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In the present review, the effect of porosity on the mechanical properties of the fabricated parts, which are additively manufactured by powder bed fusion and filament extrusion-based technologies, are discussed in detail. Usually, additive manufacturing (AM) processes based on these techniques produce the components with a significant amount of pores. The porosity in these parts typically takes two forms: pores with irregular shapes (called keyholes) and uniform (spherical) pores. These pores are present at different locations, such as surface, sub-surface, interior bulk material, between the deposited layers and at filler/matrix interface, which critically affect the corrosion resistance, fatigue strength, stiffness, mechanical strength, and fracture toughness properties, respectively. Therefore, it is essential to study and understand the influence of pores on the mechanical properties of AM fabricated parts. The technologies of AM can be employed in the manufacturing of components with the desired porous structure through the topology optimization process of scaffolds and lattices to improve their toughness under a specific load. The undesirable effect of pores can be eliminated by using defects-free raw materials, optimizing the processing parameters, and implementing suitable post-processing treatment. The current review grants a more comprehensive understanding of the effect of porous defects on mechanical performance and provides a mechanistic basis for reliable applications of additively manufactured components.

In the present work, we performed nanoindentation tests using molecular dynamics (MD) simulations on graphene, native silica aerogels, and single- and multi-layered graphene-reinforced silica aerogel nanocomposites. This work mainly focused on the two aspects of nanoindentation simulations: first, the resultant indentation force–depth curves, and second, the associated mechanical deformation behavior. We found that in the single-layer graphene-reinforced silica aerogel nanocomposite, the indentation resistance was four-fold that of native silica aerogels. Moreover, the combined system proved to be higher in stiffness compared to the individual material. Furthermore, the indentation resistance was increased significantly as we proceeded from single- to two-layered graphene-reinforced silica aerogel nanocomposites. The results of the study provide a detailed understanding of the mechanical behavior during the indentation tests of nanocomposites, which helps to design advanced nanoscale multi-layered materials.

The third UN High-Level Meeting on Non-Communicable Diseases (NCDs) on Sept 27, 2018, will review national and global progress towards the prevention and control of NCDs, and provide an opportunity to renew, reinforce, and enhance commitments to reduce their burden. NCD Countdown 2030 is an independent collaboration to inform policies that aim to reduce the worldwide burden of NCDs, and to ensure accountability towards this aim. In 2016, an estimated 40·5 million (71%) of the 56·9 million worldwide deaths were from NCDs. Of these, an estimated 1·7 million (4% of NCD deaths) occurred in people younger than 30 years of age, 15·2 million (38%) in people aged between 30 years and 70 years, and 23·6 million (58%) in people aged 70 years and older. An estimated 32·2 million NCD deaths (80%) were due to cancers, cardiovascular diseases, chronic respiratory diseases, and diabetes, and another 8·3 million (20%) were from other NCDs. Women in 164 (88%) and men in 165 (89%) of 186 countries and territories had a higher probability of dying before 70 years of age from an NCD than from communicable, maternal, perinatal, and nutritional conditions combined. Globally, the lowest risks of NCD mortality in 2016 were seen in high-income countries in Asia-Pacific, western Europe, and Australasia, and in Canada. The highest risks of dying from NCDs were observed in low-income and middle-income countries, especially in sub-Saharan Africa, and, for men, in central Asia and eastern Europe. Sustainable Development Goal (SDG) target 3.4—a one-third reduction, relative to 2015 levels, in the probability of dying between 30 years and 70 years of age from cancers, cardiovascular diseases, chronic respiratory diseases, and diabetes by 2030—will be achieved in 35 countries (19%) for women, and 30 (16%) for men, if these countries maintain or surpass their 2010–2016 rate of decline in NCD mortality. Most of these are high-income countries with already-low NCD mortality, and countries in central and eastern Europe. An additional 50 (27%) countries for women and 35 (19%) for men are projected to achieve such a reduction in the subsequent decade, and thus, with slight acceleration of decline, could meet the 2030 target. 86 (46%) countries for women and 97 (52%) for men need implementation of policies that substantially increase the rates of decline. Mortality from the four NCDs included in SDG target 3.4 has stagnated or increased since 2010 among women in 15 (8%) countries and men in 24 (13%) countries. NCDs and age groups other than those included in the SDG target 3.4 are responsible for a higher risk of death in low-income and middle-income countries than in high-income countries. Substantial reduction of NCD mortality requires policies that considerably reduce tobacco and alcohol use and blood pressure, and equitable access to efficacious and high-quality preventive and curative care for acute and chronic NCDs.

