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The spatiotemporal structure of the human microbiome1,2, proteome3 and metabolome4,5 reflects and determines regional intestinal physiology and may have implications for disease6. Yet, little is known about the distribution of microorganisms, their environment and their biochemical activity in the gut because of reliance on stool samples and limited access to only some regions of the gut using endoscopy in fasting or sedated individuals7. To address these deficiencies, we developed an ingestible device that collects samples from multiple regions of the human intestinal tract during normal digestion. Collection of 240 intestinal samples from 15 healthy individuals using the device and subsequent multi-omics analyses identified significant differences between bacteria, phages, host proteins and metabolites in the intestines versus stool. Certain microbial taxa were differentially enriched and prophage induction was more prevalent in the intestines than in stool. The host proteome and bile acid profiles varied along the intestines and were highly distinct from those of stool. Correlations between gradients in bile acid concentrations and microbial abundance predicted species that altered the bile acid pool through deconjugation. Furthermore, microbially conjugated bile acid concentrations exhibited amino acid-dependent trends that were not apparent in stool. Overall, non-invasive, longitudinal profiling of microorganisms, proteins and bile acids along the intestinal tract under physiological conditions can help elucidate the roles of the gut microbiome and metabolome in human physiology and disease.

The objective of this study was to examine differences in parenting, psychological well-being, and economic outcomes between fathers receiving two different programs offered by FathersFamilies Support Center for economically disadvantaged fathers: (a) Family Formation (FF), a 6-week/240-h program focused on economic stability/mobility, responsible fatherhood, and healthy relationships, with case management and legal services; (b) Economic Stability (ES), a 4-week/80-h program focused only on economic stability with limited case management and legal services. A randomized controlled trial (RCT) was used to compare fathers in FF (n = 350) vs. ES (n = 342). Surveys were administered at enrollment and 3- and 12-months postintervention. Linear and generalized linear mixed models were used to assess changes in program outcomes over time and across study groups. Four hundred and eighty-two fathers responded to either follow-up survey (251 FF, 231 ES). Nearly all (98%) were non-white (93% Black, 5% other/mixed race) and were on average 34 years old. Approximately 46% attended ≥75% of program sessions (FF 48% vs. ES 44%). Both FF and ES groups experienced improvements in parenting, psychological well-being, and financial outcomes after the programs, but changes in outcomes over time did not differ significantly by program. The lack of difference in outcomes between fathers in FF and ES groups could be due to a similar core focus on employment-related curriculum for both groups. Gaining financial stability could have contributed to positive improvements in other fatherhood domains. Implications for future research and practice are discussed herein.El objetivo de este estudio fue analizar las diferencias en la crianza, el bienestar psicológico y los resultados económicos entre padres que recibían dos programas diferentes ofrecidos por el Centro de Apoyo a los Padres y las Familias (FathersFamiliares Support Center) para padres desfavorecidos económicamente: (a) Formación de una Familia (Family Formation, FF), un programa de 6 semanas/240 horas centrado en la estabilidad/movilidad económica, la paternidad responsable y las relaciones saludables, con gestión de casos y servicios legales; (b) Estabilidad Económica (Economic Stability, ES), un programa de 4 semanas/80 horas centrado solamente en la estabilidad económica con poca gestión de casos y servicios legales. Se usó un ensayo controlado aleatorizado para comparar a los padres de FF (n=350) con los de ES (n=342). Se realizaron encuestas en la inscripción y a los 3 y a los 12 meses posteriores a la intervención. Se usaron modelos lineales y modelos mixtos lineales generalizados para evaluar los cambios en los resultados de los programas con el tiempo y entre los grupos de estudio. 482 padres respondieron a cada encuesta de seguimiento (251 FF, 231 ES). Casi todos (el 98 %) eran de color (el 93 % negros, el 5 % de otra raza o de raza mestiza) y tenían, en promedio, 34 años. Aproximadamente el 46 % asistió a más del 75 % de las sesiones de los programas (el 48 % de FF frente al 44 % de ES). Tanto el grupo de FF como el de ES tuvieron mejoras en la crianza, en el bienestar psicológico y en los resultados económicos después de los programas, pero los cambios en los resultados con el tiempo no variaron significativamente por programa. La falta de diferencia en los resultados entre los padres del grupo de FF y los del grupo de ES podría deberse a un enfoque principal similar en un currículo relacionado con el empleo para ambos grupos. La adquisición de estabilidad económica podría haber contribuido a mejoras positivas en otras áreas de la paternidad. Se comentan las consecuencias para la futura investigación y la práctica.本研究旨在研究那些接受了“父亲与家庭支持中心”为经济困难的父亲提供的两种不同计划的父亲在养育子女、心理健康和经济成果方面的差异：(a) 家庭组建（FF），一个为期6周/240小时的项目，侧重于经济稳定/流动性、负责任的父亲、健康的关系，并提供个案管理和法律服务；(b) 经济稳定（ES），一个为期4周/80小时的项目，仅侧重于经济稳定，提供有限的个案管理和法律服务。一个随机对照试验（RCT）被用来比较参加FF（n=350）和ES（n=342）的父亲。调查是在入学时和干预后3个月和12个月进行的。线性和广义线性混合模型被用来评估项目结果随时间和不同研究组的变化。482名父亲都回应了随后的调查（251名FF，231名ES）。几乎所有的人（98%）都是非白人（93%为黑人，5%为其他/混合种族），平均年龄为34岁。大约46%的人参加了≥75%的项目会议（FF 48% vs ES 44%）。FF组和ES组在项目结束后，在养育子女、心理健康和财务状况方面都有所改善，但随着时间的推移，结果的变化并没有因项目而有明显的不同。FF组和ES组的父亲在结果上没有差异，这可能是由于两组在就业相关课程上的核心重点相似。获得经济稳定可能有助于其他父亲领域的积极改善。本文讨论了对未来研究和实践的影响。.

Introduction/objectives We assess the impact of switching versus staying on the same tofacitinib dose on efficacy and safety in patients with rheumatoid arthritis (RA). Methods ORAL Sequel was an open-label, long-term extension study of patients with RA receiving tofacitinib 5 or 10 mg BID for up to 9.5 years. Tofacitinib doses could be switched during the study at investigator discretion. In this post hoc analysis, data from ORAL Sequel were stratified into four groups: 5 → 10 mg BID (Dose-up); 5 mg BID (Stay-on 5); 10 → 5 mg BID (Dose-down); and 10 mg BID (Stay-on 10). Efficacy assessments over 12 months included: change from baseline in 4-component Disease Activity Score in 28 joints, erythrocyte sedimentation rate (DAS28), and DAS28 minimum clinically important difference, remission, and low disease activity (LDA) rates. Safety was assessed for the study duration. Results Generally, DAS28 improvements and minimum clinically important difference rates were significantly greater (p Conclusion In patients with RA receiving open-label tofacitinib, this analysis found that some benefited from increasing dose from 5 to 10 mg BID and did not find that reducing dose from 10 to 5 mg BID affected efficacy or that dose switching in either direction affected safety. Study registration ClinicalTrials.gov number NCT00413699. Registered December 20, 2006. https://clinicaltrials.gov/ct2/show/NCT00413699 Key Points• This post hoc analysis of data from the long-term extension study, ORAL Sequel, assessed the impact of dose switching between tofacitinib 5 and 10 mg twice daily (BID), at the investigator’s discretion, on efficacy and safety in patients with rheumatoid arthritis (RA).• Dosing up from tofacitinib 5 to 10 mg BID was associated with improved efficacy up to 12 months versus staying on 5 mg BID, and dosing down from 10 to 5 mg BID was not generally associated with a significant loss of efficacy.• Safety outcomes were generally consistent across dose groups and did not change markedly after switching dose in either direction.• These findings can help to inform physicians on what may be expected in terms of efficacy and safety when adjusting tofacitinib dose according to clinical need. The recommended tofacitinib dosage for the treatment of RA in most jurisdictions is 5 mg BID.

