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The challenge of eradicating leukemia in patients with acute myelogenous leukemia (AML) after initial cytoreduction has motivated modern efforts to combine synergistic active modalities including immunotherapy. Recently, the ETCTN/CTEP 10026 study tested the combination of the DNA methyltransferase inhibitor decitabine together with the immune checkpoint inhibitor ipilimumab for AML/myelodysplastic syndrome (MDS) either after allogeneic hematopoietic stem cell transplantation (HSCT) or in the HSCT-naïve setting. Integrative transcriptome-based analysis of 304 961 individual marrow-infiltrating cells for 18 of 48 subjects treated on study revealed the strong association of response with a high baseline ratio of T to AML cells. Clinical responses were predominantly driven by decitabine-induced cytoreduction. Evidence of immune activation was only apparent after ipilimumab exposure, which altered CD4+ T-cell gene expression, in line with ongoing T-cell differentiation and increased frequency of marrow-infiltrating regulatory T cells. For post-HSCT samples, relapse could be attributed to insufficient clearing of malignant clones in progenitor cell populations. In contrast to AML/MDS bone marrow, the transcriptomes of leukemia cutis samples from patients with durable remission after ipilimumab monotherapy showed evidence of increased infiltration with antigen-experienced resident memory T cells and higher expression of CTLA-4 and FOXP3. Altogether, activity of combined decitabine and ipilimumab is impacted by cellular expression states within the microenvironmental niche of leukemic cells. The inadequate elimination of leukemic progenitors mandates urgent development of novel approaches for targeting these cell populations to generate long-lasting responses. This trial was registered at www.clinicaltrials.gov as #NCT02890329.
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Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Humanos , Ipilimumab/uso terapêutico , Decitabina/uso terapêutico , Síndromes Mielodisplásicas/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , RecidivaRESUMO
OBJECTIVES: Teaching ultrasound imaging is on the rise in undergraduate medical anatomy education. However, there is little research exploring the use of ultrasound in preparatory graduate programs. The purpose of this study is to identify the effects of ultrasound imaging inclusion in a graduate gross anatomy course. METHODS: Master of Medical Sciences students were enrolled in a prosection-based anatomy course that included pinned cadaver stations and an ultrasound station. Using ultrasound, teaching assistants imaged volunteers demonstrating anatomical structures students previously learned at cadaver stations. Students answered one ultrasound image question on each practical exam and were asked to participate in a pre- and post-course survey. Student practical and lecture exam scores and final course grades from the 2022 cohort were compared to a historical control cohort from 2021 via statistical analysis, including a survey administered to the 2022 cohort. RESULTS: Two hundred students from the 2021 cohort and 164 students from the 2022 cohort participated in this study. Students in the 2022 cohort had significantly higher scores in 1 of the 5 practical exams (P < .05, d = .289), and 2 of the 5 written exams (P < .05, d = .207), (P < .05, d = .311). Survey data revealed increased (P < .05, d = 1.203) learning outcome achievement from pre-survey to post-survey in the intervention cohort. Students who correctly answered the ultrasound question performed significantly better on practical's 3 (P < .05) and 4 (P < .05) than those who missed the ultrasound question. CONCLUSIONS: These findings suggest that ultrasound imaging in a cadaver lab is beneficial to graduate students' learning and understanding of gross anatomy.
