Size-Dependence and High Temperature Stability of Radial Vortex Magnetic Textures Imprinted by Superconductor Stray Fields.

Swirling spin textures, including topologically nontrivial states, such as skyrmions, chiral domain walls, and magnetic vortices, have garnered significant attention within the scientific community due to their appeal from both fundamental and applied points of view. However, their creation, controlled manipulation, and stability are typically constrained to certain systems with specific crystallographic symmetries, bulk or interface interactions, and/or a precise stacking sequence of materials. Recently, a new approach has shown potential for the imprint of magnetic radial vortices in soft ferromagnetic compounds making use of the stray field of YBa2Cu3O7-δ superconducting microstructures in ferromagnet/superconductor (FM/SC) hybrids at temperatures below the superconducting transition temperature (TC). Here, we explore the lower size limit for the imprint of magnetic radial vortices in square and disc shaped structures as well as the persistence of these spin textures above TC, with magnetic domains retaining partial memory. Structures with circular geometry and with FM patterned to smaller radius than the superconductor island facilitate the imprinting of magnetic radial vortices and improve their stability above TC, in contrast to square structures where the presence of magnetic domains increases the dipolar energy. Micromagnetic modeling coupled with a SC field model reveals that the stabilization mechanism above TC is mediated by microstructural defects. Superconducting control of swirling spin textures, and their stabilization above the superconducting transition temperature by means of defect engineering holds promising prospects for shaping superconducting spintronics based on magnetic textures.

Exploring a holistic training program on tactical behavior and psychological components of elite soccer players throughout competition season: a pilot study.

This study aimed to assess the effects of a training program, considering an ecological/holistic perspective, on both tactical behavior (i.e., principles of play; PP) and psychological aspects (i.e., emotional, and cognitive components) in elite soccer teams consisting of players from the U23 and U21 age groups. The participants were 46 players from the under U-23 and U-21 teams from the same club and the first division of Argentina. A quasi-experimental design was examined after five weeks of intervention through integrated training tasks, where psychological factors were used for the development of the tactical principles of the game. Two evaluations of the improvement of game principles were performed before and after the intervention. The results showed significant changes and differences in both teams concerning the PP during the post-intervention period. Specifically, the results show significant group-by-time interactions with an increase in the percentage of tactical actions and behaviors performed during the competitions in two game principles analyzed in both teams. There were significant in the group-by-time interactions for PP 3 (i.e., the first option to pass forward; p ≤ 0.001, F = 58.96, ηp2 = 0.88) and also, significant changes were in PP 4 (i.e., immediate pressure when losing the ball) through the main effect of time (p ≤ 0.001, F = 105.41, ηp2 = 0.93) and group by time interactions (p = 0.002, F = 20.08, ηp2 = 0.72). In both groups, there were significant changes in post hoc analysis (PP3: U21: p = 0.039 vs. U23: p ≤ 0.001) and (PP4: U21: p = 0.006 vs. U23: p = 0.001). It seems the strategies and constraints used, tactical components, and integrated into the psychological aspects during specific soccer training tasks can help improve the tactical behaviors of both teams in a competition associated with the PP of a soccer team.

Large Magnetoresistance of Isolated Domain Walls in La2/3 Sr1/3 MnO3 Nanowires.

Generation, manipulation, and sensing of magnetic domain walls are cornerstones in the design of efficient spintronic devices. Half-metals are amenable for this purpose as large low field magnetoresistance signals can be expected from spin accumulation at spin textures. Among half metals, La1- x Srx MnO3 (LSMO) manganites are considered as promising candidates for their robust half-metallic ground state, Curie temperature above room temperature (Tc = 360 K, for x = 1/3), and chemical stability. Yet domain wall magnetoresistance is poorly understood, with large discrepancies in the reported values and conflicting interpretation of experimental data due to the entanglement of various source of magnetoresistance, namely, spin accumulation, anisotropic magnetoresistance, and colossal magnetoresistance. In this work, the domain wall magnetoresistance is measured in LSMO cross-shape nanowires with single-domain walls nucleated across the current path. Magnetoresistance values above 10% are found to be originating at the spin accumulation caused by the mistracking effect of the spin texture of the domain wall by the conduction electrons. Fundamentally, this result shows the importance on non-adiabatic processes at spin textures despite the strong Hund coupling to the localized t2g electrons of the manganite. These large magnetoresistance values are high enough for encoding and reading magnetic bits in future oxide spintronic sensors.

