Systems genomics of salinity stress response in rice.

Populations can adapt to stressful environments through changes in gene expression. However, the role of gene regulation in mediating stress response and adaptation remains largely unexplored. Here, we use an integrative field dataset obtained from 780 plants of Oryza sativa ssp. indica (rice) grown in a field experiment under normal or moderate salt stress conditions to examine selection and evolution of gene expression variation under salinity stress conditions. We find that salinity stress induces increased selective pressure on gene expression. Further, we show that trans-eQTLs rather than cis-eQTLs are primarily associated with rice's gene expression under salinity stress, potentially via a few master-regulators. Importantly, and contrary to the expectations, we find that cis-trans reinforcement is more common than cis-trans compensation which may be reflective of rice diversification subsequent to domestication. We further identify genetic fixation as the likely mechanism underlying this compensation/reinforcement. Additionally, we show that cis- and trans-eQTLs are under different selection regimes, giving us insights into the evolutionary dynamics of gene expression variation. By examining genomic, transcriptomic, and phenotypic variation across a rice population, we gain insights into the molecular and genetic landscape underlying adaptive salinity stress responses, which is relevant for other crops and other stresses.

A Case Study from the Overexpression of OsTZF5, Encoding a CCCH Tandem Zinc Finger Protein, in Rice Plants Across Nineteen Yield Trials.

BACKGROUND: Development of transgenic rice overexpressing transcription factors involved in drought response has been previously reported to confer drought tolerance and therefore represents a means of crop improvement. We transformed lowland rice IR64 with OsTZF5, encoding a CCCH-tandem zinc finger protein, under the control of the rice LIP9 stress-inducible promoter and compared the drought response of transgenic lines and nulls to IR64 in successive screenhouse paddy and field trials up to the T6 generation. RESULTS: Compared to the well-watered conditions, the level of drought stress across experiments varied from a minimum of - 25 to - 75 kPa at a soil depth of 30 cm which reduced biomass by 30-55% and grain yield by 1-92%, presenting a range of drought severities. OsTZF5 transgenic lines showed high yield advantage under drought over IR64 in early generations, which was related to shorter time to flowering, lower shoot biomass and higher harvest index. However, the increases in values for yield and related traits in the transgenics became smaller over successive generations despite continued detection of drought-induced transgene expression as conferred by the LIP9 promoter. The decreased advantage of the transgenics over generations tended to coincide with increased levels of homozygosity. Background cleaning of the transgenic lines as well as introgression of the transgene into an IR64 line containing major-effect drought yield QTLs, which were evaluated starting at the BC3F1 and BC2F3 generation, respectively, did not result in consistently increased yield under drought as compared to the respective checks. CONCLUSIONS: Although we cannot conclusively explain the genetic factors behind the loss of yield advantage of the transgenics under drought across generations, our results help in distinguishing among potential drought tolerance mechanisms related to effectiveness of the transgenics, since early flowering and harvest index most closely reflected the levels of yield advantage in the transgenics across generations while reduced biomass did not.

Oryza glumaepatula: A wild relative to improve drought tolerance in cultivated rice.

Developing drought-resistant rice (Oryza sativa, L.) is essential for improving field productivity, especially in rain-fed areas affected by climate change. Wild relatives of rice are potential sources for drought-resistant traits. Therefore, we compared root growth and drought response among 22 wild Oryza species, from which Oryza glumaepatula was selected as a promising source for further exploration. A geographically diverse panel of 69 O. glumaepatula accessions was then screened for drought stress-related traits, and 6 of these accessions showed lower shoot dry weight (SDW) reduction, greater percentage of deep roots, and lower stomatal density (STO) under drought than the drought tolerant O. sativa variety, Sahbhagi dhan. Based on whole-genome resequencing of all 69 O. glumaepatula accessions and variant calling to a high-quality O. glumaepatula reference genome, we detected multiple genomic loci colocating for SDW, root dry weight at 30 to 45 cm depth, and STO in consecutive drought trials. Geo-referencing indicated that the potential drought donors originated in flood-prone locations, corroborating previous hypotheses about the coexistence of flood and drought tolerance within individual Oryza genomes. These findings present potential donor accessions, traits, and genomic loci from an AA genome wild relative of rice that, together with the recently developed reference genome, may be useful for further introgression of drought tolerance into the O. sativa backgrounds.

