Usability and feasibility of E-nergEYEze: a blended vision-specific E-health based cognitive behavioral therapy and self-management intervention to reduce fatigue in adults with visual impairment.

BACKGROUND: Over 50% of adults with visual impairment experience severe fatigue. Therefore, we developed a guided E-health intervention based on cognitive behavioral therapy and self-management to reduce fatigue in this population. This pilot study evaluated the usability, feasibility, fidelity and potential effectiveness of E-nergEYEze. METHODS: E-nergEYEze was developed by a design team and customized by conducting a pilot study using an iterative development strategy. The intervention was first tested in a usability study among adults with visual impairment (n = 5). Participants were asked to think-aloud while exploring the intervention features and a semi-structured interview was performed afterwards. Subsequently, the enhanced intervention was tested in a feasibility study. Adults with visual impairment and severe fatigue (n = 10) followed the intervention partially with guidance from a social worker and one-time computer trainer support. Fatigue severity (Checklist Individual Strength), fatigue impact (Modified Fatigue Impact Scale) and cognitive behavioral therapy skills (Competencies of Cognitive Therapy Scale-Self Report) were measured at baseline and at three months follow-up and analyzed with the Wilcoxon signed-rank test. The intervention was evaluated through evaluation forms. RESULTS: The usability study resulted in adjustments to content and lay-out with regard to optically shortened text sentences, separate pages for information and assignments with one read-aloud audio and an additional descriptive explanation of page content. Digital challenges were overcome with mandatory computer training and e-platform modifications. The feasibility study showed a positive trend in reducing fatigue severity (Z -6.108; P < .001; SD 8.4), impact of fatigue (Z - 4.451; P < .001; SD 11.4) and cognitive behavioral therapy skills (Z -2.278; P = .023; SD 19.3). Participants gave useful feedback regarding accessibility, content and guidance, with an overall positive experience. The intervention was rated with a median score of 8 (range 7-10). CONCLUSION: We developed, evaluated and optimized E-nergEYEze by applying a user-centered and iterative approach. E-nergEYEze showed a promising trend to reduce fatigue severity and impact of fatigue and to increase cognitive behavioral therapy skills. The study methods were feasible and the fidelity of the intervention protocol was suitable. Performing a randomized controlled trial is warranted to give insight into whether E-nergEYEze is cost-effective in reducing severe fatigue in adults with visual impairment. TRIAL REGISTRATION: International Clinical Trial Registry Platform: NL7764. Date registered: 28-05-2019.

Baseline PET radiomics outperforms the IPI risk score for prediction of outcome in diffuse large B-cell lymphoma.

The objective of this study is to externally validate the clinical positron emission tomography (PET) model developed in the HOVON-84 trial and to compare the model performance of our clinical PET model using the international prognostic index (IPI). In total, 1195 patients with diffuse large B-cell lymphoma (DLBCL) were included in the study. Data of 887 patients from 6 studies were used as external validation data sets. The primary outcomes were 2-year progression-free survival (PFS) and 2-year time to progression (TTP). The metabolic tumor volume (MTV), maximum distance between the largest lesion and another lesion (Dmaxbulk), and peak standardized uptake value (SUVpeak) were extracted. The predictive values of the IPI and clinical PET model (MTV, Dmaxbulk, SUVpeak, performance status, and age) were tested. Model performance was assessed using the area under the curve (AUC), and diagnostic performance, using the positive predictive value (PPV). The IPI yielded an AUC of 0.62. The clinical PET model yielded a significantly higher AUC of 0.71 (P < .001). Patients with high-risk IPI had a 2-year PFS of 61.4% vs 51.9% for those with high-risk clinical PET, with an increase in PPV from 35.5% to 49.1%, respectively. A total of 66.4% of patients with high-risk IPI were free from progression or relapse vs 55.5% of patients with high-risk clinical PET scores, with an increased PPV from 33.7% to 44.6%, respectively. The clinical PET model remained predictive of outcome in 6 independent first-line DLBCL studies, and had higher model performance than the currently used IPI in all studies.

Development and internal validation of a machine learning prediction model for low back pain non-recovery in patients with an acute episode consulting a physiotherapist in primary care.

