Estimating the distribution of heterogeneous treatment effects from treatment responses and from a predictive biomarker in a parallel-group RCT: A structural model approach.

When the objective is to administer the best of two treatments to an individual, it is necessary to know his or her individual treatment effects (ITEs) and the correlation between the potential responses (PRs) Yi1 and Yi0 under treatments 1 and 0. Data that are generated in a parallel-group design RCT does not allow the ITE to be determined because only two samples from the marginal distributions of these PRs are observed and not the corresponding joint distribution. This is due to the "fundamental problem of causal inference." Here, we present a counterfactual approach for estimating the joint distribution of two normally distributed responses to two treatments. This joint distribution of the PRs Yi1 and Yi0 can be estimated by assuming a bivariate normal distribution for the PRs and by using a normally distributed baseline biomarker Zi functionally related to the sum Yi1+Yi0 . Such a functional relationship is plausible since a biomarker Zi and the sum Yi1+Yi0 encode for the same information in an RCT, namely the variation between subjects. The estimation of the joint trivariate distribution is subjected to some constraints. These constraints can be framed in the context of linear regressions with regard to the proportions of variances in the responses explained and with regard to the residual variation. This presents new insights on the presence of treatment-biomarker interactions. We applied our approach to example data on exercise and heart rate and extended the approach to survival data.

Extended RAS analysis and correlation with overall survival in advanced pancreatic cancer.

BACKGROUND: Mutations in the KRAS gene can be detected in about 70-90% of pancreatic cancer (PC) cases. Whether these mutations have a prognostic or predictive value remains elusive. Furthermore, the clinical relevance of the extended RAS (KRAS+NRAS) mutational status is unclear in PC. METHODS: We prospectively defined a PC patient population who received erlotinib-free chemotherapy regimens. A statistically significant difference between KRAS wild-type and KRAS mutated tumours in at least 160 patients in this population would support the assumption of a rather prognostic role of KRAS. RESULTS: One hundred and seventy-eight tumour samples were collected from prospective clinical studies and successfully analysed for the extended RAS status: 37 tumours were KRAS wild-type (21%), whereas 141 (79%) carried a KRAS mutation; 132 of these mutations were found in KRAS exon 2 (74%), whereas only 9 mutations (5%) were detected in KRAS exon 3. Within KRAS exon 4 and NRAS exons 2-4, no mutations were apparent. There was no significant difference in overall survival for KRAS wild-type vs mutant patients (9.9 vs 8.3 months, P=0.70). CONCLUSIONS: Together with the results of the AIO-PK-0104-trial, the present analysis supports the notion that KRAS mutation status is rather predictive than prognostic in advanced PC.

Impact of hand-foot skin reaction on treatment outcome in patients receiving capecitabine plus erlotinib for advanced pancreatic cancer: a subgroup analysis from AIO-PK0104.

BACKGROUND: Drug-induced skin toxicity may correlate with treatment efficacy in cancer patients receiving chemotherapy or biological agents. The correlation of the capecitabine-associated hand-foot skin reaction (HFS) on outcome parameters in pancreatic cancer (PC) has not yet been investigated. METHODS: Within the multicentre phase III AIO-PK0104 trial, patients with confirmed advanced PC were randomly assigned to first-line treatment with either capecitabine plus erlotinib (150 mg/day, arm A) or gemcitabine plus erlotinib (150 mg/day, arm B). A cross-over to either gemcitabine (arm A) or capecitabine (arm B) was performed after failure of the first-line regimen. Data on skin toxicity were correlated with efficacy study endpoints using uni- and multivariate analyses. To control for guarantee-time bias (GTB), we focused on subgroup analyses of patients who had completed two and three or more treatment cycles. RESULTS: Of 281 randomised patients, skin toxicity data were available for 255 patients. Median time to capecitabine-attributed HFS was two cycles, 36 of 47 (77%) HFS events had been observed by the end of treatment cycle three. Considering HFS during first-line treatment in 101 patients treated with capecitabine for at least two cycles within the capecitabine plus erlotinib arm, time to treatment failure after first- and second-line therapy (TTF2) and overall survival (OS) both were significantly prolonged for the 44 patients (44%) with HFS compared to 57 patients without HFS (56%) (TTF2: 7.8 vs. 3.8 months, HR 0.50, p = 0.001; OS: 10.4 vs. 5.9 months, HR 0.55, p = 0.005). A subgroup analysis of 70 patients on treatment with capecitabine for at least three cycles showed similar results (TTF2: 8.3 vs. 4.4 months, HR 0.53, p = 0.010; OS: 10.4 vs. 6.7 months, HR 0.62, p = 0.056). CONCLUSION: The present subgroup analysis from AIO-PK0104 suggests that HFS may serve as an independent clinical predictor for treatment outcome in capecitabine-treated patients with advanced PC.

