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Previous research has demonstrated that hearing impairment is associated with heightened subjective experiences of listening effort, fatigue, and stress, impacting daily functioning. This study aimed to evaluate whether hearing impairment alters physiological stress systems and whether different aspects of hearing impairment could vary in predicting dysregulation in these systems. Hallmark measures of parasympathetic and sympathetic nervous system activity were derived from electrocardiography, impedance cardiography, and electrodermal activity recordings taken from 133 individuals, aged 37 to 73, over two 24‐hr periods, including sleep. Using ecological momentary assessment (EMA), participants reported mood, listening effort, and fatigue seven times daily. Hearing impairment was quantified through pure tone thresholds, speech perception in noise testing, and the Amsterdam Inventory for Auditory Disability questionnaire (Amsterdam Inventory). Using mixed models, we compared average daytime and sleep values of physiological measures across the 2 days, and their daytime‐to‐sleep contrast, based on each hearing impairment assessment. Results indicated that all three hearing impairment assessments were strong predictors of EMA outcomes of listening effort and fatigue. Contrary to expectations, hearing impairment did not have a significant impact on parasympathetic activity in daily life or on skin sympathetic activity. However, individuals with higher impairment exhibited a larger change in a cardiac sympathetic measure, the pre‐ejection period, during wakefulness compared to sleep. Overall, hearing impairment had a small impact on autonomic nervous system functioning in daily life, but the effects were potentially attenuated by reduced exposure to listening demand in those with hearing impairment. [ABSTRACT FROM AUTHOR]

Summary: Systemic sclerosis (SSc) is a severe autoimmune disease characterized by vasculopathy, fibrosis, and dysregulated immunity, with hallmark autoantibodies targeting nuclear antigens such as centromere protein (ACA) and topoisomerase I (ATA). These autoantibodies are highly prevalent and disease‐specific, rarely coexisting, thus serving as crucial biomarkers for SSc diagnosis. Despite their diagnostic value, their roles in SSc pathogenesis remain unclear. This review summarizes current literature on ACA and ATA in SSc, comparing them to autoantibodies in other rheumatic diseases to elucidate their potential pathogenic roles. Similarities are drawn with anti‐citrullinated protein antibodies (ACPA) in rheumatoid arthritis, particularly regarding disease specificity and minimal pathogenic impact of antigen binding. In addition, differences between ANA and ACPA in therapeutic responses and Fab glycosylation patterns are reviewed. While ACA and ATA are valuable for disease stratification and monitoring activity, understanding their origins and the associated B cell responses is critical for advancing therapeutic strategies for SSc. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is marked by excessive complement activation, contributing to tissue damage. Complement activation can be detected in many organs including the skin, kidney, and brain. The involvement of the central nervous system is particularly relevant to understanding neuropsychiatric SLE (NPSLE), one of the poorest understood manifestations of SLE for which no biomarkers are available. We studied the levels of complement inhibitors in SLE in relation to disease activity and as possible biomarkers to identify NPSLE. Serum levels of complement inhibitors C1‐inhibitor (C1‐INH), C4b‐binding protein (C4BP), Factor I, and Factor H were measured in 345 SLE patients (including 102 with NPSLE) and 108 healthy controls. Compared with controls, SLE patients had higher C1‐INH and C4BP but lower Factor I and H levels. All inhibitors positively correlated with total C3 and C4 levels. While correlating with the SLE Disease Activity Index (SLEDAI), no distinction in inhibitor levels was found between SLE and NPSLE patients. Over time, C1‐INH and Factor H levels normalized, but no significant changes were observed for C4BP and Factor I. In SLE the levels of circulating complement inhibitors are inversely correlated to complement consumption but do not serve as biomarkers for NPSLE. [ABSTRACT FROM AUTHOR]

Objective: To investigate the feasibility of fluorescence molecular imaging (FMI), using cetuximab‐800CW, as an intraoperative tool to determine surgical margins in penile squamous cell carcinoma (PSCC). Patients and methods: A total of 11 patients with PSCC received 75 mg cetuximab followed by 15 mg cetuximab‐800CW 2 days before surgery. FMI of the whole excision specimen and tissue slices was performed. Fluorescence visualisation was correlated to histopathology. Based on tumour and healthy tissue regions of interest, mean fluorescence intensity was calculated for each individual patient. Results: Significant differences between tumour and healthy mean fluorescence intensity were found with tumour‐to‐background ratios of a median (IQR) of 1.51 (0.99) and a mean (SD) of 1.51 (0.32) in the excision specimen and tissue slices, respectively. One patient showed a high relative fluorescence intensity with a signal‐to‐background ratio of 1.79, corresponding to a tumour‐positive margin on fresh frozen sectioning. Conclusion: In this Phase I study we showed that cetuximab‐800CW seems suitable to discriminate PSCC from background tissue. The tracer was well tolerated, and no false positive spots were seen. [ABSTRACT FROM AUTHOR]

Fermented foods play a significant role in the human diet for their natural, highly nutritious and healthy attributes. Our aim was to study the effect of yeast extract, a fermented substance extracted from natural yeast, on colonic motility to better understand its potential therapeutic role. A yeast extract was given to rats by gavage for 3 days, and myogenic and neurogenic components of colonic motility were studied using spatiotemporal maps made from video recordings of the whole colon ex vivo. A control group received saline gavages. The yeast extract caused excitation of the musculature by increasing the propagation length and duration of long‐distance contractions, the major propulsive activity of the rat colon. The yeast extract also evoked rhythmic propulsive motor complexes (RPMCs) which were antegrade in the proximal and mid‐colon and retrograde in the distal colon. RPMC activity was evoked by distention‐induced neural activity, but it was myogenic in nature since we showed it to be generated by bethanechol in the presence of tetrodotoxin. In conclusion, ingestion of yeast extract stimulates rat colon motility by exciting neurogenic and myogenic control mechanisms. [ABSTRACT FROM AUTHOR]

Objective: AURORA 2 evaluated the long‐term safety, tolerability, and efficacy of voclosporin compared to placebo in patients with lupus nephritis (LN) receiving an additional two years of treatment following completion of the one‐year AURORA 1 study. Methods: Enrolled patients continued their double‐blinded treatment of voclosporin or placebo randomly assigned in AURORA 1, in combination with mycophenolate mofetil and low‐dose glucocorticoids. The primary objective was safety assessed with adverse events (AEs) and biochemical and hematological assessments. Efficacy was measured by renal response. Results: A total of 216 patients enrolled in AURORA 2. Treatment was well tolerated with 86.1% completing the study and no unexpected safety signals. AEs occurred in 86% and 80% of patients in the voclosporin and control groups, respectively, with an AE profile similar to that seen in AURORA 1, albeit with reduced frequency. Investigator reported AEs of both glomerular filtration rate (GFR) decrease and hypertension occurred more frequently in the voclosporin than the control group (10.3% vs 5.0%, and 8.6% vs 7.0%, respectively). Mean corrected estimated GFR (eGFR) was within the normal range and stable in both treatment groups. eGFR slope over the two‐year period was −0.2 mL/min/1.73 m2 (95% confidence interval [CI] −3.0 to 2.7) in the voclosporin group and −5.4 mL/min/1.73 m2 (95% CI −8.4 to −2.3) in the control group. Improved proteinuria persisted across three years of treatment, leading to more frequent complete renal responses in patients treated with voclosporin (50.9% vs 39.0%; odds ratio 1.74; 95% CI 1.00–3.03). Conclusion: Data demonstrate the safety and efficacy of long‐term voclosporin treatment over three years of follow‐up in patients with LN. [ABSTRACT FROM AUTHOR]

