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BackgroundCognitive deficits may be characteristic for only a subgroup of first-episode psychosis (FEP) and the link with clinical and functional outcomes is less profound than previously thought. This study aimed to identify cognitive subgroups in a large sample of FEP using a clustering approach with healthy controls as a reference group, subsequently linking cognitive subgroups to clinical and functional outcomes.Methods204 FEP patients were included. Hierarchical cluster analysis was performed using baseline brief assessment of cognition in schizophrenia (BACS). Cognitive subgroups were compared to 40 controls and linked to longitudinal clinical and functional outcomes (PANSS, GAF, self-reported WHODAS 2.0) up to 12-month follow-up.ResultsThree distinct cognitive clusters emerged: relative to controls, we found one cluster with preserved cognition (n = 76), one moderately impaired cluster (n = 74) and one severely impaired cluster (n = 54). Patients with severely impaired cognition had more severe clinical symptoms at baseline, 6- and 12-month follow-up as compared to patients with preserved cognition. General functioning (GAF) in the severely impaired cluster was significantly lower than in those with preserved cognition at baseline and showed trend-level effects at 6- and 12-month follow-up. No significant differences in self-reported functional outcome (WHODAS 2.0) were present.ConclusionsCurrent results demonstrate the existence of three distinct cognitive subgroups, corresponding with clinical outcome at baseline, 6- and 12-month follow-up. Importantly, the cognitively preserved subgroup was larger than the severely impaired group. Early identification of discrete cognitive profiles can offer valuable information about the clinical outcome but may not be relevant in predicting self-reported functional outcomes.

[Aims] Patients with adult congenital heart disease (ACHD) are a potentially vulnerable patient cohort in case of COVID-19. Some cardiac defects may be associated with a poor COVID-19 outcome. Risk estimation in ACHD is currently based on expert opinion. The aim of this study was to collect clinical outcome data and to identify risk factors for a complicated course of COVID-19 in patients with ACHD., [Methods] Twenty-five ACHD centres in nine European countries participated in the study. Consecutive patients with ACHD diagnosed with COVID-19 presenting to one of the participating centres between 27 March and 6 June 2020 were included. A complicated disease course was defined as hospitalisation for COVID-19 requiring non-invasive or invasive ventilation and/or inotropic support, or a fatal outcome., [Results] Of 105 patients with a mean age of 38±13 years (58% women), 13 had a complicated disease course, of whom 5 died. In univariable analysis, age (OR 1.3, 95% CI 1.1 to 1.7, per 5 years), ≥2 comorbidities (OR 7.1, 95% CI 2.1 to 24.5), body mass index of >25 kg/m2 (OR 7.2, 95% CI 1.9 to 28.3) and cyanotic heart disease (OR 13.2, 95% CI 2.5 to 68.4) were associated with a complicated disease course. In a multivariable logistic regression model, cyanotic heart disease was the most important predictor (OR 60.0, 95% CI 7.6 to 474.0)., [Conclusions] Among patients with ACHD, general risk factors (age, obesity and multiple comorbidities) are associated with an increased risk of complicated COVID-19 course. Congenital cardiac defects at particularly high risk were cyanotic lesions, including unrepaired cyanotic defects or Eisenmenger syndrome., The European Collaboration for Prospective Outcome Research in Congenital Heart Disease is funded by internal grants without support from the pharmaceutical industry.

Inactive carrier phases in chronic hepatitis B virus (HBV) infection present minimal liver disease and HBV replication activity suggesting partial immune reconstitution, although the mechanisms responsible remain elusive. Moreover, hepatitis B surface antigen (HBsAg) production—hypothesized to modulate the immune response—is unaltered. In the current study, we assessed the intrahepatic transcriptome in inactive carriers of HBV versus healthy liver donors, including in the context of diverse HBsAg levels (serum and liver), to better understand the phenomenon of immune control. We found a deregulated liver transcriptome in inactive carriers compared with healthy controls, despite normal liver function. Moreover, diverse HBsAg levels have minimal impact on the liver transcriptome in inactive carriers, although gene correlation analysis revealed that leukocyte activation, recruitment, and innate responses genes were correlated with liver HBsAg levels. These findings provide more insight into the mechanisms underlying anti-HBV strategies currently under development, aimed at interfering with HBsAg production or inducing a state of immune control.

Gut inflammation is strongly associated with spondyloarthritis (SpA), as exemplified by the high prevalence of inflammatory bowel disease (IBD) and the even higher occurrence of subclinical gut inflammation in patients with SpA. The gut-joint axis of inflammation in SpA is further reinforced by similarities in immunopathogenesis at both anatomical sites and by the clinical success of therapies blocking TNF and IL-23 in IBD and in some forms of SpA. Many genetic risk factors are shared between SpA and IBD, and changes in the composition of gut microbiota are seen in both diseases. Current dogma is that inflammation in SpA initiates in the gut and leads to joint inflammation; however, although conceptually attractive, some research does not support this causal relationship. For example, therapies targeting IL-17A are efficacious in the joint but not the gut, and interfering with gut trafficking by targeting molecules such as alpha 4 beta 7 in IBD can lead to onset or flares of SpA. Several important knowledge gaps remain that must be addressed in future studies. Determining the true nature of the gut-joint axis has real-world implications for the treatment of patients with co-incident IBD and SpA and for the repurposing of therapeutics from one disease to the other.In this article, the authors summarize the latest clinical and basic research on gut inflammation in spondyloarthritis and highlight important questions to address in future research.

Objectives To delineate the impact of peripheral musculoskeletal manifestations on stratification of disease phenotype and outcome in new-onset spondyloarthritis (SpA), using a prospective observational nationwide inception cohort, the BelGian Inflammatory Arthritis and spoNdylitis cohorT (Be-Giant). Methods Newly diagnosed adult SpA patients, fulfilling the Assessment of SpondyloArthritis International Society (ASAS) criteria for axial or peripheral SpA, were included in Be-Giant and prospectively followed every six months. Peripheral involvement (defined as arthritis, enthesitis and/or dactylitis) was determined in relation to clinically similar patient subsets at baseline and disease activity patterns during two-year follow-up, identified through K-means cluster analysis and latent class growth analysis. Results From November 2010 to March 2020, 367 patients were enrolled in Be-Giant, of whom 162 (44%) had peripheral manifestations. Two patient clusters [A, axial predominant (n = 248) and B, peripheral predominant (n = 119)] were identified at diagnosis. Longitudinal analysis (n = 115) revealed two trajectories of disease activity in each cluster: one with persistently high disease activity over time (‘High’), the other rapidly evolving to low disease activity (‘Low’). In cluster A patients, peripheral manifestations predisposed to the ‘High’ trajectory [odds ratio (OR) = 2.0, 95% CI: 1.3, 3.1, P = 0.001], despite more rapid initiation of biologics compared with patients without peripheral manifestations (hazard ratio (HR) = 2.1, 95% CI: 1.0, 4.4, P = 0.04 – Cox proportional-hazards model). Conclusion Peripheral musculoskeletal manifestations are major determinants of phenotypical diversity in new-onset SpA. Intriguingly, stratification of axial SpA according to concomitant peripheral involvement identified an endotype with an unfavorable outcome despite more prompt therapeutic intensification with biologics. These observations justify an endotype-tailored approach beyond current ASAS/EULAR management recommendations.

ObjectivesRisankizumab is an interleukin-23 inhibitor under study for the treatment of patients with psoriatic arthritis (PsA). The phase 3 KEEPsAKE 2 trial investigated the efficacy and safety of risankizumab versus placebo in patients with active PsA who had previous inadequate response or intolerance to ≤2 biological therapies (Bio-IR) and/or ≥1 conventional synthetic disease-modifying antirheumatic drug (csDMARD-IR). Results through week 24 are reported here.MethodsAdults with PsA who were Bio-IR and/or csDMARD-IR were randomised to receive subcutaneously administered risankizumab 150 mg or placebo at weeks 0, 4 and 16 during a 24-week, double-blind treatment period. The primary endpoint was the proportion of patients who achieved ≥20% improvement in American College of Rheumatology score (ACR20) at week 24. Secondary endpoints assessed key domains of PsA and patient-reported outcomes.ResultsA total of 444 patients (median age 53 years, range 23–84 years) were randomised to risankizumab (n=224) or placebo (n=220); 206 patients (46.5%) were Bio-IR. At week 24, a significantly greater proportion of patients receiving risankizumab achieved the primary endpoint of ACR20 (51.3% vs 26.5%, pConclusionTreatment with risankizumab resulted in significant improvements versus placebo in key disease outcomes and was well tolerated in patients with PsA who were Bio-IR and/or csDMARD-IR.Trial registration numberNCT03671148.