Evaluating the agreement between tumour volumetry and the estimated volumes of tumour lesions using an algorithm.

OBJECTIVES: To evaluate the agreement between tumour volume derived from semiautomated volumetry (SaV) and tumor volume defined by spherical volume using longest lesion diameter (LD) according to Response Evaluation Criteria In Solid Tumors (RECIST) or ellipsoid volume using LD and longest orthogonal diameter (LOD) according to World Health Organization (WHO) criteria. MATERIALS AND METHODS: Twenty patients with metastatic colorectal cancer from the CIOX trial were included. A total of 151 target lesions were defined by baseline computed tomography and followed until disease progression. All assessments were performed by a single reader. A variance component model was used to compare the three volume versions. RESULTS: There was a significant difference between the SaV and RECIST-based tumour volumes. The same model showed no significant difference between the SaV and WHO-based volumes. Scatter plots showed that the RECIST-based volumes overestimate lesion volume. The agreement between the SaV and WHO-based relative changes in tumour volume, evaluated by intraclass correlation, showed nearly perfect agreement. CONCLUSIONS: Estimating the volume of metastatic lesions using both the LD and LOD (WHO) is more accurate than those based on LD only (RECIST), which overestimates lesion volume. The good agreement between the SaV and WHO-based relative changes in tumour volume enables a reasonable approximation of three-dimensional tumour burden. KEY POINTS: • Tumour response in patients undergoing chemotherapy is assessed using CT images • Measurements are based on RECIST (unidimensional)-based or WHO (bidimensional)-based criteria • We calculated tumour volume from bidimensional target lesion measurements • This formula provides good tumour volume approximation, based on semiautomated volumetry.

A note on calculating asymptotic confidence intervals for the adjusted risk difference and number needed to treat in the Cox regression model.

Recently, Laubender and Bender (Stat. Med. 2010; 29: 851-859) applied the average risk difference (RD) approach to estimate adjusted RD and corresponding number needed to treat measures in the Cox proportional hazards model. We calculated standard errors and confidence intervals by using bootstrap techniques. In this paper, we develop asymptotic variance estimates of the adjusted RD measures and corresponding asymptotic confidence intervals within the counting process theory and evaluated them in a simulation study. We illustrate the use of the asymptotic confidence intervals by means of data of the Düsseldorf Obesity Mortality Study.

Multicenter evaluation of blood-based biomarkers for the detection of endometriosis and adenomyosis: A prospective non-interventional study.

OBJECTIVE: To evaluate blood-based biomarkers to detect endometriosis and/or adenomyosis across nine European centers (June 2014-April 2018). METHODS: This prospective, non-interventional study assessed the diagnostic accuracy of 54 blood-based biomarker immunoassays in samples from 919 women (aged 18-45 years) with suspicion of endometriosis and/or adenomyosis versus symptomatic controls. Endometriosis was stratified by revised American Society for Reproductive Medicine stage. Symptomatic controls were "pathologic symptomatic controls" or "pathology-free symptomatic controls". The main outcome measure was receiver operating characteristic-area under the curve (ROC-AUC) and Wilcoxon P values corrected for multiple testing (q values). RESULTS: CA-125 performed best in "all endometriosis cases" versus "all symptomatic controls" (AUC 0.645, 95% confidence interval [CI] 0.600-0.690, q < 0.001) and increased (P < 0.001) with disease stage. In "all endometriosis cases" versus "pathology-free symptomatic controls", S100-A12 performed best (AUC 0.692, 95% CI 0.614-0.769, q = 0.001) followed by CA-125 (AUC 0.649, 95% CI 0.569-0.729, q = 0.021). In "adenomyosis only cases" versus "symptomatic controls" or "pathology-free symptomatic controls", respectively, the top-performing biomarkers were sFRP-4 (AUC 0.615, 95% CI 0.551-0.678, q = 0.045) and S100-A12 (AUC 0.701, 95% CI 0.611-0.792, q = 0.004). CONCLUSION: This study concluded that no biomarkers tested could diagnose or rule out endometriosis/adenomyosis with high certainty.

