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Purpose: High-dose methotrexate (HDMTX) therapy is an important component in treatment regimens for acute lymphoblastic leukemia (ALL). Courses are associated with a risk of renal injury, delayed elimination, and increased systemic toxicity. Recently hypoalbuminemia has been recognized as yet another risk factor., Methods: To examine the impact of serum albumin we reviewed 325 HDMTX 5 g/m2 courses in a cohort of 51 children treated on the NOPHO ALL 2008 protocol, dividing the courses into four groups with different levels of baseline albumin (A < 25 g/L, B 25-29 g/L, C 30-34 g/L and D ≥ 35 g/L)., Results: Hypoalbuminemia was present in 51% of the courses, mostly in the early phases of chemotherapy while asparaginase therapy is ongoing, and especially if given less than 2 weeks after a dose (78%). Hypoalbuminemia had a significant impact on the end-of-infusion serum MTX, depending on the degree of hypoalbuminemia: MTX > 150 µM was seen in 37%, 32%, 20% and 8% in groups A to D. Serum albumin < 30 g/L was significantly associated with low MTX clearance < 10 L/h/1.73m2 (78% vs. 36%) and high AUC ≥ 1000 µM*h (44% vs. 31%). The frequency of rising creatinine or prolonged elimination was not increased, but the risk of stomatitis was significantly higher (42% vs. 19%)., Conclusion: Low serum albumin is caused by concurrent asparaginase therapy and has a clinically significant impact on MTX disposition. Guidelines for administering HDMTX may need adjustment if serum albumin < 30 g/L, and, if possible, HDMTX courses should not be scheduled soon after asparaginase doses., (© 2024. The Author(s).)

Universal screening for defective mismatch repair (dMMR) in colorectal cancer utilizes immunohistochemical staining for MLH1, MSH2, MSH6 and PSM2. Additionally, BRAF V600E mutations status and MLH1 hypermethylation should be performed to distinguish germline and somatic dMMR alterations. A decade of Danish population-based registries has been analysed regarding screening uptake, detection rate and referral to genetic counselling. MMR testing was performed in 71·8% (N = 34,664) of newly diagnosed colorectal cancers with an increasing trend to 88·8% coverage in the study's final year. The likelihood of undergoing MMR testing was reduced in males with 2% (95% CI 0·4-2·7, p = 0·008), with 4·1% in patients above age 70 years (95% CI 1·5-6·6, p = 0·003) compared in patients below age 51 years, with 16·3% in rectal cancers (95% CI 15·1-17·6, p < 0·001) and 1·4% left-sided colon cancers (95% CI 0·1-1·7, p = 0·03) compared to right-sided colon cancers. Tumour stage II and III increased the likelihood of being tested, with 3·7% for stage II (95% CI 2·2-5·6, p < 0·001) and 3·3% for stage III tumours (95% CI 1·8-4·8, p < 0·001) compared to stage I tumours, whereas the likelihood for stage IV tumours is reduced by 35·7% (95% CI 34·2-37·2, p < 0·001). Test rates significantly differed between the Danish health care regions. dMMR was identified in 15·1% (95% CI 14·8-15·6, p < 0·001) cases with somatic MMR inactivation in 6·7% of the cases. 8·3% tumours showed hereditary dMMR expression patterns, and 20·0% of those were referred to genetic counselling. Despite the high uptake rates, we found disparities between patient groups and missed opportunities for genetic diagnostics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Knowledge about effective coping strategies is important to support bereaved adolescents who have lost a parent. We used data on 104 bereaved adolescents (13-17 years) from the FALCON nationwide questionnaire study of parentally bereaved families. We examined associations between adolescents' control-oriented and escape-oriented coping strategies (KidCOPE scale) approximately two months after loss and grief symptoms (PG-13 scale) at six months follow-up. We also examined associations between the perceived efficacy of each coping strategy at baseline and grief symptoms at six months. The use of escape-oriented coping (e.g., distraction, self-criticism and social withdrawal) was associated with higher grief symptoms at six months follow-up (β = 0.4, 95% CI 0.1-0.9, p  = 0.02), but no associations were found for control-oriented coping or perceived coping efficacy. Finding alternatives to the use of escape-oriented coping strategies may be an important part of grief interventions for bereaved adolescents.

