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Objective: Chemotherapy in the last month of life for patients with metastatic lung cancer is often considered as aggressive end-of-life care. Targeted therapy with Tyrosine Kinase Inhibitors (TKIs) is a relatively new treatment of which not much is known yet about use in the last month of life. We examined what percentage of patients received chemotherapy or TKIs in the last month of life in the Netherlands., Methods: Patient files were drawn from 10 hospitals across the Netherlands. Patients had to meet the following eligibility criteria: metastatic lung cancer; died between June 1, 2013 and July 31, 2015., Results: From the included 1,322 patients, 39% received no treatment for metastatic lung cancer, 52% received chemotherapy and 9% received TKIs. A total of 232 patients (18%) received treatment in the last month of life (11% chemotherapy, 7% TKIs). From the patients who received chemotherapy, 145 (21%) received this in the last month of life and 79 (11%) started this treatment in the last month of life. TKIs were given and started more often in the last month of life: from the patients who received TKIs, 87 (72%) received this treatment in the last month of life and 15 (12%) started this treatment in the last month of life., Conclusion: A substantial percentage of patient received and even started chemotherapy or TKIs in the last month of life. For chemotherapy, this might be seen as aggressive care. TKIs are said to have less side effects, do not lead to many hospital visits and due to the rapid response, are considered good palliation. However, it is not known, yet possible that, when patients still receiving treatment until shortly before death, this might influence preparing for death in a negative way., (© 2019 The Authors. European Journal of Cancer Care published by John Wiley & Sons Ltd.)

Background: Oesophagectomy is a major complex operation associated with significant morbidity and mortality. Epidural analgesia has long been the gold standard postoperative analgesia but is associated with side-effects like hypotension, epidural haematoma and infection. In an attempt to lower morbidity and enhance recovery postoperatively, we have adopted the use of paravertebral catheter analgesia (PVCA) for patients undergoing totally minimal invasive oesophagectomy (TMIO)., Methods: Our objective was to review the current literature about the use of both PVCA and epidural analgesia. In addition, we evaluated the effect of PVCA in a large group of patients undergoing TMIO for cancer. We reviewed the records of 100 consecutive patients who had a TMIO with PVCA, spinal morphine, and PCA. Prospective independent scoring of postoperative pain, length of stay, high-dependency unit (HDU) stay, PVCA failure, the use of patient-controlled analgesia (PCA), and the use of vasoconstrictor medication postoperatively was analysed., Results: One hundred consecutive patients received PVCA with PCA after the TMIO. Catheter related failures occurred in 4 cases. The median pain score over each of the 5 days were 0. The average pain score was highest in the first 24 hours and decreased over the next 4 days postoperatively. The use of PCA was highest in the first 2 days and reduced daily over the subsequent 3 days. Seven patients required rescue analgesia in the form of intercostal nerve (ICN) block. Spinal morphine was successful in 94% of cases. Vasoconstrictors were required in 19% on day 1 and 3% on day 2, postoperatively., Conclusions: Intraoperative placement of PVCA results in good postoperative pain control after a TMIO. This technique is simple, safe, reproducible and with very low failure rates. Therefore, it should be used instead of epidural catheter analgesia., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

A preliminary report is presented by an international project team working on developing a model for a structured and holistic approach to companioning parishioners in the journey of formation in the Christian life. A holistic model involves working in three domains: positive psychology, spirituality, and personal and social ethics. Structure is provided by utilizing four self-assessment instruments to inform the work the pastor and the parishioner do together.

This meta-analysis is the first to our knowledge to evaluate the predictive properties of dynamic sex offender risk assessment instruments, which are designed to assess factors associated with recidivism that are amenable to change. Based on 52 studies (N = 13,446), we found that dynamic risk assessment instruments have small-to-moderate predictive properties, with Cohen's d ranging between 0.71 for sexual recidivism (41 studies, 22 unique samples, N = 5,699) and 0.43 for violent (including sexual) recidivism (27 studies, 14 unique samples, N = 10,368). Incremental predictive validity of dynamic over static risk assessment instruments was significant but modest; Cox hazard ratios varied between 1.08 for sexual recidivism (19 studies, 13 unique samples, N = 3,747) and 1.05 for any recidivism (11 studies, 8 unique samples, N = 2,511). Cox hazard ratios for the predictive validity of change scores on dynamic risk assessment instruments, controlling for static and initial dynamic scores, varied between 0.91 for sexual recidivism (6 studies, 6 unique samples, n = 1,980) and 0.95 for any recidivism (3 studies, 3 unique samples, n = 1,172). These findings indicate that dynamic risk assessment instruments can, in terms of Andrews and Bonta's (2010) risk and need principles, be a useful tool for improving sex offender treatment. They have the potential to contribute to the selection of appropriate, more individually tailored treatment approaches (focusing on individually relevant criminogenic need factors) and can assist in the evaluation of treatment effects. Considering this, further development of dynamic risk assessment instruments is warranted. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)