Background: The two‐staged prefabricated vascularized fibula free flap is used in maxillofacial reconstruction. We describe the possible cause and management of two cases of fibula fracture after implant placement. Methods: The patients were treated with two‐stage reconstruction with a prefabricated vascularized fibula free flap. Six dental implants were placed in both fibulas. Fibula fractures occurred during the osseointegration period before the second procedure. The reconstruction was continued as planned. Results: Both fibulas fractured in the distal segment, possibly due to a thinner cortex more distally. Harvesting of a fractured fibula flap is more difficult than normally due to callus formation and fibrosis. Both transplants became fully functional with extended healing and additional surgery. Conclusion: The fracture apparently did not compromise the vascularisation of the fibula and proved still sufficient for successful harvest and transfer of the flap. The patient should be made aware that additional corrective surgery may be indicated. [ABSTRACT FROM AUTHOR]

Objective: This integrated analysis evaluates the efficacy and safety of voclosporin, a novel calcineurin inhibitor, at 23.7 mg twice daily in combination with mycophenolate mofetil (MMF) and oral glucocorticoids in lupus nephritis (LN) using pooled data from two large phase II and phase III clinical trials. The purpose was to expand the pool of patients for safety analyses and to increase power for efficacy analyses in patient subpopulations. Methods: Aurinia Urinary Protein Reduction in Active Lupus with Voclosporin (AURA‐LV) (phase II) and Aurinia Renal Response in Active Lupus With Voclosporin (AURORA 1) (phase III) were randomized, placebo‐controlled, double‐blind trials with similar designs and end points comparing voclosporin to control in combination with MMF and oral glucocorticoids for the treatment of LN. The primary efficacy outcome of the integrated analysis was complete renal response (CRR) at approximately one year (Week 48 data from AURA‐LV and Week 52 from AURORA 1). Safety was assessed throughout the trials. Results: Overall, 534 patients (268 voclosporin; 266 control) were included in the integrated analysis. Significantly more patients achieved a CRR at one year in the voclosporin group than in the control group (43.7% vs. 23.3%; OR 2.76; 95% CI 1.88, 4.05 P < 0.0001). The incidence of adverse events (AEs) was similar (91.4% voclosporin; 87.2% control). Most AEs were mild to moderate in severity; the most commonly reported AEs were classified as infections and infestations (62.2% voclosporin; 54.9% control) and gastrointestinal disorders (45.3% voclosporin; 35.3% placebo). No new or unexpected safety signals were detected. Conclusions: This integrated analysis demonstrates the efficacy and safety of voclosporin in the treatment of LN across the diverse racial and ethnic groups studied. [ABSTRACT FROM AUTHOR]

A case study was conducted at a regulatory enforcement agency in the Netherlands to explore whether it might be affected by goal displacement and, if so, to gain insight into the possible causes of the phenomenon. The results indicate three distinct types of goal displacement, each of which appears to substantially impair the effectiveness of the agency in a specific way. It is argued that the combination of multiple, consecutive budget cuts imposed on the agency and a strong culture of output management have played a key role in generating goal displacement. In more general terms, the study shows the potential usefulness of a goal displacement perspective in investigating the effectiveness of enforcement agencies. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the prevalence and impact of cognitive impairment on health‐related‐quality of life (HRQoL) in patients with systemic lupus erythematosus (SLE) and neuropsychiatric (NP) symptoms. Methods: Patients with SLE and NP symptoms referred to the Leiden NPSLE clinic (2007–2019) were included. In a multidisciplinary evaluation, NP symptoms were attributed to SLE (NPSLE: inflammatory, ischemic, or both combined) or other causes. Four cognitive domains were determined: global cognitive function (score 0–30), learning and memory, executive function and complex attention, and psychomotor speed (all T scores). HRQoL was determined using the mental component score and physical component score of the Short Form 36 health survey. The associations between cognition and NPSLE phenotype and cognition and HRQoL were assessed with multiple regression analyses and linear mixed models corrected for confounding and expressed in SDs. Results: A total of 357 patients (86% female, mean age 44 years) were included. Of those 357 patients, 169 had a follow‐up visit (median follow‐up 11 months). Impairment in global cognitive function was present in 8% of patients, and in all other cognitive domains in ±50%. The most severe impairment (all domains) was seen in patients with a combined NPSLE phenotype. Diffuse cognitive impairment (learning and memory, executive function and complex attention, and psychomotor speed) was most common and was present more often in patients with an inflammatory phenotype. A weak association between cognition and HRQoL was found both cross‐sectionally and longitudinally. In general, 1 SD lower scores on the cognitive domains were associated with at most one‐fifth SD lower HRQoL. Conclusion: Objective cognitive impairment is common in SLE patients with NP symptoms, but may have a limited influence on HRQoL. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether established genetic predictors for rheumatoid arthritis (RA) differentiate healthy controls, patients with clinically suspect arthralgia (CSA), and RA patients. Methods: Using analyses of variance, chi‐square tests, and mean risk difference analyses, we investigated the association of an RA polygenic risk score (PRS) and HLA shared epitope (HLA‐SE) with all participant groups, both unstratified and stratified for anti–citrullinated protein antibody (ACPA) status. We used 3 separate data sets sampled from the same Dutch population (1,015 healthy controls, 479 CSA patients, and 1,146 early classified RA patients). CSA patients were assessed for conversion to inflammatory arthritis over a period of 2 years, after which they were classified as either CSA converters (n = 84) or CSA nonconverters (n = 395). Results: The PRS was increased in RA patients (mean ± SD PRS 1.31 ± 0.96) compared to the complete CSA group (1.07 ± 0.94) and compared to CSA converters (1.12 ± 0.94). In ACPA– strata, PRS distributions differed strongly when comparing the complete CSA group (mean ± SD PRS 1.05 ± 0.94) and CSA converters (0.97 ± 0.87) to RA patients (1.20 ± 0.94), while in the ACPA+ strata, the complete CSA group (1.25 ± 0.99) differed clearly from healthy controls (1.05 ± 0.94) and RA patients (1.41 ± 0.96). HLA‐SE was more prevalent in the RA group (prevalence 0.64) than the complete CSA group (0.45), with small differences between RA patients and CSA converters (0.64 versus 0.60) and larger differences between CSA converters and CSA nonconverters (0.60 versus 0.42). HLA‐SE prevalence differed more strongly within the ACPA+ strata as follows: healthy controls (prevalence 0.43), CSA nonconverters (0.48), complete CSA group (0.59), CSA converters (0.66), and RA patients (0.79). Conclusion: We observed that genetic predisposition increased across pre‐RA participant groups. The RA PRS differed in early classified RA and inflammatory pre‐disease stages, regardless of ACPA stratification. HLA‐SE prevalence differed between arthritis patients, particularly ACPA+ patients, and healthy controls. Genetics seem to fulfill different etiologic roles. [ABSTRACT FROM AUTHOR]

Objective: Symptomatic knee osteoarthritis (SKOA) is a chronic, disabling condition, requiring long‐term pain management; over 800,000 SKOA patients in the US use opioids on a prolonged basis. We aimed to characterize the societal economic burden of opioid use in this population. Methods: We used the Osteoarthritis Policy Model, a validated computer simulation of SKOA, to estimate the opioid‐related lifetime and annual cost generated by the US SKOA population. We included direct medical, lost productivity, criminal justice, and diversion costs. We modeled the SKOA cohort with a mean ± SD age of 54 ± 14 years and Western Ontario and McMaster Universities Osteoarthritis Index pain score of 29 ± 17 (0–100, 100 = worst). We estimated annual costs of strong ($1,381) and weak ($671) opioid regimens using Medicare fee schedules, Red Book, the Federal Supply Schedule, and published literature. The annual lost productivity and criminal justice costs of opioid use disorder (OUD), obtained from published literature, were $11,387 and $4,264, per‐person, respectively. The 2015–2016 Medicare Current Beneficiary Survey provided OUD prevalence. We conducted sensitivity analyses to examine the robustness of our estimates to uncertainty in input parameters. Results: Assuming 5.1% prevalence of prolonged strong opioid use, the total lifetime opioid‐related cost generated by the US SKOA population was estimated at $14.0 billion, of which only $7.45 billion (53%) were direct medical costs. Conclusion: Lost productivity, diversion, and criminal justice costs comprise approximately half of opioid‐related costs generated by the US SKOA population. Reducing prolonged opioid use may lead to a meaningful reduction in societal costs that can be used for other public health causes. [ABSTRACT FROM AUTHOR]

