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Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Medical School Brandenburg and Local Government Concil Brandenburg Background Pulmonary vein isolation (PVI) is one of the key therapies for patients with atrial fibrillation (AF), however, there are numerous recurrences after ablation. Improving cardiorespiratory fitness (CF) may result in fewer recurrences of AF. The aim of the present study (Brandenburg Enhance ACTIvity ONset after pulmonary vein isolation - BE-ACTION) was to evaluate the impact of increased physical activity in patients after PVI on the recurrence of AF. Methods From January 2018 to April 2021, 200 patients with scheduled PVI were randomized at 4 different centres and fitted with an activity tracker for 24-hour activity monitoring via mobile phone. Patients aged between 50 and 77 years with a BMI between 23 and 35 kg/m2 were included. Patients with orthopaedic limitations were excluded. Patients in the ACTION group (n=99) were contacted regularly by telephone by a physical therapist and intensively motivated if the steps fell below 6,000 steps per day. Patients in the No-ACTION group (n=101) received standard of care. A loop recorder was implanted in 74 patients; those who refused loop recorder implantation underwent 7-day Holter monitoring at 6 and 12 months after PVI. Recurrence was defined as any atrial arrhythmia >30 sec, cardioversion or need of redo ablation after blanking period (3 month) up to 12 month. Results The number of steps per day increased in all pts from 7,918 (5,725-10,989) at week 2 after PVI to 9,511 (7,230-12,800) at 6 months and to 9,788 (6,962-12,152) at 12 months (p Conclusion The level of daily physical activity was unexpectedly high in this study. The use of an activity tracker led to an increased daily physical activity in patients with AF after PVI. A further increase of activity did not reduce the recurrence of atrial arrhythmia in the ACTION group.

Introduction: The purpose of this case study was to demonstrate the clinical decision-making process of healthcare professionals within a rehabilitation program during chemoradiotherapy (CHRT) for a high-risk patient diagnosed with stage III non-small cell lung cancer (NSCLC). The course of CHRT and patient's preferences, facilitators, and barriers were considered.Case-description: The patient was a 69-year-old man with a history of rheumatoid arthritis diagnosed with stage III NSCLC.Intervention: A home-based, personalized, and partly supervised rehabilitation program during CHRT, including aerobic, resistance, and breathing exercises, as well as nutritional counseling.Outcomes: The patient suffered from side effects of CHRT, which required adjustments in the context and intensity of the exercises. An important facilitator for the patient was encouraged by his wife in following the home-based rehabilitation program. During home visits, the patient and physiotherapists performed the exercises together to help him to overcome the burden and motivate the patient to adhere to the rehabilitation program.Conclusion: This case study demonstrates that physical exercise training could be performed by adjusting training intensity and the way in which the physical exercise training was delivered, while the patient experienced side effects from CHRT. In addition, the involvement and support of (in)formal caregivers seems essential for adherence to rehabilitation.

Objective To evaluate the reproducibility and accuracy of a new, easy-to-use volumetric assessment of the alveolar cleft. Design Twelve cone-beam computed tomography (CBCT) datasets of patients with a unilateral cleft lip, alveolus, and palate were evaluated by two investigators. Residual alveolar cleft calcified volume one year after surgery was analyzed by using standardized landmarks to determine the borders of the cleft defect and semi-automatically segment the alveolar cleft defect. Results The Dice-coefficient between observers for the segmented preoperative alveolar cleft defect was 0.81. Average percentage of residual alveolar cleft calcified material was 66.7% one year postoperatively. Conclusions This study demonstrates a reliable and practical semi-automatic three-dimensional volumetric assessment method for unilateral clefts using CBCT.

The basolateral amygdala (BLA) projects widely across the macaque frontal cortex1–4, and amygdalo-frontal projections are critical for optimal emotional responding5and decision- making6. Yet, little is known about the single-neuron architecture of these projections: namely, whether single BLA neurons project to multiple parts of the frontal cortex. Here, we use MAPseq7to determine the projection patterns of over 3000 macaque BLA neurons. We found that one-third of BLA neurons have two or more distinct targets in parts of frontal cortex and of subcortical structures. Further, we reveal non-random structure within these branching patterns such that neurons with four targets are more frequently observed than those with two or three, indicative of widespread networks. Consequently, these multi-target single neurons form distinct networks within medial and ventral frontal cortex consistent with their known functions in regulating mood and decision-making. Additionally, we show that branching patterns of single neurons shape functional networks in the brain as assessed by fMRI-based functional connectivity. These results provide a neuroanatomical basis for the role of the BLA in coordinating brain-wide responses to valent stimuli8and highlight the importance of high- resolution neuroanatomical data for understanding functional networks in the brain.

Background: Particulate matter (PM) is associated with aging markers at birth, including telomeres and mito-chondria. It is unclear whether markers of the core-axis of aging, i.e. tumor suppressor p53 (p53) and peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1 alpha), are associated with prenatal air pollution and whether there are underlying mechanisms.Methods: 556 mother-newborn pairs from the ENVIRONAGE birth cohort were recruited at the East Limburg Hospital in Genk (Belgium). In placenta and cord blood, telomere length (TL) and mitochondrial DNA content (mtDNAc) were measured using quantitative real-time polymerase chain reaction (qPCR). In cord plasma, p53 and PGC-1 alpha protein levels were measured using ELISA. Daily ambient PM2.5 concentrations during gestation were calculated using a spatial temporal interpolation model. Distributed lag models (DLMs) were applied to assess the association between prenatal PM2.5 exposure and each molecular marker. Mediation analysis was performed to test for underlying mechanisms. Results: A 5 mu g/m3 increment in PM2.5 exposure was associated with-11.23 % (95 % CI:-17.36 % to-4.65 %, p = 0.0012) and-7.34 % (95 % CI:-11.56 % to-2.92 %, p = 0.0014) lower placental TL during the entire pregnancy and second trimester respectively, and with-12.96 % (95 % CI:-18.84 % to-6.64 %, p < 0.001) lower placental mtDNAc during the third trimester. Furthermore, PM2.5 exposure was associated with a 12.42 % (95 % CI:-1.07 % to 27.74 %, p = 0.059) higher cord plasma p53 protein level and a-3.69 % (95 % CI:-6.97 % to-0.31 %, p = 0.033) lower cord plasma PGC-1 alpha protein level during the third trimester. Placental TL mediated 65 % of the negative and 17 % of the positive association between PM2.5 and placental mtDNAc and cord plasma p53 protein levels, respectively.Conclusion: Ambient PM2.5 exposure during pregnancy is associated with markers of the core-axis of aging, with TL as a mediating factor. This study strengthens the hypothesis of the air pollution induced core-axis of aging, and may unravel a possible underlying mediating mechanism in an early-life epidemiological context. The authors thank all ENVIRONAGE participants, as well as the staff of the maternity ward, midwives, and the staff of the clinical laboratory of East-Limburg Hospital in Genk. The ENVIRONAGE birth cohort is supported by the Research Foundation, Belgium (Grant No. N1518119, No. G082317N and No. 1523817N), Kom Op Tegen Kanker (KOTK), and Methusalem. Dries S. Martens and Bram G. Janssen received a postdoctoral grant funded by the Research Foundation Flanders (12X9620N, and 12W3218N).

