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One of the foundations of product design is the division between production and design. This division manifests as designers aspiring to create fixed iconic archetypes and production replicates endlessly in thousands or millions. Today innovation and technological change are challenging this idea of product design and manufacturing. The evolution of Rapid Prototyping into Additive Manufacturing (AM), is challenging the notion of mass manufacture and consumer value. As AM advances in capability and capacity, the ability to economically manufacture products in low numbers with high degrees of personalisation poses questions of the accepted product development process. Removing the need for dedicated expensive tooling also eliminates the cyclical timescales and commitment to fixed designs that investment in tooling demands. The ability to alter designs arbitrarily, frequently and responsively means that the traditional design process need not be applied and because of this, design processes and practice might be radically different in the future. In this paper, we explore this possible evolution by drawing parallels with principles and development models found in software development.
Whereas genetic susceptibility increases the risk for major depressive disorder (MDD), non-genetic protective factors may mitigate this risk. In a large-scale prospective study of US Army soldiers, we examined whether trait resilience and/or unit cohesion could protect against the onset of MDD following combat deployment, even in soldiers at high polygenic risk.
Data were analyzed from 3079 soldiers of European ancestry assessed before and after their deployment to Afghanistan. Incident MDD was defined as no MDD episode at pre-deployment, followed by a MDD episode following deployment. Polygenic risk scores were constructed from a large-scale genome-wide association study of major depression. We first examined the main effects of the MDD PRS and each protective factor on incident MDD. We then tested the effects of each protective factor on incident MDD across strata of polygenic risk.
Polygenic risk showed a dose–response relationship to depression, such that soldiers at high polygenic risk had greatest odds for incident MDD. Both unit cohesion and trait resilience were prospectively associated with reduced risk for incident MDD. Notably, the protective effect of unit cohesion persisted even in soldiers at highest polygenic risk.
Polygenic risk was associated with new-onset MDD in deployed soldiers. However, unit cohesion – an index of perceived support and morale – was protective against incident MDD even among those at highest genetic risk, and may represent a potent target for promoting resilience in vulnerable soldiers. Findings illustrate the value of combining genomic and environmental data in a prospective design to identify robust protective factors for mental health.
Objectives: Studies of neurocognitively elite older adults, termed SuperAgers, have identified clinical predictors and neurobiological indicators of resilience against age-related neurocognitive decline. Despite rising rates of older persons living with HIV (PLWH), SuperAging (SA) in PLWH remains undefined. We aimed to establish neuropsychological criteria for SA in PLWH and examined clinically relevant correlates of SA. Methods: 734 PLWH and 123 HIV-uninfected participants between 50 and 64 years of age underwent neuropsychological and neuromedical evaluations. SA was defined as demographically corrected (i.e., sex, race/ethnicity, education) global neurocognitive performance within normal range for 25-year-olds. Remaining participants were labeled cognitively normal (CN) or impaired (CI) based on actual age. Chi-square and analysis of variance tests examined HIV group differences on neurocognitive status and demographics. Within PLWH, neurocognitive status differences were tested on HIV disease characteristics, medical comorbidities, and everyday functioning. Multinomial logistic regression explored independent predictors of neurocognitive status. Results: Neurocognitive status rates and demographic characteristics differed between PLWH (SA=17%; CN=38%; CI=45%) and HIV-uninfected participants (SA=35%; CN=55%; CI=11%). In PLWH, neurocognitive groups were comparable on demographic and HIV disease characteristics. Younger age, higher verbal IQ, absence of diabetes, fewer depressive symptoms, and lifetime cannabis use disorder increased likelihood of SA. SA reported increased independence in everyday functioning, employment, and health-related quality of life than non-SA. Conclusions: Despite combined neurological risk of aging and HIV, youthful neurocognitive performance is possible for older PLWH. SA relates to improved real-world functioning and may be better explained by cognitive reserve and maintenance of cardiometabolic and mental health than HIV disease severity. Future research investigating biomarker and lifestyle (e.g., physical activity) correlates of SA may help identify modifiable neuroprotective factors against HIV-related neurobiological aging. (JINS, 2019, 25, 507–519)
A common approach to one-way sensitivity analysis is to vary inputs by a constant percentage. An alternative is to derive ranges using evidence-based probability distributions from published sources. Our objective was to compare one-way sensitivity analysis results when using these two approaches for a reference case model, along with two additional case studies.
