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Objective: To assess health outcomes, including growth up to 2 years of age, in children born after embryo vitrification in comparison with children born after fresh embryo transfer. Design: A prospective cohort study. Setting: A single-center university hospital. Patient(s): Singletons born after the transfer of vitrified or fresh embryos, either at the cleavage or blastocyst stage between 2014 and 2018, were included. Intervention(s): Multiple linear and logistic regression analyses were used to study the association between outcomes after vitrified versus fresh embryo transfer, controlling for neonatal, treatment, and maternal characteristics. Subgroup analysis according to cycle protocol (hormone replacement vs. natural cycle) and strategy (freeze-all vs. previous fresh cycle) was also performed. Main Outcome Measure(s): Measurements at birth and growth in infancy and childhood, as well as health outcomes, including congenital malformations, interventions, medication use, and hospitalizations are reported. Result(s): Birth characteristics were available for 1237 and 2063 children born after embryo vitrification and fresh embryo transfer, respectively. Follow-up data were available for 582 and 757 children at infancy and for 233 and 296 children at 2 years, respectively. Birthweight, height, and head circumference SD scores of children born after embryo vitrification were higher than children born after fresh embryo transfer, even after adjustment for neonatal, treatment, and maternal characteristics. In infancy, weight and height SD scores were larger for children born after embryo vitrification, but not after adjustment for covariates. In childhood, no differences in anthropometry were observed between the groups. Weight and height gain from birth to infancy and from infancy to early childhood were comparable between the groups. Comparable rates of severe developmental problems, hospital admissions, surgical interventions, and of chronic medication use were observed up to the age of 2 years. Subgroup analysis showed that growth parameters were not affected by the cycle protocol or strategy at any age. Conclusion(s): Our study indicated that embryo vitrification is associated with higher birthweight, even after controlling for confounders. However, in early childhood, anthropometry and weight and height gain was not different in children born after vitrified or fresh embryo transfer.

Background A mechanical ankle–foot prosthesis (Talaris Demonstrator) was developed to improve prosthetic gait in people with a lower-limb amputation. This study aims to evaluate the Talaris Demonstrator (TD) during level walking by mapping coordination patterns based on the sagittal continuous relative phase (CRP). Methods Individuals with a unilateral transtibial amputation, transfemoral amputation and able-bodied individuals completed 6 minutes of treadmill walking in consecutive blocks of 2 minutes at self-selected (SS) speed, 75% SS speed and 125% SS speed. Lower extremity kinematics were captured and hip–knee and knee–ankle CRPs were calculated. Statistical non-parametric mapping was applied and statistical significance was set at 0.05. Results The hip–knee CRP at 75% SS walking speed with the TD was larger in the amputated limb of participants with a transfemoral amputation compared to able-bodied individuals at the beginning and end of the gait cycle (p = 0.009). In people with a transtibial amputation, the knee–ankle CRP at SS and 125% SS walking speeds with the TD were smaller in the amputated limb at the beginning of the gait cycle compared to able-bodied individuals (p = 0.014 and p = 0.014, respectively). Additionally, no significant differences were found between both prostheses. However, visual interpretation indicates a potential advantage of the TD over the individual's current prosthesis. Conclusion This study provides lower-limb coordination patterns in people with a lower-limb amputation and reveals a possible beneficial effect of the TD over the individuals’ current prosthesis. Future research should include a well-sampled investigation of the adaptation process combined with the prolonged effects of the TD.

Background The prediction of potentially pathogenic variant combinations in patients remains a key task in the field of medical genetics for the understanding and detection of oligogenic/multilocus diseases. Models tailored towards such cases can help shorten the gap of missing diagnoses and can aid researchers in dealing with the high complexity of the derived data. The predictor VarCoPP (Variant Combinations Pathogenicity Predictor) that was published in 2019 and identified potentially pathogenic variant combinations in gene pairs (bilocus variant combinations), was the first important step in this direction. Despite its usefulness and applicability, several issues still remained that hindered a better performance, such as its False Positive (FP) rate, the quality of its training set and its complex architecture. Results We present VarCoPP2.0: the successor of VarCoPP that is a simplified, faster and more accurate predictive model identifying potentially pathogenic bilocus variant combinations. Results from cross-validation and on independent data sets reveal that VarCoPP2.0 has improved in terms of both sensitivity (95% in cross-validation and 98% during testing) and specificity (5% FP rate). At the same time, its running time shows a significant 150-fold decrease due to the selection of a simpler Balanced Random Forest model. Its positive training set now consists of variant combinations that are more confidently linked with evidence of pathogenicity, based on the confidence scores present in OLIDA, the Oligogenic Diseases Database (https://olida.ibsquare.be). The improvement of its performance is also attributed to a more careful selection of up-to-date features identified via an original wrapper method. We show that the combination of different variant and gene pair features together is important for predictions, highlighting the usefulness of integrating biological information at different levels. Conclusions Through its improved performance and faster execution time, VarCoPP2.0 enables a more accurate analysis of larger data sets linked to oligogenic diseases. Users can access the ORVAL platform (https://orval.ibsquare.be) to apply VarCoPP2.0 on their data.

Background Stiff left atrial syndrome (SLAS) and pulmonary vein (PV) occlusion are rare yet potentially major life-long complications after radiofrequency ablation for atrial fibrillation. While mostly controlled by medical management, SLAS can progress to refractory congestive heart failure. Treatment of PV stenosis and occlusion remains a challenging problem with ongoing risk for recurrence regardless of techniques employed. Herein we present the case of a now 51-year-old male with acquired PV occlusion and SLAS who, over the course of eleven years, despite multiple interventions, ultimately required heart transplantation. Case presentation After undergoing three radiofrequency catheter procedures for paroxysmal atrial fibrillation (AF), a hybrid ablation was planned due to reappearance of symptomatic AF. Preoperative echocardiography and chest computed tomography (CT) revealed an occlusion of both left PVs. Furthermore, left atrial dysfunction, high pulmonary artery and pulmonary wedge pressures were diagnosed as well as an important reduction of the left atrial volume. The diagnosis of stiff left atrial syndrome was made. Primary surgical repair of the left-sided PVs was performed using a pericardial patch as a tubular neo-vein, combined with cryoablation in the left and right atrium to treat the patient’s arrhythmia. Initial results were favorable, however, after two years the patient experienced progressive restenosis with hemoptysis. Therefore, stenting of the common left PV was performed. Over the years, progressive right heart failure with severe tricuspid regurgitation developed, despite maximal medical therapy, which led to the need for heart transplantation. Conclusion The impact of PV occlusion and SLAS after percutaneous radiofrequency ablation can be lifelong and devastating for the clinical course of the patient. Since the presence of a small left atrium could be an important predictor for SLAS in case of redo ablation, preprocedural imaging should guide the operator to an algorithm of a decision-making containing lesion set, energy source, and safety of re-ablation.

RESEARCH QUESTION: Is there an association between FSHR sequence variants and reproductive outcomes following IVF in predicted normoresponders? DESIGN: Multicentre prospective cohort study conducted from November 2016 to June 2019 in Vietnam, Belgium and Spain including patients aged G, c.2039A>G, c.-29G>A) and one FSHB sequence variants (c.-211G>T). Clinical pregnancy rate (CPR), live birth rate (LBR) and miscarriage rate in the first embryo transfer and cumulative live birth rate (CLBR) were compared between the different genotypes. RESULTS: A total of 351 patients underwent at least one embryo transfer. Genetic model analysis that adjusted for patient age, body mass index, ethnicity, type of embryo transfer, embryo stage and number of top-quality embryos transferred revealed a higher CPR for homozygous patients for the variant allele G of c.919A>G when compared to patients with genotype AA (60.3% versus 46.3%, adjusted odds ratio [ORadj] 1.96, 95% confidence interval [CI] 1.09-3.53). Also, c.919A>G genotypes AG and GG presented a higher CPR and LBR when compared with genotype AA (59.1% versus 46.3%, ORadj 1.80, 95% CI 1.08-3.00, and 51.3% versus 39.0%, ORadj 1.69, 95% CI 1.01-2.80, respectively). Cox regression models revealed a statistically significantly lower CLBR for c.2039A>G genotype GG in the codominant model (hazard ratio [HR] 0.66, 95% CI 0.43-0.99). CONCLUSION: These results demonstrate a previously unreported association between variant c.919A>G genotype GG and higher CPR and LBR in infertile patients and reinforce a potential role for genetic background in predicting the reproductive prognosis following IVF.

