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Background: In community-acquired pneumonia (CAP), the role of biomarkers to shorten duration of antibiotic treatment has not been firmly established. We assessed the effectiveness of active feedback of treatment algorithms based on procalcitonin (PCT) and C-reactive protein (CRP), compared to standard care, on the duration of antibiotic treatment in patients hospitalized with community-acquired pneumonia (CAP) in non-ICU wards., Methods and Findings: We performed a randomised, open label, parallel group, multi-centre trial in 3 Dutch teaching hospitals. Treatment was guided by a PCT algorithm, CRP algorithm or standard care. Participants were recruited by a member of the study team and randomised at day 2-3 of admission in a 1:1:1 ratio. Treatment was discontinued upon predefined thresholds of biomarkers that were assessed on admission, day 4 and days 5-7 if indicated. The primary outcome was total days on antibiotic treatment until day 30. In total 468 participants were included in this study. The median days on antibiotics (IQR) was 7 (IQR 7-10) in the control group, 4 (IQR 3-7) in the CRP group (rate ratio (RR) of 0.70, 95% CI 0.61-0.82 compared to standard care; p <0.001), and 5.5 (IQR 3-9) in the PCT group (RR of 0.78, 95% CI 0.68-0.89 compared to standard care; p <0.001). New antibiotics within the first 30 days were prescribed to 24, 23 and 35 patients in standard care, CRP and PCT groups, respectively. The hazard ratio for a new prescription in patients in the PCT group compared to standard care 1.63 (CI 0.97-2.75; p = 0.06). No difference in time to clinical stability or length of stay was found., Conclusions: A strategy of feedback of CRP-guided and PCT-guided treatment algorithms reduced the number of days on antibiotic in the first 30 days after hospital admission in non-ICU wards for CAP. The study was not powered to determine safety of shortening duration of antibiotic treatment. (NCT01964495)., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Duijkers et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Gastro-oEsophageal Cancers (GECs) are severe diseases whose management is rapidly evolving. The European Society of Surgical Oncology (ESSO) is committed to the generation and spread of knowledge, and promotes the multidisciplinary management of cancer patients through its core curriculum. The present work discusses the approach to GECs, including the management of oligometastatic oesophagogastric cancers (OMEC), the diagnosis and management of peritoneal metastases from gastric cancer (GC), the management of Siewert Type II tumors, the importance of mesogastric excision, the role of robotic surgery, textbook outcomes, organ preserving options, the use of molecular markers and immune check-point inhibitors in the management of patients with GECs, as well as the improvement of current clinical practice guidelines for the management of patients with GECs. The aim of the present review is to provide a concise overview of the state-of-the-art on the management of patients with GECs and, at the same time, to share the latest advancements in the field and to foster the debate between surgical oncologists treating GECs worldwide. We are sure that our work will, at the same time, give an update to the advanced surgical oncologists and help the training surgical oncologists to settle down the foundations for their future practice., Competing Interests: Declaration of competing interest Johnn Henry Herrera Kok, Luigi Marano, Jan Willem van den Berg, Preethi Shetty, Yogesh Vashist, Laura Lorenzon, Beate Rau, Richard van Hillegersberg, Giovanni de Manzoni, Andrea Spallanzani, Won Jun Seo, Hiromi Nagata, Clarisse Eveno, Stefan Mönig, Karen van der Sluis, Leonardo Solaini, Bas PL Wijnhoven, Francesco Puccetti, Mickael Chevallay, Eunju Lee, and Domenico D'Ugo declare that they have no conflict of interest., (© 2024 Published by Elsevier Ltd.)

Background: Unnecessary D2-gastrectomy and associated costs can be prevented after detecting non-curable gastric cancer, but impact of staging on treatment costs is unclear. This study determined the cost impact of 18 F-fluorodeoxyglucose positron emission tomography/computed tomography ( 18F FDG-PET/CT) and staging laparoscopy (SL) in gastric cancer staging., Materials and Methods: In this cost analysis, four staging strategies were modeled in a decision tree: (1) 18F FDG-PET/CT first, then SL, (2) SL only, (3) 18F FDG-PET/CT only, and (4) neither SL nor 18F FDG-PET/CT. Costs were assessed on the basis of the prospective PLASTIC-study, which evaluated adding 18F FDG-PET/CT and SL to staging advanced gastric cancer (cT3-4 and/or cN+) in 18 Dutch hospitals. The Dutch Healthcare Authority provided 18F FDG-PET/CT unit costs. SL unit costs were calculated bottom-up. Gastrectomy-associated costs were collected with hospital claim data until 30 days postoperatively. Uncertainty was assessed in a probabilistic sensitivity analysis (1000 iterations)., Results: 18F FDG-PET/CT costs were €1104 including biopsy/cytology. Bottom-up calculations totaled €1537 per SL. D2-gastrectomy costs were €19,308. Total costs per patient were €18,137 for strategy 1, €17,079 for strategy 2, and €19,805 for strategy 3. If all patients undergo gastrectomy, total costs were €18,959 per patient (strategy 4). Performing SL only reduced costs by €1880 per patient. Adding 18F FDG-PET/CT to SL increased costs by €1058 per patient; IQR €870-1253 in the sensitivity analysis., Conclusions: For advanced gastric cancer, performing SL resulted in substantial cost savings by reducing unnecessary gastrectomies. In contrast, routine 18F FDG-PET/CT increased costs without substantially reducing unnecessary gastrectomies, and is not recommended due to limited impact with major costs., Trial Registration: NCT03208621. This trial was registered prospectively on 30-06-2017., (© 2024. The Author(s).)

