External skeletal fixation for the treatment of pelvic fractures in cats.

OBJECTIVE: To report the technique and the outcome for the repair of pelvic fractures in cats using external skeletal fixation (ESF). STUDY DESIGN: Retrospective case series. ANIMALS: Client-owned cats (n = 125). METHODS: Medical records of cats with pelvic fractures, treated with an ESF between June 2001 and June 2009, were reviewed. Preoperative, immediate postoperative, and more than 4 weeks' postoperative radiographs were compared. Clinical examination was performed 4 to 9 weeks following surgery. Longer term follow up (4 to 80 months) was conducted by client questionnaire. RESULTS: No intraoperative complications occurred. There was no change in the pelvic canal width observed on follow-up radiographs (p = .16). Implant loosening was noted on follow-up radiographs in 16/125 (13%) of cases, and 67/803 (8%) pins were palpably loose at the time of frame removal. The mean time to frame removal was 37 ± 9 days. No long-term complications were reported. Long-term mean mobility score was 95 ± 5 and median lameness was 0 (range: 0-2). CONCLUSION: An ESF may be successfully applied for the stabilization of various pelvic fractures in cats. CLINICAL SIGNIFICANCE: The application of an ESF for the management of pelvic fractures in cats provides good outcomes.

MYC acetylated lysine residues drive oncogenic cell transformation and regulate select genetic programs for cell adhesion-independent growth and survival.

The MYC oncogenic transcription factor is acetylated by the p300 and GCN5 histone acetyltransferases. The significance of MYC acetylation and the functions of specific acetylated lysine (AcK) residues have remained unclear. Here, we show that the major p300-acetylated K148(149) and K157(158) sites in human (or mouse) MYC and the main GCN5-acetylated K323 residue are reversibly acetylated in various malignant and nonmalignant cells. Oncogenic overexpression of MYC enhances its acetylation and alters the regulation of site-specific acetylation by proteasome and deacetylase inhibitors. Acetylation of MYC at different K residues differentially affects its stability in a cell type-dependent manner. Lysine-to-arginine substitutions indicate that although none of the AcK residues is required for MYC stimulation of adherent cell proliferation, individual AcK sites have gene-specific functions controlling select MYC-regulated processes in cell adhesion, contact inhibition, apoptosis, and/or metabolism and are required for the malignant cell transformation activity of MYC. Each AcK site is required for anchorage-independent growth of MYC-overexpressing cells in vitro, and both the AcK148(149) and AcK157(158) residues are also important for the tumorigenic activity of MYC transformed cells in vivo. The MYC AcK site-specific signaling pathways identified may offer new avenues for selective therapeutic targeting of MYC oncogenic activities.

Single-cell mapping identifies MSI+ cells as a common origin for diverse subtypes of pancreatic cancer.

Identifying the cells from which cancers arise is critical for understanding the molecular underpinnings of tumor evolution. To determine whether stem/progenitor cells can serve as cells of origin, we created a Msi2-CreERT2 knock-in mouse. When crossed to CAG-LSL-MycT58A mice, Msi2-CreERT2 mice developed multiple pancreatic cancer subtypes: ductal, acinar, adenosquamous, and rare anaplastic tumors. Combining single-cell genomics with computational analysis of developmental states and lineage trajectories, we demonstrate that MYC preferentially triggers transformation of the most immature MSI2+ pancreas cells into multi-lineage pre-cancer cells. These pre-cancer cells subsequently diverge to establish pancreatic cancer subtypes by activating distinct transcriptional programs and large-scale genomic changes, and enforced expression of specific signals like Ras can redirect subtype specification. This study shows that multiple pancreatic cancer subtypes can arise from a common pool of MSI2+ cells and provides a powerful model to understand and control the programs that shape divergent fates in pancreatic cancer.

Wafer-Scale Synthesis of 2D Materials by an Amorphous Phase-Mediated Crystallization Approach.