Background: Obesity is now the most common health problem in the younger population in Western societies and obesity rates are higher in lower socioeconomic status (SES) groups. We investigated whether overweight in childhood, independently of overweight in adulthood, influenced adult employment status and later risk of having disabilities. Using data from the Danish Female Nurse Cohort study, we examined associations between overweight in childhood/adolescence, and young adulthood and disabilities and early retirement in later adulthood (>44 years) and whether it was influenced by menopausal age (

Objective: This systematic review and meta-analysis aims to investigate the prevalence of cervical high-risk human papillomavirus (hrHPV) among kidney transplant recipients (KTRs) and, furthermore to compare it to that in immunocompetent controls., Methods: A systematic literature search was conducted in PubMed, EMBASE, and Cochrane Library databases from January 2000 to February 2023, to identify studies investigating the prevalence of cervical hrHPV in KTRs. Pooled cervical hrHPV prevalences, odds ratios (ORs) comparing KTRs to controls and corresponding confidence intervals (CIs) were estimated using random effects logistic regression models. Heterogeneity between studies was assessed through the I 2 statistic, and the significance was evaluated by the Cochrane's Q test., Results: Altogether, 16 studies covering >1200 KTRs were included. The prevalence of cervical hrHPV in KTRs was 27.7% (95% CI 21.3-35.1) with substantial interstudy heterogeneity. Stratification indicated a higher prevalence in recent years (2019-2023) and in Asia (39% (95% CI 11.2-61.4)). The prevalence of HPV16 and HPV18 in KTRs was 8.0% (95% CI 3.9-15.9) and 1.7% (95% CI 0.8-3.7), respectively. Comparing hrHPV prevalence in KTRs and controls based on six studies including >500 KTRs and 1000 controls, the OR for hrHPV was 2.0 (95% CI 1.1-3.6)., Conclusions: This meta-analysis establishes an increased cervical hrHPV prevalence in KTRs compared to controls. The increased risk may be associated with immunosuppressive therapy post-transplantation. Further research is needed to explore the potential benefits of HPV vaccination, including potential revaccination strategies in KTRs., Competing Interests: Declaration of competing interest No conflict of interest was reported by the other authors., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Aims: Cardiovascular disease (CVD) aggregates in families and offspring with parental CVD may have adverse risk factor levels long time before the potential onset of CVD. We compared risk factor levels in offspring of parents with atherosclerotic CVD (ASCVD) and parents with no ASCVD at different parental ages at onset., Methods: The study included 5751 participants (median age: 50 years) of the Diet, Cancer and Health - Next Generations study. Measurements included blood pressure, body composition and lipid fractions. Information on parental ASCVD and age at disease onset was obtained through register linkage. Parental ASCVD was defined as myocardial infarction, ischemic stroke or peripheral artery disease occurring <70 years, prematurely (mothers: <65 years fathers: <55 years), divided into age categories or using a broader classification of CVD. Linear regression models using Generalized Estimating Equations were used for analysis. Analyses were adjusted for age, sex, education, smoking, alcohol intake, physical activity and some additionally for BMI., Results: Offspring with parental ASCVD had a higher blood pressure, waist circumference, BMI, visceral adipose tissue, percentage of body fat and non-HDL cholesterol levels, but not other lipid levels, compared to offspring with no parental ASCVD (all p < 0.01). Overall, the same patterns were observed for parental ASCVD occurring prematurely and using a broader CVD classification., Conclusions: Offspring with parental ASCVD had a higher blood pressure, higher body composition measures and higher non-HDL cholesterol levels compared to offspring with no parental ASCVD. Findings were overall consistent across different classifications of parental ASCVD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Prehabilitation with exercise interventions during neoadjuvant chemotherapy (NACT) is effective in reducing physical and psychosocial chemotherapy-related adverse events in patients with cancer. In preclinical studies, data also support a growth inhibitory effect of aerobic exercise on the tumour microenvironment with possible improved chemotherapy delivery but evidence in human patients is limited. The aim of the study here described is to investigate if supervised exercise with high-intensity aerobic and resistance training during NACT can improve tumour reduction in patients with breast cancer., Methods: This parallel two-armed randomized controlled trial is planned to include 120 women aged ≥ 18 years with newly diagnosed breast cancer starting