Objective: The autoimmune response in rheumatoid arthritis (RA) is marked by the presence of anti–citrullinated protein antibodies (ACPAs). A notable feature of IgG ACPA is the abundant expression of N‐linked glycans in the variable domain. However, the presence of ACPA variable domain glycosylation (VDG) across disease stages, and its response to therapy, are poorly described. To understand its dynamics, we investigated the abundance of IgG ACPA VDG in 1,498 samples from individuals in different clinical stages. Methods: Using liquid chromatography, we analyzed IgG ACPA VDG profiles in 7 different cohorts from Japan, Canada, The Netherlands, and Sweden. We assessed 106 healthy individuals, 228 individuals with presymptomatic RA, 277 individuals with arthralgia, 307 patients with new‐onset/early RA, and 117 RA patients after prespecified treatment regimens. Additionally, we measured VDG in 234 samples from patients with RA who did or did not achieve long‐term drug‐free remission (DFR) during up to 16 years follow‐up. Results: IgG ACPA VDG significantly increased (P < 0.0001) toward disease onset and was associated with ACPA levels and epitope spreading prior to diagnosis. A slight increase in VDG was observed in patients with established RA, with a moderate influence of treatment (P = 0.007). In patients in whom DFR was later achieved, IgG ACPA VDG was already reduced at the time of RA onset. Conclusion: The abundance of IgG ACPA VDG increases toward RA onset and correlates with maturation of the ACPA response. While IgG ACPA VDG levels are fairly stable in established disease, a lower degree of VDG at RA onset correlates with DFR. Although the underlying biologic mechanisms remain elusive, our data support the concept that VDG relates to an expansion of the ACPA response in the pre‐disease phase and contributes to disease development. [ABSTRACT FROM AUTHOR]

Clinical efficacy of intravenous immunoglobulin treatment (IVIg) is related to its pharmacokinetic (PK) profile. Its usual evaluation, by measuring serum total IgG levels, is imprecise, because IVIg cannot be distinguished from endogenous IgG. We developed ELISAs to specifically monitor the PK of IVIg using the polymorphic determinants G1m(a), G1m(x), and G1m(f). The specificity of the IgG1 allotype assays was sufficient to determine IVIg concentrations as low as 0.1 mg/mL in sera from individuals not expressing the respective markers. IVIg was quantified in posttreatment serum from patients with Guillain–Barré syndrome (GBS) by measuring IgG1 allotypes not expressed endogenously. After serotyping, 27/28 GBS patients were found eligible for IVIg monitoring using one or two genetic markers. In 17 cases, IVIg levels could be determined by both anti‐G1m(a) and anti‐G1m(x) measurement, showing significant correlation. Longitudinal monitoring of IVIg PK in seven GBS patients showed potential differences in clearance of total IgG versus IVIg‐derived IgG, highlighting that total IgG measurements may not accurately reflect IVIg PK. To summarize, anti‐IgG1 allotype assays can discriminate between endogenous IgG and therapeutic polyclonal IgG. These assays will be an important tool to better understand the variability in IVIg PK and treatment response of all patients treated with IVIg. [ABSTRACT FROM AUTHOR]

Objective: Hematopoietic stem cell transplantation (HSCT) and cyclophosphamide (CYC) are treatment options for progressive systemic sclerosis associated with interstitial lung disease (SSc‐ILD). The aims of our retrospective observational study were to evaluate: 1) the evolution of SSc‐ILD in SSc patients treated with HSCT (assessed by high‐resolution computed tomography [HRCT]; a group of patients treated with CYC was included as frame of reference); 2) how results of pulmonary function tests (PFTs) are associated with HRCT findings; and 3) which factors predict ILD reduction. Methods: We semiquantitatively scored total ILD extent, reticulations, and ground‐glass opacities (GGO) scores at baseline and at the 1‐year HRCTs of SSc patients treated with HSCT or CYC. Linear association between changes in HRCT scores and PFT results and predictors of ILD improvement were studied. Results: We included 51 patients (those treated with HSCT [n = 20] and those treated with CYC [n = 31]). The mean change in total ILD score was –5.1% (95% confidence interval [95% CI] –10.2, 0.0) in the HSCT treatment group (P = 0.050), and –1.0% (95% CI –4.3, 2.3) in the CYC treatment group (P = 0.535). For all patients, the evolution of HRCT scores was weakly associated with relative changes in PFT results. In univariate logistic regression, higher ground‐glass opacities, higher total ILD, and lower single‐breath diffusing capacity for carbon monoxide scores at baseline predicted improvement of ILD extent after treatment, but a multivariable model could not be built to assess independency of predictors. Conclusion: One year after treatment with HSCT, a nonsignificant but clear reduction of SSc‐ILD extent was observed. Changes in PFT results were associated with changes in HRCT scores but the correlation was weak and cannot be considered conclusive. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to compare the health‐related quality of life (HRQOL) of Dutch adult male and female childhood cancer survivors (CCSs) to general population references and to study medical determinants. Methods: CCSs from the Dutch Childhood Cancer Survivor Study LATER cohort (1963‐2001) part 2, who were 18 years old or older (time since diagnosis ≥ 5 years), were invited to complete the TNO‐AZL Questionnaire for Adult Health‐Related Quality of Life. Domain scores and proportions of CCSs with impaired HRQOL (score < 25th percentile of the reference scores) were compared with references via Mann‐Whitney U tests and logistic regression analyses corrected for age and sex (P <.004). Interactions of group with sex were included if they were significant (P <.05). Moreover, medical determinants were analyzed with multivariable logistic regression analyses. Results: HRQOL scores for 1766 CCSs (mean age, 35.9 years [standard deviation, 9.4 years]; male, 51%; response rate, 71%) differed from references on most domains with small effect sizes. Both male and female CCSs were more often impaired in gross and fine motor functioning, cognitive functioning, sleep, and vitality with odds ratios (ORs) > 1.4. In addition, female CCSs were more often impaired in daily activities, pain, and sexuality (ORs, 1.4‐1.9) and were less often aggressive (OR, 0.6). CCCs of central nervous system (CNS) tumors, bone tumors, and retinoblastoma and those with cranial, abdominopelvic, or lower extremity radiotherapy were at increased risk of impairment in 1 or more domains. Conclusions: Dutch adult CCSs, especially females, have impaired HRQOL in several domains; this is most pronounced in cognitive functioning. The vulnerabilities of subgroups at risk, such as CCSs of CNS tumors, were confirmed. Surveillance of HRQOL and multidisciplinary survivor care are recommended. Lay Summary: The health‐related quality of life in a Dutch nationwide cohort of 1766 survivors of childhood cancer was studied.Survivors of childhood cancer were found to have lower health‐related quality of life in several domains (eg, motor functioning and vitality) in comparison with the general population.They most often reported low cognitive functioning (eg, memory and attention).Females had low health‐related quality of life in more domains than males.Survivors of brain tumors had low health‐related quality of life in most domains.Monitoring health‐related quality of life regularly and collaborating between disciplines in survivor care is recommended. Dutch adult survivors of childhood cancer, especially females and central nervous system tumor survivors, have impaired health‐related quality of life in several domains; this is most pronounced in cognitive functioning. Surveillance of health‐related quality of life and multidisciplinary survivor care are recommended. [ABSTRACT FROM AUTHOR]

