Statistical analysis of Goal Attainment Scaling endpoints in randomised trials.

Goal Attainment Scaling is an assessment instrument to evaluate interventions on the basis of individual, patient-specific goals. The attainment of these goals is mapped in a pre-specified way to attainment levels on an ordinal scale, which is common to all goals. This approach is patient-centred and allows one to integrate the outcomes of patients with very heterogeneous symptoms. The latter is of particular importance in clinical trials in rare diseases because it enables larger sample sizes by including a broader patient population. In this paper, we focus on the statistical analysis of Goal Attainment Scaling outcomes for the comparison of two treatments in randomised clinical trials. Building on a general statistical model, we investigate the properties of different hypothesis testing approaches. Additionally, we propose a latent variable approach to generate Goal Attainment Scaling data in a simulation study, to assess the impact of model parameters such as the number of goals per patient and their correlation, the choice of discretisation thresholds and the type of design (parallel group or cross-over). Based on our findings, we give recommendations for the design of clinical trials with a Goal Attainment Scaling endpoint. Furthermore, we discuss an application of Goal Attainment Scaling in a clinical trial in mastocytosis.

Effects of resistance exercise in prostate cancer patients: a meta-analysis.

PURPOSE: The aim of the present meta-analysis was to quantify effects of resistance exercise (RE) on physical performance and function, body composition, health-related quality of life (HRQoL), and fatigue in patients with prostate cancer. METHODS: Trial data were obtained from the databases PubMed, MEDLINE, EMBASE, SCOPUS, and the Cochrane Library as of inception to 31st of December 2016. Thirty-two trials with 1199 patients were included. Results that were measured by using the same assessment method in five or more of the original studies were pooled in a meta-analysis. RESULTS: Pooled studies showed significant improvements of muscular strength in the upper and lower body (95% CI [2.52, 7.97] kg; p < 0.001 and 95% CI [10.51, 45.88] kg; p = 0.008, respectively) after RE. Furthermore, significant improvements were seen for body composition (body fat percentage 95% CI [-0.79, -0.53] %; p < 0.001; lean body mass 95% CI [0.15, 1.84] %; p = 0.028; trunk fat mass 95% CI [-0.73, -0.08] kg; p = 0.024). Additionally, the improvement of the 400-m walk time was significant (95% CI [-21.55, -14.65] s; p < 0.001). Concerning fatigue and HRQoL, there were not sufficient data for analysis. CONCLUSIONS: RE seems to be a promising approach in order to counteract loss of muscle mass, muscle strength, and physical performance in patients suffering from prostate cancer and its treatment-related side effects. RE should play part in interdisciplinary cancer rehabilitation and care of this patient group. Nevertheless, further research should investigate RE further to determine which protocols are the most pragmatic, yet yielding best patient outcomes.

Intravitreal anti-vascular endothelial growth factor combined with half-fluence photodynamic therapy for choroidal neovascularization in chronic central serous chorioretinopathy.

PurposeTo evaluate the results of indocyanine green angiography (ICGA)-guided verteporfin photodynamic therapy (PDT) with half-fluence rate combined with intravitreal application of anti-VEGF in treating choroidal neovascularization (CNV) in chronic central serous chorioretinopathy (CSCR).Patients and methodsIn this retrospective cohort study 17 consecutive patients with secondary CNV due to chronic CSCR had their diagnosis verified with fluorescein angiography (FA) and ICGA at baseline. All eyes received either intravitreal ranibizumab (IVR) or bevacizumab (IVB). On the consecutive day following the initial IVR/IVB treatment, ICGA-guided verteporfin (6 mg/m(2)) PDT with half-fluence rate (25 J/cm(2)) was performed on every patient. IVR or IVB was rescheduled on a pro re nata regimen. Main outcome measures were changes in visual acuity (VA) according to the ETDRS letter score and changes in the central foveal thickness (CFT).ResultsBest-corrected VA at baseline was 65.6 letters (±6.7; n=17) according to the ETDRS letter score. At 12 months, mean ETDRS letter score improved to 71.2 letters (P=0.34). CFT was 309 µm and decreased to 216 µm at month 12 control (P=0.0004). Nine eyes (52.9%) received additional treatment with IVR/IVB due to recurrence of subretinal fluid, with an overall mean number of IVR/IVB treatment of 1.8±3.6 per patient with no systemic side effects during 12 months' follow-up.ConclusionsIVR or IVB combined with ICGA-guided half-fluence PDT with verteporfin is effective in treating CNV in chronic CSCR, with choroidal hyperpermeability in ICGA, resulting in stable vision and significant reduction of CFT.

