Methodological aspects of a randomized within-patient concurrent controlled design for clinical trials in spine surgery.

INTRODUCTION: Randomized controlled trials are considered the highest level of evidence, but their feasibility in the surgical field is severely hampered by methodological and practical issues. Concurrent comparison between the experimental and control conditions within the same patient can be an effective strategy to mitigate some of these challenges and improve generalizability, mainly by the elimination of between-patient variability and reduction of the required sample size. This article aims (1) to describe the methodological aspects of a randomized within-patient controlled trial and (2) to quantify the added value of this design, based on a recently completed randomized within-patient controlled trial on bone grafts in instrumented lumbar posterolateral spinal fusion. METHODS: Boundary conditions for the application of the randomized within-patient controlled trial design were identified. Between-patient variability was quantified by the intraclass correlation coefficient and concordance in the primary fusion outcome. Sample size, study duration and costs were compared with a classic randomized controlled trial design. RESULTS: Boundary conditions include the concurrent application of the experimental and control conditions to identical but physically separated sites. Moreover, the outcome of interest should be local, uncorrelated and independently assessable. The spinal fusion outcomes within a patient were found to be more similar than between different patients (intraclass correlation coefficient 32% and concordance 64%), demonstrating a clear effect of patient-related factors. The randomized within-patient controlled trial design allowed a reduction of the sample size to one-third of a parallel-group randomized controlled trial, thereby halving the trial duration and costs. CONCLUSION: When suitable, the randomized within-patient controlled trial is an efficient design that provides a solution to some of the considerable challenges of a classic randomized controlled trial in (spine) surgery. This design holds specific promise for efficacy studies of non-active bone grafts in instrumented posterolateral fusion surgery.

Anti-Müllerian hormone levels and risk of type 2 diabetes in women.

AIMS/HYPOTHESIS: Given its role in ovarian follicle development, circulating anti-Müllerian hormone (AMH) is considered to be a marker of reproductive ageing. Although accelerated reproductive ageing has been associated with a higher risk of type 2 diabetes, research on the relationship between AMH and type 2 diabetes risk is scarce. Therefore, we aimed to investigate whether age-specific AMH levels and age-related AMH trajectories are associated with type 2 diabetes risk in women. METHODS: We measured AMH in repeated plasma samples from 3293 female participants (12,460 samples in total), aged 20-59 years at recruitment, from the Doetinchem Cohort Study, a longitudinal study with follow-up visits every 5 years. We calculated age-specific AMH tertiles at baseline to account for the strong AMH-age correlation. Cox proportional hazards models adjusted for confounders were used to assess the association between baseline age-specific AMH tertiles and incident type 2 diabetes. We applied linear mixed models to compare age-related AMH trajectories for women who developed type 2 diabetes with trajectories for women who did not develop diabetes. RESULTS: During a median follow-up of 20 years, 163 women developed type 2 diabetes. Lower baseline age-specific AMH levels were associated with a higher type 2 diabetes risk (HRT2vsT3 1.24 [95% CI 0.81, 1.92]; HRT1vsT3 1.62 [95% CI 1.06, 2.48]; ptrend = 0.02). These findings seem to be supported by predicted AMH trajectories, which suggested that plasma AMH levels were lower at younger ages in women who developed type 2 diabetes compared with women who did not. The trajectories also suggested that AMH levels declined at a slower rate in women who developed type 2 diabetes, although differences in trajectories were not statistically significant. CONCLUSIONS/INTERPRETATION: We observed that lower age-specific AMH levels were associated with a higher risk of type 2 diabetes in women. Longitudinal analyses did not show clear evidence of differing AMH trajectories between women who developed type 2 diabetes compared with women who did not, possibly because these analyses were underpowered. Further research is needed to investigate whether AMH is part of the biological mechanism explaining the association between reproductive ageing and type 2 diabetes. Graphical abstract.

Informing metastatic colorectal cancer patients by quantifying multiple scenarios for survival time based on real-life data.

