Shotguns vs Lasers: Identifying barriers and facilitators to scaling-up plant molecular farming for high-value health products.

Plant molecular farming (PMF) is a convenient and cost-effective way to produce high-value recombinant proteins that can be used in the production of a range of health products, from pharmaceutical therapeutics to cosmetic products. New plant breeding techniques (NPBTs) provide a means to enhance PMF systems more quickly and with greater precision than ever before. However, the feasibility, regulatory standing and social acceptability of both PMF and NPBTs are in question. This paper explores the perceptions of key stakeholders on two European Union (EU) Horizon 2020 programmes-Pharma-Factory and Newcotiana-towards the barriers and facilitators of PMF and NPBTs in Europe. One-on-one qualitative interviews were undertaken with N = 20 individuals involved in one or both of the two projects at 16 institutions in seven countries (Belgium, France, Germany, Italy, Israel, Spain and the UK). The findings indicate that the current EU regulatory environment and the perception of the public towards biotechnology are seen as the main barriers to scaling-up PMF and NPBTs. Competition from existing systems and the lack of plant-specific regulations likewise present challenges for PMF developing beyond its current niche. However, respondents felt that the communication of the benefits and purpose of NPBT PMF could provide a platform for improving the social acceptance of genetic modification. The importance of the media in this process was highlighted. This article also uses the multi-level perspective to explore the ways in which NPBTs are being legitimated by interested parties and the systemic factors that have shaped and are continuing to shape the development of PMF in Europe

ELECTRIC BREAKDOWN AS A PROBABILITY PROCESS

ImportanceRecent estimates suggest that more than 26 million people worldwide have heart failure. The syndrome is associated with major symptoms, significantly increased mortality, and extensive use of health care. Evidence-based treatments influence all these outcomes in a proportion of patients with heart failure. Current management also often includes advice to reduce dietary salt intake, although the benefits are uncertain. ObjectiveTo systematically review randomized clinical trials of reduced dietary salt in adult inpatients or outpatients with heart failure. Evidence ReviewSeveral bibliographic databases were systematically searched, including the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, and CINAHL. The methodologic quality of the studies was evaluated, and data associated with primary outcomes of interest (cardiovascular-associated mortality, all-cause mortality, and adverse events, such as stroke and myocardial infarction) and secondary outcomes (hospitalization, length of inpatient stay, change in New York Heart Association [NYHA] functional class, adherence to dietary low-salt intake, and changes in blood pressure) were extracted. FindingsOf 2655 retrieved references, 9 studies involving 479 unique participants were included in the analysis. None of the studies included more than 100 participants. The risks of bias in the 9 studies were variable. None of the included studies provided sufficient data on the primary outcomes of interest. For the secondary outcomes of interest, 2 outpatient-based studies reported that NYHA functional class was not improved by restriction of salt intake, whereas 2 studies reported significant improvements in NYHA functional class. Conclusions and RelevanceLimited evidence of clinical improvement was available among outpatients who reduced dietary salt intake, and evidence was inconclusive for inpatients. Overall, a paucity of robust high-quality evidence to support or refute current guidance was available. This review suggests that well-designed, adequately powered studies are needed to reduce uncertainty about the use of this intervention.</p

La evolución del derecho a la educación en Colombia entre 1820 a 1876, como un derecho económico, social y cultural

In examining the evolution of the right to education in New Granada, Gran Colombia and the United States of Colombia, a major effort is evidenced by Francisco de Paula Santander, Mariano Ospina Rodriguez to promote the development of education as a right which should be free and compulsory.However, the project initiated by Santander Ospina Rodriguez and other presidents of the period covered from 1820 to 1876, is to prevent the social, political, cultural and civil wars that were designed to search for autonomy, freedom and independence.Al examinar la evolución del derecho a la educación en la Nueva Granada, la Gran Colombia y los Estados Unidos de Colombia, se evidencia un importante esfuerzo por parte de Francisco de Paula Santander y Mariano Ospina Rodríguez de promover el desarrollo de la educación como un derecho que debía ser gratuito y obligatorio.Sin embargo, el proyecto iniciado por Santander y Ospina Rodríguez y demás presidentes de la época comprendida entre 1820 a 1876, tiene como obstáculo los problemas sociales, políticos, culturales y las guerras civiles que tenían como fin la búsqueda de la autonomía, libertad e independencia

