Factors associated with physical activity in young people with haemophilia A on prophylaxis.

INTRODUCTION: Physical activity (PA) is influenced by numerous factors, and the literature describing why people with haemophilia (PWH) are physically active or not is inconclusive. AIMS: To investigate factors associated with PA (mean min/day in light (LPA), moderate (MPA), vigorous (VPA) and total PA, and proportion meeting World Health Organization (WHO) weekly moderate-to-vigorous (MVPA) recommendations) among young PWH A. METHODS: Forty PWH A on prophylaxis from the HemFitbit study were included. PA was measured using Fitbit devices and participant characteristics were collected. Potential factors associated with PA were investigated by univariable linear regression models for continuous PA outcomes, and descriptively for teenagers meeting/not meeting WHO MVPA recommendations only, because all except one adult met PA recommendations. RESULTS: Mean age (n = 40) was 19.5 years (SD 5.7). Annual bleeding rate was nearly zero and joint scores were low. We found an increase of four min/day in LPA (95% confidence interval (CI) 1-7) per year increase in age. Participants with 'Haemophilia Early Arthropathy Detection with Ultrasound' (HEAD-US) score ≥1 engaged in mean 14 min/day less MPA (95% CI -23.2 to -3.8), and 8 min less VPA (95% CI -15.0 to -0.4) compared to participants with HEAD-US score 0. Teenagers who met PA recommendations had slightly better joint status compared to those who did not meet recommendations. CONCLUSION: These findings indicate that presence of mild arthropathy does not affect LPA but may have a negative impact on PA of higher intensities. Early start of prophylaxis may be an important determinant of PA.

Physical activity in Norwegian teenagers and young adults with haemophilia A compared to general population peers.

INTRODUCTION: Limited evidence exists on objectively measured habitual physical activity (PA) of young people with haemophilia (PWH). AIMS: To compare different outcomes of objective PA between young PWH A and controls using a commercial activity tracker. METHODS: We enrolled males aged 13-30 years with moderate and severe haemophilia A, without inhibitors on regular prophylaxis. PA was measured with the activity tracker Fitbit Charge 3 for 12 weeks. Control group data was obtained from ≈60,000 Fitbit users, matched on age, sex and measurement period. PA variables [steps, intensities, volume, activity types, exercise frequencies and proportion meeting the World Health Organization's moderate-to-vigorous PA (MVPA) recommendations] were compared between groups descriptively and using Welch's two-sample t-test and two-sample test of proportions. RESULTS: Forty PWH A were enrolled (mean age 19.5 years, 50% teenagers, 50% adults, three (7.5%) with moderate and 37 (92.5%) with severe haemophilia). Mean daily steps and minutes MVPA were similar between PWH and controls. PWH spent more time in light PA (mean 227 vs. 192 min/day, P = .033) and exercised more frequently (mean 5.6 vs. 3.9 exercise sessions/week, P < .001). Among teenagers, 40% PWH and 8% controls reached MVPA recommendations, compared to 95% and 100% among adults. The most common type of PA was walking. CONCLUSION: This cohort of young PWH A on prophylactic treatment had PA levels comparable to controls. Still, a considerable proportion of teenagers did not meet the recommended weekly volume of MVPA, and we encourage clinicians to have a particular focus on promoting PA for this group.

Comparison of free-living physical activity measurements between ActiGraph GT3X-BT and Fitbit Charge 3 in young people with haemophilia.

INTRODUCTION: Measurement of physical activity (PA) using commercial activity trackers such as Fitbit devices has become increasingly popular, also for people with haemophilia (PWH). The accuracy of the Fitbit model Charge 3 has not yet been examined. AIMS: To compare the Fitbit Charge 3 against the research-grade accelerometer ActiGraph GT3X-BT in measuring average daily steps and minutes spent in different PA intensities. METHODS: Twenty-four young PWH wore a wrist-worn Fitbit Charge 3 and hip-worn ActiGraph GT3X-BT simultaneously for seven consecutive days in free-living conditions. Correlation of and differences between the devices for daily averages of PA parameters were assessed using Pearson's correlation coefficient and paired t-test, respectively. Agreement between devices was assessed using Bland-Altman plots. RESULTS: Twenty participants (mean age 21.8) were included in the analyses. We found moderate to high correlations between Fitbit and ActiGraph measured daily averages for all PA variables, but statistically significant differences between devices for all variables except daily minutes of moderate PA. Fitbit overestimated average daily steps, minutes of light, vigorous and moderate-to-vigorous PA. Bland-Altman plots showed a measurement bias between devices for all parameters with increasing overestimation by the Fitbit for higher volumes of PA. CONCLUSION: The Fitbit Charge 3 overestimated steps and minutes of light, moderate and moderate-to-vigorous PA as compared to the ActiGraph GT3X-BT, and this bias increased with PA volume. The Fitbit should therefore be used with caution in research, and we advise users of the device to be cognizant of this overestimation.

