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Non-communicable diseases (NCDs) are the leading cause of death worldwide. Inadequate and inequitable access to essential NCD medicines is a major concern, particularly in low- and middle-income countries. National Essential Medicines Lists (EMLs) are important policy tools that indicate which medicines are prioritized as essential within a country's health system. This study sought to analyze a wide range of national essential medicines lists (EMLs) for their inclusion of priority non communicable disease (NCD) interventions recommended by the World Health Organization (WHO). Three lists of WHO endorsed priority NCD interventions were included. A database with 137 national EMLs and the WHO EML was created from the WHO Repository and these EMLs were compared for listing of priority NCD interventions. Across 137 countries with national EMLs, the median percentage of 20 Best Buys interventions listed was 90% (IQR 80-95) and 31 Package of essential noncommunicable disease interventions (PEN) interventions listed was 94% (IQR 90-97), of 9 HEARTS interventions was 100% (IQR 89-100), and of the 43 unique interventions across the three priority lists was 88% (IQR 84-93). Less than 80% of the 43 interventions were listed by 22 (16%) countries and less than half of the interventions were listed by 2 countries: Angola (35%) and Cambodia (23%). Interventions listed on the fewest number of national EMLs were: influenza vaccine, HPV vaccine, hepatitis B vaccine, cervical cancer chemotherapy, codeine, promethazine, senna, and oxygen. Most NCD interventions have been prioritized in national policy in most cases. The majority of priority medicines for NCDs described within key WHO NCD technical packages are listed on nearly all national EMLs across 137 countries of all income levels. Most NCD interventions have been prioritized in national policy in most cases, but in some countries and for select interventions such as the HPV vaccine, prioritization may be reviewed.

The RNA interference (RNAi) machinery is a key cellular mechanism catalyzing biogenesis and function of miRNAs to post-transcriptionally regulate mRNA expression. The RNAi machinery includes a set of protein complexes with subcellular localization traditionally presented in a uniform fashion: the microprocessor processes miRNAs in the nucleus, whereas the DICER and the RNA-induced silencing complex (RISC) further process and enable activity of miRNAs in the cytoplasm. However, several studies have identified subcellular patterns of RNAi components that deviate from this model. We have particularly shown that RNAi complexes associate with the adherens junctions of well-differentiated epithelial cells, through the E-cadherin partner PLEKHA7. To assess the extent of these subcellular topological patterns, we examined subcellular localization of the microprocessor and RISC in a series of human cell lines and normal human tissues. Our results show that junctional localization of RNAi components is a broad characteristic of differentiated epithelia, but it is absent in transformed or mesenchymal cells and tissues. We also find extensive localization of the microprocessor in the cytoplasm, as well as of RISC in the nucleus. These findings expose a RNAi machinery with multifaceted subcellular topology that may inform its physiological role and calls for updating of the current models.

Policy approaches have been considered to address inconsistent and inequitable prescription drug coverage in Canada, including a national essential medicines list. We sought to explore key factors influencing the acceptability and feasibility of an essential medicines list in Canada. We conducted semi-structured interviews with decision-makers and other key stakeholders from government or pan-Canadian institutions, civil society and the private sector across Canada. We analyzed data using inductive thematic analysis and by applying Kingdon’s Multiple Streams Framework to analyze the emergent themes deductively. We conducted 21 interviews before thematic saturation was achieved. We categorized emergent themes to describe the problem, the essential medicines list policy (including content and process), and politics. There was consensus among participants that prescription drug coverage was an important problem to address. Participants differed in their views on how to define essential medicines and concerns about what would be excluded from an essential medicines list. There was consensus on important features for a process to develop an essential medicines list: an independent decision-making body, use of defined selection criteria based on quality evidence, and clear communication of the purpose of the essential medicines list. Federal government financing and the broader pharmacare model, engagement of various interest groups and changing political agendas emerged as core political factors to consider if developing a Canadian essential medicines list. Although stakeholders’ views on the content of a Canadian essential medicines list varied, there was consensus on the process to formulate and implement an essential medicines list or common national formulary, including choosing medicines based on best evidence. Greater understanding is now needed on how patients, clinicians and the public perceive the concept of an essential medicines list.

Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer. Most MCCs contain Merkel cell polyomavirus (virus-positive MCC; VP-MCC), and the remaining are virus-negative (VN-MCC). Immune checkpoint inhibitors are the first-line treatment for metastatic MCC, but durable responses are achieved in less than 50% of patients. To identify new treatments, we screen ~4,000 compounds for their ability to reduce MCC viability and demonstrate that VP-MCC and VN-MCC exhibit distinct response profiles. Aurora kinase inhibitors selectively reduce VP-MCC viability, with RNAi screening independently identifying AURKB as an essential gene for MCC survival, especially in VP-MCC. AZD2811, a selective AURKB inhibitor, induces mitotic dysregulation and apoptosis in MCC cells, with greater efficacy in VP-MCC. In mice, AZD2811 nanoparticles inhibit tumor growth and increase survival in both VP-MCC and VN-MCC xenograft models. Overall, our unbiased screens identify AURKB as a promising therapeutic target and AZD2811NP as a potential treatment for MCC. Merkel cell carcinoma (MCC) is a rare aggressive skin cancer with limited therapeutic options. In this work, the authors identify aurora kinase B (AURKB) as a critical therapeutic target for MCC, supported by tumour shrinkage and increased survival when using the AURKB inhibitor AZD2811 nanoparticle formulation in MCC preclinical models.

