Management of obstructive sleep apnea in Europe - A 10-year follow-up.

OBJECTIVE: In 2010, a questionnaire-based study on obstructive sleep apnea (OSA) management in Europe identified differences regarding reimbursement, sleep specialist qualification, and titration procedures. Now, 10 years later, a follow-up study was conducted as part of the ESADA (European Sleep Apnea Database) network to explore the development of OSA management over time. METHODS: The 2010 questionnaire including questions on sleep diagnostic, reimbursement, treatment, and certification was updated with questions on telemedicine and distributed to European Sleep Centers to reflect European OSA management practice. RESULTS: 26 countries (36 sleep centers) participated, representing 20 ESADA and 6 non-ESADA countries. All 21 countries from the 2010 survey participated. In 2010, OSA diagnostic procedures were performed mainly by specialized physicians (86%), whereas now mainly by certified sleep specialists and specialized physicians (69%). Treatment and titration procedures are currently quite homogenous, with a strong trend towards more Autotitrating Positive Airway Pressure treatment (in hospital 73%, at home 62%). From 2010 to 2020, home sleep apnea testing use increased (76%-89%) and polysomnography as sole diagnostic procedure decreased (24%-12%). Availability of a sleep specialist qualification increased (52%-65%) as well as the number of certified polysomnography scorers (certified physicians: 36%-79%; certified technicians: 20%-62%). Telemedicine, not surveyed in 2010, is now in 2020 used in diagnostics (8%), treatment (50%), and follow-up (73%). CONCLUSION: In the past decade, formal qualification of sleep center personnel increased, OSA diagnostic and treatment procedures shifted towards a more automatic approach, and telemedicine became more prominent.

Variable BCG efficacy in rhesus populations: Pulmonary BCG provides protection where standard intra-dermal vaccination fails.

M.bovis BCG vaccination against tuberculosis (TB) notoriously displays variable protective efficacy in different human populations. In non-human primate studies using rhesus macaques, despite efforts to standardise the model, we have also observed variable efficacy of BCG upon subsequent experimental M. tuberculosis challenge. In the present head-to-head study, we establish that the protective efficacy of standard parenteral BCG immunisation varies among different rhesus cohorts. This provides different dynamic ranges for evaluation of investigational vaccines, opportunities for identifying possible correlates of protective immunity and for determining why parenteral BCG immunisation sometimes fails. We also show that pulmonary mucosal BCG vaccination confers reduced local pathology and improves haematological and immunological parameters post-infection in animals that are not responsive to induction of protection by standard intra-dermal BCG. These results have important implications for pulmonary TB vaccination strategies in the future.

Efficacy and Safety of Outpatient Treatment Based on the Hestia Clinical Decision Rule with or without N-Terminal Pro-Brain Natriuretic Peptide Testing in Patients with Acute Pulmonary Embolism. A Randomized Clinical Trial.

