A Placebo-Controlled Trial of Percutaneous Coronary Intervention for Stable Angina.

BACKGROUND: Percutaneous coronary intervention (PCI) is frequently performed to reduce the symptoms of stable angina. Whether PCI relieves angina more than a placebo procedure in patients who are not receiving antianginal medication remains unknown. METHODS: We conducted a double-blind, randomized, placebo-controlled trial of PCI in patients with stable angina. Patients stopped all antianginal medications and underwent a 2-week symptom assessment phase before randomization. Patients were then randomly assigned in a 1:1 ratio to undergo PCI or a placebo procedure and were followed for 12 weeks. The primary end point was the angina symptom score, which was calculated daily on the basis of the number of angina episodes that occurred on a given day, the number of antianginal medications prescribed on that day, and clinical events, including the occurrence of unblinding owing to unacceptable angina or acute coronary syndrome or death. Scores range from 0 to 79, with higher scores indicating worse health status with respect to angina. RESULTS: A total of 301 patients underwent randomization: 151 to the PCI group and 150 to the placebo group. The mean (±SD) age was 64±9 years, and 79% were men. Ischemia was present in one cardiac territory in 242 patients (80%), in two territories in 52 patients (17%), and in three territories in 7 patients (2%). In the target vessels, the median fractional flow reserve was 0.63 (interquartile range, 0.49 to 0.75), and the median instantaneous wave-free ratio was 0.78 (interquartile range, 0.55 to 0.87). At the 12-week follow-up, the mean angina symptom score was 2.9 in the PCI group and 5.6 in the placebo group (odds ratio, 2.21; 95% confidence interval, 1.41 to 3.47; P<0.001). One patient in the placebo group had unacceptable angina leading to unblinding. Acute coronary syndromes occurred in 4 patients in the PCI group and in 6 patients in the placebo group. CONCLUSIONS: Among patients with stable angina who were receiving little or no antianginal medication and had objective evidence of ischemia, PCI resulted in a lower angina symptom score than a placebo procedure, indicating a better health status with respect to angina. (Funded by the National Institute for Health and Care Research Imperial Biomedical Research Centre and others; ORBITA-2 ClinicalTrials.gov number, NCT03742050.).

Maternal exercise increases infant resting energy expenditure: preliminary results.

Maternal obesity is associated with lower infant resting energy expenditure (REE), predisposing them to more rapid weight and adiposity gain through early infancy. Maternal exercise (ME) decreases infant adiposity and risk for childhood obesity; however, it remains unknown if this is in part mediated by changes in infant energy expenditure. Thus, we measured REE in 1-month-old infants from pregnant individuals who performed moderate-intensity exercise during pregnancy and compared it to infants from non-exercising controls. We observed higher oxygen respiratory rates (p = 0.003 for VO2 and p = 0.007 for VCO2) and REE (p = 0.002) in infants exposed to exercise in utero, independent of any differences in infant body composition. Furthermore, maternal BMI was significantly and inversely associated with infant REE in the control (r = -0.86, R2 = 0.74, p = 0.029), but not the exercise group (r = 0.33, R2 = 0.11, p = 0.473). Together, these findings associate ME with increasing infant energy expenditure which could be protective of subsequent infant adiposity gain. Clinical Trial: ClinicalTrials.gov Identifier: NCT03838146 and NCT04805502.

MAVEN: compound mechanism of action analysis and visualisation using transcriptomics and compound structure data in R/Shiny.

BACKGROUND: Understanding the Mechanism of Action (MoA) of a compound is an often challenging but equally crucial aspect of drug discovery that can help improve both its efficacy and safety. Computational methods to aid MoA elucidation usually either aim to predict direct drug targets, or attempt to understand modulated downstream pathways or signalling proteins. Such methods usually require extensive coding experience and results are often optimised for further computational processing, making them difficult for wet-lab scientists to perform, interpret and draw hypotheses from. RESULTS: To address this issue, we in this work present MAVEN (Mechanism of Action Visualisation and Enrichment), an R/Shiny app which allows for GUI-based prediction of drug targets based on chemical structure, combined with causal reasoning based on causal protein-protein interactions and transcriptomic perturbation signatures. The app computes a systems-level view of the mechanism of action of the input compound. This is visualised as a sub-network linking predicted or known targets to modulated transcription factors via inferred signalling proteins. The tool includes a selection of MSigDB gene set collections to perform pathway enrichment on the resulting network, and also allows for custom gene sets to be uploaded by the researcher. MAVEN is hence a user-friendly, flexible tool for researchers without extensive bioinformatics or cheminformatics knowledge to generate interpretable hypotheses of compound Mechanism of Action. CONCLUSIONS: MAVEN is available as a fully open-source tool at https://github.com/laylagerami/MAVEN with options to install in a Docker or Singularity container. Full documentation, including a tutorial on example data, is available at https://laylagerami.github.io/MAVEN .

