Comprehensive laboratory diagnosis of Fanconi anaemia: comparison of cellular and molecular analysis.

BACKGROUND: Fanconi anaemia (FA) is a rare inherited bone marrow failure disease caused by germline pathogenic variants in any of the 22 genes involved in the FA-DNA interstrand crosslink (ICL) repair pathway. Accurate laboratory investigations are required for FA diagnosis for the clinical management of the patients. We performed chromosome breakage analysis (CBA), FANCD2 ubiquitination (FANCD2-Ub) analysis and exome sequencing of 142 Indian patients with FA and evaluated the efficiencies of these methods in FA diagnosis. METHODS: We performed CBA and FANCD2-Ub analysis in the blood cells and fibroblasts of patients with FA. Exome sequencing with improved bioinformatics to detect the single number variants and CNV was carried out for all the patients. Functional validation of the variants with unknown significance was done by lentiviral complementation assay. RESULTS: Our study showed that FANCD2-Ub analysis and CBA on peripheral blood cells could diagnose 97% and 91.5% of FA cases, respectively. Exome sequencing identified the FA genotypes consisting of 45 novel variants in 95.7% of the patients with FA. FANCA (60.2%), FANCL (19.8%) and FANCG (11.7%) were the most frequently mutated genes in the Indian population. A FANCL founder mutation c.1092G>A; p.K364=was identified at a very high frequency (~19%) in our patients. CONCLUSION: We performed a comprehensive analysis of the cellular and molecular tests for the accurate diagnosis of FA. A new algorithm for rapid and cost-effective molecular diagnosis for~90% of FA cases has been established.

Missense mutations in Myc Box I influence nucleocytoplasmic transport to promote leukemogenesis.

PURPOSE: Somatic missense mutations in the phosphodegron domain of the MYC gene (MYC Box I or MBI) are detected in the dominant clones of a subset of acute myeloid leukemia (AML) patients, but the mechanisms by which they contribute to AML are unknown. EXPERIMENTAL DESIGN: To investigate the effects of MBI MYC mutations on hematopoietic cells, we employed a multi-omic approach to systematically compare the cellular and molecular consequences of expressing oncogenic doses of wild type, threonine-58 and proline-59 mutant MYC proteins in hematopoietic cells, and we developed a knockin mouse harboring the germline MBI mutation p.T58N in the Myc< gene. RESULTS: Both wild type and MBI mutant MYC proteins promote self-renewal programs and expand highly selected subpopulations of progenitor cells in the bone marrow. Compared to their wild type counterparts, mutant cells display decreased cell death and accelerated leukemogenesis in vivo, changes that are recapitulated in the transcriptomes of human AML bearing MYC mutations. The mutant phenotypes feature decreased stability and translation of mRNAs encoding proapoptotic and immune-regulatory genes, increased translation of RNA binding proteins and nuclear export machinery, and distinct nucleocytoplasmic RNAs profiles. MBI MYC mutant proteins also show a higher propensity to aggregate in perinuclear regions and the cytoplasm. Like the overexpression model, heterozygous p.T58N knockin mice displayed similar changes in subcellular MYC localization, progenitor expansion, transcriptional signatures, and develop hematopoietic tumors. CONCLUSIONS: This study uncovers that MBI MYC mutations alter RNA nucleocytoplasmic transport mechanisms to contribute to the development of hematopoietic malignancies.

Intersections between interprofessional practice, cultural competency and primary healthcare.

The concepts of interprofessional collaborative practice (IPCP), cultural competency and primary healthcare (PHC) appear to be linked in theory and practice. This discussion article provides arguments explicating the potential linkages between IPCP and cultural competency. We argue that cultural competency is an important component of IPCP both for relationships with patients and/or communities in which providers work and between team members. Organizational structures also play an important role in facilitating IPCP and cultural competency. The integration of both IPCP and cultural competency has the potential to enhance positive health outcomes. Furthermore, we argue IPCP and cultural competency have important implications for PHC service design, given interprofessional teams are a key component of PHC systems. Linking these concepts in providing PHC services can be essential for impacting outcomes at all levels of primary healthcare, including patient, provider and systems.

Beyond job placement: careers for refugees.