Disentangling the Roles of Plant Water Status and Stem Carbohydrate Remobilization on Rice Harvest Index Under Drought.

BACKGROUND: Harvest index is an important component of grain yield and is typically reduced by reproductive stage drought stress in rice. Multiple drought response mechanisms can affect harvest index including plant water status and the degree of stem carbohydrate mobilization during grain filling. In this study, we aimed to dissect the contributions of plant water status and stem carbohydrate mobilization to harvest index. Pairs of genotypes selected for contrasting harvest index but similar biomass and days to flowering were characterized at ICAR-RCER, Patna, India and at IRRI, Philippines. RESULTS: Multiple traits were related with harvest index across experiments, including mobilization efficiency at both sites as indicated by groupings in principal component analysis, and plant water status as indicated by direct correlations. Biomass-related traits were positively correlated with harvest index at IRRI but biomass was negatively correlated with harvest index at ICER-RCER, Patna. We observed that some pairs of genotypes showed differences in harvest index across environments, whereas other showed differences in harvest index only under drought. Of all time points measured when all genotypes were considered together, the stem carbohydrate levels at maturity were most consistently (negatively) correlated with harvest index under drought, but not under well-watered conditions. However, in the pairs of genotypes grouped as those whose differences in harvest index were stable across environments, improved plant water status resulted in a greater ability to both accumulate and remobilize stored carbohydrate, i.e. starch. CONCLUSION: By distinguishing between genotypes whose harvest index was improved across conditions as opposed to specifically under drought, we can attribute the mechanisms behind the stable high-harvest index genotypes to be more related to stem carbohydrate remobilization than to plant water status. The stable high-harvest index lines in this study (Aus 257 and Wanni Dahanala) may confer mechanisms to improve harvest index that are independent of drought response and therefore may be useful for breeding improved rice varieties.

The influence of genetic architecture on responses to selection under drought in rice.

Accurately predicting responses to selection is a major goal in biology and important for successful crop breeding in changing environments. However, evolutionary responses to selection can be constrained by such factors as genetic and cross-environment correlations, linkage, and pleiotropy, and our understanding of the extent and impact of such constraints is still developing. Here, we conducted a field experiment to investigate potential constraints to selection for drought resistance in rice (Oryza sativa) using phenotypic selection analysis and quantitative genetics. We found that traits related to drought response were heritable, and some were under selection, including selection for earlier flowering, which could allow drought escape. However, patterns of selection generally were not opposite under wet and dry conditions, and we did not find individual or closely linked genes that influenced multiple traits, indicating a lack of evidence that antagonistic pleiotropy, linkage, or cross-environment correlations would constrain selection for drought resistance. In most cases, genetic correlations had little influence on responses to selection, with direct and indirect selection largely congruent. The exception to this was seed mass under drought, which was predicted to evolve in the opposite direction of direct selection due to correlations. Because of this indirect effect on selection on seed mass, selection for drought resistance was not accompanied by a decrease in seed mass, and yield increased with fecundity. Furthermore, breeding lines with high fitness and yield under drought also had high fitness and yield under wet conditions, indicating that there was no evidence for a yield penalty on drought resistance. We found multiple genes in which expression influenced both water use efficiency (WUE) and days to first flowering, supporting a genetic basis for the trade-off between drought escape and avoidance strategies. Together, these results can provide helpful guidance for understanding and managing evolutionary constraints and breeding stress-resistant crops.

Response of Southeast Asian rice root architecture and anatomy phenotypes to drought stress.

Drought stress in Southeast Asia greatly affects rice production, and the rice root system plays a substantial role in avoiding drought stress. In this study, we examined the phenotypic and genetic correlations among root anatomical, morphological, and agronomic phenotypes over multiple field seasons. A set of >200 rice accessions from Southeast Asia (a subset of the 3000 Rice Genomes Project) was characterized with the aim to identify root morphological and anatomical phenotypes related to productivity under drought stress. Drought stress resulted in slight increases in the basal metaxylem and stele diameter of nodal roots. Although few direct correlations between root phenotypes and grain yield were identified, biomass was consistently positively correlated with crown root number and negatively correlated with stele diameter. The accessions with highest grain yield were characterized by higher crown root numbers and median metaxylem diameter and smaller stele diameter. Genome-wide association study (GWAS) revealed 162 and 210 significant SNPs associated with root phenotypes in the two seasons which resulted in identification of 59 candidate genes related to root development. The gene OsRSL3 was found in a QTL region for median metaxylem diameter. Four SNPs in OsRSL3 were found that caused amino acid changes and significantly associated with the root phenotype. Based on the haplotype analysis for median metaxylem diameter, the rice accessions studied were classified into five allele combinations in order to identify the most favorable haplotypes. The candidate genes and favorable haplotypes provide information useful for the genetic improvement of root phenotypes under drought stress.