standard NACT at a university hospital in Denmark (a total of 90 participants needed according to the power calculation and allowing 25% (n = 30) dropout). The participants will be randomized to usual care or supervised exercise consisting of high-intensity interval training on a stationary exercise bike and machine-based progressive resistance training offered three times a week for 24 weeks during NACT, and screening-based advice to seek counselling in case of moderate-severe psychological distress (Neo-Train program). The primary outcome is tumour size change (maximum diameter of the largest lesion in millimetre) measured by magnetic resonance imaging prior to surgery. Secondary outcomes include clinical/pathological, physical and patient-reported measures such as relative dose intensity of NACT, hospital admissions, body composition, physical fitness, muscle strength, health-related quality of life, general anxiety, depression, and biological measures such as intratumoural vascularity, tumour infiltrating lymphocytes, circulating tumour DNA and blood chemistry. Outcomes will be measured at baseline (one week before to 1-2 weeks after starting NACT), during NACT (approximately week 7, 13 and 19), pre-surgery (approximately week 21-29), at surgery (approximately week 21-30) and 3 months post-surgery (approximately 33-42 weeks from baseline)., Discussion: This study will provide novel and important data on the potential benefits of supervised aerobic and resistance exercise concomitant to NACT on tumour response and the tumour microenvironment in patients with breast cancer, with potential importance for survival and risk of recurrence. If effective, our study may help increase focus of exercise as an active part of the neoadjuvant treatment strategy., Trial Registration: The trial was registered at ClinicalTrials.gov (NCT04623554) on November 10, 2020., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Malignant liver tumours in children are rare and national outcomes for this tumour entity are rarely published. This study mapped paediatric liver tumours in Denmark over 35 years and reported on the incidence, outcomes and long-term adverse events., Methods: We identified all liver tumours from the Danish Childhood Cancer Registry and reviewed the case records for patient and tumour characteristics, treatment and clinical outcome., Results: We included 79 patients in the analyses. Overall crude incidence was ~2.29 per 1 million children (<15 yr) per year, with 61 hepatoblastomas (HB), 9 hepatocellular carcinomas and 9 other hepatic tumours. Overall 5-year survival was 84%, 78% and 44%, respectively. Nine patients had underlying liver disease or predisposition syndrome. Seventeen children underwent liver transplantation, with two late complications, biliary stenosis and liver fibrosis. For HB, age ≥ 8 years and diagnosis prior to 2000 were significant predictors of a poorer outcome. Adverse events included reduced renal function in 10%, reduced cardiac function in 6% and impaired hearing function in 60% (19% needed hearing aids). Behavioural conditions requiring additional support in school were registered in 10 children., Conclusions: In Denmark, incidences of malignant liver tumours during the last four decades have been increasing, as reported in the literature. HB survival has improved since the year 2000 and is comparable with international results. Reduced hearing is the major treatment-related side effect and affects approximately 60% of patients.

The food frequency questionnaire (FFQ) is designed to capture an individual's habitual dietary intake and is the most applied method in nutritional epidemiology. Our aim was to assess the relative validity and reproducibility of the FFQ used in the Diet, Cancer, and Health-Next Generations cohort (DCH-NG). We included 415 Danish women and men aged 18-67 years. Spearman's correlations coefficients, Bland-Altman limits of agreement and cross-classification between dietary intakes estimated from the FFQ administered at baseline (FFQ baseline ), and the mean of three 24-h dietary recalls (24-HDRs) and the FFQ administered after 12 months (FFQ 12 months ) were determined. Nutrient intakes were energy-adjusted by Nutrient Density and Residual methods. Correlation coefficients ranged from 0.18-0.58 for energy and energy-adjusted nutrient intakes, and the percentage of participants classified into the same quartile ranged from 28-47% between the FFQ baseline and the 24-HDRs. For the FFQ 12 months compared with FFQ baseline , correlation coefficients ranged from 0.52-0.88 for intakes of energy, energy-adjusted nutrients, and food groups, and the proportion of participants classified into the same quartiles ranged from 43-69%. Overall, the FFQ provided a satisfactory ranking of individuals according to energy, nutrient, and food group intakes, making the FFQ suitable for use in epidemiological studies investigating diet in relation to disease outcomes.