Background: Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied., Methods: This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1:1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials.gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants., Findings: Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31·1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0·67, 95% CI 0·48-0·94, p=0·0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6·2% (ratio of LS means 1·27, 0·78-2·06, p=0·31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported., Interpretation: This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation., Funding: Patara Pharma., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: We examined the costs and benefits of introducing migraine nurses into primary care., Background: Migraine is one of the most costly neurological diseases., Methods: We analyzed data from our earlier nonrandomized cohort study comparing an intervention group of 141 patients, whose care was supported by nurses trained in migraine management, and a control group of 94 patients receiving usual care. Estimates of per-person direct costs were based on nurses' salaries and referrals to neurologists. Indirect costs were estimated as lost productivity, including numbers of days of absenteeism or with <50% productivity at work due to migraine, and notional costs related to lost days of household activities or days of <50% household productivity. Analysis was conducted from the payer's perspective., Results: After 9 months the direct costs were €281.11 in the control group against €332.23 in the intervention group (mean difference -51.12; 95% CI: -113.20-15.56; P = .134); the indirect costs were €1985.51 in the control group against €1631.75 in the intervention group (mean difference 353.75; 95% CI: -355.53-1029.82; P = .334); and total costs were €2266.62 in the control group, against €1963.99 in the intervention group (mean difference 302.64; 95% CI: -433.46-1001.27; P = .438). When costs attributable to lost household productivity were included, total costs increased to €6076.62 in the control group and €5048.15 in the intervention group (mean difference 1028.47; 95% CI: -590.26-2603.67; P = .219)., Conclusion: Migraine nurses in primary care seemed in this study to increase practice costs but decrease total societal costs. However, it was a nonrandomized study, and the differences did not reach significance. For policy-makers concerned with headache-service organization and delivery, the important messages are that we found no evidence that nurses increased overall costs, and investment in a definitive study would therefore be worthwhile., (© 2017 American Headache Society.)

Background: Antibiotics do not reduce mortality or short-term treatment non-response in patients receiving treatment for acute exacerbations of COPD in an outpatient setting. However, the long-term effects of antibiotics are unknown. The aim of this study was to investigate if the antibiotic doxycycline added to the oral corticosteroid prednisolone prolongs time to next exacerbation in patients with COPD receiving treatment for an exacerbation in the outpatient setting., Methods: In this randomised double-blind placebo-controlled trial, we recruited a cohort of patients with COPD from outpatient clinics of nine teaching hospitals and three primary care centres in the Netherlands. Inclusion criteria were an age of at least 45 years, a smoking history of at least 10 pack-years, mild-to-severe COPD (Global Initiative of Chronic Obstructive Lung Disease [GOLD] stage 1-3), and at least one exacerbation during the past 3 years. Exclusion criteria were poor mastery of the Dutch language, poor cognitive functioning, known allergy to doxycycline, pregnancy, and a life expectancy of shorter than 1 month. If a participant had an exacerbation, we randomly assigned them (1:1; with permuted blocks of variable sizes [ranging from two to ten]; stratified by GOLD stage 1-2 vs 3) to a 7 day course of oral doxycycline 100 mg daily (200 mg on the first day) or placebo. Exclusion criteria for randomisation were fever, admission to hospital, and current use of antibiotics or use within the previous 3 weeks. Patients in both groups received a 10 day course of 30 mg oral prednisolone daily. Patients, investigators, and those assessing outcomes were masked to treatment assignment. The primary outcome was time to next exacerbation in all randomly allocated patients except for those incorrectly randomly allocated who did not meet the inclusion criteria or met the exclusion criteria. This trial is registered with the Netherlands Trial Register, number NTR2499., Findings: Between Dec 22, 2010, and Aug 6, 2013, we randomly allocated 305 (34%) patients from the cohort of 887 patients to doxycycline (152 [50%]) or placebo (153 [50%]), excluding four (1%) patients (two [1%] from each group) who were incorrectly randomly allocated from the analysis. 257 (85%) of 301 patients had a next exacerbation (131 [87%] of 150 in the doxycycline group vs 126 [83%] of 151 in the placebo group). Median time to next exacerbation was 148 days (95% CI 95-200) in the doxycycline group compared with 161 days (118-211) in the placebo group (hazard ratio 1·01 [95% CI 0·79-1·31]; p=0·91). We did not note any significant differences between groups in the frequency of adverse events during the first 2 weeks after randomisation (47 [31%] of 150 in the doxycycline group vs 53 [35%] of 151 in the placebo group; p=0·54) or in serious adverse events during the 2 years of follow-up (42 [28%] vs 43 [29%]; p=1)., Interpretation: In patients with mild-to-severe COPD receiving treatment for an exacerbation in an outpatient setting, the antibiotic doxycycline added to the oral corticosteroid prednisolone did not prolong time to next exacerbation compared with prednisolone alone. These findings do not support prescription of antibiotics for COPD exacerbations in an outpatient setting., Funding: Netherlands Organization for Health Research and Development., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Failed laparoscopic adjustable gastric banding (LAGB) can be converted to laparoscopic Roux-and-Y gastric bypass (LRYGB), which is currently the gold standard for bariatric surgery. Revisional LRYGB (rLRYGB) is associated with inferior results compared with primary LRYGB (pLRYGB), but the exact influence of the initial response to LAGB is unclear., Objectives: To compare follow-up outcomes after pLRYGB with rLRYGB in nonresponders of LAGB and rLRYGB in responders of LAGB., Setting: General-community teaching hospital, Rotterdam, the Netherlands., Methods: All patients who underwent pLRYGB and rLRYGB after LAGB were reviewed in an observational study. Postoperative outcomes, excess weight loss, total weight loss, and success and failure rate were compared in patients after pLRYGB and rLRYGB (both responders and nonresponders of LAGB) at 12, 24, and 36 months., Results: A total of 1285 primary patients, 96 nonresponders, and 120 responders were included. The median follow-up was 33.9±18.0 months. After 36 months, the mean percentage excess weight loss was significantly lower in the nonresponding group compared with the responding and primary groups (48.1% versus 58.2% versus 72.8%, P<.001); the total weight loss showed the same trend. The success rate was 38.2% versus 61.0% versus 81.6% respectively, P<.001. The failure rate was significantly higher after rLRYGB compared with pLRYGB (10.9% nonresponders, 8.5% responders, and 2.5% primary, P = .001)., Conclusion: Nonresponders of LAGB show inferior weight loss results after rLRYGB compared with responders of LAGB and pLRYGB at all moments of follow-up., (Copyright © 2017 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Objectives: To determine if mandatory adherence to a diagnostic protocol increases the rate of computed tomography pulmonary angiographies (CTPAs) positive for pulmonary embolism (PE)-the so-called diagnostic yield. Further, we aim to identify factors associated with this diagnostic yield., Methods: We included all patients with suspected PE requiring CTPA from 9 January 2014 t0 3 June 2014. The requesting physicians were forced to follow diagnostic workup for PE by calculating a Wells score and, if necessary, determining D-dimer level. The percentage of positive CTPA scans was calculated and compared with our previous cohort (Walen et al. Insights Imaging 2014;5(2):231-236). Odds ratios were calculated as a measure of association between dichotomous variables and CTPA findings., Results: Of 250 scans, 74 were positive (29.6 % [95 % CI, 24.3-35.5 %]) and 175 were negative (70 %). The percentage positive scans increased with 6.6 % and the percentage negative scans decreased with 3.1 %. This change was statistically significant (p = 0.001). Independent clinical predictors of diagnostic yield were previous deep venous thrombosis (DVT) (OR, 3.22; p = 0.013) and clinical signs of DVT (OR, 2.71; p = 0.012). Chronic obstructive pulmonary disease (COPD) was negatively associated with PE (OR, 0.33; p = 0.045)., Conclusions: This study shows that mandatory adherence to a diagnostic protocol increases the yield of CTPA for PE in our centre., Main Messages: • Mandatory adherence to diagnostic protocol increases the yield of CTPA for PE • Previous DVT and signs of DVT were associated with a higher yield • No patients with a low Wells score and a low D-dimer had PE.

