A clinically relevant pharmacokinetic interaction between cyclosporine and imatinib

PURPOSE: Cyclosporine A (CsA) and imatinib are both CYP3A4 and P-glycoprotein substrates. Concomitant use after hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML) or Philadelphia chromosome-positive (Ph+) acute lymphatic leukemia (ALL) may therefore result in a pharmacokinetic interaction. Although case reports and a recent small study in children indeed suggested there is a relevant pharmacokinetic interaction, a larger study in adults is lacking. In this study, we assessed the presence and extent of this interaction in patients with CML or Ph+ ALL undergoing HSCT. METHODS: From a large database containing data of all patients receiving HSCT in our center between 2005 and 2015, we selected 16 patients using this drug combination. The average dose-corrected CsA concentration was calculated before and after initiation of imatinib. RESULTS: The average dose-corrected CsA concentration increased during imatinib use in all patients, on average by 94 % (p < 0.001). Based on measured drug concentrations, the CsA dosage needed to be reduced, on average, by 27 % after initiation of imatinib (p = 0.004). CONCLUSIONS: Imatinib significantly increases CsA concentrations in HSCT patients, putting these patients at increased risk of CsA toxicity. We recommend intensive monitoring of CsA concentrations after initiation of imatinib; a pre-emptive CsA dose reduction of 25 % might be considered

Metabolic Syndrome Derived from Principal Component Analysis and Incident Cardiovascular Events: The Multi Ethnic Study of Atherosclerosis (MESA) and Health, Aging, and Body Composition (Health ABC).

Background. The NCEP metabolic syndrome (MetS) is a combination of dichotomized interrelated risk factors from predominantly Caucasian populations. We propose a continuous MetS score based on principal component analysis (PCA) of the same risk factors in a multiethnic cohort and compare prediction of incident CVD events with NCEP MetS definition. Additionally, we replicated these analyses in the Health, Aging, and Body composition (Health ABC) study cohort. Methods and Results. We performed PCA of the MetS elements (waist circumference, HDL, TG, fasting blood glucose, SBP, and DBP) in 2610 Caucasian Americans, 801 Chinese Americans, 1875 African Americans, and 1494 Hispanic Americans in the multiethnic study of atherosclerosis (MESA) cohort. We selected the first principal component as a continuous MetS score (MetS-PC). Cox proportional hazards models were used to examine the association between MetS-PC and 5.5 years of CVD events (n = 377) adjusting for age, gender, race, smoking and LDL-C, overall and by ethnicity. To facilitate comparison of MetS-PC with the binary NCEP definition, a MetS-PC cut point was chosen to yield the same 37% prevalence of MetS as the NCEP definition (37%) in the MESA cohort. Hazard ratio (HR) for CVD events were estimated using the NCEP and Mets-PC-derived binary definitions. In Cox proportional models, the HR (95% CI) for CVD events for 1-SD (standard deviation) of MetS-PC was 1.71 (1.54-1.90) (P &lt; 0.0001) overall after adjusting for potential confounders, and for each ethnicity, HRs were: Caucasian, 1.64 (1.39-1.94), Chinese, 1.39 (1.06-1.83), African, 1.67 (1.37-2.02), and Hispanic, 2.10 (1.66-2.65). Finally, when binary definitions were compared, HR for CVD events was 2.34 (1.91-2.87) for MetS-PC versus 1.79 (1.46-2.20) for NCEP MetS. In the Health ABC cohort, in a fully adjusted model, MetS-PC per 1-SD (Health ABC) remained associated with CVD events (HR = 1.21, 95%CI 1.12-1.32) overall, and for each ethnicity, Caucasian (HR = 1.24, 95%CI 1.12-1.39) and African Americans (HR = 1.16, 95%CI 1.01-1.32). Finally, when using a binary definition of MetS-PC (cut point 0.505) designed to match the NCEP definition in terms of prevalence in the Health ABC cohort (35%), the fully adjusted HR for CVD events was 1.39, 95%CI 1.17-1.64 compared with 1.46, 95%CI 1.23-1.72 using the NCEP definition. Conclusion. MetS-PC is a continuous measure of metabolic syndrome and was a better predictor of CVD events overall and in individual ethnicities. Additionally, a binary MetS-PC definition was better than the NCEP MetS definition in predicting incident CVD events in the MESA cohort, but this superiority was not evident in the Health ABC cohort

Outcomes of acute intraoperative surgical conversion during endovascular aortic aneurysm repair

