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The use of taboo words represents one of the most common and arguably universal linguistic behaviors, fulfilling a wide range of psychological and social functions. However, in the scientific literature, taboo language is poorly characterized, and how it is realized in different languages and populations remains largely unexplored. Here we provide a database of taboo words, collected from different linguistic communities (Study 1, N = 1046), along with their speaker-centered semantic characterization (Study 2, N = 455 for each of six rating dimensions), covering 13 languages and 17 countries from all five permanently inhabited continents. Our results show that, in all languages, taboo words are mainly characterized by extremely low valence and high arousal, and very low written frequency. However, a significant amount of cross-country variability in words' tabooness and offensiveness proves the importance of community-specific sociocultural knowledge in the study of taboo language.
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Lenguaje , Tabú , Humanos , Semántica , Comparación TransculturalRESUMEN
BACKGROUND: In 2020, at the onset of the COVID-19 pandemic, the United States experienced surges in healthcare needs, which challenged capacity throughout the healthcare system. Stay-at-home orders in many jurisdictions, cancellation of elective procedures, and closures of outpatient medical offices disrupted patient access to care. To inform symptomatic persons about when to seek care and potentially help alleviate the burden on the healthcare system, Centers for Disease Control and Prevention (CDC) and partners developed the CDC Coronavirus Self-Checker ("Self-Checker"). This interactive tool assists individuals seeking information about COVID-19 to determine the appropriate level of care by asking demographic, clinical, and nonclinical questions during an online "conversation." OBJECTIVE: This paper describes user characteristics, trends in use, and recommendations delivered by the Self-Checker between March 23, 2020, and April 19, 2021, for pursuing appropriate levels of medical care depending on the severity of user symptoms. METHODS: User characteristics and trends in completed conversations that resulted in a care message were analyzed. Care messages delivered by the Self-Checker were manually classified into three overarching conversation themes: (1) seek care immediately; (2) take no action, or stay home and self-monitor; and (3) conversation redirected. Trends in 7-day averages of conversations and COVID-19 cases were examined with development and marketing milestones that potentially impacted Self-Checker user engagement. RESULTS: Among 16,718,667 completed conversations, the Self-Checker delivered recommendations for 69.27% (n=11,580,738) of all conversations to "take no action, or stay home and self-monitor"; 28.8% (n=4,822,138) of conversations to "seek care immediately"; and 1.89% (n=315,791) of conversations were redirected to other resources without providing any care advice. Among 6.8 million conversations initiated for self-reported sick individuals without life-threatening symptoms, 59.21% resulted in a recommendation to "take no action, or stay home and self-monitor." Nearly all individuals (99.8%) who were not sick were also advised to "take no action, or stay home and self-monitor." CONCLUSIONS: The majority of Self-Checker conversations resulted in advice to take no action, or stay home and self-monitor. This guidance may have reduced patient volume on the medical system; however, future studies evaluating patients' satisfaction, intention to follow the care advice received, course of action, and care modality pursued could clarify the impact of the Self-Checker and similar tools during future public health emergencies.