Physical fitness and modifiable cardiovascular disease risk factors in survivors of childhood cancer: A report from the SURfit study.

BACKGROUND: Childhood cancer survivors are at risk for cardiovascular disease (CVD) because of intensive cancer therapies often accompanied by an unhealthy lifestyle. This study was aimed at 1) describing modifiable CVD risk factors in survivors and 2) investigating the association between different aspects of physical fitness and CVD risk factors. METHODS: The authors analyzed cross-sectional data from ≥5-year survivors who were 16 years old or younger at their cancer diagnosis and 16 years old or older at the time of the study. Single CVD risk factors (waist circumference, blood pressure, fasting glucose, inverse high-density lipoprotein, and triglycerides), a composite CVD risk score (combined z scores of all CVD risk factors), and metabolic syndrome were evaluated. Physical fitness measures included cardiopulmonary exercise testing (CPET), a handgrip test, and a 1-minute sit-to-stand test (STS). Multivariable logistic regression was used for the association between fitness measures and CVD risk factors, with adjustments made for demographic factors and cancer therapy. RESULTS: This study included 163 survivors with a median age at diagnosis of 7 years and a median age at the time of the study of 28 years. Among those survivors, 27% had a high waist circumference, 32% had high blood pressure, 19% had high triglycerides, 20% had an increased composite CVD risk score, and 10% had metabolic syndrome. A better performance during CPET, handgrip testing, and STS was associated with a lower probability of having a high waist circumference, high triglycerides, and metabolic syndrome. CONCLUSIONS: Better aerobic fitness (CPET) and, to a lesser extent, handgrip and STS were associated with fewer CVD risk factors. Further investigations are warranted to investigate which fitness measures should preferably be used to screen survivors to promote physical activity in those with impaired test performance. LAY SUMMARY: This study investigated the relationship between physical fitness of adult childhood cancer survivors and their risk factors for cardiovascular disease. Cardiovascular risk factors such as high blood pressure, a high waist circumference, and high blood lipids were frequently found in childhood cancer survivors. Survivors with better physical fitness (measured by a cycling test or simple strength and endurance tests) had a lower chance of having cardiovascular risk factors. This suggests that childhood cancer survivors could benefit from physical activity and general fitness by increasing their physical fitness and possibly decreasing their risk of cardiovascular disease.

Cancer incidence and mortality among firefighters.

Firefighters are exposed to both known and suspected carcinogens. This study aims to systematically review the literature on the association of firefighting occupation and cancer incidence and mortality, overall and for specific cancer sites. A systematic review using PubMed, Embase, and Web of Science was performed up to January 1, 2018. We extracted risk estimates of cancers and calculated summary incidence risk estimates (SIRE), summary mortality risk estimates (SMRE), and their 95% confidence intervals (CI). Publication bias and risk of bias in individual studies were assessed using Begg's and Egger's tests and the Newcastle-Ottawa scale (NOS), respectively. We included 50 papers in the review and 48 in the meta-analysis. We found significantly elevated SIREs for cancer of the colon (1.14; CI 1.06 to 1.21), rectum (1.09; CI 1.00 to 1.20), prostate (1.15; CI 1.05 to 1.27), testis (1.34; CI 1.08 to 1.68), bladder (1.12; CI 1.04 to 1.21), thyroid (1.22; CI 1.01 to 1.48), pleura (1.60; CI 1.09 to 2.34), and for malignant melanoma (1.21; CI 1.02 to 1.45). We found significant SMREs of 1.36 (1.18 to 1.57) and 1.42 (1.05 to 1.90) for rectal cancer and Non-Hodgkin's lymphoma, respectively. Considering the significantly elevated risk of some cancers in this occupational group, we suggest improving preventive measures and securing adequate and relevant medical attention for this group. Further studies with more accurate and in-depth exposure assessments are indicated.

Electronic checklists improve referral letters in gastroenterology: a randomized vignette survey.