Benchmarking causal reasoning algorithms for gene expression-based compound mechanism of action analysis.

BACKGROUND: Elucidating compound mechanism of action (MoA) is beneficial to drug discovery, but in practice often represents a significant challenge. Causal Reasoning approaches aim to address this situation by inferring dysregulated signalling proteins using transcriptomics data and biological networks; however, a comprehensive benchmarking of such approaches has not yet been reported. Here we benchmarked four causal reasoning algorithms (SigNet, CausalR, CausalR ScanR and CARNIVAL) with four networks (the smaller Omnipath network vs. 3 larger MetaBase™ networks), using LINCS L1000 and CMap microarray data, and assessed to what extent each factor dictated the successful recovery of direct targets and compound-associated signalling pathways in a benchmark dataset comprising 269 compounds. We additionally examined impact on performance in terms of the functions and roles of protein targets and their connectivity bias in the prior knowledge networks. RESULTS: According to statistical analysis (negative binomial model), the combination of algorithm and network most significantly dictated the performance of causal reasoning algorithms, with the SigNet recovering the greatest number of direct targets. With respect to the recovery of signalling pathways, CARNIVAL with the Omnipath network was able to recover the most informative pathways containing compound targets, based on the Reactome pathway hierarchy. Additionally, CARNIVAL, SigNet and CausalR ScanR all outperformed baseline gene expression pathway enrichment results. We found no significant difference in performance between L1000 data or microarray data, even when limited to just 978 'landmark' genes. Notably, all causal reasoning algorithms also outperformed pathway recovery based on input DEGs, despite these often being used for pathway enrichment. Causal reasoning methods performance was somewhat correlated with connectivity and biological role of the targets. CONCLUSIONS: Overall, we conclude that causal reasoning performs well at recovering signalling proteins related to compound MoA upstream from gene expression changes by leveraging prior knowledge networks, and that the choice of network and algorithm has a profound impact on the performance of causal reasoning algorithms. Based on the analyses presented here this is true for both microarray-based gene expression data as well as those based on the L1000 platform.

Can we achieve better trial recruitment by presenting patient information through multimedia? Meta-analysis of 'studies within a trial' (SWATs).

BACKGROUND: People need high-quality information to make decisions about research participation. Providing information in written format alone is conventional but may not be the most effective and acceptable approach. We developed a structure for the presentation of information using multimedia which included generic and trial-specific content. Our aim was to embed 'Studies Within A Trial' (SWATs) across multiple ongoing trials to test whether multimedia presentation of patient information led to better rates of recruitment. METHODS: Five trials included a SWAT and randomised their participants to receive a multimedia presentation alongside standard information, or standard written information alone. We collected data on trial recruitment, acceptance and retention and analysed the pooled results using random effects meta-analysis, with the primary outcome defined as the proportion of participants randomised following an invitation to take part. RESULTS: Five SWATs provided data on the primary outcome of proportion of participants randomised. Multimedia alongside written information results in little or no difference in recruitment rates (pooled odds ratio = 0.96, 95% CI: 0.79 to 1.17, p-value = 0.671, I2 = 0%). There was no effect on any other outcomes. CONCLUSIONS: Multimedia alongside written information did not improve trial recruitment rates. TRIAL REGISTRATION: ISRCTN71952900, ISRCTN 06710391, ISRCTN 17160087, ISRCTN05926847, ISRCTN62869767.

Microglial activation, tau and amyloid deposition in TREM2 p.R47H carriers and mild cognitive impairment patients: a multi-modal/multi-tracer PET/MRI imaging study with influenza vaccine immune challenge.

