Clinical undergraduate training and assessment in primary health care: Experiences gained from Crete, Greece

BACKGROUND: Primary Health Care (PHC) is increasingly being introduced into undergraduate medical education. In Greece, the Faculty of Medicine of the University of Crete was the first to introduce a 4-week long training in primary health care. This paper presents the experiences gained from the initial implementation of the teaching of practice-based primary care in rural Crete and reports on the assessment scale that was developed. METHODS: 284 students' case write-ups from the 6 primary care units (PCUs) where they were allocated for the period 1990 to 1994 were analysed. The demographic data of the students and patients and the number of home visits were studied. Content analysis of the students' write-ups was carried out, using an assessment scale consisting of 10 dichotomous variables, in order to quantify eight (8) primary qualitative criteria. RESULTS: Internal reliability was estimated by the index KR20 = 0.67. Face and content validity was found to conform to the standards set for the course, while logistic linear regression analysis showed that the quality criteria could be used as an assessment scale. The number of home visits carried out varied between the various different PCUs (p < 0.001) and more were reported in the write-ups that fulfilled criteria related to the biopsychosocial approach (p < 0.05). Nine quantitative criteria were fulfilled in more than 90% of case reports, but laboratory investigations were reported only in 69.0% of case reports. Statistically significant differences between the PCUs were observed in the fulfilment of criteria related to the community approach, patient assessment and information related to the patient's perception of the illness, but not to those related to aspects of clinical patient management. Differences in reporting laboratory investigations (p < 0.001) are explained by the lack of such facilities in some PCUs. Demographic characteristics of the patients or the students' do not affect the criteria. CONCLUSION: The primary health care course achieved the objectives of introducing students to comprehensive, community oriented care, although there was variation between the PCUs. The assessment scale that was developed to analyse the case-write ups of the students provided data that can be used to evaluate the course

Trailblazing precision medicine in Europe : A joint view by Genomic Medicine Sweden and the Centers for Personalized Medicine, ZPM, in Germany

Over the last decades, rapid technological and scientific advances have led to a merge of molecular sciences and clinical medicine, resulting in a better understanding of disease mechanisms and the development of novel therapies that exploit specific molecular lesions or profiles driving disease. Precision oncology is here used as an example, illustrating the potential of precision/personalized medicine that also holds great promise in other medical fields. Real-world implementation can only be achieved by dedicated healthcare connected centers which amass and build up interdisciplinary expertise reflecting the complexity of precision medicine. Networks of such centers are ideally suited for a nation-wide outreach offering access to precision medicine to patients independent of their place of residence. Two of these multicentric initiatives, Genomic Medicine Sweden (GMS) and the Centers for Personalized Medicine (ZPM) initiative in Germany have teamed up to present and share their views on core concepts, potentials, challenges, and future developments in precision medicine. Together with other initiatives worldwide, GMS and ZPM aim at providing a robust and sustainable framework, covering all components from technology development to clinical trials, ethical and legal aspects as well as involvement of all relevant stakeholders, including patients and policymakers in the field

Abstract 4869: Whole genome sequence analysis of MLL rearranged infant acute lymphoblastic leukemias reveals remarkably few somatic mutations: A Report From the St Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project

Abstract Infant acute lymphoblastic leukemia (ALL) is characterized by MLL rearrangements (MLLr) and poor prognosis. To determine the complement of somatic mutations in this high risk leukemia, we performed whole genome sequencing (WGS) on 22 infants with MLL rearranged ALL. An analysis of the structure of the MLLr revealed that over half had complex rearrangements involving either three or more chromosomes, carried cryptic rearrangements, or contained at the breakpoints deletions, amplifications, insertions, or inversion of sequences. In three cases, genetic rearrangements were predicted to generate in addition to the MLL-partner gene fusion, novel in-frame fusions including KRAS-MLL; RAD51B-MLL / AFF1-RAD51B, AFF1-RAD51B-MLL; MLLT10-ATP5L-YPEL4 / ATP5L-YPEL4. An analysis of the number of non-silent mutations revealed infant ALL to have the lowest frequency of somatic mutations of any cancer sequenced to date. After removal of SVs and CNAs associated with the MLLr, a mean of only 3.5 SVs and 2.2 SNVs affecting the coding region of annotated genes or regulatory RNAs were detected per case. Despite the paucity of mutations several pathways were recurrently targeted including PI3K/RAS pathway in 45% (KRAS (n=4), NRAS (n=2), and non-recurrent mutations in NF1, PTPN11, PIK3R1, and ARHGAP32 (p200Rho/GAP)), B cell differentiation in 23% as a result of mono-allelic deletion or gains of PAX5, 14% with deletions of the CDKN2A/B, and 2 cases with focal deletions of the non-coding RNA genes DLEU1/2. WGS of two infant ALL relapse samples and comparison with their matched diagnostic samples revealed a marked increase in the number of mutations at relapse. Moreover, an analysis of the allelic ratios of mutated genes revealed clonal heterogeneity at diagnosis with relapse appearing to arise from a minor diagnostic clone. Because of the exceedingly low number of mutations detected in infant ALL, we used exome sequencing to determine the frequency of non-silent SNVs in 20 MLLr leukemias (9 ALLs, 10 AMLs and 1 AUL) in older children (7-19 yrs). This analysis revealed that non-infant pediatric MLL leukemias harbor a significantly higher number of non-silent somatic SNVs than infant ALL (mean 7.4/case in older patients vs 2.2/case in infants, p&amp;lt;0.001). Although the higher frequency of mutations may be a reflection of age, the low number of cooperating mutations in infants raises the possibility that the target cell of transformation differs between infants and older children, with the cells present during early development requiring fewer cooperating mutations to induce leukemia. In summary our data demonstrated an exceedingly small number of mutations in infant leukemia. The number of detected somatic mutations may represent the lower limit required to transform a normal human cell into cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4869. doi:1538-7445.AM2012-4869</jats:p

