higher cadences and shorter step lengths than mid- (p ≤ .01) and post-pubertal adolescents (p ≤ .01), respectively. Mid-pubertal males and post-pubertal females also ran with higher cadences and shorter step lengths than post-pubertal males (p ≤ .01). When step length was normalized to leg length, less physically mature runners demonstrated longer normalized step lengths (p ≤ .01). Caution is advised when using a "one-size-fits-all" approach for recommending an "ideal" cadence and/or step length for adolescent long-distance runners. A runner's sex, stage of physical maturation and leg length should be considered when assessing and prescribing cadence and/or step length.
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Pelvis , Carrera , Humanos , Masculino , Adolescente , Femenino , Carrera/lesiones , Movimiento (Física) , Fenómenos BiomecánicosRESUMEN
CONTEXT: Arthrogenic muscle inhibition (AMI) is a common neurophysiological response to joint injury. While athletic trainers (ATs) are constantly treating patients with AMI, it is unclear how clinicians are using the available evidence to treat the condition. OBJECTIVE: To investigate ATs' general knowledge, clinical practice, and barriers for treating AMI. METHODS: A cross-sectional web-based survey was utilized. The survey was distributed to a random sample of 3000 ATs from the National Athletic Trainers' Association and through social media. 143 board certified ATs (age: 34.6 [10.3] y; experience: 11.7 [9.8] y) from various clinical settings and educational backgrounds were included in the analysis. RESULTS: One hundred one respondents were able to correctly identify the definition of AMI. The majority of these respondents correctly reported that joint effusion (n = 95, 94.1%) and abnormal activity from joint receptors (n = 91, 90.1%) resulted in AMI. Of the 101 respondents, only 58 (57.4%) reported using disinhibitory interventions to treat AMI. The most frequently used evidence supported interventions were transcutaneous electrical nerve stimulation (n = 38, 65.5%), neuromuscular electrical stimulation (n = 33, 56.9%), and focal joint cooling (n = 25, 43.1%). The interventions used correctly most often based on current evidence were neuromuscular electrical stimulation (n = 29/33, 87.9%) and transcutaneous electrical nerve stimulation (n = 26/38, 68.4%). Overall, difficulty quantifying AMI (n = 62, 61.24%) and lack of education (n = 71, 76.2%) were most frequently perceived as barriers. Respondents that did not use disinhibitory interventions perceived lack of experience treating AMI, understanding the terminology, and access to therapeutic modalities more often than the respondents that reported using disinhibitory interventions. CONCLUSION: Further education about concepts and treatment about AMI is warranted for ATs. Continued understanding of ATs' clinical practice in regard to AMI may help identify gaps in athletic training clinical education.
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Medicina Deportiva , Deportes , Adulto , Estudios Transversales , Humanos , Fuerza Muscular , Educación y Entrenamiento Físico , Encuestas y CuestionariosRESUMEN
Natural products have routinely been used both as sources of and inspiration for new crop protection active ingredients. The natural product UK-2A has potent anti-fungal activity but lacks key attributes for field translation. Post-fermentation conversion of UK-2A to fenpicoxamid resulted in an active ingredient with a new target site of action for cereal and banana pathogens. Here we demonstrate the creation of a synthetic variant of fenpicoxamid via identification of the structural elements of UK-2A that are needed for anti-fungal activity. Florylpicoxamid is a non-macrocyclic active ingredient bearing two fewer stereocenters than fenpicoxamid, controls a broad spectrum of fungal diseases at low use rates and has a concise, scalable route which is aligned with green chemistry principles. The development of florylpicoxamid represents the first example of using a stepwise deconstruction of a macrocyclic natural product to design a fully synthetic crop protection active ingredient.