BACKGROUND: Microglia are increasingly understood to play an important role in the pathogenesis of Alzheimer's disease. The rs75932628 (p.R47H) TREM2 variant is a well-established risk factor for Alzheimer's disease. TREM2 is a microglial cell surface receptor. In this multi-modal/multi-tracer PET/MRI study we investigated the effect of TREM2 p.R47H carrier status on microglial activation, tau and amyloid deposition, brain structure and cognitive profile. METHODS: We compared TREM2 p.R47H carriers (n = 8; median age = 62.3) and participants with mild cognitive impairment (n = 8; median age = 70.7). Participants underwent two [18F]DPA-714 PET/MRI scans to assess TSPO signal, indicative of microglial activation, before and after receiving the seasonal influenza vaccination, which was used as an immune stimulant. Participants also underwent [18F]florbetapir and [18F]AV1451 PET scans to assess amyloid and tau burden, respectively. Regional tau and TSPO signal were calculated for regions of interest linked to Braak stage. An additional comparison imaging healthy control group (n = 8; median age = 45.5) had a single [18F]DPA-714 PET/MRI. An expanded group of participants underwent neuropsychological testing, to determine if TREM2 status influenced clinical phenotype. RESULTS: Compared to participants with mild cognitive impairment, TREM2 carriers had lower TSPO signal in Braak II (P = 0.04) and Braak III (P = 0.046) regions, despite having a similar burden of tau and amyloid. There were trends to suggest reduced microglial activation following influenza vaccine in TREM2 carriers. Tau deposition in the Braak VI region was higher in TREM2 carriers (P = 0.04). Furthermore, compared to healthy controls TREM2 carriers had smaller caudate (P = 0.02), total brain (P = 0.049) and white matter volumes (P = 0.02); and neuropsychological assessment revealed worse ADAS-Cog13 (P = 0.03) and Delayed Matching to Sample (P = 0.007) scores. CONCLUSIONS: TREM2 p.R47H carriers had reduced levels of microglial activation in brain regions affected early in the Alzheimer's disease course and differences in brain structure and cognition. Changes in microglial response may underlie the increased Alzheimer's disease risk in TREM2 p.R47H carriers. Future therapeutic agents in Alzheimer's disease should aim to enhance protective microglial actions.

Estimation of the Half-Lives of Recently Detected Per- and Polyfluorinated Alkyl Ethers in an Exposed Community.

To estimate half-lives for novel fluoroethers, the GenX Exposure Study obtained two serum measurements for per- and polyfluoroalkyl substances (PFAS) for 44 participants of age 12-86 years from North Carolina, collected 5 and 11 months after fluoroether discharges into the drinking water source were controlled. The estimated half-lives for these compounds were 127 days (95% confidence interval (95% CI) = 86, 243 days) for perfluorotetraoxadecanoic acid (PFO4DA), 296 days for Nafion byproduct 2 (95% CI = 176, 924 days), and 379 days (95% CI = 199, 3870 days) for perfluoro-3,5,7,9,11-pentaoxadodecanoic acid (PFO5DoA). Using these estimates and the literature values, a model was built that predicted PFAS half-lives using structural properties. Three chemical properties predicted 55% of the variance of PFAS half-lives based on 15 PFAS. A model with only molecular weight predicted 69% of the variance. Some properties can predict the half-lives of PFAS, but a deeper understanding is needed. These fluoroethers had biological half-lives longer than published half-lives for PFHxA and PFHpA (30-60 days) but shorter than those for PFOA and PFOS (800-1200 days). These are the first and possibly only estimates of human elimination half-lives of these fluoroethers.

Factors associated with per- and polyfluoroalkyl substances (PFAS) serum concentrations in residents of New Hanover County, North Carolina: The GenX exposure study.

In 2017, people living in New Hanover County, North Carolina, learned that for ∼40 years they were unknowingly exposed to per- and polyfluoroalkyl substances (PFAS) through drinking water sourced by the Cape Fear River. Using data from the GenX Exposure Study, which measured serum PFAS levels in county residents, we aimed to understand questionnaire-measured factors associated with serum PFAS levels. Because most residents were served by the same municipal water source, we focused on surrogate factors of drinking water exposure that may contribute to variability in PFAS levels. Our analysis included 335 participants aged 6 and older. We included seven chemicals detected in ≥75% of the study population: four well-studied perfluoroalkyl acids (PFOA, PFOS, PFNA, PFHxS) and three understudied fluoroethers (Nafion byproduct 2, PFO4DA, PFO5DoA). For each PFAS, we evaluated associations of variables with serum PFAS levels adjusting for key demographic characteristics. Additionally, we developed predictive models for each PFAS. We used years of residence in the lower Cape Fear Region as a surrogate for water consumption. Duration of drinking water exposure was associated with higher serum levels of all seven PFAS. Drinking municipal water treated by home filters or other sources of water (non-city) were associated with lower PFAS concentrations for all seven PFAS compared to drinking municipal water without additional filtration. Males had higher levels of well-studied PFAS, but there was no difference for fluoroethers. For six PFAS, the predictive models explained ≥30% of the variance in serum PFAS levels. While some factors were significantly associated with levels of individual PFAS, their relative importance to overall prediction was low, such as microwave popcorn consumption. Consistently, water consumption-related variables were important for both the association and predictive investigations. These analyses provide additional evidence that drinking water is a primary source for serum PFAS concentrations among New Hanover County residents.