Reported median overall survival (mOS) in metastatic colorectal cancer (mCRC) patients participating in systemic therapy trials has increased to over 30 months. It is uncertain whether trial results translate to real-life populations. Moreover, patients prefer presentation of multiple survival scenarios. Population-based data of all stage IV CRC patients diagnosed between 2008 and 2016 were obtained from the Netherlands Cancer Registry, which has a case ascertainment completeness surpassing 95%. We calculated the following percentiles (scenarios) of OS per year of diagnosis for the total population, and for treatment subgroups: 10th (best-case), 25th (upper-typical), 50th (median), 75th (lower-typical) and 90th (worst-case). Twenty-five percent of patients did not receive any antitumor treatment. From 2008 to 2016, mOS of the total population (n = 27275) remained unchanged at approximately 12 months. OS improved only for the upper-typical and best-case patients; by 4.2 to 29.1 months (P < .001), and by 6 to 62 months (P < .001), respectively. No clinically relevant change was observed among patients who received systemic therapy, with mOS close to 15 months and best-case scenario approximately 40 months. A clinically relevant improvement in survival over time was observed in patients who initially received metastasectomy and/or HIPEC only. In contrast to the wide belief based on trial data that mOS of mCRC patients receiving systemic therapy has improved substantially, improvement could not be demonstrated in our real-life population. Clinicians should consider quoting multiple survival scenarios based on real-life data instead of point estimates from clinical trials, when informing patients about their life expectancy.

Gastro-esophageal Reflux After Laparoscopic Gastrostomy Placement in Children.

OBJECTIVES: Gastrostomy placement is frequently performed in pediatric patients who require long-term enteral tube feeding. Evidence on the influence of gastrostomy placement on gastro-oesophageal reflux disease has been inconsistent. The aim of this study was to investigate the influence of gastrostomy on gastro-oesophageal reflux. METHODS: A prospective, longitudinal cohort study was performed including 50 patients who underwent laparoscopic gastrostomy between May 2012 and April 2014. Before and 3 months after surgery 24-hour multichannel intraluminal impedance pH monitoring was performed and caregivers filled out reflux symptom questionnaires. RESULTS: Gastro-oesophageal reflux symptoms were present in a comparable number of patients before (44%) and after gastrostomy placement (40%; P = 0.73). Twenty-five of the patients (50%) underwent both the preoperative and postoperative tests and were included in impedance-pH analysis. Acid exposure time (percentage of time with pH below 4) did not change significantly after gastrostomy placement: from 6.2% (3.0-18.1) to 6.1% (2.6-14.9). The number of reflux episodes did not significantly change, for either liquid [mean difference 4.3 (-4.5 to 13.2)] or mixed liquid-gas reflux [mean difference 2.0 (-9.3 to 13.3)]. Before gastrostomy placement, 18 out of 25 patients had pathological reflux (72%) on pH-impedance measurement. In 4 patients, pathological reflux dissolved, whereas 4 patients newly developed pathological reflux. A low preoperative weight-for-height percentile was associated with increased acid exposure after gastrostomy placement. CONCLUSIONS: Overall, gastrostomy placement was not associated with an increase in acid exposure on 24-hour multichannel intraluminal impedance pH monitoring. Similarly, the prevalence of gastro-oesophageal reflux-related symptoms did not change after gastrostomy.

Health-related quality of life in children after laparoscopic gastrostomy placement.

INTRODUCTION: A gastrostomy placement (GP) is an established treatment to provide enteral feeding in pediatric patients with feeding difficulties aiming to improve nutritional status and health-related quality of life (HRQoL). The aim of this study was to evaluate HRQoL in children with severe feeding difficulties who have undergone GP. MATERIALS AND METHODS: A cross-sectional study was performed including 128 patients who had undergone laparoscopic GP (2004-2011). HRQoL was evaluated using the validated Pediatric Quality of Life 4.0 Inventory. Multiple regression analysis was performed to identify predictors of HRQoL. RESULTS: After a mean follow-up of 4.0 years (interquartile range 2.9-6.2) after GP, mean HRQoL was 53.0 out of 100 (standard deviation 21.1). HRQoL was significantly lower in children with neurologic impairment, with a mean difference of -21.4 points between neurologically impaired and neurologically normal children (p < 0.001). HRQoL was also lower in children with cardiac disease (-19.0 points; p = 0.01) and in children with a history of previous gastrointestinal surgery (-15.2 points; p = 0.03). Feeding through a gastrojejunostomy tube (-33.0 points; p = 0.01) and higher age at the time of operation (-1.2 points per year; p = 0.03) were also associated with lower HRQoL. GP-related complications requiring reintervention were associated with lower HRQoL, although this association was not statistically significant (p = 0.06). CONCLUSIONS: Children with severe feeding difficulty, who have undergone GP, have significantly lower HRQoL compared to a healthy pediatric population. Neurologic impairment, cardiac disease, a history of gastrointestinal surgery, older age, and the need for jejunal feeding through the gastrostomy were predictive of even lower HRQoL.

Vitamin D intake, serum 25-hydroxy vitamin D and pulmonary function in paediatric patients with cystic fibrosis: a longitudinal approach.

