Regulation of Carotenoid Biosynthesis and Degradation in Lettuce (Lactuca sativa L.) from Seedlings to Harvest.

Lettuce (Lactuca sativa L.) is one of the commercially important leafy vegetables worldwide. However, lettuce cultivars vary widely in their carotenoid concentrations at the time of harvest. While the carotenoid content of lettuce can depend on transcript levels of key biosynthetic enzymes, genes that can act as biomarkers for carotenoid accumulation at early stages of plant growth have not been identified. Transcriptomic and metabolomic analysis was performed on the inner and outer leaves of the six cultivars at different developmental stages to identify gene-to-metabolite networks affecting the accumulation of two key carotenoids, ß-carotene and lutein. Statistical analysis, including principal component analysis, was used to better understand variations in carotenoid concentration between leaf age and cultivars. Our results demonstrate that key enzymes of carotenoid biosynthesis pathway can alter lutein and ß-carotene biosynthesis across commercial cultivars. To ensure high carotenoids content in leaves, the metabolites sink from ß-carotene and lutein to zeaxanthin, and subsequently, abscisic acid needs to be regulated. Based on 2-3-fold carotenoids increase at 40 days after sowing (DAS) as compared to the seedling stage, and 1.5-2-fold decline at commercial stage (60 DAS) compared to the 40 DAS stage, we conclude that the value of lettuce for human nutrition would be improved by use of less mature plants, as the widely-used commercial stage is already at plant senescence stage where carotenoids and other essential metabolites are undergoing degradation.

Characteristics of multidimensional pain in women with breast cancer treated at a referral hospital: a cross-sectional study / Características da dor multidimensional em mulheres com câncer de mama atendidas em um hospital de referência: estudo observacional transversal

ABSTRACT BACKGROUND AND OBJECTIVES: Pain is composed of multiple dimensions and can affect between 10% and 30% of women with breast cancer. This study evaluated physical, emotional, social, and spiritual pain components of women with breast cancer treated in a reference hospital complex in Pernambuco, Brazil. METHODS: An observational, descriptive, and cross-sectional study was conducted with 43 women diagnosed with breast cancer and treatment started. Pain and its dimensions were assessed by using Numerical Rating Scale (NRS), Edmonton Symptom Assessment Scale (ESAS-r), part of the Brazilian version of McGill questionnaire (Br-MPQ), Spiritual Well-being Scale (SWBS) and a questionnaire for clinical and sociodemographic data. RESULTS: The majority (79.07%) of women reported some pain at the time of the interview, with a mean of moderate pain intensity (5.28 ± 3.54). The most used expressions to describe the pain were: tiring (78.57%), nauseating (57.14%), acute (47.62) and sufocating (42.86%). The impact of pain on daily life affected the sub-items: sleep (67.44%), personal hygiene (44.18%), locomotion (48.83%), appetite/food (32.56%); in the social context 55.81% of the interviewees reported some degree of loss in work, 67.44% in leisure activities, 74.91% in domestic activities and 9.30% had early retirement. The spiritual/existential/religious scores were mostly positive. CONCLUSION: Physical, emotional, social and spiritual complaints were present in women with breast cancer and indicates the need for an early approach to pain by health professionals, especially physicians.