Little is known about the frequency and clinical course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in pediatric patients with severe comorbidities. In this prospective cross-sectional trial, the seroprevalence of SARS-CoV-2-IgG in patients with life-limiting conditions being treated by a large specialized pediatric palliative home-care team was determined. In order to gain insight into the infection chain, close contacts of seropositive patients were also included in the study. We analyzed the sera of 39 patients and found a 25.6% seroprevalence for SARS-CoV-2. No SARS-CoV-2 infections were known prior to the study. No significant difference was found in the symptom load between seropositive and seronegative patients during the risk period for SARS-CoV-2 infections. Of the 20 close contacts tested, only one was seropositive for SARS-CoV-2.Conclusions: Our results indicate a substantially high prevalence of silent SARS-CoV-2 infections in pediatric palliative care patients. Surprisingly, no severe outcomes were seen in this fragile patient collective with severe comorbidities. The chain of infection and thus the reason for the high frequency of SARS-CoV-2 infections in pediatric palliative care patients remain unclear. What is Known:•Even though severe disease courses of COVID-19 have been reported in children, there are yet no established risk factors for SARS-CoV-2 in pediatric patients. What is New:•In this cross-sectional seroprevalence study of palliative pediatric patients with severe life-limiting conditions, a high rate of seropositive patients (25.6%) was found.•Surprisingly, all seropositive patients were previously unrecognized, despite the severe comorbidities of our collective.

Background Mitochondria play an important role in the energy metabolism and are susceptible to environmental pollution. Prenatal air pollution exposure has been linked with childhood obesity. Placental mtDNA mutations have been associated with prenatal particulate matter exposure and MT-ND4L10550A>G heteroplasmy has been associated with BMI in adults. Therefore, we hypothesized that in utero PM2.5 exposure is associated with cord blood MT-ND4L10550A>G heteroplasmy and early life growth. In addition, the role of cord blood MT-ND4L10550A>G heteroplasmy in overweight during early childhood is investigated. Methods This study included 386 mother-newborn pairs. Outdoor PM2.5 concentrations were determined at the maternal residential address. Cord blood MT-ND4L10550A>G heteroplasmy was determined using Droplet Digital PCR. Associations were explored using logistic regression models and distributed lag linear models. Mediation analysis was performed to quantify the effects of prenatal PM2.5 exposure on childhood overweight mediated by cord blood MT-ND4L10550A>G heteroplasmy. Results Prenatal PM2.5 exposure was positively associated with childhood overweight during the whole pregnancy (OR = 2.33; 95% CI: 1.20 to 4.51; p = 0.01), which was mainly driven by the second trimester. In addition, prenatal PM2.5 exposure was associated with cord blood MT-ND4L10550A>G heteroplasmy from gestational week 9 – 13. The largest effect was observed in week 10, where a 5 µg/m3 increment in PM2.5 was linked with cord blood MT-ND4L10550A>G heteroplasmy (OR = 0.93; 95% CI: 0.87 to 0.99). Cord blood MT-ND4L10550A>G heteroplasmy was also linked with childhood overweight (OR = 3.04; 95% CI: 1.15 to 7.50; p = 0.02). The effect of prenatal PM2.5 exposure on childhood overweight was mainly direct (total effect OR = 1.18; 95% CI: 0.99 to 1.36; natural direct effect OR = 1.20; 95% CI: 1.01 to 1.36)) and was not mediated by cord blood MT-ND4L10550A>G heteroplasmy. Conclusions Cord blood MT-ND4L10550A>G heteroplasmy was linked with childhood overweight. In addition, in utero exposure to PM2.5 during the first trimester of pregnancy was associated with cord blood MT-ND4L10550A>G heteroplasmy in newborns. Our analysis did not reveal any mediation of cord blood MT-ND4L10550A>G heteroplasmy in the association between PM2.5 exposure and childhood overweight.

Purpose We investigated longitudinal associations of sedentary behavior, light-intensity physical activity (LPA) and moderate-to-vigorous physical activity (MVPA) with body composition in colorectal cancer (CRC) survivors, between 6 weeks and 24 months post treatment. In addition, we explored whether body composition mediated associations of sedentary behavior and MVPA with fatigue. Methods A prospective cohort study was conducted in 459 stage I–III CRC patients recruited at diagnosis. Measurements were performed of accelerometer-assessed sedentary time (hours/day), self-reported LPA and MVPA (hours/week), anthropometric assessment of body mass index (BMI), waist circumference and fat percentage (measures of adiposity), and muscle circumference and handgrip strength (measures of muscle mass/function) repeated at 6 weeks, and 6, 12 and 24 months post treatment. Longitudinal associations of sedentary time and physical activity with body composition were analyzed using confounder-adjusted linear mixed models. Mediation analyses were performed to explore the role of body mass index (BMI) and handgrip strength as mediators in associations of sedentary time and MVPA with fatigue. Results Less sedentary time and LPA were, independent of MVPA, longitudinally associated with increased handgrip strength, but not with measures of adiposity. More MVPA was associated with increased adiposity and increased handgrip strength. Higher BMI partly mediated associations between higher sedentary time and more fatigue. Conclusion Within the first two years after CRC treatment, changes in sedentary behavior, physical activity and body composition are interrelated and associated with fatigue. Intervention studies are warranted to investigate causality. Trial registration The EnCoRe study is registered at trialregister.nl as NL6904 (former ID: NTR7099).

