Feasibility, acceptability and practicality of transcranial stimulation in obsessive compulsive symptoms (FEATSOCS): A randomised controlled crossover trial.

BACKGROUND: Transcranial direct current stimulation (tDCS) is a non-invasive form of neurostimulation with potential for development as a self-administered intervention. It has shown promise as a safe and effective treatment for obsessive compulsive disorder (OCD) in a small number of studies. The two most favourable stimulation targets appear to be the left orbitofrontal cortex (L-OFC) and the supplementary motor area (SMA). We report the first study to test these targets head-to-head within a randomised sham-controlled trial. Our aim was to inform the design of future clinical research studies, by focussing on the acceptability and safety of the intervention, feasibility of recruitment, adherence to and tolerability of tDCS, and the size of any treatment-effect. METHODS: FEATSOCS was a randomised, double-blind, sham-controlled, cross-over, multicentre study. Twenty adults with DSM-5-defined OCD were randomised to treatment, comprising three courses of clinic-based tDCS (SMA, L-OFC, Sham), randomly allocated and delivered in counterbalanced order. Each course comprised four 20-min 2 mA stimulations, delivered over two consecutive days, separated by a 'washout' period of at least four weeks. Assessments were carried out by raters who were blind to stimulation-type. Clinical outcomes were assessed before, during, and up to four weeks after stimulation. Patient representatives with lived experience of OCD were actively involved at all stages. RESULTS: Clinicians showed willingness to recruit participants and recruitment to target was achieved. Adherence to treatment and study interventions was generally good, with only two dropouts. There were no serious adverse events, and adverse effects which did occur were transient and mostly mild in intensity. Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores were numerically improved from baseline to 24 h after the final stimulation across all intervention groups but tended to worsen thereafter. The greatest effect size was seen in the L-OFC arm, (Cohen's d = -0.5 [95% CI -1.2 to 0.2] versus Sham), suggesting this stimulation site should be pursued in further studies. Additional significant sham referenced improvements in secondary outcomes occurred in the L-OFC arm, and to a lesser extent with SMA stimulation. CONCLUSIONS: tDCS was acceptable, practicable to apply, well-tolerated and appears a promising potential treatment for OCD. The L-OFC represents the most promising target based on clinical changes, though the effects on OCD symptoms were not statistically significant compared to sham. SMA stimulation showed lesser signs of promise. Further investigation of tDCS in OCD is warranted, to determine the optimal stimulation protocol (current, frequency, duration), longer-term effectiveness and brain-based mechanisms of effect. If efficacy is substantiated, consideration of home-based approaches represents a rational next step. TRIAL REGISTRATION: ISRCTN17937049. https://doi.org/10.1186/ISRCTN17937049.

Empagliflozin Effects on Pulmonary Artery Pressure in Patients With Heart Failure: Results From the EMBRACE-HF Trial.

BACKGROUND: Sodium glucose cotransporter 2 inhibitors (SGLT2 inhibitors) prevent heart failure (HF) hospitalizations in patients with type 2 diabetes and improve outcomes in those with HF and reduced ejection fraction, regardless of type 2 diabetes. Mechanisms of HF benefits remain unclear, and the effects of SGLT2 inhibitor on hemodynamics (filling pressures) are not known. The EMBRACE-HF trial (Empagliflozin Evaluation by Measuring Impact on Hemodynamics in Patients With Heart Failure) was designed to address this knowledge gap. METHODS: EMBRACE-HF is an investigator-initiated, randomized, multicenter, double-blind, placebo-controlled trial. From July 2017 to November 2019, patients with HF (regardless of ejection fraction, with or without type 2 diabetes) and previously implanted pulmonary artery (PA) pressure sensor (CardioMEMS) were randomized across 10 US centers to empagliflozin 10 mg daily or placebo and treated for 12 weeks. The primary end point was change in PA diastolic pressure (PADP) from baseline to end of treatment (average PADP weeks 8-12). Secondary end points included health status (Kansas City Cardiomyopathy Questionnaire score), natriuretic peptides, and 6-min walking distance. RESULTS: Overall, 93 patients were screened, and 65 were randomized (33 to empagliflozin, 32 to placebo). The mean age was 66 years; 63% were male; 52% had type 2 diabetes; 54% were in New York Heart Association class III/IV; mean ejection fraction was 44%; median NT-proBNP (N-terminal pro B-type natriuretic peptide) was 637 pg/mL; and mean PADP was 22 mm Hg. Empagliflozin significantly reduced PADP, with effects that began at week 1 and amplified over time; average PADP (weeks 8-12) was 1.5 mm Hg lower (95% CI, 0.2-2.8; P=0.02); and at week 12, PADP was 1.7 mm Hg lower (95% CI, 0.3-3.2; P=0.02) with empagliflozin versus placebo. Results were consistent for PA systolic and PA mean pressures. There was no difference in mean loop diuretic management (daily furosemide equivalents) between treatment groups. No significant differences between treatment groups were observed in Kansas City Cardiomyopathy Questionnaire scores, natriuretic peptide levels, and 6-min walking distance. CONCLUSIONS: In patients with HF and CardioMEMS PA pressure sensor, empagliflozin produced rapid reductions in PA pressures that were amplified over time and appeared to be independent of loop diuretic management. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03030222.