RESUMO JUSTIFICATIVA E OBJETIVOS: A dor é composta por múltiplas dimensões e pode afetar entre 10% e 30% das mulheres com câncer de mama. Este estudo avaliou a dor física, emocional, social e espiritual de mulheres com câncer de mama atendidas em um complexo hospitalar de referência em Pernambuco. MÉTODOS: Foi realizado um estudo observacional, descritivo e transversal com 43 mulheres com diagnóstico de câncer de mama e tratamento iniciado. A dor e suas dimensões foram avaliadas por meio da Escala Visual Numérica (EVN), da Edmonton Symptom Assessment Scale (ESAS-r), de parte da versão brasileira do questionário McGill (Br-MPQ), além da Escala de Bem-Estar Espiritual (SWBS) e de um questionário contemplando dados clínicos e sociodemográficos. RESULTADOS: A maioria (79,07%) das mulheres relatou alguma dor no momento da entrevista, com média da intensidade de dor moderada (5,28 ± 3,54). As expressões mais utilizadas para descrever a dor foram: fatigante (78,57%), nauseante (57,14%), castigante (47,62) e sufocante (42,86%). O impacto da dor na vida diária afetou os subitens: sono (67,44%), higiene pessoal (44,18%), locomoção (48,83%), apetite/alimentação (32,56%); no contexto social 55,81% das entrevistadas relataram algum grau de perda no trabalho, 67,44% em atividades de lazer, 74,91% em atividades domésticas e 9,30% aposentaram-se antecipadamente. Os escores espirituais/existenciais/religiosos foram, em sua maioria, positivos. CONCLUSÃO: Queixas físicas, emocionais, sociais e espirituais estiveram presentes em mulheres com câncer de mama, indicando a necessidade de abordagem precoce da dor pelos profissionais de saúde. DESTAQUES Este artigo analisou os aspectos multidimensionais da dor em pacientes diagnosticados com câncer de mama. Todas as pacientes apresentavam queixas físicas, emocionais, sociais e espirituais. A maioria dos profissionais de saúde não abordava os aspectos multidimensionais da dor.

Transient Carbon Reserves in Barley: Malate, Sucrose and Starch Are the Main Players, Their Quantitative Involvement Being Light Intensity Dependant.

Under natural environment plants experience different light intensities which can affect photosynthesis and consequently the availability of carbohydrates for daytime growth and their transient storage to supply night growth. We grew a spring barley cultivar, Propino, under three different light intensities under warm days and nights, and evaluated the spatial and diurnal adjustments occurring in the transient carbon stores. Leaves under high light at the end of the day accumulated mainly sucrose (30%) and malate (35%), with lower content of hexoses (5%), starch (15%) and fructans (15%). Under low light, plants presented reduced photosynthesis, with lower metabolite contents at end of day. The malate represented 51% of the total carbon accumulated at end of the day, at the expense of sucrose (12%), other metabolite contributions remaining similar to high light. The percentage of metabolites consumed at night was similar for all light intensities with around 75% of the sucrose and starch being mobilized whilst malate and fructans were only partially mobilized with 56 and 44%, respectively. Altogether, sucrose and malate were the main contributors of the total carbon used at night by barley plants, sucrose being predominant under high light (35% vs. 27%), but malate being the major metabolite used under low light with 40% of the total carbon consumed. Interestingly, light intensity also influenced the location of the C transient stores, the plants under low light prioritizing the accumulation of the metabolites, mostly malate, in the youngest tissues. Therefore, light influences quantitatively, but also qualitatively and spatially the carbon stores in the spring barley cv. Propino, suggesting a tight regulation of the primary metabolism.

Diurnal patterns of growth and transient reserves of sink and source tissues are affected by cold nights in barley.

Barley is described to mostly use sucrose for night carbon requirements. To understand how the transient carbon is accumulated and utilized in response to cold, barley plants were grown in a combination of cold days and/or nights. Both daytime and night cold reduced growth. Sucrose was the main carbohydrate supplying growth at night, representing 50-60% of the carbon consumed. Under warm days and nights, starch was the second contributor with 26% and malate the third with 15%. Under cold nights, the contribution of starch was severely reduced, due to an inhibition of its synthesis, including under warm days, and malate was the second contributor to C requirements with 24-28% of the total amount of carbon consumed. We propose that malate plays a critical role as an alternative carbon source to sucrose and starch in barley. Hexoses, malate, and sucrose mobilization and starch accumulation were affected in barley elf3 clock mutants, suggesting a clock regulation of their metabolism, without affecting growth and photosynthesis however. Altogether, our data suggest that the mobilization of sucrose and malate and/or barley growth machinery are sensitive to cold.

Thermal disruption of the food matrix of biofortified lettuce varieties modifies absorption of carotenoids by Caco-2 cells.