Background: More evidence is needed to substantiate current recommendations about removing ovaries during hysterectomy for benign conditions., Objective: To compare long-term outcomes in women with and without bilateral salpingo-oophorectomy (BSO) during hysterectomy for benign conditions., Design: Emulated target trial using data from a population-based cohort., Setting: Women in Denmark aged 20 years or older during 1977 to 2017., Participants: 142 985 women with hysterectomy for a benign condition, 22 974 with BSO and 120 011 without., Intervention: Benign hysterectomy with or without BSO., Measurements: The primary outcomes were overall hospitalization for cardiovascular disease (CVD), overall cancer incidence, and all-cause mortality through December 2018., Results: Compared with women without BSO, women with BSO who were younger than 45 years at surgery had a higher 10-year cumulative risk for hospitalization for CVD (risk difference [RD], 1.19 percentage points [95% CI, 0.09 to 2.43 percentage points]). Women with BSO had a higher 10-year cumulative risk for cancer for ages 45 to 54 years (RD, 0.73 percentage point [CI, 0.05 to 1.38 percentage points]), 55 to 64 years (RD, 1.92 percentage points [CI, 0.69 to 3.25 percentage points]), and 65 years or older (RD, 2.54 percentage points [CI, 0.91 to 4.25 percentage points]). Women with BSO had higher 10-year mortality in all age groups, although the differences were statistically significant only for ages 45 to 54 years (RD, 0.79 percentage point [CI, 0.27 to 1.30 percentage points]). The mortality at 20 years was inconsistent with that at 10 years in women aged 65 years or older., Limitation: Age was a proxy for menopausal status., Conclusion: The authors find that these results support current recommendations for conserving ovaries in premenopausal women without a high risk for ovarian cancer and suggest a cautious approach in postmenopausal women., Primary Funding Source: The Danish Cancer Society's Scientific Committee and the Mermaid Project., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M22-1628.

Introduction: Hemodialysis (HD) induces several physiological changes that can affect plasma glucose levels in patients with diabetes and in turn their glycemic control. Studies using continuous glucose monitoring (CGM) to assess glucose variations on dialysis days compared with nondialysis days report conflicting results. Here, we used CGM to examine glucose variations induced by HD in patients with type 2 diabetes., Methods: Patients with type 2 diabetes undergoing maintenance HD were included. CGM (Ipro2®, Medtronic) was performed at baseline and Week 4, 8, 12, and 16 for up to 7 days at each visit. CGM profiles on days where participants received HD were compared with days without HD using a linear mixed model., Findings: Twenty-seven patients were included. The median number of CGM days performed was 8 (interquartile range [IQR] 6-10) for dialysis days and 16 (IQR 12-17) for nondialysis days. The median sensor glucose was 9.4 (95% confidence interval [CI] 8.8-10.2) mmol/L on dialysis days compared with 9.5 (95% CI 8.9-10.2) mmol/L on nondialysis days (p = 0.58). Nocturnal mean sensor glucose was higher on dialysis days compared with nondialysis days: 8.8 (95% CI 8.0-9.6) mmol/L versus 8.4 (95% CI 7.7-9.2) mmol/L (p = 0.029)., Discussion: Similar median sensor glucose values were found for days on and off HD. Nocturnal glucose levels were modestly increased on dialysis days. Our findings indicate that antidiabetic treatment does not need to be differentiated on dialysis versus nondialysis days in patients with type 2 diabetes undergoing maintenance HD., (© 2023 The Authors. Hemodialysis International published by Wiley Periodicals LLC on behalf of International Society for Hemodialysis.)