NCDs are the leading causes of death,2 causing 16 million premature deaths annually.3 Four main groups of noncommunicable diseases - cardiovascular diseases, cancers, chronic respiratory diseases and diabetes - account for 82% of all NCD attributable deaths.3 By 2025, the global economic cost from these four groups of diseases is predicted to surpass 51 trillion United States dollars.4 Despite a common assumption that NCDs are \"diseases of affluence\" only affecting people in wealthy nations, NCDs disproportionately affect people in low- and middle-income countries.

In The Lancet (July 22, p 346),1 Richard Horton asked why the global health community is failing to effectively respond to the global rise of non-communicable diseases (NCDs). A number of opportunities for progress were highlighted. Our two organisations, NCDFREE and the Young Professionals Chronic Disease Network (YP-CDN), are firmly committed to tackling the global challenge of NCDs through advocacy and collaboration that leverages the power of young people.

The modern access-to-medicines movement grew largely out of the civil-society reaction to the HIV/AIDS pandemic three decades ago. While the movement was successful with regard to HIV/AIDS medications, the increasingly urgent challenge to address access to medicines for noncommunicable diseases has lagged behind-and, in some cases, has been forgotten. In this article we first ask what causes the access gap with respect to lifesaving essential noncommunicable disease medicines and then what can be done to close the gap. Using the example of the push for access to antiretrovirals for HIV/AIDS patients for comparison, we highlight the problems of inadequate global financing and procurement for noncommunicable disease medications, intellectual property barriers and concerns raised by the pharmaceutical industry, and challenges to building stronger civil-society organizations and a patient and humanitarian response from the bottom up to demand treatment. We provide targeted policy recommendations, specific to the public sector, the private sector, and civil society, with the goal of improving access to noncommunicable disease medications globally.

Background Several malaria vaccines are currently in clinical trials and are expected to provide an improved strategy for malaria control. Prior to introduction of a new vaccine, policymakers must consider the socio cultural environment of the region to ensure widespread community approval. This study investigated the acceptance of a malaria vaccine by child caregivers and analysed factors that influence these. Methods Interviews from a standard questionnaire were conducted with 2,003 caregivers at 695 randomly selected health facilities across Kenya during the Kenya Service Provision Assessment Survey 2010. Multinomial regression of quantitative data was conducted using STATA to analyse determinants of caregivers accepting malaria vaccination of their child. Results Mothers represented 90% of caregivers interviewed who brought their child to the health facility, and 77% of caregivers were 20-34 years old. Overall, 88% of respondents indicated that they would accept a malaria vaccine, both for a child in their community and their own child. Approval for a vaccine was highest in malaria-endemic Nyanza Province at 98.9%, and lowest in the seasonal transmission area of North Eastern Province at 23%. Although 94% of respondents who had attended at least some school reported they would accept the vaccine for a child, only 56% of those who had never attended school would do so. The likelihood of accepting one’s own child to be immunized was correlated with province, satisfaction with health care services in the facility attended, age of the caregiver, and level of education. Conclusions Results from this study indicate a need for targeted messages and education on a malaria vaccine, particularly for residents of regions where acceptance is low, older caregivers, and those with low literacy and school-attendance levels. This study provides critical evidence to inform policy for a new malaria vaccine that will support its timely and comprehensive uptake in Kenya.

Background Leukemia is a heterogeneous disease commonly associated with recurrent chromosomal translocations that involve tyrosine kinases including BCR-ABL, TEL-PDGFRB and TEL-JAK2. Most studies on the activated tyrosine kinases have focused on proximal signaling events, but little is known about gene transcription regulated by these fusions. Methods Oligonucleotide microarray was performed to compare mRNA changes attributable to BCR-ABL, TEL-PDGFRB and TEL-JAK2 after 1 week of activation of each fusion in Ba/F3 cell lines. Imatinib was used to control the activation of BCR-ABL and TEL-PDGFRB, and TEL-JAK2-mediated gene expression was examined 1 week after Ba/F3-TEL-JAK2 cells were switched to factor-independent conditions. Results Microarray analysis revealed between 800 to 2000 genes induced or suppressed by two-fold or greater by each tyrosine kinase, with a subset of these genes commonly induced or suppressed among the three fusions. Validation by Quantitative PCR confirmed that eight genes (Dok2, Mrvi1, Isg20, Id1, gp49b, Cxcl10, Scinderin, and collagen Vα1(Col5a1)) displayed an overlapping regulation among the three tested fusion proteins. Stat1 and Gbp1 were induced uniquely by TEL-PDGFRB. Conclusions Our results suggest that BCR-ABL, TEL-PDGFRB and TEL-JAK2 regulate distinct and overlapping gene transcription profiles. Many of the genes identified are known to be involved in processes associated with leukemogenesis, including cell migration, proliferation and differentiation. This study offers the basis for further work that could lead to an understanding of the specificity of diseases caused by these three chromosomal translocations.