Amongst green leafy vegetables, new varieties of lettuce enriched in lutein and ß-carotene are being developed to provide increased supply of dietary carotenoids. We investigated the effect of lettuce genotypes (varieties) and thermal treatments on lutein and ß-carotene bioaccessibility to the micellar fraction (and also carotenoid bioavailability) using a human Caco-2 cell model system. Carotenoid absorption by mammalian cells is not correlated with initial carotenoid concentration in fresh lettuce leaves. While thermal treatment of lettuce leaves increases carotenoid availability, resulting in higher lutein and ß-carotene absorption, disruption of the food matrix by prior cooking results in reduced carotenoid levels and transfer to the micellar fraction. Unless the food matrix is disrupted through breeding or post-harvest treatments, absorption of carotenoids from biofortified lettuce remains similar to lettuce cultivars with low carotenoid levels. Genetic improvement programs for biofortified lettuce varieties need to focus on increasing the carotenoid bioavailability from the food matrix.

Extensive Variations in Diurnal Growth Patterns and Metabolism Among Ulva spp. Strains.

Green macroalgae of the genus Ulva play a key role in coastal ecosystems and are of increasing commercial importance. However, physiological differences between strains and species have yet to be described in detail. Furthermore, the strains of Ulva used in aquaculture usually originate from opportunistic collection in the wild without prior selection of best performing strains. Hence, efforts are required to detect the potential variability in growth and metabolic accumulation between Ulva strains and ultimately select the best performing strains under given environmental conditions. Here, the growth, physiological, and metabolic characteristics of 49 laminar Ulva spp. strains were investigated using a custom-made high-throughput phenotyping platform, enzymatic assays, and gas chromatography-mass spectrometry. We found large natural variation for a wide range of growth and metabolic characteristics, with growth rates varying from 0.09 to 0.37 mg.mg-1d-1 among strains. Ulva spp. possess a unique diurnal growth pattern and primary metabolism compared with land plants, with higher growth rates during the night than during the light period. Starch and sucrose only contributed on average 35% of the carbon required to sustain Ulva's night growth. Nitrates accumulated during the night in Ulva tissues, and nitrate accumulation and consumption was positively correlated with growth. In addition, we identified six amino acids as possible biomarkers for high growth in Ulva The large variability in growth and metabolite accumulation recorded among morphologically similar Ulva strains justifies future efforts in strain selection for increasing biomass, metabolite yields, and nutrient removal in the growing aquaculture industry.

Left atrial volume index: Can it provide additional prognostic information in ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention?

INTRODUCTION: We sought to assess the prognostic impact of left atrial (LA) size on long-term outcomes of ST-segment elevation myocardial infarction (STEMI). METHODS: We studied 200 consecutive patients admitted to a single center between January 2010 and December 2014 with non-fatal STEMI treated with primary percutaneous coronary intervention (pPCI) who underwent a comprehensive echocardiographic examination at discharge. LA volume was estimated by the area-length method. The left atrium was classified as normal, mildly, moderately or severely enlarged by LA volume index (LAVI). The endpoints were defined as all-cause mortality, a cardiac composite endpoint (all-cause mortality, reinfarction, unplanned revascularization and hospitalization for heart failure) and a cardiovascular composite endpoint (cardiac endpoint plus atrial fibrillation and ischemic stroke) during follow-up. RESULTS: In this STEMI population, 58% had normal LA size, 22.5% had mild LA enlargement, 10% had moderate LA enlargement and 9.5% had severe LA enlargement. During a median follow-up of 28 (IQR 21-38) months, 14 (7.0%) patients died, 53 (26.5%) had the cardiac and 58 (29%) the cardiovascular composite endpoints. There was a stepwise increase in the incidence of all-cause mortality (p=0.020) and both cardiac (p<0.001) and cardiovascular (p<0.001) endpoints with each increment of LAVI class. In multivariate analysis, severe LA enlargement by LAVI was an independent predictor of all-cause mortality (HR: 11.153; 95% CI: 1.924-64.642, p=0.007) and the cardiac (HR: 4.351; 95% CI: 1.919-9.862, p<0.001) and cardiovascular (HR: 4.351; 95% CI: 1.919-9.862, p<0.001) endpoints during follow-up. CONCLUSIONS: This contemporary study confirms the prognostic effect of LA size at discharge, applying the most recent reference values in STEMI patients treated with pPCI.