Design of an electrospun tubular construct combining a mechanical and biological approach to improve tendon repair.

Hand tendon injuries represent a major clinical problem and might dramatically diminish a patient's life quality. In this study, a targeted solution for flexor tendon repair was developed by combining a mechanical and biological approach. To this end, a novel acrylate-endcapped urethane-based polymer (AUP) was synthesized and its physico-chemical properties were characterized. Next, tubular repair constructs were developed using electrospinning of the AUP material with incorporated naproxen and hyaluronic acid (i.e. anti-inflammatory and anti-adhesion compounds, respectively), and with a tubular braid as mechanical reinforcement. Tensile testing of the repair constructs using ex vivo sheep tendons showed that the developed repair constructs fulfilled the required mechanical properties for tendon repair (i.e. minimal ultimate stress of 4 MPa), with an ultimate stress of 6.4 ± 0.6 MPa. Moreover, in vitro biological assays showed that the developed repair tubes and the incorporated bioactive components were non-cytotoxic. In addition, when equine tenocytes and mesenchymal stem cells were co-cultured with the repair tubes, an increased production of collagen and non-collagenous proteins was observed. In conclusion, this novel construct in which a mechanical approach (fulfilling the required mechanical properties) was combined with a biological approach (incorporation of bioactive compounds), shows potential as flexor tendon repair application. Graphical abstract.

Aus rice root architecture variation contributing to grain yield under drought suggests a key role of nodal root diameter class.

The aus rice variety group originated in stress-prone regions and is a promising source for the development of new stress-tolerant rice cultivars. In this study, an aus panel (~220 genotypes) was evaluated in field trials under well-watered and drought conditions and in the greenhouse (basket, herbicide and lysimeter studies) to investigate relationships between grain yield and root architecture, and to identify component root traits behind the composite trait of deep root growth. In the field trials, high and stable grain yield was positively related to high and stable deep root growth (r = 0.16), which may indicate response to within-season soil moisture fluctuations (i.e., plasticity). When dissecting component traits related to deep root growth (including angle, elongation and branching), the number of nodal roots classified as 'large-diameter' was positively related to deep root growth (r = 0.24), and showed the highest number of colocated genome-wide association study (GWAS) peaks with grain yield under drought. The role of large-diameter nodal roots in deep root growth may be related to their branching potential. Two candidate loci that colocated for yield and root traits were identified that showed distinct haplotype distributions between contrasting yield/stability groups and could be good candidates to contribute to rice improvement.

Rice breeding for yield under drought has selected for longer flag leaves and lower stomatal density.

Direct selection for yield under drought has resulted in the release of a number of drought-tolerant rice varieties across Asia. In this study, we characterized the physiological traits that have been affected by this strategy in breeding trials across sites in Bangladesh, India, and Nepal. Drought- breeding lines and drought-tolerant varieties showed consistently longer flag leaves and lower stomatal density than our drought-susceptible check variety, IR64. The influence of environmental parameters other than drought treatments on leaf traits was evidenced by close grouping of treatments within a site. Flag-leaf length and width appeared to be regulated by different environmental parameters. In separate trials in the Philippines, the same breeding lines studied in South Asia showed that canopy temperature under drought and harvest index across treatments were most correlated with grain yield. Both atmospheric and soil stress strengthened the relationships between leaf traits and yield. The stable expression of leaf traits among genotypes and the identification of the environmental conditions in which they contribute to yield, as well as the observation that some breeding lines showed longer time to flowering and higher canopy temperature than IR64, suggest that selection for additional physiological traits may result in further improvements of this breeding pool.