RATIONALE: Outpatient treatment of pulmonary embolism (PE) may lead to improved patient satisfaction and reduced healthcare costs. However, trials to assess its safety and the optimal method for patient selection are scarce. OBJECTIVES: To validate the utility and safety of selecting patients with PE for outpatient treatment by the Hestia criteria and to compare the safety of the Hestia criteria alone with the Hestia criteria combined with N-terminal pro-brain natriuretic peptide (NT-proBNP) testing. METHODS: We performed a randomized noninferiority trial in 17 Dutch hospitals. We randomized patients with PE without any of the Hestia criteria to direct discharge or additional NT-proBNP testing. We discharged the latter patients as well if NT-proBNP did not exceed 500 ng/L or admitted them if NT-proBNP was greater than 500 ng/L. The primary endpoint was 30-day adverse outcome defined as PE- or bleeding-related mortality, cardiopulmonary resuscitation, or intensive care unit admission. The noninferiority margin for the primary endpoint was 3.4%. MEASUREMENTS AND MAIN RESULTS: We randomized 550 patients. In the NT-proBNP group, 34 of 275 (12%) had elevated NT-proBNP values and were managed as inpatients. No patient (0 of 34) with an elevated NT-proBNP level treated in hospital (0%; 95% confidence interval [CI], 0-10.2%), versus no patient (0 of 23) with a post hoc-determined elevated NT-proBNP level from the direct discharge group (0%; 95% CI, 0-14.8%), experienced the primary endpoint. In both trial cohorts, the primary endpoint occurred in none of the 275 patients (0%; 95% CI, 0-1.3%) subjected to NT-proBNP testing, versus in 3 of 275 patients (1.1%; 95% CI, 0.2-3.2%) in the direct discharge group (P = 0.25). During the 3-month follow-up, recurrent venous thromboembolism occurred in two patients (0.73%; 95% CI, 0.1-2.6%) in the NT-proBNP group versus three patients (1.1%; 95% CI, 0.2-3.2%) in the direct discharge group (P = 0.65). CONCLUSIONS: Outpatient treatment of patients with PE selected on the basis of the Hestia criteria alone was associated with a low risk of adverse events. Given the low number of patients with elevated NT-proBNP levels, this trial was unable to draw definite conclusions regarding the incremental value of NT-proBNP testing in patients who fulfill the Hestia criteria. Clinical trial registered with www.trialregister.nl/trialreg/admin/rctview.asp?TC=2603 (NTR2603).

A single night of sleep curtailment increases plasma acylcarnitines: Novel insights in the relationship between sleep and insulin resistance.

We have previously shown that acute sleep curtailment induces insulin resistance, both in healthy individuals as well as in patients with type 1 diabetes, suggesting a causal role for sleep disturbances in pathogenesis of insulin resistance, independent of endogenous insulin production. However, the underlying mechanisms remain unclear. This study aimed to explore the metabolic pathways affected by sleep loss using targeted metabolomics in human fasting plasma samples. Healthy individuals (n = 9) and patients with type 1 diabetes (n = 7) were studied after a single night of short sleep (4 h) versus normal sleep (8 h) in a cross-over design. Strikingly, one night of short sleep specifically increased the plasma levels of acylcarnitines, essential intermediates in mitochondrial fatty acid oxidation (FAO). Specifically, short sleep increased plasma levels of tetradecenoyl-l-carnitine (C14:1) (+32%, p = 2.67*10(-4)), octadecanoyl-l-carnitine (C18:1) (+22%, p = 1.92*10(-4)) and octadecadienyl-l-carnitine (C18:2) (+27%, p = 1.32*10(-4)). Since increased plasma acylcarnitine levels could be a sign of disturbed FAO, it is possible that sleep curtailment acutely induces inefficient mitochondrial function. Our observations provide a basis for further research into the role of acylcarnitines as a potential mechanistic pathway by which sleep deprivation - even short term - causes adverse metabolic effects, such as insulin resistance.

Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism: the ADJUST-PE study.