Extending the ecological distribution of Desmonostoc genus: proposal of Desmonostoc salinum sp. nov., a novel Cyanobacteria from a saline-alkaline lake.

Cyanobacteria is an ancient phylum of oxygenic photosynthetic microorganisms found in almost all environments of Earth. In recent years, the taxonomic placement of some cyanobacterial strains, including those belonging to the genus Nostocsensu lato, have been reevaluated by means of a polyphasic approach. Thus, 16S rRNA gene phylogeny and 16S-23S internal transcribed spacer (ITS) secondary structures coupled with morphological, ecological and physiological data are considered powerful tools for a better taxonomic and systematics resolution, leading to the description of novel genera and species. Additionally, underexplored and harsh environments, such as saline-alkaline lakes, have received special attention given they can be a source of novel cyanobacterial taxa. Here, a filamentous heterocytous strain, Nostocaceae CCM-UFV059, isolated from Laguna Amarga, Chile, was characterized applying the polyphasic approach; its fatty acid profile and physiological responses to salt (NaCl) were also determined. Morphologically, this strain was related to morphotypes of the Nostocsensu lato group, being phylogenetically placed into the typical cluster of the genus Desmonostoc. CCM-UFV059 showed identity of the 16S rRNA gene as well as 16S-23S secondary structures that did not match those from known described species of the genus Desmonostoc, as well as distinct ecological and physiological traits. Taken together, these data allowed the description of the first strain of a member of the genus Desmonostoc from a saline-alkaline lake, named Desmonostoc salinum sp. nov., under the provisions of the International Code of Nomenclature for algae, fungi and plants. This finding extends the ecological coverage of the genus Desmonostoc, contributing to a better understanding of cyanobacterial diversity and systematics.

Qualidade de vida, espiritualidade, religiosidade e esperança em pessoas com doença renal crônica em hemodiálise / Quality of life, spirituality, religiosity, and hope in chronic renal disease patients in hemodialysis

OBJETIVO: Analisar qualidade de vida, espiritualidade, religiosidade e esperança de pessoas com doença renal crônica em hemodiálise. MÉTODOS: Estudo de corte transversal realizado com pessoas acompanhadas no Instituto de Medicina Integral Prof. Fernando Figueira, em Recife (PE), entre agosto de 2016 a julho de 2017. Os dados referentes à qualidade de vida foram coletados por meio do instrumento World Health Organization Quality of Life ­ Spirituality, Religion and Personal beliefs (WHOQOL-SRPB-bref ), constituído por questões do tipo Likert, compondo cinco domínios, a saber: Físico, Psicológico, Relações Sociais, Meio Ambiente e Espiritualidade/Religiosidade/ Crenças Pessoais. Já os dados de esperança de vida foram coletados por meio da Escala de Esperança de Herth. RESULTADOS: O estudo envolveu 139 pacientes. Um bom indicador de qualidade de vida ocorreu nos domínios Espiritualidade/Religiosidade/ Crenças Pessoais (81,0%), Relações Sociais (75,8%), Psicológico (67,5%) e Meio Ambiente (64,4%). Já o domínio Físico apresentou o indicador mais baixo (58,3%) quando comparado aos demais. Com relação à esperança de vida, obteve-se variação de pontuação de 21 a 45, sendo 35 a mais frequente, significando alta esperança de vida na amostra em tela. CONCLUSÃO: Os indicadores de espiritualidade, religiosidade e esperança de vida se mostraram satisfatórios no grupo estudado. No contexto da doença renal crônica, estes aspectos surgem como medidas de enfrentamento positivo para as dificuldades da vida diária.(AU)