Early tumor shrinkage in metastatic colorectal cancer: retrospective analysis from an irinotecan-based randomized first-line trial.

Early tumor shrinkage (ETS) has been highlighted as a favorable prognostic factor related to progression-free survival (PFS) and overall survival (OS) in cytotoxic treatment of metastatic colorectal cancer. Data from a randomized phase III study comparing infusional 5-fluorouracil plus irinotecan (FUFIRI) versus irinotecan plus oxaliplatin (mIROX) were evaluated. Patient groups were analyzed according to the relative change in maximum tumor diameter between baseline and after 7 weeks of treatment. The ETS cohort was defined as a decrease of ≥20%. Additionally, the non-ETS cohort was subdivided into "minor shrinkage" (0-19%), "tumor progression" (any increase) and development of "new metastatic lesions". Progression-free survival and OS were estimated in all patient subgroups. Assessment of ETS was possible in 201 patients. Early tumor shrinkage was observed in 47% (94/201) and non-ETS in 53% (107/201) of patients. Patients with ETS had a more favorable outcome with regard to PFS (9.9 months vs 6.1 months, P = 0.029) and OS (27.5 months vs 17.8 months, P = 0.002). In the non-ETS subgroups, patients with "minor shrinkage" (PFS 8.4 months, OS 21.6 months) showed a markedly better outcome than patients with "early tumor progression" (PFS 4.0 months, OS 15.3 months) or with "new metastatic lesions (PFS 2.2 months, OS 7.6 months). In conclusion, ETS assessment offers accelerated response evaluation when compared to RECIST. In patients treated with chemotherapy alone, ETS ≥20% is associated with excellent outcome. Non-ETS is a heterogeneous subgroup where patients with minor shrinkage clearly benefit from treatment, and patients with early progression or development of new lesions have an unfavorable prognosis.

Early tumor shrinkage in patients with metastatic colorectal cancer receiving first-line treatment with cetuximab combined with either CAPIRI or CAPOX: an analysis of the German AIO KRK 0104 trial.

PURPOSE: This study investigated the impact of early tumor shrinkage (ETS) on progression-free- (PFS) and overall survival (OS) in patients with metastatic colorectal cancer (mCRC) treated within the AIO KRK 0104 trial as first-line therapy. Moreover, correlations of ETS with clinical characteristics and prognostic markers were evaluated. PATIENTS AND METHODS: In total, 121 patients were included into this analysis. Patients were treated with cetuximab combined with either CAPIRI or CAPOX. ETS at six weeks was defined as a relative change of ≥ 20% in the sum of the longest diameters of target lesions compared to baseline. Survival times were compared between patients with ETS ≥ 20% versus no-ETS. RESULTS: ETS ≥ 20% was observed in 59% of all patients with KRAS wild-type tumors. In these patients ETS ≥ 20% was associated with higher overall response rate (82% vs. 19%, p < 0.001). Also, PFS (8.9 vs. 4.7 months, p < 0.001) and OS (31.6 vs. 15.8 months, p = 0.005) were significantly superior in ETS ≥ 20% of patients compared to no-ETS. In patients with KRAS mutant mCRC ETS ≥ 20% neither had an effect on PFS nor OS. Cetuximab-induced skin toxicity correlated with the occurrence of ETS ≥ 20% (p = 0.002). CONCLUSION: In patients with KRAS wild-type tumors treated with cetuximab plus capecitabine-based chemotherapy ETS ≥ 20% is an important predictor of favorable outcome.

Impact of the specific mutation in KRAS codon 12 mutated tumors on treatment efficacy in patients with metastatic colorectal cancer receiving cetuximab-based first-line therapy: a pooled analysis of three trials.