The interest in the wafer-scale growth of two-dimensional (2D) materials, including transition metal dichalcogenides (TMDCs), has been rising for transitioning from lab-scale devices to commercial-scale systems. Among various synthesis techniques, physical vapor deposition, such as pulsed laser deposition (PLD), has shown promise for the wafer-scale growth of 2D materials. However, due to the high volatility of chalcogen atoms (e.g., S and Se), films deposited by PLD usually suffer from a lack of stoichiometry and chalcogen deficiency. To mitigate this issue, excess chalcogen is necessary during the deposition, which results in problems like uniformity or not being repeatable. This study demonstrates a condensed-phase or amorphous phase-mediated crystallization (APMC) approach for the wafer-scale synthesis of 2D materials. This method uses a room-temperature PLD process for the deposition and formation of amorphous precursors with controlled thicknesses, followed by a post-deposition crystallization process to convert the amorphous materials to crystalline structures. This approach maintains the stoichiometry of the deposited materials throughout the deposition and crystallization process and enables the large-scale synthesis of crystalline 2D materials (e.g., MoS2 and WSe2) on Si/SiO2 substrates, which is critical for future wafer-scale electronics. We show that the thickness of the layers can be digitally controlled by the number of laser pulses during the PLD phase. Optical spectroscopy is used to monitor the crystallization dynamics of amorphous layers as a function of annealing temperature. The crystalline quality, domain sizes, and the number of layers were explored using nanoscale and atomistic characterization (e.g., AFM, STEM, and EDS) along with electrical characterization to explore process-structure-performance relationships. This growth technique is a promising method that could potentially be adopted in conventional semiconductor industries for wafer-scale manufacturing of next-generation electronic and optoelectronic devices.

From design to action: participatory approach to capacity building needs for local overdose response plans.

BACKGROUND: In response to the rise in opioid-related deaths, communities across Ontario have developed opioid or overdose response plans to address issues at the local level. Public Health Ontario (PHO) leads the Community Opioid / Overdose Capacity Building (COM-CAP) project, which aims to reduce overdose-related harms at the community level by working with communities to identify, develop, and evaluate capacity building supports for local needs around overdose planning. The 'From Design to Action' co-design workshop used a participatory design approach to engage communities in identifying the requirements for capacity building support. METHODS: A participatory approach (co-design) provided opportunity for collaborative discussion around capacity building needs at the community level. The co-design workshop included three structured collaborative activities to 1) prioritize scenarios that illustrated various challenges associated with community overdose response planning, 2) prioritize the challenges within each scenario and 3) prioritize the supports to address each of these challenges. It was conducted with fifty-two participants involved in opioid/overdose-related response plans in Ontario. Participatory materials were informed by the results of a situational assessment (SA) data gathering process, including survey, interview, and focus group data. A voting system, including dot stickers and discussion notes, was applied to identify priority supports and delivery mechanisms. RESULTS: At the workshop, key challenges and top-priority supports were identified, for development and implementation. The prioritized challenges were organized into five categories of capacity building supports addressing: 1) stigma & equity; 2) trust-based relationships, consensus building & on-going communication; 3) knowledge development & on-going access to information and data; 4) tailored strategies and plan adaptation to changing structures and local context; and 5) structural enablers and responsive governance. CONCLUSION: Using a participatory approach, the workshop provided an opportunity for sharing, generating, and mobilizing knowledge to address research-practice gaps at the community level for opioid response planning. The application of health design methods such as the 'From Design to Action' co-design workshop supports teams to gain a deeper understanding of needs for capacity building as well as illustrating the application of participatory approaches in identifying capacity building needs for complex public health issues such as the overdose crisis.

Smarcd3 is an epigenetic modulator of the metabolic landscape in pancreatic ductal adenocarcinoma.

Pancreatic cancer is characterized by extensive resistance to conventional therapies, making clinical management a challenge. Here we map the epigenetic dependencies of cancer stem cells, cells that preferentially evade therapy and drive progression, and identify SWI/SNF complex member SMARCD3 as a regulator of pancreatic cancer cells. Although SWI/SNF subunits often act as tumor suppressors, we show that SMARCD3 is amplified in cancer, enriched in pancreatic cancer stem cells and upregulated in the human disease. Diverse genetic mouse models of pancreatic cancer and stage-specific Smarcd3 deletion reveal that Smarcd3 loss preferentially impacts established tumors, improving survival especially in context of chemotherapy. Mechanistically, SMARCD3 acts with FOXA1 to control lipid and fatty acid metabolism, programs associated with therapy resistance and poor prognosis in cancer. These data identify SMARCD3 as an epigenetic modulator responsible for establishing the metabolic landscape in aggressive pancreatic cancer cells and a potential target for new therapies.