Objectives RA patients who fail to respond to MTX can receive biologic dMARDs (bDMARDs). The Torque Teno Virus (TTV) is a potential novel candidate for monitoring of immunosuppression. We explore TTV in these patients and its association with clinical response to bDMARDs. Methods The BioBio Study is a multicentre randomized open-label trial, including RA patients with insufficient response to MTX. Patients were randomized to either TNFi (infliximab, INF), anti-IL-6 (tocilizumab, TCZ), CTLA4-Ig (abatacept, ABA) or anti-CD20 (rituximab, RTX) in addition to MTX. PCR was used to quantify TTV in the peripheral blood. Results TTV was measured in 95 patients (INF, n = 23; TCZ, n = 22; ABA, n = 27; RTX; n = 23). TTV increased by a median of 4.5 × 104 copies/ml [c/ml; interquartile range (IQR) 0–7.5 × 105] after 3 months. TTV levels at month 3 were associated with the Simplified Disease Activity Index (SDAI) (P = 0.03) and the Clinical Disease Activity Index (CDAI) response (P = 0.026) at month 6. A TTV cut-off level of 1.2 × 106 c/ml at month 3 had a positive likelihood ratio of 2.7 for prediction of an 85% reduction in SDAI at month 6. Conclusion Our data suggest that TTV levels increase upon TNF, CD20 and costimulation blockade and are associated with the clinical response to bDMARDs in RA patients. Trial registration ClinicalTrials.gov; https://clinicaltrials.gov; NCT01638715

BACKGROUND HIV-exposed uninfected (HEU) individuals are predisposed to adverse health outcomes, which in part may stem from the influence of an altered intrauterine milieu on fetal programming. The placenta serves as a readout for the effects of the maternal environment on the developing fetus and may itself contribute to the pathogenesis of disease. SETTING US academic health system. METHODS We leveraged a previously established registry-based cohort of HEU adolescents and young adults to identify 26 subjects for whom placental histopathology was available. We further obtained placental tissue from 29 HIV-unexposed pregnancies for comparison. We examined differences in placental histopathology between the groups and related villous vascularity in the HEU group to prenatal maternal characteristics and long-term health outcomes. RESULTS Placentas from HEU pregnancies demonstrated a higher blood vessel count per villus as compared with controls (5.9 ± 1.0 vs. 5.4 ± 0.8; P = 0.05), which was independent of maternal prenatal age, race, body mass index, smoking status, hemoglobin, and gestational age. Furthermore, within the HEU group, lower CD4+ T-cell count during pregnancy was associated with greater placental vascularity (r = -0.44; P = 0.03). No significant relationships were observed between placental blood vessel count per villus and body mass index z-score or reactive airway disease among HEU individuals later in life. CONCLUSIONS Placentas from HEU pregnancies demonstrated increased villous vascularity compared with HIV-unexposed controls in proportion to the severity of maternal immune dysfunction. Further studies are needed to examine intrauterine exposure to hypoxia as a potential mechanism of fetal programming in HIV.

A hallmark of surgical training is resident involvement in operative procedures. While resident-assisted surgeries have been deemed generally safe, few studies have rigorously isolated the impact of resident post-graduate year (PGY) level on post-operative outcomes in a neurosurgical patient population. The objective of this study is to evaluate the relationship between resident training level and outcomes following single-level, posterior-only lumbar fusion, after matching on key patient demographic/clinical characteristics and attending surgeon.This coarsened-exact matching (CEM) study analyzed 2338 consecutive adult patients who underwent single-level lumbar fusion with a resident assistant surgeon at a multi-hospital university health system from 2013 to 2019. Primary outcomes were 30-day and 90-day readmissions, Emergency Department (ED) visits, reoperations, surgical complications, and mortality. First, univariate logistic regression examined the relationship between PGY level and outcomes. Then, CEM was used to control for key patient characteristics - such as race and comorbid status - and supervising attending surgeon, between the most junior (PGY-2)-assisted cases and the most senior (PGY-7)-assisted cases, thereby isolating the relationship between training level and outcomes.Among all patients, resident training level was not associated with risk of adverse post-surgical outcomes. Similarly, between exact-matched cohorts of PGY-2- and PGY-7-assisted cases, no significant differences in adverse events or discharge disposition were observed. Patients with the most senior resident assistant surgeons demonstrated longer length of stay (mean 100.5 vs. 93.8 h, p = 0.022) and longer duration of surgery (mean 173.5 vs. 159.8 min, p = 0.036).Training level of the resident assistant surgeon did not impact adverse outcomes provided to patients in the setting of single-level, posterior-only lumbar fusion. These findings suggest that attending surgeons appropriately manage cases with resident surgeons at different levels of training.

Background Relevant atrial cardiomyopathy (ACM), defined as a left atrial (LA) low-voltage area ≥ 2 cm2 at 0.5 mV threshold on endocardial contact mapping, is associated with new-onset atrial fibrillation (AF), higher arrhythmia recurrence rates after pulmonary vein isolation (PVI), and an increased risk of stroke. The current study aimed to assess two non-invasive echocardiographic parameters, LA emptying fraction (EF) and LA longitudinal strain (LAS, during reservoir (LASr), conduit (LAScd) and contraction phase (LASct)) for the diagnosis of ACM and prediction of arrhythmia outcome after PVI. Methods We prospectively enrolled 60 consecutive, ablation-naive patients (age 66 ± 9 years, 80% males) with persistent AF. In 30 patients (derivation cohort), LA-EF and LAS cut-off values for the presence of relevant ACM (high-density endocardial contact mapping in sinus rhythm prior to PVI at 3000 ± 1249 sites) were established in sinus rhythm and tested in a validation cohort (n = 30). Arrhythmia recurrence within 12 months was documented using 72-h Holter electrocardiograms. Results An LA-EF of Conclusion The echocardiographic parameters LA-EF and LAS allow accurate, non-invasive diagnosis of ACM and prediction of arrhythmia recurrence after PVI. Graphic abstract

We contacted a random sample of social/personality psychologists in the United States and asked for copies of their graduate syllabi. We coded more than 3,400 papers referenced on these syllabi for gender of authors as well as other characteristics. Less than 30% of the papers referenced on these syllabi were written by female first authors, with no evidence of a trend toward greater inclusion of papers published by female first authors since the 1980s. The difference in inclusion rates of female first-authored papers could not be explained by a preference for including classic over contemporary papers in syllabi (there was evidence of a recency bias instead) or the relative availability of female first-authored papers in the published literature. Implications are discussed.

The coronavirus disease 2019 (COVID-19) pandemic forced the suspension of in-person education in schools serving students in kindergarten through 12th grade (K–12) across the United States. As time passed, teachers, students, and parents struggled with remote education. With limited guidance at the federal level, physicians and school leaders across the country collaborated to develop local solutions for schools. This article describes the lessons learned from the development of 4 academic-community partnerships and collaboration among these partnerships to provide national leadership on managing COVID-19 mitigation in the K–12 environment. In addition, we describe a pathway forward for using academic-community partnerships to improve child health.

The cone-shaped mature HIV-1 capsid is the main orchestrator of early viral replication. After cytosolic entry, it transports the viral replication complex along microtubules towards the nucleus. While it was initially believed that the reverse transcribed genome is released from the capsid in the cytosol, recent observations indicate that a high amount of capsid protein (CA) remains associated with subviral complexes during import through the nuclear pore complex (NPC). Observation of post-entry events via microscopic detection of HIV-1 CA is challenging, since epitope shielding limits immunodetection and the genetic fragility of CA hampers direct labeling approaches. Here, we present a minimally invasive strategy based on genetic code expansion and click chemistry that allows for site-directed fluorescent labeling of HIV-1 CA, while retaining virus morphology and infectivity. Thereby, we could directly visualize virions and subviral complexes using advanced microscopy, including nanoscopy and correlative imaging. Quantification of signal intensities of subviral complexes revealed an amount of CA associated with nuclear complexes in HeLa-derived cells and primary T cells consistent with a complete capsid and showed that treatment with the small molecule inhibitor PF74 did not result in capsid dissociation from nuclear complexes. Cone-shaped objects detected in the nucleus by electron tomography were clearly identified as capsid-derived structures by correlative microscopy. High-resolution imaging revealed dose-dependent clustering of nuclear capsids, suggesting that incoming particles may follow common entry routes.