In this article, we highlight the Australian country context to advocate for career support that extends beyond initial job placement in a segmented labor market to strengthen refugees' skills and knowledge and future career development. We address systemic barriers while advocating for access to skilled career development practitioners, whose important expertise as members of multidisciplinary teams could enhance resettlement assistance. Strengthening the preparation of career development practitioners is essential for providing career support to refugees and for building capacity in the provision of resettlement services. We encourage debate within and between country contexts about ways to enhance refugees' career development.

Au-delà du placement: Carrières pour les réfugiés. Dans cet article, nous mettons en avant le contexte du pays australien pour plaider en faveur d'un soutien de carrière qui va au-delà l'insertion professionnelle initiale dans un marché du travail segmenté, afin de renforcer les compétences et les connaissances des réfugiées et leur futur développement de carrière. Nous abordons les obstacles systémiques tout en plaidant pour l'accès à des praticiennes qualifiées en développement de carrière, dont l'expertise importante en tant que membres d'équipes multidisciplinaires pourrait améliorer l'aide à la réinsertion. Le renforcement de la préparation des praticiennes en développement de carrière est essentiel pour fournir un soutien professionnel aux réfugiées et pour renforcer les capacités de prestation de services de réinsertion. Nous encourageons le débat au sein des contextes nationaux et entre eux sur les moyens d'améliorer le développement de carrière des réfugiées.

Más allá de la colocación: Carreras para refugiados. En este artículo destacamos el contexto del país australiano para abogar por un apoyo a la carrera profesional que vaya más allá de la colocación inicial en un mercado laboral segmentado para reforzar las habilidades y conocimientos de los refugiados y su futuro desarrollo profesional. Abordamos las barreras sistémicas a la vez que abogamos por el acceso a profesionales cualificados en desarrollo profesional, cuya importante experiencia como miembros de equipos multidisciplinares podría mejorar la asistencia al reasentamiento. Reforzar la preparación de los profesionales del desarrollo profesional es esencial para proporcionar apoyo profesional a los refugiados y para crear capacidad en la prestación de servicios de reasentamiento. Alentamos el debate dentro y entre los contextos nacionales sobre las formas de mejorar el desarrollo profesional de los refugiados.

Rebuilding life after migration: Research protocol of a mixed methods study on settlement experiences of refugee and migrant youth.

Internationally, there is an urgent need to understand factors promoting successful settlement and integration of people with forced or voluntary migration experiences (i.e., refugee and non-refugee migrants). This paper provides a protocol of a mixed-methods investigation of contextual factors of successful settlement and service utilization of youth and their families, as young people could be at higher risk due to stressors associated with pre-migration trauma, post-migration settlement stressors, and adolescent development. This large-scale mixed-methods study will be conducted across three countries. A questionnaire survey will seek responses from 1200 youth aged 15-24 years residing in South Australia, Ontario, Canada, and California, United States of America. The qualitative component of the study will comprise 54 focus groups (324 participants) with youth and their parents/caregivers. The study design allows a range of important phenomena (e.g., different migration pathways and settlement countries) and key questions (e.g., regarding the intersection of migration, settlement, and wellbeing) to be addressed. It also allows for generalizability of findings to be tested across different communities and countries. Findings will support recommendations for policy and practice and may be generalized to advance research with youth and their families. This study is one of the largest, most comprehensive studies of youth settlement.

Missense mutations in Myc Box I influence MYC cellular localization, mRNA partitioning and turnover to promote leukemogenesis.

Somatic missense mutations in the phosphodegron domain of the MYC gene ( M YC Box I) are detected in the dominant clones of a subset of acute myeloid leukemia (AML) patients, but the mechanisms by which they contribute to AML are unknown. To unveil unique proprieties of MBI MYC mutant proteins, we systematically compared the cellular and molecular consequences of expressing similar oncogenic levels of wild type and MBI mutant MYC. We found that MBI MYC mutants can accelerate leukemia by driving unique transcriptional signatures in highly selected, myeloid progenitor subpopulations. Although these mutations increase MYC stability, they overall dampen MYC chromatin localization and lead to a cytoplasmic accumulation of the mutant proteins. This phenotype is coupled with increased translation of RNA binding proteins and nuclear export machinery, which results in altered RNA partitioning and accelerated decay of select transcripts encoding proapoptotic and proinflammatory genes. Heterozygous knockin mice harboring the germline MBI mutation Myc p.T73N exhibit cytoplasmic MYC localization, myeloid progenitors' expansion with similar transcriptional signatures to the overexpression model, and eventually develop hematological malignancies. This study uncovers that MBI MYC mutations alter MYC localization and disrupt mRNA subcellular distribution and turnover of select transcripts to accelerate tumor initiation and growth.