The presence of the translocation t(9;22)(q34;q11), leading to the BCR::ABL1 fusion transcript, is the hallmark of chronic myeloid leukemia (CML). Nevertheless, atypical presentation at diagnosis can be challenging. However, although most patients with CML are diagnosed with the e13a2 or e14a2 BCR::ABL1 fusion transcripts, about 5% of them carry rare BCR::ABL1 fusion transcripts, such as e19a2, e8a2, e13a3, e14a3, e1a3, and e6a2. In particular, the e6a2 fusion transcript has been associated with clinically aggressive disease frequently presenting in accelerated or blast crisis phases. To date, there is limited evidence on the efficacy of front-line second-generation tyrosine kinase inhibitors for this genotype. Here, we report two patients, in whom the diagnosis of CML was challenging. The use of primers recognizing more distant exons from the common BCR::ABL1 breakpoint region correctly identified the atypical BCR::ABL1 e6a2 fusion transcript. Treatment with the second-generation tyrosine kinase inhibitor nilotinib was effective in our patient expressing the atypical e6a2 BCR::ABL1 fusion transcript.

Aims: Some gene variants in the sodium channels, as well as calcium channels, have been associated with Brugada syndrome (BrS). However, the investigation of the human cellular phenotype and the use of drugs for BrS in presence of variant in the calcium channel subunit is still lacking. Objectives: The objective of this study was to establish a cellular model of BrS in the presence of a CACNB2 variant of uncertain significance (c.425C > T/p.S142F) using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and test drug effects using this model. Methods and results: This study recruited cells from a patient with Brugada syndrome (BrS) and recurrent ventricular fibrillation carrying a missense variant in CACNB2 as well as from three healthy independent persons. These cells (hiPSC-CMs) generated from skin biopsies of healthy persons and the BrS patient (BrS-hiPSC-CMs) as well as CRISPR/Cas9 corrected cells (isogenic control, site-variant corrected) were used for this study. The hiPSC-CMs from the BrS patient showed a significantly reduced L-type calcium channel current (ICa-L) compared with the healthy control hiPSC-CMs. The inactivation curve was shifted to a more positive potential and the recovery from inactivation was accelerated. The protein expression of CACNB2 of the hiPSC-CMs from the BrS-patient was significantly decreased compared with healthy hiPSC-CMs. Moreover, the correction of the CACNB2 site-variant rescued the changes seen in the hiPSC-CMs of the BrS patient to the normal state. These data indicate that the CACNB2 gene variant led to loss-of-function of L-type calcium channels in hiPSC-CMs from the BrS patient. Strikingly, arrhythmia events were more frequently detected in BrS-hiPSC-CMs. Bisoprolol (beta-blockers) at low concentration and quinidine decreased arrhythmic events. Conclusions: The CACNB2 variant (c.425C > T/p.S142F) causes a loss-of-function of L-type calcium channels and is pathogenic for this type of BrS. Bisoprolol and quinidine may be effective for treating BrS with this variant.

Background Prehabilitation appears to be an effective strategy to reduce postoperative complications and enhance recovery after colorectal surgery. Although many patients prefer (unsupervised) home-based prehabilitation, adherence can be problematic. Combining home-based prehabilitation with tele-monitoring might demonstrate a higher adherence than unsupervised prehabilitation; however, evidence on its feasibility and effectiveness in patients with colorectal cancer scheduled for elective surgery who are at high risk for postoperative complications is lacking. The aim of this study was to assess the feasibility of a bimodal tele-prehabilitation program in patients with colorectal cancer at high risk for postoperative complications. Methods High-risk patients (oxygen uptake at the ventilatory anaerobic threshold ≤11 mL/kg/min or oxygen uptake at peak exercise ≤ 18 mL/kg/min) with colorectal cancer were included in a home-based bimodal tele-prehabilitation program. The program consisted of a personalized tele-monitored moderate to high-intensity interval training intervention and nutritional counseling. Feasibility was measured by participation rate, dropout rate, adherence to the physical exercise training session’s frequency, intensity, and time, and retention rate. Patient appreciation was measured by a patient appreciation questionnaire. Changes in preoperative physical fitness as secondary outcomes were quantified by time to exhaustion on a constant work rate (cycle) test, number of repetitions on the 30-s chair-stand test, and walking speed on the 4-m gait speed test. Results The participation rate was 81%, there were no adverse events, and all participants managed to complete the tele-prehabilitation program (retention rate of 100%). Adherence with regard to the exercise program’s frequency, intensity, and time was respectively 91%, 84%, and 100%. All participants appreciated the tele-prehabilitation program. Time to exhaustion on the constant work rate test improved (not statistically significant) from a pre-prehabilitation median score of 317 seconds to a post-prehabilitation median score of 412 seconds (p = 0.24). Median number of repetitions on the 30-s chair-stand test improved from 12 to 16 (p = 0.01). Conclusions Tele-prehabilitation seems feasible in high-risk patients with colorectal cancer, but efforts should be made to further improve adherence to physical exercise training intensity. More research is needed to establish the (cost-)effectiveness of tele-prehabilitation regarding preoperative improvements in preoperative aerobic fitness and postoperative reduction of complications. Trial registration ISRCTN, ISRCTN64482109. Registered 09 November 2021 - Retrospectively registered.