Wiskostatin and other carbazole scaffolds as off target inhibitors of dynamin I GTPase activity and endocytosis.

Wiskostatin (1-(3,6-dibromo-9H-carbazol-9-yl)-3-(dimethylamino)propan-2-ol) (1) is a carbazole-based compound reported as a specific and relatively potent inhibitor of the N-WASP actin remodelling complex (S-isomer EC50 = 4.35 µM; R-isomer EC50 = 3.44 µM). An NMR solution structure showed that wiskostatin interacts with a cleft in the regulatory GTPase binding domain of N-WASP. However, numerous studies have reported wiskostatin's actions on membrane transport and cytokinesis that are independent of the N-WASP-Arp2/3 complex pathway, but offer limited alternative explanation. The large GTPase, dynamin has established functional roles in these pathways. This study reveals that wiskostatin and its analogues, as well as other carbazole-based compounds, are inhibitors of helical dynamin GTPase activity and endocytosis. We characterise the effects of wiskostatin on in vitro dynamin GTPase activity, in-cell endocytosis, and determine the importance of wiskostatin functional groups on these activities through design and synthesis of libraries of wiskostatin analogues. We also examine whether other carbazole-based scaffolds frequently used in research or the clinic also modulate dynamin and endocytosis. Understanding off-targets for compounds used as research tools is important to be able to confidently interpret their action on biological systems, particularly when the target and off-targets affect overlapping mechanisms (e.g. cytokinesis and endocytosis). Herein we demonstrate that wiskostatin is a dynamin inhibitor (IC50 20.7 ± 1.2 µM) and a potent inhibitor of clathrin mediated endocytosis (IC50 = 6.9 ± 0.3 µM). Synthesis of wiskostatin analogues gave rise to 1-(9H-carbazol-9-yl)-3-((4-methylbenzyl)amino)propan-2-ol (35) and 1-(9H-carbazol-9-yl)-3-((4-chlorobenzyl)amino)propan-2-ol (43) as potent dynamin inhibitors (IC50 = 1.0 ± 0.2 µM), and (S)-1-(3,6-dibromo-9H-carbazol-9-yl)-3-(dimethylamino)propan-2-ol (8a) and (R)-1-(3,6-dibromo-9H-carbazol-9-yl)-3-(dimethylamino)propan-2-ol (8b) that are amongst the most potent inhibitors of clathrin mediated endocytosis yet reported (IC50 = 2.3 ± 3.3 and 2.1 ± 1.7 µM, respectively).

Identification of a Musashi2 translocation as a novel oncogene in myeloid leukemia.

Myeloid leukemias, diseases marked by aggressiveness and poor outcomes, are frequently triggered by oncogenic translocations. In the case of chronic myelogenous leukemia (CML) the BCR-ABL fusion initiates chronic phase disease with second hits allowing progression to blast crisis. Although Gleevec has been transformative for CML, blast crisis CML remains relatively drug resistant. Here we show that MSI2-HOXA9, a translocation with an unknown role in cancer, can serve as a second hit in driving bcCML. Compared to BCR-ABL, BCR-ABL/MSI2-HOXA9 led to a more aggressive disease in vivo with decreased latency, increased lethality and a differentiation blockade that is a hallmark of blast crisis. Domain mapping revealed that the MSI2 RNA binding domain RRM1 had a preferential impact on growth and lethality of bcCML relative to RRM2 or the HOXA9 domain. Mechanistically, MSI2-HOXA9 triggered global downstream changes with a preferential upregulation of mitochondrial components. Consistent with this, BCR-ABL/MSI2-HOXA9 cells exhibited a significant increase in mitochondrial respiration. These data suggest that MSI2-HOXA9 acts, at least in part, by increasing expression of the mitochondrial polymerase Polrmt and augmenting mitochondrial function and basal respiration in blast crisis. Collectively, our findings demonstrate for the first time that translocations involving the stem and developmental signal MSI2 can be oncogenic, and suggest that MSI, which we found to be a frequent partner for an array of translocations, could also be a driver mutation across solid cancers.

Emplacement of the Franklin large igneous province and initiation of the Sturtian Snowball Earth.