Adeno-associated virus (AAV)-mediated CRISPR-Cas9 editing holds promise to treat many diseases. The immune response to bacterial-derived Cas9 has been speculated as a hurdle for AAV-CRISPR therapy. However, immunological consequences of AAV-mediated Cas9 expression have thus far not been thoroughly investigated in large mammals. We evaluate Cas9-specific immune responses in canine models of Duchenne muscular dystrophy (DMD) following intramuscular and intravenous AAV-CRISPR therapy. Treatment results initially in robust dystrophin restoration in affected dogs but also induces muscle inflammation, and Cas9-specific humoral and cytotoxic T-lymphocyte (CTL) responses that are not prevented by the muscle-specific promoter and transient prednisolone immune suppression. In normal dogs, AAV-mediated Cas9 expression induces similar, though milder, immune responses. In contrast, other therapeutic (micro-dystrophin and SERCA2a) and reporter (alkaline phosphatase, AP) vectors result in persistent expression without inducing muscle inflammation. Our results suggest Cas9 immunity may represent a critical barrier for AAV-CRISPR therapy in large mammals. The Cas9-specific T cell response has been speculated to impair CRISPR therapy. Here, the authors show that local and systemic AAV CRISPR therapy induces cytotoxic killing and eliminates rescued dystrophin in canine models of Duchenne muscular dystrophy.

Mesenchymal stromal cell (MSC) metabolism plays a crucial role in the surrounding microenvironment in both normal physiology and pathological conditions. While MSCs predominantly utilize glycolysis in their native hypoxic niche within the bone marrow, new evidence reveals the importance of upregulation in mitochondrial activity in MSC function and differentiation. Mitochondria and mitochondrial regulators such as sirtuins play key roles in MSC homeostasis and differentiation into mature lineages of the bone and hematopoietic niche, including osteoblasts and adipocytes. The metabolic state of MSCs represents a fine balance between the intrinsic needs of the cellular state and constraints imposed by extrinsic conditions. In the context of injury and inflammation, MSCs respond to reactive oxygen species (ROS) and damage-associated molecular patterns (DAMPs), such as damaged mitochondria and mitochondrial products, by donation of their mitochondria to injured cells. Through intercellular mitochondria trafficking, modulation of ROS, and modification of nutrient utilization, endogenous MSCs and MSC therapies are believed to exert protective effects by regulation of cellular metabolism in injured tissues. Similarly, these same mechanisms can be hijacked in malignancy whereby transfer of mitochondria and/or mitochondrial DNA (mtDNA) to cancer cells increases mitochondrial content and enhances oxidative phosphorylation (OXPHOS) to favor proliferation and invasion. The role of MSCs in tumor initiation, growth, and resistance to treatment is debated, but their ability to modify cancer cell metabolism and the metabolic environment suggests that MSCs are centrally poised to alter malignancy. In this review, we describe emerging evidence for adaptations in MSC bioenergetics that orchestrate developmental fate decisions and contribute to cancer progression. We discuss evidence and potential strategies for therapeutic targeting of MSC mitochondria in regenerative medicine and tissue repair. Lastly, we highlight recent progress in understanding the contribution of MSCs to metabolic reprogramming of malignancies and how these alterations can promote immunosuppression and chemoresistance. Better understanding the role of metabolic reprogramming by MSCs in tissue repair and cancer progression promises to broaden treatment options in regenerative medicine and clinical oncology.

Racial and ethnic disparities in chronic disease are a major public health priority. To determine if the amount of federal grant funding to federally-qualified health centers (FQHCs) was associated with baseline overall prevalence of uncontrolled hypertension and uncontrolled diabetes, as well as prevalence by racial and ethnic subgroup. Cross-sectional multivariate regression analysis of Uniform Data System 2014-2019, which includes clinic-level data from each FQHC regarding demographics, chronic disease control by race and ethnicity, and grant funding. Our main exposure were the average values of the prevalence of uncontrolled hypertension and uncontrolled diabetes among the overall population and by racial and ethnic group from 2014-2016. Average federal grant funding per patient from 2017-2019, as measured by annual health center funding from the Bureau of Primary Health Care (BPHC) and overall federal grant funding. We analyzed 1,205 FQHCs from 2014-2019; the average BPHC grant per patient across all FQHCs in 2019 was $168 while the average total federal grant was $184 per patient. Increasing shares of total patients with uncontrolled hypertension or uncontrolled diabetes were not associated with increased total federal grant funding in either unadjusted or adjusted analysis. Increased shares of patients who are American Indian or Alaskan Native (AI-AN) with uncontrolled hypertension and diabetes were associated with increasing total federal grant funding in both unadjusted and adjusted analysis (adjusted beta hypertension $168.3, p <0.001; adjusted beta diabetes 59.44, p = 0.02). However, cardiovascular clinical need among other racial and ethnic groups was not significantly associated with grant funding. FQHCs with higher overall rates of uncontrolled hypertension or diabetes do not receive more federal funds, and there is no significant association between federal funding levels and rates of uncontrolled blood pressure or diabetes within most racial and ethnic groups, with the exception of AI-AN populations. To narrow inequities in cardiovascular disease, HRSA should consider more explicitly targeting federal grants to clinics with higher levels of clinical need.

