The oral health of adults attending dental practices in England in 2018: a report of a novel method and findings.

Introduction National surveys of the oral health of adults are conducted decennially. For reasons of feasibility and cost, these only provide accurate information at large geographical areas. To address this, a survey of adults attending dental practices in England was undertaken.Aim To describe and discuss the survey method and findings.Method A clinical examination and questionnaire survey was conducted in a sample of English dental practices.Results Questionnaires (n = 16,572) and clinical examinations (n = 14,270) were completed with patients from 1,173 dental practices. Poorer oral health disproportionately affected older adults and those from more socioeconomically deprived areas. Over one in three from more deprived areas had untreated caries compared with one in five in the less deprived (36.2% vs 19.9%) and impacts of oral problems were nearly three times higher in the more deprived areas (27.9% vs 11.0%). Of those receiving NHS care, 28.7% and 46.2% reported they would struggle/be unable to pay a Band 2 and Band 3 NHS patient charge, respectively.Conclusion It is feasible to undertake a survey of adults in dental practices but care must be taken generalising the findings to the general population and comparing them with other surveys undertaken using different methods.

Rise of Ruppia in Chesapeake Bay: Climate change-driven turnover of foundation species creates new threats and management opportunities.

Global change has converted many structurally complex and ecologically and economically valuable coastlines to bare substrate. In the structural habitats that remain, climate-tolerant and opportunistic species are increasing in response to environmental extremes and variability. The shifting of dominant foundation species identity with climate change poses a unique conservation challenge because species vary in their responses to environmental stressors and to management. Here, we combine 35 y of watershed modeling and biogeochemical water quality data with species comprehensive aerial surveys to describe causes and consequences of turnover in seagrass foundation species across 26,000 ha of habitat in the Chesapeake Bay. Repeated marine heatwaves have caused 54% retraction of the formerly dominant eelgrass (Zostera marina) since 1991, allowing 171% expansion of the temperature-tolerant widgeongrass (Ruppia maritima) that has likewise benefited from large-scale nutrient reductions. However, this phase shift in dominant seagrass identity now presents two significant shifts for management: Widgeongrass meadows are not only responsible for rapid, extensive recoveries but also for the largest crashes over the last four decades; and, while adapted to high temperatures, are much more susceptible than eelgrass to nutrient pulses driven by springtime runoff. Thus, by selecting for rapid post-disturbance recolonization but low resistance to punctuated freshwater flow disturbance, climate change could threaten the Chesapeake Bay seagrass' ability to provide consistent fishery habitat and sustain functioning over time. We demonstrate that understanding the dynamics of the next generation of foundation species is a critical management priority, because shifts from relatively stable habitat to high interannual variability can have far-reaching consequences across marine and terrestrial ecosystems.

A single F153Sß3 mutation causes constitutive integrin αIIbß3 activation in a variant form of Glanzmann thrombasthenia.

This report identifies a novel variant form of the inherited bleeding disorder Glanzmann thrombasthenia, exhibiting only mild bleeding in a physically active individual. The platelets cannot aggregate ex vivo with physiologic agonists of activation, although microfluidic analysis with whole blood displays moderate ex vivo platelet adhesion and aggregation consistent with mild bleeding. Immunocytometry shows reduced expression of αIIbß3 on quiescent platelets that spontaneously bind/store fibrinogen, and activation-dependent antibodies (ligand-induced binding site-319.4 and PAC-1) report ß3 extension suggesting an intrinsic activation phenotype. Genetic analysis reveals a single F153Sß3 substitution within the ßI-domain from a heterozygous T556C nucleotide substitution of ITGB3 exon 4 in conjunction with a previously reported IVS5(+1)G>A splice site mutation with undetectable platelet messenger RNA accounting for hemizygous expression of S153ß3. F153 is completely conserved among ß3 of several species and all human ß-integrin subunits suggesting that it may play a vital role in integrin structure/function. Mutagenesis of αIIb-F153Sß3 also displays reduced levels of a constitutively activated αIIb-S153ß3 on HEK293T cells. The overall structural analysis suggests that a bulky aromatic, nonpolar amino acid (F,W)153ß3 is critical for maintaining the resting conformation of α2- and α1-helices of the ßI-domain because small amino acid substitutions (S,A) facilitate an unhindered inward movement of the α2- and α1-helices of the ßI-domain toward the constitutively active αIIbß3 conformation, while a bulky aromatic, polar amino acid (Y) hinders such movements and restrains αIIbß3 activation. The data collectively demonstrate that disruption of F153ß3 can significantly alter normal integrin/platelet function, although reduced expression of αIIb-S153ß3 may be compensated by a hyperactive conformation that promotes viable hemostasis.

