Stress affects the prediction of others' behavior.

Predicting behavior of other people is vital for successful social interactions. We tested whether a stress-induced cortisol increase affects healthy young men's prediction of another individual's behavior. Forty-two participants were randomly assigned to a stress or to a control condition. Afterwards, they participated in a modified false-belief task that not only tests false-belief understanding but also the tendency to predict another person's future behavior based on his former behavior. Subjective ratings and salivary cortisol concentrations revealed a successful stress induction. Stress did not affect participants' attribution of false beliefs but it increased the probability to predict that a protagonist would act according to his former behavior. Recognizing that stress fosters the interpretation of others' behavior following their former behavior and not their current goals extends previous research showing that stress fosters our own habitual behavior.

The influence of group membership on false-belief attribution in preschool children.

The ability to infer beliefs and thoughts in interaction partners is essential in social life. However, reasoning about other people's beliefs might depend on their characteristics or our relationship with them. Recent studies indicated that children's false-belief attribution was influenced by a protagonist's age and competence. In the current experiments, we investigated whether group membership influences the way children reason about another person's beliefs. We hypothesized that 4-year-olds would be less likely to attribute false beliefs to an ingroup member than to an outgroup member. Group membership was manipulated by accent (Experiments 1-3) and gender (Experiment 4). The results indicated that group membership did not consistently influence children's false-belief attribution. Future research should clarify whether the influence of group membership on false-belief attribution either is absent or depends on other cues that we did not systematically manipulate in our study.

Infections in baricitinib clinical trials for patients with active rheumatoid arthritis.

OBJECTIVES: To evaluate the incidence of infection in patients with active rheumatoid arthritis (RA) treated with baricitinib, an oral selective Janus kinase (JAK)1 and JAK2 inhibitor. METHODS: Infections are summarised from an integrated database (8 phase 3/2/1b clinical trials and 1 long-term extension (LTE)) with data to 1 April 2017. The 'all-bari-RA' analysis set included patients who received any baricitinib dose. Placebo comparison was based on six studies with 4 mg and placebo to week 24, including four trials with 2 mg (placebo-controlled set). Dose-response assessment was based on four studies with 2 mg and 4 mg, including LTE data (2-4 mg extended set). RESULTS: There were 3492 patients who received baricitinib for 7860 patient-years (PY) of exposure (median 2.6 years, maximum 6.1 years). Treatment-emergent infections were higher for baricitinib versus placebo (exposure-adjusted incidence rate (IR)/100 PY: placebo 75.9, 2 mg 84.0 (p not significant), 4 mg 88.4 (p≤0.001)). The IR of serious infection was similar for baricitinib versus placebo and stable over time (all-bari-RA IR 3.0/100 PY). There were 11 cases of tuberculosis (all-bari-RA IR 0.1/100 PY); all occurred with 4 mg in endemic regions. Herpes zoster (HZ) IR/100 PY was higher for baricitinib versus placebo (placebo 1.0, 2 mg 3.1 (p not significant), 4 mg 4.3 (p≤0.01)); rates remained elevated and stable over time (all-bari-RA 3.3). Opportunistic infections, including multidermatomal HZ, were infrequent in the baricitinib programme (all-bari-RA IR 0.5/100 PY). CONCLUSIONS: Increased rates of treatment-emergent infections including HZ were observed in patients with RA treated with baricitinib, consistent with baricitinib's immunomodulatory mode of action.

Cardiovascular Safety During Treatment With Baricitinib in Rheumatoid Arthritis.

