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Objective: To utilise combined diffusion‐relaxation MRI techniques to interrogate antenatal changes in the placenta prior to extreme preterm birth among both women with PPROM and membranes intact, and compare this to a control group who subsequently delivered at term. Design: Observational study. Setting: Tertiary Obstetric Unit, London, UK. Population: Cases: pregnant women who subsequently spontaneously delivered a singleton pregnancy prior to 32 weeks' gestation without any other obstetric complications. Controls: pregnant women who delivered an uncomplicated pregnancy at term. Methods: All women consented to an MRI examination. A combined diffusion‐relaxation MRI of the placenta was undertaken and analysed using fractional anisotropy, a combined T2*‐apparent diffusion coefficient model and a combined T2*‐intravoxel incoherent motion model, in order to provide a detailed placental phenotype associated with preterm birth. Subgroup analyses based on whether women in the case group had PPROM or intact membranes at time of scan, and on latency to delivery were performed. Main Outcome Measures: Fractional anisotropy, apparent diffusion coefficients and T2* placental values, from two models including a combined T2*‐IVIM model separating fast‐ and slow‐flowing (perfusing and diffusing) compartments. Results: This study included 23 women who delivered preterm and 52 women who delivered at term. Placental T2* was lower in the T2*‐apparent diffusion coefficient model (p < 0.001) and in the fast‐ and slow‐flowing compartments (p = 0.001 and p < 0.001) of the T2*‐IVIM model. This reached a higher level of significance in the preterm prelabour rupture of the membranes group than in the membranes intact group. There was a reduced perfusion fraction among the cases with impending delivery. Conclusions: Placental diffusion‐relaxation reveals significant changes in the placenta prior to preterm birth with greater effect noted in cases of preterm prelabour rupture of the membranes. Application of this technique may allow clinically valuable interrogation of histopathological changes before preterm birth. In turn, this could facilitate more accurate antenatal prediction of preterm chorioamnionitis and so aid decisions around the safest time of delivery. Furthermore, this technique provides a research tool to improve understanding of the pathological mechanisms associated with preterm birth in vivo. [ABSTRACT FROM AUTHOR]

Purpose: Widening the availability of fetal MRI with fully automatic real‐time planning of radiological brain planes on 0.55T MRI. Methods: Deep learning‐based detection of key brain landmarks on a whole‐uterus echo planar imaging scan enables the subsequent fully automatic planning of the radiological single‐shot Turbo Spin Echo acquisitions. The landmark detection pipeline was trained on over 120 datasets from varying field strength, echo times, and resolutions and quantitatively evaluated. The entire automatic planning solution was tested prospectively in nine fetal subjects between 20 and 37 weeks. A comprehensive evaluation of all steps, the distance between manual and automatic landmarks, the planning quality, and the resulting image quality was conducted. Results: Prospective automatic planning was performed in real‐time without latency in all subjects. The landmark detection accuracy was 4.2 ±$$ \pm $$ 2.6 mm for the fetal eyes and 6.5 ±$$ \pm $$ 3.2 for the cerebellum, planning quality was 2.4/3 (compared to 2.6/3 for manual planning) and diagnostic image quality was 2.2 compared to 2.1 for manual planning. Conclusions: Real‐time automatic planning of all three key fetal brain planes was successfully achieved and will pave the way toward simplifying the acquisition of fetal MRI thereby widening the availability of this modality in nonspecialist centers. [ABSTRACT FROM AUTHOR]

Preterm birth remains the leading cause of mortality among under‐5's and is a major contributor to the reduction in quality‐of‐life adjusted years and reduction in human capital. Globally, there are many interventions and care bundles that aim to reduce the impact of preterm birth once preterm labor has ensued and into the neonatal period; not all of these are applicable in all settings. Here, we introduce the FIGO PremPrep‐5 initiative, which aims to disseminate key information on the most simple and effective interventions with the aim of increasing implementation globally. Before delivery, we recommend a course of antenatal corticosteroids, and intrapartum magnesium sulfate. At delivery, we recommend delayed cord clamping. Postnatally, we recommend early feeding with breast milk and immediate kangaroo care. While there are many other interventions that may improve outcomes at the time of labor and after preterm birth, these are clinically effective and relatively inexpensive options that can be practiced in most settings and supplemented with more advanced care. We include examples of a training video and infographics that will be used for dissemination. Synopsis: An introduction to simple interventions to reduce the impact of preterm birth in low‐ and middle‐income country settings. [ABSTRACT FROM AUTHOR]