PurposeOutcomes and predictors of acute surgical conversion during endovascular aortic aneurysm repair (EVAR) were examined using the American College of Surgeons-National Safety and Quality Improvement Project (ACS-NSQIP) Database (2005 to 2008).MethodsAcute intraoperative surgical conversions occurring during elective EVAR were identified using Current Procedural Terminology codes. Nonemergent EVAR and primary open surgical repairs of infrarenal aneurysms were examined for comparison. Perioperative morbidity was categorized as wound, pulmonary, venous thromboembolic, genitourinary, cardiovascular, operative, and septic. Mortality, overall morbidity, and length of stay (LOS) were examined.ResultsWe identified 72 acute conversions, 2414 open repairs, and 6332 EVAR without acute conversion. Demographics and comorbidities were generally similar among operative groups. Mean operative time was 274 minutes for acute conversion vs 226 minutes for primary open repair and 162 minutes for EVAR (conversion vs EVAR and open repair vs EVAR P < .0001 for each; conversion vs open repair P = .0014; analysis on rank operative time). Blood transfusion was required in 69% of acute conversions (mean volume, 6.0 units) vs 73% of open repairs (mean volume, 3.3 units) and 12% of EVARs (mean volume, 2.6 units; P < .0001 for each pair-wise comparison; analysis on rank number of units among those transfused). Major morbidity was 28% for acute conversions, 28% for open repairs, and 12% for EVARs. Mortality was 4.2% for acute conversions, 3.2% for open repairs, and 1.3% for EVARs. Median (quartile 1, quartile 3) LOS was 7 (5, 9) days for acute conversion and open repair, and 2 (1, 3) days for EVAR. Morbidity and mortality were significantly higher for acute conversion and open repair vs EVAR. The OR (95% confidence interval) for morbidity was 2.9 (1.7-4.8) after conversion and 2.8 (2.5-3.2) after open repair (P < .0001 for both) and for mortality was 3.4 (1.0-10.9; P = .0437) for conversion and 2.5 (1.9-3.5; P < .0001) for open repair. Morbidity and mortality were similar between acute conversion and open repair. A similar pattern among repair groups was demonstrated for LOS, with similar LOS for acute conversions and open repair, which were significantly longer than those observed for EVAR. No significant demographic or medical risk factor predictors of acute conversion during EVAR were identified.ConclusionAcute surgical conversion was a rare complication affecting 1.1% of EVAR cases, with no broadly identifiable at-risk population. When conversion did occur, morbidity and mortality rates paralleled those observed for elective open repair

A clinically relevant pharmacokinetic interaction between cyclosporine and imatinib

Purpose: Cyclosporine A (CsA) and imatinib are both CYP3A4 and P-glycoprotein substrates. Concomitant use after hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML) or Philadelphia chromosome-positive (Ph+) acute lymphatic leukemia (ALL) may therefore result in a pharmacokinetic interaction. Although case reports and a recent small study in children indeed suggested there is a relevant pharmacokinetic interaction, a larger study in adults is lacking. In this study, we assessed the presence and extent of this interaction in patients with CML or Ph+ ALL undergoing HSCT. Methods: From a large database containing data of all patients receiving HSCT in our center between 2005 and 2015, we selected 16 patients using this drug combination. The average dose-corrected CsA concentration was calculated before and after initiation of imatinib. Results: The average dose-corrected CsA concentration increased during imatinib use in all patients, on average by 94 % (p < 0.001). Based on measured drug con

Deconstructing doing well; what can we learn from care experienced young people in England, Denmark and Norway?

This paper addresses the conceptualization of ‘outcomes’ for care experienced people through an in-depth longitudinal study of 75 young adults in Denmark, England and Norway. ‘Outcome’ studies have played a crucial role in raising awareness of the risk of disadvantage that care experienced people face, across a variety of domains including education and employment. These studies may have an unintended consequence, however, if care experienced people are predominantly viewed, and studied, through a problem-focused lens. The danger is that policy and research neglects other – perhaps less readily measurable – aspects of experience, including subjective understandings – what matters to care experienced people themselves. Our analyses are based on an in-depth qualitative longitudinal study, which explored meanings of ‘doing well’ over time among care experienced people (aged 16–32), all of whom were ‘successful’ in relation to traditional indicators of participation in education and/or employment (including voluntary work). Across countries, their accounts revealed the importance of attending to subjective and dynamic understandings of ‘doing well’, and the significance of ordinary, mundane and ‘do-able’ lives. Participants’ narratives highlight aspects of doing well that raise challenging questions about how traditional outcome indicators – and corresponding policy priorities – might better capture what young people themselves see as important. A narrow interpretation of outcomes may lead to misrecognition of what it means to do well, and so to a stigmatizing ‘way of seeing’ care experienced lives. A broader conceptualization of outcomes is necessary to recognize – and so to develop policy and services to support – the complex, dynamic relationality of doing well

