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1.
Blood ; 135(1): 41-55, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31697823

RESUMO

To study the mechanisms of relapse in acute lymphoblastic leukemia (ALL), we performed whole-genome sequencing of 103 diagnosis-relapse-germline trios and ultra-deep sequencing of 208 serial samples in 16 patients. Relapse-specific somatic alterations were enriched in 12 genes (NR3C1, NR3C2, TP53, NT5C2, FPGS, CREBBP, MSH2, MSH6, PMS2, WHSC1, PRPS1, and PRPS2) involved in drug response. Their prevalence was 17% in very early relapse (<9 months from diagnosis), 65% in early relapse (9-36 months), and 32% in late relapse (>36 months) groups. Convergent evolution, in which multiple subclones harbor mutations in the same drug resistance gene, was observed in 6 relapses and confirmed by single-cell sequencing in 1 case. Mathematical modeling and mutational signature analysis indicated that early relapse resistance acquisition was frequently a 2-step process in which a persistent clone survived initial therapy and later acquired bona fide resistance mutations during therapy. In contrast, very early relapses arose from preexisting resistant clone(s). Two novel relapse-specific mutational signatures, one of which was caused by thiopurine treatment based on in vitro drug exposure experiments, were identified in early and late relapses but were absent from 2540 pan-cancer diagnosis samples and 129 non-ALL relapses. The novel signatures were detected in 27% of relapsed ALLs and were responsible for 46% of acquired resistance mutations in NT5C2, PRPS1, NR3C1, and TP53. These results suggest that chemotherapy-induced drug resistance mutations facilitate a subset of pediatric ALL relapses.

2.
World Neurosurg ; 133: e535-e539, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31562974

RESUMO

BACKGROUND: Neurosurgery is a notoriously difficult career to enter and requires medical students to engage in extracurricular activities to demonstrate their commitment to the specialty. The National Undergraduate Neuroanatomy Competition (NUNC) was established in 2013 as a means for students to display this commitment as well as academic ability. METHODS: A bespoke 22-item questionnaire was designed to determine career outcomes and the role of competition attendance in job applications. It was distributed using the SurveyMonkey website to the 87 attendees at the 2013 and 2014 competitions. RESULTS: Responses were received by 40 competitors (response rate, 46.0%). Twenty-four responders (60.0%) intended to pursue a career in either neurosurgery (n = 18) or neurology (n = 6). This included 10 responders (25.0%) who had successfully entered either neurosurgery (n = 9) or neurology (n = 1). The performance of these 10 was significantly better than the other responders (57.0 ± 13.6% vs. 46.5 ± 13.5% [n = 30]; P = 0.036). Seventeen responders (42.5%) either included their attendance at NUNC in a post-Foundation job application or intend to. CONCLUSIONS: The NUNC provides the opportunity for medical students to demonstrate their interest in neurosurgery. It has the potential to be used as a tool for recognizing medical students suitable for neurosurgery training.


Assuntos
Escolha da Profissão , Neurocirurgia , Competência Profissional , Estudantes de Medicina , Distinções e Prêmios , Humanos , Neuroanatomia
3.
Cell Syst ; 8(6): 514-522.e5, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31229560

RESUMO

Longitudinal DNA sequencing of cancer patients yields insight into how tumors evolve over time or in response to treatment. However, sequencing data from bulk tumor samples often have considerable ambiguity in clonal composition, complicating the inference of ancestral relationships between clones. We introduce Cancer Analysis of Longitudinal Data through Evolutionary Reconstruction (CALDER), an algorithm to infer phylogenetic trees from longitudinal bulk DNA sequencing data. CALDER explicitly models a longitudinally observed phylogeny incorporating constraints that longitudinal sampling imposes on phylogeny reconstruction. We show on simulated bulk tumor data that longitudinal constraints substantially reduce ambiguity in phylogeny reconstruction and that CALDER outperforms existing methods that do not leverage this longitudinal information. On real data from two chronic lymphocytic leukemia patients, we find that CALDER reconstructs more plausible and parsimonious phylogenies than existing methods, with CALDER phylogenies containing fewer tumor clones per sample. CALDER's use of longitudinal information will be advantageous in further studies of tumor heterogeneity and evolution.

