Eradication of chronic myeloid leukemia stem cells: a novel mathematical model predicts no therapeutic benefit of adding G-CSF to imatinib

Imatinib mesylate induces complete cytogenetic responses in patients with chronic myeloid leukemia (CML), yet many patients have detectable BCR-ABL transcripts in peripheral blood even after prolonged therapy. Bone marrow studies have shown that this residual disease resides within the stem cell compartment. Quiescence of leukemic stem cells has been suggested as a mechanism conferring insensitivity to imatinib, and exposure to the Granulocyte-Colony Stimulating Factor (G-CSF), together with imatinib, has led to a significant reduction in leukemic stem cells in vitro. In this paper, we design a novel mathematical model of stem cell quiescence to investigate the treatment response to imatinib and G-CSF. We find that the addition of G-CSF to an imatinib treatment protocol leads to observable effects only if the majority of leukemic stem cells are quiescent; otherwise it does not modulate the leukemic cell burden. The latter scenario is in agreement with clinical findings in a pilot study administering imatinib continuously or intermittently, with or without G-CSF (GIMI trial). Furthermore, our model predicts that the addition of G-CSF leads to a higher risk of resistance since it increases the production of cycling leukemic stem cells. Although the pilot study did not include enough patients to draw any conclusion with statistical significance, there were more cases of progression in the experimental arms as compared to continuous imatinib. Our results suggest that the additional use of G-CSF may be detrimental to patients in the clinic

Conceptualizing pathways linking women's empowerment and prematurity in developing countries.

BackgroundGlobally, prematurity is the leading cause of death in children under the age of 5. Many efforts have focused on clinical approaches to improve the survival of premature babies. There is a need, however, to explore psychosocial, sociocultural, economic, and other factors as potential mechanisms to reduce the burden of prematurity. Women's empowerment may be a catalyst for moving the needle in this direction. The goal of this paper is to examine links between women's empowerment and prematurity in developing settings. We propose a conceptual model that shows pathways by which women's empowerment can affect prematurity and review and summarize the literature supporting the relationships we posit. We also suggest future directions for research on women's empowerment and prematurity.MethodsThe key words we used for empowerment in the search were "empowerment," "women's status," "autonomy," and "decision-making," and for prematurity we used "preterm," "premature," and "prematurity." We did not use date, language, and regional restrictions. The search was done in PubMed, Population Information Online (POPLINE), and Web of Science. We selected intervening factors-factors that could potentially mediate the relationship between empowerment and prematurity-based on reviews of the risk factors and interventions to address prematurity and the determinants of those factors.ResultsThere is limited evidence supporting a direct link between women's empowerment and prematurity. However, there is evidence linking several dimensions of empowerment to factors known to be associated with prematurity and outcomes for premature babies. Our review of the literature shows that women's empowerment may reduce prematurity by (1) preventing early marriage and promoting family planning, which will delay age at first pregnancy and increase interpregnancy intervals; (2) improving women's nutritional status; (3) reducing domestic violence and other stressors to improve psychological health; and (4) improving access to and receipt of recommended health services during pregnancy and delivery to help prevent prematurity and improve survival of premature babies.ConclusionsWomen's empowerment is an important distal factor that affects prematurity through several intervening factors. Improving women's empowerment will help prevent prematurity and improve survival of preterm babies. Research to empirically show the links between women's empowerment and prematurity is however needed

Person-centred care in interventions to limit weight gain in pregnant women with obesity - a systematic review

Background Person-centred care, asserting that individuals are partners in their care, has been associated with care satisfaction but the value of using it to support women with obesity during pregnancy is unknown. Excessive gestational weight gain is associated with increased risks for both mother and baby and weight gain therefore is an important intervention target. The aims of this review was to 1) explore to what extent and in what manner interventions assessing weight in pregnant women with obesity use person-centred care and 2) assess if interventions including aspects of person-centred care are more effective at limiting weight gain than interventions not employing person-centred care. Methods Ten databases were systematically searched in January 2014. Studies had to report an intervention offered to pregnant women with obesity and measure gestational weight gain to be included. All included studies were independently double coded to identify to what extent they included three defined aspects of person-centred care: 1) “initiate a partnership” including identifying the person’s circumstances and motivation; 2) “working the partnership” through sharing the decision-making regarding the planned action and 3) “safeguarding the partnership through documentation” of care preferences. Information on gestational weight gain, study quality and characteristics were also extracted. Results Ten studies were included in the review, of which five were randomised controlled trials (RCT), and the remaining observational studies. Four interventions included aspects of person-centred care; two observational studies included both “initiating the partnership”, and “working the partnership”. One observational study included “initiating the partnership” and one RCT included “working the partnership”. No interventions included “safeguarding the partnership through documentation”. Whilst all studies with person-centred care aspects showed promising findings regarding limiting gestational weight gain, so did the interventions not including person-centred care aspects. Conclusions The use of an identified person-centred care approach is presently limited in interventions targeting gestational weight gain in pregnant women with obesity. Hence to what extent person-centred care may improve health outcomes and care satisfaction in this population is currently unknown and more research is needed. That said, our findings suggest that use of routines incorporating person-centredness are feasible to include within these interventions