Pancreatic-insufficient children with cystic fibrosis (CF) receive age-group-specific vitamin D supplementation according to international CF nutritional guidelines. The potential advantageous immunomodulatory effect of serum 25-hydroxy vitamin D (25(OH)D) on pulmonary function (PF) is yet to be established and is complicated by CF-related vitamin D malabsorption. We aimed to assess whether current recommendations are optimal for preventing deficiencies and whether higher serum 25(OH)D levels have long-term beneficial effects on PF. We examined the longitudinal relationship between vitamin D intake, serum 25(OH)D and PF in 190 CF children during a 4-year follow-up period. We found a significant relationship between total vitamin D intake and serum 25(OH)D (ß = 0·02; 95 % CI 0·01, 0·03; P = 0·000). However, serum 25(OH)D decreased with increasing body weight (ß = -0·79; 95 % CI -1·28, -0·29; P = 0·002). Furthermore, we observed a significant relationship between serum 25(OH)D and forced expiratory volume in 1 s (ß = 0·056; 95 % CI 0·01, 0·102; P = 0·018) and forced vital capacity (ß = 0·045; 95 % CI 0·008, 0·082; P = 0·017). In the present large study sample, vitamin D intake is associated with serum 25(OH)D levels, and adequate serum 25(OH)D levels may contribute to the preservation of PF in children with CF. Furthermore, to maintain adequate levels of serum 25(OH)D, vitamin D supplementation should increase with increasing body weight. Adjustments of the international CF nutritional guidelines, in which vitamin D supplementation increases with increasing weight, should be considered.

A case study of nurse practitioner care compared with general practitioner care for children with respiratory tract infections.

AIM: To compare quality of care provided by nurse practitioners (NP) with care provided by general practitioners (GP) for children with respiratory tract infections (RTI) in the Netherlands. BACKGROUND: Nurse practitioners increasingly manage acute conditions in general practice, with opportunities for more protocolled care. Studies on quality of NPs' care for children with RTIs are limited to the US healthcare system and do not take into account baseline differences in illness severity. DESIGN: Retrospective observational cohort study. METHODS: Data were extracted from electronic healthcare records of children 0-6 years presenting with RTI between January-December 2013. Primary outcomes were antibiotic prescriptions and early return visits. Generalized estimating equations were used to correct for potential confounders. RESULTS: A total of 899 RTI consultations were assessed (168 seen by NP; 731 by GP). Baseline characteristics differed between these groups. Overall antibiotic prescription and early return visit rates were 21% and 24%, respectively. Adjusted odds ratio for antibiotic prescription after NP vs. GP delivered care was 1.40 (95% confidence interval 0.89-2.22) and for early return visits 1.53 (95% confidence interval 1.01-2.31). Important confounder for antibiotic prescription was illness severity. Presence of wheezing was a confounder for return visits. Complication and referral rates did not differ. CONCLUSION: Antibiotic prescription, complication and referral rates for paediatric RTI consultations did not differ significantly between NP and GP consultations, after correction for potential confounders. General practitioners, however, see more severely ill children and have a lower return visit rate. A randomised controlled study is needed to determine whether NP care quality is truly noninferior.

The predictive value of symptoms for anxiety in hospice inpatients with advanced cancer.

ABSTRACTObjective:Insight into symptoms as predictors for anxiety may help to foster early identification of anxiety and to ameliorate anxiety management. The aim of this study was to determine which frequently occurring symptoms are predictors for anxiety in advanced cancer patients recently admitted to a hospice. METHOD: Symptom burden was measured in patients admitted to a hospice who died ≤3 month after admission using the Utrecht Symptom Diary. This is a Dutch-translated and adapted version of the Edmonton Symptom Assessment System to self-assess the 11 most prevalent symptoms and overall well-being on a 0-10 numerical rating scale. Multiple linear regression analysis was employed to analyze the predictive value of fatigue, nausea, pain, dyspnea, depressed mood, insomnia, and well-being on anxiety. RESULTS: A total of 211 patients were included, 42% of whom were men, and the median age was 71 years (range = 31-95). Anxiety was uncommon and rarely severe: 25% had a score ≥1, and 14% had a score >3. After correction for age, gender, and marital status, depressed mood (p = 0.00) and dyspnea (p = 0.01) were independent predictors for anxiety and explained 23% of the variance in anxiety. SIGNIFICANCE OF RESULTS: Hospice inpatients with advanced cancer who suffer from dyspnea and/or depressed mood are at increased risk for anxiety. Treatment of dyspnea and depressed mood may contribute to adequate anxiety management. Further research should explore other factors associated with anxiety, especially in the psychological, social, and spiritual domains.