OBJECTIVE: To assess the frequency of cardiovascular and venous thromboembolic events in clinical studies of baricitinib, an oral, selective JAK1 and JAK2 inhibitor approved in more than 50 countries for the treatment of moderately-to-severely active rheumatoid arthritis (RA). METHODS: Data were pooled from 9 RA studies. Placebo comparison up to 24 weeks included data from 6 studies. Randomized dose comparison between baricitinib doses of 2 mg and 4 mg used data from 4 studies and from the associated long-term extension study. The data analysis set designated "All-bari-RA" included all baricitinib exposures at any dose. RESULTS: Overall, 3,492 RA patients received baricitinib (7,860 patient-years of exposure). No imbalance compared to the placebo group was seen in the incidence of major adverse cardiovascular events (MACE) (incidence rates [IRs] of 0.5 per 100 patient-years for placebo and 0.8 per 100 patient-years for 4 mg baricitinib), arterial thrombotic events (ATE) (IRs of 0.5 per 100 patient-years for placebo and 0.5 per 100 patient-years for 4 mg baricitinib), or congestive heart failure (CHF) broad term (IRs of 4.3 per 100 patient-years for placebo and 2.4 per 100 patient-years for 4 mg baricitinib). Deep vein thrombosis (DVT)/pulmonary embolism (PE) were reported in 0 of 1,070 patients treated with placebo and 6 of 997 patients treated with 4 mg baricitinib during the placebo-controlled period; these events were serious in 2 of 6 patients, while all 6 had risk factors and 1 patient developed DVT/PE after discontinuation of the study drug. In the 2 mg-4 mg-extended data analysis set, IRs of DVT/PE were comparable between the doses across event types (IRs of 0.5 per 100 patient-years in those receiving 2 mg baricitinib and 0.6 per 100 patient-years in those receiving 4 mg baricitinib). In the All-bari-RA data analysis set, the rates were stable over time, with an IR of DVT/PE of 0.5 per 100 patient-years. CONCLUSION: In RA clinical trials, no association was found between baricitinib treatment and the incidence of MACE, ATE, or CHF. With regard to incidence of DVT/PE, 6 events occurred in patients treated with 4 mg baricitinib, but no cases of DVT/PE were reported in the placebo group. During longer-term evaluation, the incidence of DVT/PE was similar between the baricitinib dose groups, with consistent IR values over time, and this was similar to the rates previously reported in patients with RA.

Delayed theory of mind development in children born preterm: A longitudinal study.

BACKGROUND: Children born preterm are at high risk of developmental delay in various cognitive domains. Moreover, problems in social interaction are more frequently reported in preterm children than in their full-term peers. These difficulties can be observed at two years of age and seem to persist until school age. Although closely linked to social acceptance, remarkably little research has focused on social-cognitive skills such as Theory of Mind in preterm children. AIM: The aim of the current study was to assess Theory-of-Mind development in preterm (n = 34) and full-term (n = 38) children over the course of two years. METHODS: A Theory-of-Mind scale was administered at the children's age of 3, 4, and 5 years, and we additionally assessed and controlled for general cognitive development. RESULTS: At the age of 3, mean Theory-of-Mind scores were 1.23 (SD = 0.65) for preterm and 1.58 (SD = 0.76) for full-term children. By the age of 5, preterm children's performance (M = 3.50, SD = 1.16) was similar to that of full-term children (M = 3.52, SD = 0.98), revealing a significant interaction effect between birth status and time of measurement, F(1, 44.424) = 4.76, p = .035. CONCLUSION: The interaction effect indicates that preterm children show a delay rather than a general deficit in Theory-of-Mind development. Mechanisms underlying this course of development are still unknown. To examine why problems in social interaction persist despite improving Theory-of-Mind abilities, future research should extend the focus to implicit mental reasoning in preterm children.

Effects of baricitinib on radiographic progression of structural joint damage at 1 year in patients with rheumatoid arthritis and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs.

BACKGROUND: Baricitinib was efficacious in a 24-week phase III study in patients with rheumatoid arthritis (RA) and an inadequate response to conventional synthetic disease-modifying anti rheumatic drugs (DMARDs) (csDMARDs) (RA-BUILD). OBJECTIVES: To evaluate radiographic progression of structural joint damage in RA-BUILD patients over 48 weeks of baricitinib treatment in the long-term extension study, RA-BEYOND. METHODS: In RA-BUILD, patients were randomised to placebo, baricitinib 2 mg or 4 mg once daily, with rescue possible from week 16. Patients completing RA-BUILD and entering RA-BEYOND continued to receive the baricitinib dose received at the end of RA-BUILD. Patients receiving placebo were switched to baricitinib 4 mg in RA-BEYOND. Joint damage was measured using the van der Heijde modified total Sharp score. To account for missing scores and scores obtained after rescue, switch or discontinuation of study drug, data were analysed using (1) linear extrapolation (LE) and (2) observed/last observation carried forward (LOCF). The observed/LOCF method used all available observed data, including after rescue or switch, with patients analysed according to original treatment assignment. RESULTS: Using LE, radiographic progression at 24 and 48 weeks was statistically significantly lower for both baricitinib 2 or 4 mg compared with placebo. Only baricitinib 4 mg demonstrated statistically significant inhibition of progressive radiographic joint damage compared with patients initially randomised to placebo using observed/LOCF at week 48. CONCLUSIONS: Once daily oral baricitinib inhibited radiographic progression of structural joint damage in patients with an inadequate response or intolerance to csDMARDs over 48 weeks. The most robust benefit was seen for the 4 mg dose.