Introduction: Spontaneous preterm birth prior to 32 weeks' gestation accounts for 1% of all deliveries and is associated with high rates of morbidity and mortality. A total of 70% are associated with chorioamnionitis which increases the incidence of morbidity, but for which there is no noninvasive antenatal test. Fetal adrenal glands produce cortisol and dehydroepiandosterone‐sulphate which upregulate prior to spontaneous preterm birth. Ultrasound suggests that adrenal volumes may increase prior to preterm birth, but studies are limited. This study aimed to: (i) demonstrate reproducibility of magnetic resonance imaging (MRI) derived adrenal volumetry; (ii) derive normal ranges of total adrenal volumes, and adrenal: body volume for normal; (iii) compare with those who have spontaneous very preterm birth; and (iv) correlate with histopathological chorioamnionitis. Material and methods: Patients at high risk of preterm birth prior to 32 weeks were prospectively recruited, and included if they did deliver prior to 32 weeks; a control group who delivered an uncomplicated pregnancy at term was also recruited. T2 weighted images of the entire uterus were obtained, and a deformable slice‐to‐volume method was used to reconstruct the fetal abdomen. Adrenal and body volumes were obtained via manual segmentation, and adrenal: body volume ratios generated. Normal ranges were created using control data. Differences between groups were investigated accounting for the effect of gestation by use of regression analysis. Placental histopathology was reviewed for pregnancies delivering preterm. Results: A total of 56 controls and 26 cases were included in the analysis. Volumetry was consistent between observers. Adrenal volumes were not higher in the case group (p = 0.2); adrenal: body volume ratios were higher (p = 0.011), persisting in the presence of chorioamnionitis (p = 0.017). A cluster of three pairs of adrenal glands below the fifth centile were noted among the cases all of whom had a protracted period at risk of preterm birth prior to MRI. Conclusions: Adrenal: body volume ratios are significantly larger in fetuses who go on to deliver preterm than those delivering at term. Adrenal volumes were not significantly larger, we hypothesize that this could be due to an adrenal atrophy in fetuses with fulminating chorioamnionitis. A straightforward relationship of adrenal size being increased prior to preterm birth should not be assumed. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate changes occurring in the fetal brain prior to very preterm delivery using MRI T2* relaxometry, an indirect assessment of tissue perfusion. Method: Fetuses that subsequently delivered spontaneously <32 weeks gestation and a control cohort were identified from pre‐existing datasets. Participants had undergone a 3T MRI assessment including T2* relaxometry of the fetal brain using a 2D multi‐slice gradient echo single shot echo planar imaging sequence. T2* maps were generated, supratentorial brain tissue was manually segmented and mean T2* values were generated. Groups were compared using quadratic regression. Results: Twenty five fetuses that subsequently delivered <32 weeks and 67 that delivered at term were included. Mean gestation at MRI was 24.5 weeks (SD 3.3) and 25.4 weeks (SD 3.1) and gestation at delivery 25.5 weeks (SD 3.4) and 39.7 weeks (SD 1.2) in the preterm and term cohorts respectively. Brain mean T2* values were significantly lower in fetuses that subsequently delivered before 32 weeks gestation (p < 0.001). Conclusion: Alterations in brain maturation appear to occur prior to preterm delivery. Further work is required to explore these associations, but these findings suggest a potential window for therapeutic neuroprotective agents in fetuses at high risk of preterm delivery in the future. Key points: What is already known on this topic? Few studies have been conducted exploring brain development prior to preterm birth; however, a reduction in the cerebral cortex and extracerebrospinal fluid volumes and alterations in functional connectivity have been reported in fetuses that subsequently deliver preterm. What does this study add to what is known? Mean T2* relaxometry values are significantly lower in fetuses that subsequently deliver <32 weeks in comparison with fetuses that deliver at term, indicating that alterations in tissue perfusion may be occurring prior to preterm birth. [ABSTRACT FROM AUTHOR]

Background: Preterm prelabour rupture of the membranes (PPROM) complicates 3% of pregnancies and is associated with an increased risk of maternal and perinatal morbidity and mortality. In an attempt to better understand this diagnosis, patients routinely resort to the internet for medical information. The lack of governance online leaves patients at risk of relying on low‐quality websites. Objectives: To assess systematically the accuracy, quality, readability and credibility of World Wide Web pages on PPROM. Search Strategy: Five search engines (Google, AOL, Yahoo, Ask and Bing) were searched with location services and browser history disabled. Websites from the first page of all searches were included. Selection Criteria: Websites were included if they provided at least 300 words of health information aimed at patients relating to PPROM. Data Collection and Analysis: Validated assessments of health information readability, credibility and quality were undertaken, as was an accuracy assessment. Pertinent facts for accuracy assessment were based on feedback from healthcare professionals and patients through a survey. Characteristics were tabulated. Main Results: In all, 39 websites were included, with 31 different texts. No pages were written with a reading age of 11 years or less, none were considered credible, and only three were high quality. An accuracy score of 50% or more was obtained by 45% of websites. Information that patients considered pertinent was not consistently reported. Conclusions: Search engines produce information on PPROM that is low quality, low accuracy and not credible. It is also difficult to read. This risks disempowerment. Healthcare professionals and researchers must consider how to ensure patients have access to information that they can recognise as high quality. This article includes Author Insights, a video abstract available at: https://emckclac‐my.sharepoint.com/:p:/g/personal/k2143229_kcl_ac_uk/EUmhiRWfTmdHvLKxiUglGM0B2diW2g1lkMj6sMS1fxCVzg?e=XA1Tak. [ABSTRACT FROM AUTHOR]