Visual Hallucinations in a Patient With Moyamoya Disease: A Review and Case Report.

Moyamoya disease (MMD) is characterized by the progressive development of stenosis in the distal carotid territory and an abnormal vascular network. It is a rare disease with a higher prevalence in Asian countries compared with other countries. The most common symptoms of MMD vary from stroke to epileptic seizure and headaches. However, individuals with MMD may also experience psychiatric symptoms such as depression, anxiety, and, in rare cases, psychosis. We report the case of a 34-year-old man with MMD who suffered from psychosis accompanied by visual hallucinations. The man was diagnosed with MMD and attends periodic follow-ups in our neurology outpatient clinic. After undergoing programmed neurosurgery, the man's immediate postoperative follow-up neuroimaging showed an extensive right frontotemporal acute ischemic lesion for which he was treated and released. Almost a year later, he presented to an outpatient psychiatric clinic where he complained of visual hallucinations and delusions. This time, there was no change in neuroimaging. Treatment with olanzapine was successful, and the man's symptoms were completely reversed. To our knowledge, this is the first reported case of visual hallucinations in an individual with MMD. This case is especially relevant because the visual hallucinations were not associated with an occipital ischemic lesion or with epileptic activity. We propose a topographic hypothesis to explain such findings.

Risk of obstetric anal sphincter injuries (OASIS) and anal incontinence: A meta-analysis.

BACKGROUND: Obstetric anal sphincter injuries (OASIS) are the commonest cause of anal incontinence in women of reproductive age. We determined the risk of anal sphincter defects diagnosed by ultrasound, and the risk of anal incontinence in (i) all women who deliver vaginally, (ii) in women without clinical suspicion of OASIS, and (iii) after primary repair of sphincter injury, by systematic review. METHODS: We searched major databases until June 2018, without language restrictions. Random effects meta-analysis was used to obtain pooled estimates of ultrasound diagnosed OASIS and risk of anal incontinence symptoms at various time points after delivery, and of persistent sphincter defects after primary repair. We reported the association between ultrasound diagnosed OASIS and anal incontinence symptoms using relative risk (RR) with 95 % CI. RESULTS: We included 103 studies involving 16,110 women. Of all women who delivered vaginally, OASIS were diagnosed on ultrasound in 26 % (95 %CI, 21-30, I2 = 91 %), and 19 % experienced anal incontinence (95 %CI, 14-25, I2 = 92 %). In women without clinical suspicion of OASIS (n = 3688), sphincter defects were observed in 13 % (10-17, I2 = 89 %) and anal incontinence experienced by 14 % (95 % CI: 6-24, I2 = 95 %). Following primary repair of OASIS, 55 % (46-63, I2 = 98 %) of 7549 women had persistent sphincter defect with 38 % experiencing anal incontinence (33-43, I2 = 92 %). There was a significant association between ultrasound diagnosed OASIS and anal incontinence (RR 3.74, 2.17-6.45, I2 = 98 %). INTERPRETATION: Women and clinicians should be aware of the high risk for sphincter defects following vaginal delivery even when clinically unsuspected. This underlines the need of careful and systematic perineal assessment after birth to mitigate the risk of missing OASIS. We also noted a high rate of persistent defects and symptoms following primary repair of OASIS. This dictates the need for provision of robust training for clinicians to achieve proficiency and sustain competency in repairing OASIS.