The effect of community water fluoridation on dental caries in children and young people in England: an ecological study.

BACKGROUND: The protective effect of community water fluoridation (CWF) against dental caries may be modified by secular changes in health behaviour. We aimed to determine the contemporary association between fluoride in public water supplies (PWS) and dental caries indicators and inequalities in England. METHODS: We estimated exposure to CWF and PWS fluoride concentrations from national monitoring data, using Geographic Information Systems and water supply boundaries, categorizing mean period exposure into <0.1, 0.1-<0.2, 0.2-<0.4, 0.4-<0.7 and ≥0.7 mg/l. We used area-level health outcome and confounder data in multivariable regression models to determine the association between fluoride and caries outcomes and calculated preventive fractions using these coefficients. RESULTS: The odds of caries and of severe caries in 5-year-olds fell with increasing fluoride concentration in all SES quintiles (P < 0.001 to P = 0.003). There was a negative trend between increasing fluoride concentration and dental extractions (P < 0.001). Compared to PWS with <0.2 mg/l, CWF prevented 17% (95% confidence interval (CI): 5-27%) to 28% (95% CI: 24-32%) of caries (high-low SES) and 56% (95% CI: 25-74%) of dental extractions. The association between fluoride concentration and caries prevalence/severity varied by socioeconomic status (SES) (P < 0.001). CONCLUSIONS: Exposure to fluoride in PWS appears highly protective against dental caries and reduces oral health inequalities.

Data synthesis for environmental management: A case study of Chesapeake Bay.

Synthesizing large, complex data sets to inform resource managers towards effective environmental stewardship is a universal challenge. In Chesapeake Bay, a well-studied and intensively monitored estuary in North America, the challenge of synthesizing data on water quality and land use as factors related to a key habitat, submerged aquatic vegetation, was tackled by a team of scientists and resource managers operating at multiple levels of governance (state, federal). The synthesis effort took place over a two-year period (2016-2018), and the results were communicated widely to a) scientists via peer review publications and conference presentations; b) resource managers via web materials and workshop presentations; and c) the public through newspaper articles, radio interviews, and podcasts. The synthesis effort was initiated by resource managers at the United States Environmental Protection Agencys' Chesapeake Bay Program and 16 scientist participants were recruited from a diversity of organizations. Multiple short, immersive workshops were conducted regularly to conceptualize the problem, followed by data analysis and interpretation that supported the preparation of the synthetic products that were communicated widely. Reflections on the process indicate that there are a variety of structural and functional requirements, as well as enabling conditions, that need to be considered to achieve successful outcomes from synthesis efforts.

NADPH oxidase 4 contributes to TRPV4-mediated endothelium-dependent vasodilation in human arterioles by regulating protein phosphorylation of TRPV4 channels.

Impaired endothelium-dependent vasodilation has been suggested to be a key component of coronary microvascular dysfunction (CMD). A better understanding of endothelial pathways involved in vasodilation in human arterioles may provide new insight into the mechanisms of CMD. The goal of this study is to investigate the role of TRPV4, NOX4, and their interaction in human arterioles and examine the underlying mechanisms. Arterioles were freshly isolated from adipose and heart tissues obtained from 71 patients without coronary artery disease, and vascular reactivity was studied by videomicroscopy. In human adipose arterioles (HAA), ACh-induced dilation was significantly reduced by TRPV4 inhibitor HC067047 and by NOX 1/4 inhibitor GKT137831, but GKT137831 did not further affect the dilation in the presence of TRPV4 inhibitors. GKT137831 also inhibited TRPV4 agonist GSK1016790A-induced dilation in HAA and human coronary arterioles (HCA). NOX4 transcripts and proteins were detected in endothelial cells of HAA and HCA. Using fura-2 imaging, GKT137831 significantly reduced GSK1016790A-induced Ca2+ influx in the primary culture of endothelial cells and TRPV4-WT-overexpressing human coronary artery endothelial cells (HCAEC). However, GKT137831 did not affect TRPV4-mediated Ca2+ influx in non-phosphorylatable TRPV4-S823A/S824A-overexpressing HCAEC. In addition, treatment of HCAEC with GKT137831 decreased the phosphorylation level of Ser824 in TRPV4. Finally, proximity ligation assay (PLA) revealed co-localization of NOX4 and TRPV4 proteins. In conclusion, both TRPV4 and NOX4 contribute to ACh-induced dilation in human arterioles from patients without coronary artery disease. NOX4 increases TRPV4 phosphorylation in endothelial cells, which in turn enhances TRPV4-mediated Ca2+ entry and subsequent endothelium-dependent dilation in human arterioles.