PURPOSE: This study investigated the impact of specific mutations in codon 12 of the Kirsten-ras (KRAS) gene on treatment efficacy in patients with metastatic colorectal cancer (mCRC). PATIENTS: Overall, 119 patients bearing a KRAS mutation in codon 12 were evaluated. All patients received cetuximab-based first-line chemotherapy within the Central European Cooperative Oncology Group (CECOG), AIO KRK-0104 or AIO KRK-0306 trials. RESULTS: Patients with KRAS codon 12 mutant mCRC showed a broad range of outcome when treated with cetuximab-based first-line regimens. Patients with tumors bearing a KRAS p.G12D mutation showed a strong trend to a more favorable outcome compared to other mutations (overall survival 23.3 vs. 14-18 months; hazard ratio 0.66, range 0.43-1.03). An interaction model illustrated that KRAS p.G12C was associated with unfavorable outcome when treated with oxaliplatin plus cetuximab. CONCLUSION: The present analysis suggests that KRAS codon 12 mutation may not represent a homogeneous entity in mCRC when treated with cetuximab-based first-line therapy.

Non-specific alterations of craniocervical venous drainage in multiple sclerosis revealed by cardiac-gated phase-contrast MRI.

OBJECTIVE: There is an on-going controversy about venous drainage abnormalities in multiple sclerosis (MS). We applied cardiac-gated phase-contrast and venographic magnetic resonance (MR) techniques to compare venous drainage patterns in patients with MS, healthy controls, and subjects with migraine. METHODS: A total of 27 patients with MS (21 female, age 12-59 years, mean disease duration 8.4 ± 8.5 years) and 27 age- and gender-matched healthy controls (21 female, age 12-60 years) were investigated with velocity-encoded cine-phase contrast MR sequences and a 2D time-of-flight MR venography of the cervicocranial region on a 3-T MRI. The data were compared with 26 patients with chronic migraine headaches (19 female, age 17-62 years), previously investigated with the same protocol. The degree of primary and secondary venous outflow in relation to the total cerebral blood flow (tCBF) was compared both quantitatively and qualitatively. Statistical analyses were performed using linear regression models. RESULTS: Secondary venous outflow was significantly increased in patients with MS compared with healthy controls, both qualitatively (p < 0.001) and quantitatively (p < 0.013). The observed changes were independent of age and disease duration. Very similar alterations of venous drainage were detectable with the same approach in patients with migraine, without significant differences between MS and migraine patients (p = 0.65). CONCLUSION: Our MRI-based study suggests that patients with MS have alterations of cerebral venous drainage similar to subjects with chronic migraine. These non-disease-specific changes seem to a secondary phenomenon rather than being of primary pathogenic importance.

Clinical characterization of patients with metastatic colorectal cancer depending on the KRAS status.

This retrospective study investigated the clinical characteristics of patients with metastatic colorectal cancer (mCRC) depending on the KRAS status, thereby differentiating KRAS exon 2 mutations in codon 12 versus codon 13. In total, 273 patients with mCRC receiving first-line therapy were analyzed. One hundred patients were treated within the FIRE-3 trial (FOLFIRI plus cetuximab or bevacizumab), 147 patients within the AIO KRK-0104 trial (cetuximab plus CAPIRI or CAPOX), and further 26 patients received therapy outside the study. Thirty-eight tumors with KRAS mutation in codon 13, 140 tumors with mutation in codon 12, and 95 tumors with KRAS wild type as a comparison were included in this analysis. Bivariate analyses demonstrated significant differences between KRAS wild-type, codon 12-mutated, and codon 13-mutated tumors with regard to synchronous lymph node metastasis (P=0.018), organ metastasis (76.8% vs. 65.9% vs. 89.5%, P=0.009), liver metastasis (89.5% vs. 78.2% vs. 92.1%, P=0.025), lung metastasis (29.5% vs. 42.9% vs. 50%, P=0.041), liver-only metastasis (48.4% vs. 28.8% vs. 28.9%, P=0.006), and metastases in two or more organs (49.5, 61.4, 71.1, P=0.047). Regression models indicated a significant impact of KRAS mutations in codon 12 versus codon 13 for synchronous organ and nodal metastasis (P=0.01, 0.03). This pooled analysis indicates that mCRC is a heterogeneous disease, which seems to be defined by KRAS mutations of the tumor. Compared with KRAS codon 12 mutations, codon 13-mutated mCRC presents as a more aggressive disease frequently associated with local and distant metastases at first diagnosis.

Anisotropy of transcallosal motor fibres indicates functional impairment in children with periventricular leukomalacia.