OBJECTIVES: To analyze quality of life, spirituality, religiosity, and hope in chronic kidney disease patients undergoing hemodialysis at Instituto de Medicina Integral Prof. Fernando Figueira (IMIP), located in the city of Recife, state of Pernambuco, Brazil. METHODS: A cross-sectional study was performed between August 2016 and July 2017. Quality of life data were collected through the WHOQOL-SRPB-bref, consisting of Likert-type questions, with five domains: Physical, Psychological, Social Relations, Environment, and Spirituality/ religiosity/personal beliefs. Life expectancy data were collected using Herth's Scale of Hope. RESULTS: The study involved 139 patients. A good indicator of good quality of life was observed in the spirituality/religiosity/personal beliefs (81,0%), social relations (75,8%), Psychological (67,5%), and Environment (64,4%) domains. The physical domain had the lowest indicator (58,3%) when compared to the others. Regarding life expectancy, scores ranged from 21 to 45, with 35 being the most frequent, indicating high hope in the group studied. CONCLUSIONS: The indicators of spirituality, religiosity and life expectancy were satisfactory in the group studied. In the context of chronic kidney disease, these aspects appear as positive coping measures of the difficulties of daily living.(AU)

Nitrogen metabolism in cyanobacteria: metabolic and molecular control, growth consequences and biotechnological applications.

Cyanobacteria are one of the earliest branching groups of organisms on the planet, and during their evolutionary history were submitted to varying selective pressures. Nowadays, cyanobacteria can grow in a variety of conditions, using a large number of nitrogen sources. The control of the nitrogen metabolism in cyanobacteria depends on a fine-tuning regulatory network involving 2-oxoglutarate (2-OG), PII, PipX, and NtcA. This network answers to the cellular 2-OG levels, which reflects the cellular carbon/nitrogen balance, and as an output regulates gene expression, translation, protein activities and thus metabolic pathways. Hence, the diurnal regulation of growth may be directly dependent of this network, as it coordinates the use of photoassimilates towards either growth or the accumulation of reserves, based on the environmental conditions. Therefore, analysis of the nitrogen control network is not only important to comprehend the metabolic control of growth in cyanobacteria, but is also a target to improve cyanobacterial biotechnological potential. In this review, we discuss the mechanisms involved in the control of nitrogen metabolism and its potential role in the diurnal regulation of growth. Then, we highlight why a better understanding of the mechanisms involved in the partitioning of carbon and nitrogen towards growth or storage would increase the biotechnological potential of these organisms.

Short-term prognostic effect of prior cerebrovascular and peripheral artery disease in patients with acute coronary syndrome: Can we do better?

BACKGROUND: We sought to evaluate the impact of prior cerebrovascular and/or peripheral arterial disease (PAD) on in-hospital outcomes in patients with acute coronary syndromes. METHODS: From 1 October 2010 to 26 February 2016, 13,904 acute coronary syndrome patients were enrolled in a national multicentre registry. They were divided into four groups: prior stroke/transient ischaemic attack (stroke/TIA); prior PAD; prior stroke/TIA and PAD; none. The endpoints included in-hospital mortality and a composite endpoint of death, re-infarction and stroke during hospitalization. RESULTS: 6.3% patients had prior stroke/TIA, 4.2% prior PAD and 1.4% prior stroke/TIA and PAD. Prior stroke/TIA and/or PAD patients were less likely to receive evidence-based medical therapies (dual antiplatelet therapy: stroke/TIA= 88.6%, PAD= 86.6%, stroke/TIA+PAD= 85.7%, none= 92.2%, p<0.001; ß-blockers: stroke/TIA= 77.1%, PAD= 72.1%, stroke/TIA+PAD= 71.9%, none= 80.8%, p<0.001; angiotensin-converting enzyme inhibitors/angiotensin receptor blockers: stroke/TIA= 86.3%, PAD= 83.6%, stroke/TIA+PAD= 83.2%, none= 87.1%, p=0.030) and to undergo percutaneous revascularization (stroke/TIA= 52.8%, PAD= 45.6%, stroke/TIA+PAD= 43.7%, none= 67.9%, p<0.001), despite more extensive coronary artery disease (three-vessel disease: stroke/TIA= 29.1%, PAD= 38.3%, stroke/TIA+PAD= 38.3%, none= 20.2%, p<0.001). In a multivariable analysis, prior stroke/TIA+PAD was a predictor of in-hospital mortality (odds ratio= 2.828, 95% confidence interval 1.001-7.990) and prior stroke/TIA (odds ratio= 1.529, 95% confidence interval 1.056-2.211), prior PAD (odds ratio= 1.618, 95% confidence interval 1.034-2.533) and both conditions (odds ratio= 3.736, 95% confidence interval 2.002-6.974) were associated with the composite endpoint. CONCLUSION: A prior history of stroke/TIA and/or PAD was associated with lower use of medical therapy and coronary revascularization and with worst short-term prognosis. An individualized management may improve their poor prognosis.

