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Abstract Transcription factor GATA1 controls the delicate balance between proliferation, differentiation and apoptosis in both the erythroid and megakaryocytic lineages. In addition to full-length GATA1, there is an GATA1 isoform, GATA1s, that lacks the amino-terminal transactivation domain. Somatic GATA1 mutations that lead to the exclusive production of GATA1s appear to be necessary and sufficient for the development of a preleukemic condition called transient myeloproliferative disorder (TMD) in Down syndrome newborns. Subsequent clonal evolution among latent TMD blasts leads to the development of acute megakaryoblastic leukemia (AMKL). We originally established transgenic mice that express only GATA1s, which exhibit hyperproliferation of immature megakaryocytes, thus mimicking human TMD; however, these mice never developed AMKL. Here, we report that transgenic mice expressing moderate levels of GATA1s, i.e., roughly comparable levels to endogenous GATA1, were prone to develop AMKL in young adults. However, when GATA1s is expressed at levels significantly exceeding that of endogenous GATA1, the development of leukemia was restrained in a dose dependent manner. If the transgenic increase of GATA1s in progenitors remains small, GATA1s supports the terminal maturation of megakaryocyte progenitors insufficiently, and consequently the progenitors persisted, leading to an increased probability for acquisition of additional genetic modifications. In contrast, more abundant GATA1s expression compensates for this maturation block, enabling megakaryocytic progenitors to fully differentiate. This study provides evidence for the clinical observation that the abundance of GATA1s correlates well with the progression to AMKL in Down syndrome.

Abstract GATA1 plays a critical role in differentiation, proliferation, and apoptosis during erythropoiesis. We developed a Gata1 knock-down allele (Gata1.05) that results in GATA1 expression at 5% of endogenous level. In female mice heterozygous for both the Gata1.05 and wild-type alleles, we observed a predisposition to erythroblastic leukemia three to six months after birth. Since no male Gata1.05 progeny survive gestation, we originally maintained heterozygous females in a mixed genetic background of C57BL/6J and DBA/2 strains. Around 30% of these mice reproducibly develop leukemia, but the other subset did not develop leukemia, even though they harbor a high number of preleukemic erythroblasts. These observations prompted us to hypothesize that there may be potential influence of genetic determinants on the progression of Gata1.05-driven hematopoietic precursors to full-blown leukemia. In an initial examination of Gata1.05/X mice backcrossed into C3H/He, BALB/c, DBA/2, C57BL/6J and 129X1/SvJ strains, we discerned that the backgrounds of C57BL/6J and 129X1/SvJ significantly expedited leukemia onset in Gata1.05/X mice. Conversely, backgrounds of C3H/He, BALB/c and DBA/2 did not substantially modify the effect of the Gata1 mutation. This indicates the existence of genetic modifiers that accentuate Gata1.05 leukemogenesis. Subsequent cohort studies evaluated Gata1.05/X mice within mix backgrounds of BALB/c:129X1/SvJ and BALB/c:C57BL/6J. In these settings, Gata1.05-driven leukemia manifested in autosomal dominant patterns within the 129X1/SvJ background and in autosomal recessive patterns within C57BL/6J background. To the best of our knowledge, this study provides the inaugural evidence of genetic modifiers that can reshape the outcome based on leukemia-associated gene signatures.

Objective To evaluate co-prescribing of sedatives hypnotics and opioids.Design Retrospective study evaluating the association of patient characteristics and comorbidities with coprescribing.Setting and participants Using the national Merative MarketScan Database between 2005 and 2018, we identified patients who received an incident sedative prescription with or without subsequent, incident opioid prescriptions within a year of the sedative prescription in the USA.Outcome measures Coprescription of sedative-hypnotics and opioids.Results A total of 2 632 622 patients (mean (SD) age, 43.2 (12.34) years; 1 297 356 (62.5%) female) received incident prescriptions for sedatives over the course of the study period. The largest proportion of sedative prescribing included benzodiazepines (71.1%); however, z-drugs (19.9%) and barbiturates (9%) were also common. About 557 845 (21.2%) patients with incident sedatives also received incident opioid prescriptions. About 59.2% of these coprescribed patients received opioids coprescription on the same day. Multivariate logistic regression findings showed that individuals with a comorbidity index score of 1, 2 or ≥3 (aOR 1.19 (95% CI 1.17 to 1.21), 1.17 (95% C 1.14 to 1.19) and 1.25 (95% C 1.2 to 1.31)) and substance use disorder (1.21 (95% C 1.19 to 1.23)) were more likely to be coprescribed opioids and sedatives. The likelihood of receiving both opioid and sedative prescriptions was lower for female patients (aOR 0.93; 95% CI 0.92 to 0.94), and those receiving a barbiturate (aOR 0.3; 95% CI 0.29 to 0.31) or z-drugs (aOR 0.67; 95% CI 0.66 to 0.68) prescriptions at the index date.Conclusions Coprescription of sedatives with opioids was associated with the presence of comorbidities and substance use disorder, gender and types of sedatives prescribed at the index date. Additionally, more than half of the coprescribing occurred on the same day which warrants further evaluation of current prescribing and dispensing best practice guidelines.