Background Enthesitis is a hallmark of spondyloarthritis (SpA) with a substantial impact on quality of life. Reports of treatment effectiveness across individual enthesitis sites in real-world patients with axial SpA (axSpA) are limited. We investigated the evolution of enthesitis following tumor necrosis factor inhibitor (TNFi) initiation in axSpA patients, both cumulatively and at specific axial and peripheral sites. Methods AxSpA patients in the Swiss Clinical Quality Management Registry were included if they initiated a TNFi, had an available Maastricht Ankylosing Spondylitis Enthesitis Score, modified to include the plantar fascia (mMASES, 0–15), at start of treatment and after 6 and/or 12 months and ≥12 months follow-up. Logistic regression models were utilized to analyze explanatory variables for enthesitis resolution. Results Overall, 1668 TNFi treatment courses (TCs) were included, of which 1117 (67%) had active enthesitis at baseline. Reduction in mMASES at the 6- and 12-month timepoints was experienced in 72% and 70% of TCs, respectively. Enthesitis resolution at 6/12 months occurred in 37.9%/43.0% of all TNFi TCs and 40.7%/50.9% of first TNFi TCs. At 6 months, a significant reduction in the frequency of enthesitis was observed at all sites, except for the Achilles tendon and plantar fascia among first TNFi TCs, while at 12 months, reduction was significant at all sites in both TC groups. Enthesitis resolved in 60.3–77% across anatomical sites, while new incident enthesitis occurred in 4.0–13.5% of all TNFi TCs at 12 months. Both baseline and new-incident enthesitis occurred most frequently at the posterior superior iliac spine and the fifth lumbar spinous process. Younger age and lower mMASES at baseline were predictors of complete enthesitis resolution, while female sex and second- or later-line TNFi treatment were associated with persistence of enthesitis at 12 months. Conclusion In real-world axSpA patients treated with a TNFi, enthesitis improved in the majority of patients across all anatomical sites. Significant improvement at the Achilles and plantar fascia entheses was observed only at 12 months. Complete and site-specific enthesitis resolution occurred in ≥40% and ≥60% of TCs evaluated at 12 months, with a low incidence of new site-specific enthesitis. Trial registration Not applicable.

We tested the hypothesis that single-cell RNA-sequencing (scRNA-seq) analysis of human kidney allograft biopsies will reveal distinct cell types and states and yield insights to decipher the complex heterogeneity of alloimmune injury. We selected 3 biopsies of kidney cortex from 3 individuals for scRNA-seq and processed them fresh using an identical protocol on the 10x Chromium platform; (i) HK: native kidney biopsy from a living donor, (ii) AK1: allograft kidney with transplant glomerulopathy, tubulointerstitial fibrosis, and worsening graft function, and (iii) AK2: allograft kidney after successful treatment of active antibody-mediated rejection. We did not study T-cell-mediated rejections. We generated 7217 high-quality single cell transcriptomes. Taking advantage of the recipient-donor sex mismatches revealed by X and Y chromosome autosomal gene expression, we determined that in AK1 with fibrosis, 42 months after transplantation, more than half of the kidney allograft fibroblasts were recipient-derived and therefore likely migratory and graft infiltrative, whereas in AK2 without fibrosis, 84 months after transplantation, most fibroblasts were donor-organ-derived. Furthermore, AK1 was enriched for tubular progenitor cells overexpressing profibrotic extracellular matrix genes. AK2, eight months after successful treatment of rejection, contained plasmablast cells with high expression of immunoglobulins, endothelial cell elaboration of T cell chemoattractant cytokines, and persistent presence of cytotoxic T cells. In addition to these key findings, our analysis revealed unique cell types and states in the kidney. Altogether, single-cell transcriptomics yielded novel mechanistic insights, which could pave the way for individualizing the care of transplant recipients.

Acute myeloid leukemia (AML) with t(4;12)(q12;p13) translocation is rare and often associated with an aggressive clinical course and poor prognosis. Previous reports based on fluorescence in situ hybridization (FISH) analysis have suggested that ETV6::PDGFRA fusions are present in these patients, despite the absence of eosinophilia, which is typically found in other hematopoietic malignancies with PDGFRA-containing fusions. We first detected an ETV6-SCFD2 fusion by targeted RNA sequencing in a patient with t(4;12)(q12;p13) who had been diagnosed with an ETV6-PDGFRA fusion by FISH analysis but failed to respond to imatinib. We then retrospectively identified 4 additional patients with AML and t(4;12)(q12;p13) with apparent ETV6-PDGFRA fusions using chromosome and FISH analysis and applied targeted RNA sequencing to archival material. We again detected rearrangements between ETV6 and non-PDGFRA 4q12 genes, including SCFD2, CHIC2, and GSX2. None of the 3 patients who received imatinib based on the incorrect assumption of an ETV6-PDGFRA fusion responded. Our findings highlight the importance of using a sequencing-based assay to confirm the presence of targetable gene fusions, particularly in genomic regions, such as 4q12, with many clinically relevant genes that are too close to resolve by chromosome or FISH analysis. Finally, combining our data and review of the literature, we show that sequence-confirmed ETV6-PDGFRA fusions are typically found in eosinophilic disorders (3/3 cases), and patients with t(4;12)(q12;p13) without eosinophilia are found to have other 4q12 partners on sequencing (17/17 cases).

The Coupling of Pain, Anxiety, and Stress

To analyse rheumatoid arthritis (RA)-patients depending on their individual peak radiographic progression.We selected for the individual peak radiographic progression (Δ Ratingen scores/time) in patients of the Swiss registry SCQM. The baseline disease characteristics were compared using standard descriptive statistics. The change of DAS 28 (disease activity sore) and HAQ-DI (Health Assessment Questionnaire Disability Index) before and after peak progression was analysed with Wilcoxon signed rank tests.Of the 4,033 patients in the analysis, 3,049 patients had a peak radiographic progression rate between 0 and ≤10 in the Ratingen score per year, 773 between 10 and ≤20, 150 between 20 and ≤30, and 61 of30 (defining groups A-D). Rheumatoid factor was more frequent in patient groups with a higher peak radiographic progression (71.1%, 79.2%, 85.3%, 88.5%, groups A-D). Peak radiographic progression at a rate20/year (groups C-D) was not detected after December 2012. When the rate of radiographic progression before and after peak progression was analysed, it was significantly lower. The DAS 28 was significantly higher in all patient groups before peak progression and lower thereafter (p0.001). Average HAQ-DI scores increased after peak radiographic progression in group D (p=0.005) whereas it was stable or even decreased among the patients of the other patient groups.These data show that the highest radiographic progression rates are rare and get less frequent over the last years. Higher disease activity precedes radiographic peak progression. Only the highest individual peak (change of Ratingen score30/year) radiographic progression was followed by an increase of HAQ-DI scores.

Aims Atrial cardiomyopathy (ACM) is associated with new-onset atrial fibrillation, arrhythmia recurrence after pulmonary vein isolation (PVI) and increased risk for stroke. At present, diagnosis of ACM is feasible by endocardial contact mapping of left atrial (LA) low-voltage substrate (LVS) or late gadolinium-enhanced magnetic resonance imaging, but their complexity limits a widespread use. The aim of this study was to assess non-invasive body surface electrocardiographic imaging (ECGI) as a novel clinical tool for diagnosis of ACM compared with endocardial mapping. Methods and results Thirty-nine consecutive patients (66 ± 9 years, 85% male) presenting for their first PVI for persistent atrial fibrillation underwent ECGI in sinus rhythm using a 252-electrode-array mapping system. Subsequently, high-density LA voltage and biatrial activation maps (mean 2090 ± 488 sites) were acquired in sinus rhythm prior to PVI. Freedom from arrhythmia recurrence was assessed within 12 months follow-up. Increased duration of total atrial conduction time (TACT) in ECGI was associated with both increased atrial activation time and extent of LA-LVS in endocardial contact mapping (r = 0.77 and r = 0.66, P Conclusion Analysis of TACT in non-invasive ECGI allows diagnosis of patients with ACM, which is associated with a significantly increased risk for arrhythmia recurrence following PVI.

Background Intracranial hemorrhage (ICH) has been reported to occur in up to 23% of patients with left ventricular assist devices (LVADs). Currently, limited data exists to guide neurosurgical management strategies to optimize outcomes in patients with an LVAD who develop ICH. Methods A systematic review and meta-analysis of the literature was performed to evaluate the mortality rate in these patients following medical and/or surgical management and to evaluate antithrombotic reversal and resumption strategies after hemorrhage. Results 17 studies reporting on 3869 LVAD patients and 545 intracranial hemorrhages spanning investigative periods from 1996 to 2019 were included. The rate of ICH in LVAD patients was 10.6% (411/3869) with 58.6% (231/394) being intraparenchymal hemorrhage (IPH), 23.6% (93/394) subarachnoid hemorrhage (SAH), and 15.5% (61/394) subdural hemorrhage (SDH). Total mortality rates for surgical management 65.6% (40/61) differed from medical management at 45.2% (109/241). There was an increased relative risk of mortality (RR=1.45, 95% CI: 1.10–1.91, p = 0.01) for ICH patients undergoing surgical intervention. The hemorrhage subtype most frequently managed with anticoagulation reversal was IPH 81.8% (63/77), followed by SDH 52.2% (12/23), and SAH 39.1% (18/46). Mean number of days until antithrombotic resumption ranged from 6 to 10.5 days. Conclusion Outcomes remain poor, specifically for those undergoing surgery. As experience with this population increases, prospective studies are warranted to contribute to management and prognostication .