Early and systematic administration of fibrinogen concentrate in postpartum haemorrhage following vaginal delivery: the FIDEL randomised controlled trial.

OBJECTIVE: To assess the benefits and safety of early human fibrinogen concentrate in postpartum haemorrhage (PPH) management. DESIGN: Multicentre, double-blind, randomised placebo-controlled trial. SETTING: 30 French hospitals. POPULATION: Patients with persistent PPH after vaginal delivery requiring a switch from oxytocin to prostaglandins. METHODS: Within 30 minutes after introduction of prostaglandins, patients received either 3 g fibrinogen concentrate or placebo. MAIN OUTCOME MEASURES: Failure as composite primary efficacy endpoint: at least 4 g/dl of haemoglobin decrease and/or transfusion of at least two units of packed red blood cells within 48 hours following investigational medicinal product administration. Secondary endpoints: PPH evolution, need for haemostatic procedures and maternal morbidity-mortality within 6 ± 2 weeks after delivery. RESULTS: 437 patients were included: 224 received FC and 213 placebo. At inclusion, blood loss (877 ± 346 ml) and plasma fibrinogen (4.1 ± 0.9 g/l) were similar in both groups (mean ± SD). Failure rates were 40.0% and 42.4% in the fibrinogen and placebo groups, respectively (odds ratio [OR] = 0.99) after adjustment for centre and baseline plasma fibrinogen; (95% CI 0.66-1.47; P = 0.96). No significant differences in secondary efficacy outcomes were observed. The mean plasma FG was unchanged in the Fibrinogen group and decreased by 0.56 g/l in the placebo group. No thromboembolic or other relevant adverse effects were reported in the Fibrinogen group versus two in the placebo group. CONCLUSIONS: As previous placebo-controlled studies findings, early and systematic administration of 3 g fibrinogen concentrate did not reduce blood loss, transfusion needs or postpartum anaemia, but did prevent plasma fibrinogen decrease without any subsequent thromboembolic events. TWEETABLE ABSTRACT: Early systematic blind 3 g fibrinogen infusion in PPH did not reduce anaemia or transfusion rate, reduced hypofibrinogenaemia and was safe.

Is Treatment in Patients With Suspected Nonradiographic Axial Spondyloarthritis Effective? Six-Month Results of a Placebo-Controlled Trial.

OBJECTIVE: To investigate the efficacy of 16-week treatment with etanercept (ETN) in patients with suspected nonradiographic axial spondyloarthritis (SpA). METHODS: Tumor necrosis factor inhibitor-naive patients with inflammatory back pain with at least 2 SpA features and high disease activity (Bath Ankylosing Spondylitis Disease Activity Index score ≥4), without the requirement of a positive finding on magnetic resonance imaging (MRI) of the sacroiliac (SI) joint and/or elevated C-reactive protein (CRP) level, were randomized (1:1) to receive ETN (n = 40) or placebo (n = 40) for 16 weeks and subsequently were followed up for a further 8 weeks (to 24 weeks from baseline) without study medication. The primary end point was the Assessment of SpondyloArthritis international Society 20 (ASAS20) response at 16 weeks. Secondary end points included the Ankylosing Spondylitis Disease Activity Score (ASDAS) and changes in disease parameters, including the Bath Ankylosing Spondylitis Metrology Index (BASMI), CRP level, erythrocyte sedimentation rate (ESR), and Spondyloarthritis Research Consortium of Canada index scores (MRI of the SI joint), after 16 and 24 weeks. RESULTS: Patient characteristics at baseline were comparable between the ETN and placebo groups. At 16 weeks, there was no significant difference in the percentage of patients exhibiting ASAS20 response between the ETN group (6 patients [16.7%]) and the placebo group (4 patients [11.1%]) (relative risk 0.7 [95% confidence interval 0.2-2.2], P = 0.5). Only the ESR showed more improvement in the ETN group compared to the placebo group at 16 weeks (decreases of 2.2 mm/hour and 1.4 mm/hour, respectively), but the difference did not reach statistical significance. Between 16 and 24 weeks, without study medication, the BASMI, CRP level, and ESR had worsened to a greater extent in the ETN group compared to the placebo group, with the difference being significant for the CRP level. CONCLUSION: This study shows that in patients with suspected nonradiographic axial SpA with high disease activity but without the requirement of a positive finding on SI joint MRI and/or elevated CRP level, treatment with ETN is not effective.

