Erratum: Antiplatelet effects of dietary nitrate in healthy volunteers: Involvement of cGMP and influence of sex (Free Radical Biology and Medicine (2013) 65 (1521-1532))

A correction to an error in the original published fi

Prescribing paradigm shift? Applying the 2019 European Society of Cardiology-led guidelines on ‘diabetes, pre-diabetes, and cardiovascular disease’ to assess eligibility for sodium-glucose co-transporter-2 inhibitors or glucagon-like peptide-1 receptor agonists as first-line monotherapy (or add-on to metformin monotherapy) in type 2 diabetes in Scotland

Objective: In 2019, the European Society of Cardiology led and released new guidelines for diabetes cardiovascular risk management, reflecting recent evidence of cardiovascular disease (CVD) reduction with sodium–glucose cotransporter 2 inhibitors (SGLT-2is) and some glucagon-like peptide 1 receptor agonists (GLP-1RAs) in type 2 diabetes (T2D). A key recommendation is that all those with T2D who are (antihyperglycemic) drug naïve or on metformin monotherapy should be CVD risk stratified and an SGLT-2i or a GLP-1RA initiated in all those at high or very high risk, irrespective of glycated hemoglobin. We assessed the impact of these guidelines in Scotland were they introduced as is.Research design and methods: Using a nationwide diabetes register in Scotland, we did a cross-sectional analysis, using variables in our register for risk stratification at 1 January 2019. We were conservative in our definitions, assuming the absence of a risk factor where data were not available. The risk classifications were applied to people who were drug naïve or on metformin monotherapy and the anticipated prescribing change calculated.Results: Of the 265,774 people with T2D in Scotland, 53,194 (20.0% of those with T2D) were drug naïve, and56,906(21.4%) were on metformin monotherapy. Of these, 74.5%and72.4%, respectively, were estimated as at least high risk given the guideline risk definitions.Conclusions: Thus, 80,830 (30.4%) of all those with T2D (n 5 265,774) would start one of these drug classes according to table 7 and figure 3 of the guideline. The sizeable impact on drug budgets, enhanced clinical monitoring, and the trade-off with reduced CVD-related health care costs will need careful consideration.</p

It is rocket science - why dietary nitrate is hard to ‘beet’! Part I: twists and turns in the realization of the nitrate-nitrite-NO pathway

Dietary nitrate (found in green leafy vegetables, such as rocket, and in beetroot) is now recognized to be an important source of nitric oxide (NO), via the nitrate-nitrite-NO pathway. Dietary nitrate confers several cardiovascular beneficial effects on blood pressure, platelets, endothelial function, mitochondrial efficiency and exercise. While this pathway may now seem obvious, its realization followed a rather tortuous course over two decades. Early steps included the discovery that nitrite was a source of NO in the ischaemic heart but this appeared to have deleterious effects. In addition, nitrate-derived nitrite provided a gastric source of NO. However, residual nitrite was not thought to be absorbed systemically. Nitrite was also considered to be physiologically inert but potentially carcinogenic, through N-nitrosamine formation. In Part 1 of a two-part Review on the nitrate-nitrite-NO pathway we describe key twists and turns in the elucidation of the pathway and the underlying mechanisms. This provides the critical foundation for the more recent developments in the nitrate-nitrite-NO pathway which are covered in Part 2

Effects of Control on the Dynamics of an Adjacent Protected Wolf Population in Interior Alaska