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Antifúngicos/farmacología , Productos Biológicos/farmacología , Descubrimiento de Drogas , Compuestos Macrocíclicos/farmacología , Piridinas/farmacología , Antifúngicos/síntesis química , Antifúngicos/química , Ascomicetos/efectos de los fármacos , Productos Biológicos/síntesis química , Productos Biológicos/química , Relación Dosis-Respuesta a Droga , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Piridinas/síntesis química , Piridinas/química , Relación Estructura-ActividadRESUMEN
Patellofemoral pain is a common and often debilitating musculoskeletal condition. Clinical translation and evidence synthesis of patellofemoral pain research are compromised by heterogenous and often inadequately reported study details. This consensus statement and associated checklist provides standards for REPORTing of quantitative PatelloFemoral Pain (REPORT-PFP) research to enhance clinical translation and evidence synthesis, and support clinician engagement with research and data collection. A three-stage Delphi process was initiated at the 2015 International Patellofemoral Research Network (iPFRN) retreat. An initial e-Delphi activity (n=24) generated topics and items, which were refined at the 2017 iPFRN retreat, and voted on prior to and following the 2019 iPFRN retreat (n=51 current and past retreat participants). Voting criteria included 'strongly recommended' (essential), 'recommended' (encouraged) and uncertain/unsure. An item was included in the checklist if ≥70% respondents voted 'recommended'. Items receiving ≥70% votes for 'strongly recommended' were labelled as such. The final REPORT-PFP checklist includes 31 items (11 strongly recommended, 20 recommended), covering (i) demographics (n=2,4); (ii) baseline symptoms and previous treatments (n=3,7); (iii) outcome measures (2,4); (iv) outcomes measure description (n=1,2); (v) clinical trial methodology (0,3) and (vi) reporting study results (n=3,0). The REPORT-PFP checklist is ready to be used by researchers and clinicians. Strong stakeholder engagement from clinical academics during development means consistent application by the international patellofemoral pain research community is likely. Checklist adherence will improve research accessibility for clinicians and enhance future evidence synthesis.
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Síndrome de Dolor Patelofemoral , Proyectos de Investigación/normas , Lista de Verificación , Consenso , Técnica Delphi , Humanos , Síndrome de Dolor Patelofemoral/diagnósticoRESUMEN
Running-related injuries are prevalent in adolescent long-distance runners. The aim of our retrospective study was to compare differences in sport specialization, running habits,quality of life, and sleep habits among middle-and high-school long-distance runners of different injury statuses. Middle- and high-school long-distance runners across the United States were recruited via cross-country coaches and athletic directors between January and May 2020. Participants completed an online survey with questions related to demographics, sport specialization, running habits, quality of life, sleep, and self-reported injury history. Overall, 306 participants completed the survey (male = 107, female = 176, unspecified = 23; age = 15.7 ± 1.1 years). Of the participants, 178 (58.2%) reported no history of injury, 101 (33.0%) reported a previous injury, and 27 (8.8%) reported a current injury. Middle- and high-school runners with a current injury reported significantly lower overall health (p= .01) and average distance per run (p = .05) than uninjured runners. No significant differences were found among injury status and sport specialization level, quality of life, sleep habits, or running volume (p> .05). Runners with a self-reported previous or current injury do not appear to be classified as high-specialized runners more frequently than uninjured runners.
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Calidad de Vida , Carrera , Adolescente , Femenino , Humanos , Masculino , Estudios Retrospectivos , Instituciones Académicas , Especialización , Estados UnidosRESUMEN
CONTEXT: Hip muscle strength has previously been evaluated in various sagittal plane testing positions. Altering the testing position appears to have an influence on hip muscle torque during hip extension, abduction, and external rotation. However, it is unknown how altering the testing position influences hip muscle activity during these commonly performed assessments. OBJECTIVES: To evaluate how hip sagittal plane position influences hip muscle activation and torque output. STUDY DESIGN: Cross-sectional. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 22 healthy females (age = 22.1 [1.4] y; mass = 63.4 [11.3] kg; height = 168.4 [6.2] cm) were recruited. INTERVENTION: None. MAIN OUTCOME MEASURES: Participants completed isometric contractions with surface electromyography on the superior and inferior gluteus maximus; anterior, middle, and posterior gluteus medius; biceps femoris, semitendinosus, adductor longus, and tensor fascia latae. Extension and external rotation were tested in 0°, 45°, and 90° of hip flexion and abduction was tested in -5°, 0°, and 45° of hip flexion. Repeated-measures analysis of variances were used for statistical analysis (P ≤ .01). RESULTS: Activation of gluteal (P < .007), semitendinosus (P = .002), and adductor longus (P = .001) muscles were lesser for extension at 90° versus less flexed positions. Adductor longus activity was greatest during 90° of hip flexion for external rotation torque testing (P < .001). Tensor fascia latae (P < .001) and gluteus maximus (P < .001) activities were greater in 45° of hip flexion. Significant differences in extension (P < .001) and abduction (P < .001) torque were found among positions. CONCLUSIONS: Position when assessing hip extension and abduction torque has an influence on both muscle activity and torque output but only muscle activity for hip external rotation torque. Clinicians should be aware of the influence of position on hip extension, abduction, and external rotation muscle testing and select a position most in line with their clinical goals.