Ratooning as a management strategy for lodged or drought-damaged rice crops.

Rice (Oryza sativa L.) plants have the ability to develop ratoon tillers if the terminal growing point is lost, such as when the panicle has been aborted, matured, or harvested. We examined postharvest and midseason ratooning as management strategies for damaged rice crops, both in irrigated and rainfed conditions. Genotypic variation was observed in terms of postharvest ratoon tillering, midseason ratoon crop growth after lodging, and midseason ratoon crop growth after drought stress. The genotypic variation in postharvest ratoon tillering was related to stem carbohydrate levels at the time of main crop harvest and was affected by soil moisture levels at the time of main crop harvest. Drought-tolerant varieties did not consistently show improved ratoon crop growth. After lodging, cutting stems at a height of 30 cm produced the highest numbers of ratoon tillers, and the contribution of the ratoon crop to the total harvestable grain yield was highest when the ratoon crop was initiated at earlier growth stages. The highest ratoon grain yields recovered from lodged crops ranged up to 3.58 t ha-1. Total grain yield after drought was improved by trimming the leaves and panicles only in certain conditions and did not appear to be correlated with stem carbohydrate levels. These results suggest that management strategies may be recommended to farmers that exploit the ratooning ability of rice for improved recovery after midseason crop damage.

Presence of active MRI lesions in patients suspected of non-radiographic axial spondyloarthritis with high disease activity and chance at conversion after a 6-month follow-up period.

OBJECTIVES: The primary aim is to evaluate signs of inflammation on MRI of sacroiliac joints (SIJ)/spine in inflammatory back pain (IBP) patients suspected of nr-axSpA with high disease activity. Secondary aims are to describe the onset of new inflammatory lesions at MRI after 6 months and to evaluate gender differences in the presence of inflammation. METHOD: Consecutively, patients with IBP with at least two spondyloarthritis features, high disease activity (BASDAI ≥ 4), and who were TNFi naïve, had a MRI of SIJ and spine. In the absence of active lesions, MRI was repeated after 6 months. MRI images were scored according to the Spondyloarthritis Research Consortium of Canada method. RESULTS: Sixty-nine patients were included (53% female), of whom 39% showed signs of inflammation at the first MRI: 30.9% of the SIJ, 19.1% of the spine and 2.4% at both sites, irrespective of the CRP levels. Males more often showed inflammatory signs at the MRI of the SIJ and spine compared with females (45.5% vs. 33.3%). Consistently, the median SPARCC score was higher in males: for SIJ 14.0 (IQR 2.3-25.0) and for spine 11.5 (IQR 8.5-25.6). Only one patient (4.7%) without baseline inflammatory signs showed active lesions of SIJ after 6 months. CONCLUSIONS: Almost 40% of the IBP patients suspected of nr-axSpA, with high disease activity, showed inflammatory lesions on MRI of SIJ and/or spine, which occurred more often in males compared with females. In the majority (95.3%), an MRI without inflammatory lesions remained negative after 6 months despite high disease activity.Key Points• Forty percent of inflammatory back pain patients with high disease activity showed inflammatory signs on MRI of the SIJ and/or spine.• Only 4% of baseline MRIs without inflammatory signs at baseline conversed to an MRI with inflammatory signs after 6 months.• Male inflammatory back pain patients with high disease activity showed more often inflammatory signs on MRI compared with females.

Caloric Restriction Alters Postprandial Responses of Essential Brain Metabolites in Young Adult Mice.