For the reference case, we replicated a published Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS) cost-effectiveness Markov model (zidovudine versus zidovudine plus lamivudine in the UK) using TreeAge®. Health states included three HIV/AIDS states and death. We generated one-way sensitivity analyses by varying inputs in two ways: (i) using ±15 percent for all inputs, and (ii) using the 2.5 and 97.5 percentile values of the evidence-based probability distributions for all inputs. Our outcome was the mean difference between lower and upper incremental cost-effectiveness ratios (ICERs) for each variation method for the ten most influential inputs. We assessed the number of inputs with a mean difference between lower and upper ICERs of >10 percent of the deterministic ICER.
The deterministic ICER was GBP7,654/QALY (quality adjusted life year) for combination therapy versus monotherapy. The mean difference in ICER uncertainty for the evidence-based vs. ±15 percent variation method was GBP3,251/QALY (p = .0096). Six inputs had a mean difference in ICER uncertainty of >10 percent of GBP7,654/QALY (that is, mean difference in ICER uncertainty > GBP765) for the evidence-based variation method, compared to only two inputs for the constant percentage variation method.
For the reference case, the magnitude of uncertainty in the outcome was larger for the evidence-based variation method compared to the constant percentage variation method. Evidence-based uncertainty in inputs should be used in all sensitivity analyses to reflect realistic uncertainty in an outcome and aid decision-making about future research strategies. Additional case studies will be presented using validated models in diabetes and asthma.
Investigations of drinking behavior across military deployment cycles are scarce, and few prospective studies have examined risk factors for post-deployment alcohol misuse.
Prevalence of alcohol misuse was estimated among 4645 US Army soldiers who participated in a longitudinal survey. Assessment occurred 1–2 months before soldiers deployed to Afghanistan in 2012 (T0), upon their return to the USA (T1), 3 months later (T2), and 9 months later (T3). Weights-adjusted logistic regression was used to evaluate associations of hypothesized risk factors with post-deployment incidence and persistence of heavy drinking (HD) (consuming 5 + alcoholic drinks at least 1–2×/week) and alcohol or substance use disorder (AUD/SUD).
Prevalence of past-month HD at T0, T2, and T3 was 23.3% (s.e. = 0.7%), 26.1% (s.e. = 0.8%), and 22.3% (s.e. = 0.7%); corresponding estimates for any binge drinking (BD) were 52.5% (s.e. = 1.0%), 52.5% (s.e. = 1.0%), and 41.3% (s.e. = 0.9%). Greater personal life stress during deployment (e.g., relationship, family, or financial problems) – but not combat stress – was associated with new onset of HD at T2 [per standard score increase: adjusted odds ratio (AOR) = 1.20, 95% CI 1.06–1.35, p = 0.003]; incidence of AUD/SUD at T2 (AOR = 1.54, 95% CI 1.25–1.89, p < 0.0005); and persistence of AUD/SUD at T2 and T3 (AOR = 1.30, 95% CI 1.08–1.56, p = 0.005). Any BD pre-deployment was associated with post-deployment onset of HD (AOR = 3.21, 95% CI 2.57–4.02, p < 0.0005) and AUD/SUD (AOR = 1.85, 95% CI 1.27–2.70, p = 0.001).
Alcohol misuse is common during the months preceding and following deployment. Timely intervention aimed at alleviating/managing personal stressors or curbing risky drinking might reduce risk of alcohol-related problems post-deployment.
Flow stripes seen in satellite imagery of ice streams and ice shelves are caused by surface undulations with kilometer-scale spacing and meter-scale relief and generally indicate current or recent fast ice flow. On a similar scale, folding of internal ice stratigraphy depicted in cross-flow ice-penetrating radar profiles is also a common occurrence in ice streams, suggesting a possible relationship between the two sets of features. We have traced surface flow stripes in RADARSAT and MODIS imagery on Kamb Ice Stream, West Antarctica, from the onset of streaming flow into the near-stagnant trunk. We compare the morphology and evolution of the surface flow stripes to the folds seen in the internal stratigraphy in cross-ice-stream radar profiles. We find essentially no correspondence in the observed locations or spacings between the radar internal layer folds at depths greater than 100 m and the flow stripes on the surface. The gap in the radar data and the surface mappings in the top 100 m of firn prevents a precise depiction of how the flow stripes and fold patterns at depth diverge. We explore hypotheses about how flow stripes and internal stratigraphic folds can originate and evolve differently as ice flows downstream. We suggest that flow stripes are subject to surface processes that can modify their morphology independently of the internal stratigraphy, leading to changes in the pattern of flow stripes relative to the internal layers below.