Targeted radionuclide therapy (TRT) using targeting moieties labeled with α-particle-emitting radionuclides (α-TRT) is an intensely investigated treatment approach as the short range of α-particles allows effective treatment of local lesions and micrometastases. However, profound assessment of the immunomodulatory effect of α-TRT is lacking in literature. Methods: Using flow cytometry of tumors, splenocyte restimulation, and multiplex analysis of blood serum, we studied immunologic responses ensuing from TRT with an antihuman CD20 single-domain antibody radiolabeled with 225Ac in a human CD20 and ovalbumin expressing B16-melanoma model. Results: Tumor growth was delayed with α-TRT and increased blood levels of various cytokines such as interferon-γ, C-C motif chemokine ligand 5, granulocyte-macrophage colony-stimulating factor, and monocyte chemoattractant protein-1. Peripheral antitumoral T-cell responses were detected on α-TRT. At the tumor site, α-TRT modulated the cold tumor microenvironment (TME) to a more hospitable and hot habitat for antitumoral immune cells, characterized by a decrease in protumoral alternatively activated macrophages and an increase in antitumoral macrophages and dendritic cells. We also showed that α-TRT increased the percentage of programmed death-ligand 1 (PD-L1)-positive (PD-L1pos) immune cells in the TME. To circumvent this immunosuppressive countermeasure we applied immune checkpoint blockade of the programmed cell death protein 1-PD-L1 axis. Combination of α-TRT with PD-L1 blockade potentiated the therapeutic effect, however, the combination aggravated adverse events. A long-term toxicity study revealed severe kidney damage ensuing from α-TRT. Conclusion: These data suggest that α-TRT alters the TME and induces systemic antitumoral immune responses, which explains why immune checkpoint blockade enhances the therapeutic effect of α-TRT. However, further optimization is warranted to avoid adverse events.

Oocyte in vitro maturation (IVM) is an assisted reproductive technology with a long and sometimes checked history. It is a minimally invasive technique involving the deliberate collection of immature oocytes from patients that have received no or minimal ovarian stimulation and the culture of oocytes to maturity in vitro, before standard procedures thereafter. Now, IVM is classified as nonexperimental and is primarily indicated for patients with a high antral follicle count, especially patients with polycystic ovaries or polycystic ovary syndrome, as well as for fertility preservation in cancer patients. In the recent past, IVM practice has had a confusing array of clinical protocols and has been slow to adapt to new scientific insights; however, recently, significant advances have been made in IVM culture methods based on new knowledge from animal studies, combined with defining a simple patient treatment protocol. These improvements have led to significant recent progress in IVM practice to the extent that IVM is now routinely practiced in a growing number of centers with specialized expertise around the world.

Multiple myeloma (MM) remains an incurable haematological malignancy despite substantial advances in therapy. Hypoxic bone marrow induces metabolic rewiring in MM cells contributing to survival and drug resistance. Therefore, targeting metabolic pathways may offer an alternative treatment option. In this study, we repurpose two FDA-approved drugs, syrosingopine and metformin. Syrosingopine was used as a dual inhibitor of monocarboxylate transporter 1 and 4 (MCT1/4) and metformin as an inhibitor for oxidative phosphorylation (OXPHOS). Anti-tumour effects were evaluated for single agents and in combination therapy. Survival and expression data for MCT1/MCT4 were obtained from the Total Therapy 2, Mulligan, and Multiple Myeloma Research Foundation cohorts. Cell death, viability, and proliferation were measured using Annexin V/7-AAD, CellTiterGlo, and BrdU, respectively. Metabolic effects were assessed using Seahorse Glycolytic Rate assays and LactateGlo assays. Differential protein expression was determined using western blotting, and the SUnSET method was implemented to quantify protein synthesis. Finally, the syngeneic 5T33MMvv model was used for in vivo analysis. High-level expression of MCT1 and MCT4 both correlated with a significantly lower overall survival of patients. Lactate production as well as MCT1/MCT4 expression were significantly upregulated in hypoxia, confirming the Warburg effect in MM. Dual inhibition of MCT1/4 with syrosingopine resulted in intracellular lactate accumulation and reduced cell viability and proliferation. However, only at higher doses (>10 μm) was syrosingopine able to induce cell death. By contrast, combination treatment of syrosingopine with metformin was highly cytotoxic for MM cell lines and primary patient samples and resulted in a suppression of both glycolysis and OXPHOS. Moreover, pathway analysis revealed an upregulation of the energy sensor p-AMPKα and more downstream a reduction in protein synthesis. Finally, the combination treatment resulted in a significant reduction in tumour burden in vivo. This study proposes an alternative combination treatment for MM and provides insight into intracellular effects.

Crohn disease (CD) is often complicated by bowel strictures that can lead to obstructive symptoms, resistant inflammation, and penetrating complications. Endoscopic balloon dilatation of CD strictures has emerged as a safe and effective technique for relieving these strictures, which may obviate the need for surgical intervention in the short and medium term. This technique appears to be underutilized in pediatric CD. This position paper of the Endoscopy Special Interest Group of European Society for Pediatric Gastroenterology, Hepatology and Nutrition describes the potential applications, appropriate evaluation, practical technique, and management of complications of this important procedure. The aim being to better integrate this therapeutic strategy in pediatric CD management.

RESEARCH QUESTION : What is the discontinuation rate among patients with remaining cryopreserved embryos in Belgium and what are the reasons for discontinuation? DESIGN : Multicenter, cross-sectional study performed in 11 Belgian fertility clinics (covering 80% of ART population). Patients were eligible (n=1917) in case they underwent an unsuccessful fresh embryo transfer (fresh group) or FET (in between group) and did not start a subsequent FET cycle within one year despite the presence of remaining cryopreserved embryos. Denominator were all patients with embryos cryopreserved during the same period (2012-2017) (n=21329). Data were collected through an online anonymous questionnaire. RESULTS : The discontinuation rate for patients with remaining cryopreserved embryos is 9% (1917/21329). For the final analysis, 304 completed questionnaires were included. The most important checked reasons for discontinuation of FET cycles were psychological (50%) and physical (43%) burden, impact on work (29%), woman's age (25%) and impact on relationship (25%). In 69% of the cases the patient her/himself made the decision to delay FET treatment. In 16% of the respondents, the decision to delay FET was determined by external factors: treating physician (9%), social environment (4%), close family (3%) and society (3%). Suggested improvements by the respondents were psychological support before (41%), during (51%) and after (51%) treatment, as well as lifestyle counseling (44%) and receiving digital information (43%). CONCLUSIONS : The discontinuation rate is remarkably high in patients with remaining cryopreserved embryos, who are considered to have a good prognosis. Respondents stressed the need to better integrate psychological and patient tailored care in our daily ART practice.