Caloric restriction (CR) has been shown to extend longevity and protect brain function in aging. However, the effects of CR in young adult mice remain largely unexplored. In addition to the fundamental, long-term changes, recent studies demonstrate that CR has a significant impact on transient, postprandial metabolic flexibility and turnover compared to control groups. The goal of this study was to identify the brain metabolic changes at a transient (2 h) and steady (6 h) postprandial state in young mice (5-6 months of age) fed with CR or ad libitum (AL; free eating). Using metabolomics profiling, we show that CR mice had significantly higher levels of neurotransmitters (e.g., glutamate, N-acetylglutamate), neuronal integrity markers (e.g., NAA and NAAG), essential fatty acids (e.g., DHA and DPA), and biochemicals associated carnitine metabolism (related to reduced oxidative stress and inflammation) in the cerebral cortex and hippocampus at 2-h. These biochemicals remained at high levels at the 6-h postprandial time-point. The AL mice did not show the similar increases in essential fatty acid and carnitine metabolism until the 6-h time-point, and failed to show increases in neurotransmitters and neuronal integrity markers at any time-point. On the other hand, metabolites related to glucose utilization-glycolysis and pentose phosphate pathway (PPP)-were low in the CR mice throughout the 6-h period and significantly increased at the 6-h time-point in the AL mice. Our findings suggest that CR induces distinct postprandial responses in metabolites that are essential to maintain brain functions. CR mice produced higher levels of essential brain metabolites in a shorter period after a meal and sustained the levels for an extended period, while maintaining a lower level of glucose utilization. These early brain metabolism changes in the CR mice might play a critical role for neuroprotection in aging. Understanding the interplay between dietary intervention and postprandial metabolic responses from an early age may have profound implications for impeding brain aging and reducing risk for neurodegenerative disorders.

Can point-of-care ultrasound predict spinal hypotension during caesarean section? A prospective observational study.

Spinal anaesthesia for elective caesarean section is associated with maternal hypotension, secondary to alteration of sympathetic tone and hypovolemia, in up to 70% of cases. Measurement of the subaortic variation in the velocity time integral (VTI) after passive leg raising allows prediction of fluid responsiveness. Our objective, in this prospective single-centre observational study, was to assess the ability of change in VTI after 45° passive leg raising to predict hypotension after spinal anaesthesia. Ultrasound measurements were performed just before elective caesarean section. Anaesthesia, intravenous coloading and prophylactic vasopressor treatment were standardised according to current guidelines. We studied 40 women. Hypotension occurred in 17 (45%) women. The area (95%CI) under the receiver operating characteristics (ROC) curve for the prediction of spinal hypotension was 0.8 (0.6-0.9; p = 0.0001). Seventeen women had a change in VTI with leg elevation ≤ 8%, which was predictive for not developing hypotension, and 11 had a change ≥ 21%, predictive for hypotension. The grey zone between 8% and 21%, with inconclusive values, included 12 women. We suggest that cardiac ultrasound provides characterisation of the risk of hypotension following spinal anaesthesia at elective caesarean section, and therefore may allow individualised strategies for prevention and management.

Impact of sleep deprivation on anaesthesia residents' non-technical skills: a pilot simulation-based prospective randomized trial.

BACKGROUND: Sleep deprivation is common in anaesthesia residents, but its impact on performance remains uncertain. Non-technical skills (team working, situation awareness, decision making, and task management) are key components of quality of care in anaesthesia, particularly in crisis situations occurring in the operating room. The impact of sleep deprivation on non-technical skills is unknown. We tested the hypothesis that in anaesthesia residents sleep deprivation is associated with impaired non-technical skills. METHODS: Twenty anaesthesia residents were randomly allocated to undergo a simulation session after a night shift [sleep-deprived (SLD) group, n =10] or after a night of rest [rested (R) group, n =10] from January to March 2015. The simulated scenario was a situation of crisis management in the operating room. The primary end point was a composite score of anaesthetists' non-technical skills (ANTS) assessed by two blinded evaluators. RESULTS: Non-technical skills were significantly impaired in the SLD group [ANTS score 12.2 (interquartile range 10.5-13)] compared with the R group [14.5 (14-15), P <0.02]. This difference was mainly accounted for by a difference in the team working item. On the day of simulation, the SLD group showed increased sleepiness and decreased confidence in anaesthesia skills. CONCLUSIONS: In this randomized pilot trial, sleep deprivation was associated with impaired non-technical skills of anaesthesia residents in a simulated anaesthesia intraoperative crisis scenario. TRIAL REGISTRATION: NCT02622217.

Probing Resilience: Daily Environmental Mastery, Self-Esteem, and Stress Appraisal.