Introduction: Patients with a first venous thromboembolism (VTE) are at risk of recurrence. Recurrent VTE (rVTE) can be prevented by extended anticoagulant therapy, but this comes at the cost of an increased risk of bleeding. It is still uncertain whether patients with an intermediate recurrence risk or with a high recurrence and high bleeding risk will benefit from extended anticoagulant treatment, and whether a strategy where anticoagulant duration is tailored on the predicted risks of rVTE and bleeding can improve outcomes. The aim of the Leiden Thrombosis Recurrence Risk Prevention (L-TRRiP) study is to evaluate the outcomes of tailored duration of long-term anticoagulant treatment based on individualised assessment of rVTE and major bleeding risks., Methods and Analysis: The L-TRRiP study is a multicentre, open-label, cohort-based, randomised controlled trial, including patients with a first VTE. We classify the risk of rVTE and major bleeding using the L-TRRiP and VTE-BLEED scores, respectively. After 3 months of anticoagulant therapy, patients with a low rVTE risk will discontinue anticoagulant treatment, patients with a high rVTE and low bleeding risk will continue anticoagulant treatment, whereas all other patients will be randomised to continue or discontinue anticoagulant treatment. All patients will be followed up for at least 2 years. Inclusion will continue until the randomised group consists of 608 patients; we estimate to include 1600 patients in total. The primary outcome is the combined incidence of rVTE and major bleeding in the randomised group after 2 years of follow-up. Secondary outcomes include the incidence of rVTE and major bleeding, functional outcomes, quality of life and cost-effectiveness in all patients., Ethics and Dissemination: The protocol was approved by the Medical Research Ethics Committee Leiden-Den Haag-Delft. Results are expected in 2028 and will be disseminated through peer-reviewed journals and during (inter)national conferences., Trial Registration Number: NCT06087952., Competing Interests: Competing interests: MC has received financial support for research from Bayer, CSL Behring, Roche, Novo Nordisk and UniQure and lees for lecturing or consultancy from Alexion, Bayer, CSL Behring, Daiichi Sankyo, Sobi and Viatris, all unrelated to the present work and paid to his institution. NvE has received a lecture fee from Bristol Myers Squibb, which was unrelated to this work and paid to his institution. JL reports grants or contracts from BMS-Pfizer, Viatris, AstraZeneca and Synapse, all unrelated to this work and paid to her institution. KM reports speaker fees from Alexion, Bayer and CSL Behring, participation in trial steering committees for Bayer and AstraZeneca, consulting fees from Uniqure, participation in data monitoring and endpoint adjudication committee for Octapharma. All payments are made to her institution. SM reports grants and personal fees from Daiichi-Sankyo, Bayer, Pfizer and Boehringer-Ingelheim, personal fees from Portola/Alexion, AbbVie, Pfizer/Bristol-Meyers Squibb, Norgine, Viatris and Sanofi, all paid to her institution and outside the submitted work. MVH reports grants from Dutch Heart Foundation, Netherlands Organisation for Health Research and Development, Bayer Health Care, Pfizer-BMS Leo Pharma Boehringer-Ingelheim, all outside this work. FAK reports grants or contracts from Bayer, BMS, BSCI, MSD, Leo Pharma, Actelion, Farm-X, The Netherlands Organisation for Health Research and Development, the Dutch Thrombosis Association, The Dutch Heart Foundation and the Horizon Europe Program, all unrelated to this work and paid to his institution. All others report no conflicts of interest related to this project., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The predominant approach to understand dynamic risk factors of sexual reoffending has been referred to as the Propensities Model (Thornton, 2016). According to this model, dynamic risk factors can be conceptualized as latent constructs whose change alters the risk of sexual reoffending. Despite its strengths and contributions to research, this model does not offer answers to the question of how dynamic risk factors contribute to the risk of sexual reoffending, or of how sustained change in risk might take place. In this paper we introduce the Network-Based Model of Risk of Sexual Reoffending (NBM-RSR), which addresses several limitations and constraints of the Propensities Model and offers empirically testable propositions regarding the nature and development of the risk of sexual reoffending. The NBM-RSR considers risk of sexual reoffending to involve a self-sustaining network of causally connected dynamic risk factors. Consistent with this, an increased risk of sexual reoffending is characterized through a network that contains more and stronger interconnected dynamic risk factors with a higher strength. Sustained change in risk of sexual reoffending occurs when activity in the network exceeds a critical point resulting in a new self-sustaining network. Propositions based on the NBM-RSR are introduced and translated into testable hypotheses. These propositions revolve around (a) risk of sexual reoffending resulting from the construction of a network of causally connected dynamic risk factors, (b) network stability, sudden changes, and critical transitions, and (c) dynamic risk factors' relative influence on risk of sexual reoffending., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: This study assesses the incidence of gastrointestinal symptoms in the first year after resection of esophageal or gastric cancer and its association with health-related quality of life (HRQoL), functioning, work productivity, and daily activities., Patients and Methods: Patients diagnosed with esophageal or gastric cancer between 2015 and 2021, who underwent a resection, and completed ≥ 2 questionnaires from the time intervals prior to resection and 0-3, 3-6, 6-9, and 9-12 months after resection were included. Multivariable generalized linear mixed models were used to assess changes in gastrointestinal symptoms over time and the impact of the number of gastrointestinal symptoms on HRQoL, functioning, work productivity, and daily activities for patients who underwent an esophagectomy or gastrectomy separately., Results: The study population consisted of 961 (78.8%) and 259 (21.2%) patients who underwent an esophagectomy and gastrectomy, respectively. For both groups, the majority of gastrointestinal symptoms changed significantly over time. Most clinically relevant differences were observed 0-3 after resection compared with prior to resection and included increased diarrhea, appetite loss, and eating restrictions, and specifically after esophagectomy dry mouth, trouble with coughing, and trouble talking. At 9-12 after resection one or more severe gastrointestinal symptoms were reported by 38.9% after esophagectomy and 33.7% after gastrectomy. A higher number of gastrointestinal symptoms was associated with poorer functioning, lower HRQoL, higher impairment in daily activities, and lower work productivity., Conclusions: This study shows that gastrointestinal symptoms are frequently observed and burdensome after esophagectomy or gastrectomy, highlighting the importance to address these sequelae for high quality survivorship., (© 2023. Society of Surgical Oncology.)