Thromboelastometry assessment of hemostatic properties in various murine models with coagulopathy and the effect of factor VIII therapeutics.

BACKGROUND: Rotational thromboelastometry (ROTEM) has been commonly used to assess the viscoelastic properties of the blood clotting process in the clinic for patients with a hemostatic or prothrombotic disorder. OBJECTIVE: To evaluate the capability of ROTEM in assessing hemostatic properties in whole blood from various mouse models with genetic bleeding or clotting disease and the effect of factor VIII (FVIII) therapeutics in FVIIInull mice. METHODS: Mice with a genetic deficiency in either a coagulation factor or a platelet glycoprotein were used in this study. The properties of platelet- or plasma-FVIII were also assessed. Citrated blood from mice was recalcified and used for ROTEM analysis. RESULTS: We found that blood collected from the vena cava could generate reliable results from ROTEM analysis, but not blood collected from the tail vein, retro-orbital plexus, or submandibular vein. Age and sex did not significantly affect the hemostatic properties determined by ROTEM analysis. Clotting time (CT) and clot formation time (CFT) were significantly prolonged in FVIIInull (5- and 9-fold, respectively) and FIXnull (4- and 5.7-fold, respectively) mice compared to wild-type (WT)-C57BL/6J mice. Platelet glycoprotein (GP)IIIanull mice had significantly prolonged CFT (8.4-fold) compared to WT-C57BL/6J mice. CT and CFT in factor V (FV) Leiden mice were significantly shortened with an increased α-angle compared to WT-C57BL/6J mice. Using ROTEM analysis, we showed that FVIII expressed in platelets or infused into whole blood restored hemostasis of FVIIInull mice in a dose-dependent manner. CONCLUSION: ROTEM is a reliable and sensitive assay for assessing therapeutics on hemostatic properties in mouse models with a bleeding or clotting disorder.

National patterns in paediatric hospital admissions for dental extractions in England.

OBJECTIVES: Paediatric hospital admissions for dental extractions remain a cause for concern, despite decreasing levels of dental diseases in some areas of the country. While local investigations have taken place, little is known about national patterns, and how the relationship between the number of hospital admissions and key independent variables differs across England. The aim of this study was to examine spatial differences in the number of paediatric hospital admissions for extractions in relation to four key independent variables: dental caries, deprivation, units of dental activity and child access to dentists. METHODS: Hospital admissions data (for all dental-related reasons) were taken from the Hospital Episode Statistics (HES) for England (2017/18) for children and adolescents aged up to 19 years. All data were collected at local authority level. Geographically weighted regression was used to examine associations between the number of hospital admissions and the independent variables, as well as the strength of these associations and how they differed spatially. RESULTS: Geographically weighted regression revealed considerable differences in the associations between the number of paediatric hospital admissions and the independent variables across England, with distinct regional clusters identified in the data. Some areas exhibited positive associations between independent variables and the number of hospital admissions, such as in Yorkshire and areas of south-west, south-east and north-west England, where greater mean dmft scores were associated with greater numbers of hospital admissions. Negative associations were also found, such as in south-west, north-west and North East England, where higher deprivation scores were associated with lower admission numbers. Despite the patterns found, a much smaller sample of the associations between the independent variables and the number of hospital admissions was statistically significant. CONCLUSIONS: This analysis allows for a better understanding of the spatial associations between the number of hospital admissions and key independent variables, as well as how changes to these independent variables may affect the number of admissions in each local authority. These findings should be considered in the context of the limitations of HES dataset.

Endothelin-1 potentiates TRPV1-mediated vasoconstriction of human adipose arterioles in a protein kinase C-dependent manner.