BACKGROUND: Limited data on the real-world safety and efficacy of leadless pacemakers (LPMs) post-transvenous lead extraction (TLE) are available. OBJECTIVE: The purpose of this study was to assess the long-term safety and effectiveness of LPMs following TLE in comparison with LPMs de novo implantation. METHODS: Consecutive patients who underwent LPM implantation in 12 European centers joining the International LEAdless PacemakEr Registry were enrolled. The primary end point was the comparison of LPM-related complication rate at implantation and during follow-up (FU) between groups. Differences in electrical performance were deemed secondary outcomes. RESULTS: Of the 1179 patients enrolled, 15.6% underwent a previous TLE. During a median FU of 33 (interquartile range 24-47) months, LPM-related major complications and all-cause mortality did not differ between groups (TLE group: 1.6% and 5.4% vs de novo group: 2.2% and 7.8%; P = .785 and P = .288, respectively). Pacing threshold (PT) was higher in the TLE group at implantation and during FU, with very high PT (>2 V@0.24 ms) patients being more represented than in the de novo implantation group (5.4% vs 1.6 %; P = .004). When the LPM was deployed at a different right ventricular (RV) location than the one where the previous transvenous RV lead was extracted, a lower proportion of high PT (>1-2 V@0.24 ms) patients at implantation, 1-month FU, and 12-month FU (5.9% vs 18.2%, P = .012; 3.4% vs 12.9%, P = .026; and 4.3% vs 14.5%, P = .037, respectively) was found. CONCLUSION: LPMs showed a satisfactory safety and efficacy profile after TLE. Better electrical parameters were obtained when LPMs were implanted at a different RV location than the one where the previous transvenous RV lead was extracted.

STUDY QUESTION Can early pregnancies be accurately and cost-effectively diagnosed and managed using a new medical computerized tool? SUMMARY ANSWER Compared to the standard clinical approach, retrospective implementation of the new medical software in a gynaecological emergency unit was correlated with more accurate diagnosis and more cost-effective management. WHAT IS KNOWN ALREADY Early pregnancy complications are responsible for a large percentage of consultations, mostly in emergency units, with guidelines becoming complex and poorly known/misunderstood by practitioners. STUDY DESIGN, SIZE, DURATION A total of 780 gynaecological emergency consultations (446 patients), recorded between November 2018 and June 2019 in a tertiary university hospital, were retrospectively encoded in a new medical computerized tool. The inclusion criteria were a positive hCG test result, ultrasonographical visualization of gestational sac, and/or embryo corresponding to a gestational age of 14 weeks or less. Diagnosis and management suggested by the new computerized tool are named eDiagnoses, while those provided by a gynaecologist member of the emergency department staff are called medDiagnoses. PARTICIPANTS/MATERIALS, SETTING, METHODS Usability was the primary endpoint, with accuracy and cost reduction, respectively, as secondary and tertiary endpoints. Identical eDiagnoses/medDiagnoses were considered as accurate. During follow-up visits, if the updated eDiagnoses and medDiagnoses became both identical to a previously discrepant eDiagnosis or medDiagnosis, this previous eDiagnosis or medDiagnosis was also considered as correct. Four double-blinded experts reviewed persistent discrepancies, determining the accurate diagnoses. eDiagnoses/medDiagnoses accuracies were compared using McNemar’s Chi square test, sensitivity, specificity, and predictive values. MAIN RESULTS AND THE ROLE OF CHANCE Only 1 (0.1%) from 780 registered medical records lacked data for full encoding. Out of the 779 remaining consultations, 675 eDiagnoses were identical to the medDiagnoses (86.6%) and 104 were discrepant (13.4%). From these 104, 60 reached an agreement during follow-up consultations, with 59 medDiagnoses ultimately changing into the initial eDiagnoses (98%) and only one discrepant eDiagnosis turning later into the initial medDiagnosis (2%). Finally, 24 remained discrepant at all subsequent checks and 20 were not re-evaluated. Out of these 44, the majority of experts agreed on 38 eDiagnoses (86%) and 5 medDiagnoses (11%, including four twin pregnancies whose twinness was the only discrepancy). No majority was reached for one discrepant eDiagnosis/medDiagnosis (2%). In total, the accuracy of eDiagnoses was 99.1% (675 + 59 + 38 = 772 eDiagnoses out of 779), versus 87.4% (675 + 1 + 5 = 681) for medDiagnoses (P LIMITATIONS, REASONS FOR CAUTION The retrospective study design is a limitation. Some observed improvements with the medical software could derive from the encoding by a rested and/or more experienced physician who had a better ultrasound interpretation. This software cannot replace clinical and ultrasonographical skills but may improve the compliance to published guidelines. WIDER IMPLICATIONS OF THE FINDINGS This medical computerized tool is improving. A new version considers diagnosis and management of multiple pregnancies with their specificities (potentially multiple locations, chorioamnionicity). Prospective evaluations will be required. Further developmental steps are planned, including software incorporation into ultrasound devices and integration of previously published predictive/prognostic factors (e.g. serum progesterone, corpus luteum scoring). STUDY FUNDING/COMPETING INTEREST(S) No external funding was obtained for this study. F.B. and D.G. created the new medical software. TRIAL REGISTRATION NUMBER NCT03993015

BACKGROUND: Early diagnosis of Coronary Artery Disease (CAD) plays a key role to prevent adverse cardiac events such as myocardial infarction and Left Ventricular (LV) dysfunction. Myocardial Work (MW) indices derived from echocardiographic speckle tracking data in combination with non-invasive blood pressure recordings seems promising to predict CAD even in the absence of impairments of standard echocardiographic parameters. Our aim was to compare the diagnostic accuracy of MW indices to predict CAD and to assess intra- and inter-observer variability of MW through a meta-analysis. METHODS: Electronic databases were searched for observational studies evaluating the MW indices diagnostic accuracy for predicting CAD and intra- and inter-observer variability of MW indices. Pooled sensitivity, specificity, and Summary Receiver Operating Characteristic (SROC) curves were assessed. RESULTS: Five studies enrolling 501 patients met inclusion criteria. Global Constructive Work (GCW) had the best pooled sensitivity (89%) followed by GLS (84%), Global Work Index (GWI) (82%), Global Work Efficiency (GWE) (80%), and Global Wasted Work (GWW) (75%). GWE had the best pooled specificity (78%) followed by GWI (75%), GCW (70%), GLS (68%), and GWW (61%). GCW had the best accuracy according to SROC curves, with an area under the curve of 0.86 compared to 0.84 for GWI, 0.83 for GWE, 0.79 for GLS, and 0.74 for GWW. All MW indices had an excellent intra- and inter-observer variability. CONCLUSIONS: GCW is the best MW index proving best diagnostic accuracy in the prediction of CAD with an excellent reproducibility.

Aims The multielectrode radiofrequency balloon catheter (RFB) has been developed to achieve safe and effective pulmonary vein isolation (PVI) for atrial fibrillation (AF) ablation. This single-centre study aimed to evaluate the midterm clinical outcome and predictors of single-shot PVI with the novel RFB. Methods and results All consecutive patients with symptomatic paroxysmal or persistent AF undergoing first-time PVI with the RFB were prospectively included. Clinical and procedural parameters were systematically collected. The primary safety endpoint was defined as any major periprocedural complications. The primary efficacy endpoint consisted of freedom from any atrial tachyarrhythmias (ATas) lasting >30 s during the follow-up after a 3-month blanking period. Persistent single-shot PVI was defined as PVI achieved with a single RFB application without acute reconnection. A total of 104 consecutive patients (mean age 64.3 ± 11.4 years, 56.7% males) were included. 15 patients (14.4%) presented with persistent AF. The procedure time was 59.0 min with a dwell time of 20.0 min. One major complication occurred in one patient. At a mean follow-up of 10.1 ± 5.3 months, freedom from ATas was 82.9%. ATas occurred in 14 patients, 11/69 patients (15.9%) with paroxysmal AF and 3/13 (23.1%) with persistent AF. The best cut-offs to predict persistent single-shot PVI were impedance drop >19.2 Ω [area under the receiver operator characteristic curve (AUC) 0.74] and temperature rise >11.1° C (AUC 0.77). Conclusion In a large cohort of patients undergoing PVI with the RFB, the complication rate was 1%. At a mid-term follow-up of 10.1 ± 5.3 months, freedom from ATas was 82.9%. Specific cut-offs of impedance drop and temperature rise may be useful to predict persistent single-shot isolation.

