Validation of Acute Myocardial Infarction (AMI) in the FDA’s Mini-Sentinel Distributed Database

The Food and Drug Administration’s (FDA) Mini-Sentinel is a pilot program that aims to conduct active surveillance to detect and refine safety signals that emerge for marketed medical products. The purpose of this Mini-Sentinel AMI Validation project was to: (a) develop and design an abstraction and adjudication process to use when full text medical record review is required to confirm a coded diagnosis; and (b) to test this approach by validating a code algorithm for acute myocardial infarction (AMI)

Statistics Clinic

Do you have elevated pvalues? Is the data analysis process getting you down? Do you experience anxiety when you need to respond to criticism of statistical methods in your manuscript? You may be suffering from Insufficient Statistical Support Syndrome (ISSS). For symptomatic relief of ISSS, come for a free consultation with JSC biostatisticians at our help desk during the poster sessions at the HRP Investigators Workshop. Get answers to common questions about sample size, missing data, multiple testing, when to trust the results of your analyses and more. Side effects may include sudden loss of statistics anxiety, improved interpretation of your data, and increased confidence in your results

CDK4/6 inhibitors induce replication stress to cause long-term cell cycle withdrawal

CDK4/6 inhibitors arrest the cell cycle in G1‐phase. They are approved to treat breast cancer and are also undergoing clinical trials against a range of other tumour types. To facilitate these efforts, it is important to understand why a cytostatic arrest in G1 causes long‐lasting effects on tumour growth. Here, we demonstrate that a prolonged G1 arrest following CDK4/6 inhibition downregulates replisome components and impairs origin licencing. Upon release from that arrest, many cells fail to complete DNA replication and exit the cell cycle in a p53‐dependent manner. If cells fail to withdraw from the cell cycle following DNA replication problems, they enter mitosis and missegregate chromosomes causing excessive DNA damage, which further limits their proliferative potential. These effects are observed in a range of tumour types, including breast cancer, implying that genotoxic stress is a common outcome of CDK4/6 inhibition. This unanticipated ability of CDK4/6 inhibitors to induce DNA damage now provides a rationale to better predict responsive tumour types and effective combination therapies, as demonstrated by the fact that CDK4/6 inhibition induces sensitivity to chemotherapeutics that also cause replication stress

Impacts of forestry planting on primary production in upland lakes from north-west Ireland

Planted forests are increasing in many upland regions world-wide, but knowledge about their potential effects on algal communities of catchment lakes is relatively unknown. Here the effects of afforestation were investigated using palaeolimnology at six upland lake sites in the north-west of Ireland subject to different extents of forest plantation cover (4-64% of catchment area). 210Pb dated sediment cores were analysed for carotenoid pigments from algae, stable isotopes of bulk carbon (δ13C) and nitrogen (δ15N), and C/N ratios. In lakes with >50% of their catchment area covered by plantations, there were two- to six-fold increases in pigments from cryptophytes (alloxanthin) and significant but lower increases (39-116%) in those from colonial cyanobacteria (canthaxanthin), but no response from biomarkers of total algal abundance (β-carotene). In contrast, lakes in catchments with <20% afforestation exhibited no consistent response to forestry practices, although all lakes exhibited fluctuations in pigments and geochemical variables due to peat cutting and upland grazing prior to forest plantation. Taken together, patterns suggest that increases in cyanobacteria and cryptophyte abundance reflect a combination of mineral and nutrient enrichment associated with forest fertilisation and organic matter influx which may have facilitated growth of mixotrophic taxa. This study demonstrates that planted forests can alter the abundance and community structure of algae in upland humic lakes of Ireland and Northern Ireland, despite long histories of prior catchment disturbance

A Mouse Model of Huntington’s Disease Shows Altered Ultrastructure of Transverse Tubules in Skeletal Muscle Fibers