Objective: Little is known on the disease course of very early systemic sclerosis (SSc). Among the information yet to be elucidated is whether anticentromere antibody (ACA) isotype levels can serve as biomarkers for future SSc development and for organ involvement. This study was undertaken to evaluate whether IgG, IgM, and IgA ACA levels in IgG ACA–positive patients are associated with disease severity and/or progression from very early SSc to definite SSc. Methods: IgG ACA–positive patients from 5 different cohorts who had very early SSc or SSc fulfilling the American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) 2013 criteria were included. A diagnosis of very early SSc was based on the presence of IgG ACAs and Raynaud's phenomenon, and/or puffy fingers and/or abnormal nailfold capillaroscopy, but not fulfilling the ACR/EULAR 2013 criteria for SSc. Multivariable regression analyses were performed to determine the association between baseline ACA isotype levels and progression to definite SSc with organ involvement. Results: Six hundred twenty‐five IgG ACA–positive patients were included, of whom 138 (22%) fulfilled the criteria for very early SSc and 487 (78%) had definite SSc. Levels of IgG ACAs (odds ratio 2.5 [95% confidence interval 1.8–3.7]) and IgM ACAs (odds ratio 1.8 [95% confidence interval 1.3–2.3]) were significantly higher in patients with definite SSc. Of 115 patients with very early SSc with follow‐up, progression to definite SSc occurred within 5 years in 48 (42%). Progression to definite SSc was associated with higher IgG ACA levels at baseline (odds ratio 4.3 [95% confidence interval 1.7–10.7]). Conclusion: ACA isotype levels may serve as biomarkers to identify patients with very early SSc who are at risk for disease progression to definite SSc. [ABSTRACT FROM AUTHOR]

Half of the world's population is at risk of arthropod‐borne virus (arbovirus) infections. Several arbovirus infections have been associated with Guillain‐Barré syndrome (GBS). We investigated whether arboviruses are driving GBS beyond epidemic phases of transmission and studied the antibody response to glycolipids. The protocol of the International Guillain‐Barré syndrome Outcome Study (IGOS), an observational prospective cohort study, was adapted to a case‐control design. Serum samples were tested for a recent infection with Zika virus (ZIKV), dengue virus (DENV), chikungunya (CHIKV) virus, hepatitis E virus, Epstein‐Barr virus (EBV), cytomegalovirus (CMV), Campylobacter jejuni, and Mycoplasma pneumoniae, and for antibodies to glycolipids. Forty‐nine patients were included from Brazil (63%), Argentina (14%), and Malaysia (22%). Evidence of a recent infection was found in 27/49 (55%) patients: C jejuni (n = 15, 31%), M pneumoniae (n = 5, 10%), CHIKV (n = 2, 4%), EBV (n = 1, 2%), C jejuni and M pneumoniae (n = 2, 4%), CMV and DENV (n = 1, 2%), and C jejuni and DENV (n = 1, 2%). In 22 patients, 35 paired controls were collected. Odds ratio for recent infections did not significantly differ between cases and controls. No typical anti‐ganglioside antibody binding was associated with recent arbovirus infection. We conclude that arbovirus infections occur in GBS patients outside of epidemic viral transmission, although not significantly more than in controls. Broad infection and anti‐ganglioside antibody serology are important to establish the most likely pathogenic trigger in GBS patients. Larger studies are necessary to determine the association between arboviruses and GBS. [ABSTRACT FROM AUTHOR]

Objective: Autoantibodies, such as anti–citrullinated protein antibodies (ACPAs), have been described as inducing bone loss in rheumatoid arthritis (RA), which can also be reflected by bone mineral density (BMD). We therefore examined the association between osteoporosis and autoantibodies in two independent RA cohorts. Methods: Dual x‐ray absorptiometry (DXA) of the lumbar spine and left hip was performed in 408 Dutch patients with early RA during 5 years of follow‐up and in 198 Swedish patients with early RA during 10 years of follow‐up. The longitudinal effect of ACPAs and other autoantibodies on several BMD measures was assessed using generalized estimating equations. Results: In the Dutch cohort, significantly lower BMD at baseline was observed in ACPA‐positive patients compared to ACPA‐negative patients, with an estimated marginal mean BMD in the left hip of 0.92 g/cm2 (95% confidence interval [95% CI] 0.91–0.93) versus 0.95 g/cm2 (95% CI 0.93–0.97) (P = 0.01). In line with this, significantly lower Z scores at baseline were noted in the ACPA‐positive group compared to the ACPA‐negative group (estimated marginal mean Z score in the left hip of 0.18 [95% CI 0.08–0.29] versus 0.48 [95% CI 0.33–0.63]) (P < 0.01). However, despite clear differences at baseline, ACPA positivity was not associated with greater decrease in absolute BMD or Z scores over time. Furthermore, there was no association between BMD and higher levels of ACPAs or other autoantibodies (rheumatoid factor and anti–carbamylated protein antibodies). In the Swedish cohort, ACPA‐positive patients tended to have a higher prevalence of osteopenia at baseline (P = 0.04), but again, ACPA positivity was not associated with an increased prevalence of osteopenia or osteoporosis over time. Conclusion: The presence of ACPAs is associated with significantly lower BMD at baseline, but not with greater BMD loss over time in treated RA patients. These results suggest that ACPAs alone do not appear to contribute to bone loss after disease onset when disease activity is well‐managed. [ABSTRACT FROM AUTHOR]

Objective: Microangiopathy and dysregulation of the immune system play important roles in the pathogenesis of systemic sclerosis (SSc). Factors that trigger vascular injury in SSc have not been elucidated so far. We undertook this study to evaluate whether sex or expression of specific antinuclear autoantibodies might associate with the degree of microangiopathy through performance of a systematic review that summarizes what is known about these associations.Methods: A standardized search of PubMed, Embase, Web of Science, and the Cochrane Library were performed to identify studies that described autoantibodies in SSc patients and microangiopathy and, for the second search, those that described sex and microangiopathy.Results: We included 11 studies that described the relationship between SSc-specific autoantibodies and microangiopathy and 6 studies that reported on the association between sex and microangiopathy. Contradictory results were found on the association between SSc-specific autoantibodies and microangiopathy, and no association was found between sex and microangiopathy based on the current literature.Conclusion: Based on this review of the literature, we can conclude that sex does not seem to influence degree of microangiopathy in SSc, while results on association between SSc-specific autoantibodies and degree of microangiopathy were inconclusive. [ABSTRACT FROM AUTHOR]

Background and purpose: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a clinical and electrophysiological heterogeneous immune‐mediated polyneuropathy. Intravenous immunoglobulin (IVIg), corticosteroids, and plasma exchange are proven effective treatments for CIDP. The clinical response to IVIg is variable between patients and currently unexplained. Finding biomarkers related to treatment response can help to understand the diversity of CIDP and personalise treatment choice. Methods: We investigated whether genetic variation between patients may explain some of these differences in treatment response. Based on previous publications, we selected six candidate genes that might affect immune and axonal functions, IVIg metabolism, and treatment response in CIDP. Genetic variants were assessed in 172 CIDP patients treated with at least one course of IVIg (2 g/kg). A response to IVIg was defined by ≥1 grade improvement on the modified Rankin Scale. Blood samples were tested for variations in CNTN2, PRF1, FCGRT, FCGR2B, GJB1, and SH2D2A genes. Results: In univariate analysis, patients with the FCGR2B promoter variant 2B.4/2B.1 responded more often to IVIg than patients with the 2B.1/2B.1 variant (odds ratio [OR] = 6.9, 95% confidence interval [CI] = 1.6–30; p = 0.003). Patients with the p.(Ala91Val) variant of PRF1 were less often IVIg responsive (OR = 0.34, 95% CI = 0.13–0.91; p = 0.038). In multivariate analysis, both PRF1 and FCGR2B showed discriminative ability to predict the chance of IVIg response (area under the curve = 0.67). Conclusions: Variations in PRF1 and the promoter region of FCGR2B are associated with the response to IVIg in CIDP. These findings, which require validation, are a first step towards the understanding of the heterogeneity in the treatment response in CIDP. We investigated whether genetic variation in six candidate genes was associated with the response to IVIg in CIDP patients. Variations in PRF1 and the promoter region of FCGR2B were associated with the response to IVIg in CIDP. [ABSTRACT FROM AUTHOR]

