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BACKGROUND: Post-transplant anaemia and reduced muscle mass and strength are highly prevalent in kidney transplant recipients (KTRs). Decreased haemoglobin levels, a marker of anaemia, could adversely affect muscle mass and strength through multiple mechanisms, among others, through diminished tissue oxygenation. We aimed to investigate the association between haemoglobin levels with muscle mass and strength in KTRs.METHODS: We included stable KTRs from the TransplantLines Biobank and Cohort study with a functional graft ≥1 year post-transplantation. Muscle mass was assessed using 24 h urinary creatinine excretion rate (CER) and bioelectrical impedance analysis (BIA). Muscle strength was assessed with a handgrip strength test using a dynamometer and, in a subgroup (n = 290), with the five-times sit-to-stand (FTSTS) test. We used multivariable linear and logistic regression analyses to investigate the associations of haemoglobin levels with muscle mass and strength.RESULTS: In 871 included KTRs [median age 58 (interquartile range (IQR), 48-66)] years; 60% men; eGFR 51 ± 18 mL/min/1.73 m2 ) who were 3.5 (1.0-10.2) years post-transplantation, the mean serum haemoglobin level was 13.9 ± 1.8 g/dL in men and 12.8 ± 1.5 g/dL in women. Lower haemoglobin levels were independently associated with a lower CER (std. β = 0.07, P = 0.01), BIA-derived skeletal muscle mass (std. β = 0.22, P < 0.001), handgrip strength (std. β = 0.15, P < 0.001), and worse FTSTS test scores (std. β = -0.17, P = 0.02). KTRs in the lowest age-specific and sex-specific quartile of haemoglobin levels had an increased risk of being in the worst age-specific and sex-specific quartile of CER (fully adjusted OR, 2.09; 95% CI 1.15-3.77; P = 0.02), handgrip strength (fully adjusted OR, 3.30; 95% CI 1.95-5.59; P < 0.001), and FTSTS test score (fully adjusted OR, 7.21; 95% CI 2.59-20.05; P < 0.001).CONCLUSIONS: Low haemoglobin levels are strongly associated with decreased muscle mass and strength in KTRs. Future investigation will need to investigate whether maintaining higher haemoglobin levels may improve muscle mass and strength in KTRs.

Objective. The COVID-19-pandemic caused drastic healthcare changes worldwide. To date, the impact of these changes on gynecological cancer healthcare is relatively unknown. This study aimed to assess the impact of the COVID-19-pandemic on surgical gynecological-oncology healthcare. Methods. This population-based cohort study included all surgical procedures with curative intent for gynecological malignancies, registered in the Dutch Gynecological Oncology Audit, in 2018-2020. Four periods were identified based on COVID-19 hospital admission rates: 'Pre-COVID-19', 'Firstwave', 'Interimperiod', and'Second wave'. Surgical volume, perioperative care processes, and postoperative outcomes from 2020 were compared with 2018-2019. Results. A total of 11,488 surgical procedureswere analyzed. For cervical cancer, surgical volume decreased by 17.2% in 2020 compared to 2018-2019 (mean 2018-2019: n= 542.5, 2020: n= 449). At nadir (interimperiod), only 51% of the expected cervical cancer procedures were performed. For ovarian, vulvar, and endometrial cancer, volumes remained stable. Patients with advanced-stage ovarian cancer more frequently received neoadjuvant chemotherapy in 2020 compared to 2018-2019 (67.7% (n = 432) vs. 61.8% (n = 783), p = 0.011). Median time to first treatmentwas significantly shorter in all four malignancies in 2020. For vulvar and endometrial cancer, the length of hospital staywas significantly shorter in 2020. No significant differences in complicated course and 30-day-mortality were observed. Conclusions. The COVID-19-pandemic impacted surgical gynecological-oncology healthcare: in 2020, surgical volume for cervical cancer dropped considerably, waiting time was significantly shorter for all malignancies, while neoadjuvant chemotherapy administration for advanced-stage ovarian cancer increased. The safety of perioperative healthcare was not negatively impacted by the pandemic, as complications and 30-day-mortality remained stable. (C) 2022 The Authors. Published by Elsevier Inc.

Automatic cervix-uterus segmentation of the clinical target volume (CTV) on CT and cone-beam CT (CBCT) scans is challenged by the limited visibility and the non-anatomical definition of certain border regions. We study the potential performance gain of convolutional neural networks by regulating the segmentation predictions as diffeomorphic deformations of a segmentation prior.We introduce a 3D convolutional neural network that segments the target scan by joint voxel-wise classification and the registration of a given prior. We compare this network to two other 3D baseline models: One treating segmentation as a classification problem (segmentation-only), the other as a registration problem (deformation-only). For reference and to highlight the benefits of a 3D model, these models are also benchmarked against a 2D segmentation model. Network performances are reported for CT and CBCT segmentation of the cervix-uterus CTV. We train the networks on the data of 84 patients. The prior is provided by the CTV segmentation of a planning CT. Repeat CT or CBCT scans constitute the target scans to be segmented.All 3D models outperformed the 2D segmentation model. For CT segmentation, combining classification and registration in the proposed joint model proved beneficial, achieving a Dice score of 0.87 and a mean squared error (MSE) of the surface distance below 1.7 mm. No such synergy was observed for CBCT segmentation, for which the joint and the deformation-only model performed similarly, achieving a Dice score of about 0.80 and an MSE surface distance of 2.5 mm. However, the segmentation-only model performed notably worse in this low contrast regime. Visual inspection revealed that this performance drop translated into geometric inconsistencies between the prior and target segmentation. Such inconsistencies were not observed for the deformation-based models.Constraining the solution space of admissible segmentation predictions to those reachable by a diffeomorphic deformation of the prior proved beneficial as it improved geometric consistency. Especially for CBCT, with its poor soft-tissue contrast, this type of regularization becomes important as shown by quantitative and qualitative evaluation.

Purpose To evaluate perceived access to health care and preferences for health care provision among patients (being) treated for breast cancer during the COVID-19 pandemic. Methods Longitudinal study within the prospective, multicenter UMBRELLA cohort of patients (being) treated for breast cancer. All cohort participants enrolled in UMBRELLA between October 2013 and November 2020 were sent a COVID-19-specific survey during the first and second wave of the COVID-19 pandemic, i.e., April 2020 and November 2020, respectively. Results In total, 1106 (69.3%) and 822 (50.9%) cohort participants completed the survey in the first and second wave, respectively. The proportion of patients experiencing that their treatment or follow-up care was affected due to COVID-19 decreased from 28.4% (n = 198) in April 2020 to 14.8% (n = 103) in November 2020. Throughout the pandemic, one or more hospital consultations were postponed in 10.0% (n = 82) of all patients and changed into a teleconsultation in 23.1% (n = 190). The proportion of patients who experienced a higher threshold to contact their general practitioner due to COVID-19 decreased from 29.9% (n = 204) in the first wave to 20.8% (n = 145) in the second wave. In-person consultations remained most preferred in 35.2% (n = 289) of all patients. Nearly half of all patients (48.3%, n = 396) indicated that telehealth would be a useful alternative for in-person consultations in future. Conclusion Perceived access to health care has improved substantially throughout the pandemic. Digital care is well received by patients (being) treated for breast cancer. Supplementary Information The online version contains supplementary material available at 10.1007/s10549-021-06458-3.

OBJECTIVES: This systematic review and meta-analysis was designed to determine the overall mean blood pressure and prevalence of hypertension among a representative sample of adults living with cerebral palsy by combining individual participant data. Additional objectives included estimating variations between subgroups and investigating potential risk factors for hypertension. METHODS: Potential datasets were identified by literature searches for studies published between January 2000 and November 2017 and by experts in the field. Samples of adults with cerebral palsy (n ≥ 10, age ≥ 18 years) were included if blood pressure data, cerebral palsy-related factors (e.g. cerebral palsy subtype), and sociodemographic variables (e.g. age, sex) were available. Hypertension was defined as at least 140/90 mmHg and/or use of antihypertensive medication. RESULTS: We included data from 11 international cohorts representing 444 adults with cerebral palsy [median (IQR) age of the sample was 29.0 (23.0-38.0); 51% men; 89% spastic type; Gross Motor Function Classification System levels I-V]. Overall mean SBP was 124.9 mmHg [95% confidence interval (CI) 121.7-128.1] and overall mean DBP was 79.9 mmHg (95% CI 77.2-82.5). Overall prevalence of hypertension was 28.7% (95% CI 18.8-39.8%). Subgroup analysis indicated higher blood pressure levels or higher prevalence of hypertension in adults with cerebral palsy above 40 years of age, men, those with spastic cerebral palsy or those who lived in Africa. BMI, resting heart rate and alcohol consumption were risk factors that were associated with blood pressure or hypertension. CONCLUSION: Our findings underscore the importance of clinical screening for blood pressure in individuals with cerebral palsy beginning in young adulthood.

