Generating Utilities for the Château-Santé Base: A Novel, Generic, and Patient-Centered Health-Outcome Measure.

OBJECTIVES: We have developed a new patient-centered, preference-based generic health-outcome measure, Château-Santé Base (CS-Base), which is based on a novel multiattribute preference response (MAPR) measurement framework. This study aimed to generate a first utility set for the CS-Base, making it suitable for use in health-economic evaluations. METHODS: CS-Base comprises 12 health attributes: mobility, vision, hearing, cognition, mood, anxiety, pain, fatigue, social functioning, daily activities, self-esteem, and independence, each with 4 levels. Our methodology to generate utilities for the CS-Base was 2-fold. First, we derived coefficients from patient MAPR data to calculate CS-Base values. Subsequently, these were normalized to a 0.0 to 1.0 utility scale, in which 0.0 signifies dead. The dead position was estimated using general population data from a discrete choice experiment (discrete choice experiment + dead), using a division-value strategy, which localize the position of states better or worse than dead. RESULTS: We analyzed MAPR data from 3222 patients and discrete choice experiment + dead data from 1995 respondents. All MAPR coefficients were negative, logically ordered, and significantly different from the reference level. The dead position was denoted by a division value of -148.385. Utility values spanned from -0.071 to 1.0, and only 53 of 16 777 216 states were deemed worse than dead. CONCLUSIONS: This study introduced the first CS-Base utility set, underlining a 2-step utility derivation method. This method, blending societal and patient views, surpasses traditional preference-based approaches, yielding firmer results. However, improvement of the normalization procedure is expected. Estimating CS-Base utilities is an ongoing process that gains precision over time.

Diagnostic value of transcranial doppler to predict delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage : To predict delayed cerebral ischemia.

BACKGROUND: Transcranial Doppler (TCD) is a technique to assess blood flow velocity in the cerebral arteries. TCD is frequently used to monitor aneurysmal subarachnoid hemorrhage (aSAH) patients. This study compares TCD-criteria for vasospasm and its association with Delayed Cerebral Ischemia (DCI). An overall score based on flow velocities of various intracranial arteries was developed and evaluated. METHODS: A retrospective diagnostic accuracy study was conducted between 1998 and 2017 with 621 patients included. Mean flow velocity (MFV) of the cerebral artery was measured between 2-5 days and between 6-9 days after ictus. Cutoff values from the literature, new cutoff values, and a new composite score (Combined Severity Score) were used to predict DCI. Sensitivity, specificity, and area under the curve (AUC) were determined, and logistic regression analysis was performed. RESULTS: The Combined Severity Score showed an AUC 0.64 (95%CI 0.56-.71) at days 2-5, with sensitivity 0.53 and specificity 0.74. The Combined Severity Score had an adjusted Odds Ratio of 3.41 (95CI 1.86-6.32) for DCI. MCA-measurements yielded the highest AUC to detect DCI at day 2-5: AUC 0.65 (95%CI 0.58-0.73). Optimal cutoff MFV of 83 cm/s for MCA resulted in sensitivity 0.73 and specificity 0.50 at days 2-5. CONCLUSION: TCD-monitoring of aSAH patients may be a valuable strategy for DCI risk stratification. Lower cutoff values can be used in the early phase after the ictus (day 2-5) than are commonly used now. The Combined Severity Score incorporating all major cerebral arteries may provide a meaningful contribution to interpreting TCD measurements.

Effectiveness of a vitamin D regimen in deficient multiple myeloma patients and its effect on peripheral neuropathy.