Lipid profile and effect of statin treatment in pooled phase II and phase III baricitinib studies.

OBJECTIVES: Lipid profiles are altered by active disease in patients with rheumatoid arthritis (RA) and may be further modified by treatment with Janus kinase inhibitors and other disease-modifying antirheumatic drugs. METHODS: Lipid data were analysed from phase II and III studies of 4 mg (n=997) and 2 mg (n=479) oral baricitinib administered once daily in patients with moderate-to-severe active RA. Lipoprotein particle size and number and GlycA were evaluated with nuclear magnetic resonance in one phase III study. The effect of statin therapy on lipid levels was evaluated in patients on statins at baseline and in patients who initiated statins during the study. RESULTS: Treatment with baricitinib was associated with increased levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides, but no significant change in LDL-C:HDL-C ratio. Lipid levels plateaued after 12 weeks of treatment. Baricitinib treatment increased large LDL and decreased small, dense LDL particle numbers and GlycA. Lipid changes from baseline were not significantly different between baseline statin users and non-users. In patients who initiated statin therapy during the study, LDL-C, triglycerides (baricitinib 4 mg only) and apolipoprotein B decreased to pre-baricitinib levels; HDL-C and apolipoprotein A-I levels remained elevated. CONCLUSIONS: Baricitinib was associated with increased LDL-C, HDL-C and triglyceride levels, but did not alter the LDL-C:HDL-C ratio. Evaluation of cardiovascular event rates during long-term treatment is warranted to further characterise these findings and their possible clinical implications. TRIAL REGISTRATION NUMBER: NCT00902486, NCT01469013, NCT01185353, NCT01721044, NCT01721057, NCT01711359, NCT01710358, NCT01885078.

Intrastriatally injected botulinum neurotoxin-A differently effects cholinergic and dopaminergic fibers in C57BL/6 mice.

Unilateral intrastriatal BoNT-A injection abolished apomorphine-induced rotational behavior in a rat model of hemiparkinsonism (hemi-PD) up to 6months. It was hypothesized that the beneficial effect of botulinum neurotoxin-A (BoNT-A) grounded on the reduction of the Parkinson's diseases (PD) associated striatal hypercholinism. Intrastriatal injection of BoNT-A was not cytotoxic in rat brain, but neuronal fiber swellings in the BoNT-A infiltrated striata appeared and named BoNT-A-induced varicosities (BiVs). In the rat BiVs were immunoreactive (ir) either for choline acetyltransferase (ChAT) or tyrosine hydroxylase (TH). In the present study the structural effect of unilateral intrastriatal BoNT-A injection in the naïve mouse brain was analyzed to extend possible therapeutic BoNT-A applications to genetical Parkinsonian strains. We investigated the effect of a single dose of 25pg BoNT-A injected into the right caudate-putamen (CPu) for up to 9months, and of increasing doses up to 200pg on striatal volume, number of ChAT-ir interneurons, and numeric density and volume of the ChAT-ir BiVs in comparison to the uninjected hemisphere. Intrastriatal BoNT-A injection did not alter the number of ChAT-ir interneurons irrespective of survival time and dosage tested. However, the numeric density of the ChAT-ir BiVs at a dose of 25pg increased from 1 to 3months after BoNT-A, followed by a time dependent decrease. In parallel, with increasing BoNT-A survival time, the mean BiV volume increased as the number of small BiVs decreased. Interestingly, in contrast to rats we did not find TH-ir BiVs in BoNT-A injected mouse striatum.

