Pregnancy outcome predictors in antiphospholipid syndrome: A systematic review and meta-analysis.

OBJECTIVE: To identify and assess the magnitude of effect of pregnancy outcome predictors in women with antiphospholipid syndrome (APS) by means of systematic review and meta-analysis. METHODS: PubMed and Embase were searched (13th June 2020) for studies reporting on pre-pregnancy risk factors of pregnancy outcomes in APS patients. Literature screening and data extraction were conducted by two reviewers independently, in a blinded standardized manner. Pooled univariate odds ratios (OR) were computed using a random effects model. Heterogeneity was assessed by I2%. RESULTS: The search yielded 3013 unique results; 27 records were included in this meta-analysis. Previous thrombosis was associated with a decreased live birth risk (OR 0.60, p < 0.01, I2 = 40%), increased neonatal mortality (OR 15.19, p < 0.01, I2 = 0%), an increased risk of antenatal or postpartum thrombosis (OR 6.26, p < 0.01, I2 = 0%) and an increased risk of delivering a small for gestational age neonate (SGA) (OR 2.60, p = 0.01, I2 = 0%). Patients with an APS laboratory category I (double or triple positivity) profile had a decreased live birth risk (OR 0.66, p < 0.01, I2 = 0%), an increased risk of SGA (OR 1.86, p = 0.01, I2 = 43%) and preterm birth (OR 1.35, p < 0.01, I2 = 49%). Triple positivity was associated with a decreased live birth risk (OR 0.33, p < 0.01, I2 = 68%), an increased risk of preeclampsia (OR 2.43, p = 0.02, I2 = 35%) and SGA (OR 2.47, p = 0.04, I2 = 61%). Patients with lupus anticoagulant positivity had an increased risk of preeclampsia (OR 2.10, p = 0.02, I2 = 48%), SGA (OR 1.78, p < 0.01, I2 = 0%) and preterm birth (OR 3.56, p = 0.01, I2 = 48%). Risk of bias assessment suggested considerable bias on study participation and statistical methods. CONCLUSIONS: The results of this meta-analysis identified previous thrombosis, laboratory category I, triple positivity and lupus anticoagulant positivity as the most important predictors of adverse pregnancy outcomes. This up-to-date knowledge, can be used in preconception counseling and tailoring of obstetric care.

Maternal high-fat diet consumption impairs exercise performance in offspring.

The aim of the present study was to scrutinise the influence of maternal high-fat diet (mHFD) consumption during gestation and lactation on exercise performance and energy metabolism in male mouse offspring. Female C3H/HeJ mice were fed either a semi-synthetic high-fat diet (HFD; 40 % energy from fat) or a low-fat diet (LFD; 10 % energy from fat) throughout gestation and lactation. After weaning, male offspring of both groups received the LFD. At the age of 7·5 weeks half of the maternal LFD (n 20) and the mHFD (n 21) groups were given access to a running wheel for 28 d as a voluntary exercise training opportunity. We show that mHFD consumption led to a significantly reduced exercise performance (P < 0·05) and training efficiency (P < 0·05) in male offspring. There were no effects of maternal diet on offspring body weight. Lipid and glucose metabolism was disturbed in mHFD offspring, with altered regulation of cluster of differentiation 36 (CD36) (P < 0·001), fatty acid synthase (P < 0·05) and GLUT1 (P < 0·05) gene expression in skeletal muscle. In conclusion, maternal consumption of a HFD is linked to decreased exercise performance and training efficiency in the offspring. We speculate that this may be due to insufficient muscle energy supply during prolonged exercise training. Further, this compromised exercise performance might increase the risk of obesity development in adult life.

Differences in locomotor performance between individuals: importance of parvalbumin, calcium handling and metabolism.