Evaluation framework for a multi-site practice-based interprofessional education intervention.

The interprofessional literature suggests that there is a lack of evidence of the effectiveness of interprofessional education (IPE) on patient outcomes and critiques the methodology used to determine the evidence. This paper describes and critiques a comprehensive evaluation of a practice-based IPE intervention. The evaluation was challenged by the complexity of the project such as having multiple sites with great variability in settings and participants which required a multifaceted evaluation approach. Rather than reporting evaluation findings, this paper discusses the methodological successes and challenges of the evaluation framework used. The evaluation consisted of four components: process, outcomes, context and systems evaluation. A mixed method approach was used to collect information from a variety of data sources. Each evaluation component captured distinctive but complementary aspects of the intervention, providing a more complete understanding of the intervention. However, challenges also emerged, in particular for the outcomes component. Discussion of the challenges and benefits of each evaluation component are intended to inform future evaluation designs of complex practice-based IP education interventions. Specifically, adding systems concepts into evaluation can strengthen the evidence base of the effectiveness of IP education on IP practice and patient outcomes.

Role understanding and effective communication as core competencies for collaborative practice.

The ability to work with professionals from other disciplines to deliver collaborative, patient-centred care is considered a critical element of professional practice requiring a specific set of competencies. However, a generally accepted framework for collaborative competencies is missing, which makes consistent preparation of students and staff challenging. Some authors have argued that there is a lack of conceptual clarity of the "active ingredients" of collaboration relating to quality of care and patient outcomes, which may be at the root of the competencies issue. As part of a large Health Canada funded study focused on interprofessional education and collaborative practice, our goal was to understand the competencies for collaborative practice that are considered most relevant by health professionals working at the front line. Interview participants comprised 60 health care providers from various disciplines. Understanding and appreciating professional roles and responsibilities and communicating effectively emerged as the two perceived core competencies for patient-centred collaborative practice. For both competencies there is evidence of a link to positive patient and provider outcomes. We suggest that these two competencies should be the primary focus of student and staff education aimed at increasing collaborative practice skills.

Socialization in health education: encouraging an integrated interprofessional socialization process.

There is limited research on how health professionals are currently socialized to work interprofessionally. As part of a large-scale initiative funded by Health Canada, this report adds to our understanding of socialization and how it can prepare the health care student for an interprofessional health care environment. Data were collected through semistructured individual and group interviews with 83 respondents (i.e., faculty, students, health care and academic administrators, and health care providers) at seven clinical sites and five academic institutions throughout Alberta. Respondents indicated that socialization prepares health care students for interprofessional environments by "building a professional identity" and through what we are labeling "interprofessional familiarization" (i.e., where the goal is to introduce students to the roles and function of other professionals outside their own discipline). While there is interprofessional familiarization, it is neither consistently espoused as important nor systematically embedded in curriculum and clinical placements. Interprofessional competency building is lacking during this preparatory phase, leaving students ill prepared to work in interprofessional health care environments. We argue there is a need for greater interprofessional socialization in education. By creating a deliberate, planned, and integrated interprofessional socialization process that is consistent across the health professions, barriers to interprofessional practice could be mitigated.

Intracervical block and pain perception during the performance of a hysterosalpingogram: a randomized controlled trial.