BACKGROUND AND PURPOSE: The TRPV cation channels have emerged as important regulators of vascular tone. TRPV1 channels and endothelin-1 are independently associated with the pathophysiology of coronary vasospasm, but the relationship between their vasomotor functions remains unclear. We characterized the vasomotor function of TRPV1 channels in human arterioles and investigated regulation of their vasomotor function by endothelin-1. EXPERIMENTAL APPROACH: Human arterioles (mainly from adipose tissue) were threaded on two metal wires, equilibrated in a physiological buffer at 37°C and exposed to increasing concentrations of capsaicin, with or without SB366791 (TRPV1-selective inhibitor) or GF109203X (PKC-selective inhibitor). Some arterioles were pre-constricted with endothelin-1 or phenylephrine or high potassium buffer. TRPV1 mRNA and protein expression in human arteries were also assessed. KEY RESULTS: TRPV1 transcripts and proteins were detected in human resistance arteries. Capsaicin (1 µM) induced concentration-dependent constriction of endothelium-intact and endothelium-denuded human adipose arterioles (HAA), which was significantly inhibited by SB366791. Pre-constriction of HAA with endothelin-1, but not high potassium buffer or phenylephrine, significantly potentiated capsaicin (0.1 µM)-induced constriction. GF109203X significantly inhibited potentiation of capsaicin-induced constriction by endothelin-1. CONCLUSION AND IMPLICATIONS: TRPV1 channels are expressed in the human vasculature and affect vascular tone of human arterioles on activation. Their vasomotor function is modulated by endothelin-1, mediated in part by PKC. These findings reveal a novel interplay between endothelin-1 signalling and TRPV1 channels in human VSMC, adding to our understanding of the ion channel mechanisms that regulate human arteriolar tone and may also contribute to the pathophysiology of coronary vasospasm.

Drug Use in Street Sex worKers (DUSSK) study: results of a mixed methods feasibility study of a complex intervention to reduce illicit drug use in drug dependent female sex workers.

OBJECTIVES: The majority of female street-based sex workers (SSWs) are dependent on illicit drugs and sell sex to fund their drug use. They typically face multiple traumatic experiences, starting at a young age, which continue through sex work involvement. Their trauma-related symptoms tend to increase when drug use is reduced, hindering sustained reduction. Providing specialist trauma care to address post-traumatic stress disorder (PTSD) alongside drug treatment may therefore improve treatment outcomes. Aims to (1) evaluate recruitment and retention of participants; (2) examine intervention experiences and acceptability; and (3) explore intervention costs using a mixed methods feasibility study. SETTING: Female SSW charity premises in a large UK inner city. PARTICIPANTS: Females aged 18 years or older, who have sold sex on the street and used heroin and/or crack cocaine at least once a week in the last calendar month. INTERVENTION: Female SSW-only drug treatment groups in a female SSW-only setting delivered by female staff. Targeted PTSD screening then treatment of positive diagnoses with eye movement desensitisation and reprocessing (EMDR) therapy by female staff from a specialist National Health Service trauma service. RESULTS: (1) Of 125 contacts, 11 met inclusion criteria and provided informed consent, 4 reached the intervention final stage, (2) service providers said working in collaboration with other services was valuable, the intervention was worthwhile and had a positive influence on participants. Participants viewed recruitment as acceptable and experienced the intervention positively. The unsettled nature of participant's lives was a key attendance barrier. (3) The total cost of the intervention was £11 710, with staff costs dominating. CONCLUSIONS: Recruitment and retention rates reflected study inclusion criteria targeting women with the most complex needs. Two participants received EMDR demonstrating that the three agencies working together was feasible. Staff heavy costs highlight the importance of supporting participant attendance to minimise per participant costs in a future trial.

Restoration of seagrass habitat leads to rapid recovery of coastal ecosystem services.