BACKGROUND: While low back pain occurs in nearly everybody and is the leading cause of disability worldwide, we lack instruments to accurately predict persistence of acute low back pain. We aimed to develop and internally validate a machine learning model predicting non-recovery in acute low back pain and to compare this with current practice and 'traditional' prediction modeling. METHODS: Prognostic cohort-study in primary care physiotherapy. Patients (n = 247) with acute low back pain (≤ one month) consulting physiotherapists were included. Candidate predictors were assessed by questionnaire at baseline and (to capture early recovery) after one and two weeks. Primary outcome was non-recovery after three months, defined as at least mild pain (Numeric Rating Scale > 2/10). Machine learning models to predict non-recovery were developed and internally validated, and compared with two current practices in physiotherapy (STarT Back tool and physiotherapists' expectation) and 'traditional' logistic regression analysis. RESULTS: Forty-seven percent of the participants did not recover at three months. The best performing machine learning model showed acceptable predictive performance (area under the curve: 0.66). Although this was no better than a'traditional' logistic regression model, it outperformed current practice. CONCLUSIONS: We developed two prognostic models containing partially different predictors, with acceptable performance for predicting (non-)recovery in patients with acute LBP, which was better than current practice. Our prognostic models have the potential of integration in a clinical decision support system to facilitate data-driven, personalized treatment of acute low back pain, but needs external validation first.

A simple pooling method for variable selection in multiply imputed datasets outperformed complex methods.

BACKGROUND: For the development of prognostic models, after multiple imputation, variable selection is advised to be applied from the pooled model. The aim of this study is to evaluate by using a simulation study and practical data example the performance of four different pooling methods for variable selection in multiple imputed datasets. These methods are the D1, D2, D3 and recently extended Median-P-Rule (MPR) for categorical, dichotomous, and continuous variables in logistic regression models. METHODS: Four datasets (n = 200 and n = 500), with 9 variables and correlations of respectively 0.2 and 0.6 between these variables, were simulated. These datasets included 2 categorical and 2 continuous variables with 20% missing at random data. Multiple Imputation (m = 5) was applied, and the four methods were compared with selection from the full model (without missing data). The same analyzes were repeated in five multiply imputed real-world datasets (NHANES) (m = 5, p = 0.05, N = 250/300/400/500/1000). RESULTS: In the simulated datasets, the differences between the pooling methods were most evident in the smaller datasets. The MPR performed equal to all other pooling methods for the selection frequency, as well as for the P-values of the continuous and dichotomous variables, however the MPR performed consistently better for pooling and selecting categorical variables in multiply imputed datasets and also regarding the stability of the selected prognostic models. Analyzes in the NHANES-dataset showed that all methods mostly selected the same models. Compared to each other however, the D2-method seemed to be the least sensitive and the MPR the most sensitive, most simple, and easy method to apply. CONCLUSIONS: Considering that MPR is the most simple and easy pooling method to use for epidemiologists and applied researchers, we carefully recommend using the MPR-method to pool categorical variables with more than two levels after Multiple Imputation in combination with Backward Selection-procedures (BWS). Because MPR never performed worse than the other methods in continuous and dichotomous variables we also advice to use MPR in these types of variables.

The MOMANT study, a caregiver support programme with activities at home for people with dementia: a study protocol of a randomised controlled trial.

BACKGROUND: Because of the expected increase in the number of people with dementia, and the associated social and economic costs, there is an urgent need to develop effective and cost-effective care for people with dementia and their caregivers. The intervention proposed here combines two approaches to caregiver support that have shown to be effective in empowering caregivers, i.e., multiple components for caregiver support and actively engaging caregivers to involve the person with dementia in activities at home. The aim is to investigate whether the intervention is effective in improving quality of life in the caregiver and the person with dementia. A further aim will be to investigate whether this intervention can improve caregivers' feeling of competence, experience of caregiving, and mood. METHODS: The study design is a pragmatic, cluster randomised controlled trial with cost-effectiveness analysis. The study participants are informal caregivers and home-living persons with dementia for whom they care, recruited in various regions in the Netherlands. The trial will compare outcomes in two groups of participants: 85 dyads who receive the intervention, and 85 dyads who receive care as usual. The intervention is a caregiver support training that is manual based and consists of 6 group sessions over 2 months. Training takes place in small groups of caregivers led by a health care professional presented at dementia day care centres. Randomisation occurs at the level of the day care centre. Participants are assessed on the outcome measures at baseline, prior to the intervention, and at 3 and 6 months after baseline. DISCUSSION: The study will provide insight into effectiveness and cost-effectiveness of an intervention that has not previously been evaluated or implemented in the Netherlands. The intervention potentially adds to the effective support options for informal caregivers of people with dementia without greatly increasing the workload for health- or social care professionals. TRIAL REGISTRATION: The trial is registered at the Dutch Trial Register at NTR6643 ; August 22nd, 2017.