Risks of stillbirth and neonatal death with advancing gestation at term: A systematic review and meta-analysis of cohort studies of 15 million pregnancies.

BACKGROUND: Despite advances in healthcare, stillbirth rates remain relatively unchanged. We conducted a systematic review to quantify the risks of stillbirth and neonatal death at term (from 37 weeks gestation) according to gestational age. METHODS AND FINDINGS: We searched the major electronic databases Medline, Embase, and Google Scholar (January 1990-October 2018) without language restrictions. We included cohort studies on term pregnancies that provided estimates of stillbirths or neonatal deaths by gestation week. We estimated the additional weekly risk of stillbirth in term pregnancies that continued versus delivered at various gestational ages. We compared week-specific neonatal mortality rates by gestational age at delivery. We used mixed-effects logistic regression models with random intercepts, and computed risk ratios (RRs), odds ratios (ORs), and 95% confidence intervals (CIs). Thirteen studies (15 million pregnancies, 17,830 stillbirths) were included. All studies were from high-income countries. Four studies provided the risks of stillbirth in mothers of White and Black race, 2 in mothers of White and Asian race, 5 in mothers of White race only, and 2 in mothers of Black race only. The prospective risk of stillbirth increased with gestational age from 0.11 per 1,000 pregnancies at 37 weeks (95% CI 0.07 to 0.15) to 3.18 per 1,000 at 42 weeks (95% CI 1.84 to 4.35). Neonatal mortality increased when pregnancies continued beyond 41 weeks; the risk increased significantly for deliveries at 42 versus 41 weeks gestation (RR 1.87, 95% CI 1.07 to 2.86, p = 0.012). One additional stillbirth occurred for every 1,449 (95% CI 1,237 to 1,747) pregnancies that advanced from 40 to 41 weeks. Limitations include variations in the definition of low-risk pregnancy, the wide time span of the studies, the use of registry-based data, and potential confounders affecting the outcome. CONCLUSIONS: Our findings suggest there is a significant additional risk of stillbirth, with no corresponding reduction in neonatal mortality, when term pregnancies continue to 41 weeks compared to delivery at 40 weeks. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015013785.

Maternal and perinatal mortality and complications associated with caesarean section in low-income and middle-income countries: a systematic review and meta-analysis.

BACKGROUND: Universal and timely access to a caesarean section is a key requirement for safe childbirth. We identified the burden of maternal and perinatal mortality and morbidity, and the risk factors following caesarean sections in low-income and middle-income countries (LMICs). METHODS: For this systematic review and meta-analysis, we searched electronic databases including MEDLINE and Embase (from Jan 1, 1990, to Nov 20, 2017), without language restrictions, for studies on maternal or perinatal outcomes following caesarean sections in LMICs. We excluded studies in high-income countries, those involving non-pregnant women, case reports, and studies published before 1990. Two reviewers undertook the study selection, quality assessment, and data extraction independently. The main outcome being assessed was prevalence of maternal mortality in women undergoing caesarean sections in LMICs. We used a random effects model to synthesise the rate data, and reported the association between risk factors and outcomes using odds ratios with 95% CIs. The study protocol has been registered with PROSPERO, number CRD42015029191. FINDINGS: We included 196 studies from 67 LMICs. The risk of maternal death in women who had a caesarean section (116 studies, 2 933 457 caesarean sections) was 7·6 per 1000 procedures (95% CI 6·6-8·6, τ2=0·81); the highest burden was in sub-Saharan Africa (10·9 per 1000; 9·5-12·5, τ2=0·81). A quarter of all women who died in LMICs (72 studies, 27 651 deaths) had undergone a caesarean section (23·8%, 95% CI 21·0-26·7; τ2=0·62). INTERPRETATION: Maternal deaths and perinatal deaths following caesarean sections are disproportionately high in LMICs. The timing and urgency of caesarean section pose major risks. FUNDING: Ammalife Charity and ELLY Appeal, Barts Charity, and the UK National Institute for Health Research.