Commonly used antihistamines and other cationic amphiphilic drugs (CADs) are emerging as putative cancer drugs. Their unique chemical structure enables CADs to accumulate rapidly inside lysosomes, where they increase lysosomal pH, alter lysosomal lipid metabolism, and eventually cause lysosomal membrane permeabilization. Here, we show that CAD-induced rapid elevation in lysosomal pH is caused by a lysosomal H + efflux that requires P2RX4-mediated lysosomal Ca 2+ release and precedes the lysosomal membrane permeabilization. The subsequent cytosolic acidification triggers the dephosphorylation, lysosomal translocation, and inactivation of the oncogenic signal transducer and activator of transcription 3 (STAT3) transcription factor. Moreover, CAD-induced lysosomal H + efflux sensitizes cancer cells to apoptosis induced by STAT3 inhibition and acts synergistically with STAT3 inhibition in restricting the tumor growth of A549 non-small cell lung carcinoma xenografts. These findings identify lysosomal H + efflux and STAT3 inhibition as anticancer mechanisms of CADs and reinforce the repurposing of safe and inexpensive CADs as cancer drugs with a drug combination strategy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Transurethral resection of recurrent low-grade intermediate-risk Ta bladder tumor (BT) in general anesthesia (GA) is burdensome to patients and health care system. Laser technologies enable treatment in office-based settings, reducing morbidity and costs., Objective: To compare 4-mo recurrence-free survival after outpatient department (OPD) diode laser coagulation of BT in local anesthesia and gold standard transurethral resection of BT (TUR-BT) in GA in intermediate-risk Ta low-grade BT, and to evaluate treatment-related morbidity., Design, Setting, and Participants: A prospective randomized noninferiority trial with 4-mo follow-up, in the hospital setting, was conducted in Capital Region of Denmark from 2016 to 2020. Participants were patients with histologically verified Ta low-grade BT recurrence. A total of 206 patients were randomized; 176 finished treatment and follow-up as per protocol., Intervention: Laser photocoagulation of bladder tumor (PC-BT) in OPD using a 980 nm diode laser compared with gold standard TUR-BT in GA, both performed with photodynamic diagnosis (PDD) guidance., Outcome Measurements and Statistical Analysis: Four-month recurrence-free survival was assessed; predefined inferiority criterion was set at 15%. The secondary outcomes were pain during PC-BT, postoperative morbidity, postoperative complications, and patient's preference., Results and Limitations: Four-month recurrence-free survival was 8% higher after PC-BT (95% confidence interval [CI]: -8% to 24%). The predefined noninferiority criterion was met. Pain score (1-10) during PC-BT was 2.4 (interquartile range 0.8-3.3). Postoperative lower urinary tract symptom score (0-100) was 13.9 points higher (95% CI: 6.9-21.0, p < 0.001) in the group with transurethral resection of the bladder. The frequency of minor complications was 8.1% higher after TUR-BT (95% CI: 1.0-14.6%, p = 0.026). Of the patients, 98% (95% CI: 92-100%) preferred PC-BT., Conclusions: PDD-guided PC-BT in OPD is as good as TUR-BT in GA to remove recurrent low-grade Ta BT. Postoperative quality of life is better after PC-BT and the frequency of minor complications was lower., Patient Summary: This study evaluates the efficacy of outpatient laser removal of low-grade noninvasive bladder tumor. Outpatient tumor removal with laser was as good as transurethral resection in general anesthesia and less burdensome to patients., (Copyright © 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: To examine as secondary analyses the effect the FAMily-Oriented Support (FAMOS) family therapy program on reducing parent-reported medical traumatic stress in the sub-sample of pediatric cancer survivors, age 2-5 years., Methods: The FAMOS study was a national multicenter randomized controlled trial with all four pediatric oncology departments in Denmark (Clinicaltrials.gov [NCT02200731]). Families were randomized in parallel design (1:1) to intervention or usual care. The FAMOS program includes seven home-based psychotherapeutic sessions and is based on family systems therapy to address the individuals in the family system using cognitive behavioral, problem-solving and goal-setting techniques. Questionnaires were completed by parents at baseline, 6, and 12 months. In linear mixed-effects models, the effect of FAMOS on reducing children's trauma-related behavior after 6 and 12 months was examined in 62 children (31 in the intervention and 29 in the control group, respectively). It was also examined if a trauma-related behavior effect was mediated through reduced symptoms of depression in mothers and fathers, respectively., Results: On average, children in the intervention group experienced significantly larger decreases in trauma-related behaviors at 6 and 12 months than the control group (predicted mean difference -3.89, p = .02 and -6.24, p = .003, respectively). The effect on trauma-related behavior was partly mediated through reduced symptoms of depression in mothers, but not fathers., Conclusions: Adding to previously reported positive effects of the FAMOS intervention on parents' symptoms of post-traumatic stress and depression, significant improvements were found in young children's trauma related-behavior. Further research is needed to develop therapy for children with cancer., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Comprehensive data capture systems such as the Operating Room Black Box (OR Black Box) are becoming more widely implemented to access quality data in the complex environment of