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COVID-19 , Humanos , Estados Unidos , Pandemias , Comunicación , Satisfacción del Paciente , Centers for Disease Control and Prevention, U.S.RESUMEN
BACKGROUND: To retrospectively assess liver tumor ablation margins using intraprocedural PET/CT images from FDG PET/CT-guided microwave or cryoablation procedures and to correlate minimum margin measurements with local progression outcomes. METHODS: Fifty-six patients (ages 36 to 85, median 62; 32 females) with 77 FDG-avid liver tumors underwent 60 FDG PET/CT guided, percutaneous microwave, or cryoablation procedures. Single breath-hold PET/CT images were used for intraprocedural assessment of the tumor ablation margin: liver tumors remained visible on PET immediately following ablation; microwave ablation zones were visible using contrast-enhanced CT; cryoablation zones (ice balls) were visible using unenhanced CT. Two readers retrospectively determined ablation margin assessability and measured the minimum ablation margin on intraprocedural PET/CT (n = 77) and postprocedural MRI (n = 56). Local tumor progression was assessed on all available follow-up imaging (1-49 months, mean 15). Local tumor progression was correlated with PET/CT minimum margin measurements using clustered survival models for 61 tumors. RESULTS: Minimum ablation margins were more often assessable using intraprocedural PET/CT (≥ 73/77 tumors, 95%) than postprocedural MRI (≤ 35/56 tumors, 63%). In 61 tumors with PET/CT-assessable margins (excluding tumors with overlapping ablations after PET/CT), there was a 6-fold increased risk of local tumor progression [hazard ratio (HR) 6.05; P = 0.004] for minimum ablation margins < 5 mm. CONCLUSION: Breath-hold PET/CT scans, during PET/CT-guided microwave or cryoablation procedures for FDG-avid liver tumors, enable reliable intraprocedural assessment of the entire tumor ablation margin; a minimum PET/CT ablation margin threshold of 5 mm correlates well with local tumor progression outcomes.
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Neoplasias Hepáticas , Tomografía Computarizada por Tomografía de Emisión de Positrones , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Fluorodesoxiglucosa F18 , Humanos , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/cirugía , Persona de Mediana Edad , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
Mutations that deregulate Notch1 and Ras/phosphoinositide 3 kinase (PI3K)/Akt signalling are prevalent in T-cell acute lymphoblastic leukaemia (T-ALL), and often coexist. Here we show that the PI3K inhibitor GDC-0941 is active against primary T-ALLs from wild-type and Kras(G12D) mice, and addition of the MEK inhibitor PD0325901 increases its efficacy. Mice invariably relapsed after treatment with drug-resistant clones, most of which unexpectedly had reduced levels of activated Notch1 protein, downregulated many Notch1 target genes, and exhibited cross-resistance to γ-secretase inhibitors. Multiple resistant primary T-ALLs that emerged in vivo did not contain somatic Notch1 mutations present in the parental leukaemia. Importantly, resistant clones upregulated PI3K signalling. Consistent with these data, inhibiting Notch1 activated the PI3K pathway, providing a likely mechanism for selection against oncogenic Notch1 signalling. These studies validate PI3K as a therapeutic target in T-ALL and raise the unexpected possibility that dual inhibition of PI3K and Notch1 signalling could promote drug resistance in T-ALL.
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Resistencia a Antineoplásicos , Indazoles/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Inhibidores de Proteínas Quinasas/farmacología , Receptor Notch1/metabolismo , Sulfonamidas/farmacología , Animales , Benzamidas/farmacología , Benzamidas/uso terapéutico , Células Clonales/efectos de los fármacos , Células Clonales/metabolismo , Células Clonales/patología , Difenilamina/análogos & derivados , Difenilamina/farmacología , Difenilamina/uso terapéutico , Regulación hacia Abajo/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Sinergismo Farmacológico , Genes ras/genética , Indazoles/uso terapéutico , Masculino , Ratones , Ratones Endogámicos C57BL , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor Notch1/química , Receptor Notch1/deficiencia , Receptor Notch1/genética , Transducción de Señal/efectos de los fármacos , Sulfonamidas/uso terapéuticoRESUMEN
OBJECTIVE. The purpose of this study was to evaluate the technologist productivity and accuracy in assigning protocols for abdominal CT and MRI examinations compared with a standard work flow whereby protocols are assigned by physicians. MATERIALS AND METHODS. In this quality improvement project at a large academic medical center, two CT technologists and two MRI technologists assigned protocols for examinations during a 15-week study period. The primary outcome measure was mean number of protocols assigned by technologists per hour. Secondary outcome measures were proportion of examinations with protocols assigned by technologists and rate of filing of quality assurance reports for protocols completed by technologists. A two-tailed t test was used to compare mean number of protocols; a chi-square test was used to compare proportions between CT and MRI. RESULTS. The mean number of protocols assigned by technologists per hour was not different between CT and MRI (CT, 22/h; MRI, 19/h; p = 0.28). CT and MRI technologist protocols accounted for 1650 of 4867 (33.9%) CT examinations (range, 23-275 per week) and 569 of 2388 (23.8%) MRI examinations (range, 0-95 per week) (p < 0.001). Radiologist quality assurance reports on inaccurate protocols were rare: three for CT (3/1650 [0.18%]), five for MRI (5/569 [0.88%]) (p = 0.017). A retrospective review of randomly selected CT and MRI protocols revealed no errors (80/80 correct). No patients were called back for repeat imaging due to protocol error. CONCLUSION. Technologists can efficiently and accurately assign protocols for abdominal CT and MRI examinations at an academic medical center, leading to increased radiologist time spent on other value-added activities.