In patients eligible for meniscal surgery who first receive physical therapy, multivariable prognostic models cannot predict who will eventually undergo surgery.

PURPOSE: Although physical therapy is the recommended treatment in patients over 45 years old with a degenerative meniscal tear, 24% still opt for meniscal surgery. The aim was to identify those patients with a degenerative meniscal tear who will undergo surgery following physical therapy. METHODS: The data for this study were generated in the physical therapy arm of the ESCAPE trial, a randomized clinical trial investigating the effectiveness of surgery versus physical therapy in patients of 45-70 years old, with a degenerative meniscal tear. At 6 and 24 months patients were divided into two groups: those who did not undergo surgery, and those who did undergo surgery. Two multivariable prognostic models were developed using candidate predictors that were selected from the list of the patients' baseline variables. A multivariable logistic regression analysis was performed with backward Wald selection and a cut-off of p < 0.157. For both models the performance was assessed and corrected for the models' optimism through an internal validation using bootstrapping technique with 500 repetitions. RESULTS: At 6 months, 32/153 patients (20.9%) underwent meniscal surgery following physical therapy. Based on the multivariable regression analysis, patients were more likely to opt for meniscal surgery within 6 months when they had worse knee function, lower education level and a better general physical health status at baseline. At 24 months, 43/153 patients (28.1%) underwent meniscal surgery following physical therapy. Patients were more likely to opt for meniscal surgery within 24 months when they had worse knee function and a lower level of education at baseline at baseline. Both models had a low explained variance (16 and 11%, respectively) and an insufficient predictive accuracy. CONCLUSION: Not all patients with degenerative meniscal tears experience beneficial results following physical therapy. The non-responders to physical therapy could not accurately be predicted by our prognostic models. LEVEL OF EVIDENCE: III.

Optimal timing and criteria of interim PET in DLBCL: a comparative study of 1692 patients.

Interim 18F-fluorodeoxyglucose positron emission tomography (Interim-18F-FDG-PET, hereafter I-PET) has the potential to guide treatment of patients with diffuse large B-cell lymphoma (DLBCL) if the prognostic value is known. The aim of this study was to determine the optimal timing and response criteria for evaluating prognosis with I-PET in DLBCL. Individual patient data from 1692 patients with de novo DLBCL were combined and scans were harmonized. I-PET was performed at various time points during treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. Scans were interpreted using the Deauville score (DS) and change in maximum standardized uptake value (ΔSUVmax). Multilevel Cox proportional hazards models corrected for International Prognostic Index (IPI) score were used to study the effects of timing and response criteria on 2-year progression-free survival (PFS). I-PET after 2 cycles (I-PET2) and I-PET4 significantly discriminated good responders from poor responders, with the highest hazard ratios (HRs) for I-PET4. Multivariable HRs for a PET-positive result at I-PET2 and I-PET4 were 1.71 and 2.95 using DS4-5, 4.91 and 6.20 using DS5, and 2.93 and 4.65 using ΔSUVmax, respectively. ΔSUVmax identified a larger proportion of poor responders than DS5 did. For all criteria, the negative predictive value was >80%, and positive predictive values ranged from 30% to 70% at I-PET2 and I-PET4. Unlike I-PET1, I-PET3 discriminated good responders from poor responders using DS4-5 and DS5 thresholds (HRs, 2.94 and 4.67, respectively). I-PET2 and I-PET4 predict good response equally during R-CHOP therapy in DLBCL. Optimal timing and response criteria depend on the clinical context. Good response at I-PET2 is suggested for de-escalation trials, and poor response using ΔSUVmax at I-PET4 is suggested for randomized trials that are evaluating new therapies.

Cerebroplacental ratio in predicting adverse perinatal outcome: a meta-analysis of individual participant data.