Background: Current guidelines on the management of chronic cough do not provide recommendations for the operation of specialist cough clinics. The objective of the present study was to develop expert consensus on goals and standard procedures for specialist cough clinics., Methods: We undertook a modified Delphi process, whereby initial statements proposed by experts were categorised and presented back to panellists over two ranking rounds using an 11-point Likert scale to identify consensus., Results: An international panel of 57 experts from 19 countries participated, with consensus reached on 15 out of 16 statements, covering the aims, roles and standard procedures of specialist cough clinics. Panellists agreed that specialist cough clinics offer optimal care for patients with chronic cough. They also agreed that history taking should enquire as to cough triggers, cough severity rating scales should be routinely used, and a minimum of chest radiography, spirometry and measurements of type 2 inflammatory markers should be undertaken in newly referred patients. The importance of specialist cough clinics in promoting clinical research and cough specialty training was acknowledged. Variability in healthcare resources and clinical needs between geographical regions was noted., Conclusions: The Delphi exercise provides a platform and guidance for both established cough clinics and those in planning stages., Competing Interests: Conflict of interest: W-J. Song declares grants from Merck Sharp & Dohme Corp. and AstraZeneca, consulting fees from Merck, Bellus, AstraZeneca, Shionogi and GSK, and lecture fees from Merck, AstraZeneca, GSK, Sanofi and Novartis, outside the submitted work; and is Deputy Chief Editor of this journal. K.F. Chung has received honoraria for participating on advisory board meetings of GSK, AstraZeneca, Novartis, Merck, Nocion, Shionogi and Reckitt Benckiser, and on the scientific advisory board of the Clean Breathing Institute supported by GSK Health Care Consumer Products; he has also been remunerated for speaking engagements by AstraZeneca, Novartis and Merck. M. Dąbrowska reports fees from MSD for consultations on chronic cough and fees from Chiesi Poland for lectures on chronic cough. P. Dicpinigaitis reports consultant fees from Algernon, Boehringer Ingelheim, Bellus, Chiesi, Merck and Trevi, outside the submitted work. P.G. Gibson reports grant funding to his institution from GSK, MRFF and NHMRC; and funding to present educational lectures from AstraZeneca, GSK and Novartis, outside the submitted work. C.D. Ribas has acted as consultant for GSK, AstraZeneca and Sanofi; and has received funding for travel or speaker fees from ALK, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Menarini, Novartis, Stallergenes and Pfizer. J.H. Hull has received advisory fees from MSD Pharmaceuticals and is a medical advisor to Bellus Health; he is an Associate Editor of this journal. P. Kardos received personal consultation fees from Bayer, Klosterfrau, Merck Sharp & Dohme and Shionogi; honoraria for presentations from Bionorica, Engelhard, Klosterfrau, Merck Sharp & Dohme and Schwabe; and clinical trial participation fees from Bellus and Merck Sharp & Dohme. F. Lavorini received grants for research from Chiesi Farmaceutici, GSK and MSD Italy; and honoraria for talks or participation in advisory boards from AstraZeneca, Chiesi Farmaceutici, GSK, Menarini International, MSD Italy, HIKMA, Cipla and Trudell International. A.H. Morice has received consulting fees from Bayer, Bellus, Merck, NeRRi and Shionogi; lecture fees from Boehringer Ingelheim, Merck and Chiesi; and grant support from Bayer, Bellus, Merck, Nocion, Philips, NeRRi and Shionogi, outside the submitted work; and is an Associate Editor of this journal. A. Niimi reports grants from KYORIN Pharmaceutical Co., Ltd; payment or honoraria for speaker's fees from AstraZeneca K.K., KYORIN Pharmaceutical Co. Ltd, GSK K.K., Sanofi K.K. and Novartis Pharma K.K.; and participation on a data safety monitoring or advisory board of KYORIN Pharmaceutical Co., Ltd and MSD K.K. S.M. Parker reports advisory fees from Merck and Trevi. I. Satia reports grants and personal fees from Merck Canada, Bellus Health and GSK; clinical trial participation from Bayer; and personal fees from Respiplus, Genentech and AstraZeneca, outside the submitted work; and is an Associate Editor of this journal. The other authors declare that they have no competing interests., (Copyright ©The authors 2023.)