Purpose of Review This review a highlights that to use artificial intelligence (AI) tools effectively for hypertension research, a new foundation to further understand the biology of hypertension needs to occur by leveraging genome and RNA sequencing technology and derived tools on a broad scale in hypertension. Recent Findings For the last few years, progress in research and management of essential hypertension has been stagnating while at the same time, the sequencing of the human genome has been generating many new research tools and opportunities to investigate the biology of hypertension. Cancer research has applied modern tools derived from DNA and RNA sequencing on a large scale, enabling the improved understanding of cancer biology and leading to many clinical applications. Compared with cancer, studies in hypertension, using whole genome, exome, or RNA sequencing tools, total less than 2% of the number cancer studies. While true, sequencing the genome of cancer tissue has provided cancer research an advantage, DNA and RNA sequencing derived tools can also be used in hypertension to generate new understanding how complex protein network, in non-cancer tissue, adapts and learns to be effective when for example, somatic mutations or environmental inputs change the gene expression profiles at different network nodes. The amount of data and differences in clinical condition classification at the individual sample level might be of such magnitude to overwhelm and stretch comprehension. Here is the opportunity to use AI tools for the analysis of data streams derived from DNA and RNA sequencing tools combined with clinical data to generate new hypotheses leading to the discovery of mechanisms and potential target molecules from which drugs or treatments can be developed and tested. Summary Basic and clinical research taking advantage of new gene sequencing-based tools, to uncover mechanisms how complex protein networks regulate blood pressure in health and disease, will be critical to lift hypertension research and management from its stagnation. The use of AI analytic tools will help leverage such insights. However, applying AI tools to vast amounts of data that certainly exist in hypertension, without taking advantage of new gene sequencing-based research tools, will generate questionable results and will miss many new potential molecular targets and possibly treatments. Without such approaches, the vision of precision medicine for hypertension will be hard to accomplish and most likely not occur in the near future.

Background Use of a closed-incisional negative pressure therapy (ci-NPT) dressing is an emerging strategy to reduce surgical site infections (SSIs) in spine surgery that lacks robust data. Objective To determine the impact of a ci-NPT, as compared with a standard dressing, on the development of SSIs after spine surgery. Methods This was a prospective observational study over a 2-yr period. Indications for surgery included degenerative disease, deformity, malignancy, and trauma. Exclusion criteria included anterior and lateral approaches to the spine, intraoperative durotomy, or use of minimally invasive techniques. SSIs up to 60 d following surgery were recorded. Results A total of 274 patients were included. SSI rate was significantly lower with ci-NPT dressing (n = 118) as compared with the standard dressing (n = 156) (3.4 vs 10.9%, P = .02). There was no statistical difference in infection rate for decompression alone procedures (4.2 vs 9.1%, P = .63), but there was a statistically significant reduction with the use of a negative-pressure dressing in cases that required instrumentation (3.2 vs 11.4%, P = .03). Patients at higher risk (instrumentation, deformity, and malignancy) had less SSIs with the use of ci-NPT, although this did not reach statistical significance. There were no complications in either group. Conclusion SSI rates were significantly reduced with a ci-NPT dressing vs a standard dressing in patients who underwent spinal surgery. The higher cost of a ci-NPT dressing might be justified with instrumented cases, as well as with certain high-risk patient populations undergoing spine surgery, given the serious consequences of an infection.

BACKGROUND: RNA sequencing (RNA-Seq) is a molecular tool to analyze global transcriptional changes, deduce pathogenic mechanisms, and discover biomarkers. We performed RNA-Seq to investigate gene expression and biological pathways in urinary cells and kidney allograft biopsies during an acute rejection episode and to determine whether urinary cell gene expression patterns are enriched for biopsy transcriptional profiles. METHODS: We performed RNA-Seq of 57 urine samples collected from 53 kidney allograft recipients (patients) with biopsies classified as acute T cell–mediated rejection (TCMR; n = 22), antibody-mediated rejection (AMR; n = 8), or normal/nonspecific changes (No Rejection; n = 27). We also performed RNA-Seq of 49 kidney allograft biopsies from 49 recipients with biopsies classified as TCMR (n = 12), AMR (n = 17), or No Rejection (n = 20). We analyzed RNA-Seq data for differential gene expression, biological pathways, and gene set enrichment across diagnoses and across biospecimens. RESULTS: We identified unique and shared gene signatures associated with biological pathways during an episode of TCMR or AMR compared with No Rejection. Gene Set Enrichment Analysis demonstrated enrichment for TCMR biopsy signature and AMR biopsy signature in TCMR urine and AMR urine, irrespective of whether the biopsy and urine were from the same or different patients. Cell type enrichment analysis revealed a diverse cellular landscape with an enrichment of immune cell types in urinary cells compared with biopsies. CONCLUSIONS: RNA-Seq of urinary cells and biopsies, in addition to identifying enriched gene signatures and pathways associated with TCMR or AMR, revealed genomic changes between TCMR and AMR, as well as between allograft biopsies and urinary cells.

Left ventricular assist devices (LVAD) provide mechanical circulatory support for patients with advanced heart failure. Intracranial hemorrhage in this population represent a significant management challenge. The objective of this study is to report our initial experience on same-admission outcomes with LVAD patients that presented with various types of intracranial hemorrhage (ICH).A retrospective review of a large volume center over a two-year period was performed. LVAD patients with ICH requiring a neurosurgical consultation were identified. Hemorrhage type, interventions, discharge disposition and cause of death were recorded.27 LVAD patients with ICH received a neurosurgical consultation. The average INR at the time of ICH was 2.7 (1.0-8.8). Hemorrhage types seen were lobar (10/27, 37 %), SAH (5/27, 19 %), SDH (4/27, 15 %), cerebellar ICH (3/27, 11 %), multiple ICH (3/27, 11 %), and hemorrhagic conversion (2/27, 7 %). The overall mortality rate was 48.2 % (13/27), with the highest mortality being in those patients who had multiple ICH at the time of presentation (3/3, 100 %). The majority of patients with ICH (85.2 %) were non-operative. Lobar IPH was3 cm in 80 % (8/10) of these, and 6/8 (75 %) ultimately died. 11 %(3/27) received surgical intervention. Of these, 67 % ultimately withdrew care. 77 % (10/13) of patients died as a result of the ICH. 80 % of patients with SAH were ultimately discharged home.Patients with a LVAD and ICH have a high rate of same-admission mortality (48 %). Hemorrhage location, intra-axial or extra-axial, resulted in patients being a risk for death secondary to either the hemorrhage itself or pump thrombosis, respectively.

Advances in bioinformatics allow identification of single nucleotide polymorphisms (variants) from RNA sequence data. In an allograft biopsy, 2 genomes contribute to the RNA pool, 1 from the donor organ and the other from the infiltrating recipient's cells. We hypothesize that imbalances in genetic variants of RNA sequence data of kidney allograft biopsies provide an objective measure of cellular infiltration of the allograft. We performed mRNA sequencing of 40 kidney allograft biopsies, selected to represent a comprehensive range of diagnostic categories. We analyzed the sequencing reads of these biopsies and of 462 lymphoblastoid cell lines from the 1000 Genomes Project, for RNA variants. The ratio of heterozygous to nonreference genome homozygous variants (Het/Hom ratio) on all autosomes was determined for each sample, and the estimation of stromal and immune cells in malignant tumors using expression data (ESTIMATE) score was computed as a complementary estimate of the degree of cellular infiltration into biopsies. The Het/Hom ratios (P = .02) and the ESTIMATE scores (P < .001) were associated with the biopsy diagnosis. Both measures correlated significantly (r = .67, P < .0001), even though the Het/Hom ratio is based on mRNA sequence variation, while the ESTIMATE score uses mRNA expression. Het/Hom ratio and the ESTIMATE score may offer unbiased and quantitative parameters for characterizing cellular traffic into human kidney allografts.

Background Nailfold capillaroscopy (NC) is an important tool for the diagnosis of systemic sclerosis (SSc). The capillaroscopic skin ulcer risk index (CSURI) was suggested to identify patients at risk of developing digital ulcers (DUs). This study aims to assess the reliability of the CSURI across assessors, the CSURI change during follow-up and the value of the CSURI in predicting new DUs. Methods This multicentre, longitudinal study included SSc patients with a history of DUs. NC images of all eight fingers were obtained at baseline and follow-up and were separately analysed by two trained assessors. Results Sixty-one patients were included (median observation time 1.0 year). In about 40% of patients (assessor 1, n = 24, 39%; assessor 2, n = 26, 43%) no megacapillary was detected in any of the baseline or follow-up images; hence the CSURI could not be calculated. In those 34 patients in whom CSURI scores were available from both assessors (26% male; median age 57 years) the median baseline CSURI was 5.3 according to assessor 1 (IQR 2.6–16.3), increasing to 5.9 (IQR 1.3–12.0) at follow-up. According to assessor 2, the CSURI diminished from 6.4 (IQR 2.4–12.5) to 5.0 (IQR 1.7–10.0). The ability of a CSURI ≥ 2.96 category to predict new DUs was low (for both assessors, positive predictive value 38% and negative predictive value 50%) and the inter-assessor agreements for CSURI categories were fair to moderate. Conclusions In this study, around 40% of patients could not be evaluated with the CSURI due to the absence of megacapillaries. Clinical decisions based on the CSURI should be made with caution. Trial registration Current Controlled Trials, ISRCTN04371709. Registered on 18 March 2011. Electronic supplementary material The online version of this article (10.1186/s13075-018-1733-6) contains supplementary material, which is available to authorized users.