Objective: Conventional inhaler devices have a low efficacy in targeting small airways. Smart nebulizers can be used to increase deposition to small airways by adjusting the flow and depth of each inhalation based on patients ‘individual inspiratory capacity. We investigated whether targeting of high dose inhaled corticosteroids (ICS) to small airways with a smart nebulizer could reduce exacerbation rate in children with severe asthma (SA). Methods: We conducted a retrospective study in children with SA using a smart nebulizer (Akita® Jet nebulizer) for the administration of high dose ICS in our outpatient clinic at the Erasmus MC — Sophia Children’s Hospital. Clinical data before and after start of treatment were collected. The primary outcome was exacerbation rate, defined as: number of asthma exacerbations for which oral corticosteroid courses (OCS) were prescribed. The exacerbation rate 1 year before treatment was compared with the exacerbation rate 1 year after start of treatment. Secondary outcomes were changes in spirometry parameters, hospital admissions and medication use. Results: Data on OCS use was available for 28/31 patients. Median number of asthma exacerbations requiring OCS courses 1 year before decreased from 2 (interquartile range(IQR) 2) to 0.5 (IQR 3) 1 year after treatment (p = 0.021). Hospital admission decreased from 1 (IQR 3) to 0 (IQR 1)(p = 0.028). FEV1, FEF25-75 and FEF75 were not significantly improved after one year of treatment with the smart nebulizer (p = 0.191; p = 0.248; p = 0.572). Conclusion: Targeting small airways with high dose ICS using a smart nebulizer resulted in a significant reduction in exacerbations requiring OCS after one year of treatment.

Introduction Psoriatic arthritis (PsA) has a major impact on health-related quality of life (HRQOL) and other patient-reported outcomes (PROs), important components in the assessment of therapeutic efficacy. We evaluated the impact of upadacitinib on PROs in PsA patients with inadequate responses or intolerance to biologic disease-modifying anti-rheumatic drugs (bDMARD-IR). Methods Patients enrolled in the phase 3 SELECT-PsA 2 randomized controlled trial (RCT) received 56 weeks of oral upadacitinib 15 mg QD, upadacitinib 30 mg QD, or placebo switched to either dose of upadacitinib at week 24. PROs included patient global assessment of disease activity (PtGA), pain, physical function (HAQ-DI), health-related quality of life (SF-36 physical (PCS) and mental (MCS) component summary and domain scores), fatigue (FACIT-F), psoriasis symptom severity (SAPS), and work productivity (WPAI). Mean changes from baseline in PROs, improvements ≥ minimum clinically important differences (MCID) and scores ≥ normative values, and maintenance of improvements were assessed. Results At weeks 12 and 24, patients treated with either upadacitinib dose reported statistically and nominally significant improvements from baseline across all PROs versus placebo (p ≤ 0.05), except the WPAI absenteeism domain, which were maintained or further improved to week 56. A significantly greater proportion of patients receiving either upadacitinib dose reported improvements ≥ MCID and scores ≥ normative values versus placebo (nominal p ≤ 0.01) in most PROs at weeks 12 and 24, with clinically meaningful improvements continuing to week 56. Improvements ≥ MCID were reported as early as week 2 in PtGA, pain, and HAQ-DI. Conclusions Upadacitinib provides rapid, clinically meaningful, and sustained improvements in PROs reported by bDMARD-IR PsA patients. SELECT-PsA 2 ClinicalTrials.gov number, NCT03104374. Supplementary Information The online version contains supplementary material available at 10.1007/s40744-021-00377-x.

IL-23 is a key cytokine in the pathogenesis of spondyloarthritides, including PsA and axial spondyloarthritis, as well as related conditions, such as psoriasis and IBD. Genetic associations, animal models and translational studies in humans demonstrate the key role played by IL-23, especially when coupled with downstream overexpression of IL-17 via stimulation of T helper 17 (Th17) and other cells by IL-23. Whereas IL-23 inhibition has shown clear-cut benefit in psoriasis and peripheral manifestations of PsA, trials of IL-23 inhibitors have failed in the treatment of ankylosing spondylitis. More recently, exploratory data from PsA patients with axial symptoms suggests that improvement may occur, but needs confirmation in dedicated axial spondyloarthritis (axSpA) trials. Hypotheses for these apparently conflicting findings about IL-23 inhibition in various forms of spondylitis are discussed.

PURPOSE: To evaluate the feasibility of semi-automatic Quality of Life (QOL)-weighted normal tissue complication probability (NTCP)-guided VMAT treatment plan optimisation in head and neck cancer (HNC) and compare predicted QOL to that obtained with conventional treatment.MATERIALS AND METHODS: This study included 30 HNC patients who were treated with definitive radiotherapy. QOL-weighted NTCP-guided VMAT plans were optimised directly on 80 multivariable NTCP models of 20 common toxicities and symptoms on 4 different time points (6, 12, 18 and 24 months after radiotherapy) and each NTCP model was weighted relative to its impact on QOL. Planning results, NTCP and predicted QOL were compared with the clinical conventional VMAT plans.RESULTS: QOL-weighted NTCP-guided VMAT plans were clinically acceptable, had target coverage equally adequate as the clinical plans, but prioritised sparing of organs at risk (OAR) related to toxicities and symptoms that had the highest impact on QOL. NTCP was reduced for, e.g., dysphagia (-6.1% for ≥ grade 2/ -7.6% for ≥ grade 3) and moderate-to-severe fatigue / speech problems / hoarseness (-0.7%/ -1.5%/ -2.5%) at 6 months, respectively. Concurrently, the average NTCP of toxicities related to salivary function increased with +0.4% to +5.7%. QOL-weighted NTCP-guided plans were produced in less time, were less dependent on the treatment planner experience and yielded more consistent results. The average predicted QOL improved by 0.7, 0.9, 1.0, and 1.1 points on a 0-100 scale (p < 0.001) at 6, 12, 18, and 24 months, respectively, compared to the clinical plans.CONCLUSION: Semi-automatic QOL-weighted NTCP-guided VMAT treatment plan optimisation is feasible. It prioritised sparing of OARs related to high-impact toxicities and symptoms and resulted in a systematic improvement of predicted QOL compared to conventional VMAT.

ObjectivesThe objective of COAST-Y was to evaluate the effect of continuing versus withdrawing ixekizumab (IXE) in patients with axial spondyloarthritis (axSpA) who had achieved remission.MethodsCOAST-Y is an ongoing, phase III, long-term extension study that included a double-blind, placebo (PBO)-controlled, randomised withdrawal-retreatment period (RWRP). Patients who completed the originating 52-week COAST-V, COAST-W or COAST-X studies entered a 24-week lead-in period and continued either 80 mg IXE every 2 (Q2W) or 4 weeks (Q4W). Patients who achieved remission (an Ankylosing Spondylitis Disease Activity Score (ASDAS)3.5 at any visit) after the 40-week RWRP, with time-to-flare as a major secondary endpoint.ResultsOf 773 enrolled patients, 741 completed the 24-week lead-in period and 155 entered the RWRP. Forty weeks after randomised withdrawal, 83.3% of patients in the combined IXE (85/102, pConclusionsPatients with axSpA who continued treatment with IXE were significantly less likely to flare and had significantly delayed time-to-flare compared with patients who withdrew to PBO.

