Cognitive-behavioural therapy combined with music therapy for chronic fatigue following Epstein-Barr virus infection in adolescents: a randomised controlled trial.

BACKGROUND: Cognitive-behavioural therapy (CBT) is effective in chronic fatigue (CF) syndrome. However, CBT has not been investigated in postinfectious CF, nor is it known whether addition of therapeutic elements from other disciplines might be useful. We explored combined CBT and music therapy intervention for CF following Epstein-Barr virus (EBV) infection in adolescents. METHODS: Adolescents (12-20 years old) participating in a postinfectious cohort study who developed CF 6 months after an acute EBV infection were eligible for the present study. A combined CBT and music therapy programme (10 therapy sessions and related homework) was compared with care as usual in a randomised controlled design. Therapists and participants were blinded to outcome evaluation. Endpoints included physical activity (steps/day), symptom scores, recovery rate and possible harmful effects, but the study was underpowered regarding efficacy. Total follow-up time was 15 months. Power analyses suggested that 120 participants would be needed in order to detect a moderate effect size. RESULTS: A total of 91 individuals with postinfectious CF were eligible, and a total of 43 were included (21 intervention group, 22 control group). Concern regarding school absence due to therapy sessions was the main reason for declining participation. Seven individuals left the study during the first 3 months, leaving 15 in the intervention group and 21 in the control group at 3 months follow-up. No harmful effects were recorded, and compliance with appointment was high. In intention-to-treat analyses, the primary endpoint (number of steps/day) did not differ significantly between the intervention group and the control group (difference (95% CI) =-1298 (-4874 to 2278)). Secondary outcome measures were also not significantly different among the two groups. CONCLUSION: An intervention study of combined CBT and music therapy in postinfectious CF is feasible. A fully powered trial is needed to evaluate efficacy; participants' concern regarding school absence should be properly addressed to secure recruitment. TRIAL REGISTRATION NUMBER: ClinicalTrials ID: NCT02499302, registered July 2015.

Cognitive-behavioural therapy combined with music therapy for chronic fatigue following Epstein-Barr virus infection in adolescents: a feasibility study.

​BACKGROUND: Cognitive-behavioural therapy (CBT) is effective in chronic fatigue syndrome. However, CBT has not been investigated in postinfectious chronic fatigue (CF), nor is it known whether addition of therapeutic elements from other disciplines might be feasible. We studied the feasibility of a combined CBT and music therapy intervention for CF following Epstein-Barr virus (EBV) infection in adolescents. ​METHODS: Adolescents (12-20 years old) participating in a postinfectious cohort study who developed CF 6 months after an acute EBV infection were eligible for the present feasibility study. A combined CBT and music therapy programme (10 therapy sessions and related homework) was compared with care as usual in a randomised controlled design. Therapists and participants were blinded to outcome evaluation. Endpoints included physical activity (steps/day), symptom scores, recovery rate and possible harmful effects, but the study was underpowered regarding efficacy. Total follow-up time was 15 months. ​RESULTS: A total of 43 individuals with postinfectious CF were included (21 intervention group, 22 control group). Seven individuals left the study during the first 3 months, leaving 15 in the intervention group and 21 in the control group at 3 months' follow-up. No harmful effects were recorded, and compliance with appointment was high. In intention-to-treat analyses, number of steps/day tended to decrease (difference=-1158, 95% CI -2642 to 325), whereas postexertional malaise tended to improve (difference=-0.4, 95% CI -0.9 to 0.1) in the intervention group at 3 months. At 15 months' follow-up, there was a trend towards higher recovery rate in the intervention group (62% vs 37%). ​CONCLUSION: An intervention study of combined CBT and music therapy in postinfectious CF is feasible, and appears acceptable to the participants. The tendencies towards positive effects on patients' symptoms and recovery might justify a full-scale clinical trial. ​TRIAL REGISTRATION NUMBER: NCT02499302.

Comparative effectiveness of warfarin, dabigatran, rivaroxaban and apixaban in non-valvular atrial fibrillation: A nationwide pharmacoepidemiological study.