Brincidofovir (CMX001) is an oral agent with activity against double-strand DNA viruses undergoing clinical trials in immunocompromised patients. We report a patient clinically diagnosed with brincidofovir-related gastrointestinal (GI) toxicity and his histologic findings. A 2-year-old boy with medulloblastoma undergoing autologous hematopoietic cell transplantation developed adenovirus viremia 9 days posttransplant. After initial treatment with intravenous cidofovir he was started on oral brincidofovir as part of a clinical trial. He developed hematochezia, anorexia, and emesis 11 weeks later. Sigmoid colon biopsy showed marked crypt drop out, moderate epithelial apoptosis, and lamina propria edema. The pathologic diagnosis was drug-related injury versus infection. Brincidofovir toxicity was diagnosed clinically and the drug was discontinued. His GI symptoms improved in 2 weeks with supportive care and octreotide. Brincidofovir causes GI toxicity and histologically demonstrates epithelial apoptosis and crypt injury, similar to graft versus host disease and mycophenolate mofetil toxicity.

Long-term in vitro liver models are now widely explored for human hepatic metabolic clearance prediction, enzyme phenotyping, cross-species metabolism, comparison of low clearance drugs, and induction studies. Here, we present studies using a long-term liver model, which show how metabolism and active transport, drug-drug interactions, and enzyme induction in healthy and diseased states, such as hepatitis B virus (HBV) infection, may be assessed in a single test system to enable effective data integration for physiologically based pharmacokinetic (PBPK) modeling. The approach is exemplified in the case of (3S)-4-[[(4R)-4-(2-Chloro-4-fluorophenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid RO6889678, a novel inhibitor of HBV with a complex absorption, distribution, metabolism, and excretion (ADME) profile. RO6889678 showed an intracellular enrichment of 78-fold in hepatocytes, with an apparent intrinsic clearance of 5.2 µl/min per mg protein and uptake and biliary clearances of 2.6 and 1.6 µl/min per mg protein, respectively. When apparent intrinsic clearance was incorporated into a PBPK model, the simulated oral human profiles were in good agreement with observed data at low doses but were underestimated at high doses due to unexpected overproportional increases in exposure with dose. In addition, the induction potential of RO6889678 on cytochrome P450 (P450) enzymes and transporters at steady state was assessed and cotreatment with ritonavir revealed a complex drug-drug interaction with concurrent P450 inhibition and moderate UDP-glucuronosyltransferase induction. Furthermore, we report on the first evaluation of in vitro pharmacokinetics studies using HBV-infected HepatoPac cocultures. Thus, long-term liver models have great potential as translational research tools exploring pharmacokinetics of novel drugs in vitro in health and disease.

Background Treatment of meniscus tears within the avascular region represents a significant challenge, particularly in a situation of early osteoarthritis. Cell-based tissue engineering approaches have shown promising results. However, studies have not found a consensus on the appropriate autologous cell source in a clinical situation, specifically in a challenging degenerative environment. The present study sought to evaluate the appropriate cell source for autologous meniscal repair in a demanding setting of early osteoarthritis. Methods A rabbit model was used to test autologous meniscal repair. Bone marrow and medial menisci were harvested 4 weeks prior to surgery. Bone marrow-derived mesenchymal stem cells (MSCs) and meniscal cells were isolated, expanded, and seeded onto collagen-hyaluronan scaffolds before implantation. A punch defect model was performed on the lateral meniscus and then a cell-seeded scaffold was press-fit into the defect. Following 6 or 12 weeks, gross joint morphology and OARSI grade were assessed, and menisci were harvested for macroscopic, histological, and immunohistochemical evaluation using a validated meniscus scoring system. In conjunction, human meniscal cells isolated from non-repairable bucket handle tears and human MSCs were expanded and, using the pellet culture model, assessed for their meniscus-like potential in a translational setting through collagen type I and II immunostaining, collagen type II enzyme-linked immunosorbent assay (ELISA), and gene expression analysis. Results After resections of the medial menisci, all knees showed early osteoarthritic changes (average OARSI grade 3.1). However, successful repair of meniscus punch defects was performed using either meniscal cells or MSCs. Gross joint assessment demonstrated donor site morbidity for meniscal cell treatment. Furthermore, human MSCs had significantly increased collagen type II gene expression and production compared to meniscal cells (p < 0.05). Conclusions The regenerative potential of the meniscus by an autologous cell-based tissue engineering approach was shown even in a challenging setting of early osteoarthritis. Autologous MSCs and meniscal cells were found to have improved meniscal healing in an animal model, thus demonstrating their feasibility in a clinical setting. However, donor site morbidity, reduced availability, and reduced chondrogenic differentiation of human meniscal cells from debris of meniscal tears favors autologous MSCs for clinical use for cell-based meniscus regeneration.

Objectives The aim was to evaluate patient self-assessment of RA disease activity in terms of Routine Assessment of Patient Index Data (RAPID) scores via a Web-based smartphone application (WebApp). Methods In this prospective, multicentre study, adult RA patients were examined by a rheumatologist at baseline and after 3 months. Patients were asked to complete WebApp questionnaires weekly. The time course of patient-assessed RAPID3/4 scores and their correlations with rheumatologist-assessed DAS28, as well as Clinical and Simplified Disease Activity Indices (CDAI/SDAI), were evaluated. Results Eighty patients were included in the analysis (median RA duration, 4.5 years; age, 57 years; 59% female). At baseline, there was a moderate to strong correlation between RAPID3 and DAS28 (r = 0.63), CDAI (r = 0.65) and SDAI (r = 0.61) scores. Similar or stronger correlations were seen at the 3-month follow-up visit (DAS28 r = 0.66, CDAI r = 0.71 and SDAI r = 0.61). Similar correlations were seen between RAPID4 and rheumatologist assessments. Correlations were not influenced by demographics or RA treatment. In the 3-month period, the RAPID3 score changed into a higher severity category than the category at baseline at least once in 47% of patients. When DAS28 scores were predicted from the RAPID3, 11% of patients had an increase of > 1 DAS28 unit during the 3-month observation period. Conclusion Web-based patient assessments were strongly correlated with rheumatologist assessments of RA activity and showed considerable variation during follow-up. This provides a rationale for further exploration of their use as cost-effective tools to monitor RA activity between outpatient visits and to optimize tight control strategies.

ObjectiveThis study assessed the mode of application (oral, intravenous or subcutaneous (SC)) currently employed in the treatment of rheumatoid arthritis (RA) in patients from Qatar in comparison with patients’ individual preferences for the mode of application of their treatment.MethodsThis study included 294 RA patients visiting three clinics at the main referral hospital in Qatar who were interviewed using a standard questionnaire to determine their preference of mode of application for their disease-modifying antirheumatic drug (DMARD) treatment in relation to their currently employed mode of application.ResultsThe majority of patients were female (76%), and 93% of male patients and 61% of female patients in the study clinics were of a nationality other than Qatari. The highest patient preference recorded was for an oral therapy (69%), compared with injection (23%) and intravenous (8%) therapy. In total, 85% of patients expressed a preference to remain on oral therapy compared with 63% and 58% of intravenous and SC injection patients indicating a preference to remain on their current method of administration.ConclusionsThis high preference for oral therapies highlights the considerable need for incorporation of new oral targeted synthetic DMARD therapies into clinical practice within the region.

Cervical laminectomy is a common strategy to decompress the spinal canal. The anatomy of the cervical spine and surrounding critical structures as viewed from the posterior approach is described. The use of a high-speed drill with a footplate attachment to make laminar troughs with an en-bloc subaxial cervical laminectomy is described with a discussion on surgical technique and complication avoidance. This technique allows for a safe, comfortable, and rapid decompression of the cervical spine with minimal risk. For routine cases, this may potentially be more safe and cost-effective than using a cutting bur or bone scalpel attachment.