INTRODUCTION: Research on stress-related disorders and brain imaging suggests that (acute) stress might impact the capacity to mentally simulate specific episodic future events (EFT) through the effects of cortisol on brain regions supporting this cognitive function, such as the prefrontal cortices. This study aims to examine the mechanisms underlying this link, using transcranial Direct Current Stimulation (tDCS) over the left dorsolateral prefrontal cortex. METHODS: 60 healthy participants were subjected to the Montreal Imaging Stress Task (MIST), followed by either active or sham tDCS. After stimulation, the EFT task was administered. Salivary cortisol was measured throughout the protocol. RESULTS: Higher cortisol AUCi values were linked to less specific episodic future thoughts. Moreover, active tDCS enhanced EFT specificity irrespective of cortisol, especially in high trait ruminators. We did not observe an effect from active tDCS on cortisol AUCi, and equally there was no interaction effect between cortisol AUCi and stimulation condition predictive for EFT specificity. CONCLUSION: Although we did not find evidence for the effects of tDCS on the HPA-system, our data reveal a crucial link between two critical predictors of mental health for the first time, and provide a solution to help rehabilitate EFT deficits.Trial registration: Netherlands National Trial Register identifier: ntr004..

BACKGROUND: Comparing Continuous With Flash Glucose Monitoring In Adults With Type 1 Diabetes (ALERTT1) examined whether switching from first-generation intermittently scanned continuous glucose monitoring (isCGM) without alerts to real-time continuous glucose monitoring (rtCGM) with alert functionality offers additional benefits to adults with type 1 diabetes. The extension of the randomised ALERTT1 trial assessed the effect of switching from isCGM to rtCGM up to 24 months. METHODS: In this 6-month, double-arm, parallel-group, non-masked, randomised, controlled trial, done across six hospitals in Belgium, 254 adults aged 18 years or older with type 1 diabetes previously using isCGM were randomly assigned (1:1) to rtCGM with alerts (intervention; n=127) or isCGM without alerts (control; n=127). Upon completion of the 6-month trial, the control group switched to rtCGM (is-rtCGM group), and the intervention group continued rtCGM (rt-rtCGM group). The extension focused on within-group changes in time in range (TIR; 3·9-10·0 mmol/L; primary outcome), HbA1c, time in clinically significant hypoglycaemia (

Allogeneic hematopoietic cell transplant (allo-HCT) provides the only potential route to long-term remission in patients diagnosed with blast phase transformation of mye-loproliferative neoplasm (BP-MPN). We report on a large, retrospective European Society for Blood and Marrow Transplantation registry-based study of BP-MPN patients undergoing allo-HCT. BP-MPN patients undergoing first allo-HCT between 2005 and 2019 were included. A total of 663 patients were included. With a median follow-up of 62 months, the estimated 3-year overall survival (OS) was 36% (95% confidence interval [CI], 32-36). Factors associated with lower OS were Karnofsky Performance Score (KPS) < 90 (hazard ratio [HR] 1.65, p < .001) and active disease at allo-HCT (HR 1.45, p < .001), whereas patients undergoing allo-HCT more recently associated with a higher OS (HR 0.96, p = .008). In a selected patient's population, the 3-year OS of patients undergoing allo-HCT in complete response (CR) and with a KPS >= 90 was 60%. KPS < 90 (HR 1.4, p = .001) and active disease (HR 1.44, p = .0004) were associated with a lower progression-free survival (PFS). Conversely, most recent allo-HCT associated with a higher PFS (HR 0.96, p = .008). Active dis-ease at allo-HCT (HR 1.34, p = .03) was associated with a higher cumulative inci-dence of relapse (RI) and allo-HCT in earlier calendar years (HR 0.96, p = .02) associated with a lower RI. Last, KPS < 90 (HR 1.91, p < .001), active disease (HR 1.74, p = .003) and allo-HCT from mismatched related donors were associated with a higher non-relapse mortality (HR 2.66, p = .003). In this large series of BPMPN patients, about one third were alive at 3 years after transplantation. Patients undergoing allo-HCT in the more recent era, with a KPS >= 90 and in CR at transplant had a better prognosis.

Background: The ramus artery contributes to the development of turbulence, which may influence computed tomography (CT) derived fractional flow reserve (FFR CT) even without coronary artery disease (CAD). The relationship between ramus-induced turbulence and FFR CT is unclear. Method and Results: A total of 120 patients with

This study aimed to assess, for the first time, how self-reported sleep, mental toughness, and reaction time are impacted by a professional padel tournament. In addition, we evaluated whether sex, age, and/or ranking play a role in this possible effect of a tournament on these variables. Twenty-three professional players (15 men, Mage = 24 ± 6 years; eight women, Mage = 21 ± 5 years) were evaluated on two occasions: (a) baseline, in a noncompetitive week and (b) postmeasure, the morning after an individual was eliminated from the tournament. The Pittsburgh Sleep Quality Index, the Mental Toughness Questionnaire, and the psychomotor vigilance task were used to evaluate the dependent variables. Wilcoxon tests or paired samples t tests were employed to assess the effect of participating in the tournament. To test correlations between variables, Pearson correlation coefficients (quantitative variables) or chi-square distributions (qualitative variables) were employed. Results showed that self-reported sleep (p < .01), mental toughness (p = .01), and reaction time (p = .04) were significantly impaired by the tournament. Exploring moderating variables, results showed that mental toughness did not correlate with sleep impairments (p > .05). In contrast, a nearly significant correlation between sleep impairments and higher reaction times was found (p = .066). No significant effects of age, sex, and ranking were observed. In conclusion, participating in a padel competition impairs the self-reported sleep, mental toughness, and reaction time of professional padel players. A trend toward a significant correlation between the competition-related impairment in sleep and reaction time was observed, whereas age, ranking, and sex were not found to be moderators of any of these impairments.

Prior studies suggest that the cerebellum contributes to the prediction of action sequences as well as the detection of social violations. In this dynamic causal modeling study, we explored the effective connectivity of the cerebellum with the cerebrum in processing social action sequences. A first model aimed to explore functional cerebello-cerebral connectivity when learning trait/stereotype-implying action sequences. We found many significant bidirectional connectivities between mentalizing areas of the cerebellum and the cerebrum including the temporo-parietal junction (TPJ) and medial prefrontal cortex (mPFC). Within the cerebrum, we found significant connectivity between the right TPJ and the mPFC, and between the TPJ bilaterally. A second model aimed to investigate cerebello-cerebral connectivity when conflicting information arises. We found many significant closed loops between the cerebellum and cerebral mentalizing (e.g. dorsal mPFC) and executive control areas (e.g. medial and lateral prefrontal cortices). Additional closed loops were found within the cerebral mentalizing and executive networks. The current results confirm prior research on effective connectivity linking the cerebellum with mentalizing areas in the cerebrum for predicting social sequences, and extend it to cerebral executive areas for social violations. Overall, this study emphasizes the critical role of cerebello-cerebral connectivity in understanding social sequences.