OBJECTIVE: To investigate if cerebroplacental ratio (CPR) adds to the predictive value of umbilical artery pulsatility index (UA PI) alone - standard of practice - for adverse perinatal outcome in singleton pregnancies. DESIGN AND SETTING: Meta-analysis based on individual participant data (IPD). POPULATION OR SAMPLE: Ten centres provided 17 data sets for 21 661 participants, 18 731 of which could be included. Sample sizes per data set ranged from 207 to 9215 individuals. Patient populations varied from uncomplicated to complicated pregnancies. METHODS: In a collaborative, pooled analysis, we compared the prognostic value of combining CPR with UA PI, versus UA PI only and CPR only, with a one-stage IPD approach. After multiple imputation of missing values, we used multilevel multivariable logistic regression to develop prediction models. We evaluated the classification performance of all models with receiver operating characteristics analysis. We performed subgroup analyses according to gestational age, birthweight centile and estimated fetal weight centile. MAIN OUTCOME MEASURES: Composite adverse perinatal outcome, defined as perinatal death, caesarean section for fetal distress or neonatal unit admission. RESULTS: Adverse outcomes occurred in 3423 (18%) participants. The model with UA PI alone resulted in an area under the curve (AUC) of 0.775 (95% CI 0.709-0.828) and with CPR alone in an AUC of 0.778 (95% CI 0.715-0.831). Addition of CPR to the UA PI model resulted in an increase in the AUC of 0.003 points (0.778, 95% CI 0.714-0.831). These results were consistent across all subgroups. CONCLUSIONS: Cerebroplacental ratio added no predictive value for adverse perinatal outcome beyond UA PI, when assessing singleton pregnancies, irrespective of gestational age or fetal size. TWEETABLE ABSTRACT: Doppler measurement of cerebroplacental ratio in clinical practice has limited added predictive value to umbilical artery alone.

Local recurrence after local excision of early rectal cancer: a meta-analysis of completion TME, adjuvant (chemo)radiation, or no additional treatment.

BACKGROUND: The risks of local recurrence and treatment-related morbidity need to be balanced after local excision of early rectal cancer. The aim of this meta-analysis was to determine oncological outcomes after local excision of pT1-2 rectal cancer followed by no additional treatment (NAT), completion total mesorectal excision (cTME) or adjuvant (chemo)radiotherapy (aCRT). METHODS: A systematic search was conducted in PubMed, Embase and the Cochrane Library. The primary outcome was local recurrence. Statistical analysis included calculation of the weighted average of proportions. RESULTS: Some 73 studies comprising 4674 patients were included in the analysis. Sixty-two evaluated NAT, 13 cTME and 28 aCRT. The local recurrence rate for NAT among low-risk pT1 tumours was 6·7 (95 per cent c.i. 4·8 to 9·3) per cent. There were no local recurrences of low-risk pT1 tumours after cTME or aCRT. The local recurrence rate for high-risk pT1 tumours was 13·6 (8·0 to 22·0) per cent for local excision only, 4·1 (1·7 to 9·4) per cent for cTME and 3·9 (2·0 to 7·5) per cent for aCRT. Local recurrence rates for pT2 tumours were 28·9 (22·3 to 36·4) per cent with NAT, 4 (1 to 13) per cent after cTME and 14·7 (11·2 to 19·0) per cent after aCRT. CONCLUSION: There is a substantial risk of local recurrence in patients who receive no additional treatment after local excision, especially those with high-risk pT1 and pT2 rectal cancer. The lowest recurrence risk is provided by cTME; aCRT has outcomes comparable to those of cTME for high-risk pT1 tumours, but shows a higher risk for pT2 tumours.