OBJECTIVE: To compare effectiveness and safety of warfarin and the direct oral anticoagulants (DOAC) dabigatran, rivaroxaban and apixaban in non-valvular atrial fibrillation in routine care. METHODS: From nationwide registries, we identified treatment-naïve patients initiating warfarin, dabigatran, rivaroxaban or apixaban for non-valvular atrial fibrillation from July 2013 to December 2015 in Norway. We assessed prescription duration using reverse waiting time distribution. Adjusting for confounding in a Cox proportional hazards model, we estimated one-year risks for ischemic stroke, transient ischemic attack (TIA) or systemic embolism, major or clinically relevant non-major bleeding; intracranial; gastrointestinal; and other bleeding. We censored at switch of treatment or 365 days of follow-up. RESULTS: We included 30,820 treatment-naïve patients. Compared to warfarin, the adjusted hazard ratios (HR) for ischemic stroke, TIA or systemic embolism were 0.96 (95% CI 0.71-1.28) for dabigatran, 1.12 (95% CI 0.87-1.45) for rivaroxaban and 0.97 (95% CI 0.75-1.26) for apixaban. Corresponding hazard ratios for major or clinically relevant non-major bleeding were 0.73 (95% CI 0.62-0.86) for dabigatran, 0.97 (95% CI 0.84-1.12) for rivaroxaban and 0.71 (95% CI 0.62-0.82) for apixaban. Statistically significant differences of other safety outcomes compared to warfarin were fewer intracranial bleedings with dabigatran (HR 0.28, 95% CI 0.14-0.56), rivaroxaban (HR 0.40, 95% CI 0.23-0.69) and apixaban (HR 0.56, 95% CI 0.34-0.92); fewer gastrointestinal bleedings with apixaban (HR 0.70, 95% CI 0.52-0.93); and fewer other bleedings with dabigatran (HR 0.67, 95% CI 0.55-0.81) and apixaban (HR 0.70, 95% CI 0.59-0.83). CONCLUSION: After 1 year follow-up in treatment-naïve patients initiating oral anticoagulation for non-valvular atrial fibrillation, all DOACs were similarly effective as warfarin in prevention of ischemic stroke, TIA or systemic embolism. Safety from bleedings was similar or better, including fewer intracranial bleedings with all direct oral anticoagulants, fewer gastrointestinal bleedings with apixaban and fewer other bleedings with dabigatran and apixaban.

Trends in use of warfarin and direct oral anticoagulants in atrial fibrillation in Norway, 2010 to 2015.

PURPOSE: Since 2011, several direct oral anticoagulants (DOACs; dabigatran, rivaroxaban, apixaban) have been introduced as alternatives to warfarin for stroke prophylaxis in atrial fibrillation. We wanted to investigate changes in utilization of oral anticoagulants for atrial fibrillation in Norway following the introduction of DOACs. METHODS: Using nationwide registries, we identified all adults with pharmacy dispensings for warfarin or DOACs between January 2010 and December 2015 in Norway, and used ambulatory reimbursement codes to identify atrial fibrillation as indication. We defined incident use by a 1-year washout period. We describe trends in prevalent and incident use of warfarin and DOACs between 2010 and 2015, as well as patterns of treatment switching for incident users. RESULTS: One hundred twenty-nine thousand two hundred eighty-five patients filled at least one prescription for an oral anticoagulant for atrial fibrillation; the yearly number of incident users increased from 262 to 421 per 100,000 person-years; and the yearly share of incident users who initiated a DOAC increased to 82%. Half the prevalent users were on a DOAC by 2015. Within a year of drug initiation, 6, 12, 16 and 20% of incident users of apixaban, rivaroxaban, warfarin and dabigatran, respectively, switched oral anticoagulant. CONCLUSIONS: Use of DOACs for anticoagulation in atrial fibrillation became more prevalent between 2010 and 2015 in Norway, at the expense of warfarin.

Associations of Maternal Vitamin B12 Concentration in Pregnancy With the Risks of Preterm Birth and Low Birth Weight: A Systematic Review and Meta-Analysis of Individual Participant Data.

Vitamin B12 (hereafter referred to as B12) deficiency in pregnancy is prevalent and has been associated with both lower birth weight (birth weight <2,500 g) and preterm birth (length of gestation <37 weeks). Nevertheless, current evidence is contradictory. We performed a systematic review and a meta-analysis of individual participant data to evaluate the associations of maternal serum or plasma B12 concentrations in pregnancy with offspring birth weight and length of gestation. Twenty-two eligible studies were identified (11,993 observations). Eighteen studies were included in the meta-analysis (11,216 observations). No linear association was observed between maternal B12 levels in pregnancy and birth weight, but B12 deficiency (<148 pmol/L) was associated with a higher risk of low birth weight in newborns (adjusted risk ratio = 1.15, 95% confidence interval (CI): 1.01, 1.31). There was a linear association between maternal levels of B12 and preterm birth (per each 1-standard-deviation increase in B12, adjusted risk ratio = 0.89, 95% CI: 0.82, 0.97). Accordingly, B12 deficiency was associated with a higher risk of preterm birth (adjusted risk ratio = 1.21, 95% CI: 0.99, 1.49). This finding supports the need for randomized controlled trials of vitamin B12 supplementation in pregnancy.