Background Excessive osteoclast activity, which is strongly stimulated by pro-inflammatory mediators, results in bone and cartilage degeneration as central features of many arthritides. Levels of the alarmin S100A8/A9 and interleukin (IL)-1β are both increased in arthritis patients and correlate with disease activity and progression of tissue erosion. We previously presented S100A8/A9 as a good biomarker for joint inflammation and arthritis pathology under circumstances of high IL-1 signaling in mice that lack the gene encoding IL-1 receptor antagonist (Il1rn−/− mice). Here, we investigated whether S100A8/A9 is also actively involved in the development of joint inflammation and both cartilage and bone pathology under these conditions by comparing Il1rn−/− mice with mice that have an additional deficiency for S100a9 (Il1rn−/−XS100a9−/−). Methods Il1rn−/−XS100a9−/− on a BALB/c background were obtained by crossing S100a9−/− mice and Il1rn−/− mice. Arthritis incidence and severity were macroscopically scored. Myeloid cell populations in the bone marrow and spleen were determined using flow cytometry. In vitro osteoclastogenesis of bone marrow cells was evaluated with TRAP staining. Microscopic joint inflammation, cartilage degeneration, and bone destruction were evaluated using histology of ankle joints of 12- and 20-week-old mice. Results Macroscopically scored arthritis severity was comparable between Il1rn−/− and Il1rn−/−XS100a9−/− mice. Inflammation, cartilage erosion, and bone erosion were clearly present in 12-week-old mice of both strains lacking Il1rn−/−, but not significantly different between Il1rn−/−XS100a9−/− and Il1rn−/−. Moreover, we observed that the numbers of neutrophils and monocytes were increased by the absence of Il1rn, which was affected by the absence of S100a9 only in the spleen but not in the bone marrow. In line with our other findings, the absence of S100a9 did not affect the osteoclastogenic potential of osteoclast precursors in the absence of Il1rn. Finally, in agreement with the findings in early arthritis development in 12-week-old mice, cartilage and bone erosion in 20-week-old mice was significantly higher in both Il1rn−/− strains, but the additional absence of S100a9 did not further affect tissue pathology. Conclusion S100A8/A9 deficiency does not significantly affect inflammation and joint destruction in mice with high IL1β signaling suggesting that S100A8/A9 is not essential for the development of arthritis under these conditions.

The relationship between the age-associated decline in mitochondrial function and its effect on skeletal muscle physiology and function remain unclear. In the current study, we examined to what extent physical activity contributes to the decline in mitochondrial function and muscle health during aging and compared mitochondrial function in young and older adults, with similar habitual physical activity levels. We also studied exercise-trained older adults and physically impaired older adults. Aging was associated with a decline in mitochondrial capacity, exercise capacity and efficiency, gait stability, muscle function, and insulin sensitivity, even when maintaining an adequate daily physical activity level. Our data also suggest that a further increase in physical activity level, achieved through regular exercise training, can largely negate the effects of aging. Finally, mitochondrial capacity correlated with exercise efficiency and insulin sensitivity. Together, our data support a link between mitochondrial function and age-associated deterioration of skeletal muscle., Aging is associated with a progressive loss of muscle function. Here the authors characterize mitochondrial capacity and muscle function in young and older adults with similar habitual physical activity and also compared to older adults with exercise training or with physical impairment.

Background Anomalous coronary artery originating from the opposite sinus of Vasalva with interarterial course (ACAOS-IAC) is associated with sudden cardiac death (SCD) in young athletes. If identified in adulthood prognosis is usually more benign, resulting in a dilemma regarding revascularization. Methods This is a retrospective observational single-center study, including adults with ACAOS-IAC. Medical records between 2012 and 2019 were reviewed for management approach, mortality, cardiac death and coronary related adverse events. Coronary computed tomographic angiography (CCTA) were reviewed. We provide a literature review in regard to clinical outcome. Results We identified 40 patients with ACAOS-IAC (mean age 51). Presentation was acute in 7/40 (18%). Ischemia detection with single photon emission tomography (SPECT), cardiac magnetic resonance (CMR) or dobutamine stress echocardiography were performed in 25/40 (63%) patients. Ischemia in the vascular territory of the anomaly was present in 2/25 (8%). In 39/40 (98%) patients were treated expectative. During median follow-up of 2.7 years (IQR 1.5–5.3) no cardiovascular death was observed. Mortality occurred in 1/40 (3%) and coronary related adverse events in 2/40 (5%). We identified 20 studies describing 1194 patients. Revascularization was performed in 376/1154 (32.6%) patients. Mortality stratified for clinical management was 23/431 (5.3%) in the non-revascularization versus 16/253 (6.3%) in the revascularization group during 4.0 years follow-up (weighted median). Cause of death was cardiovascular in 10/596 (1.7%) in 4.2 years (weighted median) follow up. Conclusions Both revascularization and non-invasive management have good prognosis in adults with ACAOS-IAC during early follow up. There is need for guidelines and long-term surveillance.

PURPOSE: The aim of this study is to establish the relative impact of physician-rated toxicities and patient-rated symptoms in head and neck cancer (HNC) on quality of life (QOL) and to weigh the various toxicities and symptoms during treatment plan optimization and selection.MATERIALS AND METHODS: This prospective cohort study comprised 1,083 HNC patients (development: 750, validation: 333) treated with definitive radiotherapy with or without chemotherapy. Clinical factors were scored at baseline. Physician-rated and patient-rated outcome measures and QOL (EORTC QLQ-HN35 and QLQ-C30) were prospectively scored at baseline and 6, 12, 18 and 24 months after radiotherapy. The impact of 20 common toxicities and symptoms (related to swallowing, salivary function, speech, pain and general complaints) on QOL (0-100 scale) was established for each time point by combining principal component analysis and multivariable linear regression.RESULTS: Radiation-induced toxicities and symptoms resulted in a significant decline in QOL of patients with 12.4±12.8 points at 6 months to 16.6±17.1 points at 24 months. The multivariable linear models described the QOL points subtracted for each toxicity and symptom after radiotherapy. For example, xerostomia and weight loss had a significant but minor effect (on average -0.5 and -0.6 points) while speech problems and fatigue had a much greater impact (on average -11.9 and -17.4 points) on QOL. R2 goodness-of-fit values for the QOL models ranged from 0.64 (6 months) to 0.72 (24 months).CONCLUSION: The relative impact of physician-rated toxicities and patient-rated symptoms on QOL was quantified and can be used to optimize, compare and select HNC radiotherapy treatment plans, to balance the relevance of toxicities and to achieve the best QOL for individual patients.

High-frame-rate (HFR) echo-particle image velocimetry (echoPIV) is a promising tool for measuring intracardiac blood flow dynamics. In this study, we investigate the optimal ultrasound contrast agent (UCA: SonoVue) infusion rate and acoustic output to use for HFR echoPIV (PRF = 4900 Hz) in the left ventricle (LV) of patients. Three infusion rates (0.3, 0.6, and 1.2 ml/min) and five acoustic output amplitudes (by varying transmit voltage: 5, 10, 15, 20, and 30 V - corresponding to mechanical indices of 0.01, 0.02, 0.03, 0.04, and 0.06 at 60-mm depth) were tested in 20 patients admitted for symptoms of heart failure. We assess the accuracy of HFR echoPIV against pulsed-wave Doppler acquisitions obtained for mitral inflow and aortic outflow. In terms of image quality, the 1.2-ml/min infusion rate provided the highest contrast-to-background ratio (CBR) (3-dB improvement over 0.3 ml/min). The highest acoustic output tested resulted in the lowest CBR. Increased acoustic output also resulted in increased microbubble disruption. For the echoPIV results, the 1.2-ml/min infusion rate provided the best vector quality and accuracy; mid-range acoustic outputs (corresponding to 15-20-V transmit voltages) provided the best agreement with the pulsed-wave Doppler. Overall, the highest infusion rate (1.2 ml/min) and mid-range acoustic output amplitudes provided the best image quality and echoPIV results.

Axonal Charcot-Marie-Tooth neuropathies (CMT type 2) are caused by inherited mutations in various genes functioning in different pathways. The types of genes and multiplicity of mutations reflect the clinical and genetic heterogeneity in CMT2 disease, which complicates its diagnosis and has inhibited the development of therapies. Here, we used CMT2 patient-derived pluripotent stem cells (iPSCs) to identify common hallmarks of axonal degeneration shared by different CMT2 subtypes. We compared the cellular phenotypes of neurons differentiated from CMT2 patient iPSCs with those from healthy controls and a CRISPR/Cas9-corrected isogenic line. Our results demonstrated neurite network alterations along with extracellular electrophysiological abnormalities in the differentiated motor neurons. Progressive deficits in mitochondrial and lysosomal trafficking, as well as in mitochondrial morphology, were observed in all CMT2 patient lines. Differentiation of the same CMT2 iPSC lines into peripheral sensory neurons only gave rise to cellular phenotypes in subtypes with sensory involvement, supporting the notion that some gene mutations predominantly affect motor neurons. We revealed a common mitochondrial dysfunction in CMT2-derived motor neurons, supported by alterations in the expression pattern and oxidative phosphorylation, which could be recapitulated in the sciatic nerve tissue of a symptomatic mouse model. Inhibition of a dual leucine zipper kinase could partially ameliorate the mitochondrial disease phenotypes in CMT2 subtypes. Altogether, our data reveal shared cellular phenotypes across different CMT2 subtypes and suggests that targeting such common pathomechanisms could allow the development of a uniform treatment for CMT2., See Müller and Horvath (doi:10.1093/brain/awab278) for a scientific commentary on this article. Van Lent et al. use neurons differentiated from patient-derived iPSCs to identify common hallmarks of axonal degeneration, including impaired axonal transport and mitochondrial dysfunction, shared by different CMT2 subtypes. Targeting these pathomechanisms could provide new drug development opportunities for CMT2.