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Articulación de la Cadera/fisiología , Contracción Isométrica/fisiología , Extremidad Inferior/fisiología , Músculo Esquelético/fisiología , Postura/fisiología , Nalgas , Estudios Transversales , Electromiografía , Fascia Lata/fisiología , Femenino , Músculos Isquiosurales/fisiología , Humanos , Rotación , Muslo , Torque , Adulto JovenRESUMEN
BACKGROUND: Musculoskeletal pain in youth is common but little is known about the influence of the number of pain sites on pain characteristics. The objective of this study was to compare pain characteristics, quality of life, sleep, sport participation between adolescents without pain, those with single site pain, and those with multi-site pain and investigate the relationship between pain duration and number of pain sites. METHODS: An online survey was sent via email to 7177 possible middle- and high-school students. The students completed a survey containing questions about their pain (including location, duration, intensity, frequency), health-related quality of life, sleep quantity and quality, and sports participation. Quantitative variables were analysed with one-way ANOVAs or t-tests and qualitative variables were analysed with Pearson Chi-squared tests. Relationships were investigated with a Pearson Correlation. RESULTS: Of the respondents (n = 1021), 52.9% reported no pain, 17.2% reported pain in a single-site, and 29.9% reported pain in multiple sites. Those with multi-site pain reported significantly lower quality of life than both pain-free youth (p < 0.001) and those with single-site pain (p < 0.001); those with single-site pain had lower quality of life than pain-free youth (p < 0.001). Those with pain reported worse sleep than those without pain (P < 0.05). No differences in sport participation were found (p > 0.10). Those with multi-site pain reported greater intensity (p = 0.005) and duration (p < 0.001) than those with single-site pain. A positive, moderate, and significant correlation (r = 0.437, p < 0.001) was found between the pain duration and number of pain sites. CONCLUSIONS: A large percentage of youth experience regular pain that affects their self-reported quality of life and sleep, with greater effects in those with multi-site pain.
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Dolor Musculoesquelético/epidemiología , Calidad de Vida , Sueño , Deportes/estadística & datos numéricos , Adolescente , Análisis de Varianza , Distribución de Chi-Cuadrado , Estudios Transversales , Femenino , Encuestas Epidemiológicas/estadística & datos numéricos , Humanos , Estilo de Vida , Masculino , Medio Oeste de Estados Unidos/epidemiología , Dolor Musculoesquelético/complicaciones , Dimensión del Dolor , PrevalenciaRESUMEN
HIV-1-infected cells presenting envelope glycoproteins (Env) in the CD4-bound conformation on their surface are preferentially targeted by antibody-dependent cell-mediated cytotoxicity (ADCC). HIV-1 has evolved a sophisticated mechanism to avoid exposure of ADCC-mediating Env epitopes by down-regulating CD4 and by limiting the overall amount of Env at the cell surface. Here we report that small-molecule CD4-mimetic compounds induce the CD4-bound conformation of Env, and thereby sensitize cells infected with primary HIV-1 isolates to ADCC mediated by antibodies present in sera, cervicovaginal lavages, and breast milk from HIV-1-infected individuals. Importantly, we identified one CD4 mimetic with the capacity to sensitize endogenously infected ex vivo-amplified primary CD4 T cells to ADCC killing mediated by autologous sera and effector cells. Thus, CD4 mimetics hold the promise of therapeutic utility in preventing and controlling HIV-1 infection.