Effect of a low-fat diet enriched either with rapeseed oil or sunflower oil on plasma lipoproteins in children and adolescents with familial hypercholesterolaemia. Results of a pilot study.

BACKGROUND/OBJECTIVES: There is convincing evidence that unsaturated fatty acids exert favourable effects on plasma cholesterol levels. However, it is not clear which type of oil has the most pronounced effect, especially not in paediatric patients. The aim was to compare two low-fat diet regimes enriched with either monounsaturated fatty acids by rapeseed oil (RO) or polyunsaturated fatty acids by sunflower oil (SO) in children affected with familial hypercholesterolaemia (FH). SUBJECTS/METHODS: Twenty-one children aged 6-18 years affected with FH were enrolled in this randomized and double-blind pilot trial. The subjects and their families were trained to adhere to a low-fat/low-cholesterol diet. All visible fats were to be replaced by either RO or SO (14-27 g/day) for 13 weeks. Dietary adherence was controlled by repeated 4-day dietary records; plasma lipids, lipoproteins and risk markers were assessed at baseline and post-intervention. Out of 21 subjects, 16 could be followed-up after 6 months. RESULTS: Both fat-modified diets resulted in significant reduction in total cholesterol concentrations of 9.4% (RO P<0.005 vs SO P<0.05) and low-density lipoprotein (LDL) cholesterol concentrations of 12.7% (P<0.005) for RO and 11.3% (P<0.05) for SO. The reduction of the LDL/high-density lipoprotein (HDL) cholesterol ratio (RO 9% vs SO 3.5%) and high-sensitivity C-reactive protein (RO 16.8% vs SO 1.7%) were not statistically significant, respectively. In most participating families, a change in eating habits could be observed. CONCLUSIONS: A fat-modified diet enriched with RO seems to have very similar effects on cholesterol levels as with SO. However, our study suggests that RO has possibly more favourable effects concerning cardiovascular risk profile. Both diets appear to be feasible and were well accepted among our subjects. Although these results are promising, larger trials will be required to validate our findings.

Impact of preoperative serum creatinine on short- and long-term mortality after cardiac surgery: a cohort study.

BACKGROUND: Preoperative renal insufficiency is an important predictor of mortality after cardiac surgery. This retrospective cohort study was designed to identify the optimal cut-off for baseline serum creatinine (bSCr) and estimated glomerular filtration rate (eGFR) to predict survival. Furthermore, we investigated the potential confounding effect of other perioperative risk indicators on short- and long-term survival. METHODS: Data of 9490 cardiac surgical patients were prospectively collected between 1997 and 2008 (follow up to 2010) at the Medical University Vienna. We identified bSCr cut-off values and calculated uni- and multivariate hazard models for short- and long-term survival and compared the results with a validation set from Zurich. The estimated survival curves defined a distinct period of increased mortality until 150 days. RESULTS: Cut-off values of >115 µmol litre(-1) for bSCr and ≤50 ml min(-1) for eGFR were identified. Increased bSCr, associated with higher mortality [hazard ratio (HR) 2.61, 95% confidence interval (CI) 2.43-2.80, P<0.0001], was present in 19.5% of patients and remained predictive for short- (HR 1.59, 95% CI 1.38-1.83, P=0.0027) and long-term survival (HR 1.46, 95% CI 1.32-1.62, P<0.0001) in the multivariate hazard models. A cut-off of >120 µmol litre(-1) for bSCr was determined for the validation set. Decreased eGFR was present in 23.6% (HR 2.86, 95% CI 2.67-3.06, P<0.0001). CONCLUSIONS: In our patients, increased bSCr was an independent predictor of mortality, which may critically influence risk evaluation and perioperative treatment guidance.