There have been increasing attempts to reverse habitat degradation through active restoration, but few large-scale successes are reported to guide these efforts. Here, we report outcomes from a unique and very successful seagrass restoration project: Since 1999, over 70 million seeds of a marine angiosperm, eelgrass (Zostera marina), have been broadcast into mid-western Atlantic coastal lagoons, leading to recovery of 3612 ha of seagrass. Well-developed meadows now foster productive and diverse animal communities, sequester substantial stocks of carbon and nitrogen, and have prompted a parallel restoration for bay scallops (Argopecten irradians) Restored ecosystem services are approaching historic levels, but we also note that managers value services differently today than they did nine decades ago, emphasizing regulating in addition to provisioning services. Thus, this study serves as a blueprint for restoring and maintaining healthy ecosystems to safeguard multiple benefits, including co-benefits that may emerge as management priorities over time.

Area-level deprivation and oral cancer in England 2012-2016.

BACKGROUND: The relationship between deprivation and oral cancer is complex. We examined magnitude and shape of deprivation-related inequalities in oral cancer in England 2012-2016. METHODS: Oral cancer was indicated by cancers of the lip and oral cavity (ICD10 C00-C06) and lip, oral cavity and pharynx (C00-C14) and deprivation by the Index of Multiple Deprivation. Deprivation inequality in incidence and mortality rates of oral cancer outcomes was measured using the Relative Index of Inequality (RII). Fractional polynomial regression was used to explore the shape of the relationships between deprivation and oral cancer outcomes. Multivariate regression models were fitted with the appropriate functions to examine the independent effect of deprivation on cancer adjusting for smoking, alcohol and ethnicity. RESULTS: Incidence rate ratios (IRRs) and mortality rate ratios (MRRs) were greater for more deprived areas. The RII values indicated significant inequalities for oral cancer outcomes but the magnitude of inequalities were greater for mortality. The relationships between deprivation and oral cancer outcomes were curvilinear. Deprivation, Asian ethnicity and alcohol consumption were associated with higher incidence and mortality rates of oral cancer. CONCLUSION: This is the first study, to our knowledge, exploring the shape of socioeconomic inequalities in oral cancer at neighbourhood level. Deprivation-related inequalities were present for all oral cancer outcomes with a steeper rise at the more deprived end of the deprivation spectrum. Deprivation predicted oral cancer even after accounting for other risk factors.

Drug use in street sex workers (DUSSK) study protocol: a feasibility and acceptability study of a complex intervention to reduce illicit drug use in drug-dependent female street sex workers.

INTRODUCTION: Poor health of sex workers continues to be a source of international concern. Sex work is frequently linked with problematic drug use and drug-dependent sex workers typically work on the street, experiencing the greatest risks to health compared with the general population. Street sex workers (SSWs) are much more likely to have experienced incidences of physical and sexual assault, increasing their risk of developing post-traumatic stress disorder (PTSD). We have developed a novel complex intervention designed to reduce illicit drug use in drug-dependent female SSWs which involves: female SSW drug treatment groups (provided by a specialist charity) in a female SSW setting (female sex worker charity premises) provided by female-only staff, PTSD care with eye movement desensitisation and reprocessing (EMDR) therapy provided by female staff from National Health Service (NHS) mental health services. METHODS AND ANALYSIS: A mixed methods study investigating the feasibility and acceptability of this intervention to inform the design of a future randomised controlled trial. The study aims to recruit up to 30 participants from November 2017 to March 2018 at a single site, with the intervention being delivered until December 2018. It will gather quantitative data using questionnaires and group attendance. Drug treatment group observations and in-depth interviews undertaken with up to 20 service users and 15 service providers to examine experiences and acceptability of the intervention. Study feasibility will be assessed by evaluating the recruitment and retention of participants to the intervention; the feasibility of NHS and third sector organisations working closely to coordinate care for a SSW population; the potential for specialist NHS mental health services to screen and provide EMDR therapy for drug-dependent SSWs and potential costs of implementing the intervention. ETHICS AND DISSEMINATION: This study was approved by South West-Frenchay Research Ethics Committee (REC reference: 17/SW/0033; IRAS ID: 220631) and the Health Research Authority (HRA). Findings will be disseminated through research conferences and peer-reviewed journals.

Long-term nutrient reductions lead to the unprecedented recovery of a temperate coastal region.

