Use of myocardial perfusion imaging and estimation of associated radiation doses in Germany from 2005 to 2012

PURPOSE: For several years the Working Group Cardiovascular Nuclear Medicine of the German Society of Nuclear Medicine has been performing a regular survey to obtain information on technique, utilization and development of myocardial perfusion scintigraphy (MPS). Currently, data of six surveys from 2005 to 2012 are available. The aim of this paper is to deliver a general and comprehensive overview of all surveys documenting the course of patient doses over time and the development of the method. METHODS: A one-page questionnaire with number of MPS patients, number of stress and rest MPS, referral structure and several technical issues was sent to all centres performing MPS in Germany and evaluated. With the data on protocol utilization, effective MPS patient doses were estimated. RESULTS: MPS per million population (pmp) varied between 2,380 and 2,770. In 2012, MPS pmp showed a slight increase for the first time. From 2005 to 2009 the angiography to MPS ratio increased from 3.4 to 4.4, and the revascularization to MPS ratio decreased from 0.66 to 0.53. In 2012, both indices demonstrated an opposite trend for the first time (4.1 and 0.55). A total of 108 centres participated in all surveys. They showed an increase in MPS patients of 4.0 % over the reporting period. In 2012, more than 50 % of the centres experienced no change or an increase in MPS numbers. The leading single competitor was MRI, followed by angiography and stress echocardiography. (201)Tl studies have decreased since 2005 from 20 to 5 %. (99m)Tc MPS studies showed a mild increase in 2-day protocols. In 2012, the average effective dose per patient was estimated at 7.4 mSv. Due to the decreasing use of (201)Tl, a mild decline over the observation period can be documented. Dynamic exercise stress was the most common stress test and adenosine the leading pharmacological stress agent, with a growing percentage. In 2012, the regadenoson percentage was 9 %. Gated single photon emission computed tomography (SPECT) noted an increasing acceptance with >70 % in 2012. The segmental scoring of perfusion studies had a low acceptance. Ambulatory care cardiologists represented the major referral group. CONCLUSION: Germany has a moderate to moderate-high MPS utilization rate. Nevertheless, coronary artery disease (CAD) diagnosis and disease management are dominated by angiography. The survey data reveal a positive trend in MPS and a decrease in average patient dose reflecting good practice with guideline adherence, the implementation of technical improvements and success in training

Scalability of digital psychological innovations for refugees: A comparative analysis in Egypt, Germany, and Sweden

E-mental health interventions may offer innovative means to increase access to psychological support and improve the mental health of refugees. However, there is limited knowledge about how these innovations can be scaled up and integrated sustainably into routine services. This study examined the scalability of a digital psychological intervention called Step-by-Step (SbS) for refugees in Egypt, Germany, and Sweden. We conducted semi-structured interviews (n = 88) with Syrian refugees, and experts in SbS or refugee' mental health systems in the three countries. Data collection and analysis were guided by a system innovation perspective. Interviewees identified three contextual factors that influenced scalability of SbS in each country: increasing use of e-health, the COVID-19 pandemic, and political instability. Nine factors lay at the interface between the innovation and potential delivery systems, and these were categorised by culture (ways of thinking), structure (ways of organising), and practice (ways of doing). Factors related to culture included: perceived need and acceptability of the innovation. Acceptability was influenced by mental health stigma and awareness, digital trust, perceived novelty of self-help interventions, and attitudes towards non-specialist (e-helper) support. Factors related to structure included financing, regulations, accessibility, competencies of e-helpers, and quality control. Factors related to practice were barriers in the initial and continued engagement of end-users. Many actors with a potential stake in the integration of SbS across the three countries were identified, with nineteen stakeholders deemed most powerful. Several context-specific integration scenarios were developed, which need to be tested. We conclude that integrating novel e-mental health interventions for refugees into routine services will be a complex task due to the many interrelated factors and actors involved. Multi-stakeholder collaboration, including the involvement of end-users, will be essential. Previous article in issu

Peer-provided psychological intervention for Syrian refugees: results of a randomised controlled trial on the effectiveness of Problem Management Plus