Background. Decision making regarding adjuvant therapy for high-risk endometrial cancer is complex. The aim of this study was to determine patients' and clinicians' minimally desired survival benefit to choose chemoradiotherapy over radiotherapy alone. Moreover, influencing factors and importance of positive and negative treatment effects (i.e. attribute) were investigated.Methods. Patients with high-risk endometrial cancer treated with adjuvant pelvic radiotherapy with or without chemotherapy and multidisciplinary gynaecologic oncology clinicians completed a trade-off questionnaire based on PORTEC-3 trial data.Results. In total, 171 patients and 63 clinicians completed the questionnaire. Median minimally desired benefit to make chemoradiotherapy worthwhile was significantly higher for patients versus clinicians (10% vs 5%, p = 0.02). Both patients and clinicians rated survival benefit most important during decision making, followed by long-term symptoms. Older patients (OR 0.92 [95%CI 0.87 & ndash;0.97]; p = 0.003) with comorbidity (OR 0.34 [95% CI 0.12 & ndash;0.89]; p = 0.035) had lower preference for chemoradiotherapy, while patients with better numeracy skills (OR 1.2 [95%CI 1.05 & ndash;1.36], p = 0.011) and chemoradiotherapy history (OR 25.0 [95%CI 8.8 & ndash;91.7]; p < 0.001) had higher preference for chemoradiotherapy.& nbsp;Conclusions. There is a considerable difference in minimally desired survival benefit of chemoradiotherapy in high-risk endometrial cancer among and between patients and clinicians. Overall, endometrial cancer patients needed higher benefits than clinicians before preferring chemoradiotherapy.(c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).

Objective To determine differences in clinical presentation and disease progression between patients with dementia due to AD with visually normal and abnormal EEG recordings. We hypothesized that patients with normal electroencephalographs (EEGs) are a representation of the heterogeneity of AD. We expected this group to have a phenotype with relatively predominant hippocampal atrophy, memory deficits, and a slower disease progression. Methods Patients were included based on diagnosis of dementia due to AD, positive amyloid and tau cerebrospinal fluid (CSF) biomarkers, and the availability of EEG recordings. Patients were categorized in groups of normal (N = 208) and abnormal (N = 336) EEG recordings based on visual assessment by experienced neurophysiologists. At baseline demographics, cognitive, MRI, and CSF measures were compared between groups. Cognitive data from follow‐up visits were assessed by linear mixed‐effects models (LMMs), and corrected for baseline value, sex, age, and educational level, to compare cognitive deterioration over time between groups. Results About 1 in 4.5 patients with AD dementia had a visually normal EEG and this group showed better overall cognitive performance compared to the abnormal group, where memory was the most prominent affected domain. The normal group showed less global and parietal but similar medial temporal atrophy. Follow‐up data showed a slower deterioration on all tested cognitive domains in the normal EEG group. Interpretation Patients with dementia due to AD and visually normal EEG recordings showed a milder clinical presentation and had a milder disease progression compared to patients with an abnormal EEG. These results provide evidence of clinical and biological heterogeneity within AD dementia.

Contains fulltext : 235277.pdf (Publisher’s version ) (Closed access) BACKGROUND: Balancing the risks of recurrent ischaemic stroke and intracranial haemorrhage is important for patients treated with antithrombotic therapy after ischaemic stroke or transient ischaemic attack. However, existing predictive models offer insufficient performance, particularly for assessing the risk of intracranial haemorrhage. We aimed to develop new risk scores incorporating clinical variables and cerebral microbleeds, an MRI biomarker of intracranial haemorrhage and ischaemic stroke risk. METHODS: We did a pooled analysis of individual-patient data from the Microbleeds International Collaborative Network (MICON), which includes 38 hospital-based prospective cohort studies from 18 countries. All studies recruited participants with previous ischaemic stroke or transient ischaemic attack, acquired baseline MRI allowing quantification of cerebral microbleeds, and followed-up participants for ischaemic stroke and intracranial haemorrhage. Participants not taking antithrombotic drugs were excluded. We developed Cox regression models to predict the 5-year risks of intracranial haemorrhage and ischaemic stroke, selecting candidate predictors on biological relevance and simplifying models using backward elimination. We derived integer risk scores for clinical use. We assessed model performance in internal validation, adjusted for optimism using bootstrapping. The study is registered on PROSPERO, CRD42016036602. FINDINGS: The included studies recruited participants between Aug 28, 2001, and Feb 4, 2018. 15 766 participants had follow-up for intracranial haemorrhage, and 15 784 for ischaemic stroke. Over a median follow-up of 2 years, 184 intracranial haemorrhages and 1048 ischaemic strokes were reported. The risk models we developed included cerebral microbleed burden and simple clinical variables. Optimism-adjusted c indices were 0·73 (95% CI 0·69-0·77) with a calibration slope of 0·94 (0·81-1·06) for the intracranial haemorrhage model and 0·63 (0·62-0·65) with a calibration slope of 0·97 (0·87-1·07) for the ischaemic stroke model. There was good agreement between predicted and observed risk for both models. INTERPRETATION: The MICON risk scores, incorporating clinical variables and cerebral microbleeds, offer predictive value for the long-term risks of intracranial haemorrhage and ischaemic stroke in patients prescribed antithrombotic therapy for secondary stroke prevention; external validation is warranted. FUNDING: British Heart Foundation and Stroke Association.

Concurrent genital-anal human papillomavirus (HPV) infections may impose an increased anal cancer risk in women with HPV-related genital lesions. High viral load may facilitate genital-anal HPV concurrence. Genital and anal HPV is reduced by a bivalent HPV16/18 vaccine, yet the effect on concurrent genital-anal HPV remains unclear. This study analyzed viral load in concurrent genital-anal HPV infections, relative to genital-only and anal-only HPV infections and the impact of vaccination in young women. We included 1074 women, who provided both genital and anal swabs. HPV detection and genotyping was performed using the SPF10-DEIA-LiPA25. HPV copy numbers were measured with type-specific qPCRs and corrected for cellular content to obtain the viral load. Concurrent genital-anal HPV often had significantly higher genital viral load (0.09–371 c/cell) than genital-only HPV (3.17E-04-15.9 c/cell, p, Highlights • Concurrent genital-anal HPV infections may impose a higher risk of anal cancer. • These infections have increased genital viral load. • The genital site is likely the main source of a concurrent genital-anal HPV infection. • Vaccination effectively reduces concurrent genital-anal HPV infections.

Novel T cell-based therapies for the treatment of B-cell malignancies, such as chronic lymphocytic leukemia (CLL) and multiple myeloma (MM), are thought to have strong potential. Progress, however, has been hampered by low efficacy and high toxicity. Tumor targeting by V gamma 9V delta 2 T cells, a conserved T-cell subset with potent intrinsic antitumor properties, mediated by a bispecific antibody represents a novel approach promising high efficacy with limited toxicity. Here, we describe the generation of a bispecific V gamma 9V delta 2 T-cell engager directed against CD40, which, due to its overexpression and biological footprint in malignant B cells, represents an attractive target. The CD40-targeting moiety of the bispecific antibody was selected because it can prevent CD4OL-induced prosurvival signaling and reduce CD40-mediated resistance of CLL cells to venetoclax. Selective activation of V gamma 9V delta 2 T cells in the presence of CD40(+) tumor cells induced potent V gamma 9V delta 2 T-cell degranulation, cytotoxicity against CLL and MM cells in vitro, and in vivo control of MM in a xenograft model. The CD40-bispecific gamma delta T-cell engager demonstrated lysis of leukemic cells by autologous V gamma 9V delta 2 T cells present in patient-derived samples. Taken together, our CD40 bispecific gamma delta T-cell engager increased the sensitivity of leukemic cells to apoptosis and induced a potent V gamma 9V delta 2 T cell-dependent antileukemic response. It may, therefore, represent a potential candidate for the development of novel treatments for B-cell malignancies.