Kauniolide synthase is a P450 with unusual hydroxylation and cyclization-elimination activity.

Guaianolides are an important class of sesquiterpene lactones with unique biological and pharmaceutical properties. They have been postulated to be derived from germacranolides, but for years no progress has been made in the elucidation of their biosynthesis that requires an unknown cyclization mechanism. Here we demonstrate the isolation and characterization of a cytochrome P450 from feverfew (Tanacetum parthenium), kauniolide synthase. Kauniolide synthase catalyses the formation of the guaianolide kauniolide from the germacranolide substrate costunolide. Unlike most cytochrome P450s, kauniolide synthase combines stereoselective hydroxylation of costunolide at the C3 position, with water elimination, cyclization and regioselective deprotonation. This unique mechanism of action is supported by in silico modelling and docking experiments. The full kauniolide biosynthesis pathway is reconstructed in the heterologous hosts Nicotiana benthamiana and yeast, paving the way for biotechnological production of guaianolide-type sesquiterpene lactones.

La incorporación de la salud comunitaria en la planificación y la transformación del entorno urbano. Informe SESPAS 2018 / The incorporation of community health in the planning and transformation of the urban environment. SESPAS Report 2018

El entorno urbanizado y edificado forma parte de los determinantes de la salud; también de la salud comunitaria. Por ello, pretendemos analizar la influencia del desarrollo urbanístico sobre la salud pública y comunitaria desde una perspectiva de género, la participación ciudadana en los proyectos de urbanismo y la accesibilidad. A partir de una revisión documental y un análisis narrativo, apoyado en la experiencia individual de los/las autores/as, encontramos diversos proyectos que ofrecen muy buenas condiciones para introducir la salud comunitaria en la planificación o la transformación de la ciudad: centros y patios escolares, vacíos urbanos y edificios en desuso, itinerarios urbanos para el paseo, y diversas actuaciones sobre el tejido residencial del barrio/municipio. En ellos, los procesos participativos, impulsados por instituciones o por la ciudadanía, que se desarrollan en el marco de proyectos de diagnóstico urbano y elaboración de planes y proyectos constituyen una doble oportunidad para trabajar en salud comunitaria: por un lado, considerándola como un objetivo, y por el otro, como una herramienta para diseñar entornos promotores del bienestar de la comunidad. La incorporación ciudadana y la colaboración de todos los agentes implicados, teniendo en cuenta su diversidad, es esencial y una responsabilidad compartida entre la Administración local y supralocal y la ciudadanía. La normativa debe construirse para ser facilitadora de los procesos, y su aplicación debe permitir que la población sea protagonista en la transformación de entornos favorecedores del bienestar y la salud

Urbanized and built-up environments are determinants of health as well as community health. Therefore, we intend to analyze the influence of urban development on both public and community health, from the perspective of gender, citizen participation in urban planning projects, and accessibility. From a bibliographic review and narrative analysis, based on the experience of the authors, we found several urban transformation projects focusing, in particular, on four large areas: school centres and playgrounds, empty urban spaces and disused buildings, pedestrian pathways, and various housing interventions. The participatory processes (driven by institutions and/or citizens) developed within the framework of urban diagnostic projects and the preparation of plans and projects, constitute a double opportunity to work on community health: on the one hand, considering them as an objective, and on the other, as a tool to design environments that promote the well-being of the community. The incorporation of citizens and the collaboration of all the agents involved, taking their diversity into account, are essential, and this is a shared responsibility between local/supra-local administration, and citizenship. Regulation must be designed to facilitate the processes and when it is applied must allow the population to take a central role in the transformation of environments that will promote well-being and health

[The incorporation of community health in the planning and transformation of the urban environment. SESPAS Report 2018]. / La incorporación de la salud comunitaria en la planificación y la transformación del entorno urbano. Informe SESPAS 2018.