Effects of Disease-Worsening Following Withdrawal of Etanercept or Methotrexate on Patient-Reported Outcomes in Patients With Rheumatoid Arthritis: Results From the SEAM-RA Trial.

BACKGROUND/OBJECTIVE: The effect of treatment withdrawal on patient-reported outcomes (PROs) in patients with rheumatoid arthritis (RA) whose disease is in sustained remission has not been well described. This analysis aimed to compare PRO changes in patients with RA following medication withdrawal and disease worsening. METHODS: SEAM-RA (Study of Etanercept and Methotrexate in Combination or as Monotherapy in Subjects With Rheumatoid Arthritis) was a phase 3, multicenter, randomized withdrawal, double-blind controlled study in patients with RA taking methotrexate plus etanercept and in remission (Simple Disease Activity Index ≤3.3). Patient's Global Assessment of Disease Activity, Patient's Assessment of Joint Pain, Health Assessment Questionnaire-Disability Index, and 36-Item Short-Form Health Survey were evaluated for 48 weeks following methotrexate or etanercept withdrawal. Treatment differences for patients with versus without disease worsening were evaluated using a 2-sample t test for continuous end points and log-rank test for time-to-event end points. RESULTS: Of 253 patients, 121 experienced disease worsening and 132 did not. All PRO scores were similar to those of a general population at baseline and deteriorated over time across the study population. The PtGA and Patient's Assessment of Joint Pain values deteriorated less in those on etanercept monotherapy compared with methotrexate monotherapy. More patients with versus without disease worsening experienced deterioration that was greater than the minimal clinically important difference (MCID) for all PROs tested. In patients with disease worsening, PtGA deterioration more than the MCID preceded Simple Disease Activity Index disease worsening. CONCLUSIONS: Etanercept monotherapy showed benefit over methotrexate in maintaining PRO scores. Patients with disease worsening experienced a more rapid worsening of PtGA beyond the MCID versus patients without disease worsening.Categories: autoinflammatory disease, biological therapy, DMARDs, rheumatoid arthritis.

Enriched Marine Oil Supplements Increase Peripheral Blood Specialized Pro-Resolving Mediators Concentrations and Reprogram Host Immune Responses: A Randomized Double-Blind Placebo-Controlled Study.

RATIONALE: Specialized pro-resolving mediators (SPM-lipoxins, resolvins, protectins, and maresins) are produced via the enzymatic conversion of essential fatty acids, including the omega-3 fatty acids docosahexaenoic acid and n-3 docosapentaenoic acid. These mediators exert potent leukocyte directed actions and control vascular inflammation. Supplementation of animals and humans with essential fatty acids, in particular omega-3 fatty acids, exerts protective actions reducing vascular and systemic inflammation. Of note, the mechanism(s) activated by these supplements in exerting their protective actions remain poorly understood. OBJECTIVE: Given that essential fatty acids are precursors in the biosynthesises of SPM, the aim of the present study was to establish the relationship between supplementation and peripheral SPM concentrations. We also investigated the relationship between changes in plasma SPM concentrations and peripheral blood platelet and leukocyte responses. METHODS AND RESULTS: Healthy volunteers were enrolled in a double-blinded, placebo-controlled, crossover study, and peripheral blood was collected at baseline, 2, 4, 6, and 24 hours post administration of placebo or one of 3 doses of an enriched marine oil supplement. Assessment of plasma SPM concentrations using lipid mediator profiling demonstrated a time- and dose-dependent increase in peripheral blood SPM concentration. Supplementation also led to a regulation of peripheral blood cell responses. Here we found a dose-dependent increase in neutrophil and monocyte phagocytosis of bacteria and a decrease in the diurnal activation of leukocytes and platelets, as measured by a reduction in adhesion molecule expression. In addition, transcriptomic analysis of peripheral blood cells demonstrated a marked change in transcript levels of immune and metabolic genes 24 hours post supplementation when compared with placebo. CONCLUSIONS: Together, these findings demonstrate that supplementation with an enriched marine oil leads to an increase in peripheral blood SPM concentrations and reprograms peripheral blood cells, indicating a role for SPM in mediating the immune-directed actions of this supplement. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT03347006.