: Objectives: To study COVID?19 (Delta Variant) cases and close contacts co?located within households. Focusing on epidemiology of transmission of COVID?19, quarantine duration and utilisation of infection control behaviours under a telehealth model of care in an elimination setting. Methods: A retrospective cohort analysis examined household spread of infection, duration of quarantine and change in PCR CT value during illness. A survey explored infection control behaviours used by household members during isolation and quarantine. Results: The cohort was 141 individuals in 35 households. Thirty?seven were index cases, and 48 became positive during quarantine, most within 10 days. Whole?household infection occurred in 12 households with multiple members. Behaviours focused on fomite transmission reduction rather than preventing aerosol transmission. The median duration of close contact household quarantine was 25 days. The majority of COVID?19 cases were de?isolated after 14 days with no evidence of further community transmission. Conclusion: Intrahousehold transmission was not universal and, if it occurred, usually occurred quickly. Behaviours utilised focused on fomites, suggesting a need for improved education regarding the potential utilisation of strategies to prevention the transmission of aerosols. Households experienced long durations of home?based quarantine. Implications for public health: The impact of long quarantine durations must be considered, particularly where most community benefit from quarantine is achieved within 10 days from exposure in the setting of the Delta Variant. Education of households regarding aerosol risk reduction is a potential strategy in the household setting of individuals at risk of disease progression., The incursion of SARS?CoV?2 into the Australian community from returning travellers and subsequent community transmission has required a significant public health response since the commencement of the pandemic. In the [...]

Abstract Ribosomal protein dysfunction causes diverse human diseases, including Diamond–Blackfan anemia (DBA). Despite the universal need for ribosomes in all cell types, the mechanisms underlying ribosomopathies, which are characterized by tissue-specific defects, are still poorly understood. In the present study, we analyzed the transcriptomes of single purified erythroid progenitors isolated from the bone marrow of DBA patients. These patients were categorized into untreated, glucocorticoid (GC)-responsive and GC-non-responsive groups. We found that erythroid progenitors from untreated DBA patients entered S-phase of the cell cycle under considerable duress, resulting in replication stress and the activation of P53 signaling. In contrast, cell cycle progression was inhibited through induction of the type 1 interferon pathway in treated, GC-responsive patients, but not in GC-non-responsive patients. Notably, a low dose of interferon alpha treatment stimulated the production of erythrocytes derived from DBA patients. By linking the innately shorter cell cycle of erythroid progenitors to DBA pathogenesis, we demonstrated that interferon-mediated cell cycle control underlies the clinical efficacy of glucocorticoids. Our study suggests that interferon administration may constitute a new alternative therapeutic strategy for the treatment of DBA. The trial was registered at www.chictr.org.cn as ChiCTR2000038510.

Abstract Background Hypoxia is a hallmark of the tumor microenvironment (TME) and in addition to altering metabolism in cancer cells, it transforms tumor-associated stromal cells. Within the tumor stromal cell compartment, tumor-associated macrophages (TAMs) provide potent pro-tumoral support. However, TAMs can also be harnessed to destroy tumor cells by monoclonal antibody (mAb) immunotherapy, through antibody dependent cellular phagocytosis (ADCP). This is mediated via antibody-binding activating Fc gamma receptors (FcγR) and impaired by the single inhibitory FcγR, FcγRIIb. Methods We applied a multi-OMIC approach coupled with in vitro functional assays and murine tumor models to assess the effects of hypoxia inducible factor (HIF) activation on mAb mediated depletion of human and murine cancer cells. For mechanistic assessments, siRNA-mediated gene silencing, Western blotting and chromatin immune precipitation were utilized to assess the impact of identified regulators on FCGR2B gene transcription. Results We report that TAMs are FcγRIIbbright relative to healthy tissue counterparts and under hypoxic conditions, mononuclear phagocytes markedly upregulate FcγRIIb. This enhanced FcγRIIb expression is transcriptionally driven through HIFs and Activator protein 1 (AP-1). Importantly, this phenotype reduces the ability of macrophages to eliminate anti-CD20 monoclonal antibody (mAb) opsonized human chronic lymphocytic leukemia cells in vitro and EL4 lymphoma cells in vivo in human FcγRIIb+/+ transgenic mice. Furthermore, post-HIF activation, mAb mediated blockade of FcγRIIb can partially restore phagocytic function in human monocytes. Conclusion Our findings provide a detailed molecular and cellular basis for hypoxia driven resistance to antitumor mAb immunotherapy, unveiling a hitherto unexplored aspect of the TME. These findings provide a mechanistic rationale for the modulation of FcγRIIb expression or its blockade as a promising strategy to enhance approved and novel mAb immunotherapies.