Anastomotic leakage is a feared complication after esophagectomy and associated with increased post-operative morbidity and mrotality. The aim of this study was to evaluate the management of leakage after robot-assisted minimally invasive esophagectomy (RAMIE) with intrathoracic anastomosis. From a single center prospectively maintained database, all patients with anastomotic leakages defined by the Esophageal Complications Consensus Group between 2016 and 2021 were included. Contained leakage was defined as presence of air or fluid at level of the anastomosis without the involvement of the mediastinum or thorax. Non-contained leakage was defined as mediastinitis and/or mediastinal/pleural fluid collections. The primary outcome was 90-day mortality and the secondary outcome was successful recovery. In this study, 40 patients with anastomotic leakage were included. The 90-day mortality rate was 3% (n = 1). Leakage was considered contained in 29 patients (73%) and non-contained in 11 patients (27%). In the contained group, the majority of the patients were treated non-surgically (n = 27, 93%) and management was successful in 22 patients (76%). In the non-contained group, all patients required a reoperation with thoracic drainage and management was successful in seven patients (64%). Management failed in 11 patients (28%) of whom 7 developed an esophagobronchial fistula, 3 had a disconnection of the anastomosis and 1 died of a septic bleeding. In conclusion, this study demonstrates that the management anastomotic leakage in patients who underwent RAMIE with an intrathoracic anastomosis was successful in 73% of the patients with a 90-day mortality rate of 3%. A differentiated approach for the management of intrathoracic anastomotic leakage is proposed., (© The Author(s) 2023. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus.)

Introduction: Survivors of COVID-19 frequently endure chronic disabilities. We hypothesise that diaphragm function has a long recovery time after COVID-19 hospitalisation and may play a role in post-COVID-19 syndrome. The aim of this study was to assess diaphragm function during COVID-19 hospitalisation and during recovery., Methods: We conducted a prospective single-centre cohort study in 49 enrolled patients, of which 28 completed 1-year follow-up. Participants were evaluated for diaphragm function. Diaphragm function was assessed using ultrasound measuring of diaphragm thickening fraction (TF) within 24 h after admission, after 7 days of admission or at discharge, whichever came first, and 3 and 12 months after hospital admission., Results: Estimated mean TF increased from 0.56 (95% CI 0.46-0.66) on admission to 0.78 (95% CI 0.65-0.89) at discharge or 7 days after admission, to 1.05 (95% CI 0.83-1.26) 3 months after admission and to 1.54 (95% CI 1.31-1.76) 12 months after admission. The improvements from admission to discharge, 3 months and 12 months were all significant (linear mixed modelling; p=0.020, p<0.001 and p<0.001, respectively), and the improvement from discharge to 3-month follow-up was borderline significant (p<0.1)., Conclusion: Diaphragm function was impaired during hospitalisation for COVID-19. During recovery in hospital and up to 1-year follow-up, diaphragm TF improved, suggesting a long recovery time of the diaphragm. Diaphragm ultrasound may be a valuable modality in the screening and follow-up of (post-)COVID-19 patients for diaphragm dysfunction., Competing Interests: Conflict of interest: The listed authors declare that there is no conflict of interest., (Copyright ©The authors 2023.)

Background: Maintenance and reliever therapy (MART) with inhaled corticosteroid (ICS)/formoterol effectively reduces exacerbations in asthma. We aimed to investigate its efficacy compared with fixed-dose fluticasone/salmeterol in chronic obstructive pulmonary disease (COPD)., Methods: Patients with COPD and ≥1 exacerbation in the previous 2 years were randomly assigned to open-label MART (Spiromax budesonide/formoterol 160/4.5 µg 2 inhalations twice daily+1 prn) or fixed-dose therapy (Diskus fluticasone propionate/salmeterol combination (FSC) 500/50 µg 1 inhalation twice daily+salbutamol 100 µg prn) for 1 year. The primary outcome was rate of moderate/severe exacerbations, defined by treatment with oral prednisolone and/or antibiotics., Results: In total, 195 patients were randomised (MART Bud/Form n=103; fixed-dose FSC n=92). No significant difference was seen between MART and FSC therapy in exacerbation rates (1.32 vs 1.32 /year, respectively, rate ratio 1.05 (95% CI 0.79 to 1.39); p=0.741). No differences in lung function parameters or health status were observed. Total ICS dose was significantly lower with MART than FSC therapy (budesonide-equivalent 928 µg/day vs 1747 µg/day, respectively, p<0.05). Similar proportions of patients reported adverse events (MART Bud/Form: 73% vs fixed-dose FSC: 68%, p=0.408) and pneumonias (MART: 5% vs FSC: 1%, p=0.216)., Conclusions: This first study of MART in COPD found that budesonide/formoterol MART might be similarly effective to fluticasone/salmeterol fixed-dose therapy in moderate to severe patients with COPD, at a lower daily ICS dosage. Further evidence is needed about long-term safety., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: P2X3 receptor antagonists seem to have a promising potential for treating patients with refractory chronic cough. In this double-blind, randomized, placebo-controlled study, we investigated the efficacy, safety, and tolerability of the novel selective P2X3 receptor antagonist filapixant (BAY1902607) in patients with refractory chronic cough., Methods: Following a crossover design, 23 patients with refractory chronic cough (age: 60.4 ± 9.1 years) received ascending doses of filapixant in one period (20, 80, 150, and 250 mg, twice daily, 4-days-on/3-days-off) and placebo in the other. The primary efficacy endpoint was the 24-h cough frequency on Day 4 of each dosing step. Further, subjective cough severity and health-related quality of life were assessed., Results: Filapixant at doses ≥ 80 mg significantly reduced cough frequency and severity and improved cough health-related quality of life. Reductions in 24-h cough frequency over placebo ranged from 17% (80 mg dose) to 37% (250 mg dose), reductions over baseline from 23% (80 mg) to 41% (250 mg) (placebo: 6%). Reductions in cough severity ratings on a 100-mm visual analog scale ranged from 8 mm (80 mg) to 21 mm (250 mg). No serious or severe adverse events or adverse events leading to discontinuation of treatment were reported. Taste-related adverse events occurred in 4%, 13%, 43%, and 57% of patients treated with filapixant 20, 80, 150, and 250 mg, respectively, and in 12% treated with placebo., Conclusions: Filapixant proved to be efficacious, safe, and-apart from the occurrence of taste disturbances, especially at higher dosages-well tolerated during the short therapeutic intervention. Clinical trial registration EudraCT, eudract.ema.europa.eu, 2018-000129-29; ClinicalTrials.gov, NCT03535168., (© 2023. The Author(s).)