Purpose: Preterm premature rupture of membranes complicates up to 40% of premature deliveries. Fetal infection may occur in the absence of maternal symptoms, delaying diagnosis and increasing morbidity and mortality. A noninvasive antenatal assessment of early signs of placental inflammation is therefore urgently required. Methods: Sixteen women with preterm premature rupture of membranes < 34 weeks gestation and 60 women with uncomplicated pregnancies were prospectively recruited. A modified diffusion‐weighted spin‐echo single shot EPI sequence with a diffusion preparation acquiring 264 unique parameter combinations in < 9 min was obtained on a clinical 3 Tesla MRI scanner. The data was fitted to a 2‐compartment T2*$$ {\mathrm{T}}_2^{\ast } $$‐intravoxel incoherent motion model comprising fast and slowly circulating fluid pools to obtain quantitative information on perfusion, density, and tissue composition. Z values were calculated, and correlation with time from between the rupture of membranes and the scan, gestational age at delivery, and time between scan and delivery assessed. Results: Placental T2*$$ {\mathrm{T}}_2^{\ast } $$ was significantly reduced in preterm premature rupture of membranes, and the 2‐compartmental model demonstrated that this decline is mainly linked to the perfusion component observed in the placental parenchyma. Multi‐modal MRI measurement of placental function is linked to gestational age at delivery and time from membrane rupture. Conclusion: More complex models and data acquisition can potentially improve fitting of the underlying etiology of preterm birth compared with individual single‐contrast models and contribute to additional insights in the future. This will need validation in larger cohorts. A multi‐modal MRI acquisition between rupture of the membranes and delivery can be used to measure placental function and is linked to gestational age at delivery. [ABSTRACT FROM AUTHOR]

Chorioamnionitis is present in up to 70% of spontaneous preterm births. It is defined as an acute inflammation of the chorion, with or without involvement of the amnion, and is evidence of a maternal immunological response to infection. A fetal inflammatory response can coexist and is diagnosed on placental histopathology postnatally. Fetal inflammatory response syndrome (FIRS) is associated with poorer fetal and neonatal outcomes. The only antenatal diagnostic test is amniocentesis which carries risks of miscarriage or preterm birth. Imaging of the fetal immune system, in particular the thymus and the spleen, and the placenta may give valuable information antenatally regarding the diagnosis of fetal inflammatory response. While ultrasound is largely limited to structural information, MRI can complement this with functional information that may provide insight into the metabolic activities of the fetal immune system and placenta. This review discusses fetal and placental imaging in pregnancies complicated by chorioamnionitis and their potential future use in achieving non‐invasive antenatal diagnosis. Key points: What's already known about the topic?Chorioamnionitis is present in up to 70% of spontaneous preterm births and is associated with more complications than unaffected spontaneous preterm birthsDiagnosis is postnatal. Antenatal diagnosis by amniocentesis carries a risk of preterm birth, and is not integrated into clinical care What does this review add?Ultrasound assessment of the fetal immune system gives structural information and limited functional information, while MRI can complement this with greater functional tissue informationImaging may play a role in the non‐invasive antenatal diagnosis of chorioamnionitis [ABSTRACT FROM AUTHOR]

To advance the field of early detection with blood‐based screening tests and for industry to be able to significantly contribute to progress, collaboration, transparency, and innovative health economic approaches are needed. To achieve this, gaps in the current versus ideal frameworks need to be addressed at the regulatory, reimbursement, and guidelines levels by adopting an integrative, system‐level thinking to bring these important technologies to market and to improve on cancer outcomes by finding more cancers at earlier stages. [ABSTRACT FROM AUTHOR]