Brain MR patterns in inherited disorders of monoamine neurotransmitters: An analysis of 70 patients

Inherited monoamine neurotransmitter disorders (iMNDs) are rare disorders with clinical manifestations ranging from mild infantile hypotonia, movement disorders to early infantile severe encephalopathy. Neuroimaging has been reported as non-specific. We systematically analysed brain MRIs in order to characterize and better understand neuroimaging changes and to re-evaluate the diagnostic role of brain MRI in iMNDs

Ancient mtDNA Genetic Variants Modulate mtDNA Transcription and Replication

Although the functional consequences of mitochondrial DNA (mtDNA) genetic backgrounds (haplotypes, haplogroups) have been demonstrated by both disease association studies and cell culture experiments, it is not clear which of the mutations within the haplogroup carry functional implications and which are “evolutionary silent hitchhikers”. We set forth to study the functionality of haplogroup-defining mutations within the mtDNA transcription/replication regulatory region by in vitro transcription, hypothesizing that haplogroup-defining mutations occurring within regulatory motifs of mtDNA could affect these processes. We thus screened >2500 complete human mtDNAs representing all major populations worldwide for natural variation in experimentally established protein binding sites and regulatory regions comprising a total of 241 bp in each mtDNA. Our screen revealed 77/241 sites showing point mutations that could be divided into non-fixed (57/77, 74%) and haplogroup/sub-haplogroup-defining changes (i.e., population fixed changes, 20/77, 26%). The variant defining Caucasian haplogroup J (C295T) increased the binding of TFAM (Electro Mobility Shift Assay) and the capacity of in vitro L-strand transcription, especially of a shorter transcript that maps immediately upstream of conserved sequence block 1 (CSB1), a region associated with RNA priming of mtDNA replication. Consistent with this finding, cybrids (i.e., cells sharing the same nuclear genetic background but differing in their mtDNA backgrounds) harboring haplogroup J mtDNA had a >2 fold increase in mtDNA copy number, as compared to cybrids containing haplogroup H, with no apparent differences in steady state levels of mtDNA-encoded transcripts. Hence, a haplogroup J regulatory region mutation affects mtDNA replication or stability, which may partially account for the phenotypic impact of this haplogroup. Our analysis thus demonstrates, for the first time, the functional impact of particular mtDNA haplogroup-defining control region mutations, paving the path towards assessing the functionality of both fixed and un-fixed genetic variants in the mitochondrial genome

Assessment of intellectual impairment, health-related quality of life, and behavioral phenotype in patients with neurotransmitter related disorders: Data from the iNTD registry

Inherited disorders of neurotransmitter metabolism are a group of rare diseases, which are caused by impaired synthesis, transport, or degradation of neurotransmitters or cofactors and result in various degrees of delayed or impaired psychomotor development. To assess the effect of neurotransmitter deficiencies on intelligence, quality of life, and behavior, the data of 148 patients in the registry of the International Working Group on Neurotransmitter Related Disorders (iNTD) was evaluated using results from standardized age-adjusted tests and questionnaires. Patients with a primary disorder of monoamine metabolism had lower IQ scores (mean IQ 58, range 40-100) within the range of cognitive impairment (<70) compared to patients with a BH4 deficiency (mean IQ 84, range 40-129). Short attention span and distractibility were most frequently mentioned by parents, while patients reported most frequently anxiety and distractibility when asked for behavioral traits. In individuals with succinic semialdehyde dehydrogenase deficiency, self-stimulatory behaviors were commonly reported by parents, whereas in patients with dopamine transporter deficiency, DNAJC12 deficiency, and monoamine oxidase A deficiency, self-injurious or mutilating behaviors have commonly been observed. Phobic fears were increased in patients with 6-pyruvoyltetrahydropterin synthase deficiency, while individuals with sepiapterin reductase deficiency frequently experienced communication and sleep difficulties. Patients with BH4 deficiencies achieved significantly higher quality of life as compared to other groups. This analysis of the iNTD registry data highlights: (a) difference in IQ and subdomains of quality of life between BH4 deficiencies and primary neurotransmitter-related disorders and (b) previously underreported behavioral traits.Dietmar Hopp Stiftung (DE); Medical Faculty of the University of Heidelberg