ANTECEDENTES: Tras una resección temprana de un cáncer de recto localizado, hay que considerar el equilibrio entre el riesgo de recidiva local y la morbilidad relacionada con el tratamiento. El objetivo de este metaanálisis era determinar los resultados oncológicos tras la resección de un cáncer de recto pT1-T2 seguida de ningún tratamiento adicional (no additional treatment, NAT), escisión total del mesorrecto (completion total mesorectal excision, cTME) o quimiorradioterapia adyuvante (adjuvant chemoradiotherapy, aCRT). METHODS: Se llevó a cabo una búsqueda sistemática en PubMed, Embase y biblioteca Cochrane. La variable principal de resultado era la recidiva local (local recurrence, LR). En el análisis estadístico se calcularon las medias ponderadas de proporciones. RESULTADOS: Se incluyeron en el análisis 76 estudios con un total de 4.793 pacientes. NAT fue evaluada en 72 estudios, cTME en 13 y aCRT en 28. La tasa de LR para NAT en tumores pT1 de bajo riesgo era de 6,7% (i.c. del 95% 4,8-9,3). No se observaron casos de LR en tumores pT1 de bajo riesgo tras cTME o aCRT. La tasa de LR para tumores pT1 de alto riesgo fue de 13,6% (i.c. del 95% 8,0-22,0) para la resección local como único tratamiento, 4,1% (i.c. del 95% 1,7-9,4) para cTME y 3,9% (i.c. del 95% 2,0-7,5) para aCRT. La tasa de LR para tumores pT2 fue de 28,9% (i.c. del 95% 22,3-36,4) para NAT, 4,3% (i.c. del 95% 1,4-12,5) para cTME y 14,7% (i.c. del 95% 11,2-19,0) para aCRT. CONCLUSIÓN: Tras la resección local de cáncer pT1 de alto riesgo y pT2, existe un riesgo sustancial de recidiva local en ausencia de tratamiento adicional. La escisión total del mesorrecto se asocia con el menor riesgo de recidiva. La quimiorradioterapia adyuvante ofrece resultados similares a la escisión total del mesorrecto en tumores pT1 de alto riesgo, pero presenta un mayor riesgo en tumores pT2.

Kinesiophobia is not required to predict chronic low back pain in workers: a decision curve analysis.

BACKGROUND: Currently used performance measures for discrimination were not informative to determine the clinical benefit of predictor variables. The purpose was to evaluate if a former relevant predictor, kinesiophobia, remained clinically relevant to predict chronic occupational low back pain (LBP) in the light of a novel discriminative performance measure, Decision Curve Analysis (DCA), using the Net Benefit (NB). METHODS: Prospective cohort data (n = 170) of two merged randomized trials with workers with LBP on sickleave, treated with Usual Care (UC) were used for the analyses. An existing prediction model for chronic LBP with the variables 'a clinically relevant change in pain intensity and disability status in the first 3 months', 'baseline measured pain intensity' and 'kinesiophobia' was compared with the same model without the variable 'kinesiophobia' using the NB and DCA. RESULTS: Both prediction models showed an equal performance according to the DCA and NB. Between 10 and 95% probability thresholds of chronic LBP risk, both models were of clinically benefit. There were virtually no differences between both models in the improved classification of true positive (TP) patients. CONCLUSIONS: This study showed that the variable kinesiophobia, which was originally included in a prediction model for chronic LBP, was not informative to predict chronic LBP by using DCA. DCA and NB have to be used more often to develop clinically beneficial prediction models in workers because they are more sensitive to evaluate the discriminate ability of prediction models.

Clinical course of pain and disability following primary lumbar discectomy: systematic review and meta-analysis.

PURPOSE: To conduct a meta-analysis to describe clinical course of pain and disability in adult patients post-lumbar discectomy (PROSPERO: CRD42015020806). METHODS: Sensitive topic-based search strategy designed for individual databases was conducted. Patients (> 16 years) following first-time lumbar discectomy for sciatica/radiculopathy with no complications, investigated in inception (point of surgery) prospective cohort studies, were included. Studies including revision surgery or not published in English were excluded. Two reviewers independently searched information sources, assessed eligibility at title/abstract and full-text stages, extracted data, assessed risk of bias (modified QUIPs) and assessed GRADE. Authors were contacted to request raw data where data/variance data were missing. Meta-analyses evaluated outcomes at all available time points using the variance-weighted mean in random-effect meta-analyses. Means and 95% CIs were plotted over time for measurements reported on outcomes of leg pain, back pain and disability. RESULTS: A total of 87 studies (n = 31,034) at risk of bias (49 moderate, 38 high) were included. Clinically relevant improvements immediately following surgery (> MCID) for leg pain (0-10, mean before surgery 7.04, 50 studies, n = 14,910 participants) and disability were identified (0-100, mean before surgery 53.33, 48 studies, n = 15,037). Back pain also improved (0-10, mean before surgery 4.72, 53 studies, n = 14,877). Improvement in all outcomes was maintained (to 7 years). Meta-regression analyses to assess the relationship between outcome data and a priori potential covariates found preoperative back pain and disability predictive for outcome. CONCLUSION: Moderate-level evidence supports clinically relevant immediate improvement in leg pain and disability following lumbar discectomy with accompanying improvements in back pain. These slides can be retrieved under Electronic Supplementary Material.