BackgroundVaginal brachytherapy is currently recommended as adjuvant treatment in patients with high-intermediate risk endometrial cancer to maximize local control and has only mild side effects and no or limited impact on quality of life. However, there is still considerable overtreatment and also some undertreatment, which may be reduced by tailoring adjuvant treatment to the patients’ risk of recurrence based on molecular tumor characteristics.Primary objectivesTo compare the rates of vaginal recurrence in women with high-intermediate risk endometrial cancer, treated after surgery with molecular-integrated risk profile-based recommendations for either observation, vaginal brachytherapy or external pelvic beam radiotherapy or with standard adjuvant vaginal brachytherapyStudy hypothesisAdjuvant treatment based on a molecular-integrated risk profile provides similar local control and recurrence-free survival as current standard adjuvant brachytherapy in patients with high-intermediate risk endometrial cancer, while sparing many patients the morbidity of adjuvant treatment and reducing healthcare costs.Trial designA multicenter, international phase III randomized trial (2:1) of molecular-integrated risk profile-based adjuvant treatment (experimental arm) or adjuvant vaginal brachytherapy (standard arm).Major inclusion/exclusion criteriaWomen aged 18 years and over with a histological diagnosis of high-intermediate risk endometrioid endometrial cancer after total abdominal or laparoscopic hysterectomy and bilateral salpingo-oophorectomy. High-intermediate risk factors are defined as: (i) International Federation of Gynecology and Obstetrics stage IA (with invasion) and grade 3; (ii) stage IB grade 1 or 2 with age ≥60 and/or lymph-vascular space invasion; (iii) stage IB, grade 3 without lymph-vascular space invasion; or (iv) stage II (microscopic and grade 1).EndpointsThe primary endpoint is vaginal recurrence. Secondary endpoints are recurrence-free and overall survival; pelvic and distant recurrence; 5-year vaginal control (including treatment for relapse); adverse events and patient-reported symptoms and quality of life; and endometrial cancer-related healthcare costs.Sample size500 eligible and evaluable patients.Estimated dates for completing accrual and presenting resultsEstimated date for completing accrual will be late 2021. Estimated date for presentation of (first) results is expected in 2023.Trial registrationThe trial is registered at clinicaltrials.gov (NCT03469674) and ISRCTN (11659025).

Objectives Parents of children with a chronic illness (CI) are at risk for psychosocial problems. The aim of this study was to refine an existing face-to-face intervention into an online psychosocial group intervention for parents by (1) exploring which themes are important, (2) determine what type of intervention parents would like and (3) assess parents’ practical preferences. Methods Parents of children with a CI (0–18 years) were invited to complete an online questionnaire. To acquire more in-depth information, focus groups and telephone interviews were conducted. Descriptive statistics were used. Results 272 parents (mean age = 43.1 years, 85% female) participated. Three focus groups (15 parents) and seven telephone interviews were conducted. Most important themes were: the CI of the child, family functioning, taking care of yourself, relationships with others and practical support. Parents preferred a group with parents of children in the same age category. At first, parents preferred face-to-face contact. After an explanation and demonstration of an online intervention, parents became more positive about online support, mostly because they could participate from home. Conclusions for Practice Parents have a need for psychosocial support focusing on different themes. Professionals should explain and demonstrate an online intervention to parents. Based on these results, Op Koers Online for parents was developed. An RCT to assess feasibility and effectiveness of the intervention is currently running.

ObjectiveTo investigate probabilities of survival and its surrogate, that is, mechanical ventilation, in patients with spinal muscular atrophy (SMA).MethodsWe studied survival in a population-based cohort on clinical prevalence of genetically confirmed, treatment-naive patients with SMA, stratified for best acquired motor milestone (i.e., none: type 1a/b; head control in supine position or rolling: type 1c; sitting independently: type 2a; standing: type 2b; walking: type 3a/b; adult onset: type 4). We also assessed the need for mechanical ventilation as a surrogate endpoint for survival.ResultsWe included 307 patients with a total follow-up of 7,141 person-years. Median survival was 9 days in SMA type 1a, 7.7 months in type 1b, and 17.0 years in type 1c. Patients with type 2a had endpoint-free survival probabilities of 74.2% and 61.5% at ages 40 and 60 years, respectively. Endpoint-free survival of SMA types 2b, 3, and 4 was relatively normal, at least within the first 60 years of life. Patients with SMA types 1c and 2a required mechanical ventilation more frequently and from younger ages compared to patients with milder SMA types. In our cohort, patients ventilated up to 12 h/d progressed not gradually, but abruptly, to ≥16 h/d.ConclusionsShortened endpoint-free survival is an important characteristic of SMA types 1 and 2a, but not types 2b, 3, and 4. For SMA types 1c and 2a, the age at which initiation of mechanical ventilation is necessary may be a more suitable endpoint than the arbitrarily set 16 h/d.

IntroductionCorticosteroids are an important pillar in many anti-inflammatory and immunosuppressive treatment regimens and are available in natural and synthetic forms, which are considered equipotent if clinical bioequivalence data are used. Current clinical bioequivalence data are however based on animal studies or studies with subjective endpoints. Furthermore, advancement in steroid physiology with regard to metabolism, intracellular handling and receptor activation have not yet been incorporated. Therefore, this study aims to re-examine the clinical bioequivalence and dose effects of the most widely used synthetic corticosteroids, prednisolone and dexamethasone.Methods and analysisIn this double-blind, randomised cross-over clinical trial, 24 healthy male and female volunteers aged 18–75 years, will be included. All volunteers will randomly receive either first a daily dose of 7.5 mg prednisolone for 1 week, immediately followed by a daily dose of 30 mg prednisolone for 1 week, or first a presumed clinical bioequivalent dose of 1.125 mg dexamethasone per day, immediately followed by 4.5 mg of dexamethasone per day for 1 week. After a wash-out period of 4–8 weeks, the other treatment will be applied. The primary study endpoint is the difference in free cortisol excretion in 24 hours urine. Secondary endpoints will include differences in immunological parameters, blood pressure and metabolic measurements.Ethics and disseminationThis study has been approved by the Medical Ethics Committee of the University Medical Center Groningen (METC 2020.398). The results of this study will be submitted for publication in peer-reviewed journals.Trial registration numberClinicalTrials.gov (Identifier: NCT04733144), and in the Dutch trial registry (NL9138).

While most preconception care (PCC) interventions are aimed at women, men are also in need of PCC to reduce risk factors affecting the spermatozoa quality. The objective of this study is to explore male perceptions regarding the need to engage in PCC.In a mixed-method cross-sectional study, 229 men participated with a questionnaire and 14 individual semi-structured interviews were conducted. Questionnaires data were analysed using multiple regression analyses. The interviews were analysed using thematic analyses.Most men did not retrieve preconceptional information (Despite high awareness of the positive influence of a healthy lifestyle, the perceived need for preparing for pregnancy among men remains low. Tailoring preconceptional information towards male needs provides a window of opportunity to improve men's reproductive health and possibly the health of future generations.

Accurate identification of the underlying cause(s) of cognitive decline and dementia is challenging due to significant symptomatic overlap between subtypes. This study presents a multi-class classification framework for subjects with subjective cognitive decline, mild cognitive impairment, Alzheimer's disease, dementia with Lewy bodies, fronto-temporal dementia and cognitive decline due to psychiatric illness, trained on source-localized resting-state magnetoencephalography data. Diagnostic profiles, describing probability estimates for each of the 6 diagnoses, were assigned to individual subjects. A balanced accuracy rate of 41% and multi-class area under the curve value of 0.75 were obtained for 6-class classification. Classification primarily depended on posterior relative delta, theta and beta power and amplitude-based functional connectivity in the beta and gamma frequency band. Dementia with Lewy bodies (sensitivity: 100%, precision: 20%) and Alzheimer's disease subjects (sensitivity: 51%, precision: 90%) could be classified most accurately. Fronto-temporal dementia subjects (sensitivity: 11%, precision: 3%) were most frequently misclassified. Magnetoencephalography biomarkers hold promise to increase diagnostic accuracy in a noninvasive manner. Diagnostic profiles could provide an intuitive tool to clinicians and may facilitate implementation of the classifier in the memory clinic.

The study aimed to compare the psychosocial development of young adult survivors of childhood cancer (YACCS) with a norm group of young adults from the general population.From 2017 to 2020, 558 YACCS (18-30 years, 51% female, 10.9% CNS cancer) who participated in the Dutch Childhood Cancer Survivor Study (DCCSS) LATER cohort (diagnosed 1963-2001) part 2 completed the Course of Life Questionnaire (CoLQ), assessing the achievement of milestones. Items were grouped into the scales autonomy, psychosexual, and social development. Differences between YACCS and norm group were examined with ANOVA and Cohen's d (CoLQ scales) and with logistic regression analysis and odds ratio (OR) (CoLQ items), for the total group and YACCS of CNS cancer.The total group of YACCS did not report a less favorable psychosocial development than the norm group. YACCS of CNS cancer scored lower than the norm group (p0.001) on the scales autonomy (d = - 0.36) and psychosexual (d = - 0.46). Additionally, on half of the items of autonomy (0.25 ≤ OR ≤ 0.34), psychosexual (0.30 ≤ OR ≤ 0.48), and social (0.23 ≤ OR ≤ 0.47) development, YACCS of CNS cancer were less likely (p0.01) than the norm group to have achieved the milestones.Overall, psychosocial development of YACCS was as favorable as the norm, but YACCS of CNS cancer were at risk of an unfavorable psychosocial development in all domains. Monitoring psychosocial development should be included in the standards of psychosocial care, especially for CNS cancer patients and survivors, to be able to trace delay. Personalized interventions should be offered to improve the psychosocial development in an early stage.