Acute rejection of human allografts has been viewed mostly through the lens of adaptive immunity, and the intragraft landscape of innate immunity genes has not been characterized in an unbiased fashion. We performed RNA sequencing of 34 kidney allograft biopsy specimens from 34 adult recipients; 16 were categorized as Banff acute T cell-mediated rejection (TCMR) and 18 as normal. Computational analysis of intragraft mRNA transcriptome identified significantly higher abundance of mRNA for pattern recognition receptors in TCMR compared with normal biopsies, as well as increased expression of mRNAs for cytokines, chemokines, interferons, and caspases. Intragraft levels of calcineurin mRNA were higher in TCMR biopsies, suggesting underimmunosuppression compared with normal biopsies. Cell-type-enrichment analysis revealed higher abundance of dendritic cells and macrophages in TCMR biopsies. Damage-associated molecular patterns, the endogenous ligands for pattern recognition receptors, as well markers of DNA damage were higher in TCMR. mRNA expression patterns supported increased calcium flux and indices of endoplasmic, cellular oxidative, and mitochondrial stress were higher in TCMR. Expression of mRNAs in major metabolic pathways was decreased in TCMR. Our global and unbiased transcriptome profiling identified heightened expression of innate immune system genes during an episode of TCMR in human kidney allografts.

Aims of the study To describe patterns of systemic lupus erythematosus (SLE) care and the clinical effectiveness of belimumab plus standard of care therapy in a real-world clinical setting in Switzerland. Methods This multicentre, observational, retrospective cohort study included adults with SLE who initiated belimumab as part of their usual care at least six months before data analysis. The primary outcome was the overall clinical response, assessed by a physician on a Physicianrs Global Assessment-like scale, to six monthsr treatment with belimumab. Secondary outcomes included improvement in disease activity, SLE manifestations and changes in corticosteroid use. Results 53 patients (81% female) from three hospitals were included. At index (belimumab initiation), 23 patients (43%) had mild, 23 (43%) had moderate, and 7 (13%) had severe SLE. Overall improvement in disease activity in patients receiving belimumab was: g80% in 6 patients (11%), g50% in 12 (23%), g20% in 31 (58%), l20% in 13 (25%), and no improvement in 9 (17%). Mean Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index score decreased from 8.0 at index to 3.6 at six months post index in the 27 patients assessed. In addition, a g50% improvement in arthritis, fatigue, rash, low complement (C3, C4 or total haemolytic complement activity), and anti-double-stranded deoxyribonucleic acid antibody levels was experienced six months post index by 10 (38%), 3 (16%), 6 (38%), 2 (12%) and 4 (16%) patients who presented the manifestations at index respectively. At index, 41 patients (77%) received oral corticosteroids at a mean dose of 11.6 mg/day, which decreased to 5.9 mg/day at six months post index. Of the 31 patients receiving a high dose of corticosteroids (g7.5 mg/day) at index, 18 required l7.5 mg/day and a further two discontinued corticosteroids at six months post index. Conclusions This study provides real-world insight into belimumab use in clinical practice in Switzerland. In line with findings from other countries, Swiss patients with SLE who received belimumab demonstrated clinical and serological improvements in SLE and a reduction in corticosteroid use after six months of treatment.

OBJECTIVE Electrical impedance tomography (EIT) is a non-invasive and radiation-free bedside monitoring technology, primarily used to monitor lung function. First experimental data shows that the descending aorta can be detected at different thoracic heights and might allow the assessment of central hemodynamics, i.e. stroke volume and pulse transit time. APPROACH First, the feasibility of localizing small non-conductive objects within a saline phantom model was evaluated. Second, this result was utilized for the detection of the aorta by EIT in ten anesthetized pigs with comparison to thoracic computer tomography (CT). Two EIT belts were placed at different thoracic positions and a bolus of hypertonic saline (10 ml, 20%) was administered into the ascending aorta while EIT data were recorded. EIT images were reconstructed using the GREIT model, based on the individual's thoracic contours. The resulting EIT images were analyzed pixel by pixel to identify the aortic pixel, in which the bolus caused the highest transient impedance peak in time. MAIN RESULTS In the phantom, small objects could be located at each position with a maximal deviation of 0.71 cm. In vivo, no significant differences between the aorta position measured by EIT and the anatomical aorta location were obtained for both measurement planes if the search was restricted to the dorsal thoracic region of interest (ROIs). SIGNIFICANCE It is possible to detect the descending aorta at different thoracic levels by EIT using an intra-aortic bolus of hypertonic saline. No significant differences in the position of the descending aorta on EIT images compared to CT images were obtained for both EIT belts.

We compared mothers who exercised predominantly in group settings, those who exercised predominantly in individual settings, and those who exercised equally in group and individual contexts among the following: (a) satisfaction of basic psychological needs (autonomy, competence, and relatedness); (b) self-determined exercise motivation; and (c) psychological well-being. With clear implications for mothers' exercise interventions we found that exercising either predominantly in group contexts or in mixed group and individual settings was associated with mothers having significantly higher satisfaction of basic psychological needs and self-determined exercise motivation than those exercising predominantly alone.

To analyse efficacy and safety of tocilizumab in patients with rheumatoid arthritis (RA) and an inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) and/or tumour necrosis factor (TNF) inhibitors of the Swiss and Austrian patients from the ACT-SURE study. This is a sub-analysis of RA patients from Switzerland and Austria, who participated in the international phase 3b, open-label, ACT-SURE study. Patients with an inadequate response to csDMARDs or TNF antagonists receiving 8 mg/kg of IV tocilizumab every 4 weeks during a 24-week time period were included into the study. Therapy with one or more csDMARDs could be continued as combination therapy with tocilizumab (Combo) or stopped, resulting in tocilizumab monotherapy (Mono), at the treating physician’s discretion. These two patient groups were analysed in separate and compared. Overall, 107 (22 on Mono vs. 85 on Combo) patients were treated with tocilizumab. The percentage of patients with at least one adverse event was significantly lower in the tocilizumab combination (58.8%) as compared to the monotherapy group (81.8%, p = 0.0458). No differences in ACR20/50/70/90 response rates were observed between both treatment groups at week 24 (Mono 63.6, 40.9, 22.7, and 18.2% vs. Combo 61.2, 43.5, 25.9, and 10.6%). The median time to low disease activity (LDA) was significantly shorter in patients treated with tocilizumab combination therapy (Mono 9.1, Combo 7.9 weeks, log rank p = 0.038). In this post hoc regional sub-analysis of the ACT-SURE study, no differences for disease activity were found comparing the two patient groups at week 24. However, median time to LDA was statistically shorter in patients treated with tocilizumab combination therapy as compared to tocilizumab monotherapy. Consequently, adding tocilizumab to csDMARD therapy rather than changing to tocilizumab monotherapy may be, in our opinion, the safest strategy to reach maximum effect in RA patients with active disease despite treatment with csDMARD. csDMARDs can be withdrawn either immediately due to adverse events or after at least low disease activity has been reached.

The scientific quality of social and personality psychology has been debated at great length in recent years. Despite research on the prevalence of Questionable Research Practices (QRPs) and the replicability of particular findings, the impact of the current discussion on research practices is unknown. The current studies examine whether and how practices have changed, if at all, over the last 10 years. In Study 1, we surveyed 1,166 social and personality psychologists about how the current debate has affected their perceptions of their own and the field's research practices. In Study 2, we coded the research practices and critical test statistics from social and personality psychology articles published in 2003-2004 and 2013-2014. Together, these studies suggest that (a) perceptions of the current state of the field are more pessimistic than optimistic; (b) the discussion has increased researchers' intentions to avoid QRPs and adopt proposed best practices, (c) the estimated replicability of research published in 2003-2004 may not be as bad as many feared, and (d) research published in 2013-2014 shows some improvement over research published in 2003-2004, a result that suggests the field is evolving in a positive direction. (PsycINFO Database Record

Transition from genetic risk to the development of systemic autoimmunity associated with rheumatoid arthritis (RA) is considered a key step for the development of RA and often referred to as the immune onset of the disease. The aim of this study is to identify predictors for the presence of anticitrullinated protein antibodies (ACPA) as a marker of systemic autoimmunity associated with RA in a high-risk population, an ongoing cohort of first-degree relatives of patients with RA. We assessed the presence of ACPA in individuals without clinical evidence of RA. We examined characteristics associated with ACPA positivity using general estimation equations to account for multiple observations per individual. A total of 1159 serum samples from 1025 subjects were analyzed, 69 samples (6%) were ACPA-positive, and 227 (20%) positive for rheumatoid factor. Participants had a median age of 45 years (interquartile range (IQR): 33-55) at baseline and 76% were women. Overall, ACPA positivity increased with age (p

To analyse the association between female hormonal factors and the development of systemic autoimmunity associated with RA in women at increased risk for RA, namely first-degree relatives of patients with RA (RA-FDRs).In an ongoing cohort study of RA-FDRs, we analysed all women with available ACPA status. The primary outcome was ACPA positivity. The predictors of interest were female hormonal factors, such as oral contraceptives, breastfeeding, post-menopausal status, early post-menopausal period and total number of ovulatory years.A total of 768 female RA-FDRs were analysed, of which 42 (5%) had developed ACPA positivity. ACPA-positive women were older (52 vs 44 years, P = 0.001). Hormonal factors significantly and independently associated with the presence of ACPA were the post-menopausal (P0.001) and the early post-menopausal periods (P = 0.040).In women at increased risk of RA, characteristic systemic autoimmunity was associated with menopause, suggesting that the acute decline in ovarian function might contribute to the development of autoimmunity associated with RA and potentially to the increased risk of RA in women.