Latent growth modeling of IRT versus CTT measured longitudinal latent variables.

Latent growth models are often used to measure individual trajectories representing change over time. The characteristics of the individual trajectories depend on the variability in the longitudinal outcomes. In many medical and epidemiological studies, the individual health outcomes cannot be observed directly and are indirectly observed through indicators (i.e. items of a questionnaire). An item response theory or a classical test theory measurement model is required, but the choice can influence the latent growth estimates. In this study, under various conditions, this influence is directly assessed by estimating latent growth parameters on a common scale for item response theory and classical test theory using a novel plausible value method in combination with Markov chain Monte Carlo. The latent outcomes are considered missing data and plausible values are generated from the corresponding posterior distribution, separately for item response theory and classical test theory. These plausible values are linearly transformed to a common scale. A Markov chain Monte Carlo method was developed to simultaneously estimate the latent growth and measurement model parameters using this plausible value technique. It is shown that estimated individual trajectories using item response theory, compared to classical test theory to measure outcomes, provide a more detailed description of individual change over time, since item response patterns (item response theory) are more informative about the health measurements than sum scores (classical test theory).

Age dependency of risk factors for cognitive decline.

BACKGROUND: Risk factors for cognitive decline might depend on chronological age. The aim of the study was to explore the age dependency of risk factors for cognitive decline in cognitively healthy subjects aged 55-85 years at baseline. METHODS: We included 2527 cognitively healthy subjects from the Longitudinal Aging Study Amsterdam (LASA). Median follow-up was 9.1 (IQR: 3.2-19.0) years. The association of genetic and cardiovascular risk factors, depressive symptoms, inflammation markers and lifestyle risk factors with decline in MMSE and memory function was tested using spline regression analyses. RESULTS: Subjects were on average 70.1 (SD 8.8) years old at baseline. Based on a spline regression model, we divided our sample in three age groups: ≤70 years (young-old), > 70-80 years (old) and > 80 years (oldest-old). The association of LDL cholesterol, homocysteine, hypertension, history of stroke, depressive symptoms, interleukin-6, a1-antichymotrypsin, alcohol use and smoking with cognitive decline significantly differed between the age groups. In general, the presence of these risk factors was associated with less cognitive decline in the oldest-old group compared to the young-old and old group. CONCLUSIONS: The negative effect of various risk factors on cognitive decline decreases with higher age. A combination of epidemiological factors, such as the selection towards healthier subjects during follow-up, but also risk factor specific features, for example ensuring the cerebral blood flow in case of hypertension, explain this diminished association at higher age. It is important to take these age differences into account when applying preventive strategies to avert cognitive decline.

Prediction of insufficient serum vitamin D status in older women: a validated model.

We developed an externally validated simple prediction model to predict serum 25(OH)D levels < 30, < 40, < 50 and 60 nmol/L in older women with risk factors for fractures. The benefit of the model reduces when a higher 25(OH)D threshold is chosen. INTRODUCTION: Vitamin D deficiency is associated with increased fracture risk in older persons. General supplementation of all older women with vitamin D could cause medicalization and costs. We developed a clinical model to identify insufficient serum 25-hydroxyvitamin D (25(OH)D) status in older women at risk for fractures. METHODS: In a sample of 2689 women ≥ 65 years selected from general practices, with at least one risk factor for fractures, a questionnaire was administered and serum 25(OH)D was measured. Multivariable logistic regression models with backward selection were developed to select predictors for insufficient serum 25(OH)D status, using separate thresholds 30, 40, 50 and 60 nmol/L. Internal and external model validations were performed. RESULTS: Predictors in the models were as follows: age, BMI, vitamin D supplementation, multivitamin supplementation, calcium supplementation, daily use of margarine, fatty fish ≥ 2×/week, ≥ 1 hours/day outdoors in summer, season of blood sampling, the use of a walking aid and smoking. The AUC was 0.77 for the model using a 30 nmol/L threshold and decreased in the models with higher thresholds to 0.72 for 60 nmol/L. We demonstrate that the model can help to distinguish patients with or without insufficient serum 25(OH)D levels at thresholds of 30 and 40 nmol/L, but not when a threshold of 50 nmol/L is demanded. CONCLUSIONS: This externally validated model can predict the presence of vitamin D insufficiency in women at risk for fractures. The potential clinical benefit of this tool is highly dependent of the chosen 25(OH)D threshold and decreases when a higher threshold is used.