In skeletal muscle fibers, mitochondria are densely packed adjacent to myofibrils because adenosine triphosphate (ATP) is needed to fuel sarcomere shortening. However, despite this close physical and biochemical relationship, the effects of mitochondrial dynamics on skeletal muscle contractility are poorly understood. In this study, we analyzed the effects of Mitochondrial Division Inhibitor 1 (mdivi-1), an inhibitor of mitochondrial fission, on the structure and function of both mitochondria and myofibrils in skeletal muscle tissues engineered on micromolded gelatin hydrogels. Treatment with mdivi-1 did not alter myotube morphology, but did increase the mitochondrial turbidity and oxidative capacity, consistent with reduced mitochondrial fission. Mdivi-1 also significantly increased basal, twitch, and tetanus stresses, as measured using the Muscular Thin Film (MTF) assay. Finally, mdivi-1 increased sarcomere length, potentially due to mdivi-1-induced changes in mitochondrial volume and compression of myofibrils. Together, these results suggest that mdivi-1 increases contractile stress generation, which may be caused by an increase in maximal respiration and/or sarcomere length due to increased volume of individual mitochondria. These data reinforce that mitochondria have both biochemical and biomechanical roles in skeletal muscle and that mitochondrial dynamics can be manipulated to alter muscle contractility. [ABSTRACT FROM AUTHOR]

To breed improved biomass cultivars of Miscanthus ×giganteus, it will be necessary to select the highest‐yielding and best‐adapted genotypes of its parental species, Miscanthus sinensis and Miscanthus sacchariflorus. We phenotyped a diverse clonally propagated panel of 569 M. sinensis and nine natural diploid M. ×giganteus at one subtropical (Zhuji, China) and five temperate locations (Sapporo, Japan; Leamington, Ontario, Canada; Fort Collins, CO; Urbana, IL; and Chuncheon, Korea) for dry biomass yield and 14 yield‐component traits, in trials grown for 3 years. Notably, dry biomass yield of four Miscanthus accessions exceeded 80 Mg/ha in Zhuji, China, approaching the highest observed for any land plant. Additionally, six M. sinensis in Sapporo, Japan and one in Leamington, Canada also yielded more than the triploid M. ×giganteus '1993‐1780' control, with values exceeding 20 Mg/ha. Diploid M. ×giganteus was the best‐yielding group at the northern sites. Genotype‐by‐environment interactions were modest among the five northern trial sites but large between Zhuji, and the northern sites. M. sinensis accessions typically yielded best at trial sites with latitudes similar to collection sites, although broad adaptation was observed for accessions from southern Japan. Genotypic heritabilities for third year yields ranged from 0.71 to 0.88 within locations. Compressed circumference was the best predictor of yield. These results establish a baseline of data for initiating selection to improve biomass yield of M. sinensis and M. ×giganteus in a diverse set of relevant geographies. [ABSTRACT FROM AUTHOR]

To improve the efficiency of breeding of Miscanthus for biomass yield, there is a need to develop genomics‐assisted selection for this long‐lived perennial crop by relating genotype to phenotype and breeding value across a broad range of environments. We present the first genome‐wide association (GWA) and genomic prediction study of Miscanthus that utilizes multilocation phenotypic data. A panel of 568 Miscanthus sinensis accessions was genotyped with 46,177 single nucleotide polymorphisms (SNPs) and evaluated at one subtropical and five temperate locations over 3 years for biomass yield and 14 yield‐component traits. GWA and genomic prediction were performed separately for different years of data in order to assess reproducibility. The analyses were also performed for individual field trial locations, as well as combined phenotypic data across groups of locations. GWA analyses identified 27 significant SNPs for yield, and a total of 504 associations across 298 unique SNPs across all traits, sites, and years. For yield, the greatest number of significant SNPs was identified by combining phenotypic data across all six locations. For some of the other yield‐component traits, greater numbers of significant SNPs were obtained from single site data, although the number of significant SNPs varied greatly from site to site. Candidate genes were identified. Accounting for population structure, genomic prediction accuracies for biomass yield ranged from 0.31 to 0.35 across five northern sites and from 0.13 to 0.18 for the subtropical location, depending on the estimation method. Genomic prediction accuracies of all traits were similar for single‐location and multilocation data, suggesting that genomic selection will be useful for breeding broadly adapted M. sinensis as well as M. sinensis optimized for specific climates. All of our data, including DNA sequences flanking each SNP, are publicly available. By facilitating genomic selection in M. sinensis and Miscanthus × giganteus, our results will accelerate the breeding of these species for biomass in diverse environments. [ABSTRACT FROM AUTHOR]