We investigated longitudinal associations of sedentary behavior, light-intensity physical activity (LPA) and moderate-to-vigorous physical activity (MVPA) with body composition in colorectal cancer (CRC) survivors, between 6 weeks and 24 months post treatment. In addition, we explored whether body composition mediated associations of sedentary behavior and MVPA with fatigue.A prospective cohort study was conducted in 459 stage I-III CRC patients recruited at diagnosis. Measurements were performed of accelerometer-assessed sedentary time (hours/day), self-reported LPA and MVPA (hours/week), anthropometric assessment of body mass index (BMI), waist circumference and fat percentage (measures of adiposity), and muscle circumference and handgrip strength (measures of muscle mass/function) repeated at 6 weeks, and 6, 12 and 24 months post treatment. Longitudinal associations of sedentary time and physical activity with body composition were analyzed using confounder-adjusted linear mixed models. Mediation analyses were performed to explore the role of body mass index (BMI) and handgrip strength as mediators in associations of sedentary time and MVPA with fatigue.Less sedentary time and LPA were, independent of MVPA, longitudinally associated with increased handgrip strength, but not with measures of adiposity. More MVPA was associated with increased adiposity and increased handgrip strength. Higher BMI partly mediated associations between higher sedentary time and more fatigue.Within the first two years after CRC treatment, changes in sedentary behavior, physical activity and body composition are interrelated and associated with fatigue. Intervention studies are warranted to investigate causality.The EnCoRe study is registered at trialregister.nl as NL6904 (former ID: NTR7099).

Skeletal muscle fibers contain hundreds of nuclei, which increase the overall transcriptional activity of the tissue and perform specialized functions. Multinucleation occurs through myoblast fusion, mediated by the muscle fusogens Myomaker (MYMK) and Myomixer (MYMX). We describe a human pedigree harboring a recessive truncating variant of the MYMX gene that eliminates an evolutionarily conserved extracellular hydrophobic domain of MYMX, thereby impairing fusogenic activity. Homozygosity of this human variant resulted in a spectrum of abnormalities that mimicked the clinical presentation of Carey-Fineman-Ziter syndrome (CFZS), caused by hypomorphic MYMK variants. Myoblasts generated from patient-derived induced pluripotent stem cells displayed defective fusion, and mice bearing the human MYMX variant died perinatally due to muscle abnormalities. In vitro assays showed that the human MYMX variant conferred minimal cell-cell fusogenicity, which could be restored with CRISPR/Cas9-mediated base editing, thus providing therapeutic potential for this disorder. Our findings identify MYMX as a recessive, monogenic human disease gene involved in CFZS, and provide new insights into the contribution of myoblast fusion to neuromuscular diseases.

Antibody-drug conjugates (ADCs) are increasingly powerful medicines for targeted cancer therapy. Inspired by the trend to further improve their therapeutic index by generation of homogenous ADCs, we report here how the clinical-stage GlycoConnect™ technology uses the globally conserved

Rehabilitation during chemoradiotherapy (CHRT) might (partly) prevent reduction in physical fitness and nutritional status and could improve treatment tolerance in patients with stage III non-small cell lung cancer (NSCLC). The aim of this proof-of-concept study was to investigate the feasibility of a multimodal program for rehabilitation during CHRT. A home-based multimodal rehabilitation program (partly supervised moderate-intensity physical exercise training and nutritional support) during CHRT was developed in collaboration with patients with stage III NSCLC and specialized healthcare professionals. A predetermined number of six patients with stage III NSCLC (aged > 50 years) who underwent CHRT and participated in this program were monitored in detail to assess its feasibility for further development and optimization of the program. The patient’s level of physical functioning (e.g., cardiopulmonary exercise test, six-minute walking test, handgrip strength, body mass index, fat free mass index, energy and protein intake) was evaluated in order to provide personalized advice regarding physical exercise training and nutrition. The program appeared feasible and well-tolerated. All six included patients managed to perform the assessments. Exercise session adherence was high in five patients and low in one patient. The performed exercise intensity was lower than prescribed for all patients. Patients were motivated to complete the home-based rehabilitation program during CHRT. Preliminary effects on physical and nutritional parameters revealed relatively stable values throughout CHRT, with inter-individual variation. Supervised and personalized rehabilitation in patients with stage III NSCLC undergoing CHRT seems feasible when the intensity of the physical exercise training was adjusted to the possibilities and preferences of the patients. Future research should investigate the feasibility of a supervised and personalized rehabilitation program during CHRT with a low-to-moderate exercise intensity with the aim to prevent physical decline during CHRT.

While previous studies have demonstrated that prenatal exposure to environmental stressors is associated with mitochondrial DNA (mtDNA) methylation, more recent investigations are questioning the accuracy of the methylation assessment and its biological relevance. In this study, we investigated placental mtDNA methylation while accounting for methodological issues such as nuclear contamination, bisulphite conversion, and PCR bias. From the ENVIRONAGE birth cohort, we selected three groups of participants (n = 20/group). One group with mothers who smoked during pregnancy (average 13.2 cig/day), one group with high air pollutant exposure (PM2.5: 16.0 +/- 1.4 mu g/m(3), black carbon: 1.8 +/- 0.3 mu g/m(3)) and one control group (non-smokers, PM2.5: 10.6 +/- 1.7 mu g/m(3), black carbon: 0.9 +/- 0.1 mu g/m(3)) with low air pollutant exposure. DNA methylation levels were quantified in two regions of the displacement loop control region (D-loopandLDLR2) by bisulphite pyrosequencing. Additionally, we measured DNA methylation on nuclear genes involved in mitochondrial maintenance (PINK1, DNA2, andPOLG1) and assessed mtDNA content using qPCR. AbsoluteD-loopmethylation levels were higher for mothers that smoked extensively (+0.36%, 95% CI: 0.06% to 0.66%), and for mothers that were highly exposed to air pollutants (+0.47%, 95% CI: 0.20% to 0.73%). The relevance of our findings is further supported, asD-loopmethylation levels were correlated with placental mtDNA content (r = -0.40, p = 0.002) and associated with birth weight (-106.98 g, 95% CI: -209.60 g to -4.36 g for an IQR increase inD-loopmethylation). Most notably, our data demonstrates relevant levels of mtDNA methylation in placenta tissue, with significant associations between prenatal exposure to environmental stressors andD-loopmethylation. This work was supported by the Research Foundation Flanders [G082317N]; Research Foundation Flanders [N1518119]. Janssen, BG (corresponding author), Hasselt Univ, Ctr Environm Sci, B-3590 Diepenbeek, Belgium. bram.janssen@uhasselt.be