Background: Delayed diagnosis of pulmonary embolism (PE) is common because symptoms can be non-specific. The few studies that have investigated diagnostic delay have not taken into account the role of primary care physicians in the diagnostic process., Aim: To document and quantify the stages of diagnostic delay of PE and to identify clinical factors associated with this delay., Design and Setting: A retrospective cohort study conducted in Zwolle and its surroundings in the Netherlands., Method: Primary and secondary care records of all patients diagnosed with PE between January 2008 and December 2009 were reviewed for dates of symptom onset, date of presentation and diagnosis, and for clinical findings. Relationships between delay and clinical parameters were tested using multivariate regression analysis., Results: The 261 patients enrolled in the study had an average total delay of 8.6 days. Patient delay (4.2 days average) and delay in primary care (3.9 days) were the major contributors to this delay. Chest pain (odds ratio [OR] 0.51, 95% confidence interval [CI] = 0.28 to 0.92, P = 0.03) and symptoms of deep venous thrombosis (calf pain) (OR 0.49, 95% CI = 0.24 to 0.98, P = 0.05) were associated with an early diagnosis. Patient delay was shorter in patients with chest pain (OR 0.49, 95% CI = 0.25 to 0.95, P = 0.03) and longer in patients with dyspnoea (OR 2.95, 95% CI = 0.99 to 8.85, P = 0.05). In primary care, chest pain (OR 0.37, 95% CI = 0.17 to 0.84, P = 0.02) and rales (OR 0.22, 95% CI = 0.06 to 0.83, P = 0.03) were associated with an early referral, whereas comorbidity led to a delayed referral., Conclusion: This study shows that the diagnostic delay of PE is substantial, especially patient delay and delay in primary care. There is room to reduce this delay by increasing the awareness of both patients and GPs. Further research is needed on clinical factors that raise suspicion of PE in primary care., (© British Journal of General Practice 2016.)

Aim: The purpose of this article is to present the results of a private cardiac surgical practice. This information could also serve as a hermeneutical text for new wisdom., Methods: A personal database of 1 750 consecutive patients who had had coronary artery bypass graft (CABG) surgery was statistically analysed. Mortality and major morbidity figures were compared with large registries. Risk factors for postoperative death were determined., Results: Over a period of 12 years, 1 344 (76.8%) males and 406 (23.2%) females were operated on. The observed mortality rate was 3.03% and the expected mortality rate (EuroSCORE) was 3.87%. After stepwise logistic regression, independent risk factors for death were urgency (intra-aortic balloon pump), renal impairment (chronic kidney disease, stage III), re-operation and an additional procedure. Apart from the 53 deaths, another 91 patients had major complications., Conclusion: Mortality and morbidity rates compared favourably with other international registries. Mortality was related to co-morbidities. This outcome contributes to a hermeneutical understanding focusing on new spiritual wisdom and meaning for the surgeon.