Overwintering ability is an important selection criterion for Miscanthus breeding in temperate regions. Insufficient overwintering ability of the currently leading Miscanthus biomass cultivar, M. ×giganteus (M×g) '1993–1780', in regions where average annual minimum temperatures are −26.1°C (USDA hardiness zone 5) or lower poses a pressing need to develop new cultivars with superior cold tolerance. To facilitate breeding of Miscanthus, this study characterized phenotypic and genetic variation of overwintering ability in an M. sinensis germplasm panel consisting of 564 accessions, evaluated in field trials at three locations in North America and two in Asia. Genome‐wide association (GWA) and genomic prediction analyses were performed. The Korea/N China M. sinensis genetic group is a valuable gene pool for cold tolerance. The Yangtze‐Qinling, Southern Japan, and Northern Japan genetic groups were also potential sources of cold tolerance. A total of 73 marker–trait associations were detected for overwintering ability. Estimated breeding value for overwintering ability based on these 73 markers could explain 55% of the variation for first winter overwintering ability among M. sinensis. Average genomic prediction ability for overwintering ability across 50 fivefold cross‐validations was high (~0.73) after accounting for population structure. Common genomic regions for overwintering ability were detected by GWA analyses and a previous parallel QTL mapping study using three interconnected biparental F1 populations. One QTL on Miscanthus LG 8 encompassed five GWA hits and a known cold‐responsive gene, COR47. The other overwintering ability QTL on Miscanthus LG 11 contained two GWA hits and three known cold stress‐related genes, carboxylesterase 13 (CEX13), WRKY2 transcription factor, and cold shock domain (CSDP1). Miscanthus accessions collected from high latitude locations with cold winters had higher rates of overwintering, and more alleles for overwintering, than accessions collected from southern locations with mild winters. [ABSTRACT FROM AUTHOR]

Background: Older adults are at greater risk for morbidity and mortality associated with COVID‐19. Spatial distancing and sequestering practices are recommended to limit viral exposure. Older adults adopting these practices are at increased risk of social isolation and adverse health outcomes. Remote technologies offer various platforms for satisfying socialization and healthcare needs while sequestering. Understanding how older adults are using technology has implications for wellbeing during a pandemic. Method: Researchers attempted to contact all participants enrolled in the University of Kentucky Alzheimer's Disease Research Center longitudinal study via telephone to survey technology use (n = 706). Participants were contacted directly, except for demented participants, whose primary caregivers were contacted to respond on their behalf, when possible. Participants and caregivers gave their assent verbally to complete the voluntary survey, the procedures of which were approved by the IRB. The surveys consisted of validated instruments to gauge the extent of use of and comfort with technology. Spearman correlations, chi‐square tests, and t‐tests were used to explore data. Result: Ultimately, 384 participants were reached and 332 consented to participate. Most reported reliable home internet access (91.5%) and some internet use (90.6%). Recent feelings of loneliness were not related to any technology‐related variables (all ps > 0.29) other than decreasing with greater willingness to use telehealth (Rho = ‐0.11, p = 0.06). Those who reported a lack of comfort with technology (n = 76) were less likely to text messaging (67% vs 78%) and social media (56% vs 69%), ps ≤ 0.06, but felt socially connected using technology at similar levels (82% vs 75%), p = 0.22. Nearly 70% of this group reported they would use technology more with training. Across all participants, willingness to use telehealth was not related to frequency of frustration with tech (Rho = 0, p = 0.99). Conclusion: The results suggest that some older adults' use of technology is limited by familiarity. Lack of familiarity does not appear to create a barrier to using telehealth nor does frustration with technology appear to limit telehealth use. The findings have implications for supporting older adults sequestered during a pandemic but potentially more broadly. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective This study aimed to develop a single-nucleotide polymorphism-based and informatics-based non-invasive prenatal test that detects sex chromosome aneuploidies early in pregnancy. Methods Sixteen aneuploid samples, including thirteen 45,X, two 47,XXY, and one 47,XYY, along with 185 euploid controls, were analyzed. Cell-free DNA was isolated from maternal plasma, amplified in a single multiplex polymerase chain reaction assay that targeted 19 488 polymorphic loci covering chromosomes 13, 18, 21, X, and Y, and sequenced. Sequencing results were analyzed using a Bayesian-based maximum likelihood statistical method to determine copy number of interrogated chromosomes, calculating sample-specific accuracies. Results Of the samples that passed a stringent quality control metric (93%), the algorithm correctly identified copy number at all five chromosomes in all but one of the 187 samples, for 934/935 correct calls as early as 9.4 weeks of gestation. We detected 45,X with 91.7% sensitivity (CI: 61.5-99.8%) and 100% specificity (CI: 97.9-100%), and 47,XXY and 47,XYY. The average calculated accuracy was 99.78%. Conclusion This method non-invasively detected 45,X, 47,XXY, and 47,XYY fetuses from cell-free DNA isolated from maternal plasma with high calculated accuracies and thus offers a non-invasive method with the potential to function as a routine screen allowing for early prenatal detection of rarely diagnosed yet commonly occurring sex aneuploidies. © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Ecosystem-based fishery management requires an understanding of relationships between fisheries and environmental variability. The purposes of this study were to investigate (1) how environmental forcing drives variability in larval settlement of the blue crab Callinectes sapidus, (2) whether larval settlement data are useful for determining recruit-stock relationships, and (3) whether environmental data can be used to predict settlement. Megalopae settling on passive collectors in the Newport River estuary, NC, were collected nightly from September to November for 13 yr from 1993 to 2009. Observed settlement was compared with winds, tides, and predicted settlement (numerical model derived from environmental data) using cross-correlation analysis. Weather events associated with settlement pulses were also identified. Recruit-stock relationships were developed by comparing observed and predicted settlement indices to lagged NC fishery data. Settlement was positively correlated with winds from the northeast, southeast and south in 12 of 13 yr and with maximum duration nighttime flood tides in all years. Settlement pulses occurred when high pressure systems formed over the southeast USA (58% of pulses) or hurricanes (25%), and nearly all occurred during nighttime flood tides (85%). Significant recruit-stock relationships occurred between observed settlement and fishery landings ( r2 = 0.96) and effort ( r2 = 0.94) in wet years and catch per unit effort ( r2 = 0.98) during dry years. The timing of settlement pulses, but not the magnitude of annual settlement, was successfully predicted using the settlement model. These results suggest that blue crab fisheries in NC are influenced both by larval settlement and post-settlement processes (freshwater inflow). [ABSTRACT FROM AUTHOR]