Bridging of childhood obsessive-compulsive personality disorder traits and adult eating disorder symptoms: A network analysis approach.

OBJECTIVES: Obsessive-compulsive personality disorder (OCDP) traits are commonly associated with eating disorders (EDs), with evidence demonstrating that these traits predispose and exacerbate the ED illness course. However, limited research has examined the symptomatic interplay between ED and OCDP traits. We used network analysis to (1) identify the most central symptoms in a network comprised of OCPD traits retrospectively assessed in childhood and ED symptoms and (2) to identify symptoms which bridged OCPD traits and ED symptoms. METHODS: Participants were 320 females with an ED (anorexia nervosa n = 227, bulimia nervosa n = 93), who completed the semi-structured EATATE interview and the Eating Disorder Inventory-2. Expected influence (EI) was computed to determine each symptom's influence in the network. Bridge symptoms were identified by computing bridge EI. RESULTS: A regularised partial correlation network showed that ascetism, social insecurity, ineffectiveness, and impulsivity had the highest EI in the OCPD and ED network. With respect to bridging symptoms, interpersonal distrust emerged as a possible bridging node between the OCPD and ED trait/symptom clusters. DISCUSSION: These findings highlight the centrality of non-specific ED symptoms in the ED symptom network and suggest that interpersonal distrust may play a functional role through which childhood OCPD traits and ED symptoms are connected.

Can we achieve better recruitment by providing better information? Meta-analysis of 'studies within a trial' (SWATs) of optimised participant information sheets.

BACKGROUND: The information given to people considering taking part in a trial needs to be easy to understand if those people are to become, and then remain, trial participants. However, there is a tension between providing comprehensive information and providing information that is comprehensible. User-testing is one method of developing better participant information, and there is evidence that user-tested information is better at informing participants about key issues relating to trials. However, it is not clear if user-testing also leads to changes in the rates of recruitment in trials, compared to standard trial information. As part of a programme of research, we embedded 'studies within a trial' (SWATs) across multiple ongoing trials to see if user-tested materials led to better rates of recruitment. METHODS: Seven 'host' trials included a SWAT evaluation and randomised their participants to receive routine information sheets generated by the research teams, or information sheets optimised through user-testing. We collected data on trial recruitment and analysed the results across these trials using random effects meta-analysis, with the primary outcome defined as the proportion of participants randomised in a host trial following an invitation to take part. RESULTS: Six SWATs (n=27,805) provided data on recruitment. Optimised participant information sheets likely result in little or no difference in recruitment rates (7.2% versus 6.8%, pooled odds ratio = 1.03, 95% CI 0.90 to 1.19, p-value = 0.63, I2 = 0%). CONCLUSIONS: Participant information sheets developed through user testing did not improve recruitment rates. The programme of work showed that co-ordinated testing of recruitment strategies using SWATs is feasible and can provide both definitive and timely evidence on the effectiveness of recruitment strategies. TRIAL REGISTRATION: Healthlines Depression (ISRCTN14172341) Healthlines CVD (ISRCTN27508731) CASPER (ISRCTN02202951) ISDR (ISRCTN87561257) ECLS (NCT01925625) REFORM (ISRCTN68240461) HeLP Diabetes (ISRCTN02123133).

Performance of composite measures used in a trial of etanercept and methotrexate as monotherapy or in combination in psoriatic arthritis.