Social Cognition in Children Born Preterm: A Perspective on Future Research Directions.

Preterm birth is a major risk factor for children's development. It affects children's cognitive and intellectual development and is related to impairments in IQ, executive functions, and well-being, with these problems persisting into adulthood. While preterm children's intellectual and cognitive development has been studied in detail, their social development and social-cognitive competencies have received less attention. Namely, preterm children show problems in interactions with others. These interaction problems are present in relationships with parents, teachers, and peers. Parents' behavior has been identified as a possible mediator of children's social behavior. Maternal sensitivity and responsiveness as well as absence of mental disorders foster children's social development. In this article, we will report on the social side of impairments that preterm children face. The review of the literature revealed that preterm infants' joint attention abilities are impaired: They are less likely to initiate joint attention with others and to respond to others' efforts to engage in joint attention. These deficits in joint attention might contribute to later impairments in social cognition, which in turn might affect social interaction skills. Based on these three domains (i.e., problems in social interaction, parental behavior, and impairments in joint attention), we suggest that preterm children's social cognitive abilities should be investigated more intensively.

Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study.

BACKGROUND: Baricitinib is an oral, reversible, selective Janus kinase 1 and 2 inhibitor. METHODS: In this phase III, double-blind 24-week study, 684 biologic disease-modifying antirheumatic drug (DMARD)-naïve patients with rheumatoid arthritis and inadequate response or intolerance to ≥1 conventional synthetic DMARDs were randomly assigned 1:1:1 to placebo or baricitinib (2 or 4 mg) once daily, stratified by region and the presence of joint erosions. Endpoint measures included American College of Rheumatology 20% response (ACR20, primary endpoint), Disease Activity Score (DAS28) and Simplified Disease Activity Index (SDAI) score ≤3.3. RESULTS: More patients achieved ACR20 response at week 12 with baricitinib 4 mg than with placebo (62% vs 39%, p≤0.001). Compared with placebo, statistically significant improvements in DAS28, SDAI remission, Health Assessment Questionnaire-Disability Index, morning joint stiffness, worst joint pain and worst tiredness were observed. In a supportive analysis, radiographic progression of structural joint damage at week 24 was reduced with baricitinib versus placebo. Rates of adverse events during the treatment period and serious adverse events (SAEs), including serious infections, were similar among groups (SAEs: 5% for baricitinib 4 mg and placebo). One patient had an adverse event of tuberculosis (baricitinib 4 mg); one patient had an adverse event of non-melanoma skin cancer (baricitinib 4 mg). Two deaths and three major adverse cardiovascular events occurred (placebo). Baricitinib was associated with a decrease in neutrophils and increases in low-density and high-density lipoprotein. CONCLUSIONS: In patients with rheumatoid arthritis and an inadequate response or intolerance to conventional synthetic DMARDs, baricitinib was associated with clinical improvement and inhibition of progression of radiographic joint damage. TRIAL REGISTRATION NUMBER: NCT01721057; Results.

Epigenetic effects of the continuous exposure to peroxisome proliferator WY-14,643 in mouse liver are dependent upon peroxisome proliferator activated receptor alpha.

Peroxisome proliferators are potent rodent liver carcinogens that act via a non-genotoxic mechanism. The mode of action of these agents in rodent liver includes increased cell proliferation, decreased apoptosis, secondary oxidative stress and other events; however, it is not well understood how peroxisome proliferators are triggering the plethora of the molecular signals leading to cancer. Epigenetic changes have been implicated in the mechanism of liver carcinogenesis by a number of environmental agents. Short-term treatment with peroxisome proliferators and other non-genotoxic carcinogens leads to global and locus-specific DNA hypomethylation in mouse liver, events that were suggested to correlate with a burst of cell proliferation. In the current study, we investigated the effects of long-term exposure to a model peroxisome proliferator WY-14,643 on DNA and histone methylation. Male SV129mice were fed a control or WY-14,643-containing (1000ppm) diet for one week, five weeks or five months. Treatment with WY-14,643 led to progressive global hypomethylation of liver DNA as determined by an HpaII-based cytosine extension assay with the maximum effect reaching over 200% at five months. Likewise, trimethylation of histone H4 lysine 20 and H3 lysine 9 was significantly decreased at all time points. The majority of cytosine methylation in mammals resides in repetitive DNA sequences. In view of this, we measured the effect of WY-14,643 on the methylation status of major and minor satellites, as well as in IAP, LINE1 and LINE2 elements in liver DNA. Exposure to WY-14,643 resulted in a gradual loss of cytosine methylation in major and minor satellites, IAP, LINE1 and LINE2 elements. The epigenetic changes correlated with the temporal effects of WY-14,643 on cell proliferation rates in liver, but no sustained effect on c-Myc promoter methylation was observed. Finally, WY-14,643 had no effect on DNA and histone methylation status in Pparalpha-null mice at any of the time points considered in this study. These data indicate the importance of epigenetic alterations in the mechanism of action of peroxisome proliferators and the key role of Pparalpha.