Introduction: Chronic cough affects ∼10% of the population and adversely impacts quality of life. This retrospective observational cohort study aimed to identify the demographics, clinical characteristics and quality of life of the chronic cough population in a Dutch chronic cough clinic, at baseline and following treatment at 6 months. Patients were categorised based on the underlying phenotype and response to treatment., Methods: Retrospective data on 2397 patients who were diagnosed according to standard guidelines of the American College of Chest Physicians were analysed. Quality of life was captured via the Leicester Cough Questionnaire, the Cough Numeric Rating Scale and the Hospital Anxiety and Depression Scale., Results: Mean patient age was 59 years; 62.5% of the patients were female; and 69.1% had at least one underlying phenotype associated with chronic cough. Of the latter, 52.1% had bronchial hyperresponsiveness/airflow limitation, 33.3% had airway reflux and 20.1% had upper airway cough syndrome. 46% of patients with a phenotype, and 51% without, experienced no improvement in their quality of life or still had significant cough remaining after 6 months. Of patients with available quality-of-life data, 37.5% were categorised as having refractory chronic cough, and 9.5% were categorised as unexplained chronic cough., Discussion: This study highlights the poor quality-of-life outcomes in patients with chronic cough, despite interventions to treat underlying conditions, and indicates a need to manage chronic cough irrespective of phenotype., Competing Interests: Conflict of interest: J.W.K. van den Berg participates on a data safety monitoring board or advisory board at GlaxoSmithKline PLC, Chiesi Ltd, Novartis AG and Merck & Co., Inc., Rahway, NJ, USA. Conflict of interest: C.A. Baxter is a full-time employee of MSD (UK) Limited, London, UK, and shareholder of Merck & Co., Inc., Rahway, NJ, USA. Conflict of interest: M.A. Edens has nothing to disclose. Conflict of interest: K.W. Patberg has nothing to disclose. Conflict of interest: H. van der Velden is a full-time employee of MSD BV, The Netherlands. Conflict of interest: A. Weijerse is a full-time employee of MSD BV, The Netherlands, and shareholder of Merck & Co., Inc., Rahway, NJ, USA. Conflict of interest: S. Salomonsson is a full-time employee of MSD Sweden, and shareholder of Merck & Co., Inc., Rahway, NJ, USA., (Copyright ©The authors 2022.)

Background: Accurate restoration of joint line height and posterior offset in primary Total Knee Arthroplasty (TKA) have been shown to be important factors in post-operative range of movement and function. The aim of this study was to assess the accuracy of joint line and posterior offset restoration in a group of patients that underwent robotic-assisted TKA (raTKA). A matched cohort of patients that underwent a TKA using a conventional jig-based technique was assessed for comparison. The null hypothesis was that there would be no difference between groups., Methods: This study was a retrospective analysis of a cohort of 120 patients with end-stage knee osteoarthritis that received a TKA using the Navio Surgical System (n = 60), or Conventional manual TKA (n = 60). Procedures were performed between 1 January 2019 and 1 October 2019 at six different centres. Joint line height and posterior offset was measured pre-operatively and post-operatively on calibrated weight bearing plain radiographs of the knee. Two observers performed measurements using validated measuring tools. A BMI and age-matched cohort of patients that underwent TKA using a conventional technique in the same six centres were assessed for comparison. Mean values, standard deviations and confidence intervals are presented for change and absolute change in joint line height and posterior offset. Student's t-test was used to compare the changes between techniques., Results: Patients that underwent robotic-assisted TKA had joint line height and posterior offset restored more accurately than patients undergoing TKA using a conventional technique. Average change from pre-operative measurement in joint line height using raTKA was -0.38mm [95% CI: -0.79 to 0.03] vs 0.91 [0.14 to 1.68] with the conventional technique. Average absolute change in joint line height using raTKA was 1.96mm [1.74 to 2.18] vs 4.00mm [3.68 to 4.32] with the conventional technique. Average change in posterior offset using raTKA was 0.08mm [-0.40 to 0.56] vs 1.64mm [2.47 to 0.81] with the conventional technique. Average absolute change in posterior offset with raTKA was 2.19mm [1.92 to 2.46] vs 4.24mm [3.79 to 4.69] with the conventional technique. There was a significant difference when comparing absolute change in joint line height and posterior offset between groups (p<0.01)., Conclusion: Robotic-assisted primary TKA restores the joint line height and posterior offset more accurately than conventional jig-based techniques., Competing Interests: AA, PB, ME, SJ, JLV & DN are reimbursed for educational activities by Smith & Nephew. This does not alter our adherence to PLOS ONE policies on sharing data and materials