Contains fulltext : 248373.pdf (Publisher’s version ) (Open Access)

AimThis study examined the association between social support perceived by parents of children aged 1–7 years and the use of additional community youth health care services.MethodsData of 749 parents of children aged 1–7 years, gathered in the CIKEO cohort study in the Netherlands, were analyzed. Social support was assessed with the Multidimensional Scale of Perceived Social Support. Data on the use of additional community youth health care services during a period of 1.5 years were obtained from the electronic records of participating youth health care organizations. Multivariable logistic regression models were used to examine the association between perceived social support and the use of additional youth health care services and to explore moderation by the parent's educational level.ResultsThe mean age of the responding parents was 33.9 years (SD = 5.1); 93.6% were mothers. Parents who perceived low to moderate levels of social support had 1.72 (95% CI: 1.11, 2.66) times higher odds of using one or more additional youth health care services during the study period compared to parents who perceived high levels of social support at baseline. This association was independent of predisposing factors, but not independent of need factors (p > 0.05). Furthermore, the association was moderated by the educational level of the parent (p = 0.015). Among parents with a high educational level, low to moderate levels of perceived social support at baseline were associated with 2.93 (95% CI: 1.47, 5.83) times higher odds of using one or more additional youth health care services during the study period independent of predisposing and need factors. Among parents with a low or middle educational level the association between perceived social support and use of additional youth health care services was not significant.ConclusionOur findings provide evidence that low to moderate levels of perceived social support are associated with a higher use of additional community youth health care services among parents of children aged 1–7 years, especially among high educated parents. Recommendations for policy and practice are provided.

Objective Sex steroid hormones like estrogens have a key role in the regulation of energy homeostasis and metabolism. In transwomen, gender-affirming hormone therapy like estradiol (in combination with antiandrogenic compounds) could affect metabolism as well. Given that the underlying pathophysiological mechanisms are not fully understood, this study assessed circulating estradiol-driven microRNAs (miRs) in transwomen and their regulation of genes involved in metabolism in mice. Methods Following plasma miR-sequencing (seq) in a transwomen discovery (n = 20) and validation cohort (n = 30), we identified miR-224 and miR-452. Subsequent systemic silencing of these miRs in male C57Bl/6 J mice (n = 10) was followed by RNA-seq-based gene expression analysis of brown and white adipose tissue in conjunction with mechanistic studies in cultured adipocytes. Results Estradiol in transwomen lowered plasma miR-224 and -452 carried in extracellular vesicles (EVs) while their systemic silencing in mice and cultured adipocytes increased lipogenesis (white adipose) but reduced glucose uptake and mitochondrial respiration (brown adipose). In white and brown adipose tissue, differentially expressed (miR target) genes are associated with lipogenesis (white adipose) and mitochondrial respiration and glucose uptake (brown adipose). Conclusion This study identified an estradiol-drive post-transcriptional network that could potentially offer a mechanistic understanding of metabolism following gender-affirming estradiol therapy.

Two hookworm vaccine candidates, Na-GST-1 and Na-APR-1, formulated with Glucopyranosyl Lipid A (GLA-AF) adjuvant, have been shown to be safe, well tolerated, and to induce antibody responses in a Phase 1 clinical trial (Clinicaltrials.gov NCT02126462) conducted in Gabon. Here, we characterized T cell responses in 24 Gabonese volunteers randomized to get vaccinated three times with Na-GST-1 and Na-APR-1 at doses of 30μg (n = 8) or 100μg (n = 10) and as control Hepatitis B (n = 6). Blood was collected pre- and post-vaccination on days 0, 28, and 180 as well as 2-weeks after each vaccine dose on days 14, 42, and 194 for PBMCs isolation. PBMCs were stimulated with recombinant Na-GST-1 or Na-APR-1, before (days 0, 28 and 180) and two weeks after (days 14, 42 and 194) each vaccination and used to characterize T cell responses by flow and mass cytometry. A significant increase in Na-GST-1 -specific CD4+ T cells producing IL-2 and TNF, correlated with specific IgG antibody levels, after the third vaccination (day 194) was observed. In contrast, no increase in Na-APR-1 specific T cell responses were induced by the vaccine. Mass cytometry revealed that, Na-GST-1 cytokine producing CD4+ T cells were CD161+ memory cells expressing CTLA-4 and CD40-L. Blocking CTLA-4 enhanced the cytokine response to Na-GST-1. In Gabonese volunteers, hookworm vaccine candidate, Na-GST-1, induces detectable CD4+ T cell responses that correlate with specific antibody levels. As these CD4+ T cells express CTLA-4, and blocking this inhibitory molecules resulted in enhanced cytokine production, the question arises whether this pathway can be targeted to enhance vaccine immunogenicity., Author summary Two hookworm vaccine candidate (Na-GST-1 and Na-APR-1) have been tested in Gabonese and found to be safe and to induce antibody response. We aimed to study the cellular immune responses among vaccinated and unvaccinated volunteers. We found that Na-GST-1 induced CD4+ T cell responses (IL-2, TNF) among the vaccinated volunteers that received the high vaccine dose (100 ug). Furthermore Na-GST-1 specific memory T cells were found to express the inhibitory molecule CTLA-4. These responses was not observed in those who received the low dose of the Na-GST-1 vaccine, or those who received Na-APR-1 or HBV. By blocking CTLA-4, we observed an increase in TNF production. Our data suggest that an intervention involving blockage of the CTLA-4 molecule in the vaccinated could be beneficial in endemic settings where vaccine responses have been shown to be lower compared to non-endemic settings.

Background Radiotherapy (RT) is part of the curative treatment of approximately 70% of breast cancer (BC) patients. Wide practice variation has been reported in RT dose, fractionation and its treatment planning for BC. To decrease this practice variation, it is essential to first gain insight into the current variation in RT treatment between institutes. This paper describes the development of the NABON Breast Cancer Audit-Radiotherapy (NBCA-R), a structural nationwide registry of BC RT data of all BC patients treated with at least surgery and RT. Methods A working group consisting of representatives of the BC Platform of the Dutch Radiotherapy Society selected a set of dose volume parameters deemed to be surrogate outcome parameters, both for tumour control and toxicity. Two pilot studies were carried out in six RT institutes. In the first pilot study, data were manually entered into a secured web-based system. In the second pilot study, an automatic Digital Imaging and Communications in Medicine (DICOM) RT upload module was created and tested. Results The NBCA-R dataset was created by selecting RT parameters describing given dose, target volumes, coverage and homogeneity, and dose to organs at risk (OAR). Entering the data was made mandatory for all Dutch RT departments. In the first pilot study (N = 1093), quite some variation was already detected. Application of partial breast irradiation varied from 0 to 17% between the 6 institutes and boost to the tumour bed from 26.5 to 70.2%. For patients treated to the left breast or chest wall only, the average mean heart dose (MHD) varied from 0.80 to 1.82 Gy; for patients treated to the breast/chest wall only, the average mean lung dose (MLD) varied from 2.06 to 3.3 Gy. In the second pilot study 6 departments implemented the DICOM-RT upload module in daily practice. Anonymised data will be available for researchers via a FAIR (Findable, Accessible, Interoperable, Reusable) framework. Conclusions We have developed a set of RT parameters and implemented registration for all Dutch BC patients. With the use of an automated upload module registration burden will be minimized. Based on the data in the NBCA-R analyses of the practice variation will be done, with the ultimate aim to improve quality of BC RT. Trial registration Retrospectively registered.