OBJECTIVES/SPECIFIC AIMS: In this pilot study, we are testing a new approach for detecting neuroinflammation in individuals who have sustained a traumatic brain injury (TBI). We hypothesize that many long-term adverse consequences of TBI are driven by abnormal inflammatory processes in the brain that occur secondary to the original neural injury. This inflammation can spread well beyond the damaged tissue and cause profound fatigue, widespread pain, cognitive impairment, and depressed mood. METHODS/STUDY POPULATION: Using a technique based on magnetic resonance spectroscopy, we can obtain precise and accurate temperature measurements throughout the human brain, which may serve as a proxy for neuroinflammation. In this study, we examine 20 men who have sustained a moderate-to-severe TBI and 10 age-matched healthy men without history of TBI. Temperature is assessed on a voxel-by-voxel basis throughout the entire brain. Cognitive ability is measured with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Information on pain, fatigue, and mood is collected through questionnaire. RESULTS/ANTICIPATED RESULTS: We anticipate that (1) average whole-brain temperature will be significantly higher in the TBI group than the healthy control group; (2) severity of (a) pain, (b) fatigue, and (c) mood symptoms will be correlated with brain temperature; and (3) severity of cognitive impairment will be correlated with brain temperature. DISCUSSION/SIGNIFICANCE OF IMPACT: If the hypotheses are confirmed, this tool will fill a need for objective tests of TBI pathology that can be used to improve diagnostic and treatment decisions and predict long-term functioning. This test would be the first completely noninvasive tool for detecting neuroinflammation, and will allow for safe and inexpensive longitudinal testing. Ultimately, we hope this noninvasive scanning technique will accurately track neuroinflammation in TBI, leading to more targeted and effective treatments.
OBJECTIVES/SPECIFIC AIMS: Platelets govern signal-dependent inflammatory responses by leukocytes. Although dysregulated inflammation is common in older adults, platelet-leukocyte signaling events and downstream inflammatory gene synthesis in aging is not known. METHODS/STUDY POPULATION: Highly-purified platelets and monocytes were isolated from healthy older (age>60, n=27) and younger (age<45, n=36) adults and incubated together in autologous and nonautologous conditions. Inflammatory gene synthesis by monocytes, basally and in the presence of activated platelets, was examined. Next-generation RNA-sequencing allowed for unbiased profiling of the platelet transcriptome in older and younger adults. Differentially expressed candidates in aged platelets were validated and recombinant granzyme A (in the presence and absence of TLR4 and Caspase-1 inhibition) identified putative ligands controlling inflammatory gene synthesis. RESULTS/ANTICIPATED RESULTS: In unstimulated or activated conditions, monocyte chemoattractant protein 1 (MCP-1) and interleukin-8 (IL-8) synthesis by monocytes alone did not differ between older and younger adults. However, in the presence of autologous activated platelets, monocytes from older adults synthesized significantly greater MCP-1 (867.150 vs. 216.36 ng/mL, p<0.0001) and IL-8 (41.5 vs. 9.2 ng/mL, p<0.0001) than younger adults. Nonautologous, or switch experiments, demonstrated that aged platelets were sufficient for upregulating MCP-1 and IL-8 synthesis by monocytes. Surprisingly, classic platelet proteins known to signal to monocytes and induce MCP-1 synthesis (p-selectin, RANTES, and PF4) were not increased in platelets from older adults. Using RNA-seq followed by validation via RT-PCR and immunoblot, we identified candidate platelet molecules increased in aging that mediate platelet-monocyte signaling and pro-inflammatory gene synthesis. We confirmed that granzyme A (GrmA), a serine protease not previously identified in platelets, is present in human platelets at the mRNA and protein level. GrmA is secreted by activated platelets in signal-dependent fashion. Moreover, GrmA in platelets is significantly increased in aging (~9-fold vs. younger adults). Blocking GrmA inhibited MCP-1 and IL-8 synthesis in older adults. Finally, we uncovered that platelet GrmA signaling to monocytes is regulated through TLR4 and Caspase-1. DISCUSSION/SIGNIFICANCE OF IMPACT: Human aging is associated with reprogramming of the platelet transcriptome. A previously unrecognized protein in platelets, GrmA, is increased in aging and causes increased MCP-1 and IL-8 gene synthesis by target monocytes in a TLR4 and Caspase-1 dependent mechanism. Increased platelet GrmA in aging may contribute to injurious inflammatory responses common in older adults.