Background The mental health burden among refugees in high-income countries (HICs) is high, whereas access to mental healthcare can be limited. Objective To examine the effectiveness of a peer-provided psychological intervention (Problem Management Plus; PM+) in reducing symptoms of common mental disorders (CMDs) among Syrian refugees in the Netherlands. Methods We conducted a single-blind, randomised controlled trial among adult Syrian refugees recruited in March 2019–December 2021 (No. NTR7552). Individuals with psychological distress (Kessler Psychological Distress Scale (K10) >15) and functional impairment (WHO Disability Assessment Schedule (WHODAS 2.0) >16) were allocated to PM+ in addition to care as usual (PM+/CAU) or CAU only. Participants were reassessed at 1-week and 3-month follow-up. Primary outcome was depression/anxiety combined (Hopkins Symptom Checklist; HSCL-25) at 3-month follow-up. Secondary outcomes included depression (HSCL-25), anxiety (HSCL-25), post-traumatic stress disorder (PTSD) symptoms (PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; PCL-5), impairment (WHODAS 2.0) and self-identified problems (PSYCHLOPS; Psychological Outcomes Profiles). Primary analysis was intention-to-treat. Findings Participants (n=206; mean age=37 years, 62% men) were randomised into PM+/CAU (n=103) or CAU (n=103). At 3-month follow-up, PM+/CAU had greater reductions on depression/anxiety relative to CAU (mean difference −0.25; 95% CI −0.385 to −0.122; p=0.0001, Cohen’s d=0.41). PM+/CAU also showed greater reductions on depression (p=0.0002, Cohen’s d=0.42), anxiety (p=0.001, Cohen’s d=0.27), PTSD symptoms (p=0.0005, Cohen’s d=0.39) and self-identified problems (p=0.03, Cohen’s d=0.26), but not on impairment (p=0.084, Cohen’s d=0.21). Conclusions PM+ effectively reduces symptoms of CMDs among Syrian refugees. A strength was high retention at follow-up. Generalisability is limited by predominantly including refugees with a resident permit. Clinical implications Peer-provided psychological interventions should be considered for scale-up in HICs

Does the Constitution Provide More Ballot Access Protection for Presidential Elections Than for U.S. House Elections?

Both the U.S. Constitution and The Federalist Papers suggest that voters ought to have more freedom to vote for the candidate of their choice for the U.S. House of Representatives than they do for the President or the U.S. Senate. Yet, strangely, for the last thirty-three years, the U.S. Supreme Court and lower courts have ruled that the Constitution gives voters more freedom to vote for the candidate of their choice in presidential elections than in congressional elections. Also, state legislatures, which have been writing ballot access laws since 1888, have passed laws that make it easier for minor-party and independent candidates to get on the ballot for President than for the U.S. House. As a result, voters in virtually every state invariably have far more choices on their general election ballots for the President than they do for the House. This Article argues that the right of a voter to vote for someone other than a Democrat or a Republican for the House is just as important as a voter’s right to do so for President, and that courts should grant more ballot access protection to minor-party and independent candidates for the House

ASXL1 mutations predict inferior molecular response to nilotinib treatment in chronic myeloid leukemia

Gene mutations independent of BCR::ABL1 have been identified in newly diagnosed patients with chronic myeloid leukemia (CML) in chronic phase, whereby mutations in epigenetic modifier genes were most common. These findings prompted the systematic analysis of prevalence, dynamics, and prognostic significance of such mutations, in a clinically well-characterized patient population of 222 CML patients from the TIGER study (CML-V) by targeted next-generation sequencing covering 54 myeloid leukemia-associated genes. In total, 53/222 CML patients (24%) carried 60 mutations at diagnosis with ASXL1 being most commonly affected (n = 20). To study mutation dynamics, longitudinal deep sequencing analysis of serial samples was performed in 100 patients after 12, 24, and 36 months of therapy. Typical patterns of clonal evolution included eradication, persistence, and emergence of mutated clones. Patients carrying an ASXL1 mutation at diagnosis showed a less favorable molecular response to nilotinib treatment, as a major molecular response (MMR) was achieved less frequently at month 12, 18, and 24 compared to all other patients. Patients with ASXL1 mutations were also younger and more frequently found in the high risk category, suggesting a central role of clonal evolution associated with ASXL1 mutations in CML pathogenesis