Opportunities and challenges of applying advanced X-ray spectroscopy to actinide and lanthanide N-donor ligand systems.

N-donor ligands such as n-Pr-BTP [2,6-bis(5,6-dipropyl-1,2,4-triazin-3-yl)pyridine] preferentially bind trivalent actinides (An3+) over trivalent lanthanides (Ln3+) in liquid-liquid separation. However, the chemical and physical processes responsible for this selectivity are not yet well understood. Here, an explorative comparative X-ray spectroscopy and computational (L3-edge) study for the An/Ln L3-edge and the N K-edge of [An/Ln(n-Pr-BTP)3](NO3)3, [Ln(n-Pr-BTP)3](CF3SO3)3 and [Ln(n-Pr-BTP)3](ClO4)3 complexes is presented. High-resolution X-ray absorption near-edge structure (HR-XANES) L3-edge data reveal additional features in the pre- and post-edge range of the spectra that are investigated using the quantum chemical codes FEFF and FDMNES. X-ray Raman spectroscopy studies demonstrate the applicability of this novel technique for investigations of liquid samples of partitioning systems at the N K-edge.

Phase 3, multicentre, randomised, placebo-controlled study evaluating the efficacy and safety of ustekinumab in patients with systemic lupus erythematosus.

OBJECTIVE: Evaluate the efficacy and safety of ustekinumab, an anti-interleukin-12/23 p40 antibody, in a phase 3, randomised, placebo-controlled study of patients with active systemic lupus erythematosus (SLE) despite receiving standard-of-care. METHODS: Active SLE patients (SLE Disease Activity Index 2000 (SLEDAI-2K) ≥6 during screening and SLEDAI-2K ≥4 for clinical features at week 0) despite receiving oral glucocorticoids, antimalarials, or immunomodulatory drugs were randomised (3:2) to receive ustekinumab (intravenous infusion ~6 mg/kg at week 0, followed by subcutaneous injections of ustekinumab 90 mg at week 8 and every 8 weeks) or placebo through week 48. The primary endpoint was SLE Responder Index (SRI)-4 at week 52, and major secondary endpoints included time to flare through week 52 and SRI-4 at week 24. RESULTS: At baseline, 516 patients were randomised to placebo (n=208) or ustekinumab (n=308). Following the planned interim analysis, the sponsor discontinued the study due to lack of efficacy but no safety concerns. Efficacy analyses included 289 patients (placebo, n=116; ustekinumab, n=173) who completed or would have had a week 52 visit at study discontinuation. At week 52, 44% of ustekinumab patients and 56% of placebo patients had an SRI-4 response; there were no appreciable differences between the treatment groups in the major secondary endpoints. Through week 52, 28% of ustekinumab patients and 32% of placebo patients had a British Isles Lupus Assessment Group flare, with a mean time to first flare of 204.7 and 200.4 days, respectively. Through week 52, 70% of ustekinumab patients and 74% of placebo patients had ≥1 adverse event. CONCLUSIONS: Ustekinumab did not demonstrate superiority over placebo in this population of adults with active SLE; adverse events were consistent with the known safety profile of ustekinumab. TRIAL REGISTRATION NUMBER: NCT03517722.

The efficacy of bone marrow mononuclear stem cell transplantation in patients with non-ischemic dilated cardiomyopathy-a meta analysis.