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Eficiencia , Imagen por Resonancia Magnética , Radiografía Abdominal , Radiólogos/estadística & datos numéricos , Tecnología Radiológica , Tomografía Computarizada por Rayos X , Carga de Trabajo/estadística & datos numéricos , Centros Médicos Académicos , Competencia Clínica , Femenino , Humanos , Masculino , Mejoramiento de la Calidad , Estudios RetrospectivosRESUMEN
OBJECTIVE: The purpose of this study is to determine both the frequency of repeat CT performed within 1 month after a patient visits the emergency department (ED) and undergoes CT evaluation for abdominal pain and the frequency of worsened or new CT-based diagnoses. SUBJECTS AND METHODS: Secondary analysis was performed on data collected during a prospective multicenter study. The parent study included patients who underwent CT in the ED for abdominal pain between 2012 and 2014, and these patients constituted the study group of the present analysis. The proportion of patients who underwent (in any setting) repeat abdominal CT within 1 month of the index CT examination was calculated. For each of these patients, results of the index and repeat CT scans were compared by an independent panel and categorized as follows: no change (group 1); same process, improved (group 2); same process, worse (group 3); or different process (group 4). The proportion of patients in groups 1 and 2 versus groups 3 and 4 was calculated, and patient and ED physician characteristics were compared. RESULTS: The parent study included 544 patients (246 of whom were men [45%]; mean patient age, 49.4 years). Of those 544 patients, 53 (10%; 95% CI, 7.5-13%) underwent repeat abdominal CT. Patients' CT comparisons were categorized as follows: group 1 for 43% of patients (23/53), group 2 for 26% (14/53), group 3 for 15% (8/53), and group 4 for 15% (8/53). New or worse findings were present in 30% of patients (16/53) (95% CI, 19-44%). When patients with findings in groups 1 and 2 were compared to patients with findings in groups 3 and 4, no significant difference was noted in patient age (p = 0.25) or sex (p = 0.76), the number of days between scans (p = 0.98), and the diagnostic confidence of the ED physician after the index CT scan was obtained (p = 0.33). CONCLUSION: Short-term, repeat abdominal CT was performed for 10% of patients who underwent CT in the ED for abdominal pain, and it yielded new or worse findings for 30% of those patients.