BCR-ABL1-independent PI3Kinase activation causing imatinib-resistance

<p>Abstract</p> <p>Background</p> <p>The <it>BCR-ABL1 </it>translocation occurs in chronic myeloid leukemia (CML) and in 25% of cases with acute lymphoblastic leukemia (ALL). The advent of tyrosine kinase inhibitors (TKI) has fundamentally changed the treatment of CML. However, TKI are not equally effective for treating ALL. Furthermore, <it>de novo </it>or <it>secondary </it>TKI-resistance is a significant problem in CML. We screened a panel of <it>BCR-ABL1 </it>positive ALL and CML cell lines to find models for imatinib-resistance.</p> <p>Results</p> <p>Five of 19 <it>BCR-ABL1 </it>positive cell lines were resistant to imatinib-induced apoptosis (KCL-22, MHH-TALL1, NALM-1, SD-1, SUP-B15). None of the resistant cell lines carried mutations in the kinase domain of <it>BCR-ABL1 </it>and all showed resistance to second generation TKI, nilotinib or dasatinib. STAT5, ERK1/2 and the ribosomal S6 protein (RPS6) are <it>BCR-ABL1 </it>downstream effectors, and all three proteins are dephosphorylated by imatinib in sensitive cell lines. TKI-resistant phosphorylation of RPS6, but responsiveness as regards JAK/STAT5 and ERK1/2 signalling were characteristic for resistant cell lines. PI3K pathway inhibitors effected dephosphorylation of RPS6 in imatinib-resistant cell lines suggesting that an oncogene other than <it>BCR-ABL1 </it>might be responsible for activation of the PI3K/AKT1/mTOR pathway, which would explain the TKI resistance of these cells. We show that the TKI-resistant cell line KCL-22 carries a PI3Kα E545G mutation, a site critical for the constitutive activation of the PI3K/AKT1 pathway. Apoptosis in TKI-resistant cells could be induced by inhibition of AKT1, but not of mTOR.</p> <p>Conclusion</p> <p>We introduce five Philadelphia-chromosome positive cell lines as TKI-resistance models. None of these cell lines carries mutations in the kinase domain of <it>BCR-ABL1 </it>or other molecular aberrations previously indicted in the context of imatinib-resistance. These cell lines are unique as they dephosphorylate ERK1/2 and STAT5 after treatment with imatinib, while PI3K/AKT1/mTOR activity remains unaffected. Inhibition of AKT1 leads to apoptosis in the imatinib-resistant cell lines. In conclusion, Ph+ cell lines show a form of imatinib-resistance attributable to constitutive activation of the PI3K/AKT1 pathway. Mutations in <it>PIK3CA</it>, as observed in cell line KCL-22, or PI3K activating oncogenes may undelie TKI-resistance in these cell lines.</p

Axl/Gas6/NFκB signalling in schwannoma pathological proliferation, adhesion and survival.

TAM family receptor tyrosine kinases comprising Tyro3 (Sky), Axl, and Mer are overexpressed in some cancers, correlate with multidrug resistance and contribute to tumourigenesis by regulating invasion, angiogenesis, cell survival and tumour growth. Mutations in the gene coding for a tumour suppressor merlin cause development of multiple tumours of the nervous system such as schwannomas, meningiomas and ependymomas occurring spontaneously or as part of a hereditary disease neurofibromatosis type 2. The benign character of merlin-deficient tumours makes them less responsive to chemotherapy. We previously showed that, amongst other growth factor receptors, TAM family receptors (Tyro3, Axl and Mer) are significantly overexpressed in schwannoma tissues. As Axl is negatively regulated by merlin and positively regulated by E3 ubiquitin ligase CRL4DCAF1, previously shown to be a key regulator in schwannoma growth we hypothesized that Axl is a good target to study in merlin-deficient tumours. Moreover, Axl positively regulates the oncogene Yes-associated protein, which is known to be under merlin regulation in schwannoma and is involved in increased proliferation of merlin-deficient meningioma and mesothelioma. Here, we demonstrated strong overexpression and activation of Axl receptor as well as its ligand Gas6 in human schwannoma primary cells compared to normal Schwann cells. We show that Gas6 is mitogenic and increases schwannoma cell-matrix adhesion and survival acting via Axl in schwannoma cells. Stimulation of the Gas6/Axl signalling pathway recruits Src, focal adhesion kinase (FAK) and NFκB. We showed that NFκB mediates Gas6/Axl-mediated overexpression of survivin, cyclin D1 and FAK, leading to enhanced survival, cell-matrix adhesion and proliferation of schwannoma. We conclude that Axl/FAK/Src/NFκB pathway is relevant in merlin-deficient tumours and is a potential therapeutic target for schwannoma and other merlin-deficient tumours