OBJECTIVE: Investigate whether gastroenterologists rate the quality of referral letters higher if electronic dynamic checklist items are added to a standard free-text referral letter. Assess how this affects the gastroenterologists' assessment of the patient's need for healthcare and the agreement between their assessments. DESIGN: Randomized vignette study. SETTING: Norwegian primary gastroenterology services. PARTICIPANTS: Thirty-two Norwegian gastroenterologists. INTERVENTION: Between June 2015 and January 2016, participants were recruited through an open invitation to all members of the Norwegian Society of Gastroenterology. They were asked to rate 16 referral letters (vignettes) in a web interface: eight letters in free text following a general template and eight letters based on a general referral template combined with diagnosis-specific checklist items. The study was completed in two subsequent rounds ≥3 months apart. MAIN OUTCOME MEASURES: Quality of referral letters assessed on a rating scale from 0 to 10. Agreement in the referral assessment and accuracy of the selection of correct preliminary diagnosis and appropriate work-up. RESULTS: The mean quality assesses on the rating scale was 7.0 (95% confidence interval [CI] 6.8-7.2) for all letters combined (n = 511), 6.5(CI 6.2-6.8) for the free-text referrals (n = 256) and 7.5(CI 7.3-7.7) for the checklist referrals (n = 255) (P < 0.001, paired t-test). No difference was observed in the triage of the patients, but fewer gastroenterologists felt the need to collect additional information about the patients in the checklist group. CONCLUSION: Checklist items may ease the assessment of the referrals for gastroenterologists. We were not able to show that checklists significantly influence the management of patients.

Physical Activity, Fitness, and Cardiovascular Disease Risk in Adolescent Childhood Cancer Survivors Compared to Controls: The Physical Activity in Childhood Cancer Survivors Study.

Purpose: Childhood cancer survivors have increased risk of cardiac late effects that can be potentially mitigated by physical activity and fitness. We aimed to (1) compare cardiovascular disease (CVD) risk between survivors and controls, and (2) examine whether the associations of moderate-to-vigorous physical activity (MVPA), cardiorespiratory fitness (CRF), and musculoskeletal fitness (MSF) with CVD risk factors differed between survivors and controls. Methods: Within the Physical Activity in Childhood Cancer Survivors (PACCS) study, we assessed CVD risk factors (android fat mass, systolic blood pressure [SBP], total cholesterol/high-density lipoprotein [HDL]-cholesterol, and glycosylated hemoglobin) in 157 childhood cancer survivors and 113 age- and sex-matched controls aged 9-18 years. We used multivariable mixed linear regression models to compare CVD risk factors between survivors and controls, and assess associations of MVPA, CRF, and MSF with CVD risk factors. Results: Compared with controls, survivors had more android fat mass (861 vs. 648 g, p = 0.001) and lower SBP (114 vs. 118 mmHg, p = 0.002). MVPA, CRF, and MSF were associated with lower levels of android fat mass and total cholesterol/HDL-cholesterol, and higher SBP in survivors. Associations of MVPA, CRF, and MSF with CVD risk factors were similar in survivors and controls (Pinteraction > 0.05), except the associations of CRF and MSF with android fat mass, which were stronger in survivors than in controls (Pinteraction ≤ 0.001). Conclusion: Owing to higher levels of android fat mass and its stronger association with physical fitness in childhood cancer survivors compared with controls, survivors should get targeted interventions to increase fitness to reduce future risk of CVD.

Maternal use of snus as smokeless tobacco in pregnancy and infant lung function.

Background: Smoking in pregnancy has detrimental effects on infant respiratory health, while the effects of other nicotine-containing products on infant lung function are unclear. We aimed to explore if smokeless tobacco such as snus used in pregnancy increased the risk of lower lung function in infancy and if the associations differed by sex. Methods: From the Scandinavian population-based Preventing Atopic Dermatitis and ALLergies in Children birth cohort, we included 1163 infants with available tidal flow-volume measurements at 3 months of age and maternal self-reported use of nicotine-containing products in pregnancy. The risk of a ratio of time to peak tidal expiratory flow to total expiratory time <25th percentile by any nicotine exposure, snus exclusively and cigarette smoking with or without other nicotine-containing products was explored by regression analyses adjusting for maternal age, education and asthma. Results: Overall 120 out of 1163 (10.3%) infants were exposed to any nicotine in utero, 71 out of 120 by snus exclusively and 49 out of 120 by smoking, with six also exposed to snus. By pregnancy week 6, 85.8% of mothers reported stopping nicotine use. The risk of lower lung function was higher in children exposed in utero to nicotine-containing products with an odds ratio (OR) of 1.63 (95% confidence interval (CI) 1.02-2.59) with a similar tendency for snus exclusively (OR 1.55, 95% CI 0.88-2.71) and smoking (OR 1.79, 0.84-3.84). Effect estimates were similar after adjusting for covariates. No differences of the effect by sex were observed. Conclusion: Our study suggests that in utero exposure to not only cigarettes, but also snus, may negatively affect infant lung function.