PURPOSE: Peripheral neuropathy (PN) is common in multiple myeloma (MM) patients. More insight has been gained concerning the role of vitamin D in preventing PN. However, studies evaluating the effects of vitamin D3 supplementation on PN are lacking. The aims of this study are to (1) evaluate the effectiveness of a vitamin D3 regimen on achieving adequate vitamin D levels in deficient MM patients and to (2) exploratively evaluate the effect of vitamin D3 supplementation on PN. METHODS: Thirty-nine MM patients with inadequate (< 75 nmol/L [= 30 ng/mL]) 25-hydroxyvitamin D (25(OH)D) levels were included in this multicenter, prospective, single-arm study, of whom 35 patients completed the study. They received oral vitamin D3 for 6 months according to a dose escalation regimen that consisted of one or two loading doses of 200,000 international units (IU), and maintenance doses of 800, 1600, or 3200 IU/day depending on the 25(OH)D level. A validated questionnaire was used to measure PN. RESULTS: Median 25(OH)D increased from 38 (IQR 32-52) nmol/L at baseline to 77 (IQR 72-87) nmol/L after 6 months (P < 0.001). Adequate 25(OH)D levels were achieved by 66% of the subjects, and 34% were within the range of 50-75 nmol/L. Furthermore, in 37% of the participants, PN severity decreased (P = 0.007). CONCLUSION: The use of substantially higher vitamin D3 doses than recommended in current guidelines resulted in a significant increase in vitamin D levels in MM patients. Furthermore, evaluation of PN showed a significant decrease in PN grading. However, this exploratory evaluation needs further confirmatory research.

Clinical view versus guideline adherence in ferritin monitoring and initiating iron chelation therapy in patients with myelodysplastic syndromes.

OBJECTIVES: In patients with myelodysplastic syndromes (MDS) with >20 transfusions and ferritin levels >1000 µg/L, international guidelines recommend iron chelation therapy (ICT). The study's objective was to determine guideline adherence and the intensity of ferritin monitoring in clinical practice. METHODS: We performed an observational population-based study using the HemoBase Registry, which contains data of all MDS patients diagnosed since 2005 in Friesland, the Netherlands. Clinical information on transfusions, ferritin measurements, ICT, and clinical performance as defined by age ≤ 80 years, Charlson Comorbidity Index <2 and lower-risk MDS was collected from health records. RESULTS: Two hundred and thirty seven of 292 patients (81.1%) received ≥1 transfusion, and 121 (41.4%) received >20 transfusions. In 57 of these 121 patients (47.1%), ferritin measurements were performed at least once. Clinical performance was significantly associated with monitoring ferritin around the 20th transfusion (RR: 2.49, p = .016). Clinical performance was also associated with initiating ICT (RR: 5.99, p < .001). ICT was offered to 22.3% (n = 25) of eligible patients. CONCLUSIONS: In this population-based study, ferritin levels were measured in <50% of MDS patients who received >20 transfusions, and clinical performance was significantly associated with measuring ferritin. Our study suggests that in heavily transfused MDS patients, ferritin monitoring is primarily based on patients' clinical performance rather than guideline recommendations.

The predictive value of the CTA Vasospasm Score on delayed cerebral ischaemia and functional outcome after aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Delayed cerebral ischaemia (DCI) is a severe complication of aneurysmal subarachnoid hemorrhage that can significantly impact clinical outcome. Cerebral vasospasm is part of the pathophysiology of DCI and therefore a computed tomography angiography (CTA) Vasospasm Score was developed and an exploration was carried out of whether this score predicts DCI and subsequent poor outcome after aneurysmal subarachnoid hemorrhage. METHODS: The CTA Vasospasm Score sums the degree of angiographic cerebral vasospasm of 17 intradural arterial segments. The score ranges from 0 to 34 with a higher score reflecting more severe vasospasm. Outcome measures were cerebral infarction due to DCI (CI-DCI), radiological and clinical DCI, and unfavorable functional outcome defined as a modified Rankin Scale >2 at 6 months. Receiver operating characteristic analyses were used to assess predictive value and to determine optimal cut-off scores. Inter-rater reliability was evaluated by Cohen's kappa coefficient. RESULTS: This study included 59 patients. CI-DCI occurred in eight patients (14%), DCI in 14 patients (24%) and unfavorable outcome in 12 patients (20%). Median CTA Vasospasm Scores were higher in patients with (CI-)DCI and poor outcome. Receiver operating characteristic analysis revealed the highest area under the curve on day 5: CI-DCI 0.89 (95% confidence interval [CI] 0.79-0.99), DCI 0.68 (95% CI 0.50-0.87) and functional outcome 0.74 (95% CI 0.57-0.91). Cohen's kappa between the two raters was moderate to substantial (0.57-0.63). CONCLUSIONS: This study demonstrates that the CTA Vasospasm Score on day 5 can reliably identify patients with a high risk of developing (CI-)DCI and unfavorable outcome.