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Dolor Abdominal/diagnóstico por imagen , Tomografía Computarizada por Rayos X/estadística & datos numéricos , Progresión de la Enfermedad , Urgencias Médicas , Servicio de Urgencia en Hospital , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Estudios Prospectivos , Factores de Tiempo , Tomografía Computarizada por Rayos X/métodosAsunto(s)
COVID-19 , Trasplante de Órganos , Obtención de Tejidos y Órganos , Adulto , Anciano , Humanos , Masculino , SARS-CoV-2 , Donantes de TejidosRESUMEN
Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. Limited treatment options have only marginally impacted patient survival over the past decades. The phophatidylinositol 3-kinase (PI3K) pathway, frequently altered in GBM, represents a potential target for the treatment of this glioma. 5-(6,6-Dimethyl-4-morpholino-8,9-dihydro-6H-[1,4]oxazino[4,3-e]purin-2-yl)pyrimidin-2-amine (GDC-0084) is a PI3K inhibitor that was specifically optimized to cross the blood-brain barrier. The goals of our studies were to characterize the brain distribution, pharmacodynamic (PD) effect, and efficacy of GDC-0084 in orthotopic xenograft models of GBM. GDC-0084 was tested in vitro to assess its sensitivity to the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) and in vivo in mice to evaluate its effects on the PI3K pathway in intact brain. Mice bearing U87 or GS2 intracranial tumors were treated with GDC-0084 to assess its brain distribution by matrix-assisted laser desorption ionization (MALDI) imaging and measure its PD effects and efficacy in GBM orthotopic models. Studies in transfected cells indicated that GDC-0084 was not a substrate of P-gp or BCRP. GDC-0084 markedly inhibited the PI3K pathway in mouse brain, causing up to 90% suppression of the pAkt signal. MALDI imaging showed GDC-0084 distributed evenly in brain and intracranial U87 and GS2 tumors. GDC-0084 achieved significant tumor growth inhibition of 70% and 40% against the U87 and GS2 orthotopic models, respectively. GDC-0084 distribution throughout the brain and intracranial tumors led to potent inhibition of the PI3K pathway. Its efficacy in orthotopic models of GBM suggests that it could be effective in the treatment of GBM. GDC-0084 is currently in phase I clinical trials.
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Neoplasias Encefálicas/metabolismo , Encéfalo/metabolismo , Glioblastoma/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Animales , Barrera Hematoencefálica/metabolismo , Encéfalo/efectos de los fármacos , Neoplasias Encefálicas/tratamiento farmacológico , Línea Celular , Línea Celular Tumoral , Perros , Femenino , Glioblastoma/tratamiento farmacológico , Glioma/tratamiento farmacológico , Glioma/metabolismo , Humanos , Indazoles/metabolismo , Indazoles/farmacología , Células de Riñón Canino Madin Darby , Ratones , Ratones Desnudos , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
BACKGROUND: To date, there has been no investigation of dissemination outcomes for cognitive-behavioral training programs for body-focused repetitive behaviors (BFRBs). METHODS: Sixty-three past participants of the Trichotillomania Learning Center (TLC) intensive professional training institutes completed an online survey assessing referral sources, skills utilization, and treatment outcomes before and after training. The intensive training focused on the treatment of trichotillomania (hair-pulling) disorder and excoriation (skin-picking) disorder using in-person or videotaped didactics, role playing, and case presentations with supervision upon request. RESULTS: Participants endorsed a greater number of referral sources and BFRB patients after attending training. Paired t tests indicated significant pre- to post-training increases in self-reported utilization of all individual cognitive-behavioral therapy (CBT) skills as well as overall mean skills usage (both P<.001). Changes after training in the reported percent of abstinent patients and mean reduction in symptom severity were also noted. CONCLUSIONS: The TLC intensive professional training institutes may be useful for disseminating CBT skills for the treatment of BFRBs, but additional research is warranted.