Urbanized and built-up environments are determinants of health as well as community health. Therefore, we intend to analyze the influence of urban development on both public and community health, from the perspective of gender, citizen participation in urban planning projects, and accessibility. From a bibliographic review and narrative analysis, based on the experience of the authors, we found several urban transformation projects focusing, in particular, on four large areas: school centres and playgrounds, empty urban spaces and disused buildings, pedestrian pathways, and various housing interventions. The participatory processes (driven by institutions and/or citizens) developed within the framework of urban diagnostic projects and the preparation of plans and projects, constitute a double opportunity to work on community health: on the one hand, considering them as an objective, and on the other, as a tool to design environments that promote the well-being of the community. The incorporation of citizens and the collaboration of all the agents involved, taking their diversity into account, are essential, and this is a shared responsibility between local/supra-local administration, and citizenship. Regulation must be designed to facilitate the processes and when it is applied must allow the population to take a central role in the transformation of environments that will promote well-being and health.

Nerolidol production in agroinfiltrated tobacco: Impact of protein stability and membrane targeting of strawberry (Fragraria ananassa) NEROLIDOL SYNTHASE1.

The sesquiterpene alcohol nerolidol, synthesized from farnesyl diphosphate (FDP), mediates plant-insect interactions across multiple trophic levels with major implications for pest management in agriculture. We compared nerolidol engineering strategies in tobacco using agroinfiltration to transiently express strawberry (Fragraria ananassa) linalool/nerolidol synthase (FaNES1) either at the endoplasmic reticulum (ER) or in the cytosol as a soluble protein. Using solid phase microextraction and gas chromatography-mass spectrometry (SPME-GCMS), we have determined that FaNES1 directed to the ER via fusion to the transmembrane domain of squalene synthase or hydroxymethylglutaryl - CoA reductase displayed significant improvements in terms of transcript levels, protein accumulation, and volatile production when compared to its cytosolic form. However, the highest levels of nerolidol production were observed when FaNES1 was fused to GFP and expressed in the cytosol. This SPME-GCMS method afforded a limit of detection and quantification of 1.54 and 5.13 pg, respectively. Nerolidol production levels, which ranged from 0.5 to 3.0 µg/g F.W., correlated more strongly to the accumulation of recombinant protein than transcript level, the former being highest in FaNES-GFP transfected plants. These results indicate that while the ER may represent an enriched source of FDP that can be exploited in metabolic engineering, protein accumulation is a better predictor of sesquiterpene production.

Type of obstetric anesthesia administered and complications in women with preeclampsia in low- and middle-income countries: A systematic review.

BACKGROUND: Delivery is often expedited with cesarean section, necessitating anesthesia, to prevent complications in women with preeclampsia. Anesthesia-associated risks in these women from low- and middle-income countries (LMICs) are not known. METHODS: We searched major databases (until February 2017) for studies on general vs. regional anesthesia in women with preeclampsia. We summarized the association between outcomes and type of anesthesia using a random effects model and reported as odds ratio (OR) with 95% confidence intervals (95% CIs). FINDINGS: We included 14 studies (10,411 pregnancies). General anesthesia was associated with an increase in the odds of maternal death sevenfold (OR 7.70, 95% CI 1.9 to 31.0, I2 = 58%) than regional anesthesia. The odds of pulmonary edema (OR 5.16, 95% CI 2.5 to 10.4, I2 = 0%), maternal intensive care unit admissions (OR 16.25, 95% CI 9.0 to 29.5, I2 = 65%), and perinatal death (OR 3.01, 95% CI 1.4 to 6.5, I2 = 56%) were increased with general vs. regional anesthesia. CONCLUSION: General anesthesia is associated with increased complications in women with preeclampsia undergoing cesarean section in LMIC.

Complex interplays between phytosterols and plastid development.