Aim To determine development curves of communication and social interaction from childhood into adulthood for individuals with cerebral palsy (CP). Method This Pediatric Rehabilitation Research in the Netherlands (PERRIN)‐DECADE study longitudinally assessed 421 individuals with CP, aged from 1 to 20 years at baseline, after 13 years (n=121 at follow‐up). Communication and social interactions were assessed using the Vineland Adaptive Behavior Scales. We estimated the average maximum performance limit (level) and age at which 90% of the limit was reached (age90) using nonlinear mixed‐effects modeling. Results One‐hundred individuals without intellectual disability were aged 21 to 34 years at follow‐up (39 females, 61 males) (mean age [SD] 28y 5mo [3y 11mo]). Limits of individuals without intellectual disability, regardless of Gross Motor Function Classification System (GMFCS) level, approached the maximum score and were significantly higher than those of individuals with intellectual disability. Ages90 ranged between 3 and 4 years for receptive communication, 6 and 7 years for expressive communication and interrelationships, 12 and 16 years for written communication, 13 and 16 years for play and leisure, and 14 and 16 years for coping. Twenty‐one individuals with intellectual disability were between 21 and 27 years at follow‐up (8 females, 13 males) (mean age [SD] 24y 7mo [1y 8mo]). Individuals with intellectual disability in GMFCS level V showed the least favourable development, but variation between individuals with intellectual disability was large. Interpretation Individuals with CP and without intellectual disability show developmental curves of communication and social interactions similar to typically developing individuals, regardless of their level of motor function. Those with intellectual disability reach lower performance levels and vary largely in individual development. What this paper adds Communication and social interactions in individuals with cerebral palsy without intellectual disability develop similarly to typically developing individuals.Communication and social interactions of individuals with intellectual disability develop less favourably and show large variation., What this paper adds Communication and social interactions in individuals with cerebral palsy without intellectual disability develop similarly to typically developing individuals.Communication and social interactions of individuals with intellectual disability develop less favourably and show large variation. This article's abstract has been translated into Spanish and Portuguese. Follow the links from the http://onlinelibrary.wiley.com/doi/10.1111/dmcn.14351/abstract to view the translations.

OBJECTIVE: In clinical trials in Alzheimer's Disease (AD), an improvement of impaired functional connectivity (FC) could provide biological support for the potential efficacy of the drug. Electroencephalography (EEG) analysis of the SAPHIR-trial showed a treatment induced improvement of global relative theta power but not of FC measured by the phase lag index (PLI). We compared the PLI with the amplitude envelope correlation with leakage correction (AEC-c), a presumably more sensitive FC measure.METHODS: Patients with early AD underwent 12 weeks of placebo or treatment with PQ912, a glutaminylcyclase inhibitor. Eyes-closed task free EEG was measured at baseline and follow-up (PQ912 n = 47, placebo n = 56). AEC-c and PLI were measured in multiple frequency bands. Change in FC was compared between treatment groups by using two models of covariates.RESULTS: A significant increase in global AEC-c in the alpha frequency band was found with PQ912 treatment compared to placebo (p = 0.004, Cohen's d = 0.58). The effect remained significant when corrected for sex, country, ApoE ε4 carriage, age, baseline value (model 1; p = 0.006) and change in relative alpha power (model 2; p = 0.004).CONCLUSIONS: Functional connectivity in early AD, measured with AEC-c in the alpha frequency band, improved after PQ912 treatment.SIGNIFICANCE: AEC-c may be a robust and sensitive FC measure for detecting treatment effects.

Background and aim Patient decision aids for oncological treatment options, provide information on the effect on recurrence rates and/or survival benefit, and on side-effects and/or burden of different treatment options. However, often uncertainty exists around the probability estimates for recurrence/survival and side-effects which is too relevant to be ignored. Evidence is lacking on the best way to communicate these uncertainties. The aim of this study is to develop a method to incorporate uncertainties in a patient decision aid for breast cancer patients to support their decision on radiotherapy. Methods Firstly, qualitative interviews were held with patients and health care professionals. Secondly, in the development phase, thinking aloud sessions were organized with four patients and 12 health care professionals, individual and group-wise. Results Consensus was reached on a pictograph illustrating the whole range of uncertainty for local recurrence risks, in combination with textual explanation that a more exact personalized risk would be given by their own physician. The pictograph consisted of 100 female icons in a 10 x 10 array. Icons with a stepwise gradient color indicated the uncertainty margin. The prevalence and severity of possible side-effects were explained using verbal labels. Conclusions We developed a novel way of visualizing uncertainties in recurrence rates in a patient decision aid. The effect of this way of communicating risk uncertainty is currently being tested in the BRASA study (NCT03375801)., Highlights • There exists uncertainty around local recurrence risks for breast cancer patients. • Little is known on how to communicate uncertainty to patients. • Patient decision aids can help communicating risks and uncertainty. • We developed pictographs to communicate numerical uncertainty in recurrence risks. • The effect of the pictographs is currently being tested in the BRASA study.

Background Different interventions are offered to children with cerebral palsy (CP) to improve the activity domain of the international classification of functioning (ICF). In therapy settings, the focus is mostly on motor capacity, but the ultimate goal is to improve motor performance. We therefore examined if changes in motor capacity outcomes are accompanied by changes in objectively measured motor performance after a 3-month intensive treatment period in ambulatory children with CP. Methods A secondary analysis on prospective clinical trial data was performed using multivariate linear regression. Sixty-five children (37 boys and 28 girls) with spastic CP, mean age 7 years and 3 months, Gross Motor Function Classification System (GMFCS) levels I-III were involved in a distinct 3-month intensive treatment period. Motor capacity (Gross Motor Function Measure [GMFM], functional muscle strength [FMS], and walking speed [WS]) and motor performance (using three Actigraph-GT3X+-derived outcome measures) were measured at baseline, 12 and 24 weeks. Results No significant associations were found for any of the change scores ( increment (12)) between motor capacity and motor performance after a 12-week intensive treatment period. After 24 weeks, increment 24FMS (p = .042) and increment 24WS (p = .036) were significantly associated with changes in motor performance outcome measure percentage of time spent sedentary ( increment (24)%sedentary). In this model, 16% of variance of increment (24)%sedentary was explained by changes in motor capacity (p = .030). Conclusions Changes in motor capacity are mostly not accompanied by changes in objectively measured motor performance after an intensive treatment period for ambulatory children with CP. These findings should be taken into account during goal setting and are important to manage expectations of both short- and longer term effects of treatment programmes.

BackgroundStudies on neighbourhood characteristics and depression show equivocal results.AimsThis large-scale pooled analysis examines whether urbanisation, socioeconomic, physical and social neighbourhood characteristics are associated with the prevalence and severity of depression.MethodCross-sectional design including data are from eight Dutch cohort studies (n= 32 487). Prevalence of depression, either DSM-IV diagnosis of depressive disorder or scoring for moderately severe depression on symptom scales, and continuous depression severity scores were analysed. Neighbourhood characteristics were linked using postal codes and included (a) urbanisation grade, (b) socioeconomic characteristics: socioeconomic status, home value, social security beneficiaries and non-Dutch ancestry, (c) physical characteristics: air pollution, traffic noise and availability of green space and water, and (d) social characteristics: social cohesion and safety. Multilevel regression analyses were adjusted for the individual's age, gender, educational level and income. Cohort-specific estimates were pooled using random-effects analysis.ResultsThe pooled analysis showed that higher urbanisation grade (odds ratio (OR) = 1.05, 95% CI 1.01–1.10), lower socioeconomic status (OR = 0.90, 95% CI 0.87–0.95), higher number of social security beneficiaries (OR = 1.12, 95% CI 1.06–1.19), higher percentage of non-Dutch residents (OR = 1.08, 95% CI 1.02–1.14), higher levels of air pollution (OR = 1.07, 95% CI 1.01–1.12), less green space (OR = 0.94, 95% CI 0.88–0.99) and less social safety (OR = 0.92, 95% CI 0.88–0.97) were associated with higher prevalence of depression. All four socioeconomic neighbourhood characteristics and social safety were also consistently associated with continuous depression severity scores.ConclusionsThis large-scale pooled analysis across eight Dutch cohort studies shows that urbanisation and various socioeconomic, physical and social neighbourhood characteristics are associated with depression, indicating that a wide range of environmental aspects may relate to poor mental health.Declaration of interestNone.

ObjectiveTo investigate the natural course of scoliosis and to estimate lifetime probability of scoliosis surgery in spinal muscular atrophy (SMA).MethodsWe analyzed cross-sectional data from 283 patients from our population-based cohort study. Additional longitudinal data on scoliosis progression and spinal surgery were collected from 36 consecutive patients who received scoliosis surgery at our center.ResultsThe lifetime probability of receiving scoliosis surgery was ≈80% in SMA types 1c and 2. Patients with type 2 who only learned to sit (type 2a) were significantly younger at time of surgery than those who learned to sit and stand (type 2b). The lifetime risk of surgery was lower in type 3a (40%) and strongly associated with age at loss of ambulation: 71% in patients losing ambulation before 10 years of age vs 22% losing ambulation after the age of 10 years (p = 0.005). In type 3a, preserving the ability to walk 1 year longer corresponded to a 15% decrease in lifetime risk of scoliosis surgery (hazard ratio 0.852, p = 0.017). Scoliosis development was characterized by initial slow progression, followed by acceleration in the 1.5- to 2-year period before surgery.ConclusionThe lifetime probability of scoliosis surgery is high in SMA types 1c and 2 and depends on age at loss of ambulation in type 3. Motor milestones such as standing that are not part of the standard classification system are of additional predictive value. Our data may act as a reference to assess long-term effects of new SMA-specific therapies.