Nicotinic acetylcholine receptors control acetylcholine and noradrenaline release in the rodent habenulo-interpeduncular complex.

BACKGROUND AND PURPOSE: Nicotinic acetylcholine receptors (nACh receptors) play a central role in the habenulo-interpeduncular system. We studied nicotine-induced release of NA and ACh in the habenula and interpeduncular nucleus (IPN). EXPERIMENTAL APPROACH: The habenula and IPN were loaded with [(3) H]-choline or [(3) H]-NA and placed in superfusion chambers. [(3) H]-ACh release was also stimulated using nicotinic agonists, electrical pulses and elevated [KCl]o in hippocampal and cortical slices from rats, wild-type mice and mice lacking α5, α7, ß2, or ß4 nACh receptor subunits. Finally, we analysed nACh receptor subtypes in the IPN using immunoprecipitation. KEY RESULTS: Nicotine induced release of [(3) H]-ACh in the IPN of rats and mice. This release was calcium-dependent but not blocked by tetrodotoxin (TTX); moreover, [(3) H]-ACh release was abolished in ß4-knockout mice but was unaffected in ß2- and α5-knockout mice. In contrast, nicotine-induced release of [(3) H]-NA in the IPN and habenula was blocked by TTX and reduced in both ß2-knockout and ß4-knockout mice, and dose-response curves were right-shifted in α5-knockout mice. Although electrical stimuli triggered the release of both transmitters, [(3) H]-ACh release required more pulses delivered at a higher frequency. CONCLUSIONS AND IMPLICATIONS: Our results confirm previous findings that ß4-containing nACh receptors are critical for [(3) H]-ACh release in the mouse IPN. Experiments using α5-knockout mice also revealed that unlike in the hippocampus, nicotine-induced [(3) H]-NA release in the habenulo-interpeduncular system is altered in this knockout model. As α5-containing nACh receptors play a key role in nicotine intake, our results add NA to the list of transmitters involved in this mechanism.

Associations of nailfold capillary abnormalities and immunological markers in early Raynaud's phenomenon.

OBJECTIVES: Nailfold capillaroscopy (NC) and laboratory tests for antinuclear antibodies (ANA) are routinely used in parallel for detection of emerging connective tissue disease (CTD) in patients with Raynaud's phenomenon (RP). The aim of this study was to assess the associations between distinct nailfold capillary abnormalities and concomitant autoantibodies in patients with incipient RP without previously known CTD. METHOD: Patients with incipient RP without previously known CTD were included in this retrospective analysis. We analysed the association of particular capillary abnormalities (reduced density, avascular fields, dilations, giant capillaries, haemorrhages, tortuosity, ramifications, oedema) with ANA and ANA subsets (anti-Scl-70, anti-CENP-B, anti-U1-RNP, anti-dsDNA, anti-SSA(Ro), anti-SSB(La), anti-Sm, and anti-Jo-1 antibodies). We also developed a score that allows the estimation of each patient's individual probability for the presence of an ANA titre ≥ 1:160. RESULTS: The final analysis comprised 2971 patients. Avascular fields, giant capillaries, reduced capillary density, and capillary oedema were closely related to an ANA titre ≥ 1:160. Both giant capillaries and avascular fields were associated with anti-Scl-70 and anti-CENP-B antibodies. Only a weak association was found between giant capillaries and anti-U1-RNP antibodies. Each patient's individual probability for the presence of an ANA titre ≥ 1:160 can be represented by a sum score comprising giant capillaries, reduced density, avascular fields, ramifications, and oedema as well as patients' sex and age. CONCLUSION: In patients with incipient RP, anti-Scl-70 and anti-CENP-B antibodies are related most specifically to distinct capillary alterations. Although a sum score can represent the patient's probability for elevated ANA titres, NC cannot substitute for immunological tests in patients with incipient RP.