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Anatomia , Currículo , Avaliação Educacional , Estudantes de Medicina , Ultrassonografia , Humanos , Anatomia/educação , Ultrassonografia/métodos , Estudantes de Medicina/estatística & dados numéricos , Avaliação Educacional/estatística & dados numéricos , Feminino , Masculino , Educação de Pós-Graduação em Medicina/métodos , Estudos de Coortes , Inquéritos e QuestionáriosRESUMO
Grenache wines from the Central Coast of California were subjected to different alcoholic fermentation temperature regimes (Cold, Cold/Hot, Hot) and cap management protocols, namely, punch down (PD), or no punch down (No PD), to determine the effect of these practices on the color, aroma, and the retronasal and mouthfeel sensory characteristics of the resulting wines. Descriptive analysis (n = 8, line scale rating 0-15) results indicated that the combination of a hot fermentation temperature and no punch downs led to a significantly higher intensity in perceived color saturation (7.89) and purple hue (8.62). A two-way analysis of variance (ANOVA) showed that cap management was significantly more impactful on the perception of orthonasal aromas than fermentation temperature. The reduction aroma was significantly higher in No PD wines (5.02) compared to PD wines (3.50), while rose and hot aromas had significantly higher intensity perception for PD wines (5.18, 6.80) than for No PD wines (6.80, 6.14). Conversely, analysis of selected volatile compounds indicated that fermentation temperature was more impactful than cap management regime. Cold/Hot wines had higher concentrations of important esters such as ethyl hexanoate (650 µg/L) and isoamyl acetate (992 µg/L). Cold wines had a higher concentration of ß-damascenone (0.719 µg/L). TCATA evaluation (n = 8) indicated that Cold/Hot PD wines had a significantly higher citation proportion of fruit flavor (1.0) and velvet astringency perception (0.80) without significant reduction flavors. Finally, the present study represents a contribution with the main volatile compounds (e.g., ß-damascenone and esters in the Cold and Cold/Hot fermented wines, respectively; hexanol in PD wines, which may be potentially responsible for a hot mouthfeel), and sensory characteristics (red fruit, tropical fruit, white pepper, and rose) of Grenache wines grown in the Mediterranean climate of the Central Coast of California.
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Vitis , Compostos Orgânicos Voláteis , Vinho , Vinho/análise , Fermentação , Temperatura , Odorantes/análise , Compostos Orgânicos Voláteis/análiseRESUMO
OBJECTIVE: There is a growing need to assess the long-term quality of life (QOL) of pediatric oncology patients since many children now survive their disease. This paper highlights the subjective perspectives of pediatric cancer patients and specifically explores how experiencing cancer at a young age impacts adolescents in the areas of social functioning, peer relationships, and QOL. The findings emerged from a qualitative research study that explored how pediatric oncology patients ascribe meaning to their illness. METHODS: Study participants were recruited from four Canadian academic pediatric hospitals. In this study, we used an interpretative description approach. Semistructured interviews were completed, transcribed verbatim, and coded through the method of constant comparison. RESULTS: A total of 37 children and adolescents (n = 19 female; 51%) participated. The majority of participants were diagnosed with leukemia (n = 16; 43%) or lymphoma (n = 9; 24%). Sixty-two percent of participants were adolescents between the ages of 13 and 18 years (n = 23). Data illustrated a unique adolescent experience, which has been reported as a subset of the original population. Adolescent participants noted an accelerated experience of maturation, which invited reflections of gratitude as well as feelings of isolation and disconnect from peers. Participants were saddened to have "missed out" on normative parts of childhood. CONCLUSION: Findings highlighted experiences of accelerated maturity that prompted adverse social outcomes for adolescent participants, which impacted their QOL. Future research is needed to explore the intersection of accelerated maturity attributed to illness, social functioning, and QOL. Peer support through technology engagement is suggested for this population.
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Adaptação Psicológica , Neoplasias/psicologia , Qualidade de Vida/psicologia , Ajustamento Social , Apoio Social , Adolescente , Canadá , Criança , Feminino , Humanos , Relações Interpessoais , Masculino , Grupo Associado , Pesquisa Qualitativa , Autoimagem , Mudança SocialRESUMO
BACKGROUND: Anonymous living donor transplantation is a potential strategy to address the shortage of available organs for transplant. A living anonymous donor (LAD) is a donor with no biological connection and whose identity is unknown to the recipient. This study captured the lived experiences of pediatric liver transplant recipient families whose child received an organ from a LAD. METHODS: Qualitative data collection and analysis were guided by a theoretical framework of phenomenology. Data analysis highlighted themes through an inductive process of reviewing transcript paragraphs to code for significant statements that represented key concepts and captured depth of experience. RESULTS: A total of nine interviews were conducted with 10 participants. Data analysis yielded themes of emotional turbulence through their transplant journey. Pre-transplant experiences were characterized by feelings of helplessness and desperation. Receiving a LAD transplant prompted shock, relief, and acceptance of the donation. Post-transplant experiences were characterized by altered life-perspectives and varied levels of connectedness to the donor, marked by gratitude and concern for donor well-being. CONCLUSION: Anonymous donation in liver transplantation is perceived by recipient families as a remarkable gift and a viable donor option. Our preliminary findings can be used to inform strategy development regarding future delivery of care.