Summary Background Primary Sjogren's syndrome is a systemic autoimmune disease characterised by secretory gland dysfunction, for which no effective therapy is available. Based on the complementary properties of leflunomide and hydroxychloroquine in inhibiting activation of key immune cells in primary Sjogren's syndrome, we aimed to evaluate the clinical efficacy and safety of leflunomide–hydroxychloroquine combination therapy in patients with primary Sjogren's syndrome. Methods We did a placebo-controlled, double-blinded, phase 2A randomised clinical trial in patients with primary Sjogren's syndrome at the University Medical Center Utrecht (Utrecht, Netherlands). Eligible patients were aged 18–75 years, had a European League Against Rheumatism (EULAR) Sjogren's syndrome disease activity index (ESSDAI) score of 5 or higher, and a lymphocytic focus score of 1 or higher in labial salivary gland biopsy specimens. Patients were randomly assigned (2:1) with block randomisation (block size of six) to receive leflunomide 20 mg and hydroxychloroquine 400 mg daily or placebo for 24 weeks. The primary endpoint was the between-group difference in change in ESSDAI scores from 0 to 24 weeks, adjusted for baseline ESSDAI score. Patients were analysed according to the intention-to-treat principle. This study is registered with EudraCT, 2014–003140–12. Findings Between March 7, 2016, and Nov 30, 2017, 37 patients were screened, of whom 29 patients (28 women and one man) were enrolled. 21 patients were assigned to receive leflunomide–hydroxychloroquine and eight patients were assigned to receive placebo. One patient in the placebo group required high-dose prednisone to treat polymyalgia rheumatica at week 13 and was excluded from the primary analysis. From 0 to 24 weeks, the mean difference in ESSDAI score, adjusted for baseline values, in the leflunomide–hydroxychloroquine group compared with the placebo group was −4·35 points (95% CI −7·45 to −1·25, p=0·0078). No serious adverse events occurred in the leflunomide–hydroxychloroquine group and two serious adverse events occurred in the placebo group (hospital admission for pancreatitis and hospital admission for nephrolithiasis). The most common adverse events in the leflunomide–hydroxychloroquine group were gastrointestinal discomfort (11 patients [52%] vs two [25%] in the placebo group), modest transient increases in alanine aminotransferase (ten [48%] vs one [13%]), and short episodes of general malaise and shivering (nine [43%] vs one [13%]). Interpretation Leflunomide–hydroxychloroquine was safe and resulted in a clinical response in patients with primary Sjogren's syndrome. These results warrant further evaluation of leflunomide–hydroxychloroquine combination therapy in larger clinical trials. Funding ZonMw.

Purpose Air pollutant exposure constitutes a serious risk factor for the emergence or aggravation of (existing) pulmonary disease. The impact of pre-intensive care ambient air pollutant exposure on the duration of artificial ventilation was, however, not yet established. Methods The medical records of 2003 patients, admitted to the intensive care unit (ICU) of the Antwerp University Hospital (Flanders, Belgium), who were artificially ventilated on ICU admission or within 48 h after admission, for the duration of at least 48 h, were analyzed. For each patient’s home address, daily air pollutant exposure [particulate matter with an aerodynamic diameter ≤ 2.5 µm (PM2.5) and ≤ 10 µm (PM10), nitrogen dioxide (NO2) and black carbon (BC)] up to 10 days prior to hospital admission was modeled using a high-resolution spatial–temporal model. The association between duration of artificial ventilation and air pollution exposure during the last 10 days before ICU admission was assessed using distributed lag models with a negative binomial regression fit. Results Controlling for pre-specified confounders, an IQR increment in BC (1.2 µg/m3) up to 10 days before admission was associated with an estimated cumulative increase of 12.4% in ventilation duration (95% CI 4.7–20.7). Significant associations were also observed for PM2.5, PM10 and NO2, with cumulative estimates ranging from 7.8 to 8.0%. Conclusion Short-term ambient air pollution exposure prior to ICU admission represents an unrecognized environmental risk factor for the duration of artificial ventilation in the ICU. Electronic supplementary material The online version of this article (10.1007/s00134-020-05999-3) contains supplementary material, which is available to authorized users.

History-matching of core-flood experimental data through numerical modeling is a powerful tool to get insight into the relevant physical parameters and mechanisms that control fluid flow in enhanced oil recovery processes. We conducted a mechanistic numerical simulation study aiming at modeling previously performed water-alternating-gas and foam-assisted chemical flooding core-flood experiments. For each experiment, a one-dimensional model was built. The obtained computed tomography scan data was used to assign varying porosity, and permeability, values to each grid block. The main goal of this study was to history-match measured phase saturation profiles along the core length, pressure drops, produced phase cuts, and the oil recovery history for each of the experiments conducted. The results show that, to obtain a good match for the water-alternating-gas experiment, gas relative permeability needs to be reduced as a function of injection time due to gas trapping. The surfactant phase behavior, for the aid of foam-assisted chemical flooding, was successfully simulated and its robustness was verified by effectively applying the same phase behavior model to the two different salinity conditions studied. It resulted in the oil mobilization, through the injection of a surfactant slug, being properly modeled. The mechanistic simulation of foam using the steady-state foam model built in UTCHEM proved inadequate for the mechanistic modeling of a foam drive in the presence of oil. An alternative heuristic approach was adopted to overcome this limitation.