BACKGROUND: Muscle mass, as determined from 24-h urinary creatinine excretion rate (CER), is an independent predictor for mortality and graft failure in renal transplant recipients (RTR). It is currently unknown whether CER is comparable with healthy controls after transplantation and whether it reflects muscle performance besides muscle mass. We aimed to compare urinary CER and muscle performance between RTR and healthy controls and to investigate whether urinary CER is associated with muscle performance in RTR.METHODS: We included RTR, transplanted between 1975 and 2016 in the University Medical Center Groningen. Healthy controls were subjects screened for kidney donation. CER was calculated from a 24-h urine collection. Muscle performance was assessed by handgrip strength, sit-to-stand test, and 2-min walk test. Statistical analyses were performed using linear regression analyses.RESULTS: We included 184 RTR (mean age 56.9 ± 11.9 years, 54% male recipient) and 78 healthy controls (age 57.9 ± 9.9, 47% male recipient). RTR were at a median time of 4.0 (1.1-8.8) years after transplantation. Mean CER was lower in RTR compared to healthy controls (11.7 ± 4.0 vs. 13.1 ± 5.2 mmol/24 h; P = 0.04). Significantly poorer results in muscle performance were found in RTR compared to controls for the handgrip strength (30.5 [23.7-41.1] N vs. 38.3 [29.3-46.0] N, P < 0.001) and the 2-min walk test (151.5 ± 49.2 m vs. 172.3 ± 12.2 m, P < 0.001) but not for the sit-to-stand (12.2 ± 3.3 m vs. 11.9 ± 2.8 m, P = 0.46). In RTR, CER was significantly associated with handgrip strength (std. β 0.33; P < 0.001), independent of adjustment for potential confounders. In RTR, CER was neither associated with the time used for the sit-to-stand test (std. β -0.09; P = 0.27) nor with the distance covered during the 2-min walk test (std. β 0.07; P = 0.40).CONCLUSIONS: Muscle mass as measured by CER in RTR is lower compared to controls. CER is positively associated with muscle performance in RTR. The results demonstrate that CER does not only reflect muscle mass but also muscle performance in this patient setting. Determination of CER could be an interesting addition to the imaging technique armamentarium available and applied for evaluation of muscle mass in clinical intervention studies and observational studies.

Speech recognition was measured in 24 normal-hearing subjects for unprocessed speech and for speech processed by a cochlear implant Advanced Combination Encoder (ACE) coding strategy in quiet and at various signal-to noise ratios (SNRs). All signals were low- or high-pass filtered to avoid ceiling effects. Surprisingly, speech recognition performance plateaus at approximately 22 dB SNR for both speech types, implying that ACE processing has no effect on the upper limit of the effective SNR range. Speech recognition improved significantly above 15 dB SNR, suggesting that the upper limit used in the Speech Intelligibility Index should be reconsidered.

ObjectiveWe provide succinct, evidence-based and/or consensus-based best practice guidance for the cardiac care of children living with Duchenne muscular dystrophy (DMD) as well as recommendations for screening and management of female carriers of mutations in theDMD-gene.MethodsInitiated by an expert working group of UK-based cardiologists, neuromuscular clinicians and DMD-patient representatives, draft guidelines were created based on published evidence, current practice and expert opinion. After wider consultation with UK-cardiologists, consensus was reached on these best-practice recommendations for cardiac care in DMD.ResultsThe resulting recommendations are presented in the form of a succinct care pathway flow chart with brief justification. The guidance signposts evidence on which they are based and acknowledges where there have been differences in opinion. Guidelines for cardiac care of patients with more advanced cardiac dystrophinopathy at any age have also been considered, based on the previous published work of Quinlivanet aland are presented here in a similar format. The recommendations have been endorsed by the British Cardiovascular Society.ConclusionThese guidelines provide succinct, reasoned recommendations for all those managing paediatric patients with early or advanced stages of cardiomyopathy as well as females with cardiac dystrophinopathy. The hope is that this will result in more uniform delivery of high standards of care for children with cardiac dystrophinopathy, so improving heart health into adulthood through timely earlier interventions across the UK.

Introduction: The Dutch Gynecological Oncology Audit (DGOA) was initiated in 2014 to serve as a nationwide audit, which registers the four most prevalent gynecological malignancies. This study presents the first results of clinical auditing for ovarian cancer in the Netherlands.Methods: The Dutch Gynecological Oncology Audit is facilitated by the Dutch Institute of Clinical Auditing (DICA) and run by a scientific committee. Items are collected through a web-based registration based on a set of predefined quality indicators. Results of quality indicators are shown, and benchmarked information is given back to the user. Data verification was done in 2016. Results: Between January 01, 2014 and December 31, 2018, 6535 patients with ovarian cancer were registered. The case ascertainment was 98.3% in 2016. The number of patients with ovarian cancer who start therapy within 28 days decreased over time from 68.7% in 2014 to 62.7% in 2018 (p < 0.001). The percentage of patients with primary cytoreductive surgery decreased over time (57.8%-39.7%, P < 0.001). However, patients with complete primary cytoreductive surgery improved over time (53.5%-69.1%, P < 0.001). Other quality indicators did not significantly change over time.Conclusion: The Dutch Gynecological Oncology Audit provides valuable data on the quality of care on patients with ovarian cancer in the Netherlands. Data show variation between hospitals with regard to pre-determined quality indicators. Results of 'best practices' will be shared with all participants of the clinical audit with the aim of improving quality of care nationwide.(c) 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license(http://creativecommons.org/licenses/by/4.0/).

Objective We aimed to test the hypothesis that computational features of the first several minutes of EEG recording can be used to estimate the risk for development of acute seizures in comatose critically-ill children. Methods In a prospective cohort of 118 comatose children, we computed features of the first five minutes of artifact-free EEG recording (spectral power, inter-regional synchronization and cross-frequency coupling) and tested if these features could help identify the 25 children who went on to develop acute symptomatic seizures during the subsequent 48 hours of cEEG monitoring. Results Children who developed acute seizures demonstrated higher average spectral power, particularly in the theta frequency range, and distinct patterns of inter-regional connectivity, characterized by greater connectivity at delta and theta frequencies, but weaker connectivity at beta and low gamma frequencies. Subgroup analyses among the 97 children with the same baseline EEG background pattern (generalized slowing) yielded qualitatively and quantitatively similar results. Conclusions These computational features could be applied to baseline EEG recordings to identify critically-ill children at high risk for acute symptomatic seizures. Significance If confirmed in independent prospective cohorts, these features would merit incorporation into a decision support system in order to optimize diagnostic and therapeutic management of seizures among comatose children.

Aim To compare Health‐Related Quality of Life (HRQOL) of paediatric patients with newly collected HRQOL data of the general Dutch population, explore responses to individual items and investigate variables associated with HRQOL. Methods Children (8–12y) and adolescents (13–17y) from the general population (N = 966) and from a paediatric population (N = 1209) completed the Pediatric Quality of Life Inventory (PedsQLTM) online via the KLIK Patient‐Reported Outcome Measures portal. PedsQLTM scale scores were compared between groups with independent t tests, by age group and gender. Responses to PedsQLTM items were explored using descriptive analyses. Linear regression analyses were performed to determine which variables were associated with HRQOL. Results Paediatric patients reported worse HRQOL than the general population on all PedsQLTM scales (p ≤ .001, d = 0.20–1.03), except social functioning, and a high proportion reported problems on PedsQLTM items, for example, ‘I have trouble sleeping’. Younger age, female gender and school absence were negatively associated with HRQOL (β = −0.37–0.10, p ≤ .008). Conclusion Paediatric patients reported lower HRQOL than the general population, and school absence, female gender and younger age were associated with lower HRQOL. The results underline the importance to structurally monitor paediatric patients’ HRQOL in clinical practice to detect problems and offer the right help on time.