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Cuidadores/psicologia , Emoções/fisiologia , Transplante de Fígado/psicologia , Doadores Vivos/provisão & distribuição , Pais/psicologia , Doadores não Relacionados/provisão & distribuição , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Pesquisa QualitativaRESUMO
We examined the relationship amongst baseline work rate (WR), phase II pulmonary oxygen uptake (VÌ(O2p)) time constant (τVÌ(O2p)) and functional gain (G(P)=ΔVÌ(O2p)/ΔWR) during moderate-intensity exercise. Transitions were initiated from a constant or variable baseline WR. A validated circulatory model was used to examine the role of heterogeneity in muscle metabolism (VÌ(O2m)) and blood flow (QÌ(m)) in determining VÌ(O2p) kinetics. We hypothesized that τVÌ(O2p) and G(P) would be invariant in the constant baseline condition but would increase linearly with increased baseline WR. Fourteen men completed three to five repetitions of ∆40 W step transitions initiated from 20, 40, 60, 80, 100 and 120 W on a cycle ergometer. The ∆40 W step transitions from 60, 80, 100 and 120 W were preceded by 6 min of 20 W cycling, from which the progressive ΔWR transitions (constant baseline condition) were examined. The VÌ(O2p) was measured breath by breath using mass spectrometry and a volume turbine. For a given ΔWR, both τVÌ(O2p) (22-35 s) and G(P) (8.7-10.5 ml min(-1) W(-1)) increased (P < 0.05) linearly as a function of baseline WR (20-120 W). The τVÌ(O2p) was invariant (P < 0.05) in transitions initiated from 20 W, but G(P) increased with ΔWR (P < 0.05). Modelling the summed influence of multiple muscle compartments revealed that τVÌ(O2p) could appear fast (24 s), and similar to in vivo measurements (22 ± 6 s), despite being derived from τVÌ(O2p) values with a range of 15-40 s and τQÌ(m) with a range of 20-45 s, suggesting that within the moderate-intensity domain phase II VÌ(O2p) kinetics are slowed dependent on the pretransition WR and are strongly influenced by muscle metabolic and circulatory heterogeneity.
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Pulmão/metabolismo , Consumo de Oxigênio/fisiologia , Circulação Pulmonar/fisiologia , Adulto , Algoritmos , Limiar Anaeróbio , Ciclismo/fisiologia , Simulação por Computador , Teste de Esforço , Humanos , Cinética , Medidas de Volume Pulmonar , Masculino , Esforço Físico/fisiologia , Mecânica Respiratória , Adulto JovemRESUMO
Online learning has become an essential part of mainstream higher education. With increasing enrollments in online anatomy courses, a better understanding of effective teaching techniques for the online learning environment is critical. Active learning has previously shown many benefits in face-to-face anatomy courses, including increases in student satisfaction. Currently, no research has measured student satisfaction with active learning techniques implemented in an online graduate anatomy course. This study compares student satisfaction across four different active learning techniques (jigsaw, team-learning module, concept mapping, and question constructing), with consideration of demographics and previous enrollment in anatomy and/or online courses. Survey questions consisted of Likert-style, multiple-choice, ranking, and open-ended questions that asked students to indicate their level of satisfaction with the active learning techniques. One hundred seventy Medical Science master's students completed the online anatomy course and all seven surveys. Results showed that students were significantly more satisfied with question constructing and jigsaw than with concept mapping and team-learning module. Additionally, historically excluded groups (underrepresented racial minorities) were generally more satisfied with active learning than non-minority groups. Age, gender, and previous experience with anatomy did not influence the level of satisfaction. However, students with a higher-grade point average (GPA), those with only a bachelor's degree, and those with no previous online course experience were more satisfied with active learning than students who had a lower GPA, those holding a graduate/professional degree, and those with previous online course experience. Cumulatively, these findings support the beneficial use of active learning in online anatomy courses.