The robotic platform can overcome technical difficulties associated with laparoscopic colon surgery. Transitioning from laparoscopic right colectomy with extracorporeal anastomosis (ECA) to robotic right colectomy with intracorporeal anastomosis (ICA) is associated with a learning phase. This study aimed at determining the length of this learning phase and its associated morbidity. We retrospectively analyzed all laparoscopic right colectomies with ECA (n = 38) and robotic right colectomies with ICA (n = 67) for (pre)malignant lesions performed by a single surgeon between January 2014 and December 2020. CUSUM-plot analysis of total procedure time was used for learning curve determination of robotic colectomies. Non-parametric tests were used for statistical analysis. Compared to laparoscopy, the learning phase robotic right colectomies (n = 35) had longer procedure times (p

PURPOSE: The aim of the present study was to evaluate the role of ejection fraction (EF), left ventricular (LV) global longitudinal strain (LVGLS) and global constructive work (GCW) as prognostic variables in patients with cardiac amyloidosis (CA). METHODS: CA patients were retrospectively identified between 2015 and 2021 at a tertiary care hospital. Comprehensive clinical, biochemical, and imaging evaluation including two-dimensional (2D) echocardiography with myocardial work (MW) analysis was performed. A clinical combined endpoint was defined as all-cause mortality and heart failure readmission. RESULTS: 70 patients were followed for 16 (7-37) months and 37 (52.9%) reached the combined endpoint. Patient with versus without clinical events had a significantly lower LVEF (40.71% vs. 48.01%, p = 0.039), LVGLS (-9.26 vs. -11.32, p = 0.034) and GCW (1034.47mmHg% vs. 1424.86mmHg%, p = 0.011). Multivariable analysis showed that LVEF ( odds ratio (OR): 0.904; 95% confidence interval (CI): 0.839-0.973, p = 0.007), LVGLS ( OR: 0.620; 95% CI: 0.415-0.926, p = 0.020) and GCW ( OR: 0.995; 95% CI: 0.990-0.999, p = 0.016) were significant predictors of outcome, but the model including GCW had the best discriminative ability to predict the combined endpoint (C-index = 0.888). A GCW less than 1443mmHg% was able to predict the clinical endpoint with a sensitivity of 94% and a specificity of 64% (Area under the curve (AUC): 0.771 (95% CI: 0.581-0.961; p = 0.005)). CONCLUSION: In CA patients, GCW may be of additional prognostic value to LVEF and GLS in predicting heart failure hospitalization and all-cause mortality.

Purpose Having advanced cancer presents many challenges for patients and family caregivers. The FOCUS program is a psychoeducational nurse-led intervention, developed in the USA, to support dyads of patients with cancer and their family caregivers to live with the illness. The program includes a conversation manual and information resources for dyads. We aimed to develop a version of the program for dyads facing advanced cancer in six European countries. Method The Participatory and Iterative Process Framework for Language Adaptation (PIPFLA) was used to guide the translation of the program to the local contexts of Belgium, Denmark, Ireland, Italy, the Netherlands, and the UK. In several rounds, potential program users (e.g., nurses, clinicians, patients, family caregivers) and researchers from all six countries reviewed program materials and advised on adaptations. Results The PIPFLA process resulted in one European version of the program in different languages (FOCUS +). The FOCUS + conversation manual is uniform across all countries. The main adaptations included additional attention to both family caregiver and patient needs; more emphasis on self-management, advance care planning, and shared responsibilities; discussing the dyad’s outlook rather than optimism; addressing the role of nurses as educational rather than therapeutic; and more suggestions to refer dyads to health care professionals for specific care needs. The information resources for dyads were adapted to fit with local contexts. Conclusion The PIPFLA methodology is an efficient and effective framework to thoroughly translate and culturally adapt a complex USA-based program for use in six European countries in collaboration with end users.

BACKGROUND: Atrial fibrillation (AF) ablation strategy is associated with a non-negligible risk of complications and often requires repeat procedures (AF ablation track), implying repetitive exposure to procedural risk. OBJECTIVE: The purpose of this study was to develop and validate a model to estimate individualized cumulative risk of complications in patients undergoing the AF ablation track (Atrial Fibrillation TRAck Complication risK [AF-TRACK] calculator). METHODS: The model was derived from a multicenter cohort including 3762 AF ablation procedures in 2943 patients. A first regression model was fitted to predict the propensity for repeat ablation. The AF-TRACK calculator computed the risk of AF ablation track complications, considering the propensity for repeat ablation. Internal (cross-validation) and external (independent cohort) validation were assessed for discrimination capacity (area under the curve [AUC]) and goodness of fit (Hosmer-Lemeshow [HL] test). RESULTS: Complications (N = 111) occurred in 3.7% of patients (2.9% of procedures). Predictors included female sex, heart failure, sleep apnea syndrome, and repeat procedures. The model showed fair discrimination capacity to predict complications (AUC 0.61 [0.55-0.67]) and likelihood of repeat procedure (AUC 0.62 [0.60-0.64]), with good calibration (HL χ2 12.5; P = .13). The model maintained adequate discrimination capacity (AUC 0.67 [0.57-0.77]) and calibration (HL χ2 5.6; P = .23) in the external validation cohort. The validated model was used to create the Web-based AF-TRACK calculator. CONCLUSION: The proposed risk model provides individualized estimates of the cumulative risk of complications of undergoing the AF ablation track. The AF-TRACK calculator is a validated, easy-to-use, Web-based clinical tool to calibrate the risk-to-benefit ratio of this treatment strategy.

The opposable thumb provides both stability and mobility and is needed to accomplish different prehensile tasks. The trapezium is a complex bone, with a distal articular surface that is convex in the sagittal plane of the thumb and concave in the coronal plane of the thumb. The numerous additional articulations with the carpus and the oblique orientation to the main plane of the hand makes it difficult to evaluate the trapeziometacarpal joint using standard hand or wrist radiographic views. This review gives an overview of the different radiological views that have been described for the thumb with an emphasis on their historical origin and positioning during radiography. We also describe different measurements and classifications that can be obtained using different thumb radiographs.

Background: Palliative care services seek to improve the wellbeing of family carers of people living with serious and life-limiting illness. To help achieve this goal, systematic reviews have recommended priority areas for family carer research and the need to improve the quality of study design. Policy makers have also advocated for enhanced family carer support. However, there are specific methodological considerations and challenges in designing and conducting carer research conducted during the course of the serious illness trajectory and in bereavement. Aim: To develop strategies to improve the design and conduct of research with family carers. Design: Expert elicitation study using an adapted version of the ‘Identify, Discuss, Estimate and Aggregate’ elicitation protocol, supplemented with strategies from peer-reviewed literature. Setting/participants: Nine members of the management committee of the European Association for Palliative Care’s Reference group on family carer research, comprising international senior research academics in family caregiving. Results: A compilation of recommended strategies and checklist was created to: (a) help researchers plan research involving family carers focussing on: preparation, conduct and dissemination and (b) assist ethics committees and funding bodies to evaluate proposals. Conclusions: The strategies and checklist for conducting research with family carers may enhance methodologically rigorous research. Consequently, researchers, practitioners and policy makers will not only gain a more comprehensive understanding of the unmet needs of family carers but also promote the development of empirically sound interventions.

Contains fulltext : 287798.pdf (Publisher’s version ) (Open Access) The Family Perceptions of Physician-Family Caregiver Communication scale (FPPFC) was developed to assess quality of physician-family end-of-life communication in nursing homes. However, its validity has been tested only in the USA and the Netherlands. The aim of this paper is to evaluate the FPPFC construct validity and its reliability, as well as the psychometric characteristics of the items comprising the scale. Data were collected in cross-sectional study in Belgium, Finland, Italy, the Netherlands and Poland. The factorial structure was tested in confirmatory factor analysis. Item parameters were obtained using an item response theory model. Participants were 737 relatives of nursing home residents who died up to 3 months prior to the study. In general, the FPPFC scale proved to be a unidimensional and reliable measure of the perceived quality of physician-family communication in nursing home settings in all five countries. Nevertheless, we found unsatisfactory fit to the data with a confirmatory model. An item that referred to advance care planning performed less well in Poland and Italy than in the Northern European countries. In the item analysis, we found that with no loss of reliability and with increased coherency of the item content across countries, the full 7-item version can be shortened to a 4-item version, which may be more appropriate for international studies. Therefore, we recommend use of the brief 4-item FPPFC version by nursing home managers and professionals as an evaluation tool, and by researchers for their studies as these four items confer the same meaning across countries. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10433-022-00742-x.