Phytochrome A and B Regulate Primary Metabolism in Arabidopsis Leaves in Response to Light.

Primary metabolism is closely linked to plant productivity and quality. Thus, a better understanding of the regulation of primary metabolism by photoreceptors has profound implications for agricultural practices and management. This study aims at identifying the role of light signaling in the regulation of primary metabolism, with an emphasis on starch. We first screened seven cryptochromes and phytochromes mutants for starch phenotype. The phyAB mutant showed impairment in starch accumulation while its biomass, chlorophyll fluorescence parameters, and leaf anatomy were unaffected, this deficiency being present over the whole vegetative growth period. Mutation of plastidial nucleoside diphosphate kinase-2 (NDPK2), acting downstream of phytochromes, also caused a deficit in starch accumulation. Besides, the glucose-1-phosphate adenylyltransferase small subunit (APS1) was down-regulated in phyAB. Those results suggest that PHYAB affect starch accumulation through NDPK2 and APS1. Then, we determined changes in starch and primary metabolites in single phyA, single phyB, double phyAB grown in light conditions differing in light intensity and/or light spectral content. PHYA is involved in starch accumulation in all the examined light conditions, whereas PHYB only exhibits a role under low light intensity (44 ± 1 µmol m-2 s-1) or low R:FR (11.8 ± 0.6). PCA analysis of the metabolic profiles in the mutants and wild type (WT) suggested that PHYB acts as a major regulator of the leaf metabolic status in response to light intensity. Overall, we propose that PHYA and PHYB signaling play essential roles in the control of primary metabolism in Arabidopsis leaves in response to light.

Development of a new Rasch-based scoring algorithm for the National Eye Institute Visual Functioning Questionnaire to improve its interpretability.

BACKGROUND: The NEI VFQ-25 has undergone psychometric evaluation in patients with varying ocular conditions and the general population. However, important limitations which may affect the interpretation of clinical trial results have been previously identified, such as concerns with reliability and validity. The purpose of this study was to evaluate the National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25) and make recommendations for a revised scoring structure, with a view to improving its psychometric performance and interpretability. METHODS: Rasch Measurement Theory analyses were conducted in two stages using pooled baseline NEI VFQ-25 data for 2487 participants with retinal diseases enrolled in six clinical trials. In stage 1, we examined: scale-to-sample targeting; thresholds for item response options; item fit statistics; stability; local dependence; and reliability. In stage 2, a post-hoc revision of the scoring structure (VFQ-28R) was created and psychometrically re-evaluated. RESULTS: In stage 1, we found that the NEI VFQ-25 was mis-targeted to the sample, and had disordered response thresholds (15/25 items) and mis-fitting items (8/25 items). However, items appeared to be stable (differential item functioning for three items), have minimal item dependency (one pair of items) and good reliability (person-separation index, 0.93). In stage 2, the modified Rasch-scored NEI VFQ-28-R was assessed. It comprised two broad domains: Activity Limitation (19 items) and Socio-Emotional Functioning (nine items). The NEI VFQ-28-R demonstrated improved performance with fewer disordered response thresholds (no items), less item misfit (three items) and improved population targeting (reduced ceiling effect) compared with the NEI VFQ-25. CONCLUSIONS: Compared with the original version, the proposed NEI VFQ-28-R, with Rasch-based scoring and a two-domain structure, appears to offer improved psychometric performance and interpretability of the vision-related quality of life scale for the population analysed.

Resource Utilization Among Glaucoma Patients in the UK Treated with Beta-Blocker and Non-Beta-Blocker Adjunctive Therapy: A Retrospective Cohort Analysis.