Cardiomyopathy refers to a wide spectrum of heart pathologies that interfere with normal heart function. Management options of patients with cardiomyopathy depended mainly on the severity of the condition. Lifestyle modifications and regular exercise together with a healthy diet is compatible for mild conditions. Severe conditions, however, rely on medications or surgery. Here, we aim to investigate the efficacy of bone marrow mononuclear stem cell transplantation in patients with dilated cardiomyopathy. We searched PubMed, Scopus, and Cochrane CENTRAL for relevant clinical trials and excluded observational studies. We performed the quality assessment of this study following GRADE guidelines. The assessment of the risk of bias was performed by the Cochrane's risk of bias tool. We present an analysis of the following outcomes: left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), and six minutes walking test. Data were pooled as mean differences (MD) and relative confidence intervals (CI). The analysis of 667 patients from 11 studies receiving autologous bone marrow cell therapy for non-ischemic dilated cardiomyopathy is presented. A total of 338 patients were allocated to the treatment group, and 329 participants entered the control group. The mean age of the patients in the treatment group is 52.4 ± 4.3 years, while that of the control is 53.7 ± 3.7 years. Seven studies (14.18-23) reported transplantation through the intracoronary route. Table 1 shows a summary of the baseline characteristics of the included studies and participants, the number of injected cells, and the type of injected cells in each trial. Table 2 summarizes and illustrates the previous treatment history of included patients in each trial, as well as the baseline values of different scores used as outcome measures in this analysis. We found that bone marrow mononuclear stem cell therapy leads to significantly increased LVEF (MD = 4.54%, 95% CI [3.52, 5.56], P < 0.0001). Patients in the transplant group experienced less left ventricular end-diastolic diameter (millimeter) than the control arm (MD = -1.86 mm, 95% CI [-4.01, 0.29], P = 0.09). Additionally, Patients in the transplant group could walk 28.53 m more than the controls (MD = 28.53 m, 95% CI [2.51, 54.55], P = 0.03). Transplantation of bone marrow stem cells yields acceptable results regarding left ventricular ejection fraction and lowers the left ventricular end-diastolic diameter. Additionally, the six minutes walking test is improved in the transplant group. Table 1 Demographic data about the included participants Study Year Sample size Age, years Males, n (%) Diabetics, n (%) Route of administration Number of injected cells Type of injected cells TTT Control TTT Control TTT Control TTT Control Bartolucci 2015 12 11 58 ± 14 57 ± 11 8 (66.7) 9 (81.8) 2 (16.7) 1 (9.1) Intracoronary 1.94 × 10^6 CD34 +  Bocchi 2010 8 15 51 ± 15 NR NR NR NR Intracoronary NR NR Frljak 2018 30 30 56 ± 9 54 ± 11 27 (90) 26 (87) 3 (10) 2 (6) Trans-endocardial NR CD34 +  Hamshere 2015 15 14 57.67 ± 12.32 56.79 ± 9.8 10 12 9(59.9%) 8(57.1%) Intracoronary 4.91 × 10^6 CD34 +  Hu 2011 31 29 56.61 ± 9.72 58.27 ± 8.86 NR NR NR NR NR NR NR Matrino 2015 82 78 51 ± 11.1 49.6 ± 11.1 73.1 68.3 NR NR Intracoronary 10^8 TTT, CD45, CD105, and CD133 Sant'Anna 2014 20 10 48.3 ± 8.71 51.6 ± 7.79 13(65) 5 (50%) NR NR Intra-myocardial 1.06 × 108 CD3, CD4, CD14, CD34, CD38, and CD45 Seth 2010 41 40 45 ± 15 49 ± 9 33 35 NR NR NR 168 × 10^6 Bone marrow mononuclear cells Vrtovec 2011 28 27 52 ± 8 54 ± 7 26 (93) 23 (85) NR NR Intracoronary 123 × 10^6 CD34 +  Vrtovec 2013 55 55 53 ± 8 55 ± 7 45 (82) 44 (80) NR NR Intracoronary NR NR Xiao 2017 16 20 49.5 ± 11.6 54.4 ± 11.6 9 (56.3) 14 (70.0) 6 (37.5) 5 (29.4) Intracoronary infusion (4.9 ± 1.7) × 108 (CD29, CD34, CD44, CD45, and CD166) Data are reported as mean ± SD or n (%) unless proved otherwise TTT treatment group, NR not reported Table 2 Previous history of treatment and drug intake by the patients Study Year Medical therapy, n (%) Baseline scores, mean (SD) Beta blockers ACE inhibitors Digoxin Diuretics LVEF, % LVEDD, mm Six minutes-walk test* TTT Control TTT Control TTT Control TTT Control TTT Control TTT Control TTT Control Bartolucci 2015 10 (83.3) 8 (72.7) NR NR 3 (25) 3 (27.3) 11 (91.6) 10 (90.9) 26.8 ± 4.9 30.3 ± 6.3 NR NR NR NR Bocchi 2010 NR NR NR NR NR NR NR NR 21.8 ± 3.8 30.6 ± 7.3 79 (10) 78 (12) NR NR Frljak 2018 30 (100) 30 (100) 31 (100) 32 (100) 2 (7) 3 (10) 32 (100) 33 (100) 32.2 ± 9.3 31.1 ± 7.8 NR NR NR NR Hamshere 2015 13 14 15 13 6 2 9 8 32.93 ± 16.46 29.75 ± 9.2 NR NR NR NR Hu* 2011 NR NR NR NR NR NR NR NR NR NR NR NR 466 (402, 495) 448 (383, 497) Matrino 2015 9 (11) 8 (10.2) 53 (64.1) 48 (61.1) 63 (77) 62 (79) 74 (89.7) 69 (88.9) 23.8 ± 7.2 24.7 ± 7.0 NR NR 347.3(146.7) 349.8(139.7) Sant'Anna 2014 NR NR NR NR NR NR NR NR NR NR NR NR 358.5 (88.69) 353 (86.67) Seth 2010 29 (70) 29 (72) 41 (100) 40 (100) NR NR NR NR NR NR NR NR NR NR Vrtovec 2011 21 (75) 22 (81) NR NR 5 (18) 6 (22) 26 (93) 24 (88) 25.6 ± 5.1 26.7 ± 3.9 69 ± 10 70 ± 7 NR NR Vrtovec 2013 43 (79) 46 (84) 51 (93) 54 (98) 9 (16) 11 (20) 51 (93) 20 (91) 24.3 ± 6.5 25.7 ± 4.1 69 ± 10 70 ± 7 NR NR Xiao 2017 16 (100) 20 (100) 16 (100) 19 (95) 4 (25.0) 8 (40.0) 5 (31.3) 6 (30.0) 33.1 ± 3.9 33.7 ± 4.0 NR NR 355.0 ± 91.2 323.3 ± 89.4 Data are reported as mean ± SD or n (%) unless proved otherwise TTT treatment group, NR not reported *Data are reported as median (IQR).