Laparoscopic antireflux surgery increases health-related quality of life in children with GERD.

INTRODUCTION: Improving health-related quality of life (HRQoL) is increasingly recognized as an essential part of patient care outcome. Little is known about the effect of laparoscopic antireflux surgery (LARS) on the HRQoL in the pediatric patients. The aims of this study were to evaluate the effect of LARS on HRQoL in children with gastroesophageal reflux disease (GERD) and to identify predictors that influence HRQoL outcome after LARS. METHODS: Between 2011 and 2013, 25 patients with therapy-resistant GERD [median age 6 (2-18) years] were included prospectively. Caregivers and children with normal neurodevelopment (>4 years) were asked to fill out the validated PedsQL 4.0 Generic Core Scales before and 3-4 months after LARS. RESULTS: The PedsQL was completed by all caregivers (n = 25) and 12 children. HRQoL total score improved significantly after LARS, both from a parental (p = 0.009) and child's perspective (p = 0.018). The psychosocial health summary and physical health summary scores also improved significantly after LARS. HRQoL before and after LARS was significantly lower in children with impaired neurodevelopment (p < 0.001). However, neurodevelopment did not influence the effect of LARS on HRQoL. The only significant predictor for improvement in HRQoL after LARS was age at the time of operation (p = 0.001). CONCLUSIONS: HRQoL significantly improves after LARS. Although children with impaired neurodevelopment had lower overall HRQoL, neurodevelopment by itself does not predict inferior improvement in HRQoL after LARS. Older children have a more favorable HRQoL outcome after LARS compared to younger children. This may suggest caution when considering LARS in younger GERD patients.

The impact of chronic fatigue syndrome on cognitive functioning in adolescents.

Chronic fatigue syndrome (CFS) is characterized by persistent fatigue and severe disability. Most adolescent patients report attention and concentration problems, with subsequent poor performance at school. This study investigated the impact of CFS on intellectual capacity by (1) assessing discrepancies between current intelligence quotient (IQ) and school level and (2) exploring differences in current IQ and pre-CFS school performance, compared with healthy individuals. Current data was cross-sectionally gathered and compared with retrospective pre-CFS school performance data. Fifty-nine CFS adolescents and 40 controls were evaluated on performance on age-appropriate intelligence tests and school level. Current IQ scores of CFS adolescents were lower than expected on the basis of their school level. Furthermore, there was a difference in intelligence performance across time when current IQ scores were compared with pre-CFS cognitive achievement. Healthy controls did not show any discrepancies. CONCLUSION: According to their pre-CFS intelligence assessments, CFS patients started with appropriate secondary school levels at the age of 12. Our data suggest that CFS may be accompanied by a decline in general cognitive functioning. Given the critical age for intellectual development, we recommend a timely diagnosis followed by appropriate treatment of CFS in adolescents. WHAT IS KNOWN: Adolescent chronic fatigue syndrome (CFS) is a debilitating condition with major impact on social and intellectual development. Most patients report concentration problems, with subsequent poor performance at school. Little is known about the influence of CFS on intellectual performances. WHAT IS NEW: IQ scores of CFS adolescents are lower than the IQ scores of healthy peers with an equivalent school level. There is a decrease in intelligence performance across time when current IQ scores are compared with pre-CFS cognitive achievement. Healthy controls do not show any discrepancies between their current IQ, school level and previous cognitive functioning. This suggest that adolescent CFS may be accompanied by a decline in general cognitive functioning.

Effect of six years intensified multifactorial treatment on levels of hs-CRP and adiponectin in patients with screen detected type 2 diabetes: the ADDITION-Netherlands randomized trial.