Long-term monitoring in primary care for chronic kidney disease and chronic heart failure: a multi-method research programme

Background: Long-term monitoring is important in chronic condition management. Despite considerable costs of monitoring, there is no or poor evidence on how, what and when to monitor. The aim of this study was to improve understanding, methods, evidence base and practice of clinical monitoring in primary care, focusing on two areas: chronic kidney disease and chronic heart failure. Objectives: The research questions were as follows: does the choice of test affect better care while being affordable to the NHS? Can the number of tests used to manage individuals with early-stage kidney disease, and hence the costs, be reduced? Is it possible to monitor heart failure using a simple blood test? Can this be done using a rapid test in a general practitioner consultation? Would changes in the management of these conditions be acceptable to patients and carers? Design: Various study designs were employed, including cohort, feasibility study, Clinical Practice Research Datalink analysis, seven systematic reviews, two qualitative studies, one cost-effectiveness analysis and one cost recommendation. Setting: This study was set in UK primary care. Data sources: Data were collected from study participants and sourced from UK general practice and hospital electronic health records, and worldwide literature. Participant: The participants were NHS patients (Clinical Practice Research Datalink: 4.5 million patients), chronic kidney disease and chronic heart failure patients managed in primary care (including 750 participants in the cohort study) and primary care health professionals. Interventions: The interventions were monitoring with blood and urine tests (for chronic kidney disease) and monitoring with blood tests and weight measurement (for chronic heart failure). Main outcome measures: The main outcomes were the frequency, accuracy, utility, acceptability, costs and cost-effectiveness of monitoring. Results: Chronic kidney disease: serum creatinine testing has increased steadily since 1997, with most results being normal (83% in 2013). Increases in tests of creatinine and proteinuria correspond to their introduction as indicators in the Quality and Outcomes Framework. The Chronic Kidney Disease Epidemiology Collaboration equation had 2.7% greater accuracy (95% confidence interval 1.6% to 3.8%) than the Modification of Diet in Renal Disease equation for estimating glomerular filtration rate. Estimated annual transition rates to the next chronic kidney disease stage are ≈ 2% for people with normal urine albumin, 3–5% for people with microalbuminuria (3–30 mg/mmol) and 3–12% for people with macroalbuminuria (> 30 mg/mmol). Variability in estimated glomerular filtration rate-creatinine leads to misclassification of chronic kidney disease stage in 12–15% of tests in primary care. Glycaemic-control and lipid-modifying drugs are associated with a 6% (95% confidence interval 2% to 10%) and 4% (95% confidence interval 0% to 8%) improvement in renal function, respectively. Neither estimated glomerular filtration rate-creatinine nor estimated glomerular filtration rate-Cystatin C have utility in predicting rate of kidney function change. Patients viewed phrases such as ‘kidney damage’ or ‘kidney failure’ as frightening, and the term ‘chronic’ was misinterpreted as serious. Diagnosis of asymptomatic conditions (chronic kidney disease) was difficult to understand, and primary care professionals often did not use ‘chronic kidney disease’ when managing patients at early stages. General practitioners relied on Clinical Commissioning Group or Quality and Outcomes Framework alerts rather than National Institute for Health and Care Excellence guidance for information. Cost-effectiveness modelling did not demonstrate a tangible benefit of monitoring kidney function to guide preventative treatments, except for individuals with an estimated glomerular filtration rate of 60–90 ml/minute/1.73 m2, aged < 70 years and without cardiovascular disease, where monitoring every 3–4 years to guide cardiovascular prevention may be cost-effective. Chronic heart failure: natriuretic peptide-guided treatment could reduce all-cause mortality by 13% and heart failure admission by 20%. Implementing natriuretic peptide-guided treatment is likely to require predefined protocols, stringent natriuretic peptide targets, relative targets and being located in a specialist heart failure setting. Remote monitoring can reduce all-cause mortality and heart failure hospitalisation, and could improve quality of life. Diagnostic accuracy of point-of-care N-terminal prohormone of B-type natriuretic peptide (sensitivity, 0.99; specificity, 0.60) was better than point-of-care B-type natriuretic peptide (sensitivity, 0.95; specificity, 0.57). Within-person variation estimates for B-type natriuretic peptide and weight were as follows: coefficient of variation, 46% and coefficient of variation, 1.2%, respectively. Point-of-care N-terminal prohormone of B-type natriuretic peptide within-person variability over 12 months was 881 pg/ml (95% confidence interval 380 to 1382 pg/ml), whereas between-person variability was 1972 pg/ml (95% confidence interval 1525 to 2791 pg/ml). For individuals, monitoring provided reassurance; future changes, such as increased testing, would be acceptable. Point-of-care testing in general practice surgeries was perceived positively, reducing waiting time and anxiety. Community heart failure nurses had greater knowledge of National Institute for Health and Care Excellence guidance than general practitioners and practice nurses. Health-care professionals believed that the cost of natriuretic peptide tests in routine monitoring would outweigh potential benefits. The review of cost-effectiveness studies suggests that natriuretic peptide-guided treatment is cost-effective in specialist settings, but with no evidence for its value in primary care settings. Limitations: No randomised controlled trial evidence was generated. The pathways to the benefit of monitoring chronic kidney disease were unclear. Conclusions: It is difficult to ascribe quantifiable benefits to monitoring chronic kidney disease, because monitoring is unlikely to change treatment, especially in chronic kidney disease stages G3 and G4. New approaches to monitoring chronic heart failure, such as point-of-care natriuretic peptide tests in general practice, show promise if high within-test variability can be overcome