Knowledge by default.

The target article presents strong empirical evidence that knowledge is basic. However, it offers an unsatisfactory account of what makes knowledge basic. Some current ideas in cognitive neuroscience - predictive coding and analysis by synthesis - point to a more plausible account that better explains the evidence.

Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction: The DEFINE-HF Trial.

BACKGROUND: Outcome trials in patients with type 2 diabetes mellitus have demonstrated reduced hospitalizations for heart failure (HF) with sodium-glucose co-transporter-2 inhibitors. However, few of these patients had HF, and those that did were not well-characterized. Thus, the effects of sodium-glucose co-transporter-2 inhibitors in patients with established HF with reduced ejection fraction, including those with and without type 2 diabetes mellitus, remain unknown. METHODS: DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients with HF with Reduced Ejection Fraction) was an investigator-initiated, multi-center, randomized controlled trial of HF patients with left ventricular ejection fraction ≤40%, New York Heart Association (NYHA) class II-III, estimated glomerular filtration rate ≥30 mL/min/1.73m2, and elevated natriuretic peptides. In total, 263 patients were randomized to dapagliflozin 10 mg daily or placebo for 12 weeks. Dual primary outcomes were (1) mean NT-proBNP (N-terminal pro b-type natriuretic peptide) and (2) proportion of patients with ≥5-point increase in HF disease-specific health status on the Kansas City Cardiomyopathy Questionnaire overall summary score, or a ≥20% decrease in NT-proBNP. RESULTS: Patient characteristics reflected stable, chronic HF with reduced ejection fraction with high use of optimal medical therapy. There was no significant difference in average 6- and 12-week adjusted NT-proBNP with dapagliflozin versus placebo (1133 pg/dL (95% CI 1036-1238) vs 1191 pg/dL (95% CI 1089-1304), P=0.43). For the second dual-primary outcome of a meaningful improvement in Kansas City Cardiomyopathy Questionnaire overall summary score or NT-proBNP, 61.5% of dapagliflozin-treated patients met this end point versus 50.4% with placebo (adjusted OR 1.8, 95% CI 1.03-3.06, nominal P=0.039). This was attributable to both higher proportions of patients with ≥5-point improvement in Kansas City Cardiomyopathy Questionnaire overall summary score (42.9 vs 32.5%, adjusted OR 1.73, 95% CI 0.98-3.05), and ≥20% reduction in NT-proBNP (44.0 vs 29.4%, adjusted OR 1.9, 95% CI 1.1-3.3) by 12 weeks. Results were consistent among patients with or without type 2 diabetes mellitus, and other prespecified subgroups (all P values for interaction=NS). CONCLUSIONS: In patients with heart failure and reduced ejection fraction, use of dapagliflozin over 12 weeks did not affect mean NT-proBNP but increased the proportion of patients experiencing clinically meaningful improvements in HF-related health status or natriuretic peptides. Benefits of dapagliflozin on clinically meaningful HF measures appear to extend to patients without type 2 diabetes mellitus. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02653482.

Lower operating volume in shoulder arthroplasty is associated with increased revision rates in the early postoperative period: long-term analysis from the Australian Orthopaedic Association National Joint Replacement Registry.

BACKGROUND: Improved short-term outcomes have been demonstrated with higher surgical volume in shoulder arthroplasty. There is however, little data regarding long-term outcomes. METHOD: Revision data from the Australian Orthopaedic Association National Joint Replacement Registry from 2004-2017 was analyzed according to 3 selected surgeon volume thresholds: <10, 10-20, and >20 shoulder arthroplasty cases per surgeon, per year. RESULTS: There was a significantly higher rate of revision for stemmed total shoulder arthroplasty (TSA) for osteoarthritis (OA) for the <10/yr compared with the >20/yr group for the first 1.5 years only (hazard ratio [HR] 1.36, 95% confidence interval [CI] 1.08-1.71, P = .009). For reverse total shoulder arthroplasty (rTSA) performed for OA, there was a higher revision rate for the <10/yr compared with the >20/yr group for the first 3 months only (HR 2.58, 95% CI 1.67-3.97, P < .001). In rTSA for cuff arthropathy, there was a significantly higher rate of revision for the <10/yr compared with the >20/yr group throughout the follow-up period (HR 1.66, 95% CI 1.21-2.28, P = .001). There was no significant difference for the primary diagnosis of fracture. CONCLUSION: Lower surgical volume was associated with higher all-cause revision rates in the early postoperative period in TSA and rTSA for OA and throughout the follow-up period in rTSA for cuff arthropathy. Despite increases in the volume of shoulder arthroplasties performed in recent years, more than 78% of surgeons undertake fewer than 10 procedures per year.

Early immune biomarkers and intermediate-term outcomes after heart transplantation: Results of Clinical Trials in Organ Transplantation-18.