OBJECTIVES: The current study explores one way the process of resilience arises by investigating the underlying process of stress appraisal. In particular, the analyses examine how resilience resources function each day to attenuate the extent to which life experiences are perceived as threatening, and how trait-like resilience resources shape the appraisal process. METHOD: Daily diary and questionnaire data from 96 participants of Successful Aging in Context: The Macroenvironment and Daily Lived Experience (SAIC; MAge = 67 years, SDAge = 4.9 years; range: 58-86 years) were analyzed using multilevel random coefficient modeling to investigate how individuals' daily perceptions of control and self-esteem impacted perceived stress on a given day. RESULTS: Results suggested that both self-esteem and environmental mastery help mitigate the experience of stress; furthermore, dispositional resilience and self-esteem stability predict differences between individuals in the extent to which self-esteem tempers the perception of stress each day. DISCUSSION: The results inform theoretical and empirical work on the nature of resilience, especially regarding how the process arises in ordinary life. From an application perspective, results imply that augmenting environmental mastery and self-esteem, both of which are malleable, can facilitate resilience by helping elders challenge their perceptions of stress each day.

MIC-1/GDF15 in Barrett's oesophagus and oesophageal adenocarcinoma.

BACKGROUND: Biomarkers are needed to improve current diagnosis and surveillance strategies for patients with Barrett's oesophagus (BO) and oesophageal adenocarcinoma (OAC). Macrophage inhibitory cytokine 1/growth differentiation factor 15 (MIC-1/GDF15) tissue and plasma levels have been shown to predict disease progression in other cancer types and was therefore evaluated in BO/OAC. METHODS: One hundred thirty-eight patients were studied: 45 normal oesophagus (NE), 37 BO, 16 BO with low-grade dysplasia (LGD) and 40 OAC. RESULTS: Median tissue expression of MIC-1/GDF15 mRNA was ⩾25-fold higher in BO and LGD compared to NE (P<0.001); two-fold higher in OAC vs BO (P=0.039); and 47-fold higher in OAC vs NE (P<0.001). Relative MIC-1/GDF15 tissue expression >720 discriminated between the presence of either OAC or LGD vs NE with 94% sensitivity and 71% specificity (ROC AUC 0.86, 95% CI 0.73-0.96; P<0.001). Macrophage inhibitory cytokine 1/growth differentiation factor 15 plasma values were also elevated in patients with OAC vs NE (P<0.001) or BO (P=0.015).High MIC-1/GDF15 plasma levels (⩾1140 pg ml(-1)) were an independent predictor of poor survival for patients with OAC (HR 3.87, 95% CI 1.01-14.75; P=0.047). CONCLUSIONS: Plasma and tissue levels of MIC-1/GDF15 are significantly elevated in patients with BO, LGD and OAC. Plasma MIC-1/GDF15 may have value in diagnosis and monitoring of Barrett's disease.

Recombinant human FVIIa for reducing the need for invasive second-line therapies in severe refractory postpartum hemorrhage: a multicenter, randomized, open controlled trial.

BACKGROUND: Case reports on recombinant human factor VIIa (rhuFVIIa) use in women with severe postpartum hemorrhage (PPH) showed encouraging results, but no randomized controlled trial (RCT) is available. PATIENTS AND METHODS: Eighty-four women with severe PPH unresponsive to uterotonics were randomized to receive one early single rhuFVIIa infusion (n = 42) or standard care (no rhuFVIIa; n = 42). The primary efficacy outcome measure was the reduction of the need for specific second-line therapies, such as interventional hemostatic procedures, for blood loss and transfusions. The primary safety outcome measure was the number of deaths and thrombotic events during the 5 days following rhuFVIIa infusion. RESULTS: rhuFVIIa was associated with a reduction in the number of patients who needed second-line therapies compared with controls (standard care). Specifically, 39/42 (93%) patients in the standard care arm received second-line therapies and 22/42 (52%) patients in the rhuFVIIa arm (absolute difference, 41%; range, 18-63%; relative risk RR, 0.56 [0.42-0.76]). The delivery mode (vaginal or Cesarean section) did not affect the primary outcome. No death occurred. Two venous thrombotic events were recorded in the rhuFVIIa arm: one ovarian vein thrombosis and one deep vein thrombosis with a non-severe pulmonary embolism. CONCLUSION: This open RCT in women with severe PPH refractory to uterotonics shows that rhuFVIIa reduces the need for specific second-line therapies in about one in three patients, with the occurrence of non-fatal venous thrombotic events in one in 20 patients.