AIM: In children with bilateral spastic cerebral palsy (CP), periventricular leukomalacia (PVL) is commonly identified on magnetic resonance imaging. We characterized this white matter condition by examining callosal microstructure, interhemispheric inhibitory competence (IIC), and mirror movements. METHOD: We examined seven children (age range 11y 9mo-17y 9mo, median age 15y 10mo, four females, three males) with bilateral spastic CP/PVL (Gross Motor Function Classification System level I or II, Manual Ability Classification System level I) and 12 age-matched controls (age range 11y 7mo-17y 1mo, median age 15y 6mo, seven females, five males). Fractional anisotropy of the transcallosal motor fibres (TCMF) and the corticospinal tract (CST) of both sides were calculated. The parameters of IIC (transcranial magnetic stimulation) and mirror movements were measured using a standardized clinical examination and a computer-based hand motor test. RESULTS: Fractional anisotropy was lower in children with bilateral spastic CP/PVL regarding the TCMF, but not the left or right CST. Resting motor threshold was elevated in children with bilateral spastic CP/PVL whereas measures of IIC tended to be lower. Mirror movements were markedly elevated in bilateral spastic CP/PVL. INTERPRETATION: This study provides new information on different aspects of motor function in children with bilateral spastic CP/PVL. Decreased fractional anisotropy of TCMF is consistent with impairment of hand motor function in children with bilateral spastic CP/PVL. The previously overlooked microstructure of the TCMF may serve as a potential indicator for hand motor function in patients with bilateral spastic CP/PVL.

Multicenter evaluation of analytical characteristics of the Elecsys® Periostin immunoassay.

OBJECTIVE: The multifunctional cytokine IL-13 is thought to play a central role in Type 2 inflammation in asthma. Serum periostin has been explored as a candidate biomarker for evaluating IL-13 activity in the airway. We describe the technical performance characteristics of a novel, fully automated immunoassay for the determination of periostin in serum. DESIGN AND METHODS: Limit of blank [LoB], limit of detection [LoD] and limit of quantitation [LoQ], linearity, precision and reproducibility across sites and lots were evaluated according to Clinical and Laboratory Standards Institute guidelines. Interferences and sample stability were also investigated. RESULTS: The pre-specified values for LoB (2ng/mL), LoD (4ng/mL) and LoQ (10ng/mL) were met. The assay was linear throughout the measuring range (10-160ng/mL) with recoveries within ±10% of target at concentrations >30ng/mL and within ±3ng/mL at concentrations ≤30ng/mL. Recovered periostin concentrations were also within ±10% of target in presence of 43 potentially interfering substances and drugs. Samples were stable across various storage conditions and durations (24h at room temperature, 7days at 4°C, 12weeks at -20°C, and 3 freeze/thaw cycles). Repeatability experiments resulted in CVs across samples and controls ranging from 0.9-1.5%. Intermediate precision was 1.2-1.7% and reproducibility including 3 testing sites and 3 reagent lots was 1.7-3.1%. The final assay correlates to the assay version used in previous clinical trials (Pearson's r=0.998, bias at 50ng/mL=1.2%). CONCLUSION: The performance evaluation of the Elecsys® Periostin immunoassay including a multicenter precision analysis demonstrated that the assay is suitable for measuring serum periostin at clinically important concentrations around 50ng/mL.

High-resolution computed tomography-based length assessments of the cochlea--an accuracy evaluation.

CONCLUSION: The length of the cochlea can be determined with good precision using a 3D-curved multiplanar reconstruction analysis technique and linear reconstruction of the cochlea. The method is not time-consuming and can be applied during clinical routine. OBJECTIVE: A preoperative prediction of the best cochlear implant electrode length can help reduce the risk of intraoperative cochlear trauma in patients who need to retain residual acoustic hearing for electric-acoustic stimulation or in patients with anatomical anomalies or malformations. The goal of this study was to evaluate the accuracy and reliability of length measurement of the cochlea after linear reconstruction using 3D-curved multiplanar reconstrucion analysis of high resolution computed tomography (CT) scans. METHODS: Human cadaveric temporal bone specimens underwent cochlear implantation using custom-made electrodes with two radiopaque markers of a defined length before CTscans were made. Length measurement was performed by four readers and the results were compared to the true value. Inter-reader reliability was calculated. The time needed for analysis was recorded. RESULTS: The mean time needed for analysis of one specimen's radiologic data was 6.1 (± 3.4) min. The mean deviation of the length measurement from the true value was 0.8 (± 0.7) mm. Inter-reader reliability was excellent (0.76, p = 0.006).