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Anatomia , Estudantes de Medicina , Humanos , Aprendizagem Baseada em Problemas , Anatomia/educação , Satisfação Pessoal , DemografiaRESUMO
Compact visible wavelength achromats are essential for miniaturized and lightweight optics. However, fabrication of such achromats has proved to be exceptionally challenging. Here, using subsurface 3D printing inside mesoporous hosts we densely integrate aligned refractive and diffractive elements, forming thin high performance hybrid achromatic imaging micro-optics. Focusing efficiencies of 51-70% are achieved for 15µm thick, 90µm diameter, 0.3 numerical aperture microlenses. Chromatic focal length errors of less than 3% allow these microlenses to form high-quality images under broadband illumination (400-700 nm). Numerical apertures upwards of 0.47 are also achieved at the cost of some focusing efficiency, demonstrating the flexibility of this approach. Furthermore, larger area images are reconstructed from an array of hybrid achromatic microlenses, laying the groundwork for achromatic light-field imagers and displays. The presented approach precisely combines optical components within 3D space to achieve thin lens systems with high focusing efficiencies, high numerical apertures, and low chromatic focusing errors, providing a pathway towards achromatic micro-optical systems.
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OBJECTIVE: The primary objective was to quantify psychosocial risk in family caregivers (FCs) of children with medical complexity (CMC) during the COVID-19 pandemic using the Psychosocial Assessment Tool (PAT). The secondary objectives were to compare this finding with the average PAT score of this population before the COVID-19 pandemic and to examine potential clinical predictors of psychosocial risk in FCs of CMC. DESIGN: Cross-sectional study. PARTICIPANTS: FCs of CMC were recruited from the Long-Term Ventilation Clinic at The Hospital for Sick Children, Toronto, Ontario, Canada. A total of 91 completed the demographic and PAT questionnaires online from 10 June 2021 through 13 December 2021. MAIN OUTCOME MEASURES: Mean PAT scores in FCs were categorised as 'Universal' low risk, 'Targeted' intermediate risk or 'Clinical' high risk. The effect of sociodemographic and clinical variables on overall PAT scores was assessed using multiple linear regression analysis. Comparisons with a previous study were made using Mann-Whitney tests and χ2 analysis. RESULTS: Mean (SD) PAT score was 1.34 (0.69). Thirty-one (34%) caregivers were classified as Universal, 43 (47%) as Targeted and 17 (19%) as Clinical. The mean PAT score (1.34) was significantly higher compared with the mean PAT score (1.17) found prior to the COVID-19 pandemic. Multiple linear regression analysis demonstrated an overall significant model, with the number of hospital admissions since the onset of COVID-19 being the only variable associated with the overall PAT score. CONCLUSION: FCs of CMC are experiencing significant psychosocial stress during the COVID-19 pandemic. Timely and effective interventions are warranted to ensure these individuals receive the appropriate support.