During the Cryogenian (720 to 635 Ma ago) Snowball Earth glaciations, ice extended to sea level near the equator. The cause of this catastrophic failure of Earth's thermostat has been unclear, but previous geochronology has suggested a rough coincidence of glacial onset with one of the largest magmatic episodes in the geological record, the Franklin large igneous province. U-Pb geochronology on zircon and baddeleyite from sills associated with the paleo-equatorial Franklin large igneous province in Arctic Canada record rapid emplacement between 719.86 ± 0.21 and 718.61 ± 0.30 Ma ago, 0.9 to 1.6 Ma before the onset of widespread glaciation. Geologic observations and (U-Th)/He dates on Franklin sills are compatible with major post-Franklin exhumation, possibly due to development of mafic volcanic highlands on windward equatorial Laurentia and increased global weatherability. After a transient magmatic CO2 flux, long-term carbon sequestration associated with increased weatherability could have nudged Earth over the threshold for runaway ice-albedo feedback.

Supporting community overdose response planning in Ontario, Canada: Findings from a situational assessment.

BACKGROUND: Many communities across North America are coming together to develop comprehensive plans to address and respond to the escalating overdose crisis, largely driven by an increasingly toxic unregulated drug supply. As there is a need to build capacity for successful implementation, the objective of our mixed methods study was to identify the current planning and implementation practices, needs, and priority areas of support for community overdose response plans in Ontario, Canada. METHODS: We used a situational assessment methodology to collect data on current planning and implementation practices, needs, and challenges related to community overdose response plans in Ontario, consisting of three components. Between November 2019 to February 2020, we conducted ten semi-structured key informant interviews, three focus groups with 25 participants, and administered an online survey (N = 66). Purposeful sampling was used to identify professionals involved in coordinating, supporting, or partnering on community overdose response plans in jurisdictions with relevant information for Ontario including other Canadian provinces and American states. Key informants included evaluators, representatives involved in centralised supports, as well as coordinators and partners on community overdose response plans. Focus group participants were coordinators or leads of community overdose response plans in Ontario. RESULTS: Sixty-six professionals participated in the study. The current planning and implementation practices of community overdose response plans varied in Ontario. Our analysis generated four overarching areas for needs and support for the planning and implementation of community overdose response plans: 1) data and information; 2) evidence and practice; 3) implementation/operational factors; and 4) partnership, engagement, and collaboration. Addressing stigma and equity within planning and implementation of community overdose response plans was a cross-cutting theme that included meaningful engagement of people with living and lived expertise and meeting the service needs of different populations and communities. CONCLUSIONS: Through exploring the needs and related supports for community overdose response plans in Ontario, we have identified key priority areas for building local capacity building to address overdose-related harms. Ongoing development and refinement, community partnership, and evaluation of our project will highlight the influence of our supports to advance the capacity, motivation, and opportunities of community overdose response plans.

Density, viscosity, speed of sound, flash point, bulk modulus, and surface tension of mixtures of military jet fuel JP-5 and biodiesels dataset.

In this work, the density, viscosity, speed of sound, flash point, and surface tension of mixtures of military jet fuel JP-5 and biodiesels were measured at various temperatures. The biodiesels were synthesized from various oils (avocado, canola, castor, coconut, corn grapeseed, linseed, neem, oil, palm, peanut, soybean, and walnuts), bacon grease, and duck fat. The isentropic bulk modulus was calculated from the speed of sound and density. These physical properties are important for modeling the spray of fuel into a diesel engine cylinder.

"We are not stray leaves blowing about in the wind": exploring the impact of Family Wellbeing empowerment research, 1998-2021.