Reduction of pacemaker implantation rates after CoreValve® implantation by moderate predilatation.

AIMS: We investigated the impact of the diameter of the valvuloplasty balloon (VB) used for predilation before transcatheter aortic valve implantation (TAVI) on atrioventricular block formation with consecutive need for permanent pacemaker (PP) implantation. METHODS AND RESULTS: TAVI was performed in 269 consecutive patients using the CoreValve prosthesis (Medtronic) via transfemoral access under local anaesthesia with mild analgesic medication. After exclusion of 32 patients with previously implanted PP, 237 patients were included in a retrospective analysis of the impact of VB size on subsequent PP incidence. Implantation success rate was 99.3%. Periprocedural mortality was 0%, and 30-day mortality was 5.9%. PP implantation after TAVI was required by 21.1%. Of 114 patients treated by 25 mm balloon valvuloplasty, a PP was implanted in 27.1%. In 123 patients, who were treated by VB with a ≤23 mm diameter, the PP implantation rate decreased to 15.4% (p=0.04). In univariate analysis, larger VB size resulted in a greater prevalence of PP implantation after TAVI. After adjustment by multivariate analysis for baseline clinical and operative characteristics, VB size remained an independent predictor of PP implantation. CONCLUSIONS: Moderate balloon predilation in patients undergoing TAVI with the Medtronic CoreValve prosthesis reduces the PP rate without affecting procedural success.

MRI evidence for altered venous drainage and intracranial compliance in mild traumatic brain injury.

PURPOSE: To compare venous drainage patterns and associated intracranial hydrodynamics between subjects who experienced mild traumatic brain injury (mTBI) and age- and gender-matched controls. METHODS: Thirty adult subjects (15 with mTBI and 15 age- and gender-matched controls) were investigated using a 3T MR scanner. Time since trauma was 0.5 to 29 years (mean 11.4 years). A 2D-time-of-flight MR-venography of the upper neck was performed to visualize the cervical venous vasculature. Cerebral venous drainage through primary and secondary channels, and intracranial compliance index and pressure were derived using cine-phase contrast imaging of the cerebral arterial inflow, venous outflow, and the craniospinal CSF flow. The intracranial compliance index is the defined as the ratio of maximal intracranial volume and pressure changes during the cardiac cycle. MR estimated ICP was then obtained through the inverse relationship between compliance and ICP. RESULTS: Compared to the controls, subjects with mTBI demonstrated a significantly smaller percentage of venous outflow through internal jugular veins (60.9±21% vs. controls: 76.8±10%; p = 0.01) compensated by an increased drainage through secondary veins (12.3±10.9% vs. 5.5±3.3%; p<0.03). Mean intracranial compliance index was significantly lower in the mTBI cohort (5.8±1.4 vs. controls 8.4±1.9; p<0.0007). Consequently, MR estimate of intracranial pressure was significantly higher in the mTBI cohort (12.5±2.9 mmHg vs. 8.8±2.0 mmHg; p<0.0007). CONCLUSIONS: mTBI is associated with increased venous drainage through secondary pathways. This reflects higher outflow impedance, which may explain the finding of reduced intracranial compliance. These results suggest that hemodynamic and hydrodynamic changes following mTBI persist even in the absence of clinical symptoms and abnormal findings in conventional MR imaging.

Spirometry reference equations for central European populations from school age to old age.

BACKGROUND: Spirometry reference values are important for the interpretation of spirometry results. Reference values should be updated regularly, derived from a population as similar to the population for which they are to be used and span across all ages. Such spirometry reference equations are currently lacking for central European populations. OBJECTIVE: To develop spirometry reference equations for central European populations between 8 and 90 years of age. MATERIALS: We used data collected between January 1993 and December 2010 from a central European population. The data was modelled using "Generalized Additive Models for Location, Scale and Shape" (GAMLSS). RESULTS: The spirometry reference equations were derived from 118'891 individuals consisting of 60'624 (51%) females and 58'267 (49%) males. Altogether, there were 18'211 (15.3%) children under the age of 18 years. CONCLUSION: We developed spirometry reference equations for a central European population between 8 and 90 years of age that can be implemented in a wide range of clinical settings.

Magnetic resonance-based estimation of intracranial pressure correlates with ventriculoperitoneal shunt valve opening pressure setting in children with hydrocephalus.