Clinical trial: An open-label, randomised trial of different re-start strategies after treatment withdrawal in HBeAg negative chronic hepatitis B.

BACKGROUND: Stopping nucleos(t)ide analogue (NA) therapy in patients with chronic hepatitis B (CHB) may trigger a beneficial immune response leading to HBsAg loss, but clinical trials on re-start strategies are lacking. AIM: To assess whether it is beneficial to undergo a prolonged flare after NA cessation. METHODS: One-hundred-and-twenty-seven patients with HBeAg negative, non-cirrhotic CHB with at least 24 months of viral suppression on NA therapy were included. All study participants stopped antiviral therapy and were randomised to either low-threshold (ALT > 80 U/L and HBV DNA > 2000 IU/mL) or high-threshold (ALT > 100 U/L for >4 months, or ALT > 400 U/L for >2 months) for the re-start of therapy. The primary endpoint was HBsAg loss within 36 months of stopping antiviral treatment. The primary analysis was based on intention-to-treat allocation with last observation carried forward. RESULTS: There was a numerical but not statistically significant difference in HBsAg loss between the low-threshold (3 of 64; 4.7%) and the high-threshold (8 of 63; 12.7%) group (risk difference: 8.0%, 95% CI: -2.3 to 19.6, p = 0.123). None of the patients with end-of-treatment HBsAg > 1000 IU/mL achieved HBsAg loss; among those with end-of-treatment HBsAg < 1000 IU/mL, 8 of 15 (53.3%) achieved HBsAg loss in the high-threshold group compared to 3 of 26 (11.5%) in the low-threshold group. CONCLUSIONS: We could not confirm our hypothesis that a higher threshold for restart of therapy after NA withdrawal improves the likelihood of HBsAg loss within 36 months in patients with HBeAg negative CHB. Further studies including only patients with HBsAg level <1000 IU/mL and/or larger sample size and longer follow-up duration are recommended.

Polyneuropathy in Adolescent Childhood Cancer Survivors: The PACCS Study.

BACKGROUND: Childhood cancer survivors (CCS) are at risk of polyneuropathy due to chemotherapy, but studies in young survivors are scarce and diagnosis is challenging. We aimed to study the presence of polyneuropathy and the possible effect of cumulative doses of chemotherapeutic agents in a representative group of adolescent survivors. METHODS: CCS aged nine to 18 years and age- and sex-matched controls were recruited from the cross-sectional Physical Activity and Fitness among Childhood Cancer Survivors (PACCS) study. CCS with various cancer diagnoses who had ended cancer treatment one year or more before study were included. Polyneuropathy was evaluated clinically and with nerve conduction studies (NCSs) in three motor and five sensory nerves. We used mixed-effects linear regression models to compare CCS and controls, and investigate possible associations between cumulative chemotherapy doses and NCS amplitudes. RESULTS: A total of 127 CCS and 87 controls were included, with 14% CCS having probable or confirmed polyneuropathy. NCS amplitudes were lower in survivors compared with controls in all nerves. The largest mean difference was 3.47 µV (95% confidence interval [CI], 2.18 to 4.75) in the tibial plantar medial sensory and 1.91 mV (95% CI, 0.78 to 3.04) in the tibial motor nerve. The cumulative dose of platinum derivatives was associated with lower tibial motor nerve amplitude (-0.20; 95% CI, -0.35 to -0.04 mV for 100 mg/m2 dose increase) but not in other nerves. We found no significant associations between vinca alkaloids cumulative dose and amplitudes. CONCLUSIONS: CCS without clinical signs or symptoms of polyneuropathy may have subtle nerve affection. The clinical long-term impact of this novel observation should be evaluated in larger, longitudinal studies.

Immunoreactive trypsinogen in healthy newborns and infants with cystic fibrosis.