Locomotor performance is linked to fitness and health of animals and is expected to be under strong selection. However, interindividual variation in locomotor performance is pronounced in many species. It was our aim to investigate the relative importance of energy metabolism and calcium handling in determining sprint and sustained locomotion in the zebrafish (Danio rerio). Sprint and sustained performance (U(crit)) varied independently from each other. Using in vivo electroporation, we found that increased parvalbumin protein concentration improved both sprint and sustained locomotion. This is the first demonstration that parvalbumin plays a role in determining whole-animal performance. High sprint performance fish had greater mRNA concentrations of the metabolic regulators PPARδ and PGC1ß compared with fish with poor sprint performance. High sustained performance fish, in contrast, had greater concentrations of PGC-1α and PGC-1ß. The increased expression of these metabolic regulators indicates an enhancement of the metabolic machinery in high performance animals. Sprint performance is also enhanced by creatine kinase activity, which may be associated with increased PPARδ mRNA concentration. Ryanodine receptor (RyR) and sarcoplasmic reticulum Ca(2+)-ATPase 1 (SERCA1) mRNA concentrations were significantly increased in high sustained performance fish, while parvalbumin 2, dihydropyridine (DHPR) receptor and SERCA2 mRNA levels were increased in fish with high sprint velocities. Sustained performance was more sensitive to experimentally induced decreases in RyR and DHPR activity than sprint performance. We provide mechanistic explanations of why locomotor performance differs between individuals, which is important for understanding ecological and sporting success, disease and the evolutionary processes underlying selection.

Variation in expression of calcium-handling proteins is associated with inter-individual differences in mechanical performance of rat (Rattus norvegicus) skeletal muscle.

An important constraint on locomotor performance is the trade-off between sprint and endurance performance. One intuitive explanation for this trade-off is that an individual muscle cannot excel at generating both maximal force/power and high fatigue resistance. The underlying reasons for this muscle trade-off are poorly defined. The aim of this study was to test the hypothesis that inter-individual variation in muscle mechanics is associated with inter-individual differences in metabolic capacities and expression of calcium-handling proteins. Lateral gastrocnemius muscles were isolated from 20 rats (Rattus norvegicus) and analysed to determine metabolic capacity, sarco/endoplasmic reticulum calcium ATPase (SERCA)1 protein concentration, total SERCA activity, and mRNA concentrations of SERCA1, SERCA2, troponin I and ryanodine receptors. Isometric studies of lateral gastrocnemius muscles at 30°C showed that muscles with higher sprint performance had lower fatigue resistance. More rapid muscle contraction was correlated with higher lactate dehydrogenase activity and increased expression of ryanodine receptor 1. More rapid muscle relaxation was correlated with increased expression of troponin I type 2 (fast) isoform and decreased expression of SERCA2 (slow) isoform. Treating muscles with dantrolene confirmed that ryanodine receptor activity is important in determining tetanus force and muscle contraction rates, but has no effect on fatigue resistance. Thapsigargin treatment revealed that SERCA activity determines fatigue resistance but does not affect maximal muscle force or contraction rates. We conclude that the opposing roles of SERCA activity and expression of ryanodine receptors in determining fatigue resistance and force production, respectively, at least partly explain differences in sprint and endurance performance in isolated rat gastrocnemius muscle.

AMP-activated protein kinase controls metabolism and heat production during embryonic development in birds.

During embryonic and early juvenile development, endotherms must balance energy allocation between growth and heat production. Failure to either match the ATP demand of growing tissue or produce heat at the correct developmental stage will lead to damage of the organism. We tested the hypothesis that AMP-activated protein kinase (AMPK) is involved in the regulation of energy metabolism and heat production during development in the chicken (Gallus gallus). We show that mRNA concentrations of regulatory and catalytic AMPK subunits, AMPK total protein, and AMPK phosphorylation increase during development [3 days (-3 days) and one day (-1 day) before hatching, and +1 day and +8 days after hatching] in liver, and to a lesser extent in skeletal muscle. Chronic stimulation with 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) significantly increases AMPK phosphorylation in skeletal muscle and in liver. This increase was paralleled by significant increases in heat production, glucose utilization, and liver and skeletal muscle mitochondrial capacity (citrate synthase activity). The effects of AMPK are likely to be mediated by inhibition of acetyl CoA carboxylase (ACC) after hatching, when ACC protein concentration increases significantly, and by a significant AMPK-induced increase in PGC-1alpha mRNA concentration (at +1 day), but not in NRF-1 mRNA concentration. AMPK phosphorylation is under the control of thyroid hormone, and AMPK phosphorylation decreases significantly following the induction of hypothyroidism. We propose AMPK as a principal regulatory mechanism during the transition from ectothermy to endothermy in birds, and show that AMPK function in birds is similar to that observed in mammals.