Paracorporeal artificial lung: perioperative management for survival study in sheep.

An artificial lung may offer a bridge to recovery or transplant. Utilizing our recently developed paracorporeal artificial lung (PAL) in survival studies in sheep, we critically review our perioperative/anesthetic protocol. Adult Suffolk ewes (n = 15) underwent general anesthesia induced by ketamine (7-15 mg/kg, im) and isoflurane by mask, then intubated and maintained by 4.0-5.0% isoflurane titrated to mean arterial pressure (MAP) 70-110 mm Hg. After a latissimus-sparing thoracotomy and systemic heparinization (200 IU/kg), arterial grafts were anastomosed to the proximal and distal main pulmonary artery in an end-of-graft to side-of-artery fashion. A snare was passed around the pulmonary artery between anastomoses. When the snare was tightened, full pulmonary blood flow was diverted through the cannulae and immediately through the PAL. Perioperative crystalloids included a 500-mL prime, lactated Ringer's (LR) titrated to CVP 5-7 mm Hg, and a heparin infusion (activated clotting time [ACT] 250-300 s). Buprenorphine (0.3 mg im tid) controlled postoperative pain. Hemodynamic parameters, arterial blood gases (ABGs), and ACTs were measured every 6 h. Thirteen of 15 sheep survived the operation and were extubated in less than 20 min. Two groups were studied for up to 7-day survival. Both groups underwent immediate connection to the PAL diverting full pulmonary blood flow. Group 1 (n = 8) underwent immediate connection to a rigidly housed PAL, and 4 of 8 demonstrated immediate right heart failure. In Group 2 a compliance chamber was added to the PAL inflow, and 6 of 7 had stable hemodynamic function for the duration of the study. Incremental improvements in the PAL and our anesthetic and perioperative care have resulted in reliable survival in adult sheep allowing for artificial lung development.

Arterio-venous CO2 removal (AVCO2R) perioperative management: rapid recovery and enhanced survival.

Percutaneous arteriovenous CO2 removal (AVCO2R) uses a simple arteriovenous (A-V) shunt for near-total CO2 removal that allows significant reductions in minute ventilation. We critically reviewed our algorithm-directed perioperative anesthesia management in our LD40 ovine smoke-burn injury model of acute respiratory distress syndrome (ARDS) treated with AVCO2R. General anesthesia is required for: (1) Vascular access followed by ARDS model development by smoke insufflation (36 breaths) plus 40% TBSA III degrees burn with mechanical ventilation. Induction: 12.5 mg/kg im ketamine and 4% halothane by mask, then intubation. Maintenance: 1.0-2.5% halothane in 100% O2; (2) When PaO2/FiO2 < 200 (48-52 h), sheep randomized to the AVCO2R (n = 8) or SHAM (n = 8) procedure. Induction: 66% N2O and 5% isoflurane in balance O2. Maintenance: 1.5-2.5% isoflurane in 100% O2 for AVCO2R, cannulation (10F carotid artery, 14F jugular vein); (3) Postop, both groups had algorithm-directed ventilator management, identical heparin (ACT > 300 s), fluid, and analgesia management. All sheep met criteria for ARDS, survived anesthesia, and were standing by 0.5-5 h. There were no complications attributable to anesthesia. The absence of anesthesia-related complications allows model development for outcomes studies for ARDS in general and AVCO2R specifically.