Objective: To determine the optimal cutoff scores for the Fugl-Meyer Assessment of the Upper Extremity (FMA-UE) with regard to predicting no, poor, limited, notable, or full upper-limb capacity according to frequently used cutoff points for the Action Research Arm Test (ARAT) at 6 months poststroke., Design: Prospective., Setting: Rehabilitation center., Participants: Patients (N=460) with a first-ever ischemic stroke at 6 months poststroke., Interventions: Not applicable., Main Outcome Measures: Based on the ARAT classification of poor to full upper-limb capacity, receiver operating characteristic curves were used to calculate the area under the curve, optimal cutoff points for the FMA-UE were determined, and a weighted kappa was used to assess the agreement., Results: FMA-UE scores of 0 through 22 represent no upper-limb capacity (ARAT 0-10); scores of 23 through 31 represent poor capacity (ARAT 11-21); scores of 32 through 47 represent limited capacity (ARAT 22-42); scores of 48 through 52 represent notable capacity (ARAT 43-54); and scores of 53 through 66 represent full upper-limb capacity (ARAT 55-57). Overall, areas under the curve ranged from .916 (95% confidence interval [CI], .890-.943) to .988 (95% CI, .978-.998; P<.001)., Conclusions: There is considerable overlap in the area under the curve between the ARAT and FMA-UE. FMA-UE scores >31 points correspond to no to poor arm-hand capacity (ie, ≤21 points) on the ARAT, whereas FMA-UE scores >31 correspond to limited to full arm-hand capacity (ie, ≥22 points) on the ARAT., (Copyright © 2015 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Background and Objective: Telemedicine, care provided by electronic communication, may serve as an alternative or extension to traditional outpatient visits. This pilot study determined the effects of telemedicine on health-care utilization and health status of chronic obstructive pulmonary disease (COPD) patients., Methods: One hundred and one patients were randomized, 52 patients received telemedicine care and 49 had traditional outpatient visits. The primary outcome was COPD-specific health status, measured with the Clinical COPD Questionnaire (CCQ). Secondary outcomes included St. George's Respiratory Questionnaire (SGRQ) and the Short Form-36 (SF-36) and resource use in primary and secondary care., Results: The mean age of the participants was 68 ± 9 years and the mean per cent of predicted forced expiratory volume in 1 s was 40.4 ± 12.5. The CCQ total score deteriorated by 0.14 ± 0.13 in the telemedicine group, and improved by -0.03 ± 0.14 in the control group (difference 0.17 ± 0.19, 95% confidence interval (CI): -0.21-0.55, P = 0.38). The CCQ symptom domain showed a significant and clinically relevant difference in favour of the control group, 0.52 ± 0.24 (95% CI: 0.04-0.10, P = 0.03). Similar results were found for the SGRQ, whereas results for SF-36 were inconsistent. Patients in the control group had significantly fewer visits to the pulmonologist in comparison to patients in the telemedicine group (P = 0.05). The same trend, although not significant, was found for exacerbations after 6 months., Conclusions: This telemedicine model of initiated phone calls by a health-care provider had a negative effect on health status and resource use in primary and secondary care, in comparison with usual care and therefore cannot be recommended in COPD patients in its current form., (© 2014 Asian Pacific Society of Respirology.)

Background: In patients with acute ischemic stroke caused by a proximal intracranial arterial occlusion, intraarterial treatment is highly effective for emergency revascularization. However, proof of a beneficial effect on functional outcome is lacking., Methods: We randomly assigned eligible patients to either intraarterial treatment plus usual care or usual care alone. Eligible patients had a proximal arterial occlusion in the anterior cerebral circulation that was confirmed on vessel imaging and that could be treated intraarterially within 6 hours after symptom onset. The primary outcome was the modified Rankin scale score at 90 days; this categorical scale measures functional outcome, with scores ranging from 0 (no symptoms) to 6 (death). The treatment effect was estimated with ordinal logistic regression as a common odds ratio, adjusted for prespecified prognostic factors. The adjusted common odds ratio measured the likelihood that intraarterial treatment would lead to lower modified Rankin scores, as compared with usual care alone (shift analysis)., Results: We enrolled 500 patients at 16 medical centers in The Netherlands (233 assigned to intraarterial treatment and 267 to usual care alone). The mean age was 65 years (range, 23 to 96), and 445 patients (89.0%) were treated with intravenous alteplase before randomization. Retrievable stents were used in 190 of the 233 patients (81.5%) assigned to intraarterial treatment. The adjusted common odds ratio was 1.67 (95% confidence interval [CI], 1.21 to 2.30). There was an absolute difference of 13.5 percentage points (95% CI, 5.9 to 21.2) in the rate of functional independence (modified Rankin score, 0 to 2) in favor of the intervention (32.6% vs. 19.1%). There were no significant differences in mortality or the occurrence of symptomatic intracerebral hemorrhage., Conclusions: In patients with acute ischemic stroke caused by a proximal intracranial occlusion of the anterior circulation, intraarterial treatment administered within 6 hours after stroke onset was effective and safe. (Funded by the Dutch Heart Foundation and others; MR CLEAN Netherlands Trial Registry number, NTR1804, and Current Controlled Trials number, ISRCTN10888758.).

Reports from individual centres suggest a preponderance of females with chronic cough. Females also have heightened cough reflex sensitivity. Here we have reviewed the age and sex of unselected referrals to 11 cough clinics. To investigate the cause of any observed sex dimorphism, functional magnetic resonance imaging of putative cough centres was analysed in normal volunteers. The demographic profile of consecutive patients presenting with chronic cough was evaluated. Cough challenge with capsaicin was undertaken in normal volunteers to construct a concentration-response curve. Subsequent functional magnetic resonance imaging during repeated inhalation of sub-tussive concentrations of capsaicin observed areas of activation within the brain and differences in the sexes identified. Of the 10,032 patients presenting with chronic cough, two-thirds (6591) were female (mean age 55 years). The patient profile was largely uniform across centres. The most common age for presentation was 60-69 years. The maximum tolerable dose of inhaled capsaicin was lower in females; however, a significantly greater activation of the somatosensory cortex was observed. Patients presenting with chronic cough from diverse racial and geographic backgrounds have a strikingly homogeneous demographic profile, suggesting a distinct clinical entity. The preponderance of females may be explained by sex-related differences in the central processing of cough sensation., (©ERS 2014.)