Huntington’s disease (HD) is a fatal and progressive condition with severe debilitating motor defects and muscle weakness. Although classically recognized as a neurodegenerative disorder, there is increasing evidence of cell autonomous toxicity in skeletal muscle. We recently demonstrated that skeletal muscle fibers from the R6/2 model mouse of HD have a decrease in specific membrane capacitance, suggesting a loss of transverse tubule (t-tubule) membrane in R6/2 muscle. A previous report also indicated that Cav1.1 current was reduced in R6/2 skeletal muscle, suggesting defects in excitation–contraction (EC) coupling. Thus, we hypothesized that a loss and/or disruption of the skeletal muscle t-tubule system contributes to changes in EC coupling in R6/2 skeletal muscle. We used live-cell imaging with multiphoton confocal microscopy and transmission electron microscopy to assess the t-tubule architecture in late-stage R6/2 muscle and found no significant differences in the t-tubule system density, regularity, or integrity. However, electron microscopy images revealed that the cross-sectional area of t-tubules at the triad were 25% smaller in R6/2 compared with age-matched control skeletal muscle. Computer simulation revealed that the resulting decrease in the R6/2 t-tubule luminal conductance contributed to, but did not fully explain, the reduced R6/2 membrane capacitance. Analyses of bridging integrator-1 (Bin1), which plays a primary role in t-tubule formation, revealed decreased Bin1 protein levels and aberrant splicing of Bin1 mRNA in R6/2 muscle. Additionally, the distance between the t-tubule and sarcoplasmic reticulum was wider in R6/2 compared with control muscle, which was associated with a decrease in junctophilin 1 and 2 mRNA levels. Altogether, these findings can help explain dysregulated EC coupling and motor impairment in Huntington’s disease

Effect of increasing the time between slurry application and first rainfall event on phosphorus concentrations in runoff

Publication history: Accepted - 26 May 2021; Published online - 12 August 2021.Minimizing slurry phosphorus (P) losses in runoff requires careful management in the context of both soil P surpluses and changing patterns in rainfall. Increasing the time interval between slurry application and the first rainstorm event is known to reduce P loss in runoff although the risk period for elevated P concentrations in runoff can extend for weeks. This study investigated the impact of increasing the time interval between slurry application and first rainstorm event on P concentrations in runoff. Simulated rainfall (40 mm h−1) was applied at 2, 4, 10, 18, 30 and 49 days after dairy slurry was surface-applied to a grassland sward in Ireland. Increasing time to runoff resulted in a decrease in dissolved reactive P concentrations from 5.0 to 1.0 mg P L−1 and a P signal in runoff for 18 days. Beyond 18 days, elevated P concentrations were observed in runoff collected from natural rainfall that preceded the day 49 rainstorm event. A published surface phosphorus and runoff model (SurPhos) was used to understand the slurry P dynamics controlling P interactions with runoff. Dissolved reactive P in runoff was predicted with accuracy by SurPhos, R2 = .89. The SurPhos model implied thatslurry P mineralization occurred during the experimental period that resulted in a small spike in P concentrations beyond the defined risk period. This study shows that the experimental data have the potential to be extrapolated to different weather scenarios using SurPhos and could test when and where slurry P could be most safely spread.Open access funding provided by IReL. WOA Institution: University College Dublin Blended DEAL: IReL

Impacts of forestry planting on primary production in upland lakes from north-west Ireland

Planted forests are increasing in many upland regions worldwide, but knowledge about their potential effects on algal communities of catchment lakes is relatively unknown. Here, the effects of afforestation were investigated using palaeolimnology at six upland lake sites in the north-west of Ireland subject to different extents of forest plantation cover (4–64% of catchment area). 210Pb-dated sediment cores were analysed for carotenoid pigments from algae, stable isotopes of bulk carbon (δ13C) and nitrogen (δ15N), and C/N ratios. In lakes with >50% of their catchment area covered by plantations, there were two- to sixfold increases in pigments from cryptophytes (alloxanthin) and significant but lower increases (39–116%) in those from colonial cyanobacteria (canthaxanthin), but no response from biomarkers of total algal abundance (β-carotene). In contrast, lakes in catchments with <20% afforestation exhibited no consistent response to forestry practices, although all lakes exhibited fluctuations in pigments and geochemical variables due to peat cutting and upland grazing prior to forest plantation. Taken together, patterns suggest that increases in cyanobacteria and cryptophyte abundance reflect a combination of mineral and nutrient enrichment associated with forest fertilization and organic matter influx which may have facilitated growth of mixotrophic taxa. This study demonstrates that planted forests can alter the abundance and community structure of algae in upland humic lakes of Ireland and Northern Ireland, despite long histories of prior catchment disturbance

Air Quality Modeling for the Urban Jackson, Mississippi Region Using a High Resolution WRF/Chem Model