BACKGROUND: Levels of high-sensitivity C-reactive protein (hs-CRP) and adiponectin, reflecting chronic inflammation, are associated with cardiovascular disease in type 2 diabetes. The long-term effects of multifactorial therapy in type 2 diabetes patients on CRP and adiponectin are unknown. METHODS: The ADDITION-NL study is a randomized clinical trial among screen-detected type 2 diabetes patients, randomized to intensive treatment (HbA1c <7.0% (53 mmol/mol), blood pressure ≤135/85 mmHg, total cholesterol ≤3.5 mmol/L) or routine care. Hs-CRP and adiponectin were measured before and 1, 2 and 6 years after inclusion. We analysed the effectiveness of the intervention on hs-CRP and adiponectin levels using a mixed effects model, taking into account practice, baseline levels and different medications. RESULTS: A total of 424 patients were included (intensive care n = 235; routine care n = 189). Both groups were well matched. Body mass index, systolic blood pressure, total cholesterol and HbA1c improved significantly more in the intensive care group compared to routine care group. Levels of hs-CRP decreased significantly in both treatment groups over time. Mean hs-CRP in the routine care group was 24% higher (p = 0.0027) than in the intensive treatment group during follow-up. After an initial increase the adiponectin values levelled off to nearly baseline values in both groups. The difference between the two groups after 6 years was 0.44 µg/mL (p = 0.27). CONCLUSIONS: Intensified multifactorial treatment in type 2 diabetes results in an enhanced decrease in hs-CRP. Whether this is clinically meaningful remains uncertain. The link to adiponectin seems to be more complex.

Vitamin E intake, α-tocopherol levels and pulmonary function in children and adolescents with cystic fibrosis.

Pancreatic insufficiency cystic fibrosis (CF) patients receive vitamin E supplementation according to CF-specific recommendations in order to prevent deficiencies. It has been suggested that higher serum α-tocopherol levels could have protective effects on pulmonary function (PF) in patients with CF. Whether current recommendations are indeed optimal for preventing deficiency and whether vitamin E has therapeutic benefits are subjects of debate. Therefore, we studied vitamin E intake as well as the long-term effects of vitamin E intake, the coefficient of fat absorption (CFA) and IgG on α-tocopherol levels. We also examined the long-term effects of serum α-tocopherol and serum IgG on forced expiratory volume in 1 s expressed as percentage of predicted (FEV1% pred.) in paediatric CF patients during a 7-year follow-up period. We found that CF patients failed to meet the CF-specific vitamin E recommendations, but serum α-tocopherol below the 2·5th percentile was found in only twenty-three of the 1022 measurements (2 %). Furthermore, no clear effect of vitamin E intake or the CFA on serum α-tocopherol was found (both P≥ 0·103). FEV1% pred. was longitudinally inversely associated with age (P< 0·001) and serum IgG (P= 0·003), but it was not related to serum α-tocopherol levels. We concluded that in the present large sample of children and adolescents with CF, vitamin E intake was lower than recommended, but serum α-tocopherol deficiency was rare. We found no evidence that higher serum α-tocopherol levels had protective effects on PF. Adjustment of the recommendations to the real-life intake of these patients may be considered.

The Consumer Quality Index in an accident and emergency department: internal consistency, validity and discriminative capacity.

BACKGROUND: Patients' experiences are an indicator of health-care performance in the accident and emergency department (A&E). The Consumer Quality Index for the Accident and Emergency department (CQI A&E), a questionnaire to assess the quality of care as experienced by patients, was investigated. The internal consistency, construct validity and discriminative capacity of the questionnaire were examined. METHODS: In the Netherlands, twenty-one A&Es participated in a cross-sectional survey, covering 4883 patients. The questionnaire consisted of 78 questions. Principal components analysis determined underlying domains. Internal consistency was determined by Cronbach's alpha coefficients, construct validity by Pearson's correlation coefficients and the discriminative capacity by intraclass correlation coefficients and reliability of A&E-level mean scores (G-coefficient). RESULTS: Seven quality domains emerged from the principal components analysis: information before treatment, timeliness, attitude of health-care professionals, professionalism of received care, information during treatment, environment and facilities, and discharge management. Domains were internally consistent (range: 0.67-0.84). Five domains and the 'global quality rating' had the capacity to discriminate among A&Es (significant intraclass correlation coefficient). Four domains and the 'global quality rating' were close to or above the threshold for reliably demonstrating differences among A&Es. The patients' experiences score on the domain timeliness showed the largest range between the worst- and best-performing A&E. CONCLUSIONS: The CQI A&E is a validated survey to measure health-care performance in the A&E from patients' perspective. Five domains regarding quality of care aspects and the 'global quality rating' had the capacity to discriminate among A&Es.

The relationship between body growth and pulmonary function in children with cystic fibrosis.