Importance: The optimal staging for gastric cancer remains a matter of debate., Objective: To evaluate the value of 18F-fludeoxyglucose-positron emission tomography with computed tomography (FDG-PET/CT) and staging laparoscopy (SL) in addition to initial staging by means of gastroscopy and CT in patients with locally advanced gastric cancer., Design, Setting, and Participants: This multicenter prospective, observational cohort study included 394 patients with locally advanced, clinically curable gastric adenocarcinoma (≥cT3 and/or N+, M0 category based on CT) between August 1, 2017, and February 1, 2020., Exposures: All patients underwent an FDG-PET/CT and/or SL in addition to initial staging., Main Outcomes and Measures: The primary outcome was the number of patients in whom the intent of treatment changed based on the results of these 2 investigations. Secondary outcomes included diagnostic performance, number of incidental findings on FDG-PET/CT, morbidity and mortality after SL, and diagnostic delay., Results: Of the 394 patients included, 256 (65%) were men and mean (SD) age was 67.6 (10.7) years. A total of 382 patients underwent FDG-PET/CT and 357 underwent SL. Treatment intent changed from curative to palliative in 65 patients (16%) based on the additional FDG-PET/CT and SL findings. FDG-PET/CT detected distant metastases in 12 patients (3%), and SL detected peritoneal or locally nonresectable disease in 73 patients (19%), with an overlap of 7 patients (2%). FDG-PET/CT had a sensitivity of 33% (95% CI, 17%-53%) and specificity of 97% (95% CI, 94%-99%) in detecting distant metastases. Secondary findings on FDG/PET were found in 83 of 382 patients (22%), which led to additional examinations in 65 of 394 patients (16%). Staging laparoscopy resulted in a complication requiring reintervention in 3 patients (0.8%) without postoperative mortality. The mean (SD) diagnostic delay was 19 (14) days., Conclusions and Relevance: This study's findings suggest an apparently limited additional value of FDG-PET/CT; however, SL added considerably to the staging process of locally advanced gastric cancer by detection of peritoneal and nonresectable disease. Therefore, it may be useful to include SL in guidelines for staging advanced gastric cancer, but not FDG-PET/CT.

Cough is a physiological defense mechanism. However, excessive cough is known to have a great impact on quality of life. Cough is considered to be chronic when it lasts longer than 8 weeks. In the Netherlands, the prevalence is 10.9%. The concept as a whole is called 'cough hypersensitivity' in which there is a hypersensitivity of the cough reflex to aspecific stimuli. Specific treatment of the phenotype is important. If no specific phenotype is found it is called 'unexplained chronic cough' (UCC) and if symptoms persist despite treatment it is called 'chronic refractory cough' (CRC). Neuromodulating drugs are the main treatment in CRC. However, a suitable condition often cannot be achieved because of severe side effect and great interindividual variability in pharmacokinetics. New drugs, P2X3-antagonists, are being developed. These drugs mediate in a late phase of the cough reflex and are thereby considered to have fewer side effects.

Background: Refractory dyspnea or breathlessness is a common symptom in patients with advanced chronic obstructive pulmonary disease (COPD), with a high negative impact on quality of life (QoL). Low dosed opioids have been investigated for refractory dyspnea in COPD and other life-limiting conditions, and some positive effects were demonstrated. However, upon first assessment of the literature, the quality of evidence in COPD seemed low or inconclusive, and focused mainly on morphine which may have more side effects than other opioids such as fentanyl. For the current publication we performed a systematic literature search. We searched for placebo-controlled randomized clinical trials investigating opioids for refractory dyspnea caused by COPD. We included trials reporting on dyspnea, health status and/or QoL. Three of fifteen trials demonstrated a significant positive effect of opioids on dyspnea. Only one of four trials reporting on QoL or health status, demonstrated a significant positive effect. Two-thirds of included trials investigated morphine. We found no placebo-controlled RCT on transdermal fentanyl. Subsequently, we hypothesized that both fentanyl and morphine provide a greater reduction of dyspnea than placebo, and that fentanyl has less side effects than morphine., Methods: We describe the design of a robust, multi-center, double blind, double-dummy, cross-over, randomized, placebo-controlled clinical trial with three study arms investigating transdermal fentanyl 12 mcg/h and morphine sustained-release 10 mg b.i.d. The primary endpoint is change in daily mean dyspnea sensation measured on a numeric rating scale. Secondary endpoints are change in daily worst dyspnea, QoL, anxiety, sleep quality, hypercapnia, side effects, patient preference, and continued opioid use. Sixty patients with severe stable COPD and refractory dyspnea (FEV 1  < 50%, mMRC ≥ 3, on optimal standard therapy) will be included., Discussion: Evidence for opioids for refractory dyspnea in COPD is not as robust as usually appreciated. We designed a study comparing both the more commonly used opioid morphine, and transdermal fentanyl to placebo. The cross-over design will help to get a better impression of patient preferences. We believe our study design to investigate both sustained-release morphine and transdermal fentanyl for refractory dyspnea will provide valuable information for better treatment of refractory dyspnea in COPD. Trial registration NCT03834363 (ClinicalTrials.gov), registred at 7 Feb 2019, https://clinicaltrials.gov/ct2/show/NCT03834363 ., (© 2021. The Author(s).)

The effect of ethylene tetramerisation ligand structures on 1-octene selectivity is well studied. However, by-product formation is less understood. In this work, a range of PNP ligand structures are correlated with the full product selectivity and with catalyst activity. As steric bulk on the N-substituent increases, the product selectivity shifts from >10 % to < 3% of both C6 cyclics and C16+ by-products. 1-Octene peaks at ca. 70%. Thereafter, only 1-hexene increases. Similar selectivity changes were observed for ortho-Ph-substituted PNP ligands. The C10-14 selectivity was less affected by the ligand structure. The ligand effect on the changes in selectivity is explained mechanistically. Lastly, an increase in ligand steric bulk was found to improve catalyst activity and reduce polymer formation by an order of magnitude. It is proposed that steric bulk promotes formation of cationic catalytic species which are responsible for selective ethylene oligomerisation., (© 2020 Wiley-VCH GmbH.)