BACKGROUND: An Aboriginal-developed empowerment and social and emotional wellbeing program, known as Family Wellbeing (FWB), has been found to strengthen the protective factors that help Indigenous Australians to deal with the legacy of colonisation and intergenerational trauma. This article reviews the research that has accompanied the implementation of the program, over a 23 year period. The aim is to assess the long-term impact of FWB research and identify the key enablers of research impact and the limitations of the impact assessment exercise. This will inform more comprehensive monitoring of research impact into the future. METHODS: To assess impact, the study took an implementation science approach, incorporating theory of change and service utilisation frameworks, to create a logic model underpinned by Indigenous research principles. A research impact narrative was developed based on mixed methods analysis of publicly available data on: 1) FWB program participation; 2) research program funding; 3) program outcome evaluation (nine studies); and 4) accounts of research utilisation (seven studies). RESULTS: Starting from a need for research on empowerment identified by research users, an investment of $2.3 million in research activities over 23 years produced a range of research outputs that evidenced social and emotional wellbeing benefits arising from participation in the FWB program. Accounts of research utilisation confirmed the role of research outputs in educating participants about the program, and thus, facilitating more demand (and funding acquisition) for FWB. Overall research contributed to 5,405 recorded participants accessing the intervention. The key enablers of research impact were; 1) the research was user- and community-driven; 2) a long-term mutually beneficial partnership between research users and researchers; 3) the creation of a body of knowledge that demonstrated the impact of the FWB intervention via different research methods; 4) the universality of the FWB approach which led to widespread application. CONCLUSIONS: The FWB research impact exercise reinforced the view that assessing research impact is best approached as a "wicked problem" for which there are no easy fixes. It requires flexible, open-ended, collaborative learning-by-doing approaches to build the evidence base over time. Steps and approaches that research groups might take to build the research impact knowledge base within their disciplines are discussed.

An analysis of the impact of policies and political affiliation on racial disparities in COVID-19 infections and deaths in the USA.

This research aimed to quantify the racial disparities of COVID-19 for primarily positive tests and deaths across the US and territories individually and collectively. The first research hypothesis investigated whether positive cases and death rates were higher for people of color (POC) than the White ethnic group. The second hypothesis examined whether there is a significant difference in confirmed positive cases and death rates between ethnic groups across the US and territories. The third hypothesis investigated if political party control and governmental policies affected the number of cases and death proportion rates across ethnic groups. The research findings suggest that POC positive cases and death rates were higher in some states. Black ethnic groups were dying at a high rate in the southeastern states, the District of Columbia, and in Maryland. Specifically, in the District of Columbia, the death rate is five times higher than the White ethnic group. For Latinx ethnic groups, the high cases and death rates have mostly occurred in western states, including Texas. The Latinx ethnic group accounted for half the total deaths in Texas and California. The Latinx ethnic group death rate is higher than the White ethnic group in four states: Texas, California, New Mexico, and the District of Columbia. The research findings also show that the rate of deaths and cases per ethnic group for policies and political factors were significant except for the mask mandate policy. Based on the analyzed data, mask mandates were not a factor in the cases or death rates of any ethnic group. Each state's policies for bars, curfews, public schools, and travel-along with legislative party control-had the most influences across ethnic groups. The research results for the death rates and number of cases due to these implemented policies varied between ethnic groups.

Vulnerabilities for Drug Diversion in the Handling, Data Entry, and Verification Tasks of 2 Inpatient Hospital Pharmacies: Clinical Observations and Healthcare Failure Mode and Effect Analysis.

OBJECTIVES: Inpatient hospital pharmacies have a central role in managing controlled substances (CS) throughout the hospital medication use process (MUP). Our objectives were to identify vulnerabilities for diversion in the MUPs of 2 inpatient pharmacies, explore differences between the sites, and characterize the types of vulnerabilities identified. METHODS: We conducted clinical observations in 2 pharmacies to map their MUPs and performed a healthcare failure mode and effect analysis to proactively identify (1) the critical failure modes (CFMs) that make them vulnerable to diversion and (2) the controls that prevent, mitigate, or enhance the detectability of CFMs. RESULTS: We conducted 99 hours of observations between May-June and September-October 2018. We observed 36 pharmacy technicians, 4 pharmacists, and 1 clerk as they conducted tasks involving 4 processes common to both sites: procuring CS, receiving CS deliveries to the pharmacy, unit-dose packaging CS oral solids, and distributing CS to hospital units. The tasks and subtasks we mapped in the process flow diagrams led to the identification of 220 failure modes. Of these, 34 were deemed CFMs and were categorized as related to handling CS, data entry, or verification tasks. Three of the CFMs were unique to one site, given that the other site had a control for the CFM. CONCLUSIONS: Multiple vulnerabilities for diversion exist in inpatient pharmacy processes. Our results provide some much needed detail about how specific vulnerabilities in MUP tasks and subtasks lead to an increased risk of diversion.

Toward Learning in Neuromorphic Circuits Based on Quantum Phase Slip Junctions.