Let-7 miRNA-binding site polymorphism in the KRAS 3'UTR; colorectal cancer screening population prevalence and influence on clinical outcome in patients with metastatic colorectal cancer treated with 5-fluorouracil and oxaliplatin +/- cetuximab.

BACKGROUND: Recent studies have reported associations between a variant allele in a let-7 microRNA complementary site (LCS6) within the 3'untranslated region (3'UTR) of KRAS (rs61764370) and clinical outcome in metastatic colorectal cancer (mCRC) patients receiving cetuximab. The variant allele has also been associated with increased cancer risk. We aimed to reveal the incidence of the variant allele in a colorectal cancer screening population and to investigate the clinical relevance of the variant allele in mCRC patients treated with 1st line Nordic FLOX (bolus 5-fluorouracil/folinic acid and oxaliplatin) +/- cetuximab. METHODS: The feasibility of the variant allele as a risk factor for CRC was investigated by comparing the LCS6 gene frequencies in 197 CRC patients, 1060 individuals with colorectal polyps, and 358 healthy controls. The relationship between clinical outcome and LCS6 genotype was analyzed in 180 mCRC patients receiving Nordic FLOX and 355 patients receiving Nordic FLOX + cetuximab in the NORDIC-VII trial (NCT00145314). RESULTS: LCS6 frequencies did not vary between CRC patients (23%), individuals with polyps (20%), and healthy controls (20%) (P = 0.50). No statistically significant differences were demonstrated in the NORDIC-VII cohort even if numerically increased progression-free survival (PFS) and overall survival (OS) were found in patients with the LCS6 variant allele (8.5 (95% CI: 7.3-9.7 months) versus 7.8 months (95% CI: 7.4-8.3 months), P = 0.16 and 23.5 (95% CI: 21.6-25.4 months) versus 19.5 months (95% CI: 17.8-21.2 months), P = 0.31, respectively). Addition of cetuximab seemed to improve response rate more in variant carriers than in wild-type carriers (from 35% to 57% versus 44% to 47%), however the difference was not statistically significant (interaction P = 0.16). CONCLUSIONS: The LCS6 variant allele does not seem to be a risk factor for development of colorectal polyps or CRC. No statistically significant effect of the LCS6 variant allele on response rate, PFS or OS was found in mCRC patients treated with 1st line Nordic FLOX +/- cetuximab.

A randomized controlled trial on the effectiveness of strength training on clinical and muscle cellular outcomes in patients with prostate cancer during androgen deprivation therapy: rationale and design.

BACKGROUND: Studies indicate that strength training has beneficial effects on clinical health outcomes in prostate cancer patients during androgen deprivation therapy. However, randomized controlled trials are needed to scientifically determine the effectiveness of strength training on the muscle cell level. Furthermore, close examination of the feasibility of a high-load strength training program is warranted. The Physical Exercise and Prostate Cancer (PEPC) trial is designed to determine the effectiveness of strength training on clinical and muscle cellular outcomes in non-metastatic prostate cancer patients after high-dose radiotherapy and during ongoing androgen deprivation therapy. METHODS/DESIGN: Patients receiving androgen deprivation therapy for 9-36 months combined with external high-dose radiotherapy for locally advanced prostate cancer are randomized to an exercise intervention group that receives a 16 week high-load strength training program or a control group that is encouraged to maintain their habitual activity level. In both arms, androgen deprivation therapy is continued until the end of the intervention period.Clinical outcomes are body composition (lean body mass, bone mineral density and fat mass) measured by Dual-energy X-ray Absorptiometry, serological outcomes, physical functioning (muscle strength and cardio-respiratory fitness) assessed with physical tests and psycho-social functioning (mental health, fatigue and health-related quality of life) assessed by questionnaires. Muscle cellular outcomes are a) muscle fiber size b) regulators of muscle fiber size (number of myonuclei per muscle fiber, number of satellite cells per muscle fiber, number of satellite cells and myonuclei positive for androgen receptors and proteins involved in muscle protein degradation and muscle hypertrophy) and c) regulators of muscle fiber function such as proteins involved in cellular stress and mitochondrial function. Muscle cellular outcomes are measured on muscle cross sections and muscle homogenate from muscle biopsies obtained from muscle vastus lateralis. DISCUSSION: The findings from the PEPC trial will provide new knowledge on the effects of high-load strength training on clinical and muscle cellular outcomes in prostate cancer patients during androgen deprivation therapy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00658229.