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Citotoxicidad Celular Dependiente de Anticuerpos/inmunología , Antígenos CD4/inmunología , Infecciones por VIH/prevención & control , Infecciones por VIH/transmisión , VIH-1/inmunología , Antígenos CD4/metabolismo , Linfocitos T CD4-Positivos/inmunología , Citometría de Flujo , Células HEK293 , Humanos , Mutagénesis Sitio-Dirigida , Conformación Proteica , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/metabolismo , Productos del Gen env del Virus de la Inmunodeficiencia Humana/metabolismoRESUMEN
BACKGROUND: Genomic fusions of the anaplastic lymphoma kinase gene (ALK) are a well-established therapy target in non-small cell lung cancer (NSCLC). From a survey of 114,200 clinical cases, we determined the prevalence of ALK rearrangements (rALK) in non-NSCLC tumors and report their responsiveness to therapies targeting ALK. MATERIALS AND METHODS: Comprehensive genomic profiling of 114,200 relapsed and metastatic malignancies, including both solid tumors and hematolymphoid cancers, was performed using a hybrid-capture, adaptor ligation-based next-generation sequencing assay. RESULTS: Of 114,200 clinical samples, 21,522 (18.8%) were NSCLC and 92,678 (81.2%) were other tumor types. Of the 876 (0.8%) cases with ALK fusions (fALK) or rALK, 675 (77.1%) were NSCLC and 201 (22.9%) were other tumor types. ALK fusions were significantly more frequent in NSCLC (3.1%) than non-NSCLC (0.2%; p < .0001). Patients with non-NSCLC tumors harboring fALK were significantly younger (p < .0001) and more often female (p < .0001) than patients with fALK-positive NSCLC. EML4 was more often the fusion partner in NSCLC (83.5%) versus non-NSCLC tumors (30.9%; p < .0001). CONCLUSION: ALK rearrangements can be identified in a wide variety of epithelial and mesenchymal malignancies beyond NSCLC. Anti-ALK therapies can be effective in non-NSCLC tumors driven by fALK, and further study of therapies targeting ALK in clinical trials involving a wider variety of cancer types appears warranted. IMPLICATIONS FOR PRACTICE: Rearrangements involving the ALK gene have been detected in dozens of cancer types using next-generation sequencing. Patients whose tumors harbor ALK rearrangements or fusions respond to treatment with crizotinib and alectinib, including tumors not normally associated with ALK mutations, such as non-Langerhans cell histiocytosis or renal cell carcinoma. Comprehensive genomic profiling using next-generation sequencing can detect targetable ALK fusions irrespective of tumor type or fusions partner.
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Resistencia a Antineoplásicos/genética , Proteínas de Fusión Oncogénica/genética , Proteínas Tirosina Quinasas Receptoras/genética , Quinasa de Linfoma Anaplásico , Carbazoles/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/epidemiología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Crizotinib , Femenino , Humanos , Masculino , Terapia Molecular Dirigida , Mutación , Piperidinas/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirazoles/administración & dosificación , Piridinas/administración & dosificación , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidoresRESUMEN
Proliferative fasciitis is a rare entity in the orbit. A 16-year-old boy presented with a growing right orbital mass, which was palpable just inferior to the medial right eyebrow. MRI demonstrated a 12 × 8 × 9 mm mass located medial to and slightly above the right globe within the subcutaneous soft tissues. An anterior orbitotomy with debulking of the lesion was performed. Histopathological examination confirmed a diagnosis of proliferative fasciitis. To the authors' knowledge, there is only one prior case in the literature demonstrating proliferative fasciitis of the orbit.