Clinical Trials in Organ Transplantation-18 (CTOT-18) is a follow-up analysis of the 200-subject multicenter heart transplant CTOT-05 cohort. CTOT-18 aimed to identify clinical, epidemiologic, and biologic markers associated with adverse clinical events past 1 year posttransplantation. We examined various candidate biomarkers including serum antibodies, angiogenic proteins, blood gene expression profiles, and T cell alloreactivity. The composite endpoint (CE) included death, retransplantation, coronary stent, myocardial infarction, and cardiac allograft vasculopathy. The mean follow-up was 4.5 ± SD 1.1 years. Subjects with serum anti-cardiac myosin (CM) antibody detected at transplantation and at 12 months had a higher risk of meeting the CE compared to those without anti-CM antibody (hazard ratio [HR] = 2.9, P = .046). Plasma VEGF-A and VEGF-C levels pretransplant were associated with CE (odds ratio [OR] = 13.24, P = .029; and OR = 0.13, P = .037, respectively). Early intravascular ultrasound findings or other candidate biomarkers were not associated with the study outcomes. In conclusion, anti-CM antibody and plasma levels of VEGF-A and VEGF-C were associated with an increased risk of adverse events. Although this multicenter report supports further evaluation of the mechanisms through which anti-CM antibody and plasma angiogenesis proteins lead to allograft injury, we could not identify additional markers of adverse events or potential novel therapeutic targets.

Efficacy and safety of ustekinumab, an IL-12 and IL-23 inhibitor, in patients with active systemic lupus erythematosus: results of a multicentre, double-blind, phase 2, randomised, controlled study.

BACKGROUND: Ustekinumab is a monoclonal antibody targeting interleukin (IL)-12 and IL-23 and is approved for the treatment of plaque psoriasis, psoriatic arthritis, and Crohn's disease. IL-12 and IL-23 have been implicated in systemic lupus erythematosus. We aimed to assess the efficacy and safety of ustekinumab for the treatment of systemic lupus erythematosus in patients with moderate-to-severe disease activity despite conventional treatment. METHODS: This was a multicentre, double-blind, phase 2, randomised, controlled trial of adult patients with active, seropositive systemic lupus erythematosus, done at 44 private practices and academic centres in Argentina, Australia, Germany, Hungary, Mexico, Poland, Spain, Taiwan, and the USA. Eligible adults were aged 18-75 years, weighed at least 35 kg, and had a diagnosis of systemic lupus erythematosus at least 3 months before the first administration of study drug. Eligible patients were randomly assigned (3:2) to the ustekinumab or placebo group using an interactive web response system with stratification by skin biopsy, lupus nephritis presence, baseline systemic lupus erythematosus medications and systemic lupus erythematosus disease activity index 2000 (SLEDAI-2K) score combined factor, site, region, and race. Patients and investigators were masked to treatment allocation. Patients received an intravenous infusion of ustekinumab (260 mg for patients weighing 35-55 kg, 390 mg for patients weighing >55 kg and ≤85 kg, and 520 mg for patients weighing >85 kg) followed by subcutaneous injections of ustekinumab 90 mg every 8 weeks or intravenous infusion of placebo at week 0 followed by subcutaneous injections of placebo every 8 weeks, both in addition to standard-of-care therapy. The primary endpoint was the proportion of patients achieving a SLEDAI-2K responder index-4 (SRI-4) response at week 24. Efficacy analyses were done in a modified intention-to-treat population of patients who received at least one dose (partial or complete, intravenous or subcutaneous) of their randomly assigned study treatment. Safety analyses were done in all patients who received at least one dose of study treatment, regardless of group assignment. This study is registered at ClinicalTrials.gov, number NCT02349061. FINDINGS: Between Oct 6, 2015, and Nov 30, 2016, 166 patients were screened, of whom 102 were randomly assigned to receive ustekinumab (n=60) or placebo (n=42). At week 24, 37 (62%) of 60 patients in the ustekinumab group and 14 (33%) of 42 patients in the placebo group achieved an SRI-4 response (percentage difference 28% [95% CI 10-47], p=0·006). Between week 0 and week 24, 47 (78%) of 60 patients in the ustekinumab group and 28 (67%) of 42 patients in the placebo group had at least one adverse event. Infections were the most common type of adverse event (27 [45%] in the ustekinumab group vs 21 [50%] in the placebo group). No deaths or treatment-emergent opportunistic infections, herpes zoster, tuberculosis, or malignancies occurred between weeks 0-24. INTERPRETATION: The addition of ustekinumab to standard-of-care treatment resulted in better efficacy in clinical and laboratory parameters than placebo in the treatment of active systemic lupus erythematosus and had a safety profile consistent with ustekinumab therapy in other diseases. The results of this study support further development of ustekinumab as a novel treatment in systemic lupus erythematosus. FUNDING: Janssen Research & Development, LLC.

Allocation of attention to scenes of peer harassment: Visual-cognitive moderators of the link between peer victimization and aggression.