We explored genetic variation by sequencing a selection of 84 tomato accessions and related wild species representative of the Lycopersicon, Arcanum, Eriopersicon and Neolycopersicon groups, which has yielded a huge amount of precious data on sequence diversity in the tomato clade. Three new reference genomes were reconstructed to support our comparative genome analyses. Comparative sequence alignment revealed group-, species- and accession-specific polymorphisms, explaining characteristic fruit traits and growth habits in the various cultivars. Using gene models from the annotated Heinz 1706 reference genome, we observed differences in the ratio between non-synonymous and synonymous SNPs (dN/dS) in fruit diversification and plant growth genes compared to a random set of genes, indicating positive selection and differences in selection pressure between crop accessions and wild species. In wild species, the number of single-nucleotide polymorphisms (SNPs) exceeds 10 million, i.e. 20-fold higher than found in most of the crop accessions, indicating dramatic genetic erosion of crop and heirloom tomatoes. In addition, the highest levels of heterozygosity were found for allogamous self-incompatible wild species, while facultative and autogamous self-compatible species display a lower heterozygosity level. Using whole-genome SNP information for maximum-likelihood analysis, we achieved complete tree resolution, whereas maximum-likelihood trees based on SNPs from ten fruit and growth genes show incomplete resolution for the crop accessions, partly due to the effect of heterozygous SNPs. Finally, results suggest that phylogenetic relationships are correlated with habitat, indicating the occurrence of geographical races within these groups, which is of practical importance for Solanum genome evolution studies., (© 2014 The Authors The Plant Journal © 2014 John Wiley & Sons Ltd.)

Background: Improvement in health-related quality of life (HRQoL) is one of the main goals in treating chronic obstructive pulmonary disease (COPD). Impaired HRQoL in COPD is associated with increased morbidity and mortality, hospitalisations and burden on our health-care system. The Clinical COPD Questionnaire (CCQ) is a validated, reliable, short questionnaire for the evaluation of disease-specific HRQoL in patients with COPD in primary care., Aims: To investigate factors that might be associated with CCQ outcome in COPD in a primary care setting., Methods: In a population of COPD patients in primary care, multiple regression analyses were used to assess associations between CCQ outcome and depression, heart failure, FEV1% predicted, FEV1/FVC, age, sex, body mass index and current smoking., Results: Data from 341 patients (mean age 68.1±10.3, COPD GOLD class I-III) were used for analyses. Together, heart failure and depression explained 23% of the variance in CCQ total score (P<0.001, N=93). Heart failure was most strongly associated with CCQ functional score (27% explained variance, P<0.001, N=100), whereas depression was most strongly associated with CCQ mental score (22% explained variance, P<0.001, N=93)., Conclusions: CCQ outcomes are higher in COPD patients with heart failure and depression. These findings might imply that heart failure and depression affect HRQoL of patients with COPD, and thus emphasise the importance of a holistic approach of this complex disease, leading to a correct diagnosis of COPD and its comorbidities, to achieve better tailored treatment of chronic patients.

Background: Traditionally, outpatient visits for COPD are fixed, pre-planned by the pulmonologist. This is not a patient centered method, nor, in times of increasing COPD prevalence and resource constraints, perhaps the optimal method., Objectives: This pilot study, determined the effect of an on-demand-system, patient initiated outpatient visits, on health status, COPD-related healthcare resource-use and costs., Methods: Patients were randomized between on-demand-system (n = 49) and usual care (n = 51), with a 2-year follow-up. Primary, health status was assessed with Clinical COPD Questionnaire (CCQ). Secondary endpoints were: St. George's Respiratory Questionnaire (SGRQ), Short Form-36 (SF-36) scores, visits to general practitioners (GP), pulmonologists, and pulmonary nurse practitioners (PNP), exacerbations and total treatment costs from healthcare providers and healthcare insurance perspectives., Results: Participants had a mean FEV(1) 1.3 ± 0.4 liters and were 69 ± 9 years. CCQ total scores deteriorated in both groups, with no significant difference between them. CCQ symptom domain did show a significant and clinically relevant difference in favor of the on-demand-group, -0.4 ± 0.21, CI95% -0.87; -0.02, p = 0.04. Similar tendency was found for the SGRQ whereas results for SF-36 were inconsistent. Patients in the on-demand-group visited GP significantly less (p = 0.01), but PNP significantly more, p = 0.003. Visits to pulmonologists and exacerbations were equally frequent in both groups. Mean total costs per patient were lower in the on-demand-group in comparison with usual care, difference of €-518 (-1993; 788) from healthcare provider and €-458 (-2700; 1652) insurance perspective., Conclusions: The on-demand-system was comparable with usual care, had a cost-saving tendency, and can be instituted with confidence in the COPD outpatient care setting., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Migraine is a common illness in children associated with a negative impact on the quality of life. In the Netherlands, treatment of migraine is commonly performed by general practitioners (GPs). The migraine guideline of the Dutch College of General Practitioners recommends inactivity and acetaminophen in patients with migraine who are younger than 18 years of age., Objective: The aim of our study was to evaluate the pharmacological treatment of migraine in children by GPs before referral to the hospital. Our objective was to answer the following questions. First, are GPs inclined to prescribe medication not listed in the Dutch College of General Practitioners Guideline? Second, which clinical characteristics are associated with the use of medication not listed in this guideline?, Methods: In this retrospective cross-sectional study, prescribed medication and migraine characteristics were investigated in Dutch migraine patients (age <18 years), using hospital records and a paper-and-pencil questionnaire., Results: A total of 223 children were included. Medications not listed in the guideline were used in 41.3% of the patients before referral. In children younger than 12 years, the use of medication not listed in the guideline was associated with an older age, when compared with children who were treated according to the guideline. In the group of patients older than 11 years, the use of medication not listed in the guideline was associated with a longer history of migraine and a longer duration of the migraine attacks., Conclusions: Medications not listed in the GPs guideline were used in a large portion of the patients younger than 18 years with migraine who were referred to secondary care., (© 2014 American Headache Society.)