4.
Clin Neurol Neurosurg ; 177: 106-113, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30640139

RESUMO

OBJECTIVE: Falls from standing are common, particularly amongst the aging population, due to declining mobility, proprioception and vision. They are often complicated by fragility fractures, including vertebral fractures, that are associated with significant morbidity and may represent a pre-terminal condition with high one-year mortality rates. PATIENTS AND METHODS: A retrospective review of the Trauma Audit and Research Network database for a major trauma centre was conducted for all patients admitted between January 2011 and December 2016. Patients with a spinal fracture and a confirmed fall from standing height were eligible for inclusion. Case notes were reviewed for demographics, Injury Severity Score, Charlson co-morbidity score, treatment, complications and outcomes. RESULTS: Of 1408 patients with a spine fracture admitted during the study period, 229 (16.3%) were confirmed to be secondary to a fall from standing height. The average age of this cohort was 76.6 ± 14.5 years and 134 (58.5%) cases were female. The average ISS score was 9.7 ± 5.4. The 229 patients sustained 283 fractures with a distribution of: cervical (n = 140), thoracic (n = 65) and lumbar (n = 78) spine. Fifty-six (24.5%) patients underwent surgical intervention. Forty-three patients (18.7%) died within 6 months of admission and all-cause mortality was significantly higher in patients with increasing age and Charlson co-morbidity score. CONCLUSION: Spinal fractures due to a fall from standing height represent one sixth of the fracture workload of the emergency spinal service at a major trauma centre. Whilst the majority of patients can be managed conservatively there are still considerable implications for hospital bed usage and patient mortality.

5.
Anat Sci Educ ; 12(3): 236-244, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30332529

RESUMO

Within medical education a reduction in curriculum time for subjects, such as anatomy puts pressure on educators to ensure the same learning outcomes are conveyed in less time. This has the potential to impact negatively on student experience. Near-peer teaching (NPT) is often praised as an effective revision tool, but its use as a frontline teaching resource remains unreported. The study explores the potential for NPT to promote delivery of learning outcomes and maximize student experience within a neuroanatomy module for second year medical students. The study occurred in three educational settings, (1) frontline NPT of cranial nerves, (2) revision session NPT of cranial nerves, and (3) NPT alongside faculty staff in laboratory-based neuroanatomy practical exercises. For the first and second components, knowledge was measured using a pre- and post-session test and student perception was ascertained with a questionnaire. For the third component, student perception was assessed with an end-of-module survey. The results show that overall, NPT was well received by learners. A significant knowledge gain was seen between the pre- and post-session test of the frontline NPT session. The study presents evidence in favor of using NPTs to supplement the delivery of learning outcomes in a time and resource constrained curriculum. In particular, for the effective delivery of frontline material. Anat Sci Educ 0: 1-9. © 2018 American Association of Anatomists.


Assuntos
Anatomia/educação , Educação de Graduação em Medicina/organização & administração , Grupo Associado , Estudantes de Medicina/estatística & dados numéricos , Ensino/organização & administração , Estudos Transversais , Currículo/estatística & dados numéricos , Currículo/tendências , Educação de Graduação em Medicina/métodos , Educação de Graduação em Medicina/tendências , Avaliação Educacional , Humanos , Aprendizagem , Avaliação de Programas e Projetos de Saúde , Faculdades de Medicina/organização & administração , Faculdades de Medicina/estatística & dados numéricos , Faculdades de Medicina/tendências , Ensino/tendências
6.
Neuroscientist ; 25(3): 271-280, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30033796

RESUMO

Undergraduates often perceive neuroscience to be a challenging discipline. As the scope of neuroscience continues to expand, it is important to provide undergraduates with sufficient opportunities to develop their knowledge and skills with the aim of encouraging the future generation of basic and clinical neuroscientists. Through our experience of developing the National Undergraduate Neuroanatomy Competition (NUNC), we have accrued an extensive volume of performance data and subjective insight into the delivery of undergraduate neuroanatomy education, which has the potential to inform how to better engage students within this field. More broadly, our group has implemented a technology enhanced learning platform alongside a peer-assisted teaching program. These achieve the dual purpose of compensating for the reduction in dedicated neuroanatomy teaching hours and encouraging undergraduates to develop an interest in the neurosciences. Here, we consider how improving the learning experience at an undergraduate level encourages further engagement in the neurosciences and the importance of this within the wider neuroscience community.


Assuntos
Educação de Graduação em Medicina/métodos , Neuroanatomia/educação , Estudantes , Educação a Distância , Humanos , Ensino/tendências , Reino Unido , Universidades
7.
Elife ; 72018 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-30484770

RESUMO

Rats exhibit 'empathy' making them a model to understand the neural underpinnings of such behavior. We show data consistent with these findings, but also that behavior and dopamine (DA) release reflects subjective rather than objective evaluation of appetitive and aversive events that occur to another. We recorded DA release in two paradigms: one that involved cues predictive of unavoidable shock to the conspecific and another that allowed the rat to refrain from reward when there were harmful consequences to the conspecific. Behavior and DA reflected pro-social interactions in that DA suppression was reduced during cues that predicted shock in the presence of the conspecific and that DA release observed on self-avoidance trials was present when the conspecific was spared. However, DA also increased when the conspecific was shocked instead of the recording rat and DA release during conspecific avoidance trials was lower than when the rat avoided shock for itself.