INTRODUCTION: Few studies have examined outcomes and potential complications among glaucoma patients who are prescribed topical beta-blockers. This study examined resource usage (number of GP visits and hospitalizations) and diagnoses of respiratory or cardiovascular conditions among glaucoma patients prescribed beta-blockers compared to patients not prescribed beta-blockers. METHODS: A retrospective cohort analysis was conducted using data from the UK Clinical Practice Research Datalink (CPRD) database over the period January 1, 2006 to March 31, 2014. Adult patients with at least one diagnosis of glaucoma were categorized into beta-blocker users and non-beta-blocker users. Beta-blocker users were further separated into patients that maintained beta-blocker therapy and patients that discontinued beta-blocker treatment in year 2 of the post-index period. The CPRD data was queried directly to obtain the number of GP visits, and hospitalizations were extracted by linking the CPRD and Hospital Episode Statistics (HES) patient-level data. RESULTS: In the 12 months after being prescribed beta-blockers, patients that later discontinued beta-blocker treatment had a significantly higher average number of hospitalizations than patients that maintained beta-blocker therapy and the non-beta-blocker users (p < 0.05). In the year after beta-blocker initiation, there was a statistically significant within-group difference pre- and post-beta-blocker initiation for all groups, but the greatest number of GP visits occurred in the patients that subsequently discontinued beta-blocker treatment (mean 19.27). Patients that discontinued beta-blocker treatment were significantly more likely to have cardiovascular events than non-beta-blocker users in the post-index period (p < 0.05). CONCLUSION: This study suggests that the introduction of beta-blockers in a certain group of patients who later discontinue their use is associated with increased use of medical resources (higher number of GP visits and hospitalizations) in glaucoma patients in the UK, which may be indicative of a potential relationship between use of topical beta-blockers in glaucoma therapy and adverse outcomes.

A Novel Mechanism, Linked to Cell Density, Largely Controls Cell Division in Synechocystis.

Many studies have investigated the various genetic and environmental factors regulating cyanobacterial growth. Here, we investigated the growth and metabolism of Synechocystis sp. PCC 6803 under different nitrogen sources, light intensities, and CO2 concentrations. Cells grown on urea showed the highest growth rates. However, for all conditions tested, the daily growth rates in batch cultures decreased steadily over time, and stationary phase was obtained with similar cell densities. Unexpectedly, metabolic and physiological analyses showed that growth rates during log phase were not controlled primarily by the availability of photoassimilates. Further physiological investigations indicated that nutrient limitation, quorum sensing, light quality, and light intensity (self-shading) were not the main factors responsible for the decrease in the growth rate and the onset of the stationary phase. Moreover, cell division rates in fed-batch cultures were positively correlated with the dilution rates. Hence, not only light, CO2, and nutrients can affect growth but also a cell-cell interaction. Accordingly, we propose that cell-cell interaction may be a factor responsible for the gradual decrease of growth rates in batch cultures during log phase, culminating with the onset of stationary phase.

Cyanobacterial nitrogenases: phylogenetic diversity, regulation and functional predictions.

Cyanobacteria is a remarkable group of prokaryotic photosynthetic microorganisms, with several genera capable of fixing atmospheric nitrogen (N2) and presenting a wide range of morphologies. Although the nitrogenase complex is not present in all cyanobacterial taxa, it is spread across several cyanobacterial strains. The nitrogenase complex has also a high theoretical potential for biofuel production, since H2 is a by-product produced during N2 fixation. In this review we discuss the significance of a relatively wide variety of cell morphologies and metabolic strategies that allow spatial and temporal separation of N2 fixation from photosynthesis in cyanobacteria. Phylogenetic reconstructions based on 16S rRNA and nifD gene sequences shed light on the evolutionary history of the two genes. Our results demonstrated that (i) sequences of genes involved in nitrogen fixation (nifD) from several morphologically distinct strains of cyanobacteria are grouped in similarity with their morphology classification and phylogeny, and (ii) nifD genes from heterocytous strains share a common ancestor. By using this data we also discuss the evolutionary importance of processes such as horizontal gene transfer and genetic duplication for nitrogenase evolution and diversification. Finally, we discuss the importance of H2 synthesis in cyanobacteria, as well as strategies and challenges to improve cyanobacterial H2 production.

A Retrospective Study of Ranibizumab Treatment Regimens for Neovascular Age-Related Macular Degeneration (nAMD) in Australia and the United Kingdom.