Objectives: To determine the diagnostic yield of computed tomography scanning of the pulmonary arteries (CTPA) in our centre and factors associated with it. Differences between specialties as well as adherence to protocol were investigated., Methods: All patients receiving a first CTPA for pulmonary embolism (PE) in 2010 were included. Data about relevant clinical information and the requesting specialty were retrospectively obtained. Differences in diagnostic yield were tested using a chi-squared test. Independent predictors were identified with multivariate logistic regression., Results: PE on CTPA was found in 224 of the 974 patients (23 %). Between specialties, diagnostic yield varied from 19.5 to 23.9 % (p = 0.20). Independent predictors of diagnostic yield were: age, sex, D-dimer, cough, dyspnea, cardiac history, chronic obstructive pulmonary disease (COPD), atelectasis/consolidation, intrapulmonary mass and/or interstitial pulmonary disease on CT. Wells scores were poorly documented (n = 127, 13.0 %). Poor adherence to protocol was also shown by a high amount of unnecessary D-dimer values with a high Wells-score (35 of 58; 58.6 %)., Conclusions: The diagnostic yield of CTPA in this study was relatively high in comparison with other studies (6.7-31 %). Better adherence to protocol might improve the diagnostic yield further. A prospective study could confirm the independent predictors found in this study., Teaching Points: • Pulmonary embolism is potentially life-threatening and requires quick and reliable diagnosis. • Computed tomography of the pulmonary arteries (CTPA) provides this reliable diagnosis. • Several independent predictors of diagnostic yield of CTPA for pulmonary embolism were identified. • Diagnostic yield of CTPA did not differ between requesting specialties in our Hospital. • Better protocol adherence could improve the diagnostic yield of CTPA for pulmonary embolism.

Large ant colonies invariably use effective scent trails to guide copious ant numbers to food sources. The success of mass recruitment hinges on the involvement of many colony members to lay powerful trails. However, many ant colonies start off as single queens. How do these same colonies forage efficiently when small, thereby overcoming the hurdles to grow large? In this paper, we study the case of combined group and mass recruitment displayed by some ant species. Using mathematical models, we explore to what extent early group recruitment may aid deployment of scent trails, making such trails available at much smaller colony sizes. We show that a competition between group and mass recruitment may cause oscillatory behaviour mediated by scent trails. This results in a further reduction of colony size to establish trails successfully.

Patients with amyotrophic lateral sclerosis (ALS) often fear of dying from suffocation. This fear is also common in relatives and caregivers. Research has, however, shown that ALS patients seldom die from suffocation. More than 90% of all ALS patients die peacefully. Death is mostly preceded by a peracute decrease in consciousness due to hypercapnia caused by alveolar hypoventilation. Mechanical ventilation, especially at night, can reduce the symptoms caused by hypoventilation. However, little by little, the effectiveness of ventilation may decrease to such an extent that it is no longer useful or desirable. Termination of long-standing ventilation requires careful preparation. Intensive guidance of the relevant medical, practical and ethical aspects are necessary. Particularly in the pre-terminal and terminal phases, support given to an ALS patient requires a pro-active attitude on the part of the treating physician. To this end, physicians may seek advice from the Dutch ALS Center, a palliative care consultation team, a hospice physician or a center for home mechanical ventilation.