OBJECTIVE: Newborn screening (NBS) for cystic fibrosis (CF) was introduced in Switzerland in 2011 based on an immunoreactive trypsinogen (IRT)-DNA-IRT protocol. CF diagnosis was confirmed by sweat test and/or genetics but remained inconclusive for some newborns (cystic fibrosis transmembrane conductance regulator related metabolic syndrome (CRMS)/CF screen positive, inconclusive diagnosis (CFSPID)). We aimed to (1) Describe IRT levels in healthy newborns in the first year of life and by gestational age (GA), and (2) Compare IRT at two time points between healthy newborns and newborns with CF and CRMS/CFSPID. DESIGN: Retrospective study. SETTING: National NBS database. PATIENTS: All children with an IRT measurement by heel prick test from 2011 to 2019. INTERVENTIONS: None. MAIN OUTCOME MEASURES: IRT values were extracted from the National NBS Laboratory, and clinical characteristics of positively screened children from the CF-NBS database. Second IRT assessment in positively screened children was usually performed after 18-24 days. We calculated internal IRT Z-Scores and multiples of the median to compare our results across different laboratory tools. RESULTS: Among 815 899 children; 232 were diagnosed with CF, of whom 36 had meconium ileus (MI); 27 had CRMS/CFSPID. Among all samples analysed, mean IRT Z-Scores were higher for newborns with GA <33 weeks and ≥43 weeks (all Z-Scores >0.11) compared with term babies (all Z-Scores ≤0.06). Repeated IRT Z-Scores after a median (IQR) of 19 (17-22) days remained high for infants with CF with or without MI but decreased for infants with CRMS/CFSPID. CONCLUSIONS: Measurement of a second IRT value can help distinguish between children with CRMS/CFSPID and CF, early in life.

Graft-Versus-Host-Disease and Health-Related Quality of Life in Young Long-term Survivors of Cancer and Allogeneic Hematopoietic Stem Cell Transplantation.

Purpose: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an established treatment predominantly for malignancies. Chronic graft-versus-host disease (cGVHD) is the leading long-term complication after allo-HSCT, but knowledge on cGVHD and health-related quality of life (HRQOL) in long-term survivors of allo-HSCT performed in childhood, adolescence, and young adulthood (CAYA) is scarce. Therefore, we aimed to (1) assess prevalence and risk factors of active cGVHD using the 2014 National Institutes of Health-Consensus criteria, (2) investigate associations between cGVHD severity, patient-reported symptom burden, and HRQOL, and (3) compare HRQOL of survivors to population norms. Methods: We conducted a nationwide cross-sectional study in long-term survivors of CAYA allo-HSCT combining clinical examinations and patient-reported outcome measures. Results: We included 103 survivors, 55 (53%) females, median age of 19.6 years [range 0.3-29.9] at HSCT, 16.8 years [6.0-32.0] from HSCT, and 77 (75%) with underlying malignancy. Overall, 32 (31%) survivors were diagnosed with active cGVHD. The risk of active cGVHD was increased with prior acute GVHD and reduced with in vivo T cell depletion. cGVHD severity was associated with increased symptom burden, but not with adverse HRQOL. Compared to Norwegian population norms, allo-HSCT survivors reported significantly lower HRQOL. Conclusion: These results indicate a high prevalence of cGVHD in long-term survivors of CAYA allo-HSCT. Although we did not find an association between cGVHD severity and HRQOL, survivors reported significantly poorer HRQOL compared to population norms. Knowledge on the long-term consequences of cGVHD will be important for optimizing treatment and long-term follow-up care after CAYA allo-HSCT.

Effects of remdesivir in patients hospitalised with COVID-19: a systematic review and individual patient data meta-analysis of randomised controlled trials.

BACKGROUND: Interpretation of the evidence from randomised controlled trials (RCTs) of remdesivir in patients treated in hospital for COVID-19 is conflicting. We aimed to assess the benefits and harms of remdesivir compared with placebo or usual care in these patients, and whether treatment effects differed between prespecified patient subgroups. METHODS: For this systematic review and meta-analysis, we searched PubMed, Embase, the Cochrane COVID-19 trial registry, ClinicalTrials.gov, the International Clinical Trials Registry Platform, and preprint servers from Jan 1, 2020, until April 11, 2022, for RCTs of remdesivir in adult patients hospitalised with COVID-19, and contacted the authors of eligible trials to request individual patient data. The primary outcome was all-cause mortality at day 28 after randomisation. We used multivariable hierarchical regression-adjusting for respiratory support, age, and enrollment period-to investigate effect modifiers. This study was registered with PROSPERO, CRD42021257134. FINDINGS: Our search identified 857 records, yielding nine RCTs eligible for inclusion. Of these nine eligible RCTs, individual data were provided for eight, covering 10 480 patients hospitalised with COVID-19 (99% of such patients included in such RCTs worldwide) recruited between Feb 6, 2020, and April 1, 2021. Within 28 days of randomisation, 662 (12·5%) of 5317 patients assigned to remdesivir and 706 (14·1%) of 5005 patients assigned to no remdesivir died (adjusted odds ratio [aOR] 0·88, 95% CI 0·78-1·00, p=0·045). We found evidence for a credible subgroup effect according to respiratory support at baseline (pinteraction=0·019). Of patients who were ventilated-including those who received high-flow oxygen-253 (30·0%) of 844 patients assigned to remdesivir died compared with 241 (28·5%) of 846 patients assigned to no remdesivir (aOR 1·10 [0·88-1·38]; low-certainty evidence). Of patients who received no oxygen or low-flow oxygen, 409 (9·1%) of 4473 patients assigned to remdesivir died compared with 465 (11·2%) of 4159 patients assigned to no remdesivir (0·80 [0·70-0·93]; high-certainty evidence). No credible subgroup effect was found for time to start of remdesivir after symptom onset, age, presence of comorbidities, enrolment period, or corticosteroid use. Remdesivir did not increase the frequency of severe or serious adverse events. INTERPRETATION: This individual patient data meta-analysis showed that remdesivir reduced mortality in patients hospitalised with COVID-19 who required no or conventional oxygen support, but was underpowered to evaluate patients who were ventilated when receiving remdesivir. The effect size of remdesivir in patients with more respiratory support or acquired immunity and the cost-effectiveness of remdesivir remain to be further elucidated. FUNDING: EU-RESPONSE.