Fixed Versus Variable Dosing of Prothrombin Complex Concentrate for Bleeding Complications of Vitamin K Antagonists-The PROPER3 Randomized Clinical Trial.

STUDY OBJECTIVE: To determine if a fixed dose of 1000 IU of 4-factor prothrombin complex concentrate (4F-PCC) is as effective as traditional variable dosing based on body weight and international normalized ratio (INR) for reversal of vitamin K antagonist (VKA) anticoagulation. METHODS: In this open-label, multicenter, randomized clinical trial, patients with nonintracranial bleeds requiring VKA reversal with 4F-PCC were allocated to either a 1,000-IU fixed dose of 4F-PCC or the variable dose. The primary outcome was the proportion of patients with effective hemostasis according to the International Society of Thrombosis and Haemostasis definition. The design was noninferiority with a lower 95% confidence interval of no more than -6%. When estimating sample size, we assumed that fixed dosing would be 4% superior. RESULTS: From October 2015 until January 2020, 199 of 310 intended patients were included before study termination due to decreasing enrollment rates. Of the 199 patients, 159 were allowed in the per-protocol analysis. Effective hemostasis was achieved in 87.3% (n=69 of 79) in fixed compared to 89.9% (n=71 of 79) in the variable dosing cohort (risk difference 2.5%, 95% confidence interval -13.3 to 7.9%, P=.27). Median door-to-needle times were 109 minutes (range 16 to 796) in fixed and 142 (17 to 1076) for the variable dose (P=.027). INR less than 2.0 at 60 minutes after 4F-PCC infusion was reached in 91.2% versus 91.7% (P=1.0). CONCLUSION: The large majority of patients had good clinical outcome after 4F-PCC use; however, noninferiority of the fixed dose could not be demonstrated because the design assumed the fixed dose would be 4% superior. Door-to-needle time was shortened with the fixed dose, and INR reduction was similar in both dosing regimens.

Optical imaging compared to clinical examination in 484 rheumatoid arthritis patients: the Leeuwarden Handscan Registry.

The Handscan is a novel objective optical imaging device for disease follow-up and management in rheumatoid arthritis patients. We aim to examine the association between the baseline outcomes of the Handscan, disease activity levels and joint swelling. The Handscan measures differences in laser light absorption between joints of fingers and wrists and adjacent reference tissue, indicating the presence or absence of inflammation. The device gives an optical spectral transmission (OST) index per joint. The average of these indices is represented in the total optical score (TOS). Associations between TOS and DAS28 at subject level and OST and swelling at joint level were examined. 484 RA patients were included. Compared to patients with high disease activity (defined by DAS28), TOS was significantly lower in patients with moderate (estimated coefficient B: - 7.09, P < 0.001), low disease activity (B: - 6.99, P < 0.001) and patients in remission (B: - 7.72, P < 0.001) but could not distinguish between the latter three disease states. TOS was significantly lower in females (B: - 3.2, P < 0.001). OST was significantly higher in swollen than non-swollen joints (B: 0.28, P < 0.001). TOS was significantly higher in patients with high disease activity than in those in remission or with low and moderate disease activity. The difference in TOS between males and females should be accounted for in the interpretation of this outcome. The OST at joint level discriminates swollen from non-swollen joints and could be a more promising tool than the overall optical activity reflected in TOS.

Intramuscular short-chain acylcarnitines in elderly people are decreased in (pre-)frail females, but not in males.