Background: A standardized diagnostic program, initiated to reduce the length of the diagnostic track and to improve application of diagnostic tools for patients referred with suspicious abnormalities on standard chest radiographs, was evaluated., Methods: The findings on integrated positron emission tomography/computed tomography (PET-CT) determined the choice of invasive investigations to be performed the same day. Diagnostic results, time courses, and number and sorts of applied invasive investigations were assessed., Results: In 297 eligible patients, malignant disease was diagnosed in 72% and benign disease was diagnosed in 26% of patients. One percent of the patients had no abnormalities at all. For 85% of patients with malignancy, investigations were completed in 1 day, resulting in a diagnosis and definitive clinical disease stage. The median time from start of the analysis to informing the patient about diagnosis and tumor stage was 7 days. One invasive investigation was performed in 53% of patients in the study group, and at least 2 investigations were performed in 33% of patients. Bronchoscopies formed a part of the diagnostic process in 59% of patients. Surgical diagnostic procedures were performed in 8% of patients., Conclusion: The diagnostic program resulted in a short time to diagnosis, with finalization of invasive investigations in 1 day in the majority of patients. The imaging-based choice of invasive investigations precluded bronchoscopies in a substantial portion of the patients., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: No consensus exists on the exact treatment of pneumothorax (PTX). Some guidelines are proposing manual aspiration (MA) to be preferred over tube thoracostomy (TT) in uncomplicated primary spontaneous pneumothorax (PSP). However, only a few studies reported a direct comparison of both methods. Our aim was to re-evaluate this with a randomised trial in a single centre in the Netherlands., Methods: Patients with a first episode of symptomatic PTX admitted to the ER or asymptomatic PTX with a size of ≥20% were recruited during 2007-2009 and followed-up for one year. Randomisation between MA and TT was balanced by a computer minimisation program for cause of PTX, smoking and gender. When first MA attempt failed, a second attempt was not undertaken and patients underwent TT. (registered at ClinicalTrials.gov (NCT00556335)., Results: 56 patients were included. Baseline characteristics were similar. Immediate success rates were 68.0% for MA versus 80.6% for TT (p = 0.28). Two week success rates were 100% in both groups. There was a significant difference in hospital stay in favour of MA: 2.4 ± 2.6 versus 4.4 ± 3.3 days (p = 0.02). One year recurrence rates in MA were lower than in TT, although not statistically significant (4.0% and 12.9% p = 0.37). Predictors of immediate success were traumatic PTX and female sex. One patient died during follow-up due to heart failure., Conclusion: MA is simple, safe, cheap, minimal invasive in uncomplicated PSP/traumatic PTX with similar success and recurrence rates and a shorter hospital stay in comparison to TT and therefore the treatment of choice., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: To study the relationship between fear of movement and perceived global health status and the role of rehabilitation with graded activity in cancer survivors., Design: Longitudinal cohort study., Setting: Rehabilitation centers., Participants: Cancer survivors (N=1236)., Intervention: Twelve-week graded activity rehabilitation program., Main Outcome Measures: Fear of movement (Modified Tampa Scale for Kinesiophobia-Fatigue), fatigue (Functional Assessment of Cancer Therapy-Fatigue), and perceived global health status (European Organisation Research and Treatment of Cancer Quality of Life Questionnaire C30) were measured at baseline and after rehabilitation. We performed multiple linear regression analyses to examine the association between fear of movement and perceived global health status at baseline. Differences between baseline and postintervention scores were assessed with a paired t test and effect sizes (ESs). Hierarchical multiple regression analyses were used to investigate whether changes in fear of movement were associated with perceived global health status., Results: Fear of movement was associated with perceived global health status prior to rehabilitation (P=.001). Only participants with high scores on baseline fear of movement showed a considerable decrease in fear of movement after rehabilitation (ES=-.69; 95% confidence interval [CI], -.80 to -.57); the reduction was largest for fears because of a somatic focus (ES=-.57; 95% CI, -.68 to -.45). Changes in fear of movement because of a somatic focus were related to perceived global health status postintervention (P=.001)., Conclusions: Fear of movement is associated with the perceived global health status of cancer survivors. Fear of movement decreases after rehabilitation with graded activity in high scorers on baseline fear of movement., (Copyright © 2012 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Background: A validated instrument to assess the effects of chronic cough on health status in patients with chronic obstructive pulmonary disease (COPD) is currently not available. The Leicester Cough Questionnaire (LCQ) is a cough-specific health status questionnaire which is originally validated for a population of general patients presenting with chronic cough. We examined the psychometric performance of the LCQ in patients with COPD and chronic productive cough., Methods: Concurrent validity, internal consistency, reproducibility and responsiveness were determined. The St. George's Respiratory Questionnaire (SGRQ) and the Short Form-36 (SF-36) were used as external criteria. Questionnaires were completed at the start of the study. After 2 and 12 weeks the LCQ was repeated, together with a global rating of change., Results: In total 54 patients were included. Concurrent validity analysis showed significant correlations between corresponding domains of the LCQ and the SGRQ (r(s) -0.31 to -0.60). Corresponding domains of the LCQ and the SF-36 showed weaker correlations (r(s) 0.04 to 0.41). Internal consistency was adequate for two of the three domains (Cronbach's α 0.74 - 0.86). Test-retest reliability in stable patients was high (intraclass correlation coefficients 0.79 - 0.93). The mean difference after two weeks was 0.73 (± 1.75). Responsiveness analysis indicated that the LCQ was able to detect changes after 12 weeks., Conclusion: The LCQ is a valid, reliable, responsive instrument to measure health status in COPD patients with chronic productive cough., Trial Registration: ClinicalTrials.gov: NCT01071161., (© 2012 Berkhof et al; licensee BioMed Central Ltd.)

Initiated by IKNL (Integraal Kankercentrum Nederland), a multidisciplinary guideline for cancer rehabilitation for adult oncology patients has been developed. The guideline describes the rehabilitation care of adult patients with cancer, during and after treatment. The guideline focuses on (a) prevalence of complaints either resulting from cancer or the treatment, (b) detection of these complaints and indicated referral, (c) the intake procedure before cancer rehabilitation, (d) intervention and evaluation within cancer rehabilitation and (e) the importance of patient empowerment. The guideline is directed at all professionals giving care to patients with cancer. It concerns those (such as medical specialists, general practitioners and nurses) who are responsible for detecting cancer-related complaints and for referral to cancer rehabilitation, as well as health care professionals involved in cancer rehabilitation care (such as consultants in rehabilitation medicine, physiotherapists and psychologists). The main goal of the guideline is that every cancer patient or ex-cancer patient with (residual) complaints resulting from cancer or its treatment receives timely and appropriate cancer rehabilitation.

The systemic inflammatory response syndrome is a complex host response to a variety of clinical insults, generally leading to severe pathology. The human chorionic gonadotropin β-chain-related tetrapeptide leucine-glutamine-glycine-valine (LQGV) reduces hemorrhagic and LPS-induced systemic inflammatory response syndrome, but its mechanisms of action are not yet fully understood. Through the combination of in vivo, in vitro, and ex vivo approaches, we demonstrate that LQGV actively stimulates corticosterone production in mice and thereby suppresses in vivo TLR4-directed inflammation upon LPS administration. Blocking in vivo glucocorticosteroid receptor signaling reduced the prosurvival effect of LQGV. Also, upon multiple TLR activation by heat-killed Listeria monocytogenes, splenocytes from LQGV-treated mice produced significantly less TNF-α and IL-6, which was absent after in vitro blockage of the glucocorticosteroid receptor. Using adrenal gland and adrenal cell line cultures, we show that LQGV stimulates corticosterone production. Moreover, by using specific pharmacological inhibitors of the adrenocorticotropic hormone (ACTH) and luteinizing hormone receptors as well as of cAMP signaling, we demonstrate that LQGV stimulates the ACTH receptor. These data show that the β-human chorionic gonadotropin-related tetrapeptide LQGV stimulates adrenal glucocorticosteroid production through activation of the ACTH receptor with consequent glucocorticoid receptor activation and immunosuppression in C57BL/6 mice.