Access to medicines and vaccines to prevent and treat non-communicable diseases (NCDs) is unacceptably low worldwide. In the 2011 UN political declaration on the prevention and control of NCDs, heads of government made several commitments related to access to essential medicines, technologies, and vaccines for such diseases. 30 years of experience with policies for essential medicines and 10 years of scaling up of HIV treatment have provided the knowledge needed to address barriers to long-term effective treatment and prevention of NCDs. More medicines can be acquired within existing budgets with efficient selection, procurement, and use of generic medicines. Furthermore, low-income and middle-income countries need to increase mobilisation of domestic resources to cater for the many patients with NCDs who do not have access to treatment. Existing initiatives for HIV treatment offer useful lessons that can enhance access to pharmaceutical management of NCDs and improve adherence to long-term treatment of chronic illness; policy makers should also address unacceptable inequities in access to controlled opioid analgesics. In addition to off-patent medicines, governments can promote access to new and future on-patent medicinal products through coherent and equitable health and trade policies, particularly those for intellectual property. Frequent conflicts of interest need to be identified and managed, and indicators and targets for access to NCD medicines should be used to monitor progress. Only with these approaches can a difference be made to the lives of hundreds of millions of current and future patients with NCDs.

To design effective policy and interventions, public health officials must have an accurate and granular picture of the state of multiple chronic conditions (MCC) in their region. The objective of this research is to describe the prevalence and distribution of MCC in New York State. We performed a secondary data analysis of the Behavioral Risk Factor Surveillance System (BRFSS) from 2011 through 2016 for New York adults (n = 76,186). We analyzed the self-reported prevalence of individuals having 0, 1, 2, or ≥ 3 chronic conditions by sex, race/ethnicity, age, health insurance type, annual household income, and whether respondents lived in New York City. We also examined the most common condition dyads and triads. Finally, we assessed the prevalence of MCC (2 or more chronic conditions) by county across New York State, and neighborhood within New York City. During 2011-2016, 25.2% of adults in New York State had zero chronic conditions, 24.1% had 1 condition, 18.4% had 2 conditions, and 32.4% had 3 or more. The most prevalent dyad was hypertension and high cholesterol in 17.0% of individuals. The most prevalent triad was hypertension, high cholesterol, and arthritis in 4.5% of individuals. County prevalence of MCC ranged from 42.6% in Westchester County to 66.1% in Oneida County. The prevalence of MCC in New York City neighborhoods ranged from 33.5% in Gramercy Park-Murray Hill to 60.6% in High Bridge-Morrisania. This research contributes to the field's understanding of multiple chronic conditions and allows policy and public health leaders in New York to better understand the prevalence and distribution of MCC.

Although the WHO-developed Service Availability and Readiness Assessment (SARA) tool is a comprehensive and widely applied survey of health facility preparedness, SARA data have not previously been used to model predictors of readiness. We sought to demonstrate that SARA data can be used to model availability of essential medicines for treating non-communicable diseases (EM-NCD). We fit a Poisson regression model using 2013 SARA data from 196 Ugandan health facilities. The outcome was total number of different EM-NCD available. Basic amenities, equipment, region, health facility type, managing authority, NCD diagnostic capacity, and range of HIV services were tested as predictor variables. In multivariate models, we found significant associations between EM-NCD availability and region, managing authority, facility type, and range of HIV services. For-profit facilities' EM-NCD counts were 98% higher than public facilities (p < .001). General hospitals and referral health centers had 98% (p = .004) and 105% (p = .002) higher counts compared to primary health centers. Facilities in the North and East had significantly lower counts than those in the capital region (p = 0.015; p = 0.003). Offering HIV care was associated with 35% lower EM-NCD counts (p = 0.006). Offering HIV counseling and testing was associated with 57% higher counts (p = 0.048). We identified multiple within-country disparities in availability of EM-NCD in Uganda. Our findings can be used to identify gaps and guide distribution of limited resources. While the primary purpose of SARA is to assess and monitor health services readiness, we show that it can also be an important resource for answering complex research and policy questions requiring multivariate analysis.