This study tested the hypothesis that in human aging, a decreased intramuscular acylcarnitine status is associated with (pre-)frailty, reduced physical performance, and altered mitochondrial function. We used a cross-sectional study design with well-matched fit and (pre-)frail old males and females, using young males and females as healthy controls. Frailty was assessed according to the Fried criteria and physical performance was determined by 400 m walk test, short physical performance battery and handgrip strength. Muscle and plasma acylcarnitine status, and muscle mitochondrial gene expression was analyzed. Results showed that intramuscular total carnitine levels and short-chain acylcarnitine levels were lower in (pre-)frail old females compared to fit old females and young females, whereas no differences were observed in males. The low intramuscular short-chain acylcarnitine levels in females correlated with low physical performance, even after correction for muscle mass (%), and were accompanied with lowered expression of genes involved in mitochondrial energy production and functionality. It is, therefore, concluded that in (pre-)frail old females, intramuscular total carnitine levels and short-chain acylcarnitine levels are decreased, and this decrease is associated with reduced physical performance and low expression of a wide range of genes critical for mitochondrial function. The results stress the importance of taking sex differences into account in aging research.

Patterns of transfusion burden in an unselected population of patients with myelodysplastic syndromes: A population-based study.

BACKGROUND: Ineffective hematopoiesis in patients with myelodysplastic syndromes (MDS) often results in transfusion dependence. The burden of frequent transfusions in the real-world MDS population is largely unknown. STUDY DESIGN AND METHODS: An observational, retrospective, population-based study, using the HemoBase registry, was performed including all patients diagnosed with MDS between 2005 and 2017 in Friesland, a province in the Netherlands with approximately 650,000 inhabitants. Detailed clinical information was collected from the electronic health records. Transfusion burden was classified according to the International Working Group 2018 criteria: not transfusion dependent, low (LTB), or high transfusion burden (HTB). Univariate and multivariable regression analyses were performed. RESULTS: Of 292 patients, 136 (46.6%) had a HTB of ≥8 units/16 weeks and 17 (5.8%) had a LTB of 3-7 units/16 weeks. This was present in all types of MDS patients, but patients aged 75-84 years (odds ratio [OR] 4.02, 95% confidence interval [CI]: 1.84-8.82), high-risk MDS patients (OR 2.88, 95% CI: 1.08-7.68) and MDS-EB-2 patients (OR 7.07, 95% CI: 2.17-22.90) were particularly at risk for a HTB. DISCUSSION: This study provides a reliable estimate of the transfusion burden in real-world MDS patients, with almost half of the patients having a HTB. A HTB was observed in all MDS subtypes and both low- and high-risk MDS. Therefore, we conclude that the entire MDS population might benefit from novel agents that reduce the transfusion need and that might have beneficial effects on patient outcomes and healthcare utilization outcomes.

Impact of Treatment Delay on Outcome in the International Subarachnoid Aneurysm Trial.

Background and Purpose- ISAT (International Subarachnoid Aneurysm Trial) demonstrated that 1 year after aneurysmal subarachnoid hemorrhage, coiling resulted in a significantly better clinical outcome than clipping. After 5 years, this difference did not reach statistical significance, but mortality was still higher in the clipping group. Here, we present additional analyses, reporting outcome after excluding pretreatment deaths. Methods- Outcome measures were death with or without dependency at 1 and 5 years after treatment, after exclusion of all pretreatment deaths. Treatment differences were assessed using relative risks (RRs). With sensitivity and exploratory analyses, the relation between treatment delay and outcome was analyzed. Results- After exclusion of pretreatment deaths, at 1-year follow-up coiling was favorable over clipping for death or dependency (RR, 0.77 [95% CI, 0.67-0.89]) but not for death alone (RR, 0.88 [95% CI, 0.66-1.19]). After 5 years, no significant differences were observed, neither for death or dependency (RR, 0.88 [95% CI, 0.77-1.02]) nor for death alone (RR, 0.82 [95% CI, 0.64-1.05]). Sensitivity analyses showed a similar picture. In good-grade patients, coiling remained favorable over clipping in the long-term. Time between randomization and treatment was significantly longer in the clipping arm (mean 1.7 versus 1.1 days; P<0.0001), during which 17 patients died because of rebleeding versus 6 pretreatment deaths in the endovascular arm (RR, 2.81 [95% CI, 1.11-7.11]). Conclusions- These additional analyses support the conclusion of ISAT that at 1-year follow-up after aneurysmal subarachnoid hemorrhage coiling has a better outcome than clipping. After 5 years, with pretreatment mortality excluded, the difference between coiling and clipping is not significant. The high number of pretreatment deaths in the clipping group highlights the importance of urgent aneurysm treatment to prevent early rebleeding.