Objective: Anti–topoisomerase I (anti–topo I) autoantibodies in systemic sclerosis (SSc) are associated with diffuse skin involvement and interstitial lung fibrosis. Thus far, however, the relationship between anti–topo I antibody response and disease course has not yet been fully evaluated. This study was undertaken to gain insight into the association between characteristics of the anti–topo I antibody response and clinical disease course in SSc patients positive for anti–topo I antibodies. Methods: Levels of anti–topo I IgG, anti–topo I IgM, and anti–topo I IgA were assessed in consecutive serum samples obtained from patients at baseline who were positive for anti–topo I IgG in the Leiden Combined Care In Systemic Sclerosis (CCISS) cohort. One‐year disease progression was defined by a relevant increase in modified Rodnan skin thickness score (MRSS), decline in pulmonary function, development of digital ulcers, renal crisis, and pulmonary hypertension, and/or mortality. Validation was performed in SSc patients who were positive for anti–topo I from the Oslo University Hospital and University Hospital Zurich. Results: Of the 103 patients with anti–topo I IgG in the CCISS cohort, clinical data were available to assess 1‐year disease progression in 81 patients. Of these 81 patients, 23 (28%) had disease progression. At baseline, patients with disease progression were significantly more often anti–topo I IgM–positive than those who did not experience disease progression (21 [91%] of 23 versus 33 [57%] of 58; P < 0.01). This finding was confirmed in the independent validation samples. Conclusion: In SSc patients who were anti–topo I IgG–positive, presence of anti–topo I IgM, which might be considered as a surrogate for an ongoing autoreactive B cell immune response, is associated with disease progression. [ABSTRACT FROM AUTHOR]

Background: There is increasing recognition that heart failure (HF) and cancer are conditions with a number of shared characteristics.Objectives: To explore the association between tumour biomarkers and HF outcomes.Methods: In 2,079 patients of BIOSTAT-CHF cohort, we measured six established tumour biomarkers: CA125, CA15-3, CA19-9, CEA, CYFRA 21-1 and AFP.Results: During a median follow-up of 21 months, 555 (27%) patients reached the primary end-point of all-cause mortality. CA125, CYFRA 21-1, CEA and CA19-9 levels were positively correlated with NT-proBNP quartiles (all P < 0.001, P for trend < 0.001) and were, respectively, associated with a hazard ratio of 1.17 (95% CI 1.12-1.23; P < 0.0001), 1.45 (95% CI 1.30-1.61; P < 0.0001), 1.19 (95% CI 1.09-1.30; P = 0.006) and 1.10 (95% CI 1.05-1.16; P < 0.001) for all-cause mortality after correction for BIOSTAT risk model (age, BUN, NT-proBNP, haemoglobin and beta blocker). All tumour biomarkers (except AFP) had significant associations with secondary end-points (composite of all-cause mortality and HF hospitalization, HF hospitalization, cardiovascular (CV) mortality and non-CV mortality). ROC curves showed the AUC of CYFRA 21-1 (0.64) had a noninferior AUC compared with NT-proBNP (0.68) for all-cause mortality (P = 0.08). A combination of CYFRA 21-1 and NT-proBNP (AUC = 0.71) improved the predictive value of the model for all-cause mortality (P = 0.0002 compared with NT-proBNP).Conclusions: Several established tumour biomarkers showed independent associations with indices of severity of HF and independent prognostic value for HF outcomes. This demonstrates that pathophysiological pathways sensed by these tumour biomarkers are also dysregulated in HF. [ABSTRACT FROM AUTHOR]

Objectives: This study explores illness perceptions, risk perceptions and degree of worry in patients with recently diagnosed systemic sclerosis (SSc). Specifically, it aims to answer whether and how early diagnosis in a stage that disease is relatively mild can impact patients' lives, and if and how disease severity associates with illness perceptions and risk perception. Methods: Patients with a diagnosis of SSc <2 years were invited to participate in a focus group discussion for in‐depth exploration of illness perceptions, risk perceptions and worry. In addition, illness perceptions, risk perceptions and worries were evaluated with the use of questionnaires. To explore how patients perceive SSc, we asked them to draw their disease. Physician global assessment of disease severity was used to measure disease severity. Associations between disease severity, illness/risk perceptions, drawings and elements of the focus group were assessed. Results: We observed three dimensions of illness perception as most relevant for patients: personal control, concern and consequences. Patients with SSc experienced many symptoms and felt low personal control. Concerns about the future were often mentioned, and the majority of patients scored high on the worry questionnaire. None of the patients was preoccupied with prognosis or death. All drawings illustrate the impact of SSc on daily life and psychological well‐being. Illness perceptions were highly variable between patients and did not associate with disease severity. Conclusion: This study showed that a diagnosis of early SSc had a significant impact on patients' lives, also in the absence of severe disease complications. [ABSTRACT FROM AUTHOR]

Background: High‐resolution colonic manometry gives an unprecedented window into motor patterns of the human colon. Our objective was to characterize motor activities throughout the entire colon that possessed persistent rhythmicity and spanning at least 5 cm. Methods: High‐resolution colonic manometry using an 84‐channel water‐perfused catheter was performed in 19 healthy volunteers. Rhythmic activity was assessed during baseline, proximal balloon distention, meal, and bisacodyl administration. Key Results: Throughout the entire colon, a cyclic motor pattern occurred either in isolation or following a high‐amplitude propagating pressure wave (HAPW), consisting of clusters of pressure waves at a frequency centered on 11‐13 cycles/min, unrelated to breathing. The cluster duration was 1‐6 minutes; the pressure waves traveled for 8‐27 cm, lasting 5‐8 seconds. The clusters itself could be rhythmic at 0.5‐2 cpm. The propagation direction of the individual pressure waves was mixed with >50% occurring simultaneous. This high‐frequency cyclic motor pattern co‐existed with the well‐known low‐frequency cyclic motor pattern centered on 3‐4 cpm. In the rectum, the low‐frequency cyclic motor pattern dominated, propagating predominantly in retrograde direction. Proximal balloon distention, a meal and bisacodyl administration induced HAPWs followed by cyclic motor patterns. Conclusions and Inferences: Within cyclic motor patterns, retrograde propagating, low‐frequency pressure waves dominate in the rectum, likely keeping the rectum empty; and mixed propagation, high‐frequency pressure waves dominate in the colon, likely promoting absorption and storage, hence contributing to continence. Propagation and frequency characteristics are likely determined by network properties of the interstitial cells of Cajal. [ABSTRACT FROM AUTHOR]

We show that the parent-subsidiary structure of multinational firms created by cross-border mergers and acquisitions is affected by the prospect of international double taxation. Specifically, the likelihood of parent firm location in a country following a cross-border takeover is reduced by high international double taxation of foreign-source income. At the same time, countries with high international double taxation attract smaller numbers of parent firms. A unilateral elimination of worldwide taxation by the United States is simulated to increase the proportion of parent firms locating in the United States following cross-border mergers and acquisitions from 53% to 58%. [ABSTRACT FROM AUTHOR]