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Terapia Cognitivo-Conductual/métodos , Difusión de la Información , Conducta Autodestructiva/terapia , Piel/lesiones , Tricotilomanía/terapia , Humanos , Capacitación en ServicioRESUMEN
PURPOSE: MRI is the preferred imaging modality for primary staging of rectal cancer, used to guide treatment. Patients identified with clinical stage I disease receive upfront surgical resection; those with clinical stage II or greater undergo upfront neoadjuvant therapy. Although clinical under-/over-staging may have consequences for patients and presents opportunities for organ preservation, the correlation between clinical and pathologic staging in routine clinical practice within a single institute has not been fully established. METHODS: This retrospective, Institutional Review Board-approved study, conducted at a National Cancer Institute-Designated Comprehensive Cancer Center with a multi-disciplinary rectal cancer disease center, included patients undergoing rectal MRI for primary staging January 1, 2018-August 30, 2020. Data collection included patient demographics, initial clinical stage via MRI report, pathologic diagnosis, pathologic stage, and treatment. The primary outcome was concordance of overall clinical and pathologic staging. Secondary outcomes included reasons for mismatched staging. RESULTS: A total 105 rectal adenocarcinoma patients (64 males, mean age 57 ± 12.7 years) had staging MRI followed by surgical resection. A total of 28 patients (27%) had mismatched under-/over- staging. Ten patients (10%) were understaged with mismatched T stage group (clinical stage I, pathologic stage II), five (5%) were understaged with mismatched N stage group (clinical stage I, pathologic stage III), and 13 (12%) were overstaged (clinical stage II-III, pathologic stage 0-I). Treatment matched concordance between clinical and pathologic stages was 86%. CONCLUSION: MRI for primary rectal cancer staging has high concordance with pathology. Future studies to assess strategies for reducing clinically relevant understaging would be beneficial.
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Neoplasias del Recto , Masculino , Humanos , Adulto , Persona de Mediana Edad , Anciano , Estudios Retrospectivos , Neoplasias del Recto/diagnóstico por imagen , Neoplasias del Recto/terapia , Neoplasias del Recto/patología , Recto/diagnóstico por imagen , Terapia Neoadyuvante , Estadificación de Neoplasias , Imagen por Resonancia Magnética/métodosRESUMEN
RATIONALE AND OBJECTIVES: Professional development is important to academic radiologists. We developed, implemented, and assessed an internal professional development lecture series focusing on the non-interpretative themes of Quality, Research, Education, and Wellness (QREW). MATERIALS AND METHODS: The faculty of a 29-member abdominal radiology division at an academic hospital were invited to deliver 1-hour virtual lectures on noninterpretative topics to division colleagues. Topics were curated by division leadership based on the perceived needs of faculty. Anonymous feedback was collected from attendees for quality improvement purposes and analyzed using descriptive statistics and Fisher's exact test. RESULTS: Over 17 months, 13 QREW lectures were delivered. In total, 91 feedback forms were completed by faculty (mean 7 forms, range 2-12 per session). Of these, 57 responses (63%) were by those <7 years post training ("junior faculty"), 34 responses (37%) by those ≥ 7 years from training ("senior faculty"). Most respondents reported low levels of prior instruction (80/90, 89%) and personal knowledge (49/91, 54%) on topics. Compared to senior faculty, a greater proportion of junior faculty reported less prior instruction (73% vs 98%, P < 0.001) and less personal knowledge (32% vs 65%, P < 0.01). Most respondents agreed or strongly agreed that the topics were important to their clinical practice (87/90, 97%), professional development (86/90, 96%), and personal well-being (82/91, 90%). Faculty identified the QREW program as a major contributor to their professional development. CONCLUSION: A noninterpretative professional development lecture series delivered by radiology faculty in a virtual, interactive format is feasible and effective, particularly for junior faculty.
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Docentes , Radiología , Humanos , Escolaridad , Radiólogos , Promoción de la SaludRESUMEN
The advancement of a series of ligand efficient 2-amino-[1,2,4]triazolo[1,5-a]pyridines, initially identified from high-throughput screening, to a JAK2 inhibitor with pharmacodynamic activity in a mouse xenograft model is disclosed.