To assess the safety, adequacy and accuracy of transvaginal ultrasound-guided tru-cut biopsy of pelvic masses.We performed a retrospective analysis of consecutive women who underwent transvaginal ultrasound-guided tru-cut biopsies between June 2014 and October 2018 at the Department of Obstetrics and Gynecology of the University Hospitals Leuven. Main indications for tru-cut biopsy were tissue collection for diagnosis of pelvic tumors in cases of suspected disseminated disease or recurrence, or tissue banking for research purposes. Data about adverse events occurring within 2 weeks of the procedure (including bleeding, blood transfusion, hospital admission, urgent surgery, pelvic infection or death) were extracted from electronic medical records. Tissue samples were recorded as adequate if tumor identification and immunohistochemistry were possible. Accuracy was defined in patients who underwent surgery as the agreement between histology after tru-cut biopsy and final histology.176 tru-cut biopsies were performed in 155 patients. Procedure related events were limited to moderate blood loss (50 ml) without the need for treatment in 4.5%. There were no major complications. Biopsies were deemed adequate for histological evaluation in 84.3% of biopsies performed for diagnostic purposes and in 71.4% of research cases in whom a single tissue cylinder was available for diagnosis. When at least two cylinders were available, diagnostic adequacy increased to95%. Comparing final histology, the diagnostic accuracy of the tru-cut biopsies was 97.2%.Transvaginal tru-cut biopsy for diagnosis of pelvic masses is a safe procedure. To allow an adequate and accurate diagnosis, we advise taking at least 2 core biopsies.

Objectives:Nursing home residents with dementia are sensitive to detrimental auditory environments. This paper presents the first literature review of empirical research investigating (1) the (perceived) intensity and sources of sounds in nursing homes, and (2) the influence of sounds on health of residents with dementia and staff.Design:A systematic review was conducted in PubMed, Web of Science and Scopus. Study quality was assessed with the Mixed Methods Appraisal Tool. We used a narrative approach to present the results.Results:We included 35 studies. Nine studies investigated sound intensity and reported high noise intensity with an average of 55–68 dB(A) (during daytime). In four studies about sound sources, human voices and electronic devices were the most dominant sources. Five cross-sectional studies focused on music interventions and reported positives effects on agitated behaviors. Four randomized controlled trials tested noise reduction as part of an intervention. In two studies, high-intensity sounds were associated with decreased nighttime sleep and increased agitation. The third study found an association between music and less agitation compared to other stimuli. The fourth study did not find an effect of noise on agitation. Two studies reported that a noisy environment had negative effects on staff.Conclusions:The need for appropriate auditory environments that are responsive to residents’ cognitive abilities and functioning is not yet recognized widely. Future research needs to place greater emphasis on intervention-based and longitudinal study design.

Background Current guidelines on coronary anomalies are primarily based on expert consensus and a limited number of trials. A gold standard for diagnosis and a consensus on the treatment strategy in this patient group are lacking, especially for patients with an anomalous origin of a coronary artery from the opposite sinus of Valsalva (ACAOS) with an interarterial course. Aim To provide evidence-substantiated recommendations for diagnostic work-up, treatment and follow-up of patients with anomalous coronary arteries. Methods A clinical care pathway for patients with ACAOS was established by six Dutch centres. Prospectively included patients undergo work-up according to protocol using computed tomography (CT) angiography, ischaemia detection, echocardiography and coronary angiography with intracoronary measurements to assess anatomical and physiological characteristics of the ACAOS. Surgical and functional follow-up results are evaluated by CT angiography, ischaemia detection and a quality-of-life questionnaire. Patient inclusion for the first multicentre study on coronary anomalies in the Netherlands started in 2020 and will continue for at least 3 years with a minimum of 2 years of follow-up. For patients with a right or left coronary artery originating from the pulmonary artery and coronary arteriovenous fistulas a registry is maintained. Results Primary outcomes are: (cardiac) death, myocardial ischaemia attributable to the ACAOS, re-intervention after surgery and intervention after initially conservative treatment. The influence of work-up examinations on treatment choice is also evaluated. Conclusions Structural evidence for the appropriate management of patients with coronary anomalies, especially (interarterial) ACAOS, is lacking. By means of a structured care pathway in a multicentre setting, we aim to provide an evidence-based strategy for the diagnostic evaluation and treatment of this patient group.

Background: Right ventricular (RV) function is recognized as an important prognostic factor in adult congenital heart disease (ACHD). The accuracy of established parameters including tricuspid annular plane systolic excursion (TAME), RV fractional area change (RVFAC) and tissue Doppler imaging (TDI S') is limited as only a small RV region is reflected. We previously introduced a novel four-view approach with different RV walls visualized from one apical view using electronic plane rotation, also known as iRotate. Aim: To evaluate the entire RV function using electronic plane rotation echocardiography within the spectrum of ACHD compared with healthy subjects. Methods and results: One hundred and forty-two ACHD patients were recruited from the outpatient clinic and 89 healthy subjects. All subjects underwent a transthoracic echocardiogram with evaluation of TAPSE, TDI S' and peak systolic longitudinal RV strain (RV-LS) from all RV walls using the bur-view electronic plane rotation model. With exception of TDI S' in inferior coronal view, all parameters were lower in ACHD vs healthy subjects (p

Aim: This study aimed to describe the systolic left ventricular global longitudinal strain (LvGLS) and left ventricular peak early diastolic strain rate (Sre) in adult women with Turner syndrome (TS) and to determine its rela-tionship with exercise capacity and clinical parameters. Methods: In this cross-sectional cohort study, consecutively included adult TS women underwent an electrocardiogram, transthoracic echocardiogram (TTE) and cardiopulmonary exercise test (CPET) on the same day. LvGLS and Sre were measured using 2D speckle tracking analysis (STE) and compared with age-matched healthy female controls. Results: Ninety-four adult women (age 36 ± 13 years) with TS and 32 healthy age-matched female controls were included. Women with TS had a significantly impaired/reduced systolic LvGLS (–17.82 ± 2.98% vs. –21.80 ± 1.85%, p 0.001), compared to healthy female controls. Furthermore, TS women had reduced diastolic function as measured by conventional echocardiographic parameters: A higher A-wave (p < 0.001), lower E/A-ratio (p = 0.001), longer deceleration time (p = 0.006), and a higher E/E’-ratio (p

Background and purpose: A comprehensive individual toxicity risk profile is needed to improve radiation treatment optimisation, minimising toxicity burden, in head and neck cancer (HNC) patients. We aimed to develop and externally validate NTCP models for various toxicities at multiple time points.Materials and methods: Using logistic regression, we determined the relationship between normal tissue irradiation and the risk of 22 toxicities at ten time points during and after treatment in 750 HNC patients. The toxicities involved swallowing, salivary, mucosal, speech, pain and general complaints. Studied pre-dictors included patient, tumour and treatment characteristics and dose parameters of 28 organs. The resulting NTCP models were externally validated in 395 HNC patients.Results: The NTCP models involved 14 organs that were associated with at least one toxicity. The oral cavity was the predominant organ, associated with 12 toxicities. Other important organs included the parotid and submandibular glands, buccal mucosa and swallowing muscles. In addition, baseline toxicity, treatment modality, and tumour site were common predictors of toxicity. The median discrimination performance (AUC) of the models was 0.71 (interquartile range: 0.68-0.75) at internal validation and 0.67 (interquartile range: 0.62-0.71) at external validation.Conclusion: We established a comprehensive individual toxicity risk profile that provides essential insight into how radiation exposure of various organs translates into multiple acute and late toxicities. This comprehensive understanding of radiation-induced toxicities enables a new radiation treatment optimisation concept that balances multiple toxicity risks simultaneously and minimises the overall tox-icity burden for an individual HNC patient who needs to undergo radiation treatment. (C) 2021 The Author(s). Published by Elsevier B.V.