Repetition suppression (RS) reflects a neural attenuation during repeated stimulation. We used fMRI and the subsequent memory paradigm to test the predictive coding hypothesis for RS during visual memory processing by investigating the interaction between RS and differences due to memory in category-selective cortex (FFA, pSTS, PPA, and RSC). Fifty-six participants encoded face and house stimuli twice, followed by an immediate and delayed (48 h) recognition memory assessment. Linear Mixed Model analyses with repetition, subsequent recognition performance, and their interaction as fixed effects revealed that absolute RS during encoding interacts with probability of future remembrance in face-selective cortex. This effect was not observed for relative RS, i.e. when controlled for adapter-response. The findings also reveal an association between adapter response and RS, both for short and long term (48h) intervals, after controlling for the mathematical dependence between both measures. These combined findings are challenging for predictive coding models of visual memory and are more compatible with adapter-related and familiarity accounts., In order to examine underlying mechanisms of repetition suppression, Stam et al conducted an fMRI study in which participants were presented with face and house stimuli followed by an immediate and 48 h-delayed memory task. Their data demonstrated that adapter-related and familiarity account modelling are more likely to be more accurate for visual memory than previous predictive coding models.

To gain insight into the effect of the coronavirus measures on the number of severe injuries treated at Emergency Departments (EDs).Retrospective observational research.We compared prevalences of ED visits from the Dutch Injury Surveillance System (DISS) between the period of semi-lockdown (16 March-10 May 2020) and the same period in 2019. The same comparisons were made for the period of relaxation of measures (11 May-5 July 2020) and for the period of relaxation versus lockdown. To eliminate a possible effect of avoiding emergency care, analyses were performed on severe injury related ED-visits.The prevalence of severe injury related ED-visits during the period of lockdown was 27 percent lower compared to the same period in 2019 (6.755 versus 4.902, P0.05). This decrease was observed for all types of injuries and age groups, but was strongest for sports injuries (-53%) and among 10-19-year-olds (-55%). In contrast, the number of ED-visits increased after accidents with jobs in the house (+31%) and roller-skates (+223%). Among 0-11-year-olds, more accidents with trampolines were reported (+68%). During the period of relaxation, the number of severe injury related ED-visits increased with 19 percent, but was 11 percent lower compared to 2019.The changes in activities following the coronavirus measures have led to changes in the number of severe injuries treated at EDs. The variations observed during the periods of lockdown and relaxation seem to be correlated with the amount of exposure in sports, traffic, stay at home and leisure activity.

Background International travel is a risk factor for incident colonization with extended spectrum beta-lactamase (ESBL)-producing organisms. These and other multidrug-resistant (MDR) bacteria are major pathogens in combat casualties. We evaluated risk factors for colonization with MDR bacteria in US military personnel travelling internationally for official duty. Methods TravMil is a prospective observational study enrolling subjects presenting to military travel clinics. We analysed surveys, antimicrobial use data, and pre- and post-travel perirectal swabs in military travellers to regions outside the continental USA, Canada, Western or Northern Europe, or New Zealand, presenting to one clinic from 12/2015 to 12/2017. Recovered Gram-negative isolates underwent identification and susceptibility testing (BD Phoenix). Characteristics of trip and traveller were analysed to determine risk factors for MDR organism colonization. Results 110 trips were planned by 99 travellers (74% male, median age 38 years [IQR 31, 47.25]); 72 trips with returned pre- and post-travel swabs were completed by 64 travellers. Median duration was 21 days (IQR 12.75, 79.5). 17% travelled to Mexico/Caribbean/Central America, 15% to Asia, 57% to Africa and 10% to South America; 56% stayed in hotels and 50% in dormitories/barracks. Travellers used doxycycline (15%) for malaria prophylaxis, 11% took an antibiotic for travellers’ diarrhoea (TD) treatment (fluoroquinolone 7%, azithromycin 4%). Incident MDR organism colonization occurred in 8 travellers (incidence density 3.5/1000 travel days; cumulative incidence 11% of trips [95% CI: 4–19%]), all ESBL-producing Escherichia coli. A higher incidence of ESBL-producing E. coli acquisition was associated with travel to Asia (36% vs 7%, P = 0.02) but not with travel to other regions, TD or use of antimicrobials. No relationship was seen between fluoroquinolone or doxycycline exposure and resistance to those antimicrobials. Conclusions Incident colonization with MDR organisms occurs at a lower rate in this military population compared with civilian travellers, with no identified modifiable risk factors, with highest incidence of ESBL acquisition observed after South Asia travel.

ObjectiveType 1 diabetes (T1D) is characterised by islet autoimmunity and beta cell destruction. A gut microbiota–immunological interplay is involved in the pathophysiology of T1D. We studied microbiota-mediated effects on disease progression in patients with type 1 diabetes using faecal microbiota transplantation (FMT).DesignPatients with recent-onset (ResultsStimulated C peptide levels were significantly preserved in the autologous FMT group (n=10 subjects) compared with healthy donor FMT group (n=10 subjects) at 12 months. Small intestinal Prevotella was inversely related to residual beta cell function (r=−0.55, p=0.02), whereas plasma metabolites 1-arachidonoyl-GPC and 1-myristoyl-2-arachidonoyl-GPC levels linearly correlated with residual beta cell preservation (rho=0.56, p=0.01 and rho=0.46, p=0.042, respectively). Finally, baseline CD4 +CXCR3+T cell counts, levels of small intestinal Desulfovibrio piger and CCL22 and CCL5 gene expression in duodenal biopsies predicted preserved beta cell function following FMT irrespective of donor characteristics.ConclusionFMT halts decline in endogenous insulin production in recently diagnosed patients with T1D in 12 months after disease onset. Several microbiota-derived plasma metabolites and bacterial strains were linked to preserved residual beta cell function. This study provides insight into the role of the intestinal gut microbiome in T1D.Trial registration numberNTR3697.

Non-invasively measured brain activity is related to progression-free survival in glioma patients, suggesting its potential as a marker of glioma progression. We therefore assessed the relationship between brain activity and increasing tumor volumes on routine clinical magnetic resonance imaging (MRI) in glioma patients. Postoperative magnetoencephalography (MEG) was recorded in 45 diffuse glioma patients. Brain activity was estimated using three measures (absolute broadband power, offset and slope) calculated at three spatial levels: global average, averaged across the peritumoral areas, and averaged across the homologues of these peritumoral areas in the contralateral hemisphere. Tumors were segmented on MRI. Changes in tumor volume between the two scans surrounding the MEG were calculated and correlated with brain activity. Brain activity was compared between patient groups classified into having increasing or stable tumor volume. Results show that brain activity was significantly increased in the tumor hemisphere in general, and in peritumoral regions specifically. However, none of the measures and spatial levels of brain activity correlated with changes in tumor volume, nor did they differ between patients with increasing versus stable tumor volumes. Longitudinal studies in more homogeneous subgroups of glioma patients are necessary to further explore the clinical potential of non-invasively measured brain activity.

Background The coronavirus disease 2019 (COVID-19) pandemic (officially declared on the March 11, 2020), and the resulting measures, are impacting daily life and medical management of breast cancer patients and survivors. We evaluated to what extent these changes have affected quality of life, physical, and psychosocial well-being of patients previously or currently being treated for breast cancer. Methods This study was conducted within a prospective, multicenter cohort of breast cancer patients and survivors (Utrecht cohort for Multiple BREast cancer intervention studies and Long-term evaLuAtion). Shortly after the implementation of COVID-19 measures, an extra survey was sent to 1595 participants, including the validated European Organization for Research and Treatment of Cancer (EORTC) core (C30) and breast cancer- specific (BR23) Quality of Life Questionnaire (EORTC QLQ-C30/BR23) and Hospital Anxiety and Depression Scale (HADS) questionnaire. Patient-reported outcomes (PROs) were compared with the most recent PROs collected within UMBRELLA pre–COVID-19. The impact of COVID-19 on PROs was assessed using mixed model analysis, adjusting for potential confounders. Results 1051 patients and survivors (65.9%) completed the survey; 31.1% (n = 327) reported a higher threshold to contact their general practitioner amid the COVID-19 pandemic. A statistically significant deterioration in emotional functioning was observed (mean = 82.6 [SD = 18.7] to 77.9 [SD = 17.3]; P Conclusion During the COVID-19 pandemic, breast cancer patients and survivors were less likely to contact physicians and experienced a deterioration in their emotional functioning. Patients undergoing active treatment reported a substantial drop in social functioning. One in 2 reported loneliness that was moderate or severe. Online interventions supporting mental health and social interaction are needed during times of social distancing and lockdowns.