Development and external validation of a prediction rule for an unfavorable course of late-life depression: A multicenter cohort study.

BACKGROUND: Given the poor prognosis of late-life depression, it is crucial to identify those at risk. Our objective was to construct and validate a prediction rule for an unfavourable course of late-life depression. METHODS: For development and internal validation of the model, we used The Netherlands Study of Depression in Older Persons (NESDO) data. We included participants with a major depressive disorder (MDD) at baseline (n = 270; 60-90 years), assessed with the Composite International Diagnostic Interview (CIDI). For external validation of the model, we used The Netherlands Study of Depression and Anxiety (NESDA) data (n = 197; 50-66 years). The outcome was MDD after 2 years of follow-up, assessed with the CIDI. Candidate predictors concerned sociodemographics, psychopathology, physical symptoms, medication, psychological determinants, and healthcare setting. Model performance was assessed by calculating calibration and discrimination. RESULTS: 111 subjects (41.1%) had MDD after 2 years of follow-up. Independent predictors of MDD after 2 years were (older) age, (early) onset of depression, severity of depression, anxiety symptoms, comorbid anxiety disorder, fatigue, and loneliness. The final model showed good calibration and reasonable discrimination (AUC of 0.75; 0.70 after external validation). The strongest individual predictor was severity of depression (AUC of 0.69; 0.68 after external validation). LIMITATIONS: The model was developed and validated in The Netherlands, which could affect the cross-country generalizability. CONCLUSIONS: Based on rather simple clinical indicators, it is possible to predict the 2-year course of MDD. The prediction rule can be used for monitoring MDD patients and identifying those at risk of an unfavourable outcome.

Vitamin D status in relation to physical performance, falls and fractures in the Longitudinal Aging Study Amsterdam: A reanalysis of previous findings using standardized serum 25-hydroxyvitamin D values.

The Longitudinal Aging Study Amsterdam (LASA) is an ongoing prospective cohort study in a representative sample of Dutch older persons. In previous LASA studies, lower serum 25-hydroxyvitamin D (25(OH)D) values, as assessed by a competitive protein binding assay or radioimmunoassay, have been associated with decreased physical functioning, falls and fractures. Recently, serum 25(OHD) values in LASA were standardized using the Vitamin D Standardization Program (VDSP) protocol as part of the European ODIN project. In the current manuscript, the influence of standardizing serum 25(OH)D values will be discussed using the associations with physical functioning, falls and fractures as examples.

Prognostic accuracy of cerebroplacental ratio and middle cerebral artery Doppler for adverse perinatal outcome: systematic review and meta-analysis.

OBJECTIVE: Doppler ultrasonographic assessment of the cerebroplacental ratio (CPR) and middle cerebral artery (MCA) is widely used as an adjunct to umbilical artery (UA) Doppler to identify fetuses at risk of adverse perinatal outcome. However, reported estimates of its accuracy vary considerably. The aim of this study was to review systematically the prognostic accuracies of CPR and MCA Doppler in predicting adverse perinatal outcome, and to compare these with UA Doppler, in order to identify whether CPR and MCA Doppler evaluation are of added value to UA Doppler. METHODS: PubMed, EMBASE, the Cochrane Library and ClinicalTrials.gov were searched, from inception to June 2016, for studies on the prognostic accuracy of UA Doppler compared with CPR and/or MCA Doppler in the prediction of adverse perinatal outcome in women with a singleton pregnancy of any risk profile. Risk of bias and concerns about applicability were assessed using the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies-2) tool. Meta-analysis was performed for multiple adverse perinatal outcomes. Using hierarchal summary receiver-operating characteristics meta-regression models, the prognostic accuracy of CPR vs MCA Doppler was compared indirectly, and CPR and MCA Doppler vs UA Doppler compared directly. RESULTS: The search identified 4693 articles, of which 128 studies (involving 47 748 women) were included. Risk of bias or suboptimal reporting was detected in 120/128 studies (94%) and substantial heterogeneity was found, which limited subgroup analyses for fetal growth and gestational age. A large variation was observed in reported sensitivities and specificities, and in thresholds used. CPR outperformed UA Doppler in the prediction of composite adverse outcome (as defined in the included studies) (P < 0.001) and emergency delivery for fetal distress (P = 0.003), but was comparable to UA Doppler for the other outcomes. MCA Doppler performed significantly worse than did UA Doppler in the prediction of low Apgar score (P = 0.017) and emergency delivery for fetal distress (P = 0.034). CPR outperformed MCA Doppler in the prediction of composite adverse outcome (P < 0.001) and emergency delivery for fetal distress (P = 0.013). CONCLUSION: Calculating the CPR with MCA Doppler can add value to UA Doppler assessment in the prediction of adverse perinatal outcome in women with a singleton pregnancy. However, it is unclear to which subgroup of pregnant women this applies. The effectiveness of the CPR in guiding clinical management needs to be evaluated in clinical trials. © 2017 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Design of the SALT Osteoporosis Study: a randomised pragmatic trial, to study a primary care screening and treatment program for the prevention of fractures in women aged 65 years or older.