Aneuploidy in pluripotent stem cells and implications for cancerous transformation

Owing to a unique set of attributes, human pluripotent stem cells (hPSCs) have emerged as a promising cell source for regenerative medicine, disease modeling and drug discovery. Assurance of genetic stability over long term maintenance of hPSCs is pivotal in this endeavor, but hPSCs can adapt to life in culture by acquiring non-random genetic changes that render them more robust and easier to grow. In separate studies between 12.5% and 34% of hPSC lines were found to acquire chromosome abnormalities over time, with the incidence increasing with passage number. The predominant genetic changes found in hPSC lines involve changes in chromosome number and structure (particularly of chromosomes 1, 12, 17 and 20), reminiscent of the changes observed in cancer cells. In this review, we summarize current knowledge on the causes and consequences of aneuploidy in hPSCs and highlight the potential links with genetic changes observed in human cancers and early embryos. We point to the need for comprehensive characterization of mechanisms underpinning both the acquisition of chromosomal abnormalities and selection pressures, which allow mutations to persist in hPSC cultures. Elucidation of these mechanisms will help to design culture conditions that minimize the appearance of aneuploid hPSCs. Moreover, aneuploidy in hPSCs may provide a unique platform to analyse the driving forces behind the genome evolution that may eventually lead to cancerous transformation

The prevention of type 2 diabetes

Type 2 diabetes mellitus (T2DM) affects more than 7% of adults in the US and leads to substantial personal and economic burden. In prediabetic states insulin secretion and action—potential targets of preventive interventions—are impaired. In trials lifestyle modification (i.e. weight loss and exercise) has proven effective in preventing incident T2DM in high-risk groups, although weight loss has the greatest effect. Various medications (e.g. metformin, thiazolidinediones and acarbose) can also prevent or delay T2DM. Whether diabetes-prevention strategies also ultimately prevent the development of diabetic vascular complications is unknown, but cardiovascular risk factors are favorably affected. Preventive strategies that can be implemented in routine clinical settings have been developed and evaluated. Widespread application has, however, been limited by local financial considerations, even though cost-effectiveness might be achieved at the population level

Transport and Thermodynamic Evidence for a Marginal Fermi Liquid State in ZrZn2_2

Measurements of low temperature transport and thermodynamic properties have been used to characterize the non-Fermi liquid state of the itinerant ferromagnet ZrZn$_2$. We observe a $T^{5/3}$ temperature dependence of the electrical resistivity at zero field, which becomes $T^2$ like in an applied field of 9 T. In zero field we also measured the thermal conductivity, and we see a novel linear in $T$ dependence of the difference between the thermal and electrical resistivities. Heat capacity measurements, also at zero field, reveal an upturn in the electronic contribution at low temperatures when the phonon term is subtracted. Taken together, we argue that these properties are consistent with a marginal Fermi liquid state which is predicted by a mean-field model of enhanced spin fluctuations on the border of ferromagnetism in three dimensions. We compare our data to quantitative predictions and establish this model as a compelling theoretical framework for understanding ZrZn$_2$.Comment: 10 pages, 10 figure

Global Current Practices of Ventilatory Support Management in COVID-19 Patients: An International Survey

Background: As the global outbreak of COVID-19 continues to ravage the world, it is important to understand how frontline clinicians manage ventilatory support and the various limiting factors. / Methods: An online survey composed of 32 questions was developed and validated by an international expert panel. / Results: Overall, 502 respondents from 40 countries across six continents completed the survey. The mean number (±SD) of ICU beds was 64 ± 84. The most popular initial diagnostic tools used for treatment initiation were arterial blood gas (48%) and clinical presentation (37.5%), while the national COVID-19 guidelines were the most used (61.2%). High flow nasal cannula (HFNC) (53.8%), non-invasive ventilation (NIV) (47%), and invasive mechanical ventilation (IMV) (92%) were mostly used for mild, moderate, and severe COVID-19 cases, respectively. However, only 38.8%, 56.6% and 82.9% of the respondents had standard protocols for HFNC, NIV, and IMV, respectively. The most frequently used modes of IMV and NIV were volume control (VC) (36.1%) and continuous positive airway pressure/pressure support (CPAP/PS) (40.6%). About 54% of the respondents did not adhere to the recommended, regular ventilator check interval. The majority of the respondents (85.7%) used proning with IMV, with 48.4% using it for 12– 16 hours, and 46.2% had tried awake proning in combination with HFNC or NIV. Increased staff workload (45.02%), lack of trained staff (44.22%) and shortage of personal protective equipment (PPE) (42.63%) were the main barriers to COVID-19 management. / Conclusion: Our results show that general clinical practices involving ventilatory support were highly heterogeneous, with limited use of standard protocols and most frontline clinicians depending on isolated and varied management guidelines. We found increased staff workload, lack of trained staff and shortage of PPE to be the main limiting factors affecting global COVID-19 ventilatory support management