Purpose Patient decision aids (PtDAs) have been reported to have a positive influence on patients making a health care decision in trials. Nevertheless, post-trial implementation is poor. The aim of this study is to explore patient, clinician, and organizational success factors for implementing a PtDA designed for breast cancer patients, facing a decision on their radiation treatment. Methods We performed a process evaluation within a multi-center pre- and post-implementation trial. The PtDA was incorporated as much as possible in the logistics of 13 participating centers. Tracking data were collected on PtDA use. Process characteristics were recorded by both clinicians and patients. A logistic regression method was applied to investigate which process characteristics were significantly related to the probability that patients logged in to the PtDA. Results 189 patients received the PtDA of whom140 (77%) used the PtDA. If patients received the link via the surgery department they were more likely to use the PtDA (OR 9.77 (1.28–74.51)), compared to patients that received the link via the radiation oncology department. If the report of the multidisciplinary team stated that radiation treatment “had to be discussed with the patient”, patients were more likely to use the PtDA (OR 2.29 (1.12–4.71)). Educational level was not related to the probability of PtDA use. Conclusions We accomplished a high level of PtDA use. Patients were more likely to use the PtDA if they received the link via the surgery department and if “to be discussed with the patient” was written in the multidisciplinary team report.

Contains fulltext : 229838.pdf (Publisher’s version ) (Open Access) OBJECTIVE: The PORTEC-4a trial investigates molecular-integrated risk profile guided adjuvant treatment for endometrial cancer. The quality assurance programme included a dummy run for vaginal brachytherapy prior to site activation, and annual quality assurance to verify protocol adherence. Aims of this study were to evaluate vaginal brachytherapy quality and protocol adherence. METHODS: For the dummy run, institutes were invited to create a brachytherapy plan on a provided CT-scan with the applicator in situ. For annual quality assurance, institutes provided data of one randomly selected brachytherapy case. A brachytherapy panel reviewed and scored the brachytherapy plans according to a checklist. RESULTS: At the dummy run, 15 out of 21 (71.4%) institutes needed adjustments of delineation or planning. After adjustments, the mean dose at the vaginal apex (protocol: 100%; 7 Gy) decreased from 100.7% to 99.9% and range and standard deviation (SD) narrowed from 83.6-135.1 to 96.4-101.4 and 8.8 to 1.1, respectively. At annual quality assurance, 22 out of 27 (81.5%) cases had no or minor and 5 out of 27 (18.5%) major deviations. Most deviations were related to delineation, mean dose at the vaginal apex (98.0%, 74.7-114.2, SD 7.6) or reference volume length. CONCLUSIONS: Most feedback during the brachytherapy quality assurance procedure of the PORTEC-4a trial was related to delineation, dose at the vaginal apex and the reference volume length. Annual quality assurance is essential to promote protocol compliance, ensuring high quality vaginal brachytherapy in all participating institutes.

ObjectivesLoneliness is seen as an important problem, contributing to serious health problems. As a baseline measurement for the evaluation of a community project aimed at reducing loneliness in Rotterdam, loneliness was measured, as well as potential correlates. This article describes models of social and emotional loneliness among older adults.MethodsThis study was conducted among 3,821 randomly selected community dwelling citizens of 65 years and older. Loneliness was measured by using the Jong-Gierveld loneliness questionnaire/scale. As potential correlates demographic, health and psychological and social variables were included. Data were subjected to multiple hierarchically regression analysis.ResultsEmotional loneliness was reported by 60% and social loneliness by 47% of the sample. Women were more emotionally lonely than men , while men reported more social loneliness than women. Emotional social support and quality of life were strongest in predicting emotional loneliness and social capital in the neighbourhood, companionship and instrumental support were strongest predictors for social loneliness. Demographic variables predicted variability in emotional loneliness.ConclusionsThe strength of the correlates differed between the two dimensions of loneliness. In the design of interventions to prevent and reduce loneliness among older adults, strategies should be developed aimed at the specific dimensions of loneliness.

Aim: To investigate the health-related quality of life (HRQOL) of Dutch adult childhood cancer survivors (CCS) and to identify risk factors of impaired HRQOL.Methods: Adult CCS (age >18, diagnosed = 5 years since diagnosis) from the Dutch LATER registry completed the Medical Outcome Study Short Form 36 (SF-36) to measure HRQOL and provided sociodemographic characteristics. Age-adjusted mean SF-36 scale scores of CCS were compared to the Dutch general population for men and women separately using t-tests, with effect size d. Multivariate logistic regression models were built to identify sociodemographic and cancer-related risk factors for impaired physical and mental HRQOL.Results: Both male and female CCS (N = 2301, mean age = 35.4 years, 49.6% female) reported significantly (p

Controlled human infections provide opportunities to study the interaction between the immune system and malaria parasites, which is essential for vaccine development. Here, we compared immune signatures of malaria-naive Europeans and of Africans with lifelong malaria exposure using mass cytometry, RNA sequencing and data integration, before and 5 and 11 days after venous inoculation with Plasmodium falciparum sporozoites. We observed differences in immune cell populations, antigen-specific responses and gene expression profiles between Europeans and Africans and among Africans with differing degrees of immunity. Before inoculation, an activated/differentiated state of both innate and adaptive cells, including elevated CD161(+)CD4(+) T cells and interferon-gamma production, predicted Africans capable of controlling parasitemia. After inoculation, the rapidity of the transcriptional response and clusters of CD4(+) T cells, plasmacytoid dendritic cells and innate T cells were among the features distinguishing Africans capable of controlling parasitemia from susceptible individuals. These findings can guide the development of a vaccine effective in malaria-endemic regions.Malaria immunity can be acquired through natural infection, but the correlates of protection are still being determined. Yazdanbakhsh and colleagues combine experimental infection of volunteers with Plasmodium falciparum with systems analysis to throw light on the nature of protective immune responses.

The illicit use of anabolic androgenic steroids (AAS) among adolescents and young adults is a major concern due to the unknown and unpredictable impact of AAS on the developing brain and the consequences of this on mental health, cognitive function and behaviour. The present study aimed to investigate the effects of supra-physiological doses of four structurally different AAS (testosterone, nandrolone, stanozolol and trenbolone) on neurite development and cell viability using an in vitro model of immature primary rat cortical cell cultures. A high-throughput screening image-based approach, measuring the neurite length and number of neurons, was used for the analysis of neurite outgrowth. In addition, cell viability and expression of the Tubb3 gene (encoding the protein beta-III tubulin) were investigated. Testosterone, nandrolone, and trenbolone elicited adverse effects on neurite outgrowth as deduced from an observed reduced neurite length per neuron. Trenbolone was the only AAS that reduced the cell viability as indicated by a decreased number of neurons and declined mitochondrial function. Moreover, trenbolone downregulated the Tubb3 mRNA expression. The adverse impact on neurite development was neither inhibited nor supressed by the selective androgen receptor (AR) antagonist, flutamide, suggesting that the observed effects result from another mechanism or mechanisms of action that are operating apart from AR activation. The results demonstrate a possible AAS-induced detrimental effect on neuronal development and regenerative functions. An impact on these events, that are essential mechanisms for maintaining normal brain function, could possibly contribute to behavioural alterations seen in AAS users.

BackgroundThe success of epilepsy surgery in patients with refractory epilepsy depends upon correct identification of the epileptogenic zone (EZ) and an optimal choice of the resection area. In this study we developed individualized computational models based upon structural brain networks to explore the impact of different virtual resections on the propagation of seizures.MethodsThe propagation of seizures was modelled as an epidemic process (susceptible-infected-recovered (SIR) model) on individual structural networks derived from presurgical diffusion tensor imaging (DTI) in 19 patients. The candidate connections for the virtual resection were all connections from the clinically hypothesized EZ, from which the seizures were modelled to start, to other brain areas. As a computationally feasible surrogate for the SIR model, we also removed the connections that maximally reduced the Eigenvector Centrality (EC) (large values indicate network hubs) of the hypothesized EZ, with a large reduction meaning a large effect. The optimal combination of connections to be removed for a maximal effect were found using simulated annealing. For comparison, the same number of connections were removed randomly, or based on measures that quantify the importance of a node or connection within the network.ResultsWe found that 90% of the effect (defined as reduction of EC of the hypothesized EZ) could already be obtained by removing substantially less than 90% of the connections. Thus, a smaller, optimized, virtual resection achieved almost the same effect as the actual surgery yet at a considerably smaller cost, sparing on average 27.49% (standard deviation: 4.65%) of the connections. Furthermore, the maximally effective connections linked the hypothesized EZ to hubs. Finally, the optimized resection was more effective than random removal of the same number of connections, and equally or more effective than removal based on structural network characteristics.ConclusionThe approach of using reduced EC as a surrogate for simulating seizure propagation can suggest more restrictive resection strategies, whilst obtaining an almost optimal effect on reducing seizure propagation, by taking into account the unique topology of individual structural brain networks of patients.