In this study, an attempt was made to simulate the air quality with reference to ozone over the Jackson (Mississippi) region using an online WRF/Chem (Weather Research and Forecasting–Chemistry) model. The WRF/Chem model has the advantages of the integration of the meteorological and chemistry modules with the same computational grid and same physical parameterizations and includes the feedback between the atmospheric chemistry and physical processes. The model was designed to have three nested domains with the inner-most domain covering the study region with a resolution of 1 km. The model was integrated for 48 hours continuously starting from 0000 UTC of 6 June 2006 and the evolution of surface ozone and other precursor pollutants were analyzed. The model simulated atmospheric flow fields and distributions of NO2 and O3 were evaluated for each of the three different time periods. The GIS based spatial distribution maps for ozone, its precursors NO, NO2, CO and HONO and the back trajectories indicate that all the mobile sources in Jackson, Ridgeland and Madison contributing significantly for their formation. The present study demonstrates the applicability of WRF/Chem model to generate quantitative information at high spatial and temporal resolution for the development of decision support systems for air quality regulatory agencies and health administrators

Acquisition of pneumococci specific effector and regulatory Cd4+ T cells localising within human upper respiratory-tract mucosal lymphoid tissue

The upper respiratory tract mucosa is the location for commensal Streptococcus (S.) pneumoniae colonization and therefore represents a major site of contact between host and bacteria. The CD4(+) T cell response to pneumococcus is increasingly recognised as an important mediator of immunity that protects against invasive disease, with data suggesting a critical role for Th17 cells in mucosal clearance. By assessing CD4 T cell proliferative responses we demonstrate age-related sequestration of Th1 and Th17 CD4(+) T cells reactive to pneumococcal protein antigens within mucosal lymphoid tissue. CD25(hi) T cell depletion and utilisation of pneumococcal specific MHCII tetramers revealed the presence of antigen specific Tregs that utilised CTLA-4 and PDL-1 surface molecules to suppress these responses. The balance between mucosal effector and regulatory CD4(+) T cell immunity is likely to be critical to pneumococcal commensalism and the prevention of unwanted pathology associated with carriage. However, if dysregulated, such responses may render the host more susceptible to invasive pneumococcal infection and adversely affect the successful implementation of both polysaccharide-conjugate and novel protein-based pneumococcal vaccines

Ethical and policy issues in cluster randomized trials: rationale and design of a mixed methods research study

<p>Abstract</p> <p>Background</p> <p>Cluster randomized trials are an increasingly important methodological tool in health research. In cluster randomized trials, intact social units or groups of individuals, such as medical practices, schools, or entire communities – rather than individual themselves – are randomly allocated to intervention or control conditions, while outcomes are then observed on individual cluster members. The substantial methodological differences between cluster randomized trials and conventional randomized trials pose serious challenges to the current conceptual framework for research ethics. The ethical implications of randomizing groups rather than individuals are not addressed in current research ethics guidelines, nor have they even been thoroughly explored. The main objectives of this research are to: (1) identify ethical issues arising in cluster trials and learn how they are currently being addressed; (2) understand how ethics reviews of cluster trials are carried out in different countries (Canada, the USA and the UK); (3) elicit the views and experiences of trial participants and cluster representatives; (4) develop well-grounded guidelines for the ethical conduct and review of cluster trials by conducting an extensive ethical analysis and organizing a consensus process; (5) disseminate the guidelines to researchers, research ethics boards (REBs), journal editors, and research funders.</p> <p>Methods</p> <p>We will use a mixed-methods (qualitative and quantitative) approach incorporating both empirical and conceptual work. Empirical work will include a systematic review of a random sample of published trials, a survey and in-depth interviews with trialists, a survey of REBs, and in-depth interviews and focus group discussions with trial participants and gatekeepers. The empirical work will inform the concurrent ethical analysis which will lead to a guidance document laying out principles, policy options, and rationale for proposed guidelines. An Expert Panel of researchers, ethicists, health lawyers, consumer advocates, REB members, and representatives from low-middle income countries will be appointed. A consensus conference will be convened and draft guidelines will be generated by the Panel; an e-consultation phase will then be launched to invite comments from the broader community of researchers, policy-makers, and the public before a final set of guidelines is generated by the Panel and widely disseminated by the research team.</p