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Amitrol (Herbicida)/química , Amitrol (Herbicida)/uso terapéutico , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Janus Quinasa 2/antagonistas & inhibidores , Pirimidinas/química , Pirimidinas/uso terapéutico , Triazoles/química , Triazoles/uso terapéutico , Amitrol (Herbicida)/farmacología , Animales , Antineoplásicos/farmacología , Cristalografía por Rayos X , Humanos , Janus Quinasa 2/química , Janus Quinasa 2/metabolismo , Ratones , Modelos Moleculares , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Neoplasias/patología , Pirimidinas/farmacología , Relación Estructura-Actividad , Triazoles/farmacologíaRESUMEN
A series of suitable five-membered heterocyclic alternatives to thiophenes within a thienobenzoxepin class of PI3-kinase (PI3K) inhibitors was discovered. Specific thiazolobenzoxepin 8-substitution was identified that increased selectivity over PI3Kß. PI3Kß-sparing compound 27 (PI3Kß Ki,app/PI3Kα Ki,app=57) demonstrated dose-dependent knockdown of pAKT, pPRAS40 and pS6RP in vivo as well as differential effects in an in vitro proliferation cell line screen compared to pan PI3K inhibitor GDC-0941. A new structure-based hypothesis for reducing inhibition of the PI3K ß isoform while maintaining activity against α, δ and γ isoforms is presented.
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Benzoxepinas/química , Inhibidores Enzimáticos/química , Inhibidores de las Quinasa Fosfoinosítidos-3 , Tiazoles/química , Benzoxepinas/síntesis química , Benzoxepinas/farmacología , Sitios de Unión , Proliferación Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Células MCF-7 , Simulación del Acoplamiento Molecular , Fosfatidilinositol 3-Quinasa/metabolismo , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas c-akt/metabolismo , Relación Estructura-ActividadRESUMEN
PURPOSE: The aim of this study was to assess MRI-targeted, systematic, or combined prostate biopsy for diagnosing prostate cancer to identify opportunities for diagnostic accuracy improvement. METHODS: This institutional review board-approved, retrospective study, performed at a large, quaternary hospital, included all men undergoing prostate multiparametric MRI (mpMRI) from January 1, 2015, to December 31, 2019, with prostate-specific antigen ≥ 4 ng/mL, biopsy target on mpMRI (Prostate Imaging Reporting and Data System [PI-RADS] 3-5 lesion), and combined targeted and systematic biopsy ≤6 months after MRI. Analysis included the highest grade lesion per patient. The primary outcome was prostate cancer diagnosis by grade group (GG; 1, 2, and ≥3). Secondary outcomes were rates of cancer upgrading by biopsy type and cancer proximity to the targeted biopsy site in patients upgraded by systematic biopsy. RESULTS: Two hundred sixty-seven biopsies (267 patients) were included; 94.4% (252 of 267) were biopsy naive. The most suspicious mpMRI lesion was PI-RADS 3 in 18.7% (50 of 267), PI-RADS 4 in 52.4% (140 of 267), and PI-RADS 5 in 28.8% (77 of 267). Prostate cancer was diagnosed in 68.5% (183 of 267): 22.1% (59 of 267) GG 1, 16.1% (43 of 267) GG 2, and 30.3% (81 of 267) GG ≥ 3. Combined biopsy (124 of 267) yielded more GG ≥ 2 prostate cancer diagnoses than systematic (87 of 267) or targeted (110 of 267) biopsy alone. More GG ≥ 2 cancers were upgraded by targeted biopsy than by systematic biopsy (P = .0062). Systematic biopsy upgrades were in close proximity to the targeted biopsy site in 42.1% (24 of 57); GG ≥ 3 cancers 62.5% (15 of 24) constituted most proximal misses. CONCLUSIONS: In men with prostate-specific antigen ≥ 4 ng/mL and PI-RADS 3, 4, or 5 lesion on mpMRI, combined biopsy led to more prostate cancer diagnoses than targeted or systematic biopsy alone. Cancers upgraded by systematic biopsy proximal and distant from the targeted biopsy site may indicate opportunities for biopsy and mpMRI improvement, respectively.