Background and purpose: Radiotherapy in the head and neck area may cause vascular damage to the carotid arteries, increasing the risk of anterior circulation ischaemic cerebrovascular events (ICVEs). However, limited data exists on the relationship between radiation dose to the carotid arteries and risk of ICVE. The purpose of this study was therefore to determine the relationship between radiation dose to the carotid arteries and anterior circulation ICVE risk.Materials and methods: A retrospective analysis of a prospective study cohort of 750 head and neck cancer patients treated with definitive (chemo)radiotherapy was performed. Carotid arteries were delineated, and dose-volume parameters of the treatment plans were calculated. ICVEs were scored prospectively and checked retrospectively by analysing all patient records. Cox proportional hazards analysis was performed to analyse the dose-effect relationships.Results: The median follow-up period was 3.4 years, 27 patients experienced an ICVE and the 5-year cumulative risk was 4.6%. ICVE risk was significantly associated with dose to the carotid arteries. Multivariable analysis showed that the absolute volume (cm(3)) of the carotid arteries that received at least a radiation dose of 10 Gy was the most important prognostic factor for ICVE (HR = 1.11, AUC = 0.68, p < 0.001).Conclusion: This is the first large prospective cohort study that demonstrates an independent dose-effect relationship between radiation dose to the carotid arteries and the risk of ICVE. These findings may be used to identify patients at risk for ICVE after radiotherapy who may benefit from primary or secondary preventive measures. (C) 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction Upadacitinib is a Janus kinase inhibitor under investigation in patients with psoriatic arthritis (PsA). This study assessed the 56-week efficacy and safety of upadacitinib in patients with PsA and an inadequate response or intolerance to biologic therapy. Methods In the phase 3 SELECT-PsA 2 study, patients were randomized to 56 weeks of blinded treatment with oral upadacitinib 15 or 30 mg once daily, or placebo switched to upadacitinib 15 or 30 mg once daily at week 24. Efficacy endpoints included the proportion of patients achieving 20/50/70% improvement in American College of Rheumatology criteria (ACR20/50/70), 75/90/100% improvement in Psoriasis Area and Severity Index (PASI75/90/100), and minimal disease activity. Safety was assessed throughout the study. Results Of 641 patients who received ≥ 1 dose of study drug, 479 (74.7%) completed 56 weeks of treatment. Improvements in the proportion of patients achieving ACR20/50/70, PASI75/90/100, and minimal disease activity were maintained with both doses of upadacitinib through 56 weeks. Week 56 results for patients who switched from placebo to upadacitinib at week 24 were similar to those for patients originally randomized to the upadacitinib groups. The exposure-adjusted event rate for serious infections was 2.6 and 6.1 events/100 patient-years in the upadacitinib 15 and 30 mg groups, respectively. Herpes zoster occurred more frequently with upadacitinib 30 versus 15 mg; most cases were non-serious. Conclusion In patients with PsA who had an inadequate response or intolerance to biologic therapy, the efficacy of upadacitinib was maintained over 56 weeks with no new significant safety signals observed. Trial registration NCT03104374. Electronic supplementary material The online version of this article (10.1007/s40744-021-00305-z) contains supplementary material, which is available to authorized users.

The pathogenesis of idiopathic pulmonary arterial hypertension (IPAH) is not fully understood, but evidence is accumulating that immune dysfunction plays a significant role. We previously reported that 31-week-old Tnfaip3DNGR1-KO mice develop pulmonary hypertension (PH) symptoms. These mice harbor a targeted deletion of the TNFα-induced protein-3 (Tnfaip3) gene, encoding the NF-κB regulatory protein A20, specifically in type I conventional dendritic cells (cDC1s). Here, we studied the involvement of dendritic cells (DCs) in PH in more detail. We found various immune cells, including DCs, in the hearts of Tnfaip3DNGR1-KO mice, particularly in the right ventricle (RV). Secondly, in young Tnfaip3DNGR1-KO mice, innate immune activation through airway exposure to toll-like receptor ligands essentially did not result in elevated RV pressures, although we did observe significant RV hypertrophy. Thirdly, PH symptoms in Tnfaip3DNGR1-KO mice were not enhanced by concomitant mutation of bone morphogenetic protein receptor type 2 (Bmpr2), which is the most affected gene in PAH patients. Finally, in human IPAH lung tissue we found co-localization of DCs and CD8+ T cells, representing the main cell type activated by cDC1s. Taken together, these findings support a unique role of cDC1s in PAH pathogenesis, independent of general immune activation or a mutation in the Bmpr2 gene.

Key Points Question What genetic variants are associated with juvenile amyotrophic lateral sclerosis (ALS)? Findings In this family-based genetic study, exome sequencing was performed in 3 patients diagnosed with juvenile ALS and failure to thrive; this identified de novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient). Variants in SPTLC1 are a known cause of hereditary sensory and autonomic neuropathy, type 1A, and these data extend the phenotype associated with this gene. Meaning De novo variants in the SPTLC1 gene are associated with juvenile ALS, a fatal neurological disorder., This genetic association study identifies genetic variants associated with juvenile amyotrophic lateral sclerosis., Importance Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation. Objective To identify the genetic variants associated with juvenile ALS. Design, Setting, and Participants In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism. Main Outcomes and Measures De novo variants present only in the index case and not in unaffected family members. Results Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway. Conclusions and Relevance These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.

Compelling evidence demonstrates that miR-193a-3p is a tumor suppressor microRNA in many cancer types, and its reduced expression is linked to cancer initiation and progression, metastasis, and therapy resistance. However, its mechanism of action is not consistently described between studies, and often contradicts the pleiotropic role of a microRNA in manipulating several different mRNA targets. We therefore comprehensively investigated miRNA-193a-3p's mode of action in a panel of human cancer cell lines, with a variety of genetic backgrounds, using 1B3, a synthetic microRNA mimic. Interestingly, the exact mechanism through which 1B3 reduced cell proliferation varied between cell lines. 1B3 efficiently reduced target gene expression, leading to reduced cell proliferation/survival, cell cycle arrest, induction of apoptosis, increased cell senescence, DNA damage, and inhibition of migration. SiRNA silencing of 1B3 target mRNAs further highlighted the advantage of the pleiotropic mechanism of 1B3 action, as repression of individual targets did not achieve the same robust effect on cell proliferation in all cell lines. Importantly, a novel lipid nanoparticle-based formulation of 1B3, INT-1B3, demonstrated marked anti-tumor activity as a single agent following systemic administration in tumor-bearing mice. Together, these data strongly support the development of 1B3 as a novel therapeutic agent for treatment of human cancer.

BackgroundHigh-sensitivity C reactive protein (hs-CRP) has been associated with outcomes in adult congenital heart disease (ACHD). However, its prognostic value beyond N-terminal pro B type natriuretic peptide (NT-proBNP) or troponin T remains unknown. We studied the temporal evolution of hs-CRP, as well as the relation between hs-CRP and adverse clinical outcomes independent of NT-proBNP and troponin T in patients with ACHD.MethodsIn this prospective cohort study, we enrolled 602 patients with ACHD (2011–2013) who underwent baseline and thereafter annual blood sampling during 4 years. Hs-CRP, hs-troponin T and NT-proBNP were measured. The primary endpoint was composed of death or heart failure (HF). Cox regression and Joint Modelling was used to relate 2log hs-CRP levels with the endpoint, with adjustment for baseline characteristics and (repeated) hs-troponin T and NT-proBNP measurements.ResultsHs-CRP was measured at baseline in 591 patients, median age 33 years, 58% men, 90% New York Heart Association I with an average of 4.3 measurements per patient. Median follow-up was 5.9 (IQR 5.3–6.3) years (99.2% complete) and 69 patients met the endpoint. Higher baseline hs-CRP was independently associated with higher risk of death or HF (HR 1.36, 95% CI 1.19 to 1.55). Hs-CRP increased over time prior to death or HF, and repeated hs-CRP measurements were associated with the endpoint, independent of repeated NT-proBNP and hs-troponin T (HR 1.54, 95% CI 1.24 to 1.98).ConclusionsHs-CRP carries incremental prognostic value for the risk of death or HF, beyond NT-proBNP and hs-troponin T. Hs-CRP increased prior to the occurrence of HF or death, supporting the role of inflammation in the clinical deterioration of patients with ACHD.