Background: Hidradenitis suppurativa (HS) is a chronic debilitating skin disease, frequently located in the groin and anogenital area, leading to a substantial impact on quality of life and sexual health in patients with HS. Skin‐tissue‐sparing excision with electrosurgical peeling (STEEP) is a procedure with known low recurrence rates and high patient satisfaction in retrospective series. However, a prospective study to investigate the impact of any major surgery on specific aspects of the quality of life has not yet been performed. Objective: To assess surgical outcomes and the effect of major surgery on the general quality of life, sexual health and activity impairment in patients with HS. Materials and methods: A single centre prospective survey study was conducted among 40 patients undergoing major surgery. Surveys were completed prior to the surgery and 2, 6, 12 and 26 weeks after surgery. Besides the objective parameters (time to wound closure and surface of the wound), patient‐reported outcomes were reported. Results: Thirty‐nine patients with a total of 171 survey responses were included for analysis. Patients with Hurley stage I or II had a shorter time to wound closure (TTWC) compared to patients with Hurley stage III (P = 0.005). TTWC was significantly prolonged in patients treated with biologics (P < 0.001). Smoking did not significantly influence TTWC. For patient‐reported outcomes, DLQI and ASEX scores did not significantly improve during the study period of 6 months. However, activity and overall work impairment showed considerable improvement after surgery. Conclusion: Time to wound closure is significantly prolonged by higher Hurley stage and treatment with biologics, contrastingly not by smoking. Major surgery improved the overall work and daily activity impairment. [ABSTRACT FROM AUTHOR]

Objective: Anti–citrullinated protein antibodies (ACPAs) are disease‐specific biomarkers in rheumatoid arthritis (RA). More than 90% of IgG ACPAs harbor N‐linked glycans in the antibody variable (V) domain. The corresponding N‐glycosylation sites in ACPA V‐region sequences result from somatic hypermutation, a T cell–dependent process. As ample evidence indicates that T cells drive the maturation of the ACPA response prior to arthritis onset, we undertook this study to investigate whether the presence of glycans in IgG ACPA V domains predicts the transition from predisease autoimmunity to overt RA. Methods: We analyzed 2 independent sets of serum samples obtained from 126 ACPA‐positive first‐degree relatives (FDRs) of RA patients. Both sets originated from an Indigenous North American population and comprised cross‐sectional and longitudinal samples of individuals who did or did not develop inflammatory arthritis. Serum IgG ACPAs were affinity‐purified and subjected to ultra high‐performance liquid chromatography–based glycan analysis. Results: In both data sets, FDR‐derived IgG ACPA displayed markedly lower levels of V domain glycans (<50%) compared to IgG ACPA from RA patients. Notably, FDRs who later developed RA showed extensive V‐domain glycosylation before the onset of arthritis. Moreover, IgG ACPA V‐domain glycosylation was strongly associated with future development of RA (hazard ratio 6.07 [95% confidence interval 1.46–25.2]; P = 0.013). Conclusion: Extensive glycosylation of the IgG ACPA V domain is present in a subset of predisposed FDRs of Indigenous North American RA patients. The presence of this feature substantially increases the risk of RA development. Based on these findings, we propose that glycosylation of the IgG ACPA V domain represents a predictive marker for RA development in ACPA‐positive individuals and may serve to better target prevention measures. [ABSTRACT FROM AUTHOR]

Zoos increasingly transform their exhibitions from traditional one‐species enclosures to more natural exhibits, that is, environments that capture part of an ecosystem including a selection of animals and plants that occur there. Thus, enhancing the experience of its human visitors while also allowing its residents to possibly show more natural behavior. In 2017 Royal Burger's Zoo (Arnhem, The Netherlands) created and opened a mangrove‐like environment containing fiddler crabs. Fiddler crabs display a broad range of behaviors, and this research examines which wild‐type behavior and behavioral patterns can be observed on a seminatural mudflat. The behavior shown by Uca rapax and Uca tangeri on the mudflat was counted each hour between 07:00 and 17:00. An asymmetric tidal regime was present in the enclosure including two high water periods. Various known fiddler crab behaviors, including waving and combat, were observed but no copulation. A clear pattern in exposed crabs on the mudflat was found, with low numbers visible in the early morning and the highest numbers present in the early afternoon, while number of visitors did not have a significant effect on this pattern. Interestingly, the highest abundances were not observed around the ebbing tide (07:00–09:00), as observed in the wild, but somewhat later, possibly due to the asymmetric tidal scheme or the interaction of tidal and daily rhythms. This study shows that in captivity, fiddler crabs indeed show a range of natural behaviors which is linked to the tidal and possibly daily rhythm as well. Research Highlights: Typical fiddler crab behaviors were observed on a seminatural mudflat.Distinct patterns in activity and behavior were present throughout the day.The highest number of visual crabs was observed a couple of hours after low tide. [ABSTRACT FROM AUTHOR]

Given the importance of ex ante real interest rates to economic decision making, it is no surprise that much empirical research focuses on them.1 Several recent studies find that the ex ante real returns for short-term U.S. Treasury securities are not constant and are negatively correlated both with inflation and with nominal interest rates. This paper examines the extent to which these findings hold for assets of longer maturity, are robust with respect to the choice of price index, and are stable over time. [ABSTRACT FROM AUTHOR]

Objective: The Guillain–Barré syndrome (GBS) is an acute, immune‐mediated disease of peripheral nerves. Plasmablasts and plasma cells play a central role in GBS by producing neurotoxic antibodies. The standard treatment for GBS is high‐dose intravenous immunoglobulins (IVIg), however the working mechanism is unknown and the response to treatment is highly variable. We aimed to determine whether IVIg changes the frequency of B‐cell subsets in patients with GBS. Methods: Peripheral blood mononuclear cells were isolated from 67 patients with GBS before and/or 1, 2, 4, and 12 weeks after treatment with high‐dose IVIg. B‐cell subset frequencies were determined by flow cytometry and related to serum immunoglobulin levels. Immunoglobulin transcripts before and after IVIg treatment were examined by next‐generation sequencing. Antiglycolipid antibodies were determined by ELISA. Results: Patients treated with IVIg demonstrated a strong increase in plasmablasts, which peaked 1 week after treatment. Flow cytometry identified a relative increase in IgG2 plasmablasts posttreatment. Within IGG sequences, dominant clones were identified which were also IGG2 and had different immunoglobulin sequences compared to pretreatment samples. High plasmablast frequencies after treatment correlated with an increase in serum IgG and IgM, suggesting endogenous production. Patients with a high number of plasmablasts started to improve earlier (P = 0.015) and were treated with a higher dose of IVIg. Interpretation: High‐dose IVIg treatment alters the distribution of B‐cell subsets in the peripheral blood of GBS patients, suggesting de novo (oligo‐)clonal B‐cell activation. Very high numbers of plasmablasts after IVIg therapy may be a potential biomarker for fast clinical recovery. [ABSTRACT FROM AUTHOR]

One course of intravenous immunoglobulins (IVIg) of 2 g/kg is standard treatment in Guillain‐Barré syndrome (GBS) patients unable to walk independently. Despite treatment some patients recover poorly, in part related to rapid consumption of IVIg, indicating that they may benefit from a second course of IVIg. The aim of the study is to determine whether a second course of IVIg, administered 1 week after start of the first course in patients with GBS and predicted poor outcome improves functional outcome on the GBS disability scale after 4 weeks. Secondary outcome measures include adverse events (AEs), Medical Research Council sumscore and GBS disability score after 8, 12, and 26 weeks, length of hospital and ICU admission, mortality, and changes in serum IgG levels. GBS patients of 12 years and older with a poor prognosis, based on the modified Erasmus GBS outcome score (mEGOS) at 1 week after start of the first IVIg course are eligible for randomization in this double‐blind, placebo‐controlled (IVIg or albumin) clinical trial. This study will determine if a second course of IVIg administered in the acute phase of the disease is safe, feasible, and effective in patients with GBS and a poor prognosis. This Dutch trial is registered prospectively as NTR 2224 in the Netherlands National Trial Register (NTR) which is the Primary Registry in the WHO Registry Network for the Netherlands. [ABSTRACT FROM AUTHOR]