BACKGROUND: Several drugs have become available for the treatment of osteoporosis. However, screening and treatment of patients with a high fracture risk is currently not recommended in the Netherlands, because the effectiveness of bone sparing drugs has not been demonstrated in the general primary care population. Here we describe the design of the SALT Osteoporosis study, which aims to examine whether the screening and treatment of older, female patients in primary care can reduce fractures, in comparison to usual care. METHODS: A randomised pragmatic trial has been designed using a stepwise approach in general care practices in the Netherlands. Women aged ≥65 years, who are not prescribed bone sparing drugs or corticosteroids are eligible for the study. First, women with at least one clinical risk factor for fractures, as determined by questionnaires, are randomly assigned to the intervention or control group. Second, women in the intervention group having a high fracture risk according to our screening program, including an adapted fracture risk assessment (FRAX) tool, combined with dual-energy x-ray absorptiometry (DXA), and instant vertebral assessment (IVA), are offered a structured treatment program. The women in the control group receive care as usual and will undergo the same screening as the intervention group at the end of the trial. The follow-up duration will be three years and the primary outcome is time to first incident fracture and the total number of fractures. DISCUSSION: The results of the current study will be very important for underpinnings of the prevention strategy of the osteoporosis guidelines. TRIAL REGISTRATION: ID NTR2430 . Registered 26 July 2010.

Optimal use of anti-EGFR monoclonal antibodies for patients with advanced colorectal cancer: a meta-analysis.

This meta-analysis was performed to determine the optimal use of anti-EGFR mAb in the treatment of metastasized colorectal cancer (mCRC). Seventeen randomized clinical trials were included, all evaluating the added value of anti-EGFR mAb to standard treatment line in patients with KRAS wild-type mCRC. Hazard and odds ratios were pooled using a random effect model, weighted according to cohort size. Pooled data of six first- and two second-line studies demonstrated a significantly improved ORR (OR 1.62, CI 1.27-2.04; OR 4.78, CI 3.39-6.75, respectively) and PFS (HR 0.79, CI 0.67-0.94; HR 0.80, CI 0.71-0.91, respectively) with the addition of anti-EGFR mAb to chemotherapy, while OS remained similar. Two third-line anti-EGFR mAb monotherapy studies revealed an improved PFS and OS (HR 0.44, CI 0.35-0.52; HR 0.55, CI 0.41-0.74). Addition of anti-EGFR versus anti-VEGF mAb to first-line chemotherapy was evaluated in three studies; ORR and PFS were comparable, while OS was improved (HR 0.8, CI 0.65-0.97). The influence of the chemotherapy backbone on anti-EGFR mAb efficacy, evaluated with meta-regression, indicated a higher ORR with irinotecan-based versus oxaliplatin-based regimens, but comparable PFS and OS. Reported toxicity (≥3 grade) increased ~20% in all treatment lines with the addition of anti-EGFR mAb. Anti-EGFR treatment significantly improves response and survival outcome of patients with (K)RAS wild-type mCRC, regardless of treatment line or chemotherapeutic backbone. Saving anti-EGFR mAb as third-line monotherapy is a valid and effective option to prevent high treatment burden caused by combination therapy. Combination treatment with anti-EGFR mAb to achieve radical resection of metastases needs further investigation.