We explore the use of superconducting quantum phase slip junctions (QPSJs), an electromagnetic dual to Josephson Junctions (JJs), in neuromorphic circuits. These small circuits could serve as the building blocks of neuromorphic circuits for machine learning applications because they exhibit desirable properties such as inherent ultra-low energy per operation, high speed, dense integration, negligible loss, and natural spiking responses. In addition, they have a relatively straight-forward micro/nano fabrication, which shows promise for implementation of an enormous number of lossless interconnections that are required to realize complex neuromorphic systems. We simulate QPSJ-only, as well as hybrid QPSJ + JJ circuits for application in neuromorphic circuits including artificial synapses and neurons, as well as fan-in and fan-out circuits. We also design and simulate learning circuits, where a simplified spike timing dependent plasticity rule is realized to provide potential learning mechanisms. We also take an alternative approach, which shows potential to overcome some of the expected challenges of QPSJ-based neuromorphic circuits, via QPSJ-based charge islands coupled together to generate non-linear charge dynamics that result in a large number of programmable weights or non-volatile memory states. Notably, we show that these weights are a function of the timing and frequency of the input spiking signals and can be programmed using a small number of DC voltage bias signals, therefore exhibiting spike-timing and rate dependent plasticity, which are mechanisms to realize learning in neuromorphic circuits.

Two-Dimensional-Material-Based Field-Effect Transistor Biosensor for Detecting COVID-19 Virus (SARS-CoV-2).

The emergence of rapidly expanding infectious diseases such as coronavirus (COVID-19) demands effective biosensors that can promptly detect and recognize the pathogens. Field-effect transistors based on semiconducting two-dimensional (2D) materials (2D-FETs) have been identified as potential candidates for rapid and label-free sensing applications. This is because any perturbation of such atomically thin 2D channels can significantly impact their electronic transport properties. Here, we report the use of FET based on semiconducting transition metal dichalcogenide (TMDC) WSe2 as a promising biosensor for the rapid and sensitive detection of SARS-CoV-2 in vitro. The sensor is created by functionalizing the WSe2 monolayers with a monoclonal antibody against the SARS-CoV-2 spike protein and exhibits a detection limit of down to 25 fg/µL in 0.01X phosphate-buffered saline (PBS). Comprehensive theoretical and experimental studies, including density functional theory, atomic force microscopy, Raman and photoluminescence spectroscopies, and electronic transport properties, were performed to characterize and explain the device performance. The results demonstrate that TMDC-based 2D-FETs can potentially serve as sensitive and selective biosensors for the rapid detection of infectious diseases.

Implementing Virtual Reality technology for safety training in the precast/ prestressed concrete industry.

Thousands of people work in the precast/pre-stressed concrete industry every day. Due to the design of the precast/prestressed concrete product itself and the processes required for its production, employees are occasionally exposed to hazards. The industry recognizes this and devotes a significant amount of time and investment to mitigate these hazards and protect employees from harm. It is essential for employees to go through appropriate safety training before starting work in the plant. Practical safety training should be cost-effective, and performance guaranteed, and traditional training procedures include paper-based safety guidelines, lectures, videos, and on-site training. Virtual Reality (VR) provides an innovative approach for safety training as it could offer situational training with negligible risk and at a low cost. In this paper, a VR training module is developed to deliver safety training in a cost-effective yet repeatable manner, aiming to reduce common plant injuries. The module is developed using Unity3D and Visual Studio joint platforms and can be interfaced with using the Oculus Rift/Oculus S. The module addresses three major safety concerns in the plant: personal protective equipment (PPE), the tensioning of strand (the stressing process), and suspended loads. Efficacy and effectiveness analyses were conducted to evaluate the performance of the proposed VR module. The efficacy analysis was based on simulation sickness, user experience, and system usability. This analysis showed that the developed VR module is a user-friendly simulator with minimal simulation sickness. More than 50% of the participants reported no indications of simulation sickness. In addition, an effectiveness analysis was performed based upon a comparative study of this VR training method and the traditional video-based training method. This analysis indicated that VR training is more engaged and provides a better understanding of safety protocols and real-life experience of the precast/prestressed concrete plant.

A stem cell reporter based platform to identify and target drug resistant stem cells in myeloid leukemia.