Three days of fasting protects mice against lethal renal ischemia-reperfusion (I/R) injury. We hypothesize that the protection imposed by fasting is mediated by increased levels of corticosterone, induced by the stress of food deprivation. C57Bl/6 mice were fasted for 3 days after which serum corticosterone levels were determined. Mice underwent a bilateral adrenalectomy (ADX). Ten days later, they were either fasted or given a corticosterone receptor antagonist while fasting. Bilateral renal I/R injury was induced by clamping the artery and vein of the left and right kidney simultaneously for 37 min. Survival and kidney function were determined. Fasting significantly increased corticosterone levels. Only 8% of the ADX mice which were fasted prior to I/R injury survived, whereas all sham-ADX operated mice survived I/R injury after fasting. After ADX and fasting, 70% of the mice subjected to sham I/R succumbed to the surgical procedure. After fasting with concomitant blockade of the glucocorticoid receptor all animals survived renal I/R. Three days of fasting protects against I/R injury and increases serum corticosterone levels. ADX renders mice incapable of withstanding subsequent abdominal surgery. Glucocorticoid receptor blockade does not interfere with the protective effects of fasting. Thus, the protection against renal I/R injury induced by preoperative fasting is mediated by corticosterone-independent mechanisms., (© 2010 The Authors. Journal compilation © 2010 European Society for Organ Transplantation.)

Background: Inflammatory responses facilitate metastasis by increasing expression of adhesion molecules. Dietary restriction (30% reduction in daily calorie intake) reduces the expression of adhesion molecules and protects against surgically induced inflammation. DR might therefore beneficially interfere with surgery-induced inflammation and subsequent adhesion of circulating tumor cells., Methods: BALB/c mice were subjected to 2 weeks dietary restriction prior to inoculation with tumor cells. Intra-splenic injection of 5.0 x 10(4) C26-colon carcinoma cells was followed by splenectomy. Hepatic tumor load was scored after 10 days as a percentage (tumor surface/total liver surface) on H&E stained sections. Liver mRNA expression of adhesion molecules was determined and the effect of serum from dietary restriction mice on in vitro tumor growth and adhesion capacity was assessed., Results: Preoperative dietary restriction significantly reduced mRNA expression levels of E-selectin (P = 0.0087) and hepatic tumor load (P = 0.036). Dietary restriction serum did not affect in vitro cell growth but reduced in vitro adhesion of C26 cells to endothelial cells (P = 0.0043)., Conclusions: Preoperative dietary restriction reduces hepatic tumor load after injection with tumor cells. Reduced adhesion to endothelial cells and reduced mRNA expression of E-selectin suggest that dietary restriction reduces tumor load by lowering the adhesion of circulating tumor cells to hepatic vascular endothelium., ((c) 2010 Wiley-Liss, Inc.)

Our objective was to estimate the economic burden of patients with amyotrophic lateral sclerosis (ALS) and to examine the effect of treatment in a multidisciplinary ALS treatment centre versus general care on costs and to describe differences in costs according to clinical characteristics. In a cross-sectional study 208 patients with ALS and their caregivers were interviewed and were asked to fill in a cost diary for six months. Patients were divided in groups according to type of treatment they received and according to clinical characteristics (site of onset, severity). The direct healthcare and non-healthcare costs were calculated according to Dutch guidelines for cost analysis in healthcare research, standardized for the year 2003. Ninety-eight patients were included when they had filled in the cost diary for at least three months and were affected for three years or less. Mean monthly costs were 1336 euros for the group receiving multidisciplinary care and 1271 euros for those receiving general care. This study shows that the costs of multidisciplinary ALS care were practically identical to the costs of general care. Earlier study showed that patients receiving multidisciplinary care had a better quality of life; therefore, the present study encourages the formation of multidisciplinary teams of professionals specialized in ALS care to further improve standards of care and QoL of patients suffering from ALS.

The aim of this study was to describe the distribution of hepatitis B virus markers among the autochthonous and immigrant multicultural populations of Riau province, Indonesia, in order to define the groups at risk and their infrastructure. This investigation was part of a large hepatitis B vaccination study. A total of 9701 healthy individuals, aged 5 years or older and living in the urbanised area of Batam, near Singapore, and on the surrounding islands were included. Socio-epidemiological data were collected, blood was drawn, and sera were tested for antibodies to hepatitis B core (anti-HBc) and surface antigen (anti-HBs). Anti-HBc-positive sera were tested against hepatitis B surface antigen (HBsAg). All tests comprised immunoassays from Roche (Germany) using Elecsys 2010. Complete data were available from 9314 subjects. The results showed relatively low prevalences of anti-HBc (a marker of a previous hepatitis B infection) and HBsAg in the 5-year-old chiLdren (5.8 and 1.9%, respectively) that increased continuously with increasing age. High anti-HBs levels (>1000 IU/L) were found in all age cohorts, indicating a lifelong threat of active hepatitis B infection. In conclusion, the transmission profile of hepatitis B appeared to be mainly horizontal (person-to-person) in the highly endemic region studied. Vertical transmission was less than 5%. The horizontal transmission routes included non-sexual activities of life since children <10 years of age also showed considerable infection rates. The results underline the need for catch-up hepatitis B vaccination programs for children and adults.