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COVID-19 , Cuidadores , Criança , Humanos , Cuidadores/psicologia , Estudos Transversais , Pandemias , COVID-19/epidemiologia , Ontário/epidemiologiaRESUMO
INTRODUCTION: Mothers are often the primary caregivers for children requiring heart transplantation. Given that a mother's ability to successfully cope with the demands of her caregiving role may be predictive of positive familial psychosocial outcomes, it is critical that maternal coping is assessed and supported in paediatric healthcare. Mindfulness-based programmes are proposed as one intervention that may enhance quality of life, improve distress tolerance and coping and reduce social isolation in caregiving populations. This pilot study aims to investigate: (1) the implementation success of a mindfulness-based retreat (MBR), and (2) the effectiveness of a MBR at improving quality of life, distress tolerance, coping and perceived social support for mothers of paediatric heart transplant recipients. METHODS AND ANALYSIS: A convergent parallel, mixed-method design is proposed for this pilot, exploratory study. Twenty mothers will participate in this pilot MBR held at a resort in Ontario, Canada. Quantitative data will be obtained using five standardised instruments completed at three time points: (T1) 24-hours prior to the intervention, (T2) immediately on completion of the intervention, and (T3) three months post-intervention. Qualitative data will be collected from all participants both through semi-structured focus groups at T2 and individual telephone interviews at T3. Focus groups and individual interviews will be transcribed verbatim for thematic analysis. Quantitative and qualitative data will be merged and compared during interpretation to ensure that the intervention implementation and effectiveness of the MBR retreat are described with comprehensive accuracy. The primary outcomes will be feasibility in relation to implementation effectiveness and participants' perception of social support for efficacy of the MBR intervention. ETHICS AND DISSEMINATION: This study received Institutional Research Ethics Board approval from The Hospital for Sick Children (Number: 1000064719). Informed consent will be obtained prior to participant enrolment. Findings will be disseminated via conference presentations and submitted for publication in a peer-reviewed journal.
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Transplante de Coração , Atenção Plena , Criança , Feminino , Humanos , Atenção Plena/métodos , Mães/psicologia , Ontário , Projetos Piloto , Qualidade de VidaRESUMO
The pulmonary O2 uptake (VÌo2p) response to ramp-incremental (RI) exercise increases linearly with work rate (WR) after an early exponential phase, implying that a single time constant (τ) and gain (G) describe the response. However, variability in τ and G of VÌo2p kinetics to different step increments in WR is documented. We hypothesized that the "linear" VÌo2p-WR relationship during RI exercise results from the conflation between WR-dependent changes in τ and G. Nine men performed three or four repeats of RI exercise (30 W/min) and two step-incremental protocols consisting of four 60-W increments beginning from 20 W or 50 W. During testing, breath-by-breath VÌo2p was measured by mass spectrometry and volume turbine. For each individual, the VÌo2p RI response was characterized with exponential functions containing either constant or variable τ and G values. A relationship between τ and G vs. WR was determined from the step-incremental protocols to derive the variable model parameters. τ and G increased from 21 ± 5 to 98 ± 20 s and from 8.7 ± 0.6 to 12.0 ± 1.9 ml·min(-1)·W(-1) for WRs of 20-230 W, respectively, and were best described by a second-order (τ) and a first-order (G) polynomial function of WR (lowest Akaike information criterion score). The sum of squared residuals was not different (P > 0.05) when the VÌo2p RI response was characterized with either the constant or variable models, indicating that they described the response equally well. Results suggest that τ and G increase progressively with WR during RI exercise. Importantly, these relationships may conflate to produce a linear VÌo2p-WR response, emphasizing the influence of metabolic heterogeneity in determining the apparent VÌo2p-WR relationship during RI exercise.