Innovative game-based training methods that leverage the ubiquity of cellphones and familiarity with phone-based interfaces have the potential to transform the training of public health practitioners in low-income countries such as Liberia. This article describes the design, development, and testing of a prototype of the Figure It Out mobile game. The prototype game uses a disease outbreak scenario to promote evidence-based decision-making in determining the causative agent and prescribing intervention measures to minimize epidemiological and logistical burdens in resource-limited settings. An initial prototype of the game developed by the US team was playtested and evaluated by focus groups with 20 University of Liberia Masters of Public Health (UL MPH) students. Results demonstrate that the learning objectives—improving search skills for identifying scientific evidence and considering evidence before decision-making during a public health emergency—were considered relevant and important in a setting that has repeatedly and recently experienced severe threats to public health. However, some of the game mechanics that were thought to enhance engagement such as trial-and-error and choose-your-own-path gameplay, were perceived by the target audience as distracting or too time-consuming, particularly in the context of a realistic emergency scenario. Gameplay metrics that mimicked real-world situations around lives lost, money spent, and time constraints during public health outbreaks were identified as relatable and necessary considerations. Our findings reflect cultural differences between the game development team and end users that have emphasized the need for end users to have an integral part of the design team; this formative evaluation has critically informed next steps in the iterative development process. Our multidisciplinary, cross-cultural and cross-national design team will be guided by Liberia-based public health students and faculty, as well as community members who represent our end user population in terms of experience and needs. These stakeholders will make key decisions regarding game objectives and mechanics, to be vetted and implemented by game design experts, epidemiologists, and software developers.

In 2013, China launched its ‘Belt and Road Initiative’ (BRI) as a major effort to enhance international trade and economic development. An important feature of the BRI is that it supports free trade regimes and a world economy based upon open regional cooperation. The concept of BRI involves establishing a transport route between China and participating countries to provide more profitable trade and investment corridors. There are few comprehensive studies examining the social and environmental impact on development in recipient countries. To address this gap, this study gathered empirical evidence on railroad projects in three key countries: Indonesia, Ethiopia, and Kenya. The comparative analysis revealed that while political leaders signed agreements that welcomed China’s BRI in support of their national transport development plans, the implementation of these ambitious infrastructure projects faced significant management and operational challenges that had not been foreseen by the Chinese partners. More effective implementation of BRI infrastructure projects in the future will require better understandings of governance, specifically through harmonization with the cultural, institutional and political contexts in partner countries. Social and cultural characteristics of the countries where Chinese firms are working need to be well understood if sustainable and inclusive benefits from the BRI infrastructure projects are to be delivered. Further research on the benefits gained by local people living in the areas affected by the BRI investments is needed.

Deep venous thrombosis (DVT) and secondary pulmonary embolism cause approximately 100,000 deaths per year in the United States. Physical immobility is the most significant risk factor for DVT, but a molecular and cellular basis for this link has not been defined. We found that the endothelial cells surrounding the venous valve, where DVTs originate, express high levels of FOXC2 and PROX1, transcription factors known to be activated by oscillatory shear stress. The perivalvular venous endothelial cells exhibited a powerful antithrombotic phenotype characterized by low levels of the prothrombotic proteins vWF, P-selectin, and ICAM1 and high levels of the antithrombotic proteins thrombomodulin (THBD), endothelial protein C receptor (EPCR), and tissue factor pathway inhibitor (TFPI). The perivalvular antithrombotic phenotype was lost following genetic deletion of FOXC2 or femoral artery ligation to reduce venous flow in mice, and at the site of origin of human DVT associated with fatal pulmonary embolism. Oscillatory blood flow was detected at perivalvular sites in human veins following muscular activity, but not in the immobile state or after activation of an intermittent compression device designed to prevent DVT. These findings support a mechanism of DVT pathogenesis in which loss of muscular activity results in loss of oscillatory shear-dependent transcriptional and antithrombotic phenotypes in perivalvular venous endothelial cells, and suggest that prevention of DVT and pulmonary embolism may be improved by mechanical devices specifically designed to restore perivalvular oscillatory flow., Introduction Deep venous thrombosis (DVT) is a common vascular disease with an annual incidence of 0.1% among the general population, and more than 1% among hospitalized individuals (1). Pulmonary embolism--the [...]