the OR. Prior to installing an OR Black Box, we assessed perceptions on safety attitudes, impostor phenomenon and privacy concerns around digital information sharing among healthcare professionals in the OR. A parallel survey was conducted in Canada, hence, this study also discusses cultural and international differences when implementing new technology in healthcare., Methods: A cross-sectional survey using three previously validated questionnaires (Safety Attitudes Questionnaire (SAQ), Clance Impostor Phenomenon Scale, Dispositional Privacy Concern) was distributed through Research Electronic Data Capture to 145 healthcare professionals from the OR (July to December 2019). Analysis of variance and analysis of covariance were used to test for differences., Results: 124 responded (86%): 100 completed the survey (69%) (38 nurses, 10 anaesthesiologists, 36 obstetricians/gynaecologists, 16 residents). Significant variability in all six SAQ domains, safety climate and teamwork being the lowest ranked and job satisfaction ranked highest for all groups. The SAQ varied in all domains in Canada. Moderate to frequent impostor phenomenon was experienced by 71% predominantly among residents (p=0.003). 72% in the Canadian study. Residents were most comfortable with digital information sharing (p<0.001), only 13% of all healthcare professionals were concerned/heavy concerned compared with 45% in Canada., Conclusions: The different healthcare professional groups had diverse perceptions about safety culture, but were mainly concerned about safety climate and teamwork in the OR. Impostor phenomenon decreased with age. All groups were unconcerned about digital information sharing. The Canadian study had similar findings in terms of impostor phenomenon, but a variety within the SAQ and were more concerned about data safety, which could be due to medical litigation per se and is not widespread in Scandinavia compared with North America., Competing Interests: Competing interests: TG is the founder and Director of Surgical Safety Technologies and equity holder of Surgical Safety Technologies, Inc., Toronto, Canada., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction and Aim: Low socioeconomic position (SEP) has been shown to be strongly associated with impaired lung cancer survival. Barriers related to receiving recommended treatment among patients with lung cancer with low SEP may include adverse health behaviour and limited physical and psychosocial resources influencing the ability to react on high-risk symptoms and to navigate the healthcare system. To address the underlying factors that drive both decisions of treatment, adherence to treatment and follow-up in vulnerable patients with lung cancer, we developed the Navigate intervention. The aim of this randomised controlled trial is to investigate the effect of the intervention on survival (primary outcome), lung cancer treatment adherence, health-related quality of life and other psychosocial outcomes as well as health costs and process evaluation (secondary outcomes) in a study population of vulnerable patients with lung cancer., Methods and Analysis: This two-armed multicentre randomised trial will recruit patients from five lung cancer clinics in Denmark identified as vulnerable according to a screening instrument with nine clinical and patient-reported vulnerability criteria developed for the study. We will enrol 518 vulnerable patients > 18 years old diagnosed with non-small cell lung cancer at all stages with a performance status < 2. Participants will be randomly allocated to either standard treatment and intervention or standard treatment alone. The Navigate intervention is based on principles from motivational interviewing and includes three components of nurse navigation, systematic monitoring of patient-reported outcomes (PROs) and physical exercise in a person-centred delivery model. Data will be collected at baseline and 3, 6, 12 months after randomisation using questionnaires, clinical data and physical function tests., Ethics and Dissemination: Ethics Committee, Region Zealand (SJ-884/EMN-2020-37380) and the Data Protection Agency in Region Zealand (REG-080-2021) approved the trial. Participants will provide written informed consent. Results will be reported in peer-reviewed journals., Trial Registration Number: NCT05053997., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Poor sleep quality is common during pregnancy. Our objective was to evaluate the effect of supervised group physical exercise on self-reported sleep quality in pregnant women with or at high risk of depression, and secondly, to describe the association between sleep quality and psychological well-being during pregnancy and postpartum. This was a secondary analysis of a randomized controlled trial (n = 282) (NCT02833519) at Rigshospitalet, Denmark. Sleep quality was evaluated using the Pittsburgh Sleep Quality Index (PSQI), psychological well-being by the five-item WHO Well-Being Index (WHO-5). The intention-to-treat analysis showed no difference in mean global PSQI score neither at 29−34 weeks, 6.56 (95% CI: 6.05−7.07) in the intervention group and 7.00 (95% CI: 6.47−7.53) in the control group, p = 0.2, nor at eight weeks postpartum. Women with WHO-5 ≤ 50 reported higher mean global PSQI scores at baseline, 7.82 (95% CI: 7.26−8.38), than women with WHO-5 score > 50, mean 5.42 (95% CI: 5.02−5.82), p < 0.0001. A significant difference was also present post-intervention and eight weeks postpartum. No significant effect of group exercise regarding self-reported sleep quality was seen at 29−34 weeks of gestation or postpartum. Low psychological well-being was associated with poor sleep quality during pregnancy and postpartum.