Humans strongly impact the dynamics of coastal systems, yet surprisingly few studies mechanistically link management of anthropogenic stressors and successful restoration of nearshore habitats over large spatial and temporal scales. Such examples are sorely needed to ensure the success of ecosystem restoration efforts worldwide. Here, we unite 30 consecutive years of watershed modeling, biogeochemical data, and comprehensive aerial surveys of Chesapeake Bay, United States to quantify the cascading effects of anthropogenic impacts on submersed aquatic vegetation (SAV), an ecologically and economically valuable habitat. We employ structural equation models to link land use change to higher nutrient loads, which in turn reduce SAV cover through multiple, independent pathways. We also show through our models that high biodiversity of SAV consistently promotes cover, an unexpected finding that corroborates emerging evidence from other terrestrial and marine systems. Due to sustained management actions that have reduced nitrogen concentrations in Chesapeake Bay by 23% since 1984, SAV has regained 17,000 ha to achieve its highest cover in almost half a century. Our study empirically demonstrates that nutrient reductions and biodiversity conservation are effective strategies to aid the successful recovery of degraded systems at regional scales, a finding which is highly relevant to the utility of environmental management programs worldwide.

Transient receptor potential vanilloid 4 (TRPV4) activation by arachidonic acid requires protein kinase A-mediated phosphorylation.

Transient receptor potential vanilloid 4 (TRPV4) is a Ca2+-permeable channel of the transient receptor potential (TRP) superfamily activated by diverse stimuli, including warm temperature, mechanical forces, and lipid mediators such as arachidonic acid (AA) and its metabolites. This activation is tightly regulated by protein phosphorylation carried out by various serine/threonine or tyrosine kinases. It remains poorly understood how phosphorylation differentially regulates TRPV4 activation in response to different stimuli. We investigated how TRPV4 activation by AA, an important signaling process in the dilation of coronary arterioles, is affected by protein kinase A (PKA)-mediated phosphorylation at Ser-824. Wildtype and mutant TRPV4 channels were expressed in human coronary artery endothelial cells (HCAECs). AA-induced TRPV4 activation was blunted in the S824A mutant but was enhanced in the phosphomimetic S824E mutant, whereas the channel activation by the synthetic agonist GSK1016790A was not affected. The low level of basal phosphorylation at Ser-824 was robustly increased by the redox signaling molecule hydrogen peroxide (H2O2). The H2O2-induced phosphorylation was accompanied by an enhanced channel activation by AA, and this enhanced response was largely abolished by PKA inhibition or S824A mutation. We further identified a potential structural context dependence of Ser-824 phosphorylation-mediated TRPV4 regulation involving an interplay between AA binding and the possible phosphorylation-induced rearrangements of the C-terminal helix bearing Ser-824. These results provide insight into how phosphorylation specifically regulates TRPV4 activation. Redox-mediated TRPV4 phosphorylation may contribute to pathologies associated with enhanced TRPV4 activity in endothelial and other systems.

Performance of the Population Bioequivalence (PBE) Statistical Test Using an IPAC-RS Database of Delivered Dose from Metered Dose Inhalers.

This article reports performance characteristics of the population bioequivalence (PBE) statistical test recommended by the US Food and Drug Administration (FDA) for orally inhaled products. A PBE Working Group of the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) assembled and considered a database comprising delivered dose measurements from 856 individual batches across 20 metered dose inhaler products submitted by industry. A review of the industry dataset identified variability between batches and a systematic lifestage effect that was not included in the FDA-prescribed model for PBE. A simulation study was designed to understand PBE performance when factors identified in the industry database were present. Neglecting between-batch variability in the PBE model inflated errors in the equivalence conclusion: (i) The probability of incorrectly concluding equivalence (type I error) often exceeded 15% for non-zero between-batch variability, and (ii) the probability of incorrectly rejecting equivalence (type II error) for identical products approached 20% when product and between-batch variabilities were high. Neglecting a systematic through-life increase in the PBE model did not substantially impact PBE performance for the magnitude of lifestage effect considered. Extreme values were present in 80% of the industry products considered, with low-dose extremes having a larger impact on equivalence conclusions. The dataset did not support the need for log-transformation prior to analysis, as requested by FDA. Log-transformation resulted in equivalence conclusions that depended on the direction of product mean differences. These results highlight a need for further refinement of in vitro equivalence methodology.

Multiple stressors threaten the imperiled coastal foundation species eelgrass (Zostera marina) in Chesapeake Bay, USA.