Purpose: Despite known high-risk features, accurate identification of patients at high risk of cancer recurrence in colon cancer remains a challenge. As tumour stroma plays an important role in tumour invasion and metastasis, the easy, low-cost and highly reproducible tumour-stroma ratio (TSR) could be a valuable prognostic marker, which is also believed to predict chemo resistance. Methods: Two independent series of patients with colon cancer were selected. TSR was estimated by microscopic analysis of 4 mu m haematoxylin and eosin (H&E) stained tissue sections of the primary tumour and the corresponding metastatic lymph nodes. Patients were categorized as TSR-low ( 50%). Differences in overall survival and cancer-free survival were analysed by Kaplan-Meier curves and cox-regression analyses. Analyses were conducted for TNM-stage I-II, TNM-stage III and patients with an indication for chemotherapy separately. Results: We found that high TSR was associated with poor cancer-free survival in TNM-stage I-II colon cancer in two independent series, independent of other known high-risk features. This association was also found in TNM-stage III tumours, with an additional prognostic value of TSR in lymph node metastasis to TSR in the primary tumour alone. In addition, high TSR was found to predict chemo resistance in patients receiving adjuvant chemotherapy after surgical resection of a TNM-stage II-III colon tumour. Conclusion: In colon cancer, the TSR of both primary tumour and lymph node metastasis adds significant prognostic value to current pathologic and clinical features used for the identification of patients at high risk of cancer recurrence, and also predicts chemo resistance.

Simple Summary Using data from 459 colorectal cancer (CRC) survivors, we described how participants adhered to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) lifestyle recommendations and how this adherence was related to quality of life, level of functioning, symptoms of fatigue, and neuropathy symptoms. We found that increases in a lifestyle score was associated with better physical functioning and less fatigue. No relations with neuropathy symptoms were found. In addition, we observed that physical activity played an important role in the lifestyle score with regards to quality of life. In contrast, we observed that body composition and alcohol recommendations had a counteractive influence within the lifestyle score. Our findings suggest that CRC survivors benefit from overall adherence to the WCRF/AICR lifestyle recommendations in terms of quality of life and fatigue. Specific recommendations have a varying influence on these associations, complicating the interpretation and requiring further study. Abstract Post-treatment adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) lifestyle recommendations were associated with health-related quality of life (HRQoL), fatigue, and chemotherapy-induced peripheral neuropathy (CIPN) in colorectal cancer (CRC) survivors. In a prospective cohort among CRC survivors (n = 459), repeated home-visits were performed at 6 weeks, 6, 12, and 24 months post-treatment. Dietary intake, body composition, sedentary behaviour, and physical activity were assessed to construct a lifestyle score based on adherence to seven 2018 WCRF/AICR recommendations. Longitudinal associations of the lifestyle score with HRQoL, fatigue, and CIPN were analysed by confounder-adjusted linear mixed models. A higher lifestyle score was associated with better physical functioning and less activity-related fatigue, but not with CIPN. Adjustment for physical activity substantially attenuated observed associations, indicating its importance in the lifestyle score with regards to HRQoL. In contrast, adjustment for body composition and alcohol inflated observed associations, indicating that both recommendations had a counteractive influence within the lifestyle score. Our findings suggest that CRC survivors benefit from an overall adherence to the WCRF/AICR lifestyle recommendations in terms of HRQoL and fatigue, but not CIPN. Specific recommendations have a varying influence on these associations, complicating the interpretation and requiring further study.

Empirical evidence demonstrates that lakes and reservoirs are warming across the globe. Consequently, there is an increased need to project future changes in lake thermal structure and resulting changes in lake biogeochemistry in order to plan for the likely impacts. Previous studies of the impacts of climate change on lakes have often relied on a single model forced with limited scenario-driven projections of future climate for a relatively small number of lakes. As a result, our understanding of the effects of climate change on lakes is fragmentary, based on scattered studies using different data sources and modelling protocols, and mainly focused on individual lakes or lake regions. This has precluded identification of the main impacts of climate change on lakes at global and regional scales and has likely contributed to the lack of lake water quality considerations in policy-relevant documents, such as the Assessment Reports of the Intergovernmental Panel on Climate Change (IPCC). Here, we describe a simulation protocol developed by the Lake Sector of the Inter-Sectoral Impact Model Intercomparison Project (ISIMIP) for simulating climate change impacts on lakes using an ensemble of lake models and climate change scenarios. The protocol prescribes lake simulations driven by climate forcing from gridded observations and different Earth system models under various Representative Greenhouse Gas Concentration Pathways, all consistently bias-corrected on a 0.5° × 0.5° global grid. In ISIMIP phase 2, 11 lake models were forced with these data to project the thermal structure of 62 well-studied lakes where data were available for calibration under historical conditions, and for nearly 17,500 lakes using uncalibrated models and forcing data from the global grid where lakes are present. In ISIMIP phase 3, this approach was expanded to consider more lakes, more models, and more processes. The ISIMIP Lake Sector is the largest international effort to project future water temperature, thermal structure, and ice phenology of lakes at local and global scales and paves the way for future simulations of the impacts of climate change on water quality and biogeochemistry in lakes.

The tryptophan-kynurenine pathway has been linked to cancer aetiology and survivorship, and diet potentially affects metabolites of this pathway, but evidence to date is scarce. Among 247 stage I-III CRC survivors, repeated measurements were performed at 6 weeks, 6 months, and 1 year post-treatment. Adherence to the World Cancer Research Fund/ American Institute for Cancer Research (WCRF) and Dutch Healthy Diet (DHD) recommendations was operationalized using seven-day dietary records. Plasma kynurenines of nine metabolites were analysed. Longitudinal associations of adherence to these dietary patterns and plasma kynurenines were analysed using confounder-adjusted linear mixed-models. In general, higher adherence to the dietary WCRF/AICR and DHD recommendations was associated with lower concentrations of kynurenines with pro-oxidative, pro-inflammatory, and neurotoxic properties (3-hydroxykynurenine (HK) and quinolinic acid (QA)), and higher concentrations of kynurenines with anti-oxidative, anti-inflammatory, and neuroprotective properties (kynurenic acid (KA) and picolinic acid (Pic)), but associations were weak and not statistically significant. Statistically significant positive associations between individual recommendations and kynurenines were observed for: nuts with kynurenic-acid-to-quinolinic-acid ratio (KA/QA); alcohol with KA/QA, KA, and xanthurenic acid (XA); red meat with XA; and cheese with XA. Statistically significant inverse associations were observed for: nuts with kynurenine-to-tryptophan ratio (KTR) and hydroxykynurenine ratio; alcohol with KTR; red meat with 3-hydroxyanthranilic-to-3-hydroxykynurenine ratio; ultra-processed foods with XA and KA/QA; and sweetened beverages with KA/QA. Our findings suggest that CRC survivors might benefit from adhering to the dietary WCRF and DHD recommendations in the first year after treatment, as higher adherence to these dietary patterns is generally, but weakly associated with more favourable concentrations of kynurenines and their ratios. These results need to be validated in other studies.