AIM: To measure the weight and height of children with cystic fibrosis (CF) from 2 to 10 years of age and to investigate the relationship between these parameters and forced expiratory volume in 1 sec (FEV1) beginning at 6 years of age. METHODS: Weight and height were expressed as z-scores for weight-for-age (WFA), height-for-age (HFA), height-adjusted-for-target-height (HFA/TH) and weight-for-height (WFH). The children were categorised as having a z-score ≥0, between 0 and -1, or <-1 based on z-scores at 2 years of age. The cross-sectional and longitudinal relationships between FEV1 and WFA, HFA, HFA/TH and WFH were determined and the predictive value of these parameters for FEV1. RESULTS: We enrolled 156 CF children. Their mean weight and height were below the average for the healthy population. Both WFA and WFH increased with age (primarily before the age of 6), while the reduction in HFA and HFA/TH persisted. Importantly, the yearly decline in FEV1 was significantly slowed [by 1.8 and 1.9% for each unit increase in WFA and WFH (p < 0.015)] in children who gained weight. CONCLUSION: CF patients aged 2 to 10 years have long-term impaired growth. Nevertheless, weight gain slowed the decline in FEV1 in these patients.

Determinants of Physical Activity among Patients with Colorectal Cancer: From Diagnosis to 5 Years after Diagnosis.

INTRODUCTION: Physical activity (PA) is associated with higher quality of life and probably better prognosis among colorectal cancer (CRC) patients. This study focuses on determinants of PA among CRC patients from diagnosis until 5 yr postdiagnosis. METHODS: Sociodemographic and disease-related factors of participants of two large CRC cohort studies were combined. Moderate-to-vigorous PA during sport and leisure time (MVPA-SL) was measured at diagnosis (T0) and 6, 12, 24, and 60 months (T6 to T60) postdiagnosis, using the SQUASH questionnaire. Mixed-effects models were performed to identify sociodemographic and disease-related determinants of MVPA-SL, separately for stage I-III colon (CC), stage I-III rectal cancer (RC), and stage IV CRC (T0 and T6 only). Associations were defined as consistently present when significant at ≥4 timepoints for the stage I-III subsets. MVPA-SL levels were compared with an age- and sex-matched sample of the general Dutch population. RESULTS: In total, 2905 CC, 1459 RC and 436 stage IV CRC patients were included. Patients with higher fatigue scores, and women compared with men had consistently lower MVPA-SL levels over time, regardless of tumor type and stage. At T6, having a stoma was significantly associated with lower MVPA-SL among stage I-III RC patients. Systemic therapy and radiotherapy were not significantly associated with MVPA-SL changes at T6. Compared with the general population, MVPA-SL levels of CRC patients were lower at all timepoints, most notably at T6. CONCLUSIONS: Female sex and higher fatigue scores were consistent determinants of lower MVPA-SL levels among all CRC patients, and MVPA-SL levels were lowest at 6 months postdiagnosis. Our results can inform the design of intervention studies aimed at improving PA, and guide healthcare professionals in optimizing individualized support.

Effect of early intensive multifactorial therapy compared with routine care on self-reported health status, general well-being, diabetes-specific quality of life and treatment satisfaction in screen-detected type 2 diabetes mellitus patients (ADDITION-Europe): a cluster-randomised trial.