Isoprenoids comprise the largest class of natural compounds and are found in all kinds of organisms. In plants, they participate in both primary and specialized metabolism, playing essential roles in nearly all aspects of growth and development. The enormous diversity of this family of compounds is extensively exploited for biotechnological and biomedical applications as biomaterials, biofuels or drugs. Despite their variety of structures, all isoprenoids derive from the common C5 precursor isopentenyl diphosphate (IPP). Plants synthesize IPP through two different metabolic pathways, the mevalonic acid (MVA) and the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathways that operate in the cytosol-RE and plastids, respectively. MEP-derived isoprenoids include important compounds for chloroplast function and as such, knock-out mutant plants affected in different steps of this pathway display important alterations in plastid structure. These alterations often lead to albino phenotypes and lethality at seedling stage. MVA knock-out mutant plants show, on the contrary, lethal phenotypes already exhibited at the gametophyte or embryo developmental stage. However, the recent characterization of conditional knock-down mutant plants of farnesyl diphosphate synthase (FPS), a central enzyme in cytosolic and mitochondrial isoprenoid biosynthesis, revealed an unexpected role of this pathway in chloroplast development and plastidial isoprenoid metabolism in post-embryonic stages. Upon FPS silencing, chloroplast structure is severely altered, together with a strong reduction in the levels of MEP pathway-derived major end products. This phenotype is associated to misregulation of genes involved in stress responses predominantly belonging to JA and Fe homeostasis pathways. Transcriptomic experiments and analysis of recent literature indicate that sterols are the cause of the observed alterations through an as yet undiscovered mechanism.

External validation of preexisting first trimester preeclampsia prediction models.

OBJECTIVE: To validate the increasing number of prognostic models being developed for preeclampsia using our own prospective study. STUDY DESIGN: A systematic review of literature that assessed biomarkers, uterine artery Doppler and maternal characteristics in the first trimester for the prediction of preeclampsia was performed and models selected based on predefined criteria. Validation was performed by applying the regression coefficients that were published in the different derivation studies to our cohort. We assessed the models discrimination ability and calibration. RESULTS: Twenty models were identified for validation. The discrimination ability observed in derivation studies (Area Under the Curves) ranged from 0.70 to 0.96 when these models were validated against the validation cohort, these AUC varied importantly, ranging from 0.504 to 0.833. Comparing Area Under the Curves obtained in the derivation study to those in the validation cohort we found statistically significant differences in several studies. CONCLUSION: There currently isn't a definitive prediction model with adequate ability to discriminate for preeclampsia, which performs as well when applied to a different population and can differentiate well between the highest and lowest risk groups within the tested population. The pre-existing large number of models limits the value of further model development and future research should be focussed on further attempts to validate existing models and assessing whether implementation of these improves patient care.

Global variation in pregnancy complications in women with epilepsy: A meta-analysis.

OBJECTIVE: Women with epilepsy are at risk of pregnancy complications. Whether these vary globally is unknown. We undertook a systematic review to assess the overall rates of obstetric outcomes in women with epilepsy, and variations in estimates across geographical region, economic status of country, and over time. STUDY DESIGN: We searched Medline, Embase, Cochrane, AMED and CINAHL, (January 1, 1990 and November 29, 2016), without any language restrictions for studies reporting core maternal and fetal outcomes in women with epilepsy. We pooled the results using Freeman-Tukey Transformation random effectsanalysis, and reported our findings as rates of complications per 100 pregnancies with 95% confidence intervals (CI). We assessed for differences in risk across World Health Organisation (WHO) regions, income status, and year of publication. RESULTS: From the 7420 articles screened, we included 60 studies (62 articles). In women with epilepsy (116,105 pregnancies), the commonest complications were caesarean section (29.2 per 100 pregnancies; 95% CI 25.4-33.1, I2=98.44%), and admission to the neonatal intensive care unit (12.5 per 100 pregnancies; 95% CI 9.6-15.8, I2=60.63%). There were significant differences across the WHO regions, with the highest rates of caesarean section (37%, 95% CI 32%-42%); spontaneous miscarriage (39%, 95% CI 35%-44%) and preterm birth (10%, 95% CI 8%-12%) in the Americas; postpartum haemorrhage (9%, 95% CI 7%-12%), hypertensive disorders (14%, 95% CI 8%-21%) and perinatal death (2%, 95% CI 1%-7%) in the Western Pacific; induction of labour (30%, 95% CI 19%-41%) in South East Asia and antepartum haemorrhage (10%, 95% CI 5%-17%) in the Eastern Mediterranean. The reported rates of antepartum haemorrhage, caesarean section, gestational diabetes and spontaneous miscarriage were highest in high income and high-middle income countries. Over time, there was a significant increase in caesarean section, and reduction in stillbirths, perinatal deaths and admission to the neonatal intensive care unit in women with epilepsy. CONCLUSION: There is significant variation in reported maternal and offspring outcomes in pregnant women with epilepsy across geographical regions, economic status of country and over time, which needs to be considered in setting priorities for clinical management and research.