Endothermy in birds: underlying molecular mechanisms.

Endothermy is significant in vertebrate evolution because it changes the relations between animals and their environment. How endothermy has evolved in archosaurs (birds, crocodiles and dinosaurs) is controversial especially because birds do not possess brown adipose tissue, the specialized endothermic tissue of mammals. Internal heat production is facilitated by increased oxidative metabolic capacity, accompanied by the uncoupling of aerobic metabolism from energy (ATP) production. Here we show that the transition from an ectothermic to an endothermic metabolic state in developing chicken embryos occurs by the interaction between increased basal ATP demand (Na(+)/K(+)-ATPase activity and gene expression), increased oxidative capacity and increased uncoupling of mitochondria; this process is controlled by thyroid hormone via its effect on PGC1alpha and adenine nucleotide translocase (ANT) gene expression. Mitochondria become more uncoupled during development, but unlike in mammals, avian uncoupling protein (avUCP) does not uncouple electron transport from oxidative phosphorylation and therefore plays no role in heat production. Instead, ANT is the principal uncoupling protein in birds. The relationship between oxidative capacity and uncoupling indicates that there is a continuum of phenotypes that fall between the extremes of selection for increased heat production and increased aerobic activity, whereas increased cellular ATP demand is a prerequisite for increased oxidative capacity.

Why 'knowledge transfer' is misconceived for applied social research.

'Knowledge transfer' has become established as shorthand for a wide variety of activities linking the production of academic knowledge to the potential use of such knowledge in non-academic environments. While welcoming the attention now being paid to non-academic applications of social research, we contend that terms such as knowledge transfer (and its subordinate sibling, knowledge translation) misrepresent the tasks that they seek to support. By articulating the complex and contested nature of applied social research, and then highlighting the social and contextual complexities of its use, we can see that other terms may serve us better. Following from this analysis, we suggest that 'knowledge interaction' might more appropriately describe the messy engagement of multiple players with diverse sources of knowledge, and that 'knowledge intermediation' might begin to articulate some of the managed processes by which knowledge interaction can be promoted. While it might be hard to shift the terminology of knowledge transfer in the short term, awareness of its shortcomings can enhance understanding about how social research can have wider impacts.

Tracing and identifying the impact of evidence-use of a modified pipeline model.

AIM: This paper opens up a discussion about effective ways of tracing and identifying impact of evidence implementation in the field of nursing, through the use of Nutley et al.'s concept of an impact continuum, and Glasziou's Pipeline Model. APPROACH: Work to date on improving and evaluating the use of evidence in health care settings has tended to focus on evidence implementation as an endpoint or entity, often seen and measured in terms of change in practice. However, the direct application of evidence to practice is not straightforward. Glasziou's Pipeline Model of the different stages through which evidence flows, in the process of implementation, is critically reviewed in relation to five key issues: the type of evidence entering the pipeline; the linearity of the model; leakages and blockages in the pipeline; levels of impact; and impact measurement. The Pipeline Model is then combined with Nutley et al.'s continuum of impacts in order to present a Modified Pipeline Model. DISCUSSION AND CONCLUSIONS: The Modified Pipeline Model enables evidence implementation to be viewed as a process rather than an entity in itself, which in turn enables longitudinal assessment of barriers and facilitators to evidence "flow." By flow we mean the way in which evidence is transferred from reporting or publication stages to patient outcomes. It also allows identification of the multiple impacts that can occur through the process of evidence implementation, which may be impact on the way the nurse thinks about practice to the healing rate of a leg ulcer. Finally, the Modified Model raises the issue of impacts beyond the pipeline, that is, those outcomes for patients that result from adherence to evidence-based care. This Modified Pipeline Model thus has the potential to support individuals and organizations in enhanced implementation planning, evaluation and management.