As approximately one-third of peer-victimized children evidence heightened aggression (Schwartz, Proctor, & Chien, 2001), it is imperative to identify the circumstances under which victimization and aggression co-develop. The current study explored two potential moderators of victimization-aggression linkages: (a) attentional bias toward cues signaling threat and (b) attentional bais toward cues communicating interpersonal support. Seventy-two fifth- and sixth-grade children (34 boys; Mage = 11.67) were eye tracked while watching video clips of bullying. Each scene included a bully, a victim, a reinforcer, and a defender. Children's victimization was measured using peer, parent, and teacher reports. Aggression was measured using peer reports of overt and relational aggression and teacher reports of aggression. Victimization was associated with greater aggression at high levels of attention to the bully. Victimization was also associated with greater aggression at low attention to the defender for boys, but at high attention to the defender for girls. Attention to the victim was negatively correlated with aggression regardless of victimization history. Thus, attentional biases to social cues integral to the bullying context differentiate whether victimization is linked to aggression, necessitating future research on the development of these biases and concurrent trajectories of sociobehavioral development.

Using Facebook to reduce smoking among Australian Aboriginal and Torres Strait Islander people: a participatory grounded action study.

BACKGROUND: There is limited evidence for the effectiveness of social media to promote healthy behaviour among Indigenous Australians, including to reduce smoking. Social media has significant potential to stimulate interpersonal influence to quit, however an important knowledge gap is how and what content people choose to share with friends and family. This paper explores the decision making processes of community members for sharing tobacco control content with family and friends on Facebook. METHODS: Community researchers were paid to choose and share at least one tobacco control post per week for a period of 6 months on their personal Facebook page. They documented reasons for their choices, which were coded and analysed to determine features of messages most likely to be shared, and salient considerations in the decision-making process. RESULTS: Posts which are child-focused, feature Indigenous content, and are perceived as practical, relevant and credible, with a direct and unambiguous message, were most likely to be shared. Posts which included disgusting imagery about health impacts, were focused on the environment, or were ambiguous or sarcastic were less likely to be shared. Decisions were also based on whether content was perceived to contain new information, to be helpful for their friends, and to be consistent with the participant's online identity, as well as the perceived sensitivity of content. The potential impact on expensive mobile data for videos was also a factor. CONCLUSIONS: When designing tobacco control messages to be shared on social media, health promoters should take into account how information will align with positive self-image and can contribute to social capital among the intended audience, and generate interpersonal engagement. Content should complement, rather than attempt to replicate, some message features that are effective on traditional broadcast media. This study shows the potential for health services to incorporate a strategy of using paid local social media 'champions' or 'ambassadors' to disseminate tobacco control messages on Facebook through community networks.

Toll-like receptor 3 blockade in rhinovirus-induced experimental asthma exacerbations: A randomized controlled study.

BACKGROUND: Human rhinoviruses (HRVs) commonly precipitate asthma exacerbations. Toll-like receptor 3, an innate pattern recognition receptor, is triggered by HRV, driving inflammation that can worsen asthma. OBJECTIVE: We sought to evaluate an inhibitory mAb to Toll-like receptor 3, CNTO3157, on experimental HRV-16 inoculation in healthy subjects and asthmatic patients. METHODS: In this double-blind, multicenter, randomized, parallel-group study in North America and Europe, healthy subjects and patients with mild-to-moderate stable asthma received single or multiple doses of CNTO3157 or placebo, respectively, and were then inoculated with HRV-16 within 72 hours. All subjects were monitored for respiratory symptoms, lung function, and nasal viral load. The primary end point was maximal decrease in FEV1 during 10 days after inoculation. RESULTS: In asthmatic patients (n = 63) CNTO3157 provided no protection against FEV1 decrease (least squares mean: CNTO3157 [n = 30] = -7.08% [SE, 8.15%]; placebo [n = 25] = -5.98% [SE, 8.56%]) or symptoms after inoculation. In healthy subjects (n = 12) CNTO3157 versus placebo significantly attenuated upper (P = .03) and lower (P = .02) airway symptom scores, with area-under-the-curve increases of 9.1 (15.1) versus 34.9 (17.6) and 13.0 (18.4) versus 50.4 (25.9) for the CNTO3157 (n = 8) and placebo (n = 4) groups, respectively, after inoculation. All of the severe and 4 of the nonserious asthma exacerbations occurred while receiving CNTO3157. CONCLUSION: In summary, CNTO3157 was ineffective in attenuating the effect of HRV-16 challenge on lung function, asthma control, and symptoms in asthmatic patients but suppressed cold symptoms in healthy subjects. Other approaches, including blockade of multiple pathways or antiviral agents, need to be sought for this high unmet medical need.

Targeting Bacteria and Methanogens To Understand the Role of Residual Slurry as an Inoculant in Stored Liquid Dairy Manure.