Utilization of outpatient services in refugee settlement health facilities: a comparison by age, gender, and refugee versus host national status

<p>Abstract</p> <p>Background</p> <p>Comparisons between refugees receiving health care in settlement-based facilities and persons living in host communities have found that refugees have better health outcomes. However, data that compares utilization of health services between refugees and the host population, and across refugee settlements, countries and regions is limited. The paper will address this information gap. The analysis in this paper uses data from the United Nations High Commissioner of Refugees (UNHCR) Health Information System (HIS).</p> <p>Methods</p> <p>Data about settlement populations and the use of outpatient health services were exported from the UNHCR health information system database. Tableau Desktop was used to explore the data. STATA was used for data cleaning and statistical analysis. Differences in various indicators of the use of health services by region, gender, age groups, and status (host national vs. refugee population) were analyzed for statistical significance using generalized estimating equation models that adjusted for correlated data within refugee settlements over time.</p> <p>Results</p> <p>Eighty-one refugee settlements were included in this study and an average population of 1.53 million refugees was receiving outpatient health services between 2008 and 2009. The crude utilization rate among refugees is 2.2 visits per person per year across all settlements. The refugee utilization rate in Asia (3.5) was higher than in Africa on average (1.8). Among refugees, females have a statistically significant higher utilization rate than males (2.4 visits per person per year vs. 2.1). The proportion of new outpatient attributable to refugees is higher than that attributable to host nationals. In the Asian settlements, only 2% outpatient visits, on average, were attributable to host community members. By contrast, in Africa, the proportion of new outpatient (OPD) visits by host nationals was 21% on average; in many Ugandan settlements, the proportion of outpatient visits attributable to host community members was higher than that for refugees. There was no statistically significant difference between the size of the male and female populations across refugee settlements. Across all settlements reporting to the UNHCR database, the percent of the refugee population that was less than five years of age is 16% on average.</p> <p>Conclusions</p> <p>The availability of a centralized database of health information across UNHCR-supported refugee settlements is a rich resource. The SPHERE standard for emergencies of 1-4 visits per person per year appears to be relevant for Asia in the post-emergency phase, but not for Africa. In Africa, a post-emergency standard of 1-2 visits per person per year should be considered. Although it is often assumed that the size of the female population in refugee settlements is higher than males, we found no statistically significant difference between the size of the male and female populations in refugee settlements overall. Another assumption---that the under-fives make up 20% of the settlement population during the emergency phase---does not appear to hold for the post-emergency phase; under-fives made up about 16% of refugee settlement populations.</p

Chronic Leukemias

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66325/1/j.1365-4362.1982.tb03146.x.pd

The PRIMED Consortium: Reducing disparities in polygenic risk assessment.

By improving disease risk prediction, polygenic risk scores (PRSs) could have a significant impact on health promotion and disease prevention. Due to the historical oversampling of populations with European ancestry for genome-wide association studies, PRSs perform less well in other, understudied populations, leading to concerns that clinical use in their current forms could widen health care disparities. The PRIMED Consortium was established to develop methods to improve the performance of PRSs in global populations and individuals of diverse genetic ancestry. To this end, PRIMED is aggregating and harmonizing multiple phenotype and genotype datasets on AnVIL, an interoperable secure cloud-based platform, to perform individual- and summary-level analyses using population and statistical genetics approaches. Study sites, the coordinating center, and representatives from the NIH work alongside other NHGRI and global consortia to achieve these goals. PRIMED is also evaluating ethical and social implications of PRS implementation and investigating the joint modeling of social determinants of health and PRS in computing disease risk. The phenotypes of interest are primarily cardiometabolic diseases and cancer, the leading causes of death and disability worldwide. Early deliverables of the consortium include methods for data sharing on AnVIL, development of a common data model to harmonize phenotype and genotype data from cohort studies as well as electronic health records, adaptation of recent guidelines for population descriptors to global cohorts, and sharing of PRS methods/tools. As a multisite collaboration, PRIMED aims to foster equity in the development and use of polygenic risk assessment