The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and the International Classification of Diseases (ICD-11) proposed a dimensional approach to the assessment of personality disorders (PDs). Both models dictate that the clinician first determines PD severity before assessing maladaptive traits, invoking the level of personality functioning (LPF) construct. We consider LPF a promising dimensional construct for translational research because of its clinical importance and conceptual overlap with the Research Domain Criteria (RDoC) Social Processes. We aim to identify biomarkers that co-vary with fluctuations in LPF in adulthood, ultimately to predict persistent decrease in LPF, associated with suicidality and morbidity. However, a theoretical framework to investigate stress-related oscillations in LPF is currently missing. In this article, we aim to fill this hiatus with a critical review about stress and LPF. First, we discuss acute stress and LPF. We briefly present the basics of the neurophysiological stress response and review the literature on momentary and daily fluctuations in LPF, both at a subjective and physiological level. Second, we review the effects of chronic stress on brain function and social behaviour and recapitulate the main findings from prospective cohort studies. This review underlies our suggestions for multimethod assessment of stress-related oscillations in LPF and our theoretical framework for future longitudinal studies, in particular studies using the experience sampling method (ESM). ispartof: CLINICAL PSYCHOLOGY & PSYCHOTHERAPY vol:28 issue:5 pages:1181-1193 ispartof: location:England status: published

BACKGROUND: Appendicitis is a frequent cause of abdominal pain. Symptoms may be atypical, and the appendix may not be visualised through abdominal ultrasonography. This case report illustrates the important role transvaginal ultrasound examination may have in the diagnostic workup of abdominal pain. METHODS: A case report focussing on imaging through transvaginal ultrasonography and comparing the ultrasonographic findings with CT‐scan, as well as macroscopic examination and microscopy. RESULTS: A 33‐year‐old woman presenting at the emergency department with lower abdominal pain since 1 week. Transvaginal ultrasound shows a typical ‘target sign’ together with a blind‐ending fluid‐filled structure posterolateral right of the uterus, suggestive of appendicitis. These findings are confirmed on CT‐scan, and a laparoscopic appendectomy is performed. We present the typical ultrasound imaging alongside the correlates on CT‐scan as well as on macroscopy and on microscopic examination. CONCLUSION: As gynaecologists, we must maintain a high degree of suspicion for non‐gynaecological findings. This case report illustrates the value of transvaginal ultrasound in diagnosing appendicitis.

Objectives Treatment with golimumab monotherapy in early peripheral SpA (pSpA) results in higher rates of clinical remission compared with treatment in more longstanding disease. When reaching remission, treat-to-target recommendations suggest tapering of treatment. We therefore explored whether addition of MTX would permit discontinuation of golimumab in patients with pSpA in sustained clinical remission. Methods After a 2-year extension phase with golimumab treatment, patients with pSpA reaching clinical remission in the CRESPA trial were offered a tapering strategy leading to discontinuation of golimumab and replacement by MTX monotherapy. Patients were prospectively followed to assess the rate of sustained biologic-free clinical remission. In case of relapse of arthritis, enthesitis or dactylitis under MTX monotherapy, golimumab was restarted. Results Of the original 60 pSpA patients, 25 entered the step-down strategy. Currently, only 4 patients (16%) are still in sustained remission under MTX monotherapy. In 21 patients (84%), golimumab was reinstalled because of relapse of disease activity (n = 19) or development of adverse events related to MTX (n = 2). Restarting golimumab treatment promptly restored clinical remission in all patients within 12 weeks. Conclusion In patients with early pSpA achieving clinical remission after 2 years of golimumab treatment, step-down therapy to monotherapy with MTX led to high rates of clinical relapse. This underscores the overall weak efficacy of MTX in maintaining clinical remission in pSpA. Trial registration ClinicalTrials.gov, https://clinicaltrials.gov, NCT01426815.

Objective Electronic health records (EHR) are increasingly being recognized as a major source of data reusable for medical research and quality monitoring, although patient identification and assessment of symptoms (characterization) remain challenging, especially in complex diseases such as systemic lupus erythematosus (SLE). Current coding systems are unable to assess information recorded in the physician's free-text notes. This study shows that text mining can be used as a reliable alternative. Methods In a multidisciplinary research team of data scientists and medical experts, a text mining algorithm on 4607 patient records was developed to assess the diagnosis of 14 different immune-mediated inflammatory diseases and the presence of 18 different symptoms in the EHR. The text mining algorithm included key words in the EHR, while mining the context for exclusion phrases. The accuracy of the text mining algorithm was assessed by manually checking the EHR of 100 random patients suspected of having SLE for diagnoses and symptoms and comparing the outcome with the outcome of the text mining algorithm. Results After evaluation of 100 patient records, the text mining algorithm had a sensitivity of 96.4% and a specificity of 93.3% in assessing the presence of SLE. The algorithm detected potentially life-threatening symptoms (nephritis, pleuritis) with good sensitivity (80%-82%) and high specificity (97%-97%). Conclusion We present a text mining algorithm that can accurately identify and characterize patients with SLE using routinely collected data from the EHR. Our study shows that using text mining, data from the EHR can be reused in research and quality control.

OA is a complex and highly prevalent degenerative disease affecting the whole joint, in which factors like genetic predisposition, gender, age, obesity and traumas contribute to joint destruction. ∼50–80% of OA patients develop synovitis. OA-associated risk factors contribute to joint instability and the release of cartilage matrix fragments, activating the synovium to release pro-inflammatory factors and catabolic enzymes in turn damaging the cartilage and creating a vicious circle. Currently, no cure is available for OA. Mesenchymal stromal cells (MSCs) have been tested in OA for their chondrogenic and anti-inflammatory properties. Interestingly, MSCs are most effective when administered during synovitis. This review focusses on the interplay between joint inflammation and the immunomodulation by MSCs in OA. We discuss the potential of MSCs to break the vicious circle of inflammation and describe current perspectives and challenges for clinical application of MSCs in treatment and prevention of OA, focussing on preventing post-traumatic OA.

Renin production by the kidney is of vital importance for salt, volume, and blood pressure homeostasis. The lack of human models hampers investigation into the regulation of renin and its relevance for kidney physiology. To develop such a model, we used human induced pluripotent stem cell–derived kidney organoids to study the role of renin and the renin-angiotensin system in the kidney. Extensive characterization of the kidney organoids revealed kidney-specific cell populations consisting of podocytes, proximal and distal tubular cells, stromal cells and endothelial cells. We examined the presence of various components of the renin-angiotensin system such as angiotensin II receptors, angiotensinogen, and angiotensin-converting enzymes 1 and 2. We identified by single-cell sequencing, immunohistochemistry, and functional assays that cyclic AMP stimulation induces a subset of pericytes to increase the synthesis and secretion of enzymatically active renin. Renin production by the organoids was responsive to regulation by parathyroid hormone. Subcutaneously implanted kidney organoids in immunodeficient IL2Ry -/-Rag2 -/- mice were successfully vascularized, maintained tubular and glomerular structures, and retained capacity to produce renin two months after implantation. Thus, our results demonstrate that kidney organoids express renin and provide insights into the endocrine potential of human kidney organoids, which is important for regenerative medicine in the context of the endocrine system.

Patients with inflammatory bowel disease (IBD) show large variability in disease course, and also treatment response. The variability in treatment response has led to many initiatives in search of genetic markers to optimize treatment and avoid severe side effects. This has been very successful for thiopurines, one of the drugs used to induce and maintain remission in IBD. However, for the newer treatment options for IBD, like biologicals, the search for genetic predictors has not yielded any candidate biomarkers with clinical utility. In this review, a summary of recent advances in pharmacogenetics focusing on thiopurines and anti-TNF agents is given. Tweetable abstract In this paper, recent advances in pharmacogenetics in inflammatory bowel disease are discussed, focusing on thiopurines and anti-TNF agents.