The main goal of this study was to analyse whether initial addition of glucocorticoid to DMARD therapy influences the long-term course of the disease in patients with early rheumatoid arthritis. All patients from the Swiss RA cohort SCQM with recent-onset arthritis (disease duration ≤1 year) were analysed. The exposure of interest was the use of glucocorticoids (GCs) at baseline. As primary outcome, we considered clinical and radiographic disease progression, assessed by the disease activity (disease activity score, DAS-28), function (health assessment questionnaire disability index, HAQ-DI) and structural joint damage (Ratingen erosion score). The baseline disease characteristics were compared using standard descriptive statistics. The effects of initial GC use on disease progression during follow-up were estimated using linear mixed models with random slope and random intercept, adjusted for potential confounders. In total, 592 patients with early disease were available, with 4.3 years of follow-up (average). Of these, 363 were initially treated with glucocorticoids (GC patients) and 228 were not (no-GC patients). DAS-28 (4.6 vs. 4.3, p = 0.01) and the HAQ-DI (0.94 vs. 0.82, p = 0.01) were higher at baseline in GC patients, while other prognostic factors were balanced at baseline. Neither the change of DAS-28, of HAQ-DI nor of the development of joint erosions differed between the two groups during follow-up. Escalation of treatment employing biologics was documented in 18.0% of the no-GC patients and 27.3% of the GC patients (p

Deep brain stimulation (DBS) represents an established treatment option in a growing number of movement disorders. Recent case reports suggest beneficial effect of globus pallidus internus (GPi)-DBS in selected patients suffering from Huntington's disease with marked disabling chorea. We present a 41-year-old man with genetically confirmed HD following quadruple GPi- and subthalamic nucleus (STN)-DBS. Motor function was assessed by Abnormal Involuntary Movement Scale (AIMS) and by Unified Huntington Disease Rating Scale (UHDRS) presurgery and postsurgery for up to 4 years. Furthermore, cognitive, neuropsychiatric state and quality of life (QoL) including life satisfaction (QLS) were annually evaluated. Chorea assessed by AIMS and UHDRS subscores improved by 52 and 55 %, 45 and 60 %, 35 and 45 % and 55-66 % at 1-4 years, respectively, compared to presurgical state following GPi-STN-DBS. During these time periods bradykinesia did not increase following separate STN- and combined GPi-STN-DBS compared to presurgical state. Mood, QoL and QLS were ameliorated. However, dysexecutive symptoms increased at 4 years postsurgery. The present case report suggests that bilateral GPi- and STN-DBS may represent a new treatment avenue in selected HD patients. Clinically, GPi-DBS attenuated chorea and was associated with a larger effect-adverse effect window compared to STN-DBS. However, GPi-DBS-induced bradykinesia may emerge as one main limitation of GPi-DBS in HD. Thus, quadruple GPi-STN-DBS may be indicated, if separate GPi-DBS does not result in sufficient control of motor symptoms. Future controlled studies need to confirm if the present anecdotal observation of additive beneficial effects of GPi- and STN-DBS in a HD patient with severe generalized chorea and relatively intact cognitive and affective functions indeed represents a new therapeutic option.

Background Rivastigmine is the only cholinesterase inhibitor (ChEI) available as transdermal patch. The patch was developed to improve gastrointestinal tolerability and treatment adherence to higher dosages as compared with oral medication. Preferences of patients and caregivers for the patch were reported; however, neither patient compliance nor caregiver burden has yet been measured under routine practice conditions. Methods This was a prospective, multi-centre, observational study in patients with Alzheimer's disease treated with rivastigmine patch in Germany. To compare the transdermal with oral dosage forms, physicians were asked to enrol patients who recently switched from oral to transdermal medication. Beyond effectiveness and tolerability, outcome measures were drug adherence evaluated by the Morisky questionnaire, and caregiver burden, measured as the daily time expenditure for dressing the patient, controlling appearance and administration of medication. Results In total, 1104 outpatients (57.5% female gender; mean age 77 ± 7 years) were enrolled in 220 sites. After 6 months of treatment, 67.5% of patients had an improved Clinical Global Impression and the Mini-Mental State Examination score increased from 19.0 ± 5.1 to 20.0 ± 5.2 (p

OBJECTIVE: RA can be categorized into late-onset RA (LORA, >60-65 years) and young-onset RA (YORA, 30-55 years), depending on the patient's age at disease onset. Since the average age of the population is continuously increasing, LORA will most probably gain in importance in the future. Despite this growing importance, LORA has not been the focus of much interest in the past. The aim of this study was to analyse radiographic damage progression of early disease in LORA compared with YORA patients. METHODS: We included all patients from the Swiss RA registry, Swiss Clinical Quality Management in RA, with recent-onset arthritis, either RA (disease duration ≤1 year) or undifferentiated arthritis, as diagnosed by the data-entering physician. Patients were followed for 5 years. The cut-off between YORA and LORA was operationally set at 60 years of age. The primary outcome of this study was disease progression and activity, which was assessed based on the 28-joint DAS (DAS28) and the progression of joint erosions using a validated scoring system (Ratingen score). RESULTS: A total of 592 patients with early disease were analysed. The age at disease onset had a Gaussian distribution, with a single peak at 54 years of age; 366 patients were categorized as YORA and 226 as LORA at disease onset. DAS28 scores were significantly higher among LORA as compared with YORA patients (4.8 vs 4.5, P = 0.049). Corticosteroids were used in 68% of LORA patients as a first-line treatment, compared with 25.4% in YORA patients (χ(2) test: 54.58; P < 0.0001). In contrast, DMARDs were used in 100% of the YORA patients as first-line treatment, compared with 91.2% of the LORA patients. During follow-up, new glucocorticoids, synthetic DMARDs or biologic DMARDs were initiated in 32.8%, 61.1% and 14.1% of all YORA patients and 17.5%, 54.6% and 6.6% of LORA patients, respectively (χ(2) test: 7.08, 22.53, 54.4; all P < 0.01). The DAS28 scores decreased in both groups during the observed time period, and the initial differences in disease activity vanished after 6 months and during the subsequent follow-up. The Ratingen score was higher in LORA than in YORA patients at inclusion (12.7 vs 5.6, P < 0.0001). The rate of radiographic progression at 5 years was similar when comparing LORA and YORA (3.3 vs 2.6, respectively, P = 0.64). The Ratingen scores at onset and during follow-up over 5 years did not clearly separate LORA and YORA into two groups, but rather, increased linearly when comparing the patients in groups per decade from 20 to 92 years of age. CONCLUSION: Our results did not show LORA as a separate subgroup of RA with a different prognosis with regard to radiographic progression.

The angiopoietin/Tie (ANG/Tie) receptor system controls developmental and tumor angiogenesis, inflammatory vascular remodeling, and vessel leakage. ANG1 is a Tie2 agonist that promotes vascular stabilization in inflammation and sepsis, whereas ANG2 is a context-dependent Tie2 agonist or antagonist. A limited understanding of ANG signaling mechanisms and the orphan receptor Tie1 has hindered development of ANG/Tie-targeted therapeutics. Here, we determined that both ANG1 and ANG2 binding to Tie2 increases Tie1-Tie2 interactions in a β1 integrin–dependent manner and that Tie1 regulates ANG-induced Tie2 trafficking in endothelial cells. Endothelial Tie1 was essential for the agonist activity of ANG1 and autocrine ANG2. Deletion of endothelial Tie1 in mice reduced Tie2 phosphorylation and downstream Akt activation, increased FOXO1 nuclear localization and transcriptional activation, and prevented ANG1- and ANG2-induced capillary-to-venous remodeling. However, in acute endotoxemia, the Tie1 ectodomain that is responsible for interaction with Tie2 was rapidly cleaved, ANG1 agonist activity was decreased, and autocrine ANG2 agonist activity was lost, which led to suppression of Tie2 signaling. Tie1 cleavage also occurred in patients with hantavirus infection. These results support a model in which Tie1 directly interacts with Tie2 to promote ANG-induced vascular responses under noninflammatory conditions, whereas in inflammation, Tie1 cleavage contributes to loss of ANG2 agonist activity and vascular stability.