Exposure to arsenic (As) through drinking water is a substantial problem worldwide. The methylation of As, a reactive metalloid, generates monomethyl- (MMA) and dimethyl-arsenical (DMA) species. The biochemical pathway that catalyzes these reactions, one-carbon metabolism, is regulated by folate and other micronutrients. Arsenic methylation exerts a critical influence on both its urinary elimination and chemical reactivity. Mice having the As methyltransferase null genotype show reduced urinary As excretion, increased As retention, and severe systemic toxicity. The most toxic As metabolite in vitro is MMAIII, an intermediate in the generation of DMAV, a much less toxic metabolite. These findings have raised the question of whether As methylation is a detoxification or bioactivation pathway. Results of population-based studies suggest that complete methylation of inorganic As to DMA is associated with reduced risk for As-induced health outcomes, and that nutrients involved in one-carbon metabolism, such as folate, can facilitate As methylation and elimination. [ABSTRACT FROM AUTHOR]

• Local adaptation is a well-established phenomenon whereby habitat-mediated natural selection drives the differentiation of populations. However, little is known about how specific traits and loci combine to cause local adaptation. • Here, we conducted a set of experiments to determine which physiological mechanisms contribute to locally adaptive divergence in salt tolerance between coastal perennial and inland annual ecotypes of Mimulus guttatus. Quantitative trait locus (QTL) mapping was used to discover loci involved in salt spray tolerance and leaf sodium (Na+) concentration. To determine whether these QTLs confer fitness in the field, we examined their effects in reciprocal transplant experiments using recombinant inbred lines (RILs). • Coastal plants had constitutively higher leaf Na+ concentrations and greater levels of tissue tolerance, but no difference in osmotic stress tolerance. Three QTLs contributed to salt spray tolerance and two QTLs to leaf Na+ concentration. All three salt-spray tolerance QTLs had a significant fitness effects at the coastal field site but no effects inland. Leaf Na+ QTLs had no detectable fitness effects in the field. • Physiological results are consistent with adaptation of coastal populations to salt spray and soil salinity. Field results suggest that there may not be trade-offs across habitats for alleles involved in local salt spray adaptations. [ABSTRACT FROM AUTHOR]