Investigating survival, quality of life and cognition in PROton versus photon therapy for IDH-mutated diffuse grade 2 and 3 GLIOmas (PRO-GLIO): a randomised controlled trial in Norway and Sweden.

INTRODUCTION: The use of proton therapy increases globally despite a lack of randomised controlled trials demonstrating its efficacy and safety. Proton therapy enables sparing of non-neoplastic tissue from radiation. This is principally beneficial and holds promise of reduced long-term side effects. However, the sparing of seemingly non-cancerous tissue is not necessarily positive for isocitrate dehydrogenase (IDH)-mutated diffuse gliomas grade 2-3, which have a diffuse growth pattern. With their relatively good prognosis, yet incurable nature, therapy needs to be delicately balanced to achieve a maximal survival benefit combined with an optimised quality of life. METHODS AND ANALYSIS: PRO-GLIO (PROton versus photon therapy in IDH-mutated diffuse grade 2 and 3 GLIOmas) is an open-label, multicentre, randomised phase III non-inferiority study. 224 patients aged 18-65 years with IDH-mutated diffuse gliomas grade 2-3 from Norway and Sweden will be randomised 1:1 to radiotherapy delivered with protons (experimental arm) or photons (standard arm). First intervention-free survival at 2 years is the primary endpoint. Key secondary endpoints are fatigue and cognitive impairment, both at 2 years. Additional secondary outcomes include several survival measures, health-related quality of life parameters and health economy endpoints. ETHICS AND DISSEMINATION: To implement proton therapy as part of standard of care for patients with IDH-mutated diffuse gliomas grade 2-3, it should be deemed safe. With its randomised controlled design testing proton versus photon therapy, PRO-GLIO will provide important information for this patient population concerning safety, cognition, fatigue and other quality of life parameters. As proton therapy is considerably more costly than its photon counterpart, cost-effectiveness will also be evaluated. PRO-GLIO is approved by ethical committees in Norway (Regional Committee for Medical & Health Research Ethics) and Sweden (The Swedish Ethical Review Authority) and patient inclusion has commenced. Trial results will be published in international peer-reviewed journals, relevant conferences, national and international meetings and expert forums. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT05190172).

Device-measured physical activity and cardiovascular disease risk in adolescent childhood cancer survivors. A physical activity in childhood cancer survivors (PACCS) study.