Dermatofibrosarcoma protuberans treated by micrographic surgery

Dermatofibrosarcoma protuberans is an uncommon cutaneous tumour which rarely metastasises. However, local recurrence following apparently adequate surgical excision is well recognised, presumably as a result of sub-clinical contiguous growth, for which micrographically controlled excision would be a logical treatment. A retrospective study of all patients treated by micrographic surgery, from April 1995–March 2000, at a tertiary skin oncology centre. Twenty-one patients (11 males), age 14 to 71 years with dermatofibrosarcoma protuberans on the trunk (10 patients), groin (four), head and neck (four), and limbs (three) were treated. In 15 patients one micrographic layer cleared the tumour, and four were cleared with two layers. For one patient the second stage was completed by conventional excision guided by positive margins. Another patient with a multiply recurrent perineal dermatofibrosarcoma protuberans, not cleared in one area after two layers, died from a pulmonary embolus before total clearance could be achieved. There was no correlation between tumour size and lateral excision margin. No recurrence was observed during the follow-up, from 21 to 80 months, median 47 months. The study provides further support for micrographic surgery as the treatment of choice for dermatofibrosarcoma protuberans

Atlanto-axial rotatory fixation in a girl with Spondylocarpotarsal synostosis syndrome

We report a 15-year-old girl who presented with spinal malsegmentation, associated with other skeletal anomalies. The spinal malsegmentation was subsequently discovered to be part of the spondylocarpotarsal synostosis syndrome. In addition, a distinctive craniocervical malformation was identified, which included atlanto-axial rotatory fixation. The clinical and the radiographic findings are described, and we emphasise the importance of computerised tomography to characterize the craniocervical malformation complex. To the best of our knowledge, this is the first clinical report of a child with spondylocarpotarsal synostosis associated with atlanto-axial rotatory fixation

Association between egg consumption and cardiovascular disease events, diabetes and all-cause mortality