AIMS/HYPOTHESIS: The study aimed to examine the effects of intensive treatment (IT) vs routine care (RC) on patient-reported outcomes after 5 years in screen-detected diabetic patients. METHODS: In a pragmatic, cluster-randomised, parallel-group trial, 343 general practices in Denmark, Cambridge and Leicester (UK) and the Netherlands were randomised to screening for type 2 diabetes mellitus plus IT of multiple risk factors in people 40-69 years without known diabetes (n = 1,678 patients) or screening plus RC (n = 1,379 patients). Practices were randomised in a 1:1 ratio according to a computer-generated list. Diabetes mellitus was diagnosed according to WHO criteria. Exclusions were: life expectancy <1 year, housebound, pregnant or lactating, or psychological or psychiatric problems. Treatment targets for IT were: HbA1c <7.0% (53 mmol/mol), BP ≤135/85 mmHg, cholesterol <5 mmol/l in the absence of a history of coronary heart disease and <4.5 mmol/l in patients with cardiovascular (CV) disease; prescription of aspirin to people taking antihypertensive medication and, in cases of CV disease or BP >120/80 mmHg, ACE inhibitors were recommended. After 2003, the treatment algorithm recommended statins to all patients with cholesterol of ≥3.5 mmol/l. Outcome measures were: health status (Euroqol 5 Dimensions [EQ-5D]) at baseline and at follow-up; and health status (36-item Short Form Health Survey [SF-36] and Euroquol Visual Analogue Scale [EQ-VAS]), well-being (12-item Short Form of the Well-Being Questionnaire), diabetes-specific quality of life (Audit of Diabetes-Dependent Quality of Life) and satisfaction with diabetes treatment (Diabetes Treatment Satisfaction Questionnaire) at follow-up. At baseline, standardised self-report questionnaires were used to collect information. Questionnaires were completed at the same health assessment visit as the anthropometric and biochemical measurements. The patients and the staff assessing the outcomes were unaware of the group assignments. Participants were followed for a mean of 5.7 years. Outcome data were available for 1,250 participants in the intensive treatment group (74%) and 967 participants in the routine care group (70%). The estimated differences in means from the four centres were pooled using random effects meta-analysis. Baseline EQ-5D level was used as a covariate in all analyses. RESULTS: EQ-5D values did not change between diagnosis and follow-up, with a median (interquartile range) of 0.85 (0.73-1.00) at baseline and 0.85 (0.73-1.00) at 5 year follow-up. Health status, well-being, diabetes-specific quality of life and treatment satisfaction did not differ between the intensive treatment and routine care groups. There was some heterogeneity between centres (I 2 being between 13% [SF-36 physical functioning] and 73% [EQ-VAS]). CONCLUSIONS/INTERPRETATION: There were no differences in health status, well-being, quality of life and treatment satisfaction between screen-detected type 2 diabetes mellitus patients receiving intensive treatment and those receiving routine care. These results suggest that intensive treatment does not adversely affect patient-reported outcomes. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT00237549 FUNDING: ADDITION-Denmark was supported by the National Health Services, the Danish Council for Strategic Research, the Danish Research Foundation for General Practice, Novo Nordisk Foundation, the Danish Centre for Evaluation and Health Technology Assessment, the Diabetes Fund of the National Board of Health, the Danish Medical Research Council and the Aarhus University Research Foundation. In addition, unrestricted grants from pharmaceutical companies were received. ADDITION-Cambridge was supported by the Wellcome Trust, the Medical Research Council, the NIHR Health Technology Assessment Programme, National Health Service R&D support funding and the National Institute for Health Research. SJG received support from the Department of Health NIHR grant funding scheme. ADDITION-Leicester was supported by Department of Health, the NIHR Health Technology Assessment Programme, National Health Service R&D support funding and the National Institute for Health Research. ADDITION-Netherlands was supported by unrestricted grants from Novo Nordisk, Glaxo Smith Kline and Merck, and by the Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht.

Age-related changes in mammographic density and breast cancer risk.

High mammographic density is a strong breast cancer risk factor. Density normally declines with aging. We investigated whether the level of decline in mammographic density is related to breast cancer risk using a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Prospect cohort. This cohort was recruited among participants of a population-based breast cancer screening program in the Netherlands between 1993 and 1997. We examined whether age-related changes in mammographic density were different for 533 cases and 1,367 controls who were 49-69 years of age at the time of recruitment into the cohort. We used mixed models with linear and quadratic terms for age and interaction terms between age terms and case status. The percent mammographic density at the first available mammogram was higher for cases than for controls (25.2% vs. 22.5%) (P = 0.003). The average decline in density over 10 years was 11% in both cases and controls (P = 0.56). When studying changes among 4 categories of density, we saw some indication that large changes may influence breast cancer risk. Although no difference was seen in the average decline, we cannot exclude that large changes may influence breast cancer risk.

Quality of Life and Survival of Metastatic Colorectal Cancer Patients Treated With Trifluridine-Tipiracil (QUALITAS).

INTRODUCTION: The RECOURSE trial demonstrated a modest benefit in overall survival (OS) for trifluridine/tipiracil (FTD/TPI) versus placebo in pretreated metastatic colorectal cancer (mCRC) patients. Unfortunately, quality of life (QoL) was not assessed. We evaluated QoL and survival of patients treated with FTD/TPI in daily practice. PATIENTS AND METHODS: QUALITAS is a substudy of the Prospective Dutch CRC cohort (PLCRC). From 150 mCRC patients treated with FTD/TPI, QoL (EORTC QLQ-C30 and QLQ-CR29) was assessed monthly from study entry, and linked to clinical data of the Netherlands Cancer Registry. Joint models were constructed combining mixed effects models with Cox PH models. Primary endpoint was difference in QoL over time (which was deemed clinically relevant if ≥10 points). Secondary endpoints were progression-free survival (PFS), time to treatment failure (TTF), and OS. We analyzed the association between QLQ-C30 Summary Score (QoL-SS) at FTD/TPI initiation (baseline) and survival. RESULTS: There was no clinically relevant change in QoL-SS from baseline to 10 months post-baseline (i.e. the cut-off point after which 90% of patients had discontinued FTD/TPI treatment): -5.3 [95% CI -8.7;-1.5]. Patients who were treated with FTD/TPI for ≥ 3 months (n = 85) reported 6.3 [1.6;11.1] points higher baseline QoL, compared to patients treated < 3 months (n = 65, "poor responders"). In the latter, time to a clinically relevant QoL deterioration was < 2 months. Median PFS, TTF and OS were 2.9 [2.7;3.1], 3.1 [2.9;3.2] and 7.7 [6.6;8.8] months, respectively. Worse baseline QoL-SS was independently associated with shorter OS (HR 0.45 [0.32;0.63]), PFS (0.63 [0.48;0.83]), and TTF (0.64 [0.47;0.86]). CONCLUSION: The maintenance of QoL during FTD/TPI treatment in daily practice supports its use. The QoL deterioration in "poor responders" is likely due to disease progression. The strong association between worse baseline QoL and shorter survival suggests that clinicians should take QoL into account when determining prognosis and treatment strategy for individual patients.