Microbial communities in residual slurry left after removal of stored liquid dairy manure have been presumed to increase methane emission during new storage, but these microbes have not been studied. While actual manure storage tanks are filled gradually, pilot- and farm-scale studies on methane emissions from such systems often use a batch approach. In this study, six pilot-scale outdoor storage tanks with (10% and 20%) and without residual slurry were filled (gradually or in batch) with fresh dairy manure, and methane and methanogenic and bacterial communities were studied during 120 days of storage. Regardless of filling type, increased residual slurry levels resulted in higher abundance of methanogens and bacteria after 65 days of storage. However, stronger correlation between methanogen abundance and methane flux was observed in gradually filled tanks. Despite some variations in the diversity of methanogens or bacteria with the presence of residual slurry, core phylotypes were not impacted. In all samples, the phylum Firmicutes predominated (∼57 to 70%) bacteria: >90% were members of ClostridiaMethanocorpusculum dominated (∼57 to 88%) archaeal phylotypes, while Methanosarcina gradually increased with storage time. During peak flux of methane, Methanosarcina was the major player in methane production. The results suggest that increased levels of residual slurry have little impact on the dominant methanogenic or bacterial phylotypes, but large population sizes of these organisms may result in increased methane flux during the initial phases of storage.IMPORTANCE Methane is the major greenhouse gas emitted from stored liquid dairy manure. Residual slurry left after removal of stored manure from tanks has been implicated in increasing methane emissions in new storages, and well-adapted microbial communities in it are the drivers of the increase. Linking methane flux to the abundance, diversity, and activity of microbial communities in stored slurries with different levels of residual slurry can help to improve the mitigation strategy. Mesoscale and lab-scale studies conducted so far on methane flux from manure storage systems used batch-filled tanks, while the actual condition in many farms involves gradual filling. Hence, this study provides important information toward determining levels of residual slurry that result in significant reduction of well-adapted microbial communities prior to storage, thereby reducing methane emissions from manure storage tanks filled under farm conditions.

Visual Attention to Dynamic Scenes of Ambiguous Provocation and Children's Aggressive Behavior.

Research on biases in attention related to children's aggression has yielded mixed results. Some research suggests that inattention to social cues and reliance on maladaptive social schemas underlie aggression. Other research suggests that maladaptive social schemas lead aggressive individuals to attend to nonhostile cues. The primary objective of this study was to test the proposition that aggression is related to delayed attention to cues followed by selective attention to nonhostile cues after the provocation has occurred. A second objective was to test whether these biases are associated with aggression only when children hold negative social schemas. The eye fixations of 70 children (34 boys, 36 girls; Mage = 11.71 years) were monitored with an eye tracker as they watched video clips of child actors portraying scenes of ambiguous provocation. Aggression was measured using peer-, teacher-, and parent-reports, and children completed a measure of antisocial and prosocial peer beliefs. Aggressive behavior was associated with greater time until fixation on the provocateur among youth who held antisocial peer beliefs. Aggression was also associated with greater time until fixation on an actor displaying empathy for the victim among children reporting low levels of prosocial peer beliefs. After the provocation, aggression was associated with suppressed attention to an amused peer among children who held negative peer beliefs. Increasing attention to cues in a scene of ambiguous provocation, in conjunction with fostering more positive beliefs about peers, may be effective in reducing hostile responding among aggressive youth.

Sodium Persulfate and Potassium Permanganate Inhibit Methanogens and Methanogenesis in Stored Liquid Dairy Manure.

Stored liquid dairy manure is a hotspot for methane (CH) emission, thus effective mitigation strategies are required. We assessed sodium persulfate (NaSO), potassium permanganate (KMnO), and sodium hypochlorite (NaOCl) for impacts on the abundance of microbial communities and CH production in liquid dairy manure. Liquid dairy manure treated with different rates (1, 3, 6, and 9 g or mL L slurry) of these chemicals or their combinations were incubated under anoxic conditions at 22.5 ± 1.3°C for 120 d. Untreated and sodium 2-bromoethanesulfonate (BES)-treated manures were included as negative and positive controls, respectively, whereas sulfuric acid (HSO)-treated manure was used as a reference. Quantitative real-time polymerase chain reaction was used to quantify the abundances of bacteria and methanogens on Days 0, 60, and 120. Headspace CH/CO ratios were used as a proxy to determine CH production. Unlike bacterial abundance, methanogen abundance and CH/CO ratios varied with treatments. Addition of 1 to 9 g L slurry of NaSO and KMnO reduced methanogen abundance (up to ∼28%) and peak CH/CO ratios (up to 92-fold). Except at the lowest rate, chemical combinations also reduced the abundance of methanogens (up to ∼17%) and CH/CO ratios (up to ninefold), although no impacts were observed when 3% NaOCl was used alone. With slurry acidification, the ratios reduced up to twofold, whereas methanogen abundance was unaffected. Results suggest that NaSO and KMnO may offer alternative options to reduce CH emission from stored liquid dairy manure, but this warrants further assessment at larger scales for environmental impacts and characteristics of the treated manure.

Invasive fungal infection after heart transplantation: A 7-year, single-center experience.