Prediction of Outcome After Aneurysmal Subarachnoid Hemorrhage.

Background and Purpose- Early prediction of clinical outcome after aneurysmal subarachnoid hemorrhage (aSAH) is still lacking accuracy. In this observational cohort study, we aimed to develop and validate an accurate bedside prediction model for clinical outcome after aSAH, to aid decision-making at an early stage. Methods- For the development of the prediction model, a prospectively kept single-center cohort of 1215 aSAH patients, admitted between 1998 and 2014, was used. For temporal validation, a prospective cohort of 224 consecutive aSAH patients from the same center, admitted between 2015 and 2017, was used. External validation was performed using the ISAT (International Subarachnoid Aneurysm Trial) database (2143 patients). Primary outcome measure was poor functional outcome 2 months after aSAH, defined as modified Rankin Scale score 4-6. The model was constructed using multivariate regression analyses. Performance of the model was examined in terms of discrimination and calibration. Results- The final model included 4 predictors independently associated with poor outcome after 2 months: age, World Federation of Neurosurgical Societies grade after resuscitation, aneurysm size, and Fisher grade. Temporal validation showed high discrimination (area under the receiver operating characteristic curve, 0.90; 95% CI, 0.85-0.94), external validation showed fair to good discrimination (area under the receiver operating characteristic curve, 0.73; 95% CI, 0.70-0.76). The model showed satisfactory calibration in both validation cohorts. The SAFIRE grading scale was derived from the final model: size of the aneurysm, age, Fisher grade, world federation of neurosurgical societies after resuscitation. Conclusions- The SAFIRE grading scale is an accurate, generalizable, and easily applicable model for early prediction of clinical outcome after aSAH.

Effective excision of cutaneous squamous cell carcinoma of the face using analysis of intra-operative frozen sections from the whole specimen.

BACKGROUND AND OBJECTIVES: We excised cutaneous squamous cell carcinoma (cSCC) of the face while using intra-operative frozen section analysis of the margins in an optimized bread-loafing fashion (WIFSA). METHODS: Medical records were reviewed of 160 cSCCs of the face that were treated by surgical excision with WIFSA between April 2007 and January 2013. The accuracy of WIFSA was verified by comparing results with postoperative formalin-fixed paraffin-embedded (FFPE) sections. Also, recurrence and metastasis during follow-up were studied and duration of treatment and complications were analyzed. RESULTS: The 160 cSCCs affected 152 patients. In 131 cSCCs (mean follow-up: 41.0 months, SD: ±26.3, range: 3.0-110.7) occurred 6 (4.6%) recurrences and 2 (1.5%) metastases. Of the WIFSA results, 98.8% corresponded with postoperative FFPE sections. Mean duration of treatment was 77 min (SD: ±25, range: 34-159) and complication rate was 8.1%. CONCLUSIONS: Surgical excision with WIFSA is an excellent treatment modality for cSCC of the face because of its accurate method for assessment of complete tumor removal, low recurrence and metastasis rate, short average duration of treatment, and low complication rate.

Effectiveness and safety of dabigatran versus acenocoumarol in 'real-world' patients with atrial fibrillation.