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Exercício Físico/fisiologia , Músculo Esquelético/fisiologia , Consumo de Oxigênio/fisiologia , Adulto , Teste de Esforço/métodos , Humanos , Cinética , Pulmão/fisiologia , Masculino , Esforço Físico/fisiologia , Troca Gasosa Pulmonar/fisiologia , RespiraçãoRESUMO
UNLABELLED: Critical power (CP), respiratory compensation point (RCP), maximal lactate steady state (MLSS), and deoxyhemoglobin breakpoint ([HHb]BP) are alternative functional indices that are thought to demarcate the highest exercise intensity that can be tolerated for long durations. PURPOSE: We tested the hypothesis that CP, RCP, MLSS, and [HHb]BP occur at the same metabolic intensity by examining the pulmonary oxygen uptake (VË)O2p and power output (PO) associated with each "threshold." METHODS: Twelve healthy men (mean ± SD age, 27 ± 3 yr) performed the following tests on a cycle ergometer: i) four to five exhaustive tests for determination of CP, ii) two to three 30-min constant-power trials for MLSS determination, and iii) a ramp incremental exercise test from which the VËO2p and PO at RCP and [HHb]BP were determined. During each trial, breath-by-breath VËO2p and ventilatory variables were measured with a metabolic cart and flowmeter turbine; near-infrared spectroscopy-derived [HHb] was monitored using a frequency domain multidistance system, and arterialized capillary blood lactate was sampled at regular intervals. RESULTS: There were no differences (P > 0.05) among the VËO2p values associated with CP, RCP, MLSS, and [HHb]BP (CP, 3.29 ± 0.48; RCP, 3.34 ± 0.45; MLSS, 3.27 ± 0.44; [HHb]BP, 3.41 ± 0.46 L·min(-1)); however, the PO associated with RCP (262 ± 48 W) and [HHb]BP (273 ± 41 W) were greater (P < 0.05) than both CP (226 ± 45 W) and MLSS (223 ± 39 W), which, themselves, were not different (P > 0.05). CONCLUSIONS: Although the standard methods for determination of CP, RCP, MLSS, and [HHb]BP are different, these indices occur at the same VËO2p, suggesting that i) they may manifest as a result of similar physiological phenomenon and ii) each provides a valid delineation between tolerable and intolerable constant-power exercise.
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Exercício Físico/fisiologia , Hemoglobinas/metabolismo , Ácido Láctico/sangue , Resistência Física/fisiologia , Mecânica Respiratória , Adulto , Limiar Anaeróbio/fisiologia , Teste de Esforço , Humanos , Masculino , Adulto JovemRESUMO
Naturally occurring coumarins (NOCs) are anti-carcinogenic in the mouse skin model. To characterize the chemopreventive potential of NOCs against breast cancer, we first examined their effects on 7,12-dimethylbenz[a]anthracene (DMBA)-DNA adduct formation in mouse mammary gland. We hypothesized that those NOCs that both inhibited cytochrome P450 1A1/1B1 and induced hepatic glutathione S-transferases (GSTs) would be the most effective in blocking DMBA-DNA adduct formation in mouse mammary gland. To address this hypothesis, simple coumarins (e.g. coumarin and limettin, which induced mouse hepatic GSTs but had little effect on P4501A1/1B1) and linear furanocoumarins (e.g. imperatorin and isopimpinellin, which induced hepatic GSTs and were potent inhibitors of P4501A1/1B1) were compared. Mice were pretreated with NOCs (150 mg/kg body wt, by gavage) prior to either a single dose of DMBA (50 microg) or multiple doses of DMBA (20 microg daily for 3 and 6 weeks). Mammary DMBA-DNA adduct formation was quantitated by the nuclease P1-enhanced 32P-postlabeling assay. With the single dose of DMBA, coumarin, limettin, imperatorin and isopimpinellin inhibited DMBA-DNA adduct formation by 50, 41, 79 and 88%, respectively. Coumarin, limettin and imperatorin blocked DMBA-DNA adduct formation by 36, 60, and 66% at 3 weeks, and by 0, 49 and 55% at 6 weeks of DMBA dosing, respectively. In a 6 week dose-response study of select NOCs and 7,8-benzoflavone (a potent P4501 inhibitor that had little effect on GSTs), DMBA-DNA adduct formation was inhibited by 0, 43 and 24% in the limettin groups; by 26, 26 and 69% in the isopimpinellin groups; and by 80, 96 and 97% in the 7,8- benzoflavone groups at 35, 70 and 150 mg/kg, respectively. Taken together, these results suggest that linear furanocoumarins had a greater inhibitory effect on DMBA-DNA adduct formation in mouse mammary glands compared with simple coumarins, and that the predominant effect may be P4501 inhibition.