Background: Older adults are susceptible to negative cognitive effects induced by inappropriate medication use.1 Some individuals may accumulate amyloid‐β deposits before symptomatic expression, suggesting preclinical Alzheimer's disease (pAD). Inappropriate medication use may interact with this neuropathology to hasten symptomatic AD onset. Thus, we designed INCREASE: a randomized controlled trial (RCT) to improve medication use through targeted medication therapy management (tMTM) and ultimately delay AD symptomatic expression.2 Methods: Community‐dwelling non‐demented adults ≥ 65 years old who regularly used ≥1 potentially inappropriate medication3 were recruited for the RCT. Board certified geriatric pharmacists reviewed medication lists and identified medication‐related problems (MRPs) at baseline for all participants before conducting the tMTM intervention. Here, we describe this initial medication review, stratified by pAD status. pAD was defined as total brain relative standardized uptake values > 1.4 for PET amyloid.3 Group differences were identified using Student's t‐tests. Results: 79 participants were included in this analysis (mean age 73.9 years [SD 5.9]; 66% female). 12.9 (4.9) baseline medication were reported on average, which did not differ significantly between participants with (14.2 [4.8]) and without (12.3 [5.1]) pAD. The most commonly reported medication classes were proton pump inhibitors, antihistamines, non‐steroidal anti‐inflammatory drugs, and vitamins/supplements. On average, 4.9 (SD 2.3) MRPs were identified per participant (389 MRPs total). The most common causes of MRPs were: 1) a medication not appropriate given the participants' age and/or medical conditions; 2) dose/frequency too high; and 3) untreated medical condition. The most common recommendation by the pharmacist was to deprescribe the problem medication. There were no differences in the number or causes of MRPs based on pAD status. Conclusion: Non‐demented older adults enrolled in an MTM RCT used more than ten medications concurrently, with about 5 MRPs identified in each participant. INCREASE will test the hypothesis that deprescribing these inappropriate medications may delay symptomatic AD. Given that the pharmacokinetics and pharmacodynamics of this population puts them at high risk for adverse drug events including cognitive impairment, future work should continue to optimize medication use to prevent cognitive decline. References: 1. Moga DC, et al. Trials. 2019;20(1):806. 2. Jack CR, et al. Brain. 2015;138(12):3747‐3759. 3. American Geriatrics Society. J Am Geriatr Soc. 2015;63(11):2227‐2246. [ABSTRACT FROM AUTHOR]

Background: Falls, a leading cause of disability and mortality in older adults,1 are associated cognitive impairment and inappropriate medication use.2 We propose a novel construct, "mobility reserve" (MR), which describes an individual's resilience against mobility decline. We hypothesize that augmenting MR may delay fall‐associated morbidity. Here, we investigate the association between MR and inappropriate medication use among participants with and without preclinical Alzheimer's disease (pAD) enrolled in a randomized medication therapy management trial.3 Methods: Non‐demented older adults who used ≥1 potentially inappropriate medication4 were recruited for the RCT. The Medication Appropriateness Index was calculated for all medications (MAI) and for potentially inappropriate medications (MAI‐PIM). Participants' gait speed (cm/s) was measured under normal conditions and while challenged with 1.5mg of scopolamine to unmask vulnerability. The difference in gait speeds was calculated as mobility reserve change score (MRCS). PET amyloid total brain relative standardized uptake values > 1.4 was used to define pAD.5Spearman correlation coefficients (rs) assessed the relationship between medication appropriateness and MRCS. Results: 36 participants were included in this analysis (mean age 75.0 years [SD 6.0]; 78% female); 10 (27.8%) were classified as pAD. The mean (SD) MAI and MAI‐PIM were 10.3 (5.1) and 5.4 (4.0) respectively, not differing by pAD status (p=0.92 and 0.11 for MAI and MAI‐PIM). The mean (SD) MRCS was ‐0.39 cm/s (9.4) (no difference by pAD status; p=0.84). Among those with pAD, MAI and MAI‐PIM were negatively correlated with MRCS (r = ‐0.53 and ‐0.46 respectively), which was not the case among those without pAD (r = 0.37 and 0.34), though a larger sample size is needed to add confidence to these estimates. Conclusion: Among community‐dwelling non‐demented older adults, more inappropriate medication use was associated with lower mobility reserve among those with pAD. These results support the hypothesized relationship between MR and medication appropriateness. Future studies should further operationalize measures of MR to open a novel intervention pathway for reducing fall‐related morbidity in cognitively at‐risk populations. References: 1. Katz R, Shah P. JAMA. 2010;303(3):273‐274. 2. Enderlin C et al. Geriatr Nurs. 2015;36(5):397‐406. 3. Moga DC et al. Trials. 2019;20(1):806. 4. American Geriatrics Society. J Am Geriatr Soc. 2015;63(11):2227‐2246. 5.Jack CR et al. Brain. 2015;138(12):3747‐3759. [ABSTRACT FROM AUTHOR]