OBJECTIVES: To examine which composite measures are most sensitive to change when measuring psoriatic arthritis (PsA) disease activity, analyses compared the responsiveness of composite measures used in a 48-week randomized, controlled trial of MTX and etanercept in patients with PsA. METHODS: The trial randomised 851 patients to receive weekly: MTX (20 mg/week), etanercept (50 mg/week) or MTX plus etanercept. Dichotomous composite measures examined included ACR 20/50/70 responses, minimal disease activity (MDA) and very low disease activity (VLDA). Continuous composite measures examined included Disease Activity Score (28 joints) using CRP (DAS28-CRP), Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI), Disease Activity for Psoriatic Arthritis (DAPSA) and Psoriatic Arthritis Disease Activity Score (PASDAS). RESULTS: At week 24, etanercept-treated groups were significantly more effective than MTX monotherapy to achieve ACR 20 (primary end point) and MDA (key secondary end point). When examining score changes from baseline at week 24 across the five continuous composite measures, PASDAS demonstrated relatively greater changes in the etanercept-treated groups compared with MTX monotherapy and had the largest effect size and standardized response. Joint count changes drove overall score changes at week 24 from baseline in all the continuous composite measures except for PASDAS, which was driven by the Physician and Patient Global Assessments. CONCLUSION: PASDAS was the most sensitive continuous composite measure examined with results that mirrored the protocol-defined primary and key secondary outcomes. Composite measures with multiple domains, such as PASDAS, may better quantify change in PsA disease burden. TRAIL REGISTRATION: https://ClinicalTrials.gov, number NCT02376790.

AIP variant causing familial prolactinoma.

Pathogenic variants in the aryl hydrocarbon receptor-interacting protein (AIP) gene are increasingly recognised as a cause of familial isolated pituitary adenoma. AIP-associated tumours are most commonly growth hormone (GH) producing. In our cohort of 175 AIP mutation positive patients representing 93 kindreds, 139 (79%) have GH excess, 19 have prolactinoma (17 familial and 2 sporadic cases) and out of the 17 clinically non-functioning tumours 4 were subsequently operated and found to be GH or GH & prolactin immunopositive adenoma. Here we report a family with an AIP variant, in which multiple family members are affected by prolactinoma, but none with GH excess. To our knowledge this is the first reported family with an AIP pathogenic variant to be affected solely by prolactinoma. These data suggest that prolactinoma families represent a small subset of AIP mutation positive kindreds, and similar to young-onset sporadic prolactinomas, AIP screening would be indicated.

The influence of exercise during pregnancy on racial/ethnic health disparities and birth outcomes.

BACKGROUND: Non-Hispanic black (NHB) pregnant women disproportionately experience adverse birth outcomes compared to Non-Hispanic white (NHW) pregnant women. The positive effects of prenatal exercise on maternal and neonatal health may mitigate these disparities. This study evaluated the influence of prenatal exercise on racial/ethnic disparities in gestational age (GA), birthweight (BW), and risks of preterm birth (PTB), cesarean section (CS), and low-birthweight (LBW) neonates. METHODS: This study performed a secondary data analysis using data from a 24-week, two-arm exercise intervention trial (ENHANCED by Mom). Women with singleton pregnancies (< 16 weeks), aged 18-40 years, BMI between 18.5-34.99 kg/m2, and no preexisting health conditions were eligible. The aerobic exercisers (EX) participated in 150 min of moderate-intensity weekly exercise while non-exercising controls (CON) attended low-intensity stretching/breathing sessions. Data on GA, PTB (< 37 weeks), BW, LBW (< 2.5 kg), and delivery mode were collected. Poisson, median and linear regressions were performed. RESULTS: Participants with complete data (n = 125) were eligible for analyses (EX: n = 58, CON: n = 67). NHB pregnant women delivered lighter neonates (ß = - 0.43 kg, 95% CI: - 0.68, - 0.18, p = 0.001). After adjusting for prenatal exercise, racial/ethnic disparities in BW were reduced (ß = - 0.39 kg, 95% CI: - 0.65, - 0.13, p = 0.004). Prenatal exercise reduced borderline significant racial/ethnic disparities in PTB (p = 0.053) and GA (p = 0.07) with no effects found for CS and LBW. CONCLUSIONS: The findings of this study demonstrate that prenatal exercise may attenuate the racial/ethnic disparities observed in neonatal BW, and possibly GA and PTB. Larger, diverse samples and inclusion of maternal biomarkers (e.g., cytokines) are encouraged to further evaluate these relationships.

TractaViewer: a genome-wide tool for preliminary assessment of therapeutic target druggability.