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.)

Context: Metastatic lung cancer is an incurable disease that results in a high burden of symptoms, a poor quality of life, and an expected prognosis of less than one year after diagnosis. Treatment shortly before death may result in potential burdensome and inappropriate hospital admissions and hospital deaths. Dying at home is, at a population level, considered a quality for good end-of-life care., Objectives: We examined what percentage of patients with metastatic lung cancer died inside the hospital and if hospital death, or other characteristics of the patient, oncologist or health care, were associated with treatment in the last month of life., Methods: This retrospective cohort study evaluated the medical records of 1322 patients with metastatic lung cancer who received care at one of 10 hospitals across The Netherlands and died between 1/6/2013 and 31/7/2015. Demographic and clinical characteristics were obtained from the medical records., Results: In total, 18% of the patients died during a hospital admission. This percentage was higher for patients who received chemotherapy (42%) or targeted therapy with tyrosine kinase inhibitors (25%) in the last month of life. Patients younger than 60 years of age, patients who received chemotherapy in the last month of life, and patients in whom tyrosine kinase inhibitors were started in the last month of life were more likely to die inside the hospital., Conclusion: In The Netherlands, fewer than one in five patients with metastatic lung cancer died in the hospital and in-hospital death was associated with the relatively late use of chemotherapy or targeted therapy. Careful selection of patients for disease-modifying therapy might enhance the opportunity for patients to die at their preferred place., (Copyright © 2019 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Objectives: Older patients with chronic obstructive pulmonary disease (COPD), hospitalized for an acute exacerbation, often do not receive recommended post-acute pulmonary rehabilitation. This underuse might be related to the impaired clinical and functional status of these patients, who are more likely to present with frailty, comorbidities, and disability. Having developed and implemented a geriatric rehabilitation program for these patients (GR&#95;COPD), the primary aim of this study was to investigate the effectiveness of this program., Design and Intervention: A prospective cohort study with a 3-month follow-up period. Patients who declined the GR&#95;COPD program were considered as controls., Setting and Participants: The study was conducted at the pulmonary department of 2 hospitals. Patients were eligible when hospitalized as a result of an acute exacerbation of COPD and indicated for the GR&#95;COPD program based on standardized criteria., Methods: Primary outcome was defined as change in disease-specific health status measured with the clinical COPD questionnaire (CCQ), secondary outcome as the exacerbation rate ratio during follow-up. To balance potential confounders between the intervention and control group, propensity score-based weighted linear regression analyses were performed., Results: Of the 158 included patients [78 (49.4%) male, mean age 70.8 (±8.1) years, mean forced expiratory volume in 1 second: 35.5 (±12.8) as % of predicted], 78 received the GR&#95;COPD program. The results of the CCQ showed a significant and clinically relevant treatment effect of -0.56 points [95% confidence interval (CI) -0.89, -0.23; P = .001). Patients in the control group had 2.77 times more exacerbations compared with the intervention group (95% CI 2.13, 3.58; P < .001)., Conclusions/implications: This study shows a clinically relevant effect of the GR&#95;COPD program on disease-specific health status and exacerbation rate. Implementation of the program for older patients with severe COPD hospitalized for an acute exacerbation is recommended., (Copyright © 2019 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

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: Despite growing evidence on safe and feasible outpatient treatment for acute pulmonary embolism (PE), the majority of patients is still treated in an inpatient setting. This is probably due to a lack of clear guidelines on this subject., Objectives: To evaluate safety and patient reported outcome measures (PROM) on outpatient treatment of acute PE., Methods: We conducted a prospective cohort study. 250 patients presenting with acute PE and Pulmonary Embolism Severity Index (PESI) class I or II were enrolled. Safety of outpatient treatment was assessed by measuring all-cause mortality, recurrent venous thromboembolism (VTE) and episodes of relevant bleeding, with a follow-up period of four weeks and six months. Additionally, PROM's on outpatient treatment were evaluated by repeatedly measuring VAS-scores for pain and dyspnea during the recovery, and by assessing the improvement in SF-36 scores between admission and after six months., Results: We found an all-cause mortality rate of 0.4% (95% CI 0.07-2.23), rate of recurrent VTE of 0% (95% CI 0-1.51) and rate of relevant bleeding episodes of 6.4% (95% CI 3.98-10.14). VAS-scores improved significantly during the first 24-h after admission, and continued to improve significantly after five days of home treatment. SF-36 scores on 6 out of 8 domains improved significantly between admission and after six months., Conclusions: Our study shows that outpatient treatment is safe in selected low-risk patients based on their PESI score. Additionally, our data on patient reported outcome measures support the presumption of a good course of recovery during outpatient treatment., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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.)