OBJECTIVE: To estimate whether an intracervical block of 1% lidocaine decreased pain perception compared with placebo during the performance of a hysterosalpingogram. METHODS: A randomized controlled trial was conducted with 120 patients assessing pain perception during a hysterosalpingogram. Patients were randomly assigned to one of three groups. Patients received either a 1% lidocaine intracervical block, an intracervical saline injection, or no injection. Visual analog (VAS) and qualitative scales were used to assess study participants' pain at six different time points during the hysterosalpingogram. RESULTS: Subjects receiving the lidocaine block had significantly less pain (P<.001) by VAS during tenaculum placement (approximately 61% less, 1.303 cm) and with tenaculum traction (approximately 40% less, 2.804 cm) compared with both the intracervical saline injection group and the no injection group (tenaculum placement, 3.384 cm and 3.354 cm, and tenaculum traction, 4.705cm and 4.961 cm, respectively). There was no improvement seen with pain perception during instillation of the contrast in the lidocaine group compared with the saline or no injection group (P<.073). Subjects who received the saline injection had statistically more pain (P<.001) by VAS (2.647 cm) immediately after the injection compared with the lidocaine (approximately 79% greater, 1.476 cm) and no injection groups (115% greater, 1.232 cm). CONCLUSION: Lidocaine intracervical block provides better pain relief than placebo during tenaculum placement and tenaculum traction during a hysterosalpingogram. This study suggests that patients should be offered an intracervical block before placement of the cervical tenaculum to decrease pain during the performance of a hysterosalpingogram. CLINICAL TRIAL REGISTRATION: (www.ClinicalTrials.gov), NCT00372658 LEVEL OF EVIDENCE: I.

How can frontline managers demonstrate leadership in enabling interprofessional practice?

Interprofessional practice has been proposed to address many of the current health system challenges. Little attention has been paid to the role of frontline managers in supporting effective interprofessional practice. Qualitative interviews suggest that frontline managers can demonstrate leadership in enabling interprofessional practice by creating an organizational culture for interprofessional practice, eliminating barriers to collaboration, and acting as role models and facilitators. New management approaches may be needed to meet these demands.

ATP-binding casette transporter expression in acute myeloid leukemia: association with in vitro cytotoxicity and prognostic markers.

INTRODUCTION: Drug resistance and relapse are considered to be the major reasons for treatment failure in acute myeloid leukemia (AML). There is limited data on the role of ABC transporter expression on in vitro sensitivity to cytarabine (Ara-C) and daunorubicin (Dnr) in primary AML cells. PATIENTS & METHODS: RNA expression levels of 12 ABC transporters were analyzed by real-time quantitative PCR in 233 de novo adult acute myeloid leukemia patients. Based on cytarabine or Dnr IC50, the samples were categorized as sensitive, intermediate and resistant. Role of candidate ABC transporter RNA expression on in vitro cytotoxicity, treatment outcome post therapy as well as the influence of various prognostic markers on ABC transporter expression were analyzed. RESULTS: Expression of ABCC3 and ABCB6 were significantly higher in Dnr-resistant samples when compared with Dnr-sensitive samples. Increased ABCC1 expression was associated with poor disease-free survival in this cohort of patients. CONCLUSION: This comprehensive analysis suggests ABCC1, ABCC3, ABCB6 and ABCA5 as probable targets which can be modulated for improving chemotherapeutic responses.

Positioning of Weight Bias: Moving towards Social Justice.

Weight bias is a form of stigma with detrimental effects on the health and wellness of individuals with large bodies. Researchers from various disciplines have recognized weight bias as an important topic for public health and for professional practice. To date, researchers from various areas have approached weight bias from independent perspectives and from differing theoretical orientations. In this paper, we examined the similarities and differences between three perspectives (i.e., weight-centric, non-weight-centric (health-centric), and health at every size) used to understand weight bias and approach weight bias research with regard to (a) language about people with large bodies, (b) theoretical position, (c) identified consequences of weight bias, and (d) identified influences on weight-based social inequity. We suggest that, despite differences, each perspective acknowledges the negative influences that position weight as being within individual control and the negative consequences of weight bias. We call for recognition and discussion of weight bias as a social justice issue in order to change the discourse and professional practices extended towards individuals with large bodies. We advocate for an emphasis on social justice as a uniting framework for interdisciplinary research on weight bias.

Population pharmacokinetics of Daunorubicin in adult patients with acute myeloid leukemia.