Intratumoral heterogeneity is a common feature of many myeloid leukemias and a significant reason for treatment failure and relapse. Thus, identifying the cells responsible for residual disease and leukemia re-growth is critical to better understanding how they are regulated. Here, we show that a knock-in reporter mouse for the stem cell gene Musashi 2 (Msi2) allows identification of leukemia stem cells in aggressive myeloid malignancies, and provides a strategy for defining their core dependencies. Specifically, we carry out a high throughput screen using Msi2-reporter blast crisis chronic myeloid leukemia (bcCML) and identify several adhesion molecules that are preferentially expressed in therapy resistant bcCML cells and play a key role in bcCML. In particular, we focus on syndecan-1, whose deletion triggers defects in bcCML growth and propagation and markedly improves survival of transplanted mice. Further, live imaging reveals that the spatiotemporal dynamics of leukemia cells are critically dependent on syndecan signaling, as loss of this signal impairs their localization, migration and dissemination to distant sites. Finally, at a molecular level, syndecan loss directly impairs integrin ß7 function, suggesting that syndecan exerts its influence, at least in part, by coordinating integrin activity in bcCML. These data present a platform for delineating the biological underpinnings of leukemia stem cell function, and highlight the Sdc1-Itgß7 signaling axis as a key regulatory control point for bcCML growth and dissemination.

Leveraging a Bayesian network approach to model and analyze supplier vulnerability to severe weather risk: A case study of the U.S. pharmaceutical supply chain following Hurricane Maria.

The United States government has identified the health care sector as part of the critical infrastructure for homeland security to protect citizens against health risks arising from terrorism, natural disasters, and epidemics. Citizens also have expectations about the role that health care plays in enjoying a good quality of life, by providing response systems to handle emergencies and other illness situations adequately. Among the systems required to supportdesired performance levels is a robust and resilient pharmaceutical supply chain that is free of disruption. Shortages of drugs place undue pressure on healthcare providers to devise alternative approaches to administer patient care. With climate change expected to result in increasingly severe weather patterns in the future, it is critical that logistics engineers understand the impact that a catastrophic weather event could have on supply chain disruption to facilitate the design of supply systems that are robust and resilient. This study investigates the main causal and intermediate events that led to risk propagation in, and disruption of, the U.S. pharmaceutical supply chain following Hurricane Maria. A causality Bayesian model is developed to depict linkages between risk events and quantify the associated cumulative risk. The quantification is further examined through different advanced techniques such as predictive inference reasoning and sensitivity analysis. The general interpretation of these analyses suggests that port resilience is imperative to pharmaceutical supply chain performance in the case of Puerto Rico.

Opioid losses in terms of dosage and value, January 2012 to September 2017: a retrospective analysis of Health Canada data.

BACKGROUND: Canadian health care facilities must report losses or thefts of opioids to Health Canada. To broaden the understanding of opioid loss in Canada, we analyzed data describing these losses to estimate the amount of opioid lost, estimate the wholesale and street value, compare the distribution of loss types between facility types and compare loss trends. METHODS: We analyzed Health Canada records of losses of codeine, fentanyl, hydromorphone, morphine and oxycodone reported by Canadian facilities from January 2012 to September 2017. We conducted descriptive analyses of the opioid losses by calculating milligrams of drug lost, oral morphine equivalents, daily defined doses, approximate wholesale value and approximate street value, and compared loss trends when counted by incidents, dosage units or milligrams. RESULTS: There were 64 963 reports of loss of codeine, fentanyl, hydromorphone, morphine or oxycodone over the study period. Over 112 kg of opioids were lost, an estimated $8.7 million in wholesale cost and $136 million in street value. The dominant loss categories varied by facility type: armed robbery (30.9 kg [31.1%]) for community pharmacies, unexplained losses (6.4 kg [55.8%]) for companies and pilferage (0.8 kg [57.4%]) for hospitals. Loss trends over the study period varied by reporting metric and facility type: community pharmacy losses increased when measured by dosage units and incidents of loss, and remained stable when measured by milligrams; hospital losses increased when measured by milligrams and showed no clear trend when measured by dosage units and incidents of loss. Companies showed no clear loss trend with any reporting metric. INTERPRETATION: Large quantities of opioids were lost or stolen from community pharmacies, companies and hospitals over the study period, and these losses are valued in millions of dollars. Publishing milligrams of opioids lost annually alongside metrics such as dosage units and incidents of loss would help characterize the economic cost and the magnitude of drug losses.