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Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patología , Imagen por Resonancia Magnética/métodos , Antígeno Prostático Específico , Estudios Retrospectivos , Biopsia Guiada por Imagen/métodos , BiopsiaRESUMEN
PURPOSE: With the United States Medical Licensing Examination Step 1 transition to pass/fail in 2022, uncertainty exists regarding how other residency application components, including research conducted during medical school, will inform interview and ranking decisions. The authors explore program director (PD) views on medical student research, the importance of disseminating that work, and the translatable skill set of research participation. METHOD: Surveys were distributed to all U.S. residency PDs and remained open from August to November 2021 to query the importance of research participation in assessing applicants, whether certain types of research were more valued, productivity measures that reflect meaningful research participation, and traits for which research serves as a proxy. The survey also queried whether research would be more important without a numeric Step 1 score and the importance of research vs other application components. RESULTS: A total of 885 responses from 393 institutions were received. Ten PDs indicated that research is not considered when reviewing applicants, leaving 875 responses for analysis. Among 873 PDs (2 nonrespondents), 358 (41.0%) replied that meaningful research participation will be more important in offering interviews. A total of 164 of 304 most competitive specialties (53.9%) reported increased research importance compared with 99 of 282 competitive (35.1%) and 95 of 287 least competitive (33.1%) specialties. PDs reported that meaningful research participation demonstrated intellectual curiosity (545 [62.3%]), critical and analytical thinking skills (482 [55.1%]), and self-directed learning skills (455 [52.0%]). PDs from the most competitive specialties were significantly more likely to indicate that they value basic science research vs PDs from the least competitive specialties. CONCLUSIONS: This study demonstrates how PDs value research in their review of applicants, what they perceive research represents in an applicant, and how these views are shifting as the Step 1 exam transitions to pass/fail.
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Internado y Residencia , Medicina , Humanos , Estados Unidos , Facultades de Medicina , Concesión de Licencias , Encuestas y CuestionariosRESUMEN
(S)-1-{4-[2-(2-Amino-pyrimidin-5-yl)-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-piperazin-1-yl}-2-hydroxy-propan-1-one (GDC-0980) is a potent and selective inhibitor of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin, two key components of the PI3K pathway, the deregulation of which is associated with the development of many cancers. The objectives of these studies were to characterize the absorption and disposition of GDC-0980 and assess its efficacy in an MCF7-neo/HER2 human breast cancer xenograft model in immunocompromised mice. Studies in parental Madin-Darby canine kidney cells indicated that GDC-0980 had high permeability (P(app) = 18 × 10â»6 cm/s), suggesting good absorption potential. However, it was found to be a P-glycoprotein and breast cancer resistance protein substrate in transfected cells and in knockout mice studies. Plasma protein binding was low, with the fraction unbound ranging from 29 to 52% across species. GDC-0980 hepatic clearance (CL) was predicted to be low in all of the species tested from hepatocyte incubations. The plasma CL of GDC-0980 was low in mouse (6.30 ml · min⻹ · kg⻹), rat (15.4 ml · min⻹ · kg⻹), and dog (6.37 ml · min⻹ · kg⻹) and moderate in cynomolgus monkey (18.9 ml · min⻹ · kg⻹). Oral bioavailability ranged from 14.4% in monkey to 125% in dog. Predicted human plasma CL and volume of distribution using allometry were 5.1 ml · min⻹ · kg⻹ and 1.8 l/kg, respectively. Parameters estimated from the pharmacokinetic/pharmacodynamic modeling of the MCF7-neo/HER2 xenograft data indicated that the GDC-0980 plasma concentration required for tumor stasis was approximately 0.5 µM. These parameters, combined with the predicted human pharmacokinetic profile, suggested that 55 mg once daily may be a clinically efficacious dose. GDC-0980 preclinical characterization and the predictions of its human properties supported its clinical development; it is currently in Phase II clinical trials.