PURPOSE: Chemotherapy drug resistance and relapse of the disease have been the major factors limiting the success of acute myeloid leukemia (AML) therapy. Several factors, including the pharmacokinetics (PK) of Cytarabine (Ara-C) and Daunorubicin (Dnr), could contribute to difference in treatment outcome in AML. METHODS: In the present study, we evaluated the plasma PK of Dnr, the influence of genetic polymorphisms of genes involved in transport and metabolism of Dnr on the PK, and also the influence of these factors on clinical outcome. Plasma levels of Dnr and its major metabolite, Daunorubicinol (DOL), were available in 70 adult de novo AML patients. PK parameters (Area under curve (AUC) and clearance (CL)) of Dnr and DOL were calculated using nonlinear mixed-effects modeling analysis performed with Monolix. Genetic variants in ABCB1, ABCG2, CBR1, and CBR3 genes as well as RNA expression of CBR1, ABCB1, and ABCG2 were compared with Dnr PK parameters. RESULTS: The AUC and CL of Dnr and DOL showed wide inter-individual variation. Patients with an exon1 variant of rs25678 in CBR1 had significantly higher plasma Dnr AUC [p = 0.05] compared to patients with wild type. Patients who achieved complete remission (CR) had significantly lower plasma Dnr AUC, Cmax, and higher CL compared to patients who did not achieve CR. CONCLUSION: Further validation of these findings in a larger cohort of AML patients is warranted before establishing a therapeutic window for plasma Dnr levels and targeted dose adjustment.

Efficacy of brief couples support groups developed to manage the stress of in vitro fertilization treatment.

OBJECTIVE: To assess the efficacy of brief couples support groups offered concurrently with in vitro fertilization (IVF) treatment. PATIENTS AND METHODS: Couples in IVF treatment were given the option of participating in a biweekly support group at the IVF clinic at Wilford Hall Medical Center, San Antonio, Tex. At least 1 member of 26 couples participated in the brief couples support groups, and at least 1 member of 19 other couples completed the questionnaires but did not attend the support group sessions and so comprised the control group. Facilitators used cognitive behavioral techniques to help participants process their feelings and cognitions about their infertility. Emotional and cognitive factors were assessed both before and after group attendance by using the Beck Depression Inventory; the Beck Anxiety Inventory; the Life Orientation Test, which assesses optimism and pessimism; the Survey of Personal Views, which measures irrational beliefs; and the Social Provisions Scale, which measures social support. RESULTS: Women who attended group sessions were significantly less anxious after the IVF treatment than they were before the cycle (P < .001). Men who attended the group sessions were more optimistic than nongroup men or the women at the completion of the IVF cycle (P < .001) but endorsed greater numbers of irrational beliefs (P < .001). CONCLUSIONS: Despite the fact that the service was relatively inexpensive compared with IVF in the civilian community, the complexity of IVF treatment and the logistic and psychological stress experienced by couples made it hard to form and maintain such groups. Nevertheless, both men and women derived psychological benefit from the group: women reported less anxiety and men greater optimism on completion of the group sessions.

Optimizing diabetes literacy: lessons from African Canadians in Calgary about type 2 diabetes diagnosis.

OBJECTIVE: With the aim of optimizing diabetes education, type 2 diabetes awareness, primary prevention and secondary prevention, we studied how African Canadians experience type 2 diabetes. Specifically, we studied stories told by African Canadians living in Calgary, Alberta, Canada, about significant events and experiences at the time of their diagnosis with type 2 diabetes. METHODS: From recorded interviews, we extracted themes from stories about diagnosis, using hermeneutic phenomenology. Participants included 11 African Canadians older than age 18 and at least 1-year post-diagnosis. Transcribed stories were analyzed for units of meaning describing significant themes/experiences about the diagnosis. Extracted units of meaning were organized into themes that were presented to a focus group of African Canadians in Calgary to garner their perspective on the findings, discuss the implications and make recommendations for improvements. RESULTS: All participants reported experiencing shock, disbelief, fear and a sense of helplessness immediately after their diagnosis. These rendered them unable to think clearly or start their treatment regimen until propelled by additional forces. Also, 73% of participants reported experiencing anger/denial about the diagnosis for some time, whereas 18% reported a short-lived relief that they could finally put a name to their symptoms. However, the overarching issue associated with all of the themes appeared to emanate from a lack of type 2 diabetes awareness. CONCLUSIONS: Emotions experienced by participants seemed precipitated by a lack of type 2 diabetes awareness. Some community-specific factors contributed to the lack of type 2 diabetes awareness, which appeared to impede primary and secondary prevention among participants. Recommendations for ameliorating these factors are presented.