OBJECTIVES: The aim of this study was to investigate the relationship between the pressure setting of the ventriculoperitoneal (VP) shunt valve and a magnetic resonance (MR)-based estimate of intracranial pressure (ICP) in children with shunt-treated hydrocephalus without clinical signs of shunt malfunction. MATERIALS AND METHODS: Institutional review board approval was obtained before the study, and all subjects and/or their legal guardians provided written informed consent. In this prospective study, 15 consecutive patients (median age, 8.25 years; range, 2.2-18.4 years; 6 girls and 9 boys) with shunt-treated hydrocephalus without signs of shunt malfunction were examined with retrospectively gated phase contrast sequences to quantify arterial inflow, venous outflow, and cerebrospinal fluid (CSF) flow to and from the cranial vault. The ratio of the maximal intracranial volume change and the pulse pressure gradient change was used to derive MR-ICP. Spearman ρ was used to test for the association of setting of the shunt valve opening pressure and MR-ICP. RESULTS: Shunt valve opening pressure settings and MR-ICP were positively correlated (Spearman ρ = 0.64, P < 0.01). Median MR-ICP was 8.67 mm Hg (interquartile range [IQR], 1.59 mm Hg) and median setting of the VP-shunt valve was 6.62 mm Hg (IQR, 1.47 mm Hg). The median MR-ICP was 1.9 mm Hg (IQR, 0.73 mm Hg) higher than the setting of the shunt valve. CONCLUSION: There is a positive correlation between MR-ICP and VP shunt valve opening pressure setting. The systematically higher assessment of MR-ICP is most likely a result of outflow resistance within the shunt tubing system and well within the known fluctuation rates of VP shunt systems.

Increased pericardial adipose tissue is correlated with atrial fibrillation and left atrial dilatation.

INTRODUCTION: Pericardial adipose tissue (PAT), a visceral fat depot surrounding the heart, serves as an endocrine active organ and is associated with inflammation. There is growing evidence that atrial fibrillation (AF) is linked with inflammation, which in turn can be a promoter of left atrial remodeling. The aim of this study was to evaluate a potential correlation of PAT to AF and left atrial structural remodeling represented by LA size. METHODS: PAT was measured in 1,288 patients who underwent coronary artery calcium-scanning for coronary risk stratification. LA size was determined by two independent readers. Patients were subdivided into patients without AF, patients with paroxysmal and persistent AF. RESULTS: PAT was independently correlated with AF, persistent AF, and LA size (all p values <0.001). No association could be observed between paroxysmal AF and PAT. These associations persisted after multivariate adjustment for AF risk factors such as age, hypertension, valvular disease, heart failure, and body mass index (AF: OR 1.52, 95 % CI 1.15-2.00, p = 0.003; persistent AF: OR 2.58, 95 % CI 1.69-3.99, p = 0.001; LA size: regression coefficient 0.15 with 95 % CI 0.10-0.20, p < 0.001). CONCLUSION: PAT is associated with AF, in particular with persistent AF and LA size. These findings suggest that PAT could be an independent risk factor for the development of AF and for LA remodeling.

Use of the 28-joint count yields significantly higher concordance between different examiners than the 66/68-joint count.

OBJECTIVE: Joint counts are the key outcome measure in rheumatoid arthritis (RA). There is a great variability between different assessors of the same patient; this variability can be reduced by standardized training. The training effect is far less pronounced for the 66/68-joint count compared to the 28-joint count. We evaluated the reason for the higher interrater disagreement in the 66/68 compared to the 28-joint count. METHODS: Participants in joint examination seminars evaluated a patient with RA before and after training in the European League Against Rheumatism technique. Joints were rated positive or negative for tenderness and swelling. The number of positive joints and the variability between examiners before and after the training were compared. Concordance was calculated for every single joint using the Fleiss-Kappa test. RESULTS: In total, 256 health professionals were instructed in the 66/68-joint count and 84 in the 28-joint count. The disagreement between examiners was higher for swelling than for tenderness. After the training, there was a significant reduction of interrater variability, which was more pronounced in the 28 than in the 66/68-joint count. Comparisons between joint counts revealed that the joints of the feet were more likely to be rated negative, yet interrater disagreement was still high. CONCLUSION: Standardization of joint examination significantly reduces variability between assessors. The better performance of the 28-joint count is due to the lower number of joints examined, especially the foot joints, which remain difficult to assess reliably even after training.