Antibodies to the ganglioside GD1b have been reported in various forms of immune‐mediated neuropathy, but their clinical relevance for diagnosis and prognosis is unknown. We investigated the prevalence of anti‐GD1b antibodies in acute and chronic immune‐mediated neuropathies, and the clinical presentation and outcome in Guillain‐Barré syndrome (GBS) and Miller Fisher‐GBS overlap syndrome (MF‐GBS). Anti‐GD1b, anti‐GM1 and anti‐GQ1b antibodies were tested in serum of patients with GBS (N = 165), Miller Fisher syndrome (N = 10), MF‐GBS (N = 28), monoclonal gammopathy of unknown significance neuropathy (MGUS; N = 101), chronic inflammatory demyelinating polyneuropathy (N = 29), paraneoplastic syndrome with anti‐Hu‐associated neuropathy (PNS; N = 11), other auto‐immune diseases (AID; N = 60), and healthy controls (HC; N = 60). All samples were tested by enzyme‐linked immunosorbent assay according to the Inflammatory Neuropathy Cause and Treatment protocol. IgM anti‐GD1b antibodies were found in GBS (N = 4; 2.4%), MGUS (N = 3; 3.0%), and PNS patients (N = 1; 9.1%). IgG anti‐GD1b antibodies were found in GBS (N = 20; 12.1%) and MF‐GBS (N = 4; 14.3%) patients, but not in the AID and HC group. In the combined group of MF‐GBS and GBS patients ((MF‐)GBS), 14/36 (38.9%) patients with IgG anti‐GD1b antibodies also had IgG anti‐GM1 antibodies, and IgG anti‐GD1b and IgG anti‐GQ1b antibodies were found in 3/29 (10.3%) patients. Patients with (MF‐)GBS and anti‐GD1b without anti‐GM1 antibodies did not differ regarding sensory disturbances or disease severity but recovered faster regarding the ability to walk independently compared with patients without anti‐GD1b antibodies (P = 0.031) and with patients with both anti‐GD1b and anti‐GM1 antibodies (P = 0.034). In conclusion, testing for anti‐GD1b antibodies may identify a specific group of immune‐mediated neuropathies and (MF‐)GBS patients with only anti‐GD1b antibodies tend to recover faster. [ABSTRACT FROM AUTHOR]

Objective: In rheumatoid arthritis (RA), anti–citrullinated protein antibodies (ACPAs) and rheumatoid factor (RF) are commonly used to aid in the diagnosis. Although these autoantibodies are mainly found in RA, their specificity is not optimal. It is therefore difficult to identify RA patients, especially in very early disease, based on the presence of ACPAs and RF alone. In addition, anti–carbamylated protein (anti‐CarP) antibodies have diagnostic and prognostic value, since their presence is associated with joint damage in RA patients and also associated with the future development of RA in patients with arthralgia. Therefore, the aim of the present study was to investigate the value of combined antibody testing in relation to prediction and diagnosis of (early) RA. Methods: A literature search resulted in identification of 12 relevant studies, consisting of RA patients, pre‐RA individuals, disease controls, healthy first‐degree relatives of RA patients, and healthy control subjects, in which data on RF, ACPAs, and anti‐CarP antibody status were available. Using these data, random effects meta‐analyses were carried out for several antibody combinations. Results: The individual antibodies were highly prevalent in patients with RA (34–80%) compared to the control groups, but were also present in non‐RA controls (0–23%). For the classification of most subjects correctly as having RA or as a non‐RA control, the combination of ACPAs and/or RF often performed well (specificity 65–100%, sensitivity 59–88%). However, triple positivity for ACPAs, RF, and anti‐CarP antibodies resulted in a higher specificity for RA (98–100%), accompanied by a lower sensitivity (11–39%). Conclusion: As the rheumatology field is moving toward very early identification of RA and possible screening for individuals at maximum risk of RA in populations with a low pretest probability, an autoantibody profile of triple positivity for ACPAs, RF, and anti‐CarP provides interesting information that might help identify individuals at risk of developing RA. [ABSTRACT FROM AUTHOR]

The gut is enmeshed by a number of cellular networks, but there is only a limited understanding of how these networks generate the complex patterns of activity that drive gut contractile functions. Here we review two fundamental types of cell behaviour, excitable and oscillating, and the patterns that networks of such cells generate, trigger waves and phase waves, respectively. We use both the language of biophysics and the theory of nonlinear dynamics to define these behaviours and understand how they generate patterns. Based on this we look for evidence of trigger and phase waves in the gut, including some of our recent work on the small intestine. The membrane potential of an excitable cell depolarises in response to a depolarising trigger. In a network of excitable cells, coupled electrically by gap junctions, a wave of electrical excitation can thus spread like falling dominoes. This is a trigger wave. In a network of cells whose membrane potentials oscillate autonomously, gap junction coupling causes synchronisation with a lag, giving the appearance of a propagating wave. This is a phase wave. The same phenomenon can be seen in a variety of coupled oscillator systems, such as fireflies, electrical circuits, fluid vortices and metronomes. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study? What is the nature of slow wave‐driven contraction frequency gradients in the small intestine? What is the main finding and its importance? Frequency plateaux are composed of discrete waves of increased interval, each wave associated with a contraction dislocation. Smooth frequency gradients are generated by localized neural modulation of wave frequency, leading to functionally important wave turbulence. Both patterns are emergent properties of a network of coupled oscillators, the interstitial cells of Cajal. Abstract: A gut‐wide network of interstitial cells of Cajal generates electrical oscillations (slow waves) that orchestrate waves of muscle contraction. In the small intestine there is a gradient in slow wave frequency from high at the duodenum to low at the terminal ileum. Time‐averaged measurements of frequency have suggested either a smooth or a stepped (plateaued) gradient. We measured individual contraction intervals from diameter maps of the mouse small intestine to create interval maps (IMaps). The IMaps showed that each frequency plateau was composed of discrete waves of increased interval. Each interval wave originated at a terminating contraction wave, a ‘dislocation’, at the proximal boundary of the plateau. In a model chain of coupled phase oscillators, interval wave frequency increased as coupling decreased or as the natural frequency gradient or noise increased. Injuring the intestine at a proximal point, to destroy coupling, suppressed distal steps, which then reappeared with gap junction block by carbenoxolone. This lent further support to our previous hypothesis that lines of dislocations were fixed by points of low coupling strength. Dislocations, induced by electrical field pulses in the intestine and by equivalent phase shift in the model, were associated with interval waves. When the enteric nervous system was active, IMaps showed a chaotic, turbulent pattern of interval change, with no frequency steps or plateaux. This probably resulted from local, stochastic release of neurotransmitters. Plateaux, dislocations, interval waves and wave turbulence arise from a dynamic interplay between natural frequency and coupling in the network of interstitial cells of Cajal. [ABSTRACT FROM AUTHOR]

New Findings What is the central question of this study? What are the dynamical rules governing interstitial cell of Cajal (ICC)-generated slow wave contractions in the small intestine, as reflected in their phase response curve and state space?, What is the main finding and its importance? The phase response curve has a region of phase advance surrounding a phase delay peak. This pattern is important in generating a stable synchrony within the ICC network and is related to the state space of the ICC; in particular, the phase delay peak corresponds to the unstable equilibrium point that threads the ICC's limit cycle., Interstitial cells of Cajal (ICCs) generate electrical oscillations in the gut. Synchronization of the ICC population is required for generation of coherent electrical waves ('slow waves') that cause muscular contraction and thereby move gut content. The phase response curve (PRC) is an experimental measure of the dynamical rules governing a population of oscillators that determine their synchrony and gives an experimental window onto the state space of the oscillator, its dynamical landscape. We measured the PRC of slow wave contractions in the mouse small intestine by the novel combination of diameter mapping and single pulse electrical field stimulation. Phase change (τ) was measured as a function of old phase (ϕ) and distance from the stimulation electrode ( d). Plots of τ(ϕ, d) showed an arrowhead-shaped region of phase advance enclosing at its base a phase delay peak. The phase change mirrored the perturbed pattern of contraction waves in response to a pulse. The (ϕ, d) plane is the surface of a displacement tube extending from the limit cycle through state space. To visualize the state space vector field on this tube, latent phase (ϕlat) was calculated from τ. At the transition from advance to delay, isochrons made boomerang turns before tightening and winding around the phase delay peak corresponding to the unstable equilibrium point that threads the limit cycle. This isochron foliation had previously been observed in oscillator models such as the Fitzhugh-Nagumo but has not been demonstrated experimentally. The spatial extension of the PRC afforded by diameter mapping allows a better understanding of the dynamical properties of ICCs and how they synchronize as a population. [ABSTRACT FROM AUTHOR]