Interprofessional mentoring: enhancing students' clinical learning.

Interprofessional (IP) collaboration is recognized as critical for patient-centred care. The clinical setting is an ideal environment for students to learn the competencies required to effectively work with providers from other professions. To enhance traditional clinical placements, we propose an IP mentoring approach, defined as learning that takes place between providers and students who are from different disciplines or health professions. In IP mentoring, students have primary relationships with their preceptors, but also have interactions with providers from other professions. We implemented IP mentoring with the support of two faculties of nursing in Alberta, Canada who provided an IP clinical focus for interested fourth year students. We emphasized to providers and students that there are no prescribed interactions that comprise IP mentoring; experiences between providers and students are context-specific and often informal. Through our evaluation we demonstrated that in IP mentoring, provider commitment was important, students engaged in IP activities of varying complexity, and students learned about roles of other professions and how to work together to provide patient-centred care. IP mentoring is an effective learning strategy to enhance students' knowledge and skills in IP collaboration without radical changes to the structure of the placements or to the educational curricula.

Impact of day 3 or day 5 embryo transfer on pregnancy rates and multiple gestations.

OBJECTIVE: To test the hypothesis that day 5 ET (D5ET) is superior to day 3 ET (D3ET) in pregnancy outcome and that it also reduces multiple gestations. DESIGN: Retrospective cohort study. SETTING: Assisted reproductive technologies program at Wilford Hall Medical Center. PATIENT(S): Patients electing for either D3ET or D5ET. INTERVENTION(S): Participants meeting inclusion criteria for D5ET elected either D3ET or D5ET. MAIN OUTCOME MEASURE(S): Cycles were compared by day of transfer and further stratified by patient age (<35 years and 35-40 years). The number of oocytes retrieved, embryos on day 3, embryos transferred, pregnancy rate, implantation rate, and twin and high order multiples (>or=triplets) rates were compared. RESULT(S): Of the 274 patients who met our inclusion criteria, 153 underwent a D3ET and 121 underwent a D5ET. The D5ET group had a significantly lower mean age and number of embryos transferred and a higher implantation rate (56% vs. 42%) than the D3ET group. Patients who were 35-40 years old had a significantly higher live-birth rate (68% vs. 40%). Although not statistically significant, the D5ET groups had higher clinical pregnancy (73% vs. 65%) and twin pregnancy (33% vs. 25%) rates. CONCLUSION(S): Blastocyst transfer resulted in fewer embryos transferred, with a trend toward improved clinical pregnancy and higher twin pregnancy rates. Live-birth rates were improved in patients 35-40 years of age. Younger patients opting for D5ET should do so with a commitment toward single ET.

Targeting students, teachers and parents in a wellness-based prevention program in schools.

This study examines the effectiveness of a wellness-based prevention program on elementary and junior high students' body image, personal attitudes, and eating behaviors. Group differences in measures of student attitudes and eating behaviors are examined to determine the effect of targeting different participant combinations (students, parents, and teachers) in 10 groups. For elementary schools, student participants consisted of control (no intervention) (n = 36), student only (n = 81), student/parent (n = 124), student/parent/teacher (n = 103), and parent/teacher (n = 149). For junior high schools, student participants consisted of control (n = 143), student only (n=215), student/parent (n=65), student/parent/teacher (n = 14), and parent/teacher (n = 177). Overall, complete data was available for 1,095 students, 114 parents and 92 teachers. Results indicate that self-concept and eating attitudes and behaviors were positively affected by participation in the program. For example, in elementary schools posttest scores on the behavior subscale of the self-concept measure are significantly higher for the student/parent/teacher group than for the control group. Results indicate that a one-time wellness-based eating disorder prevention program with students, which have in the past shown to be minimally effective, may be more effective in changing attitudes and behaviors when teachers and parents are involved.