The adoption of Directive 2010/63/EU on the protection of animals used for scientific purposes has given a major push to the formation of Three Rs initiatives in the form of centres and platforms. These centres and platforms are dedicated to the so-called Three Rs, which are the Replacement, Reduction and Refinement of animal use in experiments. ATLA’s 50th Anniversary year has seen the publication of two articles on European Three Rs centres and platforms. The first of these was about the progressive rise in their numbers and about their founding history; this second part focuses on their current status and activities. This article takes a closer look at their financial and organisational structures, describes their Three Rs focus and core activities (dissemination, education, implementation, scientific quality/translatability, ethics), and presents their areas of responsibility and projects in detail. This overview of the work and diverse structures of the Three Rs centres and platforms is not only intended to bring them closer to the reader, but also to provide role models and show examples of how such Three Rs centres and platforms could be made sustainable. The Three Rs centres and platforms are very important focal points and play an immense role as facilitators of Directive 2010/63/EU ‘on the ground’ in their respective countries. They are also invaluable for the wide dissemination of information and for promoting the implementation of the Three Rs in general.

Intrinsic capacity, a crucial concept in healthy ageing, is defined by WHO as “the composite of all the physical and mental capacities that an individual can draw on at any point in time”. Vitality capacity is considered the underlying physiological determinant of intrinsic capacity. To advance the measurement and monitoring of vitality capacity, a working group of WHO staff members and twenty experts representing six WHO regions was convened to discuss and clarify the attributes of vitality capacity and to develop a clear working definition of the concept. Potential biomarkers to measure vitality capacity were identified, and the following consensual working definition was developed: vitality capacity is a physiological state (due to normal or accelerated biological ageing processes) resulting from the interaction between multiple physiological systems, reflected in (the level of) energy and metabolism, neuromuscular function, and immune and stress response functions of the body.

Objectives Clinical decision-making in emergency medicine is under constant pressure from demand and performance requirements, with blood tests being a fundamental part of this. However, the preanalytical process has received little attention. Therefore, this study aimed to investigate the quality of preanalytical phase processes in European emergency departments (EDs) from the perspectives of the three main providers: clinicians, nurses, and laboratory specialists. Methods This online survey, distributed among European EDs and laboratories, was supported by the European Society for Emergency Nursing (EUSEN), European Society for Emergency Medicine (EuSEM), and the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM). The size of the centres, the European region, the responder’s profession and the country’s economic condition were used as co-variables. Results We included 376 responses from all ED-related professions from 306 European centres. In 66.9% of all ED visits, at least one blood test was performed. Tests were requested mostly by nurses (44.6%) using electronic Order/Entry systems (65.4%). Only a minority (19%) reported not using laboratory quality indicators (QIs). Most responders defined the TAT starting point “when the laboratory receives the sample” (66.1%), defining the goal to be “less than 60 min” (69.9%), but only 42.4% of the centres estimated achieving this goal. Conclusions Our survey illustrates the current situation on preanalytical blood sample processing in European EDs from the clinical and laboratory perspectives. The results emphasise the importance of the IT infrastructure and QI usage in this process and highlight some differences between European regions.

Abstract Raised blood pressure (BP) is the leading cause of preventable death in the world. Yet, its global prevalence is increasing, and it remains poorly detected, treated, and controlled in both high- and low-resource settings. From the perspective of members of the International Society of Hypertension based in all regions, we reflect on the past, present, and future of hypertension care, highlighting key challenges and opportunities, which are often region-specific. We report that most countries failed to show sufficient improvements in BP control rates over the past three decades, with greater improvements mainly seen in some high-income countries, also reflected in substantial reductions in the burden of cardiovascular disease and deaths. Globally, there are significant inequities and disparities based on resources, sociodemographic environment, and race with subsequent disproportionate hypertension-related outcomes. Additional unique challenges in specific regions include conflict, wars, migration, unemployment, rapid urbanization, extremely limited funding, pollution, COVID-19-related restrictions and inequalities, obesity, and excessive salt and alcohol intake. Immediate action is needed to address suboptimal hypertension care and related disparities on a global scale. We propose a Global Hypertension Care Taskforce including multiple stakeholders and societies to identify and implement actions in reducing inequities, addressing social, commercial, and environmental determinants, and strengthening health systems implement a well-designed customized quality-of-care improvement framework.

Background: Frailty and hypertension are interrelated, but it remains unclear whether this relationship is modified by antihypertensive drugs. Methods and results: A systematic review of PubMed and Web of Science databases was performed to review the influence of hypertension management on preventing the occurrence or progression of frailty in older people aged 65 and over. Studies providing information on this association regardless of the study setting, or definition of hypertension and frailty were included. Among the initial 2298 articles identified, 7 were included in the review. Three observational studies assessed the association between frailty and hypertension. Two of them reported no relationship between Aldosterone Antagonists use and frailty prevention. No relationship between BP and incidence frailty after adjustment for hypertension treatment was observed in two other articles. An indirect relationship was reported in the RCTs included. Higher AT11RaAb levels (control group), can lead to a generalized weakness/frailty risk shown by a decrease in grip strength (r = –0.57, p < 0.005) and walking speed (r = – 0.47, p < 0.005). No significant differences between int-hypertensive intervention and control were observed in frailty status after a 12-weeks follow-up after applying three different frailty measurement tools in the other RCT. Conclusions: Based on the results of this systematic review we conclude that BP and frailty occur together but whether the treatment with anti-hypertensive drugs modifies this relationship remains unclear and needs to be further investigated.

Experts have highlighted the importance of coaches knowing the level of mental fatigue (MF) induced by different tasks. This study aimed to compare the mentally fatiguing nature of cognitive, physical, and combined tasks and, additionally, assess the effect of different moderating variables on MF. Twenty-three physically active (16 males: Mage = 24 years; seven females: Mage = 22.57 years) participants performed three experimental sessions: (a) physically fatiguing: 30 min of cycloergometer work (at 65%–75% of maximum heart rate), (b) mentally fatiguing: 30 min of an incongruent Stroop task, and (c) mixed fatiguing: 30 min of combining the physically and mentally fatiguing protocols. Subjective MF (visual analog scale), reaction time (psychomotor vigilance task), and cognitive performance (Stroop) were measured throughout the different protocols. Results showed significant increments in subjective MF after all tasks, with the mental and mixed protocols showing significantly higher increases. Only the mentally fatiguing protocol caused significant impairments in reaction time. No significant effects of sex, years of experience, or degree of mental toughness were observed. These results suggest that the use of all these tasks, and especially the mentally fatiguing exercises, should be avoided immediately prior to competitions due to the negative consequences of MF on performance. Moreover, this effect seems to be independent of the sex, years of experience, or mental toughness of athletes.

BACKGROUND: In the phase II multicohort CheckMate 142 study, nivolumab plus low-dose (1 mg/kg) ipilimumab provided robust and durable clinical benefit with a manageable safety profile in previously treated patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) at 13.4- and 25.4-month median follow-up (Overman MJ, Lonardi S, Wong KYM et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 2018;36:773-779. Overman MJ, Lonardi S, Wong KYM, et al. Nivolumab plus low-dose ipilimumab in previously treated patients with microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: long-term follow-up. J Clin Oncol. 2019;37:635). Here, we present results from the 4-year follow-up of these patients. PATIENTS AND METHODS: Patients received nivolumab (3 mg/kg) plus low-dose (1 mg/kg) ipilimumab every 3 weeks (four doses) followed by nivolumab (3 mg/kg) every 2 weeks until disease progression. Primary endpoint was investigator-assessed objective response rate (ORR; as per RECIST version 1.1). RESULTS: A total of 119 patients were treated; 76% had ≥2 prior lines of therapy. Median follow-up was 50.9 months (range 46.9-62.7 months). Median duration of therapy was 24.9 months [95% confidence interval (CI) 15.8-33.2 months]. Investigator-assessed ORR increased from 55% (95% CI 45% to 64%) at 13.4 months to 65% (95% CI 55% to 73%) at 50.9 months with a disease control rate of 81% (95% CI 72% to 87%). The complete response rate increased from 3% at 13.4 months to 13% at 50.9 months. Partial responses were observed in 52% of patients; 21% had stable disease, and 12% had progressive disease. Median time to response was 2.8 months (range 1.1-37.1 months), and median duration of response was not reached (range 1.4+ to 58.0+ months). At data cut-off, 37 (48%) patients had ongoing responses. Median progression-free survival was not reached [95% CI 38.4 months-not estimable (NE)], and median overall survival was not reached (95% CI NE). Grade 3-4 treatment-related adverse events (TRAEs) were observed in 32% of patients; 13% of patients had any-grade TRAEs leading to discontinuation. CONCLUSIONS: The results confirm long-term benefit of nivolumab plus low-dose ipilimumab for previously treated patients with MSI-H/dMMR mCRC. The safety profile was manageable with no new safety signals. ispartof: ANNALS OF ONCOLOGY vol:33 issue:10 pages:1052-1060 ispartof: location:England status: published