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Fascitis/diagnóstico , Órbita/patología , Enfermedades Orbitales/diagnóstico , Adolescente , Biopsia , Diagnóstico Diferencial , Humanos , Imagen por Resonancia Magnética , MasculinoRESUMEN
PURPOSE: To describe severe lymphedema of the eyelids, known as Morbihan disease, a previously characterized but infrequently reported and poorly understood entity related to rosacea that features solid mid-facial and eyelid lymphedema. METHODS: Retrospective chart review, histopathologic and immunohistochemical analysis, and pertinent literature consideration. RESULTS: Five cases of Morbihan disease were identified. Histopathologic examination revealed pleomorphic perivascular and perilymphatic inflammation with profound lymphangiectasis and lymph stasis, thus suggesting elements of both rosacea and localized, chronic lymphedema. Multiple therapeutic interventions were performed including systemic anti-inflammatory therapy, surgical debulking, and corticosteroid injection. CONCLUSIONS: Extreme eyelid edema associated with characteristic skin changes and histopathologic findings represents an entity known as Morbihan disease which is rare and difficult to treat. While multiple modalities have been employed with variable results, future therapeutic considerations may include the use of targeted biologic agents.
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Antiinflamatorios/uso terapéutico , Enfermedades de los Párpados/etiología , Linfedema/etiología , Procedimientos Quirúrgicos Oftalmológicos/métodos , Rosácea/complicaciones , Anciano , Enfermedades de los Párpados/diagnóstico , Enfermedades de los Párpados/terapia , Femenino , Humanos , Linfedema/diagnóstico , Linfedema/terapia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Rosácea/diagnóstico , Rosácea/terapiaRESUMEN
Plerixafor (P) together with granulocyte colony-stimulating factor (G) is now recognized as an important strategy for mobilizing hematopoietic cells for use in patients given myelosuppressive therapies. However, quantitative comparisons of their ability to mobilize human cells with different hematopoietic activities in vitro or in vivo (in immunodeficient mice) and their interrelationships have not been investigated. To address these questions, we collected samples from 5 normal adult volunteers before and after administering P alone and from another 5 before and after a 4-day course of G and again after a subsequent injection of P. Measurements of their blood content of CD34+ cells, in vitro myeloid colony-forming cells, 3- and 6-week long-term culture (LTC) cell outputs, and levels of circulating human platelets, as well as myeloid and lymphoid cells obtained in immunodeficient mice that received transplants, showed all activities were maximal 4 hours after P preceded by G, and 3-week LTC outputs showed the highest concordance with the 3-week circulating human neutrophil levels obtained in mice that received transplants. Thus, human cells capable of producing neutrophils rapidly in vivo were optimally mobilized by the G + P protocol, and the 3-week LTC assay appears to offer a more specific predictor of their levels than conventional CD34+ cell or colony-forming cell counts.
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Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Movilización de Célula Madre Hematopoyética/métodos , Compuestos Heterocíclicos/administración & dosificación , Animales , Antígenos CD34/sangre , Antígenos CD34/efectos de los fármacos , Bencilaminas , Plaquetas/citología , Plaquetas/efectos de los fármacos , Recuento de Células , Técnicas de Cultivo de Célula , Ciclamas , Xenoinjertos , Humanos , Ratones , Ratones SCID , Neutrófilos/citología , Neutrófilos/efectos de los fármacosRESUMEN
UNLABELLED: Approaches to prevent human immunodeficiency virus (HIV-1) transmission are urgently needed. Difficulties in eliciting antibodies that bind conserved epitopes exposed on the unliganded conformation of the HIV-1 envelope glycoprotein (Env) trimer represent barriers to vaccine development. During HIV-1 entry, binding of the gp120 Env to the initial receptor, CD4, triggers conformational changes in Env that result in the formation and exposure of the highly conserved gp120 site for interaction with the coreceptors, CCR5 and CXCR4. The DMJ compounds (+)-DMJ-I-228 and (+)-DMJ-II-121 bind gp120 within the conserved Phe 43 cavity near the CD4-binding site, block CD4 binding, and inhibit HIV-1 infection. Here we show that the DMJ compounds sensitize primary HIV-1, including transmitted/founder viruses, to neutralization by monoclonal antibodies directed against CD4-induced (CD4i) epitopes and the V3 region, two gp120 elements involved in coreceptor binding. Importantly, the DMJ compounds rendered primary HIV-1 sensitive to neutralization by antisera elicited by immunization of rabbits with HIV-1 gp120 cores engineered to assume the CD4-bound state. Thus, small molecules like the DMJ compounds may be useful as microbicides to inhibit HIV-1 infection directly and to sensitize primary HIV-1 to neutralization by readily elicited antibodies. IMPORTANCE: Preventing HIV-1 transmission is a priority for global health. Eliciting antibodies that can neutralize many different strains of HIV-1 is difficult, creating problems for the development of a vaccine. We found that certain small-molecule compounds can sensitize HIV-1 to particular antibodies. These antibodies can be elicited in rabbits. These results suggest an approach to prevent HIV-1 sexual transmission in which a virus-sensitizing microbicide is combined with a vaccine.