Objectives: We aimed to compare cardiovascular disease (CVD) risk factors in childhood cancer survivors (CCS) with age- and sex-stratified reference material and examine the association between physical activity (PA) intensities and CVD risk factors in CCS. Materials and methods: Within the cross-sectional, multicenter Physical Activity in Childhood Cancer Survivors (PACCS) study, we collected data on CVD risk factors [VO2-peak (mL⋅kg-1⋅min-1), body mass index (BMI, kg/m2), systolic blood pressure (SBP, mmHg), and total-cholesterol/HDL-cholesterol (Total/HDL)] among CCS aged 9-18 years. CVD risk factors were compared to references with immediate t-tests. We transformed CVD risk factors into z-scores based on international references and generated an individual CVD risk score: [inverse ZVO2-peak + Z BMI + Z SBP + Z Total/HDL )/4]. Multivariable mixed linear regression models were used to analyze the associations between device-measured PA intensities and CVD risk factors. Results: We included 157 CCS aged on average 13.4 years at inclusion and 8.2 years from diagnosis. Male CCS had lower VO2-peak compared to references (45.4 vs. 49.4 mL⋅kg-1⋅min-1, P = 0.001), higher diastolic BP (67 vs. 63 mmHg, P < 0.001), lower HDL (1.35 vs. 1.44 mmol/L, P = 0.012), as well as a tendency to higher CVD risk score (z-score=0.14 vs. 0.00, P = .075). Female CCS' CVD risk factors were comparable to references. Vigorous-intensity PA (VPA) was associated with CVD risk factors. A 10-min increase in VPA was associated with higher VO2-peak (ß = 4.9, 95% CI, 2.1-7.7), lower Total/HDL (ß = -0.3, 95% CI, -0.6 to -0.1) and a lower CVD risk score (ß = -0.4, 95% CI, -0.6 to -0.2). Conclusion: Male adolescent CCS had less favorable values of CVD risk factors compared to references. VPA in adolescent CCS is associated with clinically meaningful favorable values of CVD risk factors.

Infant lung function: criteria for selecting tidal flow-volume loops.

Background: Tidal flow-volume (TFV) loops are commonly recorded in infants during sleep, due to the more regular breathing patterns compared to the awake state. Standardised deselection of loops outside pre-specified ranges are based on periods of regular breathing, while criteria and available software for visual evaluation of TFV loops are lacking. We aimed to determine the reliability of standardised criteria for manual selection of infant TFV loops. Methods: Using a pre-defined set of criteria, three independent raters manually evaluated TFV loops among 57 randomly selected awake healthy 3-month-old infants with available TFV measurements in the Scandinavian Preventing Atopic Dermatitis and ALLergies in children (PreventADALL) study. The TFV loops were sampled using the Eco Medics Exhalyzer D. Criteria for selecting TFV loops included reproducible shape and volume with only one peak in tidal expiratory flow (PTEF), excluding loops with no clear or uneven flow towards PTEF. By intraclass coefficient (ICC), the reliability of agreement between raters was determined for the time to PTEF (t PTEF) to expiratory time (t E) and other TFV loop parameters. Results: Five infants had unsuccessful tests. Among the remaining 52 infants, the raters selected a median of 25, 26 and 15 loops per test. The ICCs (95% CI) were 0.97 (0.92-0.98) for t PTEF/t E, 0.99 (0.99-1.00) for respiratory rate, 0.98 (0.97-0.99) for tidal volume per kg and 0.98 (0.97-0.99) for expiratory volume, reflecting excellent agreement in all categories. Conclusion: Manual TFV loop selection using standardised criteria provides a reliable alternative for lung function measures in awake infants with interrupted breathing cycles in a real-life setting.

The Physical Activity and Fitness in Childhood Cancer Survivors (PACCS) Study: Protocol for an International Mixed Methods Study.

BACKGROUND: Survivors of childhood cancer represent a growing population with a long life expectancy but high risks of treatment-induced morbidity and premature mortality. Regular physical activity (PA) may improve their long-term health; however, high-quality empirical knowledge is sparse. OBJECTIVE: The Physical Activity and Fitness in Childhood Cancer Survivors (PACCS) study comprises 4 work packages (WPs) aiming for the objective determination of PA and self-reported health behavior, fatigue, and quality of life (WP 1); physical fitness determination (WP 2); the evaluation of barriers to and facilitators of PA (WP 1 and 3); and the feasibility testing of an intervention to increase PA and physical fitness (WP 4). METHODS: The PACCS study will use a mixed methods design, combining patient-reported outcome measures and objective clinical and physiological assessments with qualitative data gathering methods. A total of 500 survivors of childhood cancer aged 9 to 18 years with ≥1 year after treatment completion will be recruited in follow-up care clinics in Norway, Denmark, Finland, Germany, and Switzerland. All participants will participate in WP 1, of which approximately 150, 40, and 30 will be recruited to WP 2, WP3, and WP 4, respectively. The reference material for WP 1 is available from existing studies, whereas WP 2 will recruit healthy controls. PA levels will be measured using ActiGraph accelerometers and self-reports. Validated questionnaires will be used to assess health behaviors, fatigue, and quality of life. Physical fitness will be measured by a cardiopulmonary exercise test, isometric muscle strength tests, and muscle power and endurance tests. Limiting factors will be identified via neurological, pulmonary, and cardiac evaluations and the assessment of body composition and muscle size. Semistructured, qualitative interviews, analyzed using systematic text condensation, will identify the perceived barriers to and facilitators of PA for survivors of childhood cancer. In WP 4, we will evaluate the feasibility of a 6-month personalized PA intervention with the involvement of local structures. RESULTS: Ethical approvals have been secured at all participating sites (Norwegian Regional Committee for Medical Research Ethics [2016/953 and 2018/739]; the Oslo University Hospital Data Protection Officer; equivalent institutions in Finland, Denmark [file H-19032270], Germany, and Switzerland [Ethics Committee of Northwestern and Central Switzerland, project ID: 2019-00410]). Data collection for WP 1 to 3 is complete. This will be completed by July 2022 for WP 4. Several publications are already in preparation, and 2 have been published. CONCLUSIONS: The PACCS study will generate high-quality knowledge that will contribute to the development of an evidence-based PA intervention for young survivors of childhood cancer to improve their long-term care and health. We will identify physiological, psychological, and social barriers to PA that can be targeted in interventions with immediate benefits for young survivors of childhood cancer in need of rehabilitation. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/35838.