IMPORTANCE: D-dimer measurement is an important step in the diagnostic strategy of clinically suspected acute pulmonary embolism (PE), but its clinical usefulness is limited in elderly patients. OBJECTIVE: To prospectively validate whether an age-adjusted D-dimer cutoff, defined as age × 10 in patients 50 years or older, is associated with an increased diagnostic yield of D-dimer in elderly patients with suspected PE. DESIGN, SETTINGS, AND PATIENTS: A multicenter, multinational, prospective management outcome study in 19 centers in Belgium, France, the Netherlands, and Switzerland between January 1, 2010, and February 28, 2013. INTERVENTIONS: All consecutive outpatients who presented to the emergency department with clinically suspected PE were assessed by a sequential diagnostic strategy based on the clinical probability assessed using either the simplified, revised Geneva score or the 2-level Wells score for PE; highly sensitive D-dimer measurement; and computed tomography pulmonary angiography (CTPA). Patients with a D-dimer value between the conventional cutoff of 500 µg/L and their age-adjusted cutoff did not undergo CTPA and were left untreated and formally followed-up for a 3-month period. MAIN OUTCOMES AND MEASURES: The primary outcome was the failure rate of the diagnostic strategy, defined as adjudicated thromboembolic events during the 3-month follow-up period among patients not treated with anticoagulants on the basis of a negative age-adjusted D-dimer cutoff result. RESULTS: Of the 3346 patients with suspected PE included, the prevalence of PE was 19%. Among the 2898 patients with a nonhigh or an unlikely clinical probability, 817 patients (28.2%) had a D-dimer level lower than 500 µg/L (95% CI, 26.6%-29.9%) and 337 patients (11.6%) had a D-dimer between 500 µg/L and their age-adjusted cutoff (95% CI, 10.5%-12.9%). The 3-month failure rate in patients with a D-dimer level higher than 500 µg/L but below the age-adjusted cutoff was 1 of 331 patients (0.3% [95% CI, 0.1%-1.7%]). Among the 766 patients 75 years or older, of whom 673 had a nonhigh clinical probability, using the age-adjusted cutoff instead of the 500 µg/L cutoff increased the proportion of patients in whom PE could be excluded on the basis of D-dimer from 43 of 673 patients (6.4% [95% CI, 4.8%-8.5%) to 200 of 673 patients (29.7% [95% CI, 26.4%-33.3%), without any additional false-negative findings. CONCLUSIONS AND RELEVANCE: Compared with a fixed D-dimer cutoff of 500 µg/L, the combination of pretest clinical probability assessment with age-adjusted D-dimer cutoff was associated with a larger number of patients in whom PE could be considered ruled out with a low likelihood of subsequent clinical venous thromboembolism. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01134068.

[Surgery in patients with centrally-situated non-small cell lung carcinoma: lung-parenchymal sparing procedure versus pneumonectomy]. / Chirurgie bij patiënten met centraal gelegen niet-kleincellig longcarcinoom: longparenchymsparende ingreep versus pneumonectomie.

OBJECTIVE: To examine if lung-parenchymal sparing resection ('sleeve' resection) is a safe and oncologically responsible alternative to pneumonectomy in patients with central tumours. Further, to evaluate in how far this technique is being used in the Netherlands. DESIGN: Retrospective cohort study. METHOD: Patients undergoing either lung-parenchymal sparing procedure or pneumonectomy for centrally situated non-small cell lung carcinoma (NSCLC) between January 1995 and January 2010 were included. Early mortality, perioperative complications, survival and disease-free survival in both groups were compared. Survival was calculated using the Kaplan-Meier method. RESULTS: A total 78 patients underwent sleeve resection and 89 pneumonectomy. Early mortality (during admission or within 30 days of operation) in the sleeve-resection group was 1.3% (1 patient), and 9.0% (8) (p = 0.038) in the pneumonectomy group. In the sleeve-resection group 6.4% (5) developed a bronchopleural fistula; in the pneumonectomy group this was 4.5% (4) (p=0.735). Median survival in the sleeve-resection group was 90 months, and 1- and 5-year-survival were 88 (SD: 4) and 61% (SD: 6), respectively. Median survival in the pneumonectomy group was 17 months, with a 1- and 5-year survival of 63 (SD: 5) and 24% (SD: 5), respectively. The difference in survival was significant (p <0.001; hazard ratio: 3.27; 95% CI: 2.11-5.08). The effect of TNM stage was not statistically significant in addition to operation (p = 0.079) and TNM stage was not a clear confounder: even after analysis the hazard ratio was 2.74. In the sleeve-resection group, after 5 years disease-free survival was 62% (SD: 7). In the pneumonectomy group, this was 34% (SD: 7) (p = 0.05). CONCLUSION: Patients with centrally-situated NSCLC who undergo a lung-parenchymal sparing procedure have lower mortality and better survival than patients who undergo pneumonectomy.