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Antineoplásicos/farmacocinética , Neoplasias de la Mama/tratamiento farmacológico , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Absorción Intestinal , Modelos Biológicos , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacocinética , Pirimidinas/farmacocinética , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/deficiencia , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Transportadoras de Casetes de Unión a ATP/deficiencia , Transportadoras de Casetes de Unión a ATP/genética , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/sangre , Área Bajo la Curva , Disponibilidad Biológica , Biotransformación , Encéfalo/metabolismo , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/sangre , Permeabilidad de la Membrana Celular , Perros , Cálculo de Dosificación de Drogas , Femenino , Semivida , Hepatocitos/metabolismo , Humanos , Inyecciones Intravenosas , Hígado/metabolismo , Células MCF-7 , Macaca fascicularis , Células de Riñón Canino Madin Darby , Masculino , Tasa de Depuración Metabólica , Ratones , Ratones Noqueados , Fosfatidilinositol 3-Quinasa/metabolismo , Unión Proteica , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/sangre , Pirimidinas/administración & dosificación , Pirimidinas/sangre , Ratas , Ratas Sprague-Dawley , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Especificidad de la Especie , Serina-Treonina Quinasas TOR/metabolismo , Distribución Tisular , Transfección , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
STUDY OBJECTIVE: Erector spinae plane (ESP) blocks have been recently described for postoperative pain management following spine surgery but their effects on intraoperative neuromonitoring are unknown. DESIGN: Retrospective cohort study. SETTING: Pediatric patients at a tertiary care center. PATIENTS: 26 pediatric patients who received bilateral surgically-placed ESP catheters for single-stage posterior spine fusion (PSF) from August 2020 to June 2021. INTERVENTIONS: Patients in this study did not receive any special interventions as part of this observational retrospective study. MEASUREMENTS: This retrospective study investigated the effects of local anesthesia administration through bilateral surgically-placed ESP catheters on intraoperative intercostal transcranial motor evoked potentials (tcMEPs) in the setting of a disrupted erector spinae fascial plane in pediatric patients undergoing single-stage posterior spine fusion. MAIN RESULTS: Of the 26 patients that received bilateral surgically-placed ESP catheters for pediatric posterior spine fusion surgery, none exhibited any changes in intercostal tcMEPs attributable to intraoperative lidocaine administration through the ESP catheters. CONCLUSIONS: The administration of a local anesthetic into a disrupted erector spinae fascial plane does not appear to interfere with intraoperative neuromonitoring of posterior spine fusion surgeries.
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Bloqueo Nervioso , Niño , Potenciales Evocados Motores , Humanos , Lidocaína , Dolor Postoperatorio , Estudios RetrospectivosRESUMEN
RATIONALE: Substantial organizational changes, increasing clinical volumes, and the COVID-19 pandemic presented compound stressors to faculty radiologists in our large academic abdominal radiology division and necessitated multiple changes in our practice. METHODS: To address the challenges and establish group consensus, we conducted a virtual divisional faculty retreat centered on themes of team building, clinical work, trainee education, and faculty mentorship. A pre-retreat survey evaluated satisfaction with aspects of professional life and clinical work practices and invited personal reflections. Survey data were presented in the retreat segments focused on each theme, and subsequent discussion was facilitated in small group breakouts. RESULTS: Responses to the team-building survey revealed common values and sources of gratitude, including health, family and meaningful work and relationships. Faculty reported a strong sense of personal accomplishment, but with varied emotional exhaustion scores. Faculty were satisfied with remote work assignments but identified opportunities to improve the clinical work schedule including reversion of some remote assignments to in-person and increased interventional radiology shift staggering. Compared to pre-COVID practice, faculty respondents perceived giving lower quality and less frequent feedback to trainees; evolving educational resource needs were identified. A more formal approach to faculty mentoring was sought. A post-retreat survey revealed high participant satisfaction. OUTCOMES: In the future, we plan to continue divisional retreat activities to respond to evolving challenges and further improve team building, clinical workflow, trainee education, and faculty mentorship.