Meeting the United Nations’ (UN’s) 17 Sustainable Development Goals (SDGs) has become a worldwide mission. How these SDGs interrelate, however, is not well known. We assess the interactions between SDGs for the case of water pollution by nutrients in China. The results show 319 interactions between SDGs for clean water (SDGs 6 and 14) and other SDGs, of which 286 are positive (synergies) and 33 are negative (tradeoffs) interactions. We analyze six scenarios in China accounting for the cobenefits of water pollution control using a large-scale water quality model. We consider scenarios that benefit from synergies and avoid tradeoffs. Our results show that effective pollution control requires accounting for the interactions between SDGs. For instance, combining improved nutrient management, efficient food consumption, and climate mitigation is effective for simultaneously meeting SDGs 6 and 14 as well as other SDGs for food, cities and climate. Our study serves as an example of assessing SDG interactions in environmental policies in China as well as in other regions of the world.

Introduction Patients with a low cardiorespiratory fitness (CRF) undergoing colorectal cancer surgery have a high risk for postoperative complications. Cardiopulmonary exercise testing (CPET) to assess CRF is the gold standard for preoperative risk assessment. To aid interpretation of raw breath-by-breath data, different methods of data-averaging can be applied. This study aimed to investigate the influence of different data-averaging intervals on CPET variables used for preoperative risk assessment, as well as to evaluate whether different data-averaging intervals influence preoperative risk assessment. Methods A total of 21 preoperative CPETs were interpreted by two exercise physiologists using stationary time-based data-averaging intervals of 10, 20, and 30 seconds and rolling average intervals of 3 and 7 breaths. Mean values of CPET variables between different data averaging intervals were compared using repeated measures ANOVA. The variables of interest were oxygen uptake at peak exercise (VO2peak), oxygen uptake at the ventilatory anaerobic threshold (VO2VAT), oxygen uptake efficiency slope (OUES), the ventilatory equivalent for carbon dioxide at the ventilatory anaerobic threshold (VE/VCO2VAT), and the slope of the relationship between the minute ventilation and carbon dioxide production (VE/VCO2-slope). Results Between data-averaging intervals, no statistically significant differences were found in the mean values of CPET variables except for the ventilatory equivalent for carbon dioxide at the ventilatory anaerobic threshold (P = 0.001). No statistically significant differences were found in the proportion of patients classified as high or low risk regardless of the used data-averaging interval. Conclusion There appears to be no significant or clinically relevant influence of the evaluated data-averaging intervals on the mean values of CPET outcomes used for preoperative risk assessment. Clinicians may choose a data-averaging interval that is appropriate for optimal interpretation and data visualization of the preoperative CPET. Nevertheless, caution should be taken as the chosen data-averaging interval might lead to substantial within-patient variation for individual patients. Clinical trial registration Prospectively registered at ClinicalTrials.gov (NCT05353127).

Significant treatment variation exists in the Netherlands between teams treating patients with cleft lip, alveolus, and/or palate, resulting in a confusing and undesirable situation for patients, parents, and practitioners. Therefore, to optimize cleft care, clinical practice guidelines (CPGs) were developed. The aim of this report is to describe CPG development, share the main recommendations, and indicate knowledge gaps regarding cleft care. Together with patients and parents, a multidisciplinary working group of representatives from all relevant disciplines assisted by two experienced epidemiologists identified the topics to be addressed in the CPGs. Searching the Medline, Embase, and Cochrane Library databases identified 5157 articles, 60 of which remained after applying inclusion and exclusion criteria. We rated the quality of the evidence from moderate to very low. The working group formulated 71 recommendations regarding genetic testing, feeding, lip and palate closure, hearing, hypernasality, bone grafting, orthodontics, psychosocial guidance, dentistry, osteotomy versus distraction, and rhinoplasty. The final CPGs were obtained after review by all stakeholders and allow cleft teams to base their treatment on current knowledge. With high-quality evidence lacking, the need for additional high-quality studies has become apparent.

Despite known high-risk features, accurate identification of patients at high risk of cancer recurrence in colon cancer remains a challenge. As tumour stroma plays an important role in tumour invasion and metastasis, the easy, low-cost and highly reproducible tumour-stroma ratio (TSR) could be a valuable prognostic marker, which is also believed to predict chemo resistance.Two independent series of patients with colon cancer were selected. TSR was estimated by microscopic analysis of 4 µm haematoxylin and eosin (HE) stained tissue sections of the primary tumour and the corresponding metastatic lymph nodes. Patients were categorized as TSR-low (≤ 50%) or TSR-high ( 50%). Differences in overall survival and cancer-free survival were analysed by Kaplan-Meier curves and cox-regression analyses. Analyses were conducted for TNM-stage I-II, TNM-stage III and patients with an indication for chemotherapy separately.We found that high TSR was associated with poor cancer-free survival in TNM-stage I-II colon cancer in two independent series, independent of other known high-risk features. This association was also found in TNM-stage III tumours, with an additional prognostic value of TSR in lymph node metastasis to TSR in the primary tumour alone. In addition, high TSR was found to predict chemo resistance in patients receiving adjuvant chemotherapy after surgical resection of a TNM-stage II-III colon tumour.In colon cancer, the TSR of both primary tumour and lymph node metastasis adds significant prognostic value to current pathologic and clinical features used for the identification of patients at high risk of cancer recurrence, and also predicts chemo resistance.