Objective: Our aim was to investigate the feasibility of completing an exercise program in patients with advanced cancer and to obtain preliminary data of its impact on physical and quality of life (QoL) outcomes., Methods: We conducted a nonrandomized pilot study. Participants were 26 palliative care patients with advanced cancer (mean age=54.5 years; standard deviation [SD] 8.9 years) of the outpatient clinic of the medical oncology and the urology departments of a medical center in The Netherlands. Participants followed an individually graded group exercise program, consisting of resistance training and aerobic exercise, twice a week during 6 weeks. Feasibility of the training program, muscle strength, aerobic fitness, body composition, QoL, fatigue, and physical role, social, and activities of daily living (ADL) functioning were assessed at baseline and immediately after the intervention., Results: Dropout rate during the training period was 35% due to disease progression. After the training period, based on intention to treat analysis, muscle strength and aerobic functional fitness had increased significantly (p≤0.01). A significant decrease in fat percentage (p≤0.02) was observed. QoL had increased significantly (p≤0.02), as well as social (p≤0.04), physical role (p≤0.01), and ADL functioning (p≤0.05). Fatigue decreased significantly on the Checklist Individual Strength (CIS) and RAND-36 questionnaires (p≤0.02), however not on the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 (p=0.48). No change in physical functioning was observed with the EORTC QLQ-C30 and RAND-36 (respectively, p=0.33 and p=0.09)., Conclusions: These preliminary results show that physical exercise in patients with advanced cancer is feasible. A significant impact was observed on physical and QoL outcomes. These findings need to be confirmed with a larger-scale, randomized controlled trial.

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: Chronic obstructive pulmonary disease (COPD) and heart failure (HF) are both common diseases that coexist frequently. Patients with both diseases have worse stable state health status when compared with patients with one of these diseases. In many outpatient clinics, health status is monitored routinely in COPD patients using the Clinical COPD Questionnaire (CCQ) and in HF patients with the Minnesota Living with Heart Failure Questionnaire (MLHF-Q). This study validated and compared which questionnaire, ie, the CCQ or the MLHF-Q, is suited best for patients with coexistent COPD and HF., Methods: Patients with both COPD and HF and aged ≥40 years were included. Construct validity, internal consistency, test-retest reliability, and agreement were determined. The Short-Form 36 was used as the external criterion. All questionnaires were completed at baseline. The CCQ and MLHF-Q were repeated after 2 weeks, together with a global rating of change., Results: Fifty-eight patients were included, of whom 50 completed the study. Construct validity was acceptable. Internal consistency was adequate for CCQ and MLHF-Q total and domain scores, with a Cronbach's alpha ≥0.70. Reliability was adequate for MLHF-Q and CCQ total and domain scores, and intraclass correlation coefficients were 0.70-0.90, except for the CCQ symptom score (intraclass correlation coefficient 0.42). The standard error of measurement on the group level was smaller than the minimal clinical important difference for both questionnaires. However, the standard error of measurement on the individual level was larger than the minimal clinical important difference. Agreement was acceptable on the group level and limited on the individual level., Conclusion: CCQ and MLHF-Q were both valid and reliable questionnaires for assessment of health status in patients with coexistent COPD and HF on the group level, and hence for research. However, in clinical practice, on the individual level, the characteristics of both questionnaires were not as good. There is room for a questionnaire with good evaluative properties on the individual level, preferably tested in a setting of patients with COPD or HF, or both.

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.

Background: Macrolides reduce exacerbations in patients with COPD. Their effects on health status has not been assessed as primary outcome and is less clear. This study assessed the effects of prophylactic azithromycin on cough-specific health status in COPD-patients with chronic productive cough., Methods: In this randomised controlled trial 84 patients met the eligibility criteria: age of ≥40 years, COPD GOLD stage ≥2 and chronic productive cough. The intervention-group (n = 42) received azithromycin 250 mg 3 times a week and the control-group (n = 42) received a placebo. Primary outcome was cough-specific health status at 12 weeks, measured with the Leicester Cough Questionnaire (LCQ). Secondary outcomes included generic and COPD-specific health status and exacerbations. Changes in adverse events and microbiology were monitored., Results: Mean age of participants was 68 ± 10 years and mean FEV1 was 1.36 ± 0.47 L. The improvement in LCQ total score at 12 weeks was significantly greater with azithromycin (difference 1.3 ± 0.5, 95% CI 0.3;2.3, p = 0.01) and met the minimal clinically important difference. Similar results were found for the domain scores, and COPD-specific and generic health status questionnaires. Other secondary endpoints were non-significant. No imbalances in adverse events were found., Conclusions: Prophylactic azithromycin improved cough-specific health status in COPD-patients with chronic productive cough to a clinically relevant degree., Trial Registration: ClinicalTrials.gov NCT01071161.

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: Exacerbations of chronic obstructive pulmonary disease (COPD) are a major burden to patients and to society. Little is known about the possible role of day-to-day patient-reported outcomes during an exacerbation. This study aims to describe the day-to-day course of patient-reported health status during exacerbations of COPD and to assess its value in predicting clinical outcomes., Methods: Data from two randomized controlled COPD exacerbation trials (n = 210 and n = 45 patients) were used to describe both the feasibility of daily collection of and the day-to-day course of patient-reported outcomes during outpatient treatment or admission to hospital. In addition to clinical parameters, the BORG dyspnea score, the Clinical COPD Questionnaire (CCQ), and the St George's Respiratory Questionnaire were used in Cox regression models to predict treatment failure, time to next exacerbation, and mortality in the hospital study., Results: All patient-reported outcomes showed a distinct pattern of improvement. In the multivariate models, absence of improvement in CCQ symptom score and impaired lung function were independent predictors of treatment failure. Health status and gender predicted time to next exacerbation. Five-year mortality was predicted by age, forced expiratory flow in one second % predicted, smoking status, and CCQ score. In outpatient management of exacerbations, health status was found to be less impaired than in hospitalized patients, while the rate and pattern of recovery was remarkably similar., Conclusion: Daily health status measurements were found to predict treatment failure, which could help decision-making for patients hospitalized due to an exacerbation of COPD.

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.)