Between Power and Persuasion: On International Institutions' Authority in Making Law

Drawing on the work of Hannah Arendt, this contribution places authority between power and persuasion. It first argues that authority is a specific kind of power that claims to be legitimate because it connects to the consent of the addressee. But at the same time, authority needs to constrain even if it is not met with agreement. Otherwise it would collapse into persuasion through arguments. What sustains authority between power and persuasion is a discursive practice that builds up a social expectation and that ties actors to the command of the authority. It is with attention to the larger discursive practices that international institutions’ authority in making law is best understood. The notion of semantic authority is introduced in order to capture international institutions’ capacity to establish reference points for legal discourse that other actors can hardly escape

Whole Genome Sequence Analysis of 22 MLL Rearranged Infant Acute Lymphoblastic Leukemias Reveals Remarkably Few Somatic Mutations: A Report From the St Jude Children‘s Research Hospital - Washington University Pediatric Cancer Genome Project

Abstract Abstract 69 Infant (&lt; 1 year of age) acute lymphoblastic leukemia (ALL) is a rare disease characterized by rearrangements of the Mixed Lineage Leukemia (MLL) gene at 11q23 and a poor prognosis. In an effort to determine the total complement of somatic mutations occurring in this high risk leukemia, we performed paired-end whole genome sequencing (WGS) on diagnostic leukemia blasts and matched germ line samples from 22 infants with MLL rearranged ALL using the Illumina platform. In addition, we sequenced 2 paired relapse samples. Somatic alterations, including single nucleotide variations (SNV), and structural variations (SV) including insertions, deletions, inversion, and inter- and intra-chromosomal rearrangements were detected using complementary analysis pipelines including Bambino, CREST and CONSERTING. Validation of identified somatic mutations was performed using PCR amplification of the leukemia and germ line DNA followed by Sanger or 454-based sequencing, or by array-based capture followed by Illumina-based sequencing. Analysis of the structure of MLL rearrangements at the base pair level revealed that over half had complex rearrangements that involved either three or more chromosomes, or contained at the breakpoints deletions, amplifications, insertions, or inversion of sequences. In five of the complex cases, chromosomal rearrangements were predicted to generate not only a MLL-partner gene fusion, but also novel in-frame fusions including KRAS-MLL; RAD51B-MLL / AFF1-RAD51B; MLLT10-CTNNAP3B; MLLT10-ATP5L / ATP5L-YPEL4; and CRTAM-GNL3. An analysis of the sequence surrounding the breakpoints of MLL and its partner genes suggest that the predominant mechanism of rearrangement involved non-homologous end joining. An analysis of the total number of non-silent mutations revealed infant ALL to have the lowest frequency of non-silent somatic mutations of any cancer sequenced to date. After removal of SVs and CNAs associated with the MLL rearrangements, a mean of only 2 somatic SVs and 2 SNVs affecting the coding region of annotated genes or regulatory RNAs were detected per case, with a range of non-silent mutation of between 0 and 11 per case (0–7 SV and 0–5 SNV). Despite the paucity of mutations several pathways were recurrently targeted. Mutations leading to activation of signaling through the PI3K/RAS pathway was observed in 45% of the cases with mutation of individual components including KRAS (n=4), NRAS (n=2), and non-recurrent mutations in NF1, PTPN11, PIK3R1, and the GTPase activating protein ARHGAP32 (p200Rho/GAP), which mediates cross-talk between RAS and Rho signaling. Other pathways altered include B cell differentiation, with 23% of cases containing mono-allelic deletion or gains of PAX5, 14% with deletions of the CDKN2A/B, and 2 cases with focal deletions of the non-coding RNA genes DLEU1/2. WGS of two infant ALL relapse samples and comparison with the data from their matched diagnostic samples revealed a marked increase in the number of mutations at relapse with additional SVs, SNVs, and CNAs identified. Moreover, an analysis of the allelic ratios of mutated genes revealed clonal heterogeneity at diagnosis with relapse appearing to arise from a minor diagnostic clone. Because of the exceedingly low frequency of mutations detected in infant ALL, we decided to define the frequency of non-silent SNVs in MLL rearranged leukemia occurring in older children (7–19 years of age). Exome sequencing was performed on 13 MLL leukemias (8 ALLs and 5 AMLs). This analysis revealed that non-infant pediatric MLL rearranged leukemias harbor a significantly higher number of non-silent somatic SNVs than infant ALL (mean 8/case in older patients versus 2/case in infants, p&lt;0.001). Although the increased frequency of mutations may be a reflection of the older age, the low number of cooperating mutations in infants raises the possibility that the target cell of transformation differs between infants and older children, with the cells present during early development requiring fewer cooperating mutations to induce leukemia. In summary our analysis demonstrated an exceedingly small number of mutations required to generate infant MLL rearranged leukemia. The number of detected somatic mutations may represent the lower limit of mutations required to transform a normal human cell into cancer. Disclosures: Fioretos: Cantargia AB: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Qlucore AB: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. </jats:sec