AIMS: Randomized trials showed non-inferior or superior results of the non-vitamin-K-antagonist oral anticoagulants (NOACs) compared with warfarin. The aim of this study was to assess the effectiveness and safety of dabigatran (direct thrombin inhibitor) vs. acenocoumarol (vitamin K antagonist) in patients with atrial fibrillation (AF) in daily clinical practice. METHODS AND RESULTS: In this observational study, we evaluated all consecutive patients who started anticoagulation because of AF in our outpatient clinic from 2010 to 2013. Data were collected from electronic patient charts. Primary outcomes were stroke or systemic embolism and major bleeding. Propensity score matching was applied to address the non-randomized design. In total, 920 consecutive AF patients were enrolled (442 dabigatran, 478 acenocoumarol), of which 2 × 383 were available for analysis after propensity score matching. Mean follow-up duration was 1.5 ± 0.56 year. The mean calculated stroke risk according to the CHA2DS2-VASc score was 3.5%/year in dabigatran vs. 3.7%/year acenocoumarol-treated patients. The actual incidence rate of stroke or systemic embolism was 0.8%/year [95% confidence interval (CI): 0.2-2.1] vs. 1.0%/year (95% CI: 0.4-2.1), respectively. Multivariable analysis confirmed this lower but non-significant risk in dabigatran vs. acenocoumarol after adjustment for the CHA2DS2-VASc score [hazard ratio (HR)dabigatran = 0.72, 95% CI: 0.20-2.63, P = 0.61]. According to the HAS-BLED score, the mean calculated bleeding risk was 1.7%/year in both groups. Actual incidence rate of major bleeding was 2.1%/year (95% CI: 1.0-3.8) in the dabigatran vs. 4.3%/year (95% CI: 2.9-6.2) in acenocoumarol. This over 50% reduction remained significant after adjustment for the HAS-BLED score (HRdabigatran = 0.45, 95% CI: 0.22-0.93, P = 0.031). CONCLUSION: In 'real-world' patients with AF, dabigatran appears to be as effective, but significantly safer than acenocoumarol.

Validity, reliability and support for implementation of independence-scaled procedural assessment in laparoscopic surgery.

BACKGROUND: There is no widely used method to evaluate procedure-specific laparoscopic skills. The first aim of this study was to develop a procedure-based assessment method. The second aim was to compare its validity, reliability and feasibility with currently available global rating scales (GRSs). METHODS: An independence-scaled procedural assessment was created by linking the procedural key steps of the laparoscopic cholecystectomy to an independence scale. Subtitled and blinded videos of a novice, an intermediate and an almost competent trainee, were evaluated with GRSs (OSATS and GOALS) and the independence-scaled procedural assessment by seven surgeons, three senior trainees and six scrub nurses. Participants received a short introduction to the GRSs and independence-scaled procedural assessment before assessment. The validity was estimated with the Friedman and Wilcoxon test and the reliability with the intra-class correlation coefficient (ICC). A questionnaire was used to evaluate user opinion. RESULTS: Independence-scaled procedural assessment and GRS scores improved significantly with surgical experience (OSATS p = 0.001, GOALS p < 0.001, independence-scaled procedural assessment p < 0.001). The ICCs of the OSATS, GOALS and independence-scaled procedural assessment were 0.78, 0.74 and 0.84, respectively, among surgeons. The ICCs increased when the ratings of scrub nurses were added to those of the surgeons. The independence-scaled procedural assessment was not considered more of an administrative burden than the GRSs (p = 0.692). DISCUSSION/CONCLUSION: A procedural assessment created by combining procedural key steps to an independence scale is a valid, reliable and acceptable assessment instrument in surgery. In contrast to the GRSs, the reliability of the independence-scaled procedural assessment exceeded the threshold of 0.8, indicating that it can also be used for summative assessment. It furthermore seems that scrub nurses can assess the operative competence of surgical trainees.

The predictive value of aptitude assessment in laparoscopic surgery: a meta-analysis.

