Looking beneath the surface: the importance of subcortical structures in frontotemporal dementia.

Funder: National Institute for Health Research (NIHR) Queen Square Dementia Biomedical Research UnitFunder: Alzheimer's Research UK, Brain Research Trust and The Wolfson FoundationFunder: Medical Research CouncilFunder: Alzheimer’s Society and Alzheimer’s Research UKFunder: NIHR UCL/H Biomedical Research Centre and the Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research FacilityFunder: DRI LtdWhilst initial anatomical studies of frontotemporal dementia focussed on cortical involvement, the relevance of subcortical structures to the pathophysiology of frontotemporal dementia has been increasingly recognized over recent years. Key structures affected include the caudate, putamen, nucleus accumbens, and globus pallidus within the basal ganglia, the hippocampus and amygdala within the medial temporal lobe, the basal forebrain, and the diencephalon structures of the thalamus, hypothalamus and habenula. At the most posterior aspect of the brain, focal involvement of brainstem and cerebellum has recently also been shown in certain subtypes of frontotemporal dementia. Many of the neuroimaging studies on subcortical structures in frontotemporal dementia have been performed in clinically defined sporadic cases. However, investigations of genetically- and pathologically-confirmed forms of frontotemporal dementia are increasingly common and provide molecular specificity to the changes observed. Furthermore, detailed analyses of sub-nuclei and subregions within each subcortical structure are being added to the literature, allowing refinement of the patterns of subcortical involvement. This review focuses on the existing literature on structural imaging and neuropathological studies of subcortical anatomy across the spectrum of frontotemporal dementia, along with investigations of brain-behaviour correlates that examine the cognitive sequelae of specific subcortical involvement: it aims to 'look beneath the surface' and summarize the patterns of subcortical involvement have been described in frontotemporal dementia

Leveraging the Interdependencies Between Barrier Islands and Backbarrier Saltmarshes to Enhance Resilience to Sea-Level Rise

Barrier islands and their backbarrier saltmarshes have a reciprocal relationship: aeolian and storm processes transport sediment from the beaches and dunes to create and build marshes along the landward fringe of the island. In turn, these marshes exert a stabilizing influence on the barrier by widening the barrier system and forming a platform onto which the island migrates, consequently slowing landward barrier migration and inhibiting storm breaching. Here, we present a novel framework for applying these natural interdependencies to managing coastal systems and enhancing barrier-island resilience. Further, we detail application of these principles through a case study of the design of a marsh creation project that showcases the interdisciplinary engagement of scientists, engineers, stakeholders, and policymakers. Specifically, we describe: (1) the ecologic, sedimentologic, stratigraphic, and morphologic data obtained from the southern 4 km of Cedar Island (Virginia, United States) and nearby backbarrier tidal channels, tidal flats, and flood-tidal deltas, and (2) the use of those data to develop an engineering and design plan for the construction of a high (46 ha) and low (42 ha) fringing marsh platform located behind the island, proximal to a former ephemeral inlet. Additionally, we chronicle the process used to narrow five initial alternative designs to the optimal final plan. This process involved balancing best-available existing science and models, considering design and financial constraints, identifying stakeholder preferences, and maximizing restoration benefits of habitat provision and shoreline protection. Construction of this marsh would: (1) provide additional habitat and ecosystem benefits, (2) slow the rapid migration (up to 15 m/yr at present) of the barrier island, and (3) hinder island breaching. Ultimately, this project – presently at the final design and permitting stage – may enhance the storm and sea-level rise resilience of the island, backbarrier marshes and lagoons, and the mainland town community; and provide an example of a novel science-based approach to coastal resilience that could be applied to other global barrier settings

Population-average mediation analysis for zero-inflated count outcomes

Mediation analysis is an increasingly popular statistical method for explaining causal pathways to inform intervention. While methods have increased, there is still a dearth of robust mediation methods for count outcomes with excess zeroes. Current mediation methods addressing this issue are computationally intensive, biased, or challenging to interpret. To overcome these limitations, we propose a new mediation methodology for zero-inflated count outcomes using the marginalized zero-inflated Poisson (MZIP) model and the counterfactual approach to mediation. This novel work gives population-average mediation effects whose variance can be estimated rapidly via delta method. This methodology is extended to cases with exposure-mediator interactions. We apply this novel methodology to explore if diabetes diagnosis can explain BMI differences in healthcare utilization and test model performance via simulations comparing the proposed MZIP method to existing zero-inflated and Poisson methods. We find that our proposed method minimizes bias and computation time compared to alternative approaches while allowing for straight-forward interpretations.Comment: 34 pages, 2 figures, 4 tables, 49 pages of Supplemental material, 2 supplemental figure

Glycolytic requirement for NK cell cytotoxicity and cytomegalovirus control

NK cell activation has been shown to be metabolically regulated in vitro; however, the role of metabolism during in vivo NK cell responses to infection is unknown. We examined the role of glycolysis in NK cell function during murine cytomegalovirus (MCMV) infection and the ability of IL-15 to prime NK cells during CMV infection. The glucose metabolism inhibitor 2-deoxy-ᴅ-glucose (2DG) impaired both mouse and human NK cell cytotoxicity following priming in vitro. Similarly, MCMV-infected mice treated with 2DG had impaired clearance of NK-specific targets in vivo, which was associated with higher viral burden and susceptibility to infection on the C57BL/6 background. IL-15 priming is known to alter NK cell metabolism and metabolic requirements for activation. Treatment with the IL-15 superagonist ALT-803 rescued mice from otherwise lethal infection in an NK-dependent manner. Consistent with this, treatment of a patient with ALT-803 for recurrent CMV reactivation after hematopoietic cell transplant was associated with clearance of viremia. These studies demonstrate that NK cell-mediated control of viral infection requires glucose metabolism and that IL-15 treatment in vivo can reduce this requirement and may be effective as an antiviral therapy

Short-term and long-term cardiovascular risk, metabolic syndrome and HIV in Tanzania.

OBJECTIVE: To compare short-term and long-term cardiovascular disease (CVD) risk scores and prevalence of metabolic syndrome in HIV-infected adults receiving and not receiving antiretroviral therapy (ART) to HIV-negative controls. METHODS: A cross-sectional study including 151 HIV-infected, ART-naive, 150 HIV-infected on ART and 153 HIV-negative adults. Traditional cardiovascular risk factors were determined by standard investigations. The primary outcome was American College of Cardiology/American Heart Association Atherosclerotic CVD (ASCVD) Risk Estimator lifetime CVD risk score. Secondary outcomes were ASCVD 10-year risk, Framingham risk scores, statin indication and metabolic syndrome. RESULTS: Compared with HIV-negative controls, more HIV-infected adults on ART were classified as high lifetime CVD risk (34.7% vs 17.0%, p<0.001) although 10-year risk scores were similar, a trend which was similar across multiple CVD risk models. In addition, HIV-infected adults on ART had a higher prevalence of metabolic syndrome versus HIV-negative controls (21.3% vs 7.8%, p=0.008), with two common clusters of risk factors. More than one-quarter (28.7%) of HIV-infected Tanzanian adults on ART meet criteria for statin initiation. CONCLUSIONS: HIV-infected ART-treated individuals have high lifetime cardiovascular risk, and this risk seems to develop rapidly in the first 3-4 years of ART as does the development of clusters of metabolic syndrome criteria. These data identify a new subgroup of low short-term/high-lifetime risk HIV-infected individuals on ART who do not currently meet criteria for CVD risk factor modification but require further study

Training Mid-Level Providers to Treat Severe Non-Communicable Diseases in Neno, Malawi through PEN-Plus Strategies.

Background: Non-communicable diseases (NCDs) are a leading cause of worldwide morbidity and mortality, yet access to care in lower-income countries is limited. Rural communities, where poverty levels are high, feel the greatest burden. In Malawi, as elsewhere in the African region, it is particularly challenging for patients in rural districts to obtain care for locally endemic and severe NCDs such as type 1 diabetes, rheumatic heart disease, and sickle cell disease. The Package of Essential NCD Interventions - Plus (PEN-Plus) is a strategy to decentralize care for these severe conditions by enabling local clinicians at intermediate-care facilities to provide services otherwise available only through specialty clinics at central hospitals. Objectives: The primary objective of this study was to evaluate the impact of training mid-level providers to treat severe and chronic NCDs in newly established PEN-Plus clinics in Neno, Malawi. Methods: Our team developed a logic model to describe the anticipated impacts of the intervention on provider knowledge, patient recruitment, and care provision. We applied a retrospective review of routinely collected clinical and administrative data to assess changes along these hypothesized pathways. Findings: Didactic trainings improved provider test scores immediately following training (25-point improvement; p < 0.01), with demonstrated retention of knowledge after 6 months (21-point improvement, p < 0.01). Over 350 patients were enrolled in the first 18 months of program initiation. The PEN-Plus clinic led to significant improvement in the provision of medications and testing across a range of services. Conclusion: Mid-level providers can be successfully trained to treat severe NCDs with physician-guided education, mentorship, and supervision. The PEN-Plus clinic improved patient enrollment, the quality of clinical care and access to essential medications and laboratory supplies. These lessons learned can guide decentralization of NCD care to district hospitals in Malawi and expansion of PEN-Plus services in the African region

RNA-Seq identifies SPGs as a ventral skeletal patterning cue in sea urchins

The sea urchin larval skeleton offers a simple model for formation of developmental patterns. The calcium carbonate skeleton is secreted by primary mesenchyme cells (PMCs) in response to largely unknown patterning cues expressed by the ectoderm. To discover novel ectodermal cues, we performed an unbiased RNA-Seq-based screen and functionally tested candidates; we thereby identified several novel skeletal patterning cues. Among these, we show that SLC26a2/7 is a ventrally expressed sulfate transporter that promotes a ventral accumulation of sulfated proteoglycans, which is required for ventral PMC positioning and skeletal patterning. We show that the effects of SLC perturbation are mimicked by manipulation of either external sulfate levels or proteoglycan sulfation. These results identify novel skeletal patterning genes and demonstrate that ventral proteoglycan sulfation serves as a positional cue for sea urchin skeletal patterning

N-Terminal Pro-B-Type Natriuretic Peptide and Microsize Myocardial Infarction Risk in the Reasons for Geographic and Racial Differences in Stroke Study

Background: N-terminal pro B-type peptide (NT-proBNP) has been associated with risk of myocardial infarction (MI), but less is known about the relationship between NT-proBNP and very small non ST-elevation MI, also known as microsize MI. These events are now routinely detectable with modern troponin assays and are emerging as a large proportion of all MI. Here, we sought to compare the association of NT-proBNP with risk of incident typical MI and microsize MI in the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study. Methods: The REGARDS Study is a national cohort of 30,239 US community-dwelling black and white adults aged ≥ 45 years recruited from 2003 to 2007. Expert-adjudicated outcomes included incident typical MI (definite/probable MI with peak troponin ≥ 0.5 μg/L), incident microsize MI (definite/probable MI with peak troponin \u3c 0.5 μg/L), and incident fatal CHD. Using a case-cohort design, we estimated the hazard ratio of the outcomes as a function of baseline NT-proBNP. Competing risk analyses tested whether the associations of NT-proBNP differed between the risk of incident microsize MI and incident typical MI as well as if the association of NT-proBNP differed between incident non-fatal microsize MI and incident non-fatal typical MI, while accounting for incident fatal coronary heart disease (CHD) as well as heart failure (HF). Results: Over a median of 5 years of follow-up, there were 315 typical MI, 139 microsize MI, and 195 incident fatal CHD. NT-proBNP was independently and strongly associated with all CHD endpoints, with significantly greater risk observed for incident microsize MI, even after removing individuals with suspected HF prior to or coincident with their incident CHD event. Conclusion: NT-proBNP is associated with all MIs, but is a more powerful risk factor for microsize than typical MI