Assuntos
Comportamento Animal , Dopamina/metabolismo , Comportamento Social , Animais , Eletrochoque , Masculino , Ratos Sprague-Dawley , Recompensa
8.
Acta Neurochir (Wien) ; 160(6): 1115-1119, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29644406

RESUMO

BACKGROUND: The Wessex Modified Richmond Sedation Scale (WMRSS) has been developed with the aim of improving the early identification of patients requiring decompressive hemicraniectomy for malignant middle cerebral artery syndrome (MMS). The objective of this study was to evaluate the WMRSS against the Glasgow Coma Scale (GCS). METHODS: A retrospective study was conducted of patients admitted to our unit for observation of MMS. Data were obtained on WMRSS and GCS recordings from admission up to 120-h post-ictus. Patients' meeting inclusion criteria were recommended for theatre based on subsequent deteriorations in consciousness on either WMRSS or GCS from a 6-h post-stroke baseline, after ruling out non-neurological causes. RESULTS: Approximately, 60% of those eligible for monitoring were not recommended for theatre, and none died; however, these patients continued to demonstrate some variability in recorded conscious level. Patients requiring surgical intervention showed earlier drops in WMRSS compared to GCS. Neither the GCS nor the WMRSS on admission predicted the subsequent need for decompressive surgery. There was no increase in mortality with the introduction of WMRSS. CONCLUSIONS: WMRSS adds value to monitoring MMS by indicating need for surgery prior to GCS. Early reduction in consciousness may not be sufficient for proceeding to surgical intervention, but subsequent reduction in consciousness may be a more appropriate criterion for surgery.


Assuntos
Escala de Coma de Glasgow , Infarto da Artéria Cerebral Média/patologia , Monitorização Fisiológica/métodos , Adulto , Idoso , Estado de Consciência , Descompressão Cirúrgica , Feminino , Humanos , Infarto da Artéria Cerebral Média/cirurgia , Masculino , Pessoa de Meia-Idade
9.
Clin Teach ; 15(5): 403-407, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29573152

RESUMO

BACKGROUND: Near-peer teaching is used in anatomy education because of its benefits to the learner, teacher and faculty members. Despite the range of reports focusing on the learner, the advantages for the teacher, which are thought to include communication skills, subject knowledge and employability, are only beginning to be explored. METHOD: A questionnaire was distributed to the teachers involved in anatomy near-peer teaching at the University of Southampton and Brighton and Sussex Medical School (BSMS). This questionnaire was designed using a rating scale of 0-10 to assess teacher perspectives on their level of knowledge, teaching skills and enjoyment of teaching. Free-text responses determined the teachers' motivation and perceived benefits from the teaching. RESULTS: Twenty-eight questionnaires were gathered (54.9% response rate), including 20 from Southampton and eight from BSMS. Long-term knowledge retention and better understanding of the material were rated 8.1 and 7.9 out of 10, respectively. Eight responses were from currently practising doctors, who rated how much they now use their teaching skills as doctors as 8.9 out of 10. Of the eight doctors, seven gained points for their foundation programme applications as a direct result of near-peer teaching. The most common motivator for engaging in teaching was to improve subject matter knowledge and the most common benefit was improved communication skills. There are numerous advantages to being a near-peer teacher in medical school DISCUSSION: There are numerous advantages to being a near-peer teacher in medical school, which include knowledge improvement, transferrable professional skills and employability. These initial results support the hypothesised benefits to the teachers and provide a foundation for further longitudinal studies.


Assuntos
Educação de Graduação em Medicina/métodos , Grupo Associado , Estudantes de Medicina/psicologia , Ensino/organização & administração , Competência Clínica , Comunicação , Currículo , Humanos , Conhecimento , Motivação , Ensino/normas , Reino Unido
10.
Eur. j. anat ; 22(2): 183-193, mar. 2018. ilus, graf, tab
Artigo em Inglês | IBECS | ID: ibc-172192

RESUMO

Neurological conditions are common so a knowledge of neuroanatomy is necessary for junior doctors. Additionally, some students have a particular interest in neuroscience. However, little time is dedicated to neuroanatomy in the medical curriculum, and many students struggle with neuroanatomy. The National Undergraduate Neuroanatomy Competition (NUNC) aims to support the development of neuroanatomical knowledge among medical students and promote interest in neurosciences. Students who attended the NUNC completed a series of neuroanatomy-based examinations and a questionnaire investigating aspects of neuroanatomy teaching and resources at their home university. 387 students attended the NUNC between 2013 and 2017, of which 382 had a complete data set (response rate 98.7%). Male students significantly outperformed female students (p<0.0001) and clinical students outperformed pre-clinical students (p<0.05). Best answered questions were on the spine (average score 53.9%), and the most poorly answered questions were on the vasculature (average score 44.7%). Students felt that the neuroanatomy teaching, time spent on neuroanatomy and dissection/prosection resources were all reasonable (6-7/10) at their home institution. Elearning resources were rated more poorly (5.4/10). We conclude that the NUNC gives students the opportunity to enhance their neuroanatomical knowledge and gives keen students the chance to develop their interest


No disponible


Assuntos
Humanos , Masculino , Feminino , Neuroanatomia/educação , Neuroanatomia , Educação Médica/métodos , Neuroanatomia/organização & administração , Neuroanatomia/normas , Estudantes de Medicina/estatística & dados numéricos , Inquéritos e Questionários
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