OBJECTIVES/SPECIFIC AIMS: Endogenous RT (eRT) is necessary for the function of retrotransposons, elements that replicate via an RNA intermediate. One source of eRT activity is long interspersed elements (LINE). LINEs, of which there are several subgroups (L1, L2, L3), are retrotransposons that regulate cellular growth and gene expression. Given their diverse and important roles, we hypothesized that L1 elements regulate functional responses in megakaryocytes and platelets; a concept not yet examined in the field. METHODS/STUDY POPULATION: To study eRT in human platelets we used RT activity assays, PCR, and Western blot approaches. Furthermore, we used an RT-inhibitor to dissect the function of eRT, analyzed RT-dependent protein synthetic capacity, and immunoprecipitated RNA-DNA hybrids. RNA-DNA hybrids were also detected by means of ICC and automated analysis using CellProfiler software. RNA-DNA hybrids were validated by PCR and eRT regulated synthesis of target proteins was analyzed using autoradiography and Western blot techniques. Platelets from patients with HIV+ were examined in parallel. RESULTS/ANTICIPATED RESULTS: We identified that highly purified, isolated platelets from healthy subjects possess eRT activity. eRT activity was blocked with the non-nucleoside RT inhibitor nevirapine at concentrations within the therapeutic drug range. L1 elements are bicistronic, containing 2 open reading frames (ORFs), ORF1 and ORF2. Thus, we next identified that human platelets express full-length L1 mRNA containing ORF1 and ORF2. In human platelets, eRT activity was localized to L1 protein containing ribonucleo particles. Platelet eRT reverse transcribed exogenous RNAs, a process inhibited by nevirapine, acting in trans using the 3′-UTR of exogenous mRNAs as a template. To dissect the function of eRT in platelets, we next examined cytoskeletal and protein synthetic events in the presence or absence of nevirapine. Inhibition of eRT in isolated platelets led to characteristically beaded platelets in appearance, strongly resembling bone marrow proplatelets. Parallel increases in platelet reactivity were also observed. As these changes occurred over hours, not minutes, we hypothesized that inhibition of eRT would affect platelet protein synthetic events. Consistent with this, RT inhibition resulted in upregulation of global platelet protein synthesis. We validated upregulation of the synthesis of specific proteins (mitofilin, p-selectin, and L26—a component of the 60S ribosomal subunit essential for mRNA translation). RNA-DNA hybrids, noncanonical nucleic acid structures that regulate gene expression, are enriched in regions where L1 is abundant. RNA-DNA hybrids were present in platelets and expression confirmed via differential digestion of RNAs (eg, with RNase A and RNAse I). Next-generation sequencing of pulled down (eg, immunoprecipitated) platelet RNA-DNA hybrids identified numerous differentially expressed transcripts and we focused on MAP1LC3B (LC3B), a primary regulator of autophagy. Hybrid sequencing results for LC3B were validated using qPCR and we confirmed that LC3B RNA binds to L1-encoded RNA binding protein. Platelets treated with nevirapine had increased total LC3B protein expression. As RT inhibition is an important mechanism to control HIV infection, we examined platelet morphology, activation, and LC3B expression in platelets from HIV+ subjects treated with nevirapine. HIV+ patients treated with RT inhibitors had higher numbers of platelets that were beaded in appearance at baseline, increased platelet reactivity, and differential LC3B expression compared with healthy controls. DISCUSSION/SIGNIFICANCE OF IMPACT: Taken together, these results demonstrate that platelets possess eRT activity that regulates platelet morphology, platelet hyperreactivity, and protein synthetic events. We postulate that eRT activity in platelets may be a new post-transcriptional regulatory checkpoint. Moreover, our findings have implications in HIV+ patients treated with RT inhibitors, where off-target effects may contribute to platelet activation and an increased risk of thrombosis.
Both analytical and numerical studies of the effect of a magnetic field at the base of the convection zone on p-modes are presented. It is argued that the recently reported changes in the low degree p-mode frequencies, from 1980 to 1984, may result from corresponding changes in the magnetic field strength. A lower limit of some 5 × 105–106 gauss is implied for the field strength at the base of the convection zone.
Excavations at Tell Khaiber in southern Iraq by the Ur Region Archaeological Project have revealed a substantial building (hereafter the Public Building) dating to the mid-second millennium b.c. The results are significant for the light they shed on Babylonian provincial administration, particularly of food production, for revealing a previously unknown type of fortified monumental building, and for producing a dated archive, in context, of the little-understood Sealand Dynasty. The project also represents a return of British field archaeology to long-neglected Babylonia, in collaboration with Iraq's State Board for Antiquities and Heritage. Comments on the historical background and physical location of Tell Khaiber are followed by discussion of the form and function of the Public Building. Preliminary analysis of the associated archive provides insights into the social milieu of the time. Aspects of the material culture, including pottery, are also discussed.