Molecular mechanisms underlying the development of endothermy in birds (Gallus gallus): a new role of PGC-1 alpha?

In endotherms, plasticity of internal heat production in response to environmental variability is an important component of thermoregulation. During embryogenesis endotherms cannot regulate their body temperature metabolically and are therefore similar to ectotherms. The transition from ectothermy to endothermy occurs by the development of metabolic capacity during embryogenesis. Here we test the hypothesis that the development of metabolism during embryogenesis in birds is under transcriptional control and that metabolic capacity is upregulated in colder environments. The peroxisome proliferator-activated receptor-gamma (PPAR gamma) coactivator-1 alpha (PGC-1 alpha) is the major metabolic regulator in mammals. PGC-1 alpha and its target PPAR gamma were significantly elevated during development in pectoral muscle and liver of chickens (Gallus gallus) compared with adults. However, the timing of upregulation of PGC-1 alpha and PPAR gamma was not in synchrony. In cool incubation temperatures (35 degrees C) both PGC-1 alpha and PPAR gamma gene expression was increased in liver but not in skeletal muscle, compared with a 38 degrees C incubation treatment. Cytochrome c oxidase and citrate synthase enzyme activities and ATP synthase gene expression increased during embryonic development in liver and muscle, and there was a significant effect of incubation temperature on these parameters. Our findings suggest that PGC-1 alpha might be important for establishing endothermic metabolic capacity during embryogenesis in birds.

Evidence for Nr4a1 as a cold-induced effector of brown fat thermogenesis.

Acute cold exposure leads to norepinephrine release in brown adipose tissue (BAT) and activates uncoupling protein (UCP)1-mediated nonshivering thermogenesis. Chronic sympathetic stimulation is known to initiate mitochondrial biogenesis, UCP1 expression, hyperplasia of BAT, and recruitment of brown adipocytes in white adipose tissue (WAT) depots. Despite distinct functions of BAT and WAT in energy balance, only a few genes are exclusively expressed in either tissue. We identified NUR77 (Nr4a1), an orphan receptor, to be induced transiently in brown adipocytes in response to beta-adrenergic stimulation and in BAT of cold-exposed mice. Subsequent reporter gene assays demonstrated an inhibitory action of NUR77 on basal and peroxisome proliferator-activated receptor (PPAR)gamma/retinoid X receptor (RXR)alpha-mediated transactivation of the Ucp1 enhancer in heterologous cotransfection experiments. Despite this function of NUR77 in the control of Ucp1 gene expression, nonshivering thermogenesis was not affected in Nur77 knockout mice. However, we observed a superinduction of Nor1 in BAT of cold-exposed knockout mice. We conclude that NUR77 is a cold-induced negative regulator of Ucp1, but phenotypic consequences in knockout mice are compensated by functional redundancy of Nor1.

Increasing research impact through partnerships: evidence from outside health care.

There is growing interest in using closer partnerships between researchers and research users to increase the appropriate application of research evidence in policy and practice. While this supplement reports and assesses a number of these initiatives in health care, this article reviews the evidence in support of partnerships from elsewhere. Drawing on a substantial cross-sector review of research impact initiatives, we extract lessons for health care from partnership evaluations in social care, education and criminal justice services. A reasonable and robust evidence base supports the use of partnerships as one means of increasing research uptake. Although requiring substantial investments of time, resources and commitment, and suffering from a number of possible pitfalls, we conclude that such partnerships offer great potential for increasing research use.