Oligodendrocyte dysfunction has been implicated in the pathophysiology of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by progressive motor neuron loss. The failure of trophic support provided by oligodendrocytes is associated with a concomitant reduction in oligodendroglial monocarboxylate transporter 1 (MCT1) expression and is detrimental for the long-term survival of motor neuron axons. Therefore, we established an adeno-associated virus 9 (AAV9)-based platform by which MCT1 was targeted mostly to white matter oligodendrocytes to investigate whether this approach could provide a therapeutic benefit in the SOD1G93A mouse model of ALS. Despite good oligodendrocyte transduction and AAV-mediated MCT1 transgene expression, the disease outcome of SOD1G93A mice was not altered. Our study further increases our current understanding about the complex nature of oligodendrocyte pathology in ALS and provides valuable insights into the future development of therapeutic strategies to efficiently modulate these cells., Graphical Abstract, Dysfunctional oligodendrocytes contribute to motor neuron degeneration in ALS. Eykens et al. developed an AAV-based approach to stimulate oligodendrocyte protection in the SOD1G93A ALS mouse model. Using intracerebroventricular AAV9 delivery at postnatal day 10, they investigated the effect of restoring the expression of the oligodendroglial protein MCT1 on ALS pathology.

Introduction Clinical remission in patients with ankylosing spondylitis (AS) has been determined using composite indices such as the AS Disease Activity Score inactive disease (ASDAS-ID), Assessment of SpondyloArthritis international Society criteria partial remission (ASAS-PR), and low Bath AS Disease Activity Index (BASDAI) scores. The objective of this exploratory analysis was to evaluate the proportion of secukinumab-treated patients with AS achieving remission defined based on the ASDAS-ID (score < 1.3), ASAS-PR or BASDAI score ≤ 2. Methods The analysis pooled data from the MEASURE 1 and 2 studies over 3 years. The proportion of patients who achieved ASDAS-ID, ASAS-PR, or BASDAI ≤ 2 with secukinumab was compared with placebo at week 16; results for secukinumab-treated patients were summarized through week 156. Sustainability of each criterion was assessed from week 16 to 156 using shift analysis. The association between each of these criteria and specific patient-reported outcomes (PROs), such as health-related quality of life, function, fatigue, and work impairment, was also explored. Results At week 16, a higher proportion of secukinumab-treated patients versus placebo achieved ASDAS-ID (17.6 vs. 3.5%), ASAS-PR (15.4 vs. 4.1%), or BASDAI ≤ 2 (22.3 vs. 6.4%) criteria (all P

In 2018, the position paper ‘Imaging the adult with congenital heart disease: a multimodality imaging approach’ was published. The paper highlights, in the first part, the different imaging modalities applied in adult congenital heart disease patients. In the second part, these modalities are discussed more detailed for moderate to complex anatomical defects. Because of the length of the paper, simple lesions were not touched on. However, imaging modalities to use for simple shunt lesions are still poorly known. One is looking for structured recommendations on which they can rely when dealing with an (undiscovered) shunt lesion. This information is lacking for the initial diagnostic process, during repair and at follow-up. Therefore, this paper will focus on atrial septal defect, ventricular septal defect, and persistent arterial duct. Pre-, intra-, and post-procedural imaging techniques will be systematically discussed. This position paper will offer algorithms that might help at a glance. The document is prepared for general cardiologists, trainees, medical students, imagers/technicians to select the most appropriate imaging modality and to detect the requested information for each specific lesion. It might serve as reference to which researchers could refer when setting up a (imaging) study.

ObjectivesTo evaluate efficacy and safety of immediate switch from upadacitinib to adalimumab, or vice versa, in patients with rheumatoid arthritis with non-response or incomplete-response to the initial therapy.MethodsSELECT-COMPARE randomised patients to upadacitinib 15 mg once daily (n=651), placebo (n=651) or adalimumab 40 mg every other week (n=327). A treat-to-target study design was implemented, with blinded rescue occurring prior to week 26 for patients who did not achieve at least 20% improvement in both tender and swollen joint counts (‘non-responders’) and at week 26 based on Clinical Disease Activity Index (CDAI) >10 (‘incomplete-responders’) without washout.ResultsA total of 39% (252/651) and 49% (159/327) of patients originally randomised to upadacitinib and adalimumab were rescued to the alternate therapy. In both switch groups (adalimumab to upadacitinib and vice versa) and in non-responders and incomplete-responders, improvements in disease activity were observed at 3 and 6 months following rescue. CDAI low disease activity was achieved by 36% and 47% of non-responders and 45% and 58% of incomplete-responders switched to adalimumab and upadacitinib, respectively, 6 months following switch. Overall, approximately 5% of rescued patients experienced worsening in disease activity at 6 months postswitch. The frequency of adverse events was similar between switch groups.ConclusionsThese observations support a treat-to-target strategy, in which patients who fail to respond initially (or do not achieve sufficient response) are switched to a therapy with an alternate mechanism of action and experience improved outcomes. No new safety findings were observed despite immediate switch without washout.

RationalePaediatric laryngotracheal stenosis (LTS) is often successfully corrected with open airway surgery. However, respiratory and vocal sequelae frequently remain. Clinical care and surgical interventions could be improved with better understanding of these sequelae.ObjectiveThe objective of this cross-sectional study was to develop an upper airway MRI protocol to obtain information on anatomical and functional sequelae post-LTS repair.MethodsForty-eight patients (age 14.4 (range 7.5–30.7) years) and 11 healthy volunteers (15.9 (8.2–28.8) years) were included. Spirometry and static and dynamic upper airway MRI (3.0 T, 30 min protocol) were conducted. Analysis included assessment of postoperative anatomy and airway lumen measurements during static and dynamic (inspiration and phonation) acquisitions.Main resultsGood image quality without artefacts was achieved for static and dynamic images in the majority of MRIs. MRI showed vocal cord thickening in 80.9% of patients and compared with volunteers, a significant decrease in vocal cord lumen area (22.0 (IQR 17.7–30.3) mm2 vs 35.1 (21.2–54.7) mm2, p=0.03) but not cricoid lumen area (62.3±27.0 mm2 vs 66.2±34.8 mm2, p=0.70). Furthermore, 53.2% of patients had an A-frame deformation at site of previous tracheal cannula, showing lumen collapse during inspiration. Dynamic imaging showed incomplete vocal cord abduction during inspiration in 42.6% and incomplete adduction during phonation in 61.7% of patients.ConclusionsStatic and dynamic MRI is an excellent modality to non-invasively image anatomy, tissue characteristics and vocal cord dynamics of the upper airways. MRI-derived knowledge on postsurgical LTS sequelae might be used to improve surgery.

Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disease selectively affecting motor neurons, leading to progressive paralysis. Although most cases are sporadic, ∼10% are familial. Similar proteins are found in aggregates in sporadic and familial ALS, and over the last decade, research has been focused on the underlying nature of this common pathology. Notably, TDP-43 inclusions are found in almost all ALS patients, while FUS inclusions have been reported in some familial ALS patients. Both TDP-43 and FUS possess 'low-complexity domains' (LCDs) and are considered as 'intrinsically disordered proteins', which form liquid droplets in vitro due to the weak interactions caused by the LCDs. Dysfunctional 'liquid-liquid phase separation' (LLPS) emerged as a new mechanism linking ALS-related proteins to pathogenesis. Here, we review the current state of knowledge on ALS-related gene products associated with a proteinopathy and discuss their status as LLPS proteins. In addition, we highlight the therapeutic potential of targeting LLPS for treating ALS. ispartof: JOURNAL OF MOLECULAR CELL BIOLOGY vol:13 issue:1 pages:15-28 ispartof: location:United States status: published

Achondroplasia is a genetic disorder that results in disproportionate short stature. The true prevalence of achondroplasia is unknown as estimates vary widely. This systematic literature review and meta‐analysis was conducted to better estimate worldwide achondroplasia birth prevalence. PubMed, Embase, Scielo, and Google Scholar were searched, complemented by manual searching, for peer‐reviewed articles published between 1950 and 2019. Eligible articles were identified by two independent researchers using predefined selection criteria. Birth prevalence estimates were extracted for analysis, and the quality of evidence was assessed. A meta‐analysis using a quality effects approach based on the inverse variance fixed effect model was conducted. The search identified 955 unique articles, of which 52 were eligible and included. Based on the meta‐analysis, the worldwide birth prevalence of achondroplasia was estimated to be 4.6 per 100,000. Substantial regional variation was observed with a considerably higher birth prevalence reported in North Africa and the Middle East compared to other regions, particularly Europe and the Americas. Higher birth prevalence was also reported in specialized care settings. Significant heterogeneity (Higgins I 2 of 84.3) was present and some indication of publication bias was detected, based on visual asymmetry of the Doi plot with a Furuya‐Kanamori index of 2.73. Analysis of pooled data from the current literature yields a worldwide achondroplasia birth prevalence of approximately 4.6 per 100,000, with considerable regional variation. Careful interpretation of these findings is advised as included studies are of broadly varying methodological quality.