Background: Augmenting cognitive reserve (CR) may delay the progression from preclinical Alzheimer's disease (pAD) to symptomatic AD. Because studies have shown that potentially inappropriate medication (PIM) use may lower CR,1 optimizing individual medication regimens may protect against AD dementia symptomatic onset. We investigated the association between baseline measures of CR and PIM use among participants enrolled in a randomized medication therapy management trial.2 Methods: Participants completed cognitive tests –Trail Making Tests A and B (TMT) and California Verbal Learning Test Trials 1‐5 (CVLT) – while wearing a 1.5mg scopolamine patch ("challenged") and again four weeks later under normal conditions ("unchallenged"). Change scores between the challenged and unchallenged tests (standardized for age, sex, and education) were used as a surrogate for CR. The Medication Appropriateness Index for medications considered potentially inappropriate for older adults based on the 2015 Beers Criteria3 served as a measure of PIM use (MAI‐PIM). pAD was defined as total brain relative standardized uptake values > 1.4 using amyloid PET.4Spearman correlation coefficients (rs) assessed the relationship between MAI‐PIM and CR. Results: Included participants (N=79) had mean age 73.9 years [SD 5.9] and were 66% female; 31.6% met pAD criteria. The median (IQR) PIMs reported at baseline was 2 (2‐3). Participants with and without pAD had similar mean (SD) baseline change scores for TMT B minus A (‐0.17 [1.37] and ‐0.13 [1.10] respectively; p=0.90), but lower total CVLT change scores (‐0.85 [0.84] and ‐0.29 [0.83]; p=0.01). Higher MAI‐PIM was also correlated with lower baseline CVLT change scores (rs=‐0.16), driven by the participants with pAD (rs=‐0.33). TMT B minus A change scores and MAI‐PIM were uncorrelated (rs=0.02). Conclusion: Among community‐dwelling non‐demented older adults, executive function and total learning CR was operationalized via participants' abilities to compensate for anticholinergic challenge. There was a moderate negative correlation between MAI‐PIM and low total learning CR among participants with pAD, but not for those without. These results support the hypothesized relationship between CR and medication appropriateness. References: 1. Moga DC et al. Alzheimers Res Ther. 2017;9(1):36. 2. Moga DC, et al. Trials. 2019;20(1):806. 3. American Geriatrics Society. J Am Geriatr Soc. 2015;63(11):2227‐2246.4. Jack CR et al. Brain. 2015;138(12):3747‐3759. [ABSTRACT FROM AUTHOR]

R2883 --> Introduction: During most cases of myocardial infarction (MI), an atherosclerotic plaque occludes a coronary artery, thereby obstructing the flow of blood and oxygen (O2) to the myocardial tissue. A localized site of hypoxia develops with subsequent massive cardiomyocyte (CM) cell death. As a result of the distorted cardiac blood supply, steep O2 gradients develop at the MI border zone region between the injured, hypoxic myocardial tissue and the surrounding viable, normoxic myocardial tissue. Although the border zone is understood to be a transition region in electromechanical properties of CMs, little is known about the effect of O2 gradients on the function of human myocardial tissue, including the effect of hypoxic CMs on nearby normoxic CMs and vice versa. The objective of this study was to engineer an O2 landscape microphysiological system to expose CMs to O2 gradients that mimic an MI border zone and study its effect on CM calcium transients and calcium wave propagation velocity (CPV). We hypothesize that hypoxic CMs alter the calcium handling in adjacent normoxic CMs across an O2 gradient landscape via cell‐cell contact and/or paracrine‐mediated mechanisms. Methods: We engineered a polydimethylsiloxane (PDMS) microphysiological system with buried, gas‐perfused microchannels to maintain a spatial O2 gradient. An overlying PDMS gas diffusion membrane was microcontact printed with a fibronectin line pattern to culture anisotropic monolayers of neonatal rat ventricular myocytes (NRVMs) on the device surface. The O2 gradient profile was validated using fluorescent O2 sensors. After 4 hours of O2 modulation, the fluorescent calcium indicator Fluo‐4 was used to measure calcium transients and CPV during 1 Hz electrical pacing. Results: Calcium transient analysis showed an increase in the time to peak in normoxic NRVMs within the O2 gradient as compared to adjacent hypoxic NRVMs in the gradient (p < 0.05) and homogenous hypoxic (p < 0.01) and homogenous normoxic (p < 0.001) control devices. The presence of the O2 gradient also increased the time constant of decay as compared to the controls (p < 0.01). CPV results showed that transverse velocity was slower in normoxic NRVMs within the O2 gradient compared to the homogenous normoxic control (5.3 ± 3.9 vs. 13.4 ± 3.2 cm/s, p=0.02). Conclusions: Overall, the data demonstrate that there is a delayed excitation and delayed recovery of calcium transients in CMs exposed to normoxia in an O2 gradient. Additionally, the transverse CPV in normoxic CMs in the gradient is driven by the nearby hypoxic CMs. Our in vitro border zone O2 landscape allows us to investigate ongoing interactions between normoxic and hypoxic CMs, which is key to developing a better understanding of the effects of acute MI, uncovering the mechanisms of post‐MI remodeling, and creating novel therapies to minimize myocardial damage and the expansion of hypoxic cardiac injury. [ABSTRACT FROM AUTHOR]