The effect of nicotine-containing products and fetal sex on placenta-associated circulating midpregnancy biomarkers.

BACKGROUND: In utero exposure to nicotine, largely assessed by smoking, is a risk factor for impaired offspring health, while potential effects of non-combustible nicotine use such as snus (oral moist tobacco), are less well-known. Maternal serum concentrations of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) may be viewed as "placenta health markers", known to differ by fetal sex. Maternal smoking during pregnancy has been associated with lower levels of circulating sFlt-1, while the effect of snus on placenta-associated angiogenic factors is unknown. Our aim was to explore if snus and/or smoking exposure was associated with midpregnancy maternal levels of sFlt-1, PlGF and sFlt-1/PlGF ratio if these associations were modified by fetal sex. METHODS: Midpregnancy (16-22 gestational weeks) serum from 2603 Scandinavian women enrolled in the population-based multi-center PreventADALL (Preventing Atopic Dermatitis and ALLergies in children) study was analysed for sFlt-1 and PlGF concentrations by electrochemiluminescence, deriving the sFlt-1/PGF ratio. Nicotine use was assessed by electronic questionnaires at enrollment in 2278 of the women. Univariable and multivariable linear regression models on log transformed outcomes were used to assess the association between nicotine use and biomarker levels. Interaction terms were included to identify whether the associations were modified by fetal sex. RESULTS: Median sFlt-1, PlGF and sFlt-1/PlGF ratios among women with nicotine exposure information were similar to those of all included women and differed by fetal sex. Current snus use was significantly associated with reduced maternal circulating PlGF levels in adjusted analyses [ß - 0.12, (95% CI - 0.20; 0.00) compared to never use, p = 0.020]. A significant interaction between fetal sex and snus exposure was observed for PIGF (p = 0.031). Prior or periconceptional snus use was significantly associated with PIGF in male fetus pregnancies [ß - 0.05 (95% CI - 0.09 to (- 0.02)) and ß - 0.07 (95% CI - 0.12 to (- 0.02)) compared to never use, p = 0.002]. Smoking was not significantly associated with any circulating biomarkers levels. CONCLUSIONS: Midpregnancy maternal angiogenic profile differed by periconceptional snus use and fetal sex. Snus exposure, perceived as "safe" by users, before or during pregnancy seems to affect midpregnancy placental health in a sex dimorphic manner.

Validity of a point-of-care viral load test for hepatitis B in a low-income setting.

The recent launch of the first point-of-care Xpert® hepatitis B virus (HBV) viral load kit from Cepheid could help to scale up treatment for chronic hepatitis B (CHB) in resource-limited settings. This study aimed to assess the performance of the Xpert kit under field conditions in Ethiopia. One-hundred-and-thirty CHB patients with viral loads ranging from <1 log10 to>7 log10 IU/mL were randomly sampled. The viral load was assessed with both the Xpert and the gold standard Abbott RealTime HBV Viral Load assay in each patient. There was a high correlation between the viral loads assessed by Xpert and Abbott (r = 0.948, p < 0.001). The Bland-Altman plot showed a small bias between the two assays, with an on average 0.23 log10 IU/mL higher viral load result of the Xpert kit; 4 samples differed by>1 log10 IU/mL. Using the treatment threshold of 2000 IU/mL in both tests, Xpert had a sensitivity of 94 %, specificity of 71 %, positive predictive value of 70 %, and negative predictive value of 95 %. In conclusion, the Xpert kit demonstrated good validity for the measurement of HBV viral load in a real-life setting.