Short Communication: Maraviroc Once-Daily: Experience in Routine Clinical Practice.

To assess the efficacy and safety of maraviroc (MVC) administered once-daily in routine clinical practice. A retrospective multicenter study (27 centers in Spain) was conducted. Data were collected from the records of patients starting a regimen with MVC. Laboratory and clinical data were recorded every 3 months the first year and every 6 months thereafter. Data are presented as median and interquartile range. Among 667 patients treated with MVC, 142 (21.3%) received MVC once-daily: 108 (76.1%), 150 mg and 34 (23.9%), and 300 mg. Age was 47 (42-45) years, there were 76.1% men, and 81 (57%) patients had baseline HIV-RNA <50 copies/mL. Viral tropism was R5 in 118 (83.1%) patients. Reasons for prescribing MVC: salvage therapy (36.6%), drug toxicity (31.2%), simplification (16.9%), and immunodiscordant response (7.1%). Median follow-up was 13 (9-16) months. In 95.8%, a PI/r was part of the regimen (67% on dual therapy). At months 12 and 24, 73.3% and 68.2% of patients had HIV-RNA <50 copies/mL, respectively (p = .041 and p < .001 vs. baseline). CD4+ cell count increased by a median of 52 (-36,135) and 84 (-9.5,180) cells/mm3 at 12 and 24 months, respectively (p < .001 and p = .039 vs. baseline). Twenty-five (17.6%) patients discontinued MVC: virologic failure (6), medical decision (5), and other reasons (14). Two patients presented grade 3 adverse events (hypertransaminasemia, hypertriglyceridemia) without the need for MVC withdrawal, whereas MVC was discontinued in two patients due to gastrointestinal toxicity. In routine clinical practice, MVC once-daily combined with at least PI/r was virologically effective and well tolerated in a high percentage of pretreated patients.

A Single Arabidopsis Gene Encodes Two Differentially Targeted Geranylgeranyl Diphosphate Synthase Isoforms.

A wide diversity of isoprenoids is produced in different plant compartments. Most groups of isoprenoids synthesized in plastids, and some produced elsewhere in the plant cell derive from geranylgeranyl diphosphate (GGPP) synthesized by GGPP synthase (GGPPS) enzymes. In Arabidopsis (Arabidopsis thaliana), five genes appear to encode GGPPS isoforms localized in plastids (two), the endoplasmic reticulum (two), and mitochondria (one). However, the loss of function of the plastid-targeted GGPPS11 isoform (referred to as G11) is sufficient to cause lethality. Here, we show that the absence of a strong transcription initiation site in the G11 gene results in the production of transcripts of different lengths. The longer transcripts encode an isoform with a functional plastid import sequence that produces GGPP for the major groups of photosynthesis-related plastidial isoprenoids. However, shorter transcripts are also produced that lack the first translation initiation codon and rely on a second in-frame ATG codon to produce an enzymatically active isoform lacking this N-terminal domain. This short enzyme localizes in the cytosol and is essential for embryo development. Our results confirm that the production of differentially targeted enzyme isoforms from the same gene is a central mechanism to control the biosynthesis of isoprenoid precursors in different plant cell compartments.