Exploring the relation between modelled and perceived workload of nurses and related job demands, job resources and personal resources; a longitudinal study.

AIM: Calculating a modelled workload based on objective measures. Exploring the relation between this modelled workload and workload as perceived by nurses, including the effects of specific job demands, job resources and personal resources on the relation. DESIGN: Academic hospital in the Netherlands. Six surgical wards, capacity 15-30 beds. Data collected over 15 consecutive day shifts. METHODS: Modelled workload is calculated as a ratio of required care time, based on patient characteristics, baseline care time and time for non-patient related activities, and allocated care time, based on the amount of available nurses. Both required and allocated care time are corrected for nurse proficiency. Five dimensions of perceived workload were determined by questionnaires. Both the modelled and the perceived workloads were measured on a daily basis. Linear mixed effects models study the longitudinal relation between this modelled and workload as perceived by nurses and the effects of personal resources, job resources and job demands. ANOVA and post-hoc tests were used to identify differences in modelled workload between wards. RESULTS: Modelled workload varies roughly between 70 and 170%. Significant differences in modelled workload between wards were found but confidence intervals were wide. Modelled workload is positively associated with all five perceived workload measures (work pace, amount of work, mental load, emotional load, physical load). In addition to modelled workload, the job resource support of colleagues and job demands time spent on direct patient care and time spent on registration had the biggest significant effects on perceived workload. CONCLUSIONS: The modelled workload does not exactly predict perceived workload, however there is a correlation between the two. The modelled workload can be used to detect differences in workload between wards, which may be useful in distributing workload more evenly in order prevent issues of over- and understaffing and organizational justice. Extra effort to promote team work is likely to have a positive effect on perceived workload. Nurse management can stimulate team cohesion, especially when workload is high. Registered nurses perceive a higher workload than other nurses. When the proportion of direct patient care in a workday is higher, the perceived workload is also higher. Further research is recommended. The findings of this research can help nursing management in allocating resources and directing their attention to the most relevant factors for balancing workload.

Anti-Müllerian Hormone Levels and Risk of Cancer in Women.

OBJECTIVES: To examine if age-specific anti-Müllerian hormone (AMH) levels are associated with cancer risk; and to investigate if age-related AMH trajectories differ between women who develop cancer and women who do not. More specifically, we examined associations with breast cancer, cancers in other tissues expressing AMH receptor AMHR2, and cancers in non-AMHR2-expressing tissues. STUDY DESIGN: We included longitudinal data from 3025 women in the prospective Doetinchem Cohort Study. Cox proportional hazards models were used to assess the association of baseline age-specific AMH tertiles with cancer. We applied linear mixed models to compare age-related AMH trajectories between women who were diagnosed with cancer and women who were not. MAIN OUTCOME MEASURES: Cancer (n = 385; 139 breast cancers, 112 cancers in other AMHR2-expressing tissues, 134 cancers in non-AMHR2-expressing tissues). RESULTS: Overall, baseline age-specific AMH levels were not associated with cancer risk, although in women ≤ 40 years an increased risk was suggested for breast cancer (HRT2:T1 = 2.06, 95%CI = 0.95-4.48; HRT3:T1 = 2.03, 95%CI = 0.91-4.50). Analysis of age-related AMH trajectories suggested that AMH levels were higher at younger ages and declined faster in women who were diagnosed with cancer compared with women who were not, but our results did not provide evidence for actual differences in trajectories. CONCLUSIONS: Our results did not provide evidence for an association between age-specific AMH levels and age-related trajectories and risk of cancer. However, effect estimates for breast cancer were in line with risk-increasing effects found in previous studies.