BACKGROUND Vacation can present a major problem to patients with rheumatoid arthritis (RA) treated with weekly subcutaneous biologics, including subcutaneous (SC) abatacept. Therefore, the replacement of four SC doses of abatacept by a single dose of intravenous (IV) abatacept may present an acceptable alternative to cover a 4-week interval needed for vacations. In the study presented, we analyzed the efficacy and safety of this intervention followed by a switch back to SC abatacept after 4 weeks. METHOD This open-label, prospective, single-arm, 24-week trial recruited patients with established RA in low disease activity (LDA) or in remission on treatment with SC abatacept for at least 3 months to receive a single dose of IV abatacept (baseline) followed by a break of 4 weeks and then continuation of weekly SC abatacept from day 28 on. Disease-modifying anti-rheumatic drug (DMARD)-inadequate or biologic-inadequate responders (or both) were included. RESULTS The baseline characteristics of the 49 patients (per protocol) were typical for a cohort of RA patients with established disease (mean disease duration of 8.31 years) in LDA under treatment with synthetic DMARDs and a biologic. Two patients (one flare and one patient decision) dropped out of the study. The proportions of patients with disease activity score in 28 joints (DAS-28) of not more than 3.2 at day 28 were 93.9 % (95 % confidence interval (CI) 83.5-97.9) and 93.6 % (95 % CI 82.8-97.8) at the end of the study (day 168). The average DAS-28 values were 1.74 (standard deviation (SD) ± 0.72) at baseline, 2.03 (SD ± 1.03) at day 28, and 1.96 (SD ± 0.92) at the end of the study (day 168). Pre-exposure to IV abatacept and having failed methotrexate or anti-tumor necrosis factor (anti-TNF) did not influence the average DAS-28 or the proportion of patients maintaining LDA over time. The average health assessment questionnaire disability index (HAQ-DI) was stable throughout the study. Adverse events (AEs) occurred in 75 % of subjects. Four serious AEs were described during the study. None of them was related to the investigational product, and all serious AEs could be resolved during hospitalization. CONCLUSION This prospective, open-label study of abatacept shows for the first time that switching from weekly SC to IV abatacept and back after 4 weeks is an effective and safe way to bridge vacations in RA patients in LDA or remission. (NCT1846975, registered April 19, 2013.).

Aims To investigate the outcome of intravitreal bevacizumab (IVB) compared with laser photocoagulation in type I retinopathy of prematurity (ROP). Methods Case records of 54 consecutive very low birth weight (VLBW) infants with type I ROP (posterior ROP, n=33; peripheral zone II, n=21) who were treated either with IVB (n=37) or laser photocoagulation (n=17) between 2011 and 2015 were retrospectively evaluated. Results Patients with posterior ROP displayed significantly faster regression of active ROP within 12 days (range 9–15 days) if treated with IVB compared with laser photocoagulation, where active ROP regressed within 57 days (range 28–63 days) (p>0.001). No difference was observed in peripheral zone II. Five of seven patients (12%) who developed a recurrence in both eyes after IVB required additional laser photocoagulation within a mean of 12.7 weeks (11.3–15.6 weeks) after the previous treatment. After laser photocoagulation one patient with posterior ROP developed macular dragging and another patient developed a temporary exudative retinal detachment in both eyes. 12 months after treatment the spherical equivalent was not statistically significant different between IVB and laser photocoagulation in posterior ROP patients. However, IVB lead to a significant lower spherical equivalent in infants with posterior ROP (+0.37 dioptres, range −0.5 to +1.88 dioptres) compared with peripheral zone II (+3.0 dioptres range +2.0 to +4.0 dioptres, p Conclusions IVB leads to faster regression of active ROP in infants with posterior ROP compared with laser photocoagulation. Spherical equivalent after 12 months was comparable in those treated with IVB and laser photocoagulation, but it was significantly lower in posterior ROP than in peripheral zone II.

The treatment of large full thickness cartilage defects with matrix guided autologous chondrocyte transplantation shows promising results. However, in many cases an arthrotomy is needed to implant the cell seeded scaffolds. Recently techniques have been developed for arthroscopically guided ACT implantation. Correct defect mapping, to assess size and depth of the chondral lesions, and precise scaffold preparation and fixation are crucial for successful chondrocyte transplantation and remain to be not sufficiently optimized. In the present study, the geometries of two cartilage defects in cadaver knees were three times assessed, measured and transferred to biodegradable scaffolds with a navigation system by three different executors. The scaffolds were arthroscopically implanted into the cartilage defects. The cartilage defect assessment was reproducible between all executors for all defect geometries. The implanted scaffolds showed a correct defect filling. The study showed the feasibility of an arthroscopic implantation of scaffolds for autologous chondrocytes transplantation. Navigation was a useful tool to exactly assess the cartilage defect geometry and allowed a precise transfer of navigated cartilage defect geometries for individualized scaffold preparation. Navigation can help to accomplish and optimize arthroscopically guided chondrocyte transplantations.

Osteoarthritis is the most common degenerative musculoskeletal disease. In healthy cartilage, a low turnover of extracellular matrix molecules occurs. Proper balance of anabolic and catabolic activities is thus crucial for the maintenance of cartilage tissue integrity and for the repair of molecular damages sustained during daily usage. In persons with degenerative diseases such as osteoarthritis, this balance of anabolic and catabolic activities is compromised, and the extent of tissue degradation predominates over the capacity of tissue repair. This mismatch eventually results in cartilage loss in persons with osteoarthritis. Tissue homeostasis is controlled by coordinated actions and crosstalk among a number of proanabolic and antianabolic and procatabolic and anticatabolic factors. In osteoarthritis, an elevation of antianabolic and catabolic factors occurs. Interestingly, anabolic activity is also increased, but this response fails to repair the tissue because of both quantitative and qualitative insufficiency. This review presents an overview of the anabolic and catabolic activities involved in cartilage degeneration and the interplay among different signaling and metabolic factors. Understanding the basic molecular mechanisms responsible for tissue degeneration is critical to identifying and developing means to efficiently block or reverse the pathobiological symptoms of osteoarthritis.

We evaluated the biomechanical characteristics of the transiliac internal fixator (TIFI) as compared to two well-established methods of internal posterior pelvic ring fixation.Six freshly frozen human pelves were used for simulated single-leg stance loading of an AO type C injury model (pubic symphysis diastasis and unilateral sacroiliac joint disruption). The symphysis rupture was stabilized with a dynamic compression plate. Afterwards the three internal stabilization systems (TIFI, iliosacral screws and ventral plate osteosynthesis) were analysed. Fragment movement was measured in a contact-free manner with a stereophotometric infrared system.No significant differences in the three-dimensional deformation tolerated by the TIFI as compared to the other internal fixation systems were found.The transiliac internal fixator provides the same biomechanical stability as the other reference implants tested. We suggest the use of this device as a suitable alternative to the other implants.

Summary Insulin autoantibodies (IAA) can appear in children within months of introducing solid foods to the diet and before clinical type 1 diabetes. The aim of this study was to determine whether infant dietary antigens could be immunizing agents of IAA. To this end, IAA binding to [125I]insulin was competed with food preparations and extracts of foods encountered in the infant diet (milk formulas, bovine milk, wheat flour, fowl meal). Bovine milk powder extracts inhibited IAA-positive samples from six of 53 children (age 0·3–14·0 years) participating in German prospective cohorts. Inhibition in these sera ranged from 23 to 100%. Competition was abolished when hydrolyzed milk powder was used. Competition with protein components of bovine milk found that two of the six milk-reactive sera were inhibited strongly by alpha- and beta-casein; none were inhibited by the milk proteins bovine serum albumin or lactoglobulins. The two casein-reactive sera had high affinity to alpha-casein (1·7 × 109; 3·1 × 109 l/mol), and lesser affinity to beta-casein (4·0 × 108; 7·0 × 107 l/mol) and insulin (2·6 × 108; 1·6 × 108 l/mol). No children with milk-reactive IAA developed autoantibodies to other islet autoantigens or diabetes (median follow-up 9·8 years). These results suggest that autoimmunity to insulin can occur infrequently via cross-reactivity to food proteins, but this form of IAA immunization does not appear to be associated with progression to diabetes.