Sexual function in females after radiotherapy for rectal cancer.

BACKGROUND: Knowledge about female sexual problems after pre- or postoperative (chemo-)radiotherapy and radical resection of rectal cancer is limited. The aim of this study was to compare self-rated sexual functioning in women treated with or without radiotherapy (RT+ vs. RT-), at least two years after surgery for rectal cancer. METHODS AND MATERIALS: Female patients diagnosed from 1993 to 2003 were identified from a national database, the Norwegian Rectal Cancer Registry. Eligible patients were without recurrence or metastases at the time of the study. The Sexual function and Vaginal Changes Questionnaire (SVQ) was used to measure sexual functioning. RESULTS: Questionnaires were returned from 172 of 332 invited and eligible women (52%). The mean age was 65 years (range 42-79) and the time since surgery for rectal cancer was 4.5 years (range 2.6-12.4). Sexual interest was not significantly impaired in RT+ (n=62) compared to RT- (n=110) women. RT+ women reported more vaginal problems in terms of vaginal dryness (50% vs. 24%), dyspareunia (35% vs. 11%) and reduced vaginal dimension (35% vs. 6%) compared with RT- patients; however, they did not have significantly more worries about their sex life. CONCLUSION: An increased risk of dyspareunia and vaginal dryness was observed in women following surgery combined with (chemo-)radiotherapy compared with women treated with surgery alone. Further research is required to determine the effect of adjuvant therapy on female sexual function.

Monitoring of disseminated tumor cells in bone marrow in high-risk breast cancer patients treated with high-dose chemotherapy.

The present study aimed to investigate the clinical relevance of disseminated tumor cells (DTC) in breast cancer patients before and after high-dose adjuvant chemotherapy with or without progenitor stem-cell support. One hundred and eighteen high-risk stage II breast cancer patients entering the Scandinavian Study Group multicenter trial were randomized to 9 cycles of tailored and dose-escalated FEC (5-fluorouracil, epirubicin, cyclophosphamide) or 3 cycles of standard FEC followed by high-dose chemotherapy. Bone marrow (BM) samples at diagnosis and 6 months after completion of chemotherapy were assessed for the presence of cytokeratin positive (CK+) cells. Before treatment, 29% of the patients were CK+ (21% in the dose-escalated group and 36% in the high-dose-group). Six months after treatment, 17% of the patients were CK+ (17 and 16% respectively). Of the 95 patients who were evaluated 6 months after treatment, 60% were consistently CK-. CK+ cells in BM was evaluated as a prognostic and predictive marker and compared to other defined prognostic factors of the primary tumor. Monitoring BM changes at the time of diagnosis and 6 months posttreatment is an independent predictive factor for breast-cancer-specific survival (BCS) (p = 0.001). Those who have consistent CK negative (-) BM findings constitute a group of patients with good prognosis. Our results suggest that changes in CK+ cells in BM before and after chemotherapy can be used clinically as a surrogate maker to predict outcome in breast cancer patients.

Isolated soya protein with standardised levels of isoflavones, cotyledon soya fibres and soya phospholipids improves plasma lipids in hypercholesterolaemia: a double-blind, placebo-controlled trial of a yoghurt formulation.

The objective was to study whether a yoghurt containing isolated soya protein with standardised levels of isoflavones, cotyledon soya fibres and soya phospholipids is more effective in lowering total and LDL-cholesterol than a placebo. One hundred and forty-three subjects were randomised to the soya group (n 69) or to the placebo (n 74). The mean baseline levels were 7.6 and 5.1 mmol/l for total and LDL-cholesterol, respectively. Fasting serum lipoproteins were assessed five times during the 8-week intervention period, and 4 weeks thereafter. The results were analysed by a mixed model for unbalanced repeated measurements. During the intervention, there were highly significant differences in lipid-lowering effect in favour of the active soya intervention group compared with the control group. The significant differences were for total cholesterol (estimated mean difference 0.40 mmol/l; P<0.001), LDL-cholesterol (0.39 mmol/l; P<0.001), non-HDL-cholesterol (0.40 mmol/l; P<0.001) and for the total:HDL-cholesterol ratio (0.23; P=0.005). There was no difference in the effects on HDL-cholesterol, triacylglycerols or homocysteine. The lipid-lowering effect occurred within 1-2 weeks of intervention, and was not due to weight loss. The safety profile for active soya was similar to the placebo group, except for gastrointestinal symptoms, which caused a significantly higher dropout rate (fourteen v. three subjects) among the subjects taking active soya.