BACKGROUND: Invasive fungal infections (IFIs) are an infrequent but major complication of heart transplantation (HT). We sought to describe the epidemiology at our institution. METHODS: A prospective cohort study of 159 heart transplant recipients was performed from June 2005 to December 2012. IFIs were defined by European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria. RESULTS: By univariate analysis, Hispanic ethnicity was associated with IFI (P=.01, odds ratio [OR] 7.0, 95% confidence interval [CI] 1.7-27.9). Subsequently, a multivariate logistic regression was performed adjusting for Hispanic ethnicity, age, and gender. Seventeen IFIs were identified, occurring at a median 110 days post HT (interquartile range: 32-411 days). Five IFIs (29% of IFIs and 3.1% of all HT) occurred during the HT hospitalization, with 13 IFIs during the first year (incidence 8.2%). CONCLUSIONS: The cumulative incidence was 10.7%. IFIs were associated with pre- and post-HT vancomycin-resistant Enterococcus colonization and/or infection, post-HT renal replacement therapy, anti-thymocyte globulin induction, and antibody-mediated rejection. There were no associations with diabetes mellitus, desensitization, 2R/3R cellular rejection, treatments for rejection, re-operation, neutropenia, or cytomegalovirus infection. IFIs were associated with death (P=.02, OR 3.9, 95% CI 1.3-12.1) and 1-year mortality (P<.001, OR 9.0, 95% CI 2.3-35.7), but not 3-year mortality. Associations with Hispanic ethnicity must be validated. Optimal strategies for risk reduction and prophylaxis remain undefined.

Micrometeorological measurements over 3 years reveal differences in N2 O emissions between annual and perennial crops.

Perennial crops can deliver a wide range of ecosystem services compared to annual crops. Some of these benefits are achieved by lengthening the growing season, which increases the period of crop water and nutrient uptake, pointing to a potential role for perennial systems to mitigate soil nitrous oxide (N2 O) emissions. Employing a micrometeorological method, we tested this hypothesis in a 3-year field experiment with a perennial grass-legume mixture and an annual corn monoculture. Given that N2 O emissions are strongly dependent on the method of fertilizer application, two manure application options commonly used by farmers for each crop were studied: injection vs. broadcast application for the perennial; fall vs. spring application for the annual. Across the 3 years, lower N2 O emissions (P < 0.001) were measured for the perennial compared to the annual crop, even though annual N2 O emissions increased tenfold for the perennial after ploughing. The percentage of N2 O lost per unit of fertilizer applied was 3.7, 3.1 and 1.3 times higher for the annual for each consecutive year. Differences in soil organic matter due to the contrasting root systems of these crops are probably a major factor behind the N2 O reduction. We found that a specific manure management practice can lead to increases or reductions in annual N2 O emissions depending on environmental variables. The number of freeze-thaw cycles during winter and the amount of rainfall after fertilization in spring were key factors. Therefore, general manure management recommendations should be avoided because interannual weather variability has the potential to determine if a specific practice is beneficial or detrimental. The lower N2 O emissions of perennial crops deserve further research attention and must be considered in future land-use decisions. Increasing the proportion of perennial crops in agricultural landscapes may provide an overlooked opportunity to regulate N2 O emissions.

The separation of adult separation anxiety disorder.

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) categorization of mental disorders places "separation anxiety disorder" within the broad group of anxiety disorders, and its diagnosis no longer rests on establishing an onset during childhood or adolescence. In previous editions of DSM, it was included within the disorders usually first diagnosed in infancy, childhood, or adolescence, with the requirement for an onset of symptoms before the age of 18 years: symptomatic adults could only receive a retrospective diagnosis, based on establishing this early onset. The new position of separation anxiety disorder is based upon the findings of epidemiological studies that revealed the unexpectedly high prevalence of the condition in adults, often in individuals with an onset of symptoms after the teenage years; its prominent place within the DSM-5 group of anxiety disorders should encourage further research into its epidemiology, etiology, and treatment. This review examines the clinical features and boundaries of the condition, and offers guidance on how it can be distinguished from other anxiety disorders and other mental disorders in which "separation anxiety" may be apparent.

Does Fall Removal of the Dairy Manure Sludge in a Storage Tank Reduce Subsequent Methane Emissions?

When liquid manure is removed from storages for land application, "sludge" generally remains at the bottom of the tank. This may serve as an inoculum when fresh manure is subsequently added, thereby increasing methane (CH) emissions. Previous pilot-scale studies have shown that completely emptying storages can decrease CH emissions; however, no farm-scale studies have been conducted to quantify the effect of sludge removal. In this study, a commercial dairy farm removed as much manure and sludge from their concrete storage as possible in the fall (∼2% by volume remained). Emissions of CH were measured during the following winter, spring, and summer, and compared with emissions measured the preceding 2 yr when most of the sludge had not been removed (∼14% of tank volume remained). Emissions were measured using a micrometeorological technique, utilizing open-path CH lasers. Contrary to what was hypothesized, removing the majority of sludge in fall did not delay the onset of CH emissions and did not decrease emissions the following summer. In fact, annual CH emissions were ∼16% higher. It is possible that fall removal provided sufficient time for microbial dynamics to be restored before the following summer when emissions were high. Future farm-scale research should examine the effect of spring (rather than fall) emptying for on-farm CH mitigation in both concrete tanks and earthen storages.