Objective Prevention of rheumatoid arthritis (RA) was the aim of several trials in undifferentiated arthritis (UA), with overall negative results. As preparatory work has revealed that only ∼30% of UA patients progress to having RA, we hypothesized that inclusion of patients without imminent RA could lead to false-negative results. We undertook this study to evaluate this hypothesis by reinvestigating the Probable Rheumatoid Arthritis: Methotrexate versus Placebo Treatment (PROMPT) trial (a 1-year course of methotrexate [MTX] versus placebo in UA) after excluding patients without a high risk of developing RA. Methods A validated prediction model was used to determine the risk of RA in all patients included in the PROMPT trial. Patients with a prediction score of ≥8 (positive predictive value of ≥84% for developing RA) were considered to have a high risk of developing RA. The effect of a 1-year course of MTX during 5 years of follow-up was reinvestigated in these patients. Results Twenty-two of the 110 patients in the PROMPT trial had a high risk of RA at baseline. In the MTX arm, 6 of 11 patients (55%) developed RA, compared to 11 of 11 patients (100%) in the placebo arm ( P = 0.011). Time to RA development was longer in the MTX arm than in the placebo arm (median 22.5 months versus 3 months; P < 0.001). Drug-free remission was achieved by 4 of 11 patients (36%) in the MTX arm compared to 0 of 11 patients (0%) in the placebo arm ( P = 0.031). These beneficial effects of MTX were observed both in anti-citrullinated protein antibody (ACPA)-positive and in ACPA-negative UA patients with a high risk of RA, but not in UA patients without a high risk of RA. In retrospect, 43 of 110 patients fulfilled the American College of Rheumatology/European League Against Rheumatism 2010 classification criteria for RA at baseline. In addition, beneficial effects were observed only in patients with a high prediction score. Conclusion A 1-year course of MTX delayed and prevented RA development in high-risk UA patients. This emphasizes the importance of adequate risk prediction in trials that aim to prevent RA. [ABSTRACT FROM AUTHOR]

Objective: To determine associations between magnetic resonance imaging (MRI) lesions originating from either axial spondyloarthritis (SpA) or from degeneration and pain in patients with chronic back pain of <2 years duration.Methods: Patients from the Spondyloarthritis Caught Early (SPACE) cohort identified the sites of pain (thoracic, lumbar, buttock). The average MRI scores from 2 readers for axial SpA lesions and from 2 different readers for degenerative lesions were used. Associations between sacroiliac (SI) joint lesions and buttock pain were investigated by logistic regression analysis, and associations between axial SpA or degenerative lesions and pain in the spine (thoracic and lumbar) were investigated using generalized estimating equations. Interactions with sex, age, HLA-B27, and fulfillment of Assessment of SpondyloArthritis international Society (ASAS) criteria were tested.Results: In 348 patients (126 males, 127 fulfilling ASAS criteria, mean age 29.4 years), spinal MRI (and SI joint images in 342) were available. Pain was localized in the thoracic spine (35.9%), the lumbar spine (82.5%), or in the buttock(s) (57.8%). Inflammatory lesions of the SI joint (odds ratio [OR] 1.06; P = 0.04) and erosions of the SI joint in patients <25 years (OR 1.16; P = 0.04) were associated with buttock pain. Axial SpA spinal lesions were not associated with pain. Modic type 1 lesions in patients >35 years (OR 5.19; P = 0.001), high-intensity zone lesions in females not fulfilling ASAS criteria (OR 5.09; P = 0.001), and herniation in various subgroups (OR range 2.07-4.66) were associated with pain.Conclusion: Specific degenerative lesions, but not typical axial SpA lesions, of the spine are associated with pain at the same location in some subgroups. Inflammatory lesions in the SI joint are associated with buttock pain. [ABSTRACT FROM AUTHOR]

New Findings What is the central question of this study? What are the effects of interstitial cells of Cajal (ICC) network perturbations on intestinal pacemaker activity and motor patterns?, What is the main finding and its importance? Two-dimensional modelling of the ICC pacemaker activity according to a phase model of weakly coupled oscillators showed that network properties (coupling strength between oscillators, frequency gradient and frequency noise) strongly influence pacemaker network activity and subsequent motor patterns. The model explains motor patterns observed in physiological conditions and provides predictions and testable hypotheses for effects of ICC loss and frequency modulation on the motor patterns., Interstitial cells of Cajal (ICC) are the pacemaker cells of gut motility and are associated with motility disorders. Interstitial cells of Cajal form a network, but the contributions of its network properties to gut physiology and dysfunction are poorly understood. We modelled an ICC network as a two-dimensional network of weakly coupled oscillators with a frequency gradient and showed changes over time in video and graphical formats. Model parameters were obtained from slow-wave-driven contraction patterns in the mouse intestine and pacemaker slow-wave activities from the cat intestine. Marked changes in propagating oscillation patterns (including changes from propagation to non-propagating) were observed by changing network parameters (coupling strength between oscillators, the frequency gradient and frequency noise), which affected synchronization, propagation velocity and occurrence of dislocations (termination of an oscillation). Complete uncoupling of a circumferential ring of oscillators caused the proximal and distal section to desynchronize, but complete synchronization was maintained with only a single oscillator connecting the sections with high enough coupling. The network of oscillators could withstand loss; even with 40% of oscillators lost randomly within the network, significant synchronization and anterograde propagation remained. A local increase in pacemaker frequency diminished anterograde propagation; the effects were strongly dependent on location, frequency gradient and coupling strength. In summary, the model puts forth the hypothesis that fundamental changes in oscillation patterns (ICC slow-wave activity or circular muscle contractions) can occur through physiological modulation of network properties. Strong evidence is provided to accept the ICC network as a system of coupled oscillators. [ABSTRACT FROM AUTHOR]

Objective: Guillain-Barré syndrome (GBS) is an acute postinfectious immune-mediated polyneuropathy. Although preceding respiratory tract infections with Mycoplasma pneumoniae have been reported in some cases, the role of M. pneumoniae in the pathogenesis of GBS remains unclear. We here cultured, for the first time, M. pneumoniae from a GBS patient with antibodies against galactocerebroside (GalC), which cross-reacted with the isolate. This case prompted us to unravel the role of M. pneumoniae in GBS in a case-control study.Methods: We included 189 adults and 24 children with GBS and compared them to control cohorts for analysis of serum antibodies against M. pneumoniae (n = 479) and GalC (n = 198).Results: Anti-M. pneumoniae immunoglobulin (Ig) M antibodies were detected in GBS patients and healthy controls in 3% and 0% of adults (p = 0.16) and 21% and 7% of children (p = 0.03), respectively. Anti-GalC antibodies (IgM and/or IgG) were found in 4% of adults and 25% of children with GBS (p = 0.001). Anti-GalC-positive patients showed more-frequent preceding respiratory symptoms, cranial nerve involvement, and a better outcome. Anti-GalC antibodies correlated with anti-M. pneumoniae antibodies (p < 0.001) and cross-reacted with different M. pneumoniae strains. Anti-GalC IgM antibodies were not only found in GBS patients with M. pneumoniae infection, but also in patients without neurological disease (8% vs 9%; p = 0.87), whereas anti-GalC IgG was exclusively found in patients with GBS (9% vs 0%; p = 0.006).Interpretation: M. pneumoniae infection is associated with GBS, more frequently in children than adults, and elicits anti-GalC antibodies, of which specifically anti-GalC IgG may contribute to the pathogenesis of GBS. Ann Neurol 2016;80:566-580. [ABSTRACT FROM AUTHOR]