Purpose The association between egg consumption and cardiovascular disease (CVD) or type 2 diabetes (T2D) remains controversial. We investigated the association between egg consumption and risk of CVD (primary outcome), T2D and mortality in the Caerphilly prospective cohort study (CAPS) and National Diet and Nutritional Survey (NDNS). Methods CAPS included 2512 men aged 45–59 years (1979–1983). Dietary intake, disease incidence and mortality were updated at 5-year intervals. NDNS included 754 adults aged 19–64 years from 2008 to 2012. Results Men free of CVD (n = 1781) were followed up for a mean of 22.8 years, egg consumption was not associated with new incidence of CVD (n = 715), mortality (n = 1028) or T2D (n = 120). When stroke (n = 248), MI (n = 477),heart failure (n = 201) were investigated separately, no associations between egg consumption and stroke and MI were identified, however, increased risk of stroke in subjects with T2D and/or impaired glucose tolerance (IGT, fasting plasma glucose ≥ 6.1 mmol/L), adjusted hazard ratios (95% CI) were 1.0 (reference), 1.09 (0.41, 2.88), 0.96 (0.37, 2.50), 1.39 (0.54, 3.56) and 2.87 (1.13, 7.27) for egg intake (n) of 0 ≤ n ≤ 1, 1 < n ≤ 2, 2 < n ≤ 3, 3 < n < 5, and n ≥ 5 eggs/wk, respectively (P = 0.01). In addition, cross-sectional analyses revealed that higher egg consumption was significantly associated with elevated fasting glucose in those with T2D and/or IGT (CAPS: baseline P = 0.02 and 5-year P = 0.04; NDNS: P = 0.05). Conclusions Higher egg consumption was associated with higher blood glucose in subjects with T2D and/or IGT. The increased incidence of stroke with higher egg consumption among T2D and/or IGT sub-group warrants further investigation

Combination Therapy Is Superior to Sequential Monotherapy for the Initial Treatment of Hypertension:A Double-Blind Randomized Controlled Trial

Background: Guidelines for hypertension vary in their preference for initial combination therapy or initial monotherapy, stratified by patient profile; therefore, we compared the efficacy and tolerability of these approaches. Methods and Results: We performed a 1‐year, double‐blind, randomized controlled trial in 605 untreated patients aged 18 to 79 years with systolic blood pressure (BP) ≥150 mm Hg or diastolic BP ≥95 mm Hg. In phase 1 (weeks 0–16), patients were randomly assigned to initial monotherapy (losartan 50–100 mg or hydrochlorothiazide 12.5–25 mg crossing over at 8 weeks), or initial combination (losartan 50–100 mg plus hydrochlorothiazide 12.5–25 mg). In phase 2 (weeks 17–32), all patients received losartan 100 mg and hydrochlorothiazide 12.5 to 25 mg. In phase 3 (weeks 33–52), amlodipine with or without doxazosin could be added to achieve target BP. Hierarchical primary outcomes were the difference from baseline in home systolic BP, averaged over phases 1 and 2 and, if significant, at 32 weeks. Secondary outcomes included adverse events, and difference in home systolic BP responses between tertiles of plasma renin. Home systolic BP after initial monotherapy fell 4.9 mm Hg (range: 3.7–6.0 mm Hg) less over 32 weeks (P&lt;0.001) than after initial combination but caught up at 32 weeks (difference 1.2 mm Hg [range: −0.4 to 2.8 mm Hg], P=0.13). In phase 1, home systolic BP response to each monotherapy differed substantially between renin tertiles, whereas response to combination therapy was uniform and at least 5 mm Hg more than to monotherapy. There were no differences in withdrawals due to adverse events. Conclusions: Initial combination therapy can be recommended for patients with BP &gt;150/95 mm Hg. Clinical Trial Registration URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00994617

Immunomodulatory role of Keratin 76 in oral and gastric cancer

Keratin 76 (Krt76) is an epithelial differentiation marker that is downregulated in oral squamous cell carcinomas, correlating with poor prognosis. Here the authors show that genetic ablation of Krt76 in a mouse model results in increased susceptibility to carcinogenesis via enhanced accumulation of Tregs