SUMMARY: We present software to characterize and rank potential therapeutic (drug) targets with data from public databases and present it in a user-friendly format. By understanding potential obstacles to drug development through the gathering and understanding of this information, combined with robust approaches to target validation to generate therapeutic hypotheses, this approach may provide high quality targets, leading the process of drug development to become more efficient and cost-effective. AVAILABILITY AND IMPLEMENTATION: The information we gather on potential targets concerns small-molecule druggability (ligandability), suitability for large-molecule approaches (e.g. antibodies) or new modalities (e.g. antisense oligonucleotides, siRNA or PROTAC), feasibility (availability of resources such as assays and biological knowledge) and potential safety risks (adverse tissue-wise expression, deleterious phenotypes). This information can be termed 'tractability'. We provide visualization tools to understand its components. TractaViewer is available from https://github.com/NeilPearson-Lilly/TractaViewer. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Benefits of glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI) in improving lung function and reducing exacerbations in patients with moderate-to-very severe COPD: a pooled analysis of the PINNACLE studies.

BACKGROUND: The Phase III PINNACLE studies assessed the efficacy and safety of glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI), a dual long-acting bronchodilator for chronic obstructive pulmonary disease (COPD). Here we present a pre-specified pooled analysis of PINNACLE-1, PINNACLE-2, and PINNACLE-4. METHODS: PINNACLE-1, -2, and -4 were multicenter, double-blind, randomized controlled trials that enrolled patients with moderate-to-very severe COPD, with no requirement for exacerbation history or a high symptom burden. Patients received GFF MDI 18/9.6 µg, glycopyrrolate (GP) MDI 18 µg, formoterol fumarate (FF) MDI 9.6 µg, or placebo MDI, twice-daily for 24 weeks. The primary endpoint of the pooled analysis was the change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) at week 24. Secondary endpoints included COPD exacerbations and clinically important deterioration (CID). Adverse events were also assessed. RESULTS: The pooled intent-to-treat population included 4983 patients; of these, 61.9% had a COPD assessment test (CAT) score ≥15, and 25.0% had experienced ≥1 moderate/severe exacerbation in the past year. At week 24, GFF MDI improved morning pre-dose trough FEV1 versus GP MDI (least squares mean [LSM] difference [95% confidence interval (CI)]: 59 mL [43, 75]), FF MDI (65 mL [48, 81]), and placebo MDI (146 mL [125, 166]); all p < 0.0001. GFF MDI reduced the risk of a moderate/severe exacerbation by 18% (p = 0.0168), 15% (p = 0.0628), and 28% (p = 0.0012) compared with GP MDI, FF MDI, and placebo MDI, respectively. In general, exacerbation risk reduction with GFF MDI versus comparators was greater in subgroups of symptomatic patients (CAT ≥15) and those who had an exacerbation history, than in the pooled intent-to-treat population. The risk of CID was also lower with GFF MDI versus GP MDI (23% decrease), FF MDI (17%), and placebo MDI (49%); all p < 0.0001. All treatments were well tolerated, with no unexpected safety signals. CONCLUSIONS: This pooled analysis of the PINNACLE studies demonstrated that GFF MDI improved lung function and reduced the risk of exacerbations compared with monocomponents and placebo in patients with COPD. Exacerbation reductions with GFF MDI versus comparators were generally greater in patients with higher symptom burden and those with exacerbation history. TRIAL REGISTRATION: ClinicalTrials.gov NCT01854645, NCT01854658, and NCT02343458. Registered 13 May 2013 (NCT01854645, NCT01854658) and 6 January 2015 (NCT02343458).

A genome-wide association study in individuals of African ancestry reveals the importance of the Duffy-null genotype in the assessment of clozapine-related neutropenia.

Individuals of African ancestry in the United States and Europe are at increased risk of developing schizophrenia and have poorer clinical outcomes. The antipsychotic clozapine, the only licensed medication for treatment-resistant schizophrenia, is under-prescribed and has high rates of discontinuation in individuals of African ancestry, due in part to increased rates of neutropenia. The genetic basis of lower neutrophil levels in those of African ancestry has not previously been investigated in the context of clozapine treatment. We sought to identify risk alleles in the first genome-wide association study of neutrophil levels during clozapine treatment, in 552 individuals with treatment-resistant schizophrenia and robustly inferred African genetic ancestry. Two genome-wide significant loci were associated with low neutrophil counts during clozapine treatment. The most significantly associated locus was driven by rs2814778 (ß = -0.9, P = 4.21 × 10-21), a known regulatory variant in the atypical chemokine receptor 1 (ACKR1) gene. Individuals homozygous for the C allele at rs2814778 were significantly more likely to develop neutropenia and have to stop clozapine treatment (OR = 20.4, P = 3.44 × 10-7). This genotype, also termed "Duffy-null", has previously been shown to be associated with lower neutrophil levels in those of African ancestry. Our results indicate the relevance of the rs2814778 genotype for those taking clozapine and its potential as a pharmacogenetic test, dependent on the outcome of additional safety studies, to assist decision making in the initiation and on-going management of clozapine treatment.

Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial.

BACKGROUND: Symptomatic relief is the primary goal of percutaneous coronary intervention (PCI) in stable angina and is commonly observed clinically. However, there is no evidence from blinded, placebo-controlled randomised trials to show its efficacy. METHODS: ORBITA is a blinded, multicentre randomised trial of PCI versus a placebo procedure for angina relief that was done at five study sites in the UK. We enrolled patients with severe (≥70%) single-vessel stenoses. After enrolment, patients received 6 weeks of medication optimisation. Patients then had pre-randomisation assessments with cardiopulmonary exercise testing, symptom questionnaires, and dobutamine stress echocardiography. Patients were randomised 1:1 to undergo PCI or a placebo procedure by use of an automated online randomisation tool. After 6 weeks of follow-up, the assessments done before randomisation were repeated at the final assessment. The primary endpoint was difference in exercise time increment between groups. All analyses were based on the intention-to-treat principle and the study population contained all participants who underwent randomisation. This study is registered with ClinicalTrials.gov, number NCT02062593. FINDINGS: ORBITA enrolled 230 patients with ischaemic symptoms. After the medication optimisation phase and between Jan 6, 2014, and Aug 11, 2017, 200 patients underwent randomisation, with 105 patients assigned PCI and 95 assigned the placebo procedure. Lesions had mean area stenosis of 84·4% (SD 10·2), fractional flow reserve of 0·69 (0·16), and instantaneous wave-free ratio of 0·76 (0·22). There was no significant difference in the primary endpoint of exercise time increment between groups (PCI minus placebo 16·6 s, 95% CI -8·9 to 42·0, p=0·200). There were no deaths. Serious adverse events included four pressure-wire related complications in the placebo group, which required PCI, and five major bleeding events, including two in the PCI group and three in the placebo group. INTERPRETATION: In patients with medically treated angina and severe coronary stenosis, PCI did not increase exercise time by more than the effect of a placebo procedure. The efficacy of invasive procedures can be assessed with a placebo control, as is standard for pharmacotherapy. FUNDING: NIHR Imperial Biomedical Research Centre, Foundation for Circulatory Health, Imperial College Healthcare Charity, Philips Volcano, NIHR Barts Biomedical Research Centre.

Utility of administrative and clinical data to predict major change in medical treatment in US Veterans enrolled in the Veterans Affairs Rheumatoid Arthritis (VARA) registry.

OBJECTIVES: To examine factors associated with major therapeutic changes (MTC) among US Veterans with moderate/severe rheumatoid arthritis (RA) based on Disease Activity Score based on 28 joints (DAS28). METHODS: We used data from patients enrolled in the Veterans Affairs Rheumatoid Arthritis (VARA) registry from 1/1/2006 through 12/31/2014. The index date was a clinic visit with DAS28 >3.2 (moderate/severe disease) following an 18-month pre-index period that included ≥2 DAS28 measurements ≥60 days apart. The patients were followed for MTC from 7 days pre-index through 90 days post-index. Poisson multivariable regression models were used to identify associations with MTC. Chart review of a subset of randomly selected patients explored factors that impacted therapeutic decisions. RESULTS: Among 941 patients, 396 (42.1%) had MTC. Of these, 369 (39.2%) patients had worsening DAS28 at index, 118 (12.5%) had DAS28 improvements, and 454 (48.2%) patients had no change in DAS28 versus pre-index DAS28. Of the patients with worsening DAS28, no change in DAS28, and improved DAS28, respectively, 50.5%, 62.6%, and 70.3% had no MTC. Regression analyses showed index DAS28, oral steroid or non-biologic disease-modifying anti-rheumatic drug (nbDMARD) use in the previous year were associated with an increased likelihood of MTC; use of nbDMARDs in the previous 90 days was associated with a decreased likelihood of MTC. The most common reason for not modifying therapy despite DAS28 >3.2 was a judgement of mild disease. CONCLUSIONS: Clinicians frequently do not institute major therapeutic changes despite DAS28 indicating moderate/severe disease activity; multiple factors are involved in real-world treatment decisions.