Item does not contain fulltext Aim: Timing of radium-223 (Ra-223) in metastatic castration-resistant prostate cancer (mCRPC) remains challenging due to alternative options and short window of opportunity. Methods: Ra-223 treated patients in the CAPRI-registry were included. Outcomes were evaluated based on treatment line of Ra-223. Results: Out of 285 patients, 49% received Ra-223 in line >/=3. 51% completed six Ra-223 injections and 34% had a symptomatic skeletal event after first Ra-223 without differences between subgroups. After correction of known prognostic factors Ra-223 in line >/=3 (HR: 3.267; 95% CI: 1.689-6.317; p < 0.01) remained associated with worse OS. Conclusion: In the Netherlands, Ra-223 was mainly started as second or third mCRPC-treatment in 2014-2018. Later timing of Ra-223 did affect OS, but not treatment completion and occurrence of symptomatic skeletal events.

Immunotherapy for metastatic colorectal cancer is effective only for mismatch repair-deficient tumors with high microsatellite instability that demonstrate immune infiltration, suggesting that tumor cells can determine their immune microenvironment. To understand this cross-talk, we analyzed the transcriptome of 91,103 unsorted single cells from 23 Korean and 6 Belgian patients. Cancer cells displayed transcriptional features reminiscent of normal differentiation programs, and genetic alterations that apparently fostered immunosuppressive microenvironments directed by regulatory T cells, myofibroblasts and myeloid cells. Intercellular network reconstruction supported the association between cancer cell signatures and specific stromal or immune cell populations. Our collective view of the cellular landscape and intercellular interactions in colorectal cancer provide mechanistic information for the design of efficient immuno-oncology treatment strategies.

OBJECTIVE: As part of the value-based healthcare programme in our hospital, a set of patient-reported outcome measures was developed together with patients and implemented in the dedicated Turner Syndrome (TS) outpatient clinic. This study aims to investigate different aspects of health-related quality of life (HR-QoL) and psychosocial functioning in women with TS in order to establish new possible targets for therapy.DESIGN/PARTICIPANTS: A comprehensive set of questionnaires (EQ-5D, PSS-10, CIS-20, Ferti-QoL, FSFI) was developed and used to capture different aspects of HR-QoL and psychosocial functioning in a large cohort of adult women with Turner syndrome. All consecutive women, ≥18 years, who visited the outpatient clinic of our tertiary centre were eligible for inclusion.RESULTS: Of the eligible 201 women who were invited to participate, 177 women (age 34 ± 12 years, mean ± SD) completed at least one of the validated questionnaires (88%). Women with TS reported a lower health-related quality of life (EQ-5D: 0.857 vs 0.892, P = .003), perceived more stress (PSS-10:14.7 vs 13.3; P = .012) and experienced increased fatigue (CIS-20: P < .001) compared to the general Dutch population. A relationship between noncardiac comorbidities (eg diabetes, orthopaedic complaints) and HR-QoL was found (R = .508).CONCLUSIONS: We showed that TS women suffer from impaired HR-QoL, more perceived stress and increased fatigue compared to healthy controls. A relationship between noncardiac comorbidities and HR-QoL was found. Especially perceived stress and increased fatigue can be considered targets for improvement of HR-QoL in TS women.

ObjectivesBone marrow oedema (BMO) on MRI of sacroiliac joints (SIJs) represents a hallmark of axial spondyloarthritis (SpA), yet such lesions may also occur under augmented mechanical stress in healthy subjects. We therefore sought to delineate the relationship between pregnancy/delivery and pelvic stress through a prospective study with repeated MRI. Results were matched with maternal, child and birth characteristics.MethodsThirty-five women underwent a baseline MRI-SIJ within the first 10 days after giving birth. MRI was repeated after 6 months and, if positive for sacroiliitis according to the Assessment of SpondyloArthritis International Society (ASAS) definition, after 12 months. BMO and structural lesions were scored by three trained readers using the Spondyloarthritis Research Consortium of Canada (SPARCC) method.ResultsSeventy-seven per cent of the subjects (27/35) displayed sacroiliac BMO immediately postpartum, 60% fulfilled the ASAS definition of a positive MRI. After 6 months, 46% of the subjects (15/33) still showed BMO, representing 15% (5/33) with a positive MRI. After 12 months, MRI was still positive in 12% of the subjects (4/33). Few structural lesions were detected. Intriguingly, in this study, the presence of BMO was related to a shorter duration of labour and lack of epidural anaesthesia.ConclusionA surprisingly high prevalence of sacroiliac BMO occurs in women immediately postpartum. Our data reveal a need for a waiting period of at least 6 months to perform an MRI-SIJ in postpartum women with back pain. This study also underscores the importance of interpreting MRI-SIJ findings in the appropriate clinical context.

Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Hemodiàlisi; Mortalitat Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Hemodiálisis; Mortalidad Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Haemodialysis; Mortality Age and chronic kidney disease have been described as mortality risk factors for coronavirus disease 2019 (COVID-19). Currently, an important percentage of patients in haemodialysis are elderly. Herein, we investigated the impact of age on mortality among haemodialysis patients with COVID-19. Data was obtained from the Spanish COVID-19 chronic kidney disease (CKD) Working Group Registry. From 18 March 2020 to 27 August 2020, 930 patients on haemodialysis affected by COVID-19 were included in the Registry. A total of 254 patients were under 65 years old and 676 were 65 years or older (elderly group). Mortality was 25.1% higher (95% CI: 22.2–28.0%) in the elderly as compared to the non-elderly group. Death from COVID-19 was increased 6.2-fold in haemodialysis patients as compared to the mortality in the general population in a similar time frame. In the multivariate Cox regression analysis, age (hazard ratio (HR) 1.59, 95% CI: 1.31–1.93), dyspnea at presentation (HR 1.51, 95% CI: 1.11–2.04), pneumonia (HR 1.74, 95% CI: 1.10–2.73) and admission to hospital (HR 4.00, 95% CI: 1.83–8.70) were identified as independent mortality risk factors in the elderly haemodialysis population. Treatment with glucocorticoids reduced the risk of death (HR 0.68, 95% CI: 0.48–0.96). In conclusion, mortality is dramatically increased in elderly haemodialysis patients with COVID-19. Our results suggest that this high risk population should be prioritized in terms of protection and vaccination. The authors are current recipients of FONDOS DE INVESTIGACIÓN SANITARIA—FEDER (ISCIII) PI17/00257, REDINREN RD16/0009/0030, RD/16/0009/0026, and EIN2020-112338.

Survival rates of cancer patients vary widely within and between malignancies. While genetic aberrations are at the root of all cancers, individual genomic features cannot explain these distinct disease outcomes. In contrast, intra-tumour heterogeneity (ITH) has the potential to elucidate pan-cancer survival rates and the biology that drives cancer prognosis. Unfortunately, a comprehensive and effective framework to measure ITH across cancers is missing. Here, we introduce a scalable measure of chromosomal copy number heterogeneity (CNH) that predicts patient survival across cancers. We show that the level of ITH can be derived from a single-sample copy number profile. Using gene-expression data and live cell imaging we demonstrate that ongoing chromosomal instability underlies the observed heterogeneity. Analysing 11,534 primary cancer samples from 37 different malignancies, we find that copy number heterogeneity can be accurately deduced and predicts cancer survival across tissues of origin and stages of disease. Our results provide a unifying molecular explanation for the different survival rates observed between cancer types., Intratumour heterogeneity (ITH) is associated with worse prognosis in cancer, and efficient frameworks to measure it are needed. Here the authors develop a method to estimate copy number heterogeneity, and propose that it is driven by chromosomal instability and can predict pan-cancer survival.