CONTEXT: Current methods of assessing candidates for medical specialties that involve laparoscopic skills suffer from a lack of instruments to assess the ability to work in a minimally invasive surgery environment. OBJECTIVES: A meta-analysis was conducted to investigate whether aptitude assessment can be used to predict variability in the acquisition and performance of laparoscopic skills. METHODS: PubMed, PsycINFO and Google Scholar were searched to November 2014 for published and unpublished studies reporting the measurement of a form of aptitude for laparoscopic skills. The quality of studies was assessed with QUADAS-2. Summary correlations were calculated using a random-effects model. RESULTS: Thirty-four studies were found to be eligible for inclusion; six of these studies used an operating room performance measurement. Laparoscopic skills correlated significantly with visual-spatial ability (r = 0.32, 95% confidence interval [CI] 0.25-0.39; p < 0.001), perceptual ability (r = 0.31, 95% CI 0.22-0.39; p < 0.001), psychomotor ability (r = 0.26, 95% CI 0.10-0.40; p = 0.003) and simulator-based assessment of aptitude (r = 0.64, 95% CI 0.52-0.73; p < 0.001). Three-dimensional dynamic visual-spatial ability showed a significantly higher correlation than intrinsic static visual-spatial ability (p = 0.024). CONCLUSIONS: In general, aptitude assessments are associated with laparoscopic skill level. Simulator-based assessment of aptitude appears to have the potential to represent a job sample and to enable the assessment of all forms of aptitude for laparoscopic surgery at once. A laparoscopy aptitude test can be a valuable additional tool in the assessment of candidates for medical specialties that require laparoscopic skills.

Vitamin D reduces eosinophilic airway inflammation in nonatopic asthma.

BACKGROUND: Low levels of vitamin D are associated with asthma severity, airway remodeling, and exacerbation rate increase, especially in nonatopic asthma. Reduced steroid responsiveness or impaired antimicrobial defense might be underlying mechanisms. OBJECTIVE: We sought to evaluate the effect of vitamin D supplementation on eosinophilic and neutrophilic airway inflammation in patients with nonatopic asthma. METHODS: In a double-blind, randomized, placebo-controlled trial, we investigated the effect of long-acting vitamin D3 (400,000 IU) on sputum neutrophils and eosinophils in 44 patients with nonatopic asthma with neutrophilic (≥53%) and/or eosinophilic (≥3%) airway inflammation. Sputum induction was performed at baseline and after 9 weeks. Other measurements included questionnaires, blood samples, and pulmonary function. RESULTS: Treatment with vitamin D did not significantly affect sputum neutrophils or eosinophils compared with treatment with placebo in the total group. Regarding sputum eosinophils, the effect of vitamin D appeared to be dependent on baseline sputum eosinophil levels (interaction P = .015). In patients with eosinophil levels of 26.2% or more (median in patients with sputum eosinophilia, >3%), eosinophils decreased from a median of 41.0% to 11.8% after vitamin D treatment as compared with an increase from 51.8% to 63.3% in patients receiving placebo (P = .034). Vitamin D treatment also resulted in slightly better Asthma Control Questionnaire scores (P = .08). CONCLUSIONS: Vitamin D supplementation reduced eosinophilic airway inflammation in patients with nonatopic asthma with severe eosinophilic airway inflammation, but did not affect sputum neutrophils. Also, a small effect on asthma control was observed. These findings suggest that vitamin D might have potential as an add-on treatment option in eosinophilic asthma.

Predictive Factors for Rebleeding After Aneurysmal Subarachnoid Hemorrhage: Rebleeding Aneurysmal Subarachnoid Hemorrhage Study.