Minimal residual disease (MRD) constitutes the most important prognostic factor in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Flow cytometry is widely used in MRD assessment, yet little is known regarding the effect of different immunophenotypic subsets on outcome. In this study of 200 BCP-ALL patients, we found that a CD34-positive, CD38 dim-positive, nTdT dim-positive immunophenotype on the leukemic blasts was associated with poor induction therapy response and predicted an MRD level at the end of induction therapy (EOI) of ≥ 0.001. CD34 expression was strongly and positively associated with EOI MRD, whereas CD34-negative patients had a low relapse risk. Further, CD34 expression increased from diagnosis to relapse. CD34 is a stemness-associated cell-surface molecule, possibly involved in cell adhesion/migration or survival. Accordingly, genes associated with stemness were overrepresented among the most upregulated genes in CD34-positive leukemias, and protein-protein interaction networks showed an overrepresentation of genes associated with cell migration, cell adhesion, and negative regulation of apoptosis. The present work is the first to demonstrate a CD34-negative immunophenotype as a good prognostic factor in ALL, whereas high CD34 expression is associated with poor therapy response and an altered gene expression profile reminiscent of migrating cancer stem-like cells., (© 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Children with rheumatic disease and compromised immune system have an increased risk of infection. Streptococcus pneumoniae is a frequent pathogen, and immunization is recommended. In this study, we investigated whether immunocompromised children with rheumatic disease do respond to pneumococcal immunization with 13-valent pneumococcal conjugate vaccine followed by 23-valent pneumococcal polysaccharide vaccine. The study was conducted at two tertiary referral hospitals in Denmark from 2015 to 2018. Patients with rheumatic disease and compromised immune system aged 2-19 years were eligible. Patients were vaccinated with 13-valent pneumococcal conjugate vaccine followed by 23-valent pneumococcal polysaccharide vaccine. A blood sample was collected before vaccination and after each vaccination. IgG antibodies were quantified for twelve serotypes. Seroprotection for each serotype was defined as IgG ≥0.35 µg/mL. A total of 27 patients were enrolled. After the conjugate vaccine, an increase in antibody titres compared with pre-vaccination was found for all serotypes and 9/12 were significant. After the polysaccharide vaccine, the antibody titres for all serotypes but one was seen to increase but none reached significance. The proportion of patients protected before immunization ranged from 20.8% to 100% for the individual serotypes. Odds ratio for achieving seroprotection after the conjugate vaccine was >1 for 10/12 serotypes but only significant for three serotypes. After the polysaccharide vaccine, the odds ratio was >1 for 9/12 serotypes but none reached significance. In conclusion, children with rheumatic disease and compromised immune system respond to pneumococcal immunization with 13-valent pneumococcal conjugate vaccine and maintain antibody levels upon subsequent immunization with 23-valent pneumococcal polysaccharide vaccine., (© 2021 The Scandinavian Foundation for Immunology.)

Introduction: The accuracy of hemoglobin A1c (HbA1c) as a glycemic marker in patients with type 2 diabetes (T2D) receiving hemodialysis (HD) remains unknown. To assess accuracy, we compared HbA1c and fructosamine levels with interstitial glucose measured by continuous glucose monitoring (CGM) in patients with T2D receiving HD., Methods: Thirty patients in the HD group and 36 patients in the control group (T2D and an estimated glomerular filtration rate >60 mL/min/1.73 m2) completed the study period of 17 weeks. CGM (Ipro2®, Medtronic) was performed 5 times for periods of up to 7 days (with 4-week intervals) during a 16-week period. HbA1c (mmol/mol), the estimated mean plasma glucose from HbA1c (eMPGA1c [mmol/L]) and fructosamine (μmol/L) was measured at week 17 and compared with mean sensor glucose levels from CGM., Findings: In the HD group, mean sensor glucose was 1.4 mmol/L (95% confidence interval [CI]: 1.0-1.8) higher than the eMPGA1c, whereas the difference for controls was 0.1 mmol/L (95% CI: -0.1-[0.4]; p < 0.001). Adjusted for mean sensor glucose, HbA1c was lower in the HD group (-7.3 mmol/mol, 95% CI: -10.0-[-4.7]) than in the control group (p < 0.001), with no difference detected for fructosamine (p = 0.64)., Discussion: HbA1c evaluated by CGM underestimates plasma glucose levels in patients receiving HD. The underestimation represents a clinical challenge in optimizing glycemic control in the HD population. Fructosamine is unaffected by the factors affecting HbA1c and appears to be more accurate for glycemic monitoring. CGM or fructosamine could thus complement HbA1c in obtaining more accurate glycemic control in this patient group., (© 2021 S. Karger AG, Basel.)