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Vacunas contra el SIDA/inmunología , Antivirales/farmacología , Antígenos CD4/inmunología , Anticuerpos Anti-VIH/inmunología , Proteína gp120 de Envoltorio del VIH/antagonistas & inhibidores , Infecciones por VIH/inmunología , VIH-1/efectos de los fármacos , Vacunas contra el SIDA/administración & dosificación , Animales , Antígenos CD4/genética , Línea Celular , Femenino , Proteína gp120 de Envoltorio del VIH/inmunología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/genética , VIH-1/inmunología , Humanos , Pruebas de Neutralización , ConejosRESUMEN
BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a subtype of primary liver cancer that is rarely curable by surgery and is rapidly increasing in incidence. Relapsed ICC has a poor prognosis, and current systemic nontargeted therapies are commonly extrapolated from those used in other gastrointestinal malignancies. We hypothesized that genomic profiling of clinical ICC samples would identify genomic alterations that are linked to targeted therapies and that could facilitate a personalized approach to therapy. METHODS: DNA sequencing of hybridization-captured libraries was performed for 3,320 exons of 182 cancer-related genes and 36 introns of 14 genes frequently rearranged in cancer. Sample DNA was isolated from 40 µm of 28 formalin-fixed paraffin-embedded ICC specimens and sequenced to high coverage. RESULTS: The most commonly observed alterations were within ARID1A (36%), IDH1/2 (36%), and TP53 (36%) as well as amplification of MCL1 (21%). Twenty cases (71%) harbored at least one potentially actionable alteration, including FGFR2 (14%), KRAS (11%), PTEN (11%), CDKN2A (7%), CDK6 (7%), ERBB3 (7%), MET (7%), NRAS (7%), BRCA1 (4%), BRCA2 (4%), NF1 (4%), PIK3CA (4%), PTCH1 (4%), and TSC1 (4%). Four (14%) of the ICC cases featured novel gene fusions involving the tyrosine kinases FGFR2 and NTRK1 (FGFR2-KIAA1598, FGFR2-BICC1, FGFR2-TACC3, and RABGAP1L-NTRK1). CONCLUSION: Two thirds of patients in this study harbored genomic alterations that are associated with targeted therapies and that have the potential to personalize therapy selection for to individual patients.