Previous studies have shown that differences in experimental design factors may alter the potency of genotoxic compounds in in vitro genotoxicity tests. Most of these studies used traditional statistical methods based on the lowest observed genotoxic effect levels, whereas more appropriate methods, such as the benchmark dose (BMD) approach, are now available to compare genotoxic potencies under different test conditions. We therefore investigated the influence of two parameters, i.e. cell type and exposure duration, on the potencies of two known genotoxicants [aflatoxin B1 and ethyl methanesulfonate (EMS)] in the in vitro micronucleus (MN) assay and comet assay (CA). Both compounds were tested in the two assays using two cell types (i.e. CHO-K1 and TK6 cells). To evaluate the effect of exposure duration, the genotoxicity of EMS was assessed after 3 and 24 h of exposure. Results were analyzed using the BMD covariate approach, also referred to as BMD potency ranking, and the outcome was compared with that of more traditional statistical methods based on lowest observed genotoxic effect levels. When comparing the in vitro MN results obtained in both cell lines with the BMD covariate approach, a difference in potency was detected only when EMS exposures were conducted for 24 h, with TK6 cells being more sensitive. No difference was observed in the potency of both EMS and aflatoxin B1 in the in vitro CA using both cell lines. In contrast, EMS was more potent after 24 h exposure compared with a 3 h exposure under all tested conditions, i.e. in the in vitro MN assay and CA in both cell lines. Importantly, for several of the investigated factors, the BMD covariate method could not be used to confirm the differences in potencies detected with the traditional statistical methods, thus highlighting the need to evaluate the impact of experimental design factors with adequate approaches.

Purpose In hospital settings, patients, visitors, and staff engage in many interactions outside formal clinical encounters. Whilst many of these may be inconsequential, others contribute significantly to how patients and their carers experience cancer and its treatment. This article aims to explore the experiences and significance of interactions that occur outside formal clinical encounters in hospital cancer treatment settings. Methods Semi-structured interviews were conducted with cancer patients, carers, and staff recruited from two hospital sites and cancer support groups. Hermeneutic phenomenology informed lines of questioning and data analysis. Results Thirty-one people participated in the study: 18 cancer patients, four carers, and nine staff members. The experiences of informal interactions were grouped into three themes: connecting, making sense, and enacting care. The participants described how these encounters allowed connection with others in the hospital spaces, facilitating a sense of belonging, normality, and self-worth. Through these interactions, individuals participated in making sense of their experiences, to better anticipate the decisions and challenges that might lie ahead. By connecting with other individuals, they cared for others and felt cared for themselves, and were able to learn from, teach, and support each other. Conclusions Outside the confines of the clinical discourses participants negotiate terms of engagement, sharing of information, expertise, and their own personal stories that they may employ to contribute to the individuals around them. These interactions occur within a loose and evolving framework of social interactions, an ‘informal community’, in which cancer patients, carers, and staff members play active and meaningful roles.

Background and purpose: Head and neck cancer (HNC) patients experiencing anatomical changes during their radiotherapy (RT) course may benefit from adaptive RT (ART). We investigated the sensitivity of an electronic portal imaging device (EPID)-based in-vivo dosimetry (EIVD) system to detect patients that require ART and identified its limitations. Materials and methods: A retrospective study was conducted for 182 HNC patients: laryngeal cancer without elective lymph nodes (group A), postoperative RT (group B) and primary RT including elective lymph nodes (group C). The effect of anatomical changes on the dose distribution and volumetric changes was quantified. The receiver operating characteristic curve was used to obtain the optimal cut-off value for the gamma passing rate (%GP) with a dose difference of 3% and a distance to agreement of 3 mm. Results: Fifty HNC patients receiving ART were analyzed: 1 in group A, 10 in group B and 39 in group C. Failed fractions (FFs) occurred in 1/1, 6/10 and 23/39 cases before ART in group A, B and C respectively. In the four cases in group B without FFs, only minor dosimetric changes were observed. One of the cases in group C without FFs had significant dosimetric changes (false negative). Three cases received ART because of clinical reasons that cannot be detected by EIVD. The optimal cut-off value for the %GP was 95%/95.2% for old/new generation machines respectively. Conclusion: EIVD combined with 3D imaging techniques can be synergistic in the detection of anatomical changes in HNC patients who benefit from ART.

INTRODUCTION: Minimal invasive Robotic Assisted Cochlear Implant Surgery (RACIS) is a keyhole surgery by definition. It is therefore not possible to visualize the electrode array during insertion in the scala tympani. Hitherto, surgeons visualised the round window via the external auditory canal by folding over the tympanic membrane. However, the opening of a tympanomeatal flap is not minimal invasive and is especially in conventional cochlear implantation surgery not even necessary. Here we prove that image guided and robot assisted surgery can also allow correct electrode array insertion without opening the tympanomeatal flap. AIM: The aim is to report the first experience of robotic cochlear implantation surgery fully based on image guided surgery and without the opening of a tympanomeatal flap for electrode array insertion. INTERVENTION: RACIS with a straight flexible lateral wall electrode. PRIMARY OUTCOME MEASUREMENTS: Electrode cochlear insertion depth with RACIS and autonomous inner ear access withfull electrode insertion of a flexible lateral wall electrode array. SECONDARY OUTCOME MEASUREMENTS: The audiological outcome in terms of mean hearing thresholds. CONCLUSION: After a series of 33 cases and after fine-tuning the insertion angles and yet another new version of planning software to depict the round window approach, a new clinical routine for inserting electrodes fully based on image guided surgery without opening a tympanomeatal flap was developed in robotic-assisted cochlear implant surgery.

ObjectiveTo report the parent-reported behavioural outcomes of infants included in the Systemic Hydrocortisone To Prevent Bronchopulmonary Dysplasia in preterm infants study at 2 years’ corrected age (CA).DesignRandomised placebo-controlled trial.SettingDutch and Belgian neonatal intensive care units.PatientsInfants born InterventionInfants were randomly assigned to a 22-day course of systemic hydrocortisone (cumulative dose 72.5 mg/kg; n=182) or placebo (n=190).Main outcome measuresParent-reported behavioural outcomes at 2 years’ CA assessed with the Child Behavior Checklist (CBCL 1½−5).ResultsParents completed the CBCL of 183 (70% (183/262)) infants (hydrocortisone group, n=96; placebo group, n=87). Multiple imputation was used to account for missing data. Infants with critically elevated T-scores (>55) were found in 22.9%, 19.1% and 29.4% of infants for total, internalising and externalising problems, respectively; these scores were not significantly different between groups (mean difference −1.52 (95% CI −4.00 to 0.96), −2.40 (95% CI −4.99 to 0.20) and −0.81 (95% CI −3.40 to 1.77), respectively). In the subscales, we found a significantly lower T-score for anxiety problems in the hydrocortisone group (mean difference −1.26, 95% CI −2.41 to –0.12).ConclusionThis study found high rates of behaviour problems at 2 years’ CA following very preterm birth, but these problems were not associated with hydrocortisone treatment initiated between 7 and 14 days after birth in ventilated preterm infants.Trial registration numberNTR2768; EudraCT 2010-023777-19.