Elucidation of the biosynthesis of carnosic acid and its reconstitution in yeast.

Rosemary extracts containing the phenolic diterpenes carnosic acid and its derivative carnosol are approved food additives used in an increasingly wide range of products to enhance shelf-life, thanks to their high anti-oxidant activity. We describe here the elucidation of the complete biosynthetic pathway of carnosic acid and its reconstitution in yeast cells. Cytochrome P450 oxygenases (CYP76AH22-24) from Rosmarinus officinalis and Salvia fruticosa already characterized as ferruginol synthases are also able to produce 11-hydroxyferruginol. Modelling-based mutagenesis of three amino acids in the related ferruginol synthase (CYP76AH1) from S. miltiorrhiza is sufficient to convert it to a 11-hydroxyferruginol synthase (HFS). The three sequential C20 oxidations for the conversion of 11-hydroxyferruginol to carnosic acid are catalysed by the related CYP76AK6-8. The availability of the genes for the biosynthesis of carnosic acid opens opportunities for the metabolic engineering of phenolic diterpenes, a class of compounds with potent anti-oxidant, anti-inflammatory and anti-tumour activities.

Prospective risk of stillbirth and neonatal complications in twin pregnancies: systematic review and meta-analysis.

OBJECTIVE: To determine the risks of stillbirth and neonatal complications by gestational age in uncomplicated monochorionic and dichorionic twin pregnancies. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, and Cochrane databases (until December 2015). REVIEW METHODS: Databases were searched without language restrictions for studies of women with uncomplicated twin pregnancies that reported rates of stillbirth and neonatal outcomes at various gestational ages. Pregnancies with unclear chorionicity, monoamnionicity, and twin to twin transfusion syndrome were excluded. Meta-analyses of observational studies and cohorts nested within randomised studies were undertaken. Prospective risk of stillbirth was computed for each study at a given week of gestation and compared with the risk of neonatal death among deliveries in the same week. Gestational age specific differences in risk were estimated for stillbirths and neonatal deaths in monochorionic and dichorionic twin pregnancies after 34 weeks' gestation. RESULTS: 32 studies (29 685 dichorionic, 5486 monochorionic pregnancies) were included. In dichorionic twin pregnancies beyond 34 weeks (15 studies, 17 830 pregnancies), the prospective weekly risk of stillbirths from expectant management and the risk of neonatal death from delivery were balanced at 37 weeks' gestation (risk difference 1.2/1000, 95% confidence interval -1.3 to 3.6; I(2)=0%). Delay in delivery by a week (to 38 weeks) led to an additional 8.8 perinatal deaths per 1000 pregnancies (95% confidence interval 3.6 to 14.0/1000; I(2)=0%) compared with the previous week. In monochorionic pregnancies beyond 34 weeks (13 studies, 2149 pregnancies), there was a trend towards an increase in stillbirths compared with neonatal deaths after 36 weeks, with an additional 2.5 per 1000 perinatal deaths, which was not significant (-12.4 to 17.4/1000; I(2)=0%). The rates of neonatal morbidity showed a consistent reduction with increasing gestational age in monochorionic and dichorionic pregnancies, and admission to the neonatal intensive care unit was the commonest neonatal complication. The actual risk of stillbirth near term might be higher than reported estimates because of the policy of planned delivery in twin pregnancies. CONCLUSIONS: To minimise perinatal deaths, in uncomplicated dichorionic twin pregnancies delivery should be considered at 37 weeks' gestation; in monochorionic pregnancies delivery should be considered at 36 weeks. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014007538.