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Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/terapia , Colangiocarcinoma/genética , Colangiocarcinoma/terapia , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Análisis de Secuencia de ADN/métodos , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/patología , Colangiocarcinoma/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Pronóstico , Adulto JovenRESUMEN
BACKGROUND: Expression of integrin α3ß1 is associated with tumor progression, metastasis, and poor prognosis in several cancers, including breast cancer. Moreover, preclinical studies have revealed important pro-tumorigenic and pro-metastatic functions for this integrin, including tumor growth, survival, invasion, and paracrine induction of angiogenesis. Our previously published work in a preclinical breast cancer model showed that integrin α3ß1 promotes expression of cyclooxygenase-2 (COX2/PTGS2), a known driver of breast cancer progression. However, the clinical significance of this regulation was unknown. The objective of the current study was to assess the clinical relevance of the relationship between integrin α3ß1 and COX2 by testing for their correlated expression among various forms of human breast cancer. METHODS: Immunohistochemistry was performed to assess co-expression of α3 and COX2 in specimens of human invasive ductal carcinoma (IDC), either on a commercial tissue microarray (n = 59 samples) or obtained from Albany Medical Center archives (n = 68 samples). Immunostaining intensity for the integrin α3 subunit or COX2 was scored, and Spearman's rank correlation coefficient analysis was performed to assess their co-expression across and within different tumor subtypes or clinicopathologic criteria. RESULTS: Although expression of integrin α3 or COX2 varied among clinical IDC samples, a statistically significant, positive correlation was detected between α3 and COX2 in both tissue microarrays (r(s) = 0.49, p < 0.001, n = 59) and archived samples (r(s) = 0.59, p < 0.0001, n = 68). In both sample sets, this correlation was independent of hormone receptor status, histological grade, or disease stage. CONCLUSIONS: COX2 and α3 are correlated in IDC independently of hormone receptor status or other clinicopathologic features, supporting the hypothesis that integrin α3ß1 is a determinant of COX2 expression in human breast cancer. These results support the clinical relevance of α3ß1-dependent COX2 gene expression that we reported previously in breast cancer cells. The findings also suggest that COX2-positive breast carcinomas of various subtypes might be vulnerable to therapeutic strategies that target α3ß1, and that α3 expression might serve as an independent prognostic biomarker.
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Neoplasias de la Mama/metabolismo , Ciclooxigenasa 2/metabolismo , Integrina alfa3beta1/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Ciclooxigenasa 2/genética , Femenino , Expresión Génica , Humanos , Inmunohistoquímica , Integrina alfa3beta1/genética , Clasificación del Tumor , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia , Estadificación de NeoplasiasRESUMEN
BACKGROUND: Adolescents undergo a period of motor incoordination during puberty characterized by high movement variability. It is unknown if differences in running kinematics variability exist among adolescent long-distance runners. RESEARCH QUESTION: Is kinematic variability different among male and female adolescent long-distance runners of different stages of physical maturation? METHODS: We enrolled 114 adolescent long-distance runners (ages 8-19, F = 55, M = 59) in this secondary analysis of a larger cross-sectional study. Participants completed a three-dimensional overground running analysis at a comfortable self-selected speed. Peak frontal, sagittal, and transverse plane hip, knee, and ankle/shoe joint angles from the right leg were identified during stance phase for at least five trials. Variability in running kinematics was quantified as the standard deviation of the peak joint angles among the running trials for each participant. Participants were stratified by sex and stage of physical maturation (pre-, mid-, post-pubertal) and two-way ANOVAs compared between-subjects variability among groups (p ≤ .05). RESULTS: Significant sex by maturation interactions were observed for hip external rotation and ankle external rotation variability. Sex differences were observed for hip internal rotation, with males demonstrating greater variability, and ankle internal rotation, with females demonstrating greater variability. Pre-pubertal runners demonstrated significantly greater variability than mid-pubertal runners for hip flexion, and greater variability than post-pubertal runners for hip flexion, hip adduction, hip internal rotation, and knee flexion. SIGNIFICANCE: Pre-pubertal adolescent long-distance runners demonstrate greater stance phase variability in running kinematics than post-pubertal adolescent long-distance runners, while adolescent males and females demonstrate similar variability. Anthropometric and neuromuscular changes that occur during puberty likely influence running patterns and may contribute to more consistent kinematic patterns for post-pubertal runners.