Long-term wolf (Canis lupus) research programs have provided many insights into wolf population dynamics. Understanding the mechanisms controlling responses of wolf populations to changes in density, environmental conditions, and human-caused mortality are important as wolf management becomes increasingly intensive. Competition with humans for ungulate prey has led to large-scale wolf control programs, particularly in Alaska, and although wolf populations may sustain relatively high (e.g., 22–29%) rates of conventional harvest, control programs are specifically designed to have lasting population-level effects. Understanding the broader impacts of wolf control efforts on the surrounding area is of particular concern for conservation agencies such as the United States National Park Service, whose mandates generally preclude the artificial reduction of populations of native predators, particularly for the primary purpose of increasing available prey biomass for human harvest. Detailed assessments of the factors influencing population vital rates (i.e., survival, natality, dispersal) and population trajectory in the context of control efforts are critical for understanding complex ecological relationships between wolves and their prey and informing management of each. Using a long-term dataset and a powerful new integrated modeling approach, we assessed the effects of wolf control on the dynamics of a monitored wolf population residing primarily within an adjacent protected area where wolf control activities were prohibited. We monitored wolf population dynamics in Yukon-Charley Rivers National Preserve (YUCH) in interior Alaska, USA for 22 years (1993–2014). During our study, 2 large-scale wolf control programs were implemented in the surrounding area with the primary goal of increasing the size of the Fortymile caribou herd. We used known-fate data based on relocations of marked wolves and repeated counts of associated pack mates to estimate survival, dispersal, and natality rates. We jointly analyzed these data using an integrated modeling approach, thereby providing inference to the entire resident, pack-dwelling population of wolves using YUCH. Apparent survival (i.e., including mortalities and dispersals) was lower in the study area during the lethal control period, indicating a direct additive effect of control despite the prohibition of control efforts inside YUCH boundaries. Apparent survival was higher in years following winters with above-average snowfall, corresponding with a predicted increase in ungulate prey vulnerability the following year. Extraterritorial forays were associated with lower apparent survival rates, particularly after the initiation of lethal wolf control in the surrounding area. In general, mortalities tended to occur evenly throughout the year, whereas dispersal rates increased during late winter and early spring. Dispersals accounted for approximately half of the observed losses in our collared sample across all age classes (excluding known breeders), although yearlings were the most likely to disperse. Sustained reductions in wolf densities outside the YUCH boundary during both wolf control programs also allowed us to directly assess the effects of reduced density on vital rates. Natality rates (estimated number of individuals added to each pack over the May–Aug interval) increased sharply over the course of each control program, suggesting a strong reproductive response to large-scale reductions in wolf densities in the surrounding area. Natality rates dropped rapidly between the 2 control programs, further supporting this conclusion. Smaller pack sizes and losses of known breeders were associated with lower natality rates per pack in the following year, suggesting human-caused mortality could have direct short-term effects on productivity by reducing pack sizes and removing breeders. However, although control can reduce the fecundity of individual packs in the short term, adjacent populations quickly respond to reduced wolf density by increasing natality rates. Estimates of wolf density based on relocations of marked individuals within packs were dependent on sample size and could not be used to reliably estimate population growth rate (λ). As an alternative, we developed a new metric, λ*, which assessed whether natality was sufficient to offset population losses on an annual basis, under the assumption that the minimum functional unit in a wolf population is a breeding pair. When λ* decreased below 1.0 because of a combination of loss of individuals and the dissolution of packs, the population of interest effectively became a population sink reliant on immigrants from surrounding areas for maintenance. Based on estimates of λ*, we determined the YUCH study population was a source of wolves for the surrounding area in most years before implementation of lethal wolf control but became a population sink largely reliant on immigration from surrounding areas afterwards, despite the prohibition on control activities within YUCH. This finding has important implications for the management of protected areas, particularly in areas such as Alaska where wolf control is commonly implemented at large spatial scales. We expect λ* will be a useful tool for understanding wolf ecology and managing populations in other areas as well. Overall, wolf vital rates were quite dynamic and responded quickly to changing conditions. The rapid increase in natality in an apparent response to decreased density strongly suggests that density dependence plays an important role in regulating wolf populations. Flexibility in dispersal and natality rates likely allow wolf populations to respond to variation in prey resources, wolf density, and mortality. These findings also suggest that sustainable harvest rates depend on annual variation in population vital rates. The clear impacts of management schemes in the area adjacent to YUCH suggests that effective conservation of protected areas may require more active management decisions than are often employed, particularly if the maintenance of unaltered system dynamics is a primary objective

Incidence and phenotypes of childhood-onset genetic epilepsies:a prospective population-based national cohort

Epilepsy is common in early childhood. In this age group it is associated with high rates of therapy-resistance, and with cognitive, motor, and behavioural comorbidity. A large number of genes, with wide ranging functions, are implicated in its aetiology, especially in those with therapy-resistant seizures. Identifying the more common single-gene epilepsies will aid in targeting resources, the prioritization of diagnostic testing and development of precision therapy. Previous studies of genetic testing in epilepsy have not been prospective and population-based. Therefore, the population-incidence of common genetic epilepsies remains unknown. The objective of this study was to describe the incidence and phenotypic spectrum of the most common single-gene epilepsies in young children, and to calculate what proportion are amenable to precision therapy. This was a prospective national epidemiological cohort study. All children presenting with epilepsy before 36 months of age were eligible. Children presenting with recurrent prolonged (&gt;10 min) febrile seizures; febrile or afebrile status epilepticus (&gt;30 min); or with clusters of two or more febrile or afebrile seizures within a 24-h period were also eligible. Participants were recruited from all 20 regional paediatric departments and four tertiary children’s hospitals in Scotland over a 3-year period. DNA samples were tested on a custom-designed 104-gene epilepsy panel. Detailed clinical information was systematically gathered at initial presentation and during follow-up. Clinical and genetic data were reviewed by a multidisciplinary team of clinicians and genetic scientists. The pathogenic significance of the genetic variants was assessed in accordance with the guidelines of UK Association of Clinical Genetic Science (ACGS). Of the 343 patients who met inclusion criteria, 333 completed genetic testing, and 80/333 (24%) had a diagnostic genetic finding. The overall estimated annual incidence of single-gene epilepsies in this well-defined population was 1 per 2120 live births (47.2/100 000; 95% confidence interval 36.9–57.5). PRRT2 was the most common single-gene epilepsy with an incidence of 1 per 9970 live births (10.0/100 000; 95% confidence interval 5.26–14.8) followed by SCN1A: 1 per 12 200 (8.26/100 000; 95% confidence interval 3.93–12.6); KCNQ2: 1 per 17 000 (5.89/100 000; 95% confidence interval 2.24–9.56) and SLC2A1: 1 per 24 300 (4.13/100 000; 95% confidence interval 1.07–7.19). Presentation before the age of 6 months, and presentation with afebrile focal seizures were significantly associated with genetic diagnosis. Single-gene disorders accounted for a quarter of the seizure disorders in this cohort. Genetic testing is recommended to identify children who may benefit from precision treatment and should be mainstream practice in early childhood onset epilepsy

The Spanish Influence on the Texas Law of Civil Procedure.

Reprint from the November, 1959, issue of the Texas Law Reviewhttps://ecollections.law.fiu.edu/diaz-cruz-pamphlets/1381/thumbnail.jp

Texas Community Property Law - Its Course of Development and Reform.

Reprinted from California Western Law Review, Vol. 8, Fall 1971, Number 1https://ecollections.law.fiu.edu/diaz-cruz-pamphlets/1383/thumbnail.jp