Interactions among global change stressors and their effects at large scales are often proposed, but seldom evaluated. This situation is primarily due to lack of comprehensive, sufficiently long-term, and spatially extensive datasets. Seagrasses, which provide nursery habitat, improve water quality, and constitute a globally important carbon sink, are among the most vulnerable habitats on the planet. Here, we unite 31 years of high-resolution aerial monitoring and water quality data to elucidate the patterns and drivers of eelgrass (Zostera marina) abundance in Chesapeake Bay, USA, one of the largest and most valuable estuaries in the world, with an unparalleled history of regulatory efforts. We show that eelgrass area has declined 29% in total since 1991, with wide-ranging and severe ecological and economic consequences. We go on to identify an interaction between decreasing water clarity and warming temperatures as the primary drivers of this trend. Declining clarity has gradually reduced eelgrass cover the past two decades, primarily in deeper beds where light is already limiting. In shallow beds, however, reduced visibility exacerbates the physiological stress of acute warming, leading to recent instances of decline approaching 80%. While degraded water quality has long been known to influence underwater grasses worldwide, we demonstrate a clear and rapidly emerging interaction with climate change. We highlight the urgent need to integrate a broader perspective into local water quality management, in the Chesapeake Bay and in the many other coastal systems facing similar stressors.

Information-Theoretic Compressive Measurement Design.

An information-theoretic projection design framework is proposed, of interest for feature design and compressive measurements. Both Gaussian and Poisson measurement models are considered. The gradient of a proposed information-theoretic metric (ITM) is derived, and a gradient-descent algorithm is applied in design; connections are made to the information bottleneck. The fundamental solution structure of such design is revealed in the case of a Gaussian measurement model and arbitrary input statistics. This new theoretical result reveals how ITM parameter settings impact the number of needed projection measurements, with this verified experimentally. The ITM achieves promising results on real data, for both signal recovery and classification.

Megakaryocyte- and megakaryocyte precursor-related gene therapies.

Hematopoietic stem cells (HSCs) can be safely collected from the body, genetically modified, and re-infused into a patient with the goal to express the transgene product for an individual's lifetime. Hematologic defects that can be corrected with an allogeneic bone marrow transplant can theoretically also be treated with gene replacement therapy. Because some genetic disorders affect distinct cell lineages, researchers are utilizing HSC gene transfer techniques using lineage-specific endogenous gene promoters to confine transgene expression to individual cell types (eg, ITGA2B for inherited platelet defects). HSCs appear to be an ideal target for platelet gene therapy because they can differentiate into megakaryocytes which are capable of forming several thousand anucleate platelets that circulate within blood vessels to establish hemostasis by repairing vascular injury. Platelets play an essential role in other biological processes (immune response, angiogenesis) as well as diseased states (atherosclerosis, cancer, thrombosis). Thus, recent advances in genetic manipulation of megakaryocytes could lead to new and improved therapies for treating a variety of disorders. In summary, genetic manipulation of megakaryocytes has progressed to the point where clinically relevant strategies are being developed for human trials for genetic disorders affecting platelets. Nevertheless, challenges still need to be overcome to perfect this field; therefore, strategies to increase the safety and benefit of megakaryocyte gene therapy will be discussed.

Integrin binding by Borrelia burgdorferi†P66 facilitates dissemination but is not required for infectivity.

P66, a Borrelia burgdorferi surface protein with porin and integrin-binding activities, is essential for murine infection. The role of P66 integrin-binding activity in B. burgdorferi infection was investigated and found to affect transendothelial migration. The role of integrin binding, specifically, was tested by mutation of two amino acids (D205A,D207A) or deletion of seven amino acids (Del202-208). Neither change affected surface localization or channel-forming activity of P66, but both significantly reduced binding to αv ß3 . Integrin-binding deficient B. burgdorferi strains caused disseminated infection in mice at 4 weeks post-subcutaneous inoculation, but bacterial burdens were significantly reduced in some tissues. Following intravenous inoculation, the Del202-208 bacteria were below the limit of detection in all tissues assessed at 2 weeks post-inoculation, but bacterial burdens recovered to wild-type levels at 4 weeks post-inoculation. The delay in tissue colonization correlated with reduced migration of the Del202-208 strains across microvascular endothelial cells, similar to Δp66 bacteria. These results indicate that integrin binding by P66 is important to efficient dissemination of B. burgdorferi, which is critical to its ability to cause disease manifestations in incidental hosts and to its maintenance in the enzootic cycle.