Objectives: Survival among children diagnosed with acute lymphoblastic leukaemia (ALL) has increased considerably. However, morbidity in survivors constitutes a potential increasing burden not limited to secondary health care. Our objectives were to compare health care utilisation, including both primary and secondary health care, between childhood ALL survivors and matched references up to 15 years after curative treatment. Moreover, to increase knowledge on survivors' health service seeking behaviour as time from treatment elapsed., Design and Setting: A Danish population-based matched cohort study linking multiple nationwide registries., Participants: 675 cases, diagnosed with childhood (1.0-17.9 years) ALL between 1994 and 2015, and 6750 matched references sampled randomly from the source population (matched on age, gender and geographical region)., Primary Outcome Measures: Repeated consultations in general practice and hospital (outpatient and inpatient) estimated as yearly rates from 2.5 years after diagnosis and onwards. We compared cases and references with yearly incidence rate ratios (IRRs) from negative binomial regression models., Results: Survivors of childhood ALL had a mean number of yearly daytime contacts in general practice of 4.75 (95% CI 4.41 to 5.11) the first year, corresponding to an IRR of 1.85 (95% CI 1.71 to 2.00); decreasing to 1.16 (1.01 to 1.34) after 15 years, and without significant impact of gender (p=0.894) or age (p=0.399). For hospital contacts, ALL survivors had a mean number of yearly contacts of 14.21 (13.38-15.08) the first year, corresponding to an IRR of 31.50 (28.29-35.07); decreasing to 2.42 (1.59-3.68) after 15 years. No differences were found across calendar time., Conclusions: ALL survivors used significantly more health care services across sectors than the reference population. Decreasing use over 15 years illustrated the dynamics of health care needs; this knowledge may inform the future organisation of integrated follow-up programmes., Trial Registration Number: NCT03985826., Competing Interests: Competing interests: BKA declares the following: sponsor for the investigator initiated NOR-GRASPALL 2016 study. KS declares the following: Speaker and/or Advisory Board Honoraria from Jazz Pharmaceuticals (2020) and Servier (2020); speaker fee from Amgen (2020) and Medscape (2020); Educational grant from Servier (2020)., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The classic Bernard-Soulier syndrome (BSS) is a rare inherited thrombocytopenia (IT) associated with severe thrombocytopenia, giant platelets, and bleeding tendency caused by homozygous or compound heterozygous variants in GP1BA, GP1BB, or GP9. Monoallelic BSS (mBSS) associated with mild asymptomatic macrothrombocytopenia caused by heterozygous variants in GP1BA or GP1BB may be a frequent cause of mild IT., Objective: We aimed to examine the frequency of mBSS in a consecutive cohort of patients with IT and to characterize the geno- and phenotype of mBSS probands and their family members. Additionally, we set out to examine if thrombopoietin (TPO) levels differ in mBSS patients., Patients/methods: We screened 106 patients suspected of IT using whole exome- or whole genome sequencing and performed co-segregation analyses of mBSS families. All probands and family members were phenotypically characterized. Founder mutation analysis was carried out by certifying that the probands were unrelated and the region around the variant was shared by all patients. TPO was measured by solid phase sandwich ELISA., Results: We diagnosed 14 patients (13%) with mBSS associated with heterozygous variants in GP1BA and GP1BB. Six unrelated probands carried a heterozygous variant in GP1BA (c.58T>G, p.Cys20Gly) and shared a 2.0 Mb region on chromosome 17, confirming that it is a founder variant. No discrepancy of TPO levels between mBSS patients and wild-type family members (P > .05) were identified., Conclusion: We conclude that the most frequent form of IT in Denmark is mBSS caused by the Copenhagen founder variant., (© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)