BACKGROUND AND PURPOSE: Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating type of stroke associated with high morbidity and mortality. One of the most feared complications is an early rebleeding before aneurysm repair. Predictors for such an often fatal rebleeding are largely unknown. We therefore aimed to determine predictors for an early rebleeding after aSAH in relation with time after ictus. METHODS: This observational prospective cohort study included all consecutive patients admitted with aSAH between January 1998 and December 2014 (n=1337) at our University Neurovascular Center. Clinical predictors for rebleeding ≤24 hours were identified using multivariable Cox regression analyses. Kaplan-Meier analyses were applied to evaluate the time of rebleeding ≤72 hours after aSAH. RESULTS: A modified Fisher grade of 3 to 4 was a predictor for an in-hospital rebleeding ≤24 hours after ictus (adjusted hazard ratio, 4.4; 95% confidence interval, 2.1-10.6; P<0.001). The numbers needed to treat to prevent 1 rebleeding ≤24 hours was calculated 15 (95% confidence interval, 10-25). Also, the initiation of external cerebrospinal fluid-drainage (adjusted hazard ratio, 1.9; 95% confidence interval, 1.4-2.5; P<0.001) was independently associated with a rebleeding ≤24 hours. Cumulative in-hospital rebleeding rates were 5.8% ≤24 hours, and 1.2% in the time frame 24-72 hours after ictus. CONCLUSIONS: In our opinion, timing of treatment of aSAH patients, especially those with an modified Fisher grade of 3 or 4 in a good clinical condition, should be reconsidered. These aSAH patients might be regarded a medical emergency, requiring aneurysm repair as soon as possible. In this respect, our findings should provoke the debate on timing of aneurysm repair, especially in patients considered to be at high risk for rebleeding.

Comorbidity is an independent prognostic factor in patients with advanced-stage diffuse large B-cell lymphoma treated with R-CHOP: a population-based cohort study.

An observational population-based cohort study was performed to investigate the role of comorbidity on outcome and treatment-related toxicity in patients with newly diagnosed advanced-stage diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). Data for the clinical characteristics of 154 patients (median age 69 years), including Charlson Comorbidity Index (CCI), treatment, toxicity and outcome were evaluated. Forty-five percent of the patients had an International Prognistic index ≥3 and 16% had a CCI ≥2. The planned R-CHOP schedule was completed by 84% and 75% reached complete remission (CR). In those with CCI ≥2, 67% completed treatment with 46% CR. In patients with a CCI <2, overall survival (OS) after 1, 2 and 5 years was 84%, 79% and 65% respectively and it was 64%, 48% and 48% for those with CCI ≥2. Grade III/IV toxicity was documented in 53%, most frequently febrile neutropenia (27%) and infections (23%). In multivariate analysis CCI ≥2 and IPI ≥3 were independent risk indicators for OS and grade III/IV toxicity. In conclusion, comorbidity is an independent risk indicator for worse OS in patients with advanced DLBCL treated with R-CHOP by interference with intensive treatment schedules and more grade III/IV toxicity. Future studies are warranted to determine the optimal treatment approach in patients with significant comorbidities.

Children with asthma have significantly lower long-term cortisol levels in their scalp hair than healthy children.

AIM: Noninvasive measurement of long-term cortisol levels is a useful way of evaluating the effect of chronic disease on the hypothalamic-pituitary-adrenal axis in children. The aim of this pilot study was to compare hair cortisol levels in children using inhaled corticosteroids for asthma and healthy children and to determine the association with short-term salivary cortisol levels. METHODS: Cortisol levels were measured in the scalp hair and saliva of prepubertal children with asthma (n = 10) and without asthma (n = 10). Asthma control was assessed using an asthma questionnaire and pulmonary function tests. RESULTS: The median (95% CI) cortisol level in the scalp hair of the children with asthma (2.0 pg/mg; 1.4-4.1) was significantly lower than the healthy children (4.3 pg/mg; 1.8-5.9). Morning salivary cortisol levels were significantly lower for the children with asthma (5.9 nmol/L; 3.2-11.1) than the healthy children (9.0 nmol/L; 4.4-31.6). There was no significant association between cortisol levels in hair and saliva. CONCLUSION: Long-term cortisol levels were significantly lower in children with asthma than healthy children. Measuring long-term cortisol levels in scalp hair is an attractive, noninvasive tool that can evaluate the effect of asthma and its treatment on the hypothalamic-pituitary-adrenal axis.