INTRODUCTION: Neovascular age-related macular degeneration (nAMD) is the leading cause of vision loss among persons aged 65 years and older. Anti-vascular endothelial growth factor (anti-VEGF) treatment is the recommended standard of care. The current study compares the effectiveness of ranibizumab in routine clinical practice in two countries that generally apply two different treatment regimens, treat-and-extend (T&E) in Australia or pro re nata (PRN) in the UK. METHODS: This retrospective, comparative, non-randomised cohort study is based on patients' data from electronic medical record (EMR) databases in Australia and the UK. Treatment regimens were defined based on location, with Australia as a proxy for analysing T&E and UK as a proxy for analysing PRN. The study included patients with a diagnosis of nAMD who started treatment with ranibizumab between January 2009 and July 2014. A total of 647 eyes of 570 patients in Australia and 3187 eyes of 2755 patients in the UK with complete 12-months follow-up were analysed. RESULTS: Baseline patient characteristics were comparable between the two cohorts. After 1 year of treatment, T&E-treated eyes achieved higher mean (±SE) visual acuity (VA) gains (5.00 ± 0.54 letters [95% confidence interval (CI) 3.93-6.06]) than PRN-treated eyes [3.04 ± 0.24 letters (95% CI 2.57-3.51); difference in means 2.07 ± 0.69 (95% CI 0.73-3.41), p < 0.001]. Non-inferiority of T&E compared to PRN was concluded based on the change in mean visual acuity gains at 12 months. Over the 12-month follow-up, T&E-treated eyes received a higher mean [±standard deviation (SD)] number of injections (9.29 ± 2.43) than PRN-treated eyes (6.04 ± 2.19) (p < 0.0001). Australian patients had a lower mean (±SD) number of total clinic visits (10.29 ± 2.90) than UK patients (11.47 ± 2.93) (p < 0.0001). CONCLUSION: The higher injection frequency in the T&E cohort may account for the trend toward improved vision. FUNDING: Novartis Pharma AG, Basel, Switzerland.

The Clinical Effectiveness of Ranibizumab Treat and Extend Regimen in nAMD: Systematic Review and Network Meta-Analysis.

INTRODUCTION: Neovascular age-related macular degeneration (nAMD) is a chronic eye condition that causes severe deterioration of vision and ultimately blindness. Two vascular endothelial growth factor inhibitors are approved for nAMD treatment in Europe: ranibizumab and aflibercept. The European license for ranibizumab was updated with an individualized "treat and extend" (T&E) regimen, which involves more proactive treatment based on changes in best corrected visual acuity (BCVA) and/or anatomical outcomes. The aim of this publication is to compare the efficacy of the ranibizumab T&E regimen with other approved dosing regimens for nAMD on the basis of outcomes identified from a systematic review and subsequent NMA. METHODS: Following a systematic search of publications, to identify relevant studies, a repeated-measures network meta-analysis (NMA) was performed to estimate the relative effectiveness of ranibizumab T&E versus approved dosing regimens of ranibizumab and aflibercept. The analysis focused on licensed treatment regimens for nAMD. We examined mean change from baseline in BCVA on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. RESULTS: The systematic literature review identified 22,949 records, of which 23 studies were included in the NMA. At 12 months, the ranibizumab T&E dosing regimen vs ranibizumab pro re nata (PRN) was associated with small differences in change in BCVA, between 1.86 letter gain at 12 months and 2.35 letter gain at 24 months. A similar difference was observed in the aflibercept dosing regimen versus ranibizumab T&E ; 1.94 letter gain at 12 months and 3.31 letter gain at 24 months. All doses of ranibizumab and aflibercept showed similar effectiveness, and the differences between treatment options were not significant. CONCLUSION: This study used novel repeated-measures NMA to synthesize efficacy results when treatment effects were reported at multiple follow-up times. This repeated-measures NMA suggests that treating patients with the ranibizumab T&E regimen yields similar effectiveness compared to other approved ranibizumab and aflibercept dosing regimens for nAMD treatment. FUNDING: Novartis Pharmaceuticals UK Ltd, Surrey, UK.