Asunto(s)
Rodilla , Extremidad Inferior , Adolescente , Humanos , Masculino , Femenino , Fenómenos Biomecánicos , Estudios Transversales , Articulación de la Rodilla , Articulación de la CaderaRESUMEN
BACKGROUND: Patellofemoral pain (PFP) is a prevalent musculoskeletal disorder associated with functional impairments. Although postural control is commonly assessed in people with PFP, there are inconsistent results regarding potential postural control deficits in this population. RESEARCH QUESTION: This review aims to evaluate whether postural control is impaired in people with patellofemoral pain (PFP) and the effectiveness of interventions on postural control measures. METHODS: We searched six databases from their inception to May 5, 2023. We included studies assessing clinic- or laboratory-based postural control measures in people with PFP compared to pain-free controls, and intervention studies with PFP populations. We assessed risk of bias using the Joanna Briggs Institute critical appraisal checklists and the Cochrane Risk of Bias 2 tool. We assessed the certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. We used random-effects meta-analyses considering subgroups based on type of task, measure, and intervention. RESULTS: Fifty-three studies were included. Very low certainty evidence indicated that people with PFP have shorter anterior (SMD = 0.53, 95 %CI:0.16,0.90), posteromedial (SMD = 0.54, 95 %CI:0.04,1.03) and posterolateral (SMD = 0.59, 95 %CI:0.11,1.07) reach distance, and worse composite score (SMD = 0.46, 95 %CI:0.22,0.70). Very low to moderate certainty evidence indicated that people with PFP have worse anterior-posterior and overall stability indexes during single-leg stance (SMD = -0.71, 95 %CI:-1.29,-0.14; SMD = -0.63, 95 %CI:-0.94,-0.32) and overall stability index during double-leg stance (SMD = -0.39, 95 %CI:-0.78,-0.00), but no differences in center of pressure area during stair ascent (SMD = 0.32, 95 %CI:-2.72, 3.36). Low certainty evidence indicated that kinesio taping improved anterior reach distance (SMD = -0.49, 95 %CI:-0.89,-0.09), while no significant differences were observed between pre- and post-intervention outcomes for conventional rehabilitation and rigid taping. SIGNIFICANCE: Clinicians should use clinic- (star excursion or Y-balance tests) and laboratory-based (stability indexes) measures to identify impairments of postural control in people with PFP. Low certainty of evidence suggests short-term improvement in postural control with kinesio taping.
Asunto(s)
Lagunas en las Evidencias , Síndrome de Dolor Patelofemoral , Equilibrio Postural , Humanos , Síndrome de Dolor Patelofemoral/fisiopatología , Equilibrio Postural/fisiologíaRESUMEN
Background/Purpose: Return to sport decision-making may be improved by assessing an athlete's ability to coordinate movement with opponents in sport. The purpose was to investigate whether previous injuries associated with female soccer players' interpersonal coordination during a collision avoidance task. The authors hypothesized that external perturbations would disrupt the strength and stability of coordinated movement, and that individuals with a history of injury would be less likely to recover coordinated movement. Study Design: Cross-Sectional. Methods: Nine female athletes with a history of lower extremity injuries and nine without injuries were paired into dyads. Each dyad completed twenty trials of an externally paced collision-avoidance agility task with an unanticipated perturbation. Participant trajectories were digitized and analyzed using cross-recurrence quantification analysis (CRQA) to determine the strength and stability of interpersonal coordination dynamics. Trials in which participants with injury history assumed leader or follower roles within each dyad were then used to study how dyadic coordination varied across task stages (early, perturbation, and late) using linear mixed effect models. Cohen's d effect sizes were calculated to demonstrate magnitude of differences. In exploratory analysis, psychological readiness (i.e., self-reported knee functioning, fear of injury, and risk-taking propensity) was evaluated for their association with leader-follower status. Results: Perturbation disrupted the strength (R2=0.65, p<0.001, early=49.7±1.7, perturbation=41.1±1.7, d=0.39) and stability (R2=0.71, p < 0.001, early=65.0±1.6, perturbation=58.0±1.7, d=0.38) of interpersonal coordination regardless of leader-follower status. Individuals with injury history failed to restore coordination after the perturbation compared to control participants (injury=44.2.0±2.1, control=50.8±2.6, d=0.39). Neither demographic nor psychological measures were associated with leader-follower roles (B=0.039, p=0.224). Conclusion: Individuals with a history of lower extremity injury may have a diminished ability to adapt interpersonal coordination to perturbations, possibly contributing to a higher risk of re-injury. Level of Evidence: 3.