AIMS: This systematic review and meta-analysis evaluates the additional effect of exercise to hypocaloric diet on body weight, body composition, glycaemic control and cardio-respiratory fitness in adults with overweight or obesity and type 2 diabetes. METHODS: Embase, Medline, Web of Science and Cochrane Central databases were evaluated, and 11 studies were included. Random-effects meta-analysis was performed on body weight and measures of body composition and glycaemic control, to compare the effect of hypocaloric diet plus exercise with hypocaloric diet alone. RESULTS: Exercise interventions consisted of walking or jogging, cycle ergometer training, football training or resistance training and duration varied from 2 to 52 weeks. Body weight and measures of body composition and glycaemic control decreased during both the combined intervention and hypocaloric diet alone. Mean difference in change of body weight (-0.77 kg [95% CI: -2.03; 0.50]), BMI (-0.34 kg/m 2 [95% CI: -0.73; 0.05]), waist circumference(-1.42 cm [95% CI: -3.84; 1.00]), fat-free mass (-0.18 kg [95% CI: -0.52; 0.17]), fat mass (-1.61 kg [95% CI: -4.42; 1.19]), fasting glucose (+0.14 mmol/L [95% CI: -0.02; 0.30]), HbA 1c (-1 mmol/mol [95% CI: -3; 1], -0.1% [95% CI: -0.2; 0.1]) and HOMA-IR (+0.01 [95% CI: -0.40; 0.42]) was not statistically different between the combined intervention and hypocaloric diet alone. Two studies reported VO 2max and showed significant increases upon the addition of exercise to hypocaloric diet. CONCLUSIONS: Based on limited data, we did not find additional effects of exercise to hypocaloric diet in adults with overweight or obesity and type 2 diabetes on body weight, body composition or glycaemic control, while cardio-respiratory fitness improved.

BackgroundPreterm infants commonly receive red blood cell (RBC), platelet and fresh frozen plasma (FFP) transfusions. The aim of this Neonatal Transfusion Network survey was to describe current transfusion practices in Europe and to compare our findings to three recent randomised controlled trials to understand how clinical practice relates to the trial data.MethodsFrom October to December 2020, we performed an online survey among 597 neonatal intensive care units (NICUs) caring for infants with a gestational age (GA) of ResultsResponses from 343 NICUs (response rate: 57%) are presented and showed substantial variation in clinical practice. For RBC transfusions, 70% of NICUs transfused at thresholds above the restrictive thresholds tested in the recent trials and 22% below the restrictive thresholds. For platelet transfusions, 57% of NICUs transfused at platelet count thresholds above 25×109/L in non-bleeding infants of GA of 9/L threshold was associated with a lower risk of harm in a recent trial. FFP transfusions were administered for coagulopathy without active bleeding in 39% and for hypotension in 25% of NICUs. Transfusion volume, duration and rate varied by factors up to several folds between NICUs.ConclusionsTransfusion thresholds and aspects of administration vary widely across European NICUs. In general, transfusion thresholds used tend to be more liberal compared with data from recent trials supporting the use of more restrictive thresholds. Further research is needed to identify the barriers and enablers to incorporation of recent trial findings into neonatal transfusion practice.

Due to a combination of rapid disease progression and the lack of curative treatment options, hepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide. Infiltrated, monocyte-derived, tumor-associated macrophages are known to play a role in HCC pathogenesis, but the involvement of Kupffer cells (KCs) remains elusive. Here, we used the Clec4F-diphteria toxin receptor transgenic mouse model to specifically investigate the effect of KC depletion on HCC initiation, progression and neoplastic growth following liver resection. For this purpose, several HCC mouse models with varying underlying etiologies were used and partial hepatectomy was performed. Our results show that in HCC, developed on a fibrotic or non-alcoholic steatohepatitis background, depletion of embryonic KCs at the onset of HCC induction and the subsequent replacement by monocyte-derived KCs does not affect the tumor burden, tumor microenvironment or the phenotype of isolated KCs at end-stage disease. In non-chronic liver disease-associated diethylnitrosamine-induced HCC, ablation of Clec4F+ KCs did not alter tumor progression or neoplastic growth following liver resection. Our results show that temporal ablation of resident KCs does not impact HCC pathogenesis, neither in the induction phase nor in advanced disease, and indicate that bone marrow-derived KCs are able to swiftly repopulate the available KC niche and adopt their phenotype.

Aim: The aim of the study was to develop a deep convolutional neural networks (CNNs) algorithm for automated assessment of stool consistency from diaper photographs and test its performance under real-world conditions. Methods: Diaper photographs were enrolled via a mobile phone application. The stool consistency was assessed independently according to the Brussels Infant and Toddler Stool Scale (BITSS) by paediatricians. These images were randomised into a training data set and a test data set. After training and testing, the new algorithm was used under real-world conditions by parents. Results: There was an overall agreement of 92.9% between paediatricians and the CNN-generated algorithm. Post hoc classification into the validated 4 categories of the BITSS yielded an agreement of 95.4%. Spearman correlation analysis across the ranking of 7 BITSS photographs and validated 4 categories showed a significant correlation of rho = 0.93 (95% CI, 0.92, 0.94; p < 0.001) and rho = 0.92 (95% CI, 0.90, 0.93; p < 0.001), respectively. The real-world application yielded further insights into changes in stool consistency between age categories and mode of feeding. Conclusion: The new CNN-based algorithm is able to reliably identify stool consistency from diaper photographs and may support the communication between parents and paediatricians.

Objective: Congenital malformations are frequently diagnosed prenatally even at a viable stage. No adequate registration of incidence and characteristics of late termination of pregnancy (TOP) or abortion for medical reasons exists in Flanders. Methods: Nationwide mortality follow-back survey sent to physicians signing death certificates of all stillbirths for 22 weeks gestation onward (September 2016–December 2017) in Flanders, Belgium. Questions measured whether late TOP preceded stillbirth, and which clinical and sociodemographic characteristics were indicated. Questionnaire data were linked with sociodemographic information from death certificates. Results: Response rate was 56% (203/366). 38% of stillbirths (77/203) concerned late TOP. In 88.3% of late TOPs, physicians classified congenital anomalies of the foetus as serious or very serious (incompatibility with life outside the womb or severe neurological or physical impairment). In 26% of cases, late TOP was first suggested by the physician rather thanspontaneously requested by parents (73%). 88% of late TOPs were discussed in open team meetings. Conclusions: 2/5 stillbirths were preceded by late TOP, indicating severe underreportation by existing registrations and a dire need for adequate registration methods. Although late TOP was most often explicitly requested by parents, in ¼ cases termination was suggested first by physicians. Parents are sometimes hesitant to bring up late TOP themselves, indicating that TOP should always be counselled as an equivalent option.

BACKGROUND: Functioning is considered a third indicator of health and a key outcome in rehabilitation. A universal practical tool for collecting functioning information is essential. This tool would be ideally based on the International Classification of Functioning, Disability and Health. AIM: To report the results of the development of country/language-specific versions of an ICF-based clinical tool in six European countries. DESIGN: Consensus process. SETTING: Expert conferences. POPULATION: Multi-professional group of rehabilitation professionals in six European countries. METHODS: 1) Developed an initial proposal by translating the published English-language version of the simple descriptions into the targeted language ; 2) conducted a multi-stage consensus conference to finalize the descriptions ; 3) employed a three-stage multi-professional expert panel translation back to English. The consensus conference model was modified for geographically large countries. RESULTS: Croatian, Flemish/Dutch, Greek, Polish, and Turkish versions were produced. CONCLUSIONS: The creation of the country/language-specific simple descriptions is a significant part of the “system-wide implementation of the ICF” initiative that will pave the way for the implementation of the ICF in national health systems. CLINICAL REHABILITATION IMPACT: The practical ICF-based clinical tool with country/language specific versions for standardized reporting of functioning will serve as a means of integrating functioning information in national health systems and additionally for monitoring the effects of rehabilitation interventions.