A digital mental health intervention to reduce depressive symptoms among overseas Filipino workers: Protocol for a pilot hybrid type 1 effectiveness-implementation randomized controlled trial

Background: The current pilot randomized controlled trial (RCT) protocol will comprehensively describe the implementation of a culturally adapted Filipino version of the World Health Organization Step-by-Step (SbS-F) program, unguided online psychological intervention for people with depression based on behavioral activation, among overseas Filipino workers (OFWs) in Macao (Special Administrative Region). The main objective of this pilot study is to explore the preliminary effectiveness of the SbS-F program to decrease participant-reported depressive symptoms compared to enhanced care as usual (ECAU); and the secondary objectives are to explore the preliminary effectiveness of the SbS-F to decrease participant-reported anxiety symptoms and improve wellbeing, and to evaluate the potential for SbS-F implementation in real-world settings. Methods: This trial will follow an effectiveness-implementation hybrid type 1 trial design and utilize the Reach, Efficacy/Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework to accelerate the translation of clinical research into more effective implementation strategies and policies. Participants will be randomized 1:1 to control and treatment groups. Control group participants will receive ECAU that consists of brief depression psychoeducation and referral to local community partners. Treatment group participants will receive a 5-session of digital intervention through a mobile phone application. The primary outcome (depression) and psychological secondary outcomes (anxiety symptoms and wellbeing) will be measured using validated instruments. To evaluate study implementation, an embedded mixed-methods design will be used to collect data from various stakeholders. Data then will be analyzed using intention to treat principle and reported following the Consolidated Standards of Reporting Trials (CONSORT) guideline

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

Effectiveness of a peer-refugee delivered psychological intervention to reduce psychological distress among adult Syrian refugees in the Netherlands: study protocol

Background: Syrian refugees face multiple hardships and adversities which put them at risk for the development of mental health problems. However, access to adequate mental health care in host countries is limited. The WHO has developed Problem Management Plus (PM+), a brief, scalable psychological intervention, delivered by non-specialist helpers, that addresses common mental disorders in people affected by adversity. This study is part of the STRENGTHS project, that aims to evaluate peer-refugee delivered psychological interventions for Syrian refugees in Europe and the Middle East. Objective: To evaluate the effectiveness and cost-effectiveness of the peer-refugee delivered PM+ intervention among Syrian refugees with elevated levels of psychological distress in the Netherlands. Methods: PM+ will be tested in a randomized controlled trial (RCT) among Arabic-speaking Syrian refugees in the Netherlands aged 18 years and above with self-reported psychological distress (Kessler Psychological Distress Scale; K10 >15) and impaired daily functioning (WHO Disability Assessment Schedule; WHODAS 2.0 >16). Participants (N = 380) will be randomized into care as usual with PM+ (CAU/PM+, n = 190) or CAU only (CAU, n = 190). Baseline, 1-week post-intervention, and 3-month and 12-month follow-up assessments will be conducted. Primary outcomes are symptoms of depression and anxiety. Secondary outcomes are functional impairment, posttraumatic stress disorder symptoms, self-identified problems, anger, health and productivity costs, and hair cortisol concentrations. A process evaluation will be carried out to evaluate treatment dose, protocol fidelity and stakeholder views on barriers and facilitators to implementing PM+. Results and Conclusions: PM+ has proved effectiveness in other populations and settings. After positive evaluation, the adapted manual and training materials for individual PM+ will be made available through the WHO to encourage further replication and scaling up. Trial registration: Trial registration Dutch Trial Registry, NL7552, registered prospectively on March 1, 2019. Medical Ethics Review Committee VU Medical Center Protocol ID 2017.320, 7 September 2017

Symptoms of anxiety and depression during the COVID-19 pandemic in six European countries and Australia - Differences by prior mental disorders and migration status

Background: Little is known about changes of mental health during the COVID-19 pandemic in potentially disadvantaged groups. We investigated changes in anxiety and depression symptoms during the first year of the pandemic in six European countries and Australia by prior mental disorders and migration status. Methods: Overall, 4674 adults answered a web-based survey in May-June 2020 and were followed by three repeated surveys up to February 2021. Information on psychosocial, financial and demographic, living conditions, prior mental disorders, depression and anxiety symptoms during the pandemic and migration status was collected. Weighted general estimation equations modelling was used to investigate the association between prior mental disorders, migration status, and symptoms over time. Results: Most participants were <40 years old (48%), women (78%) and highly educated (62%). The baseline prevalence of depressive and anxiety symptoms ranged between 19%-45% and 13%-35%, respectively. In most countries, prevalence rates remained unchanged throughout the pandemic and were higher among people with prior mental disorders than without even after adjustment for several factors. We observed interactions between previous mental disorders and symptoms of anxiety or depression over time in two countries. No difference by migration status was noted. Limitations: Convenience sampling limits generalizability. Self-assessed symptoms of depression and anxiety might involve some misclassification. Conclusions: Depression and anxiety symptoms were worse among individuals with prior mental disorders than without, but there was no clear trend of worsening mental health in the observed groups during the observed period

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

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

mTOR signaling: implications for cancer and anticancer therapy

Mounting evidence links deregulated protein synthesis to tumorigenesis via the translation initiation factor complex eIF4F. Components of this complex are often overexpressed in a large number of cancers and promote malignant transformation in experimental systems. mTOR affects the activity of the eIF4F complex by phosphorylating repressors of the eIF4F complex, the eIF4E binding proteins. The immunosuppressant rapamycin specifically inhibits mTOR activity and retards cancer growth. Importantly, mutations in upstream negative regulators of mTOR cause hamartomas, haemangiomas, and cancers that are sensitive to rapamycin treatment. Such mutations lead to increased eIF4F formation and consequently to enhanced translation initiation and cell growth. Thus, inhibition of translation initiation through targeting the mTOR-signalling pathway is emerging as a promising therapeutic option

SoK: Layer-Two Blockchain Protocols

Blockchains have the potential to revolutionize markets and services. However, they currently exhibit high latencies and fail to handle transaction loads comparable to those managed by traditional financial systems. Layer-two protocols, built on top of layer-one blockchains, avoid disseminating every transaction to the whole network by exchanging authenticated transactions off-chain. Instead, they utilize the expensive and low-rate blockchain only as a recourse for disputes. The promise of layer-two protocols is to complete off-chain transactions in sub-seconds rather than minutes or hours while retaining asset security, reducing fees and allowing blockchains to scale. We systematize the evolution of layer-two protocols over the period from the inception of cryptocurrencies in 2009 until today, structuring the multifaceted body of research on layer-two transactions. Categorizing the research into payment and state channels, commit-chains and protocols for refereed delegation, we provide a comparison of the protocols and their properties. We provide a systematization of the associated synchronization and routing protocols along with their privacy and security aspects. This Systematization of Knowledge (SoK) clears the layer-two fog, highlights the potential of layer-two solutions and identifies their unsolved challenges, indicating propitious avenues of future work

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