Life-limiting conditions in children in specialized pediatric palliative care (PPC) are manifold. The "Together for Short Lives" (TfSL) association established four disease categories, which represent the most common illness trajectories. Better understanding the palliative care needs and symptoms of children within these TfSL groups will result in improved anticipation of clinical problems and tailored care. During this retrospective single-center cohort study, 198 children, adolescents, and young adults (CAYAs) were in PPC. Mean age at referral was 8.7 years (range 0.0-25.0), mean duration of care 355 days (range 1-2754). One hundred six (53.5%) CAYAs died during the study period. Sixty-five (32.8%) CAYAs were assigned to TfSL-1, 13 (6.6%) to TfSL-2, 49 (24.7%) to TfSL-3, and 71 (35.9%) to TfSL-4. Home visits were conducted on average every 9.6 days in TfSL-1, 18.9 days in TfSL-2, 31.7 days in TfSL-3, and 31.8 days in TfSL-4 (p value 0.01).Conclusions: Intensity of palliative care significantly differed between the TfSL groups. Neurological and gastrointestinal symptoms were most prominent across all TfSL groups. Symptom cluster analysis showed distinct clusters in TfSL-1 (cluster 1, fatigue/lack of appetite/nausea/somnolence; cluster 2, dyspnea/fear/myoclonus/seizures/spasticity) and TfSL-3/4 (cluster 1, spasticity; cluster 2, all other symptoms).What is Known:• The four TfSL (together for short lives) groups represent the four most common illness trajectories of pediatric palliative care patients.• Better understanding the palliative care needs and symptoms of children within these four TfSL groups will result in improved anticipation of clinical problems and tailored care.What is New:• In our study, TfSL-1 represented the largest individual group of patients, also requiring the most intensive care (defined by the number of visits per days of care).• Symptom cluster analysis revealed distinct symptom clusters in TfSL-1 and TfSL-3/4, which can be used to anticipate clinically common challenges in these patients.

The choice of binder material, added to a zeolite‐based catalyst body, can significantly influence the catalyst performance during a reaction, i. e. its deactivation and selectivity. In this work the influence of the binder in catalyst extrudates on the formation of hydrocarbon deposits was explored during the transalkylation of toluene with 1,2,4‐trimethylbenzene (1,2,4‐TMB). Using in situ UV‐vis micro‐spectroscopy and ex situ confocal fluorescence microscopy approach, coke species were revealed to predominantly form on the rim of zeolite crystals within Al2O3‐bound extrudates. It was found that this was due to Al migration between the zeolite crystals and the Al2O3‐binder creating additional acid sites near the zeolite external surface. In contrast, minimal isomerization of 1,2,4‐TMB in the SiO2‐bound extrudate allowed greater access to the zeolite internal pore network, creating a more homogeneous coke distribution throughout the zeolite crystals.

Summary Alkaline/surfactant/foam (ASF) flooding is a novel enhanced–oil–recovery (EOR) process that increases oil recovery over waterflooding by combining foaming with a decrease in the oil/water interfacial tension (IFT) by two to three orders of magnitude. We conducted an experimental study regarding the formation of an oil bank and its displacement by foam drives with foam qualities within the range of 57 to 97%. The experiments included bulk phase behavior tests using n–hexadecane and a single internal olefin sulfonate surfactant, and a series of computed–tomography (CT) –scanned coreflood experiments using Bentheimer Sandstone cores. The main goal of this study was to investigate the effect of drive–foam quality on oil–bank displacement. The surfactant formulation was found to lower the oil/water IFT by at least two orders of magnitude. Coreflood results, at under-optimum salinity conditions yielding an oil/water IFT on the order of 10–1 mN/m, showed similar ultimate–oil–recovery factors for the range of drive–foam qualities studied. A more distinct frontal oil–bank displacement was observed at lower drive–foam qualities investigated, yielding an increased oil–production rate. The findings in this study suggested that dispersive characteristics at the leading edge of the generated oil bank in this work were strongly related to the surfactant slug size used, the lowest drive–foam quality assessed yielded the highest apparent foam viscosity (and, thus, the most stable oil–bank displacement), and drive–foam strength increased upon touching the oil bank when using drive–foam qualities of 57 and 77%.

Mitochondria] DNA (mtDNA) content and telomere length are putative aging biomarkers and are sensitive to environmental stressors, including pollutants. Our objective was to identify, from a set of environmental exposures, which exposure is associated with leukocyte mtDNA content and telomere length in adults. This study includes 175 adults from 50 to 65 years old from the cross-sectional Flemish Environment and Health study, of whom leukocyte telomere length and mtDNA content were determined using qPCR. The levels of exposure of seven metals, 11 organohalogens, and four perfluorinated compounds (PFHxS, PFNA, PFOA, PFOS) were measured. We performed sparse partial least-squares regression analyses followed by ordinary least-squares regression to assess the multipollutant associations. While accounting for possible confounders and coexposures, we identified that urinary cadmium (6.52%, 95% confidence interval, 1.06, 12.28), serum hexachlorobenzene (2.89%, 018, 5.68), and perfluorooctanesulfonic acid (11.38%, 5.97, 17.08) exposure were positively associated (p < 0.05) with mtDNA content, while urinary copper (-9.88%, -14.82, -4.66) and serum perfluorohexanesulfonic acid (-4.75%, -8.79, -0.54) exposure were inversely associated with mtDNA content. Urinary antimony (2.69%, 0.45, 4.99) and mercury (1.91%, 0.42, 3.43) exposure were positively associated with leukocyte telomere length, while urinary copper (-3.52%, -6.60, -0.34) and serum perfluorooctanesulfonic acid (-3.64%, -6.60, -0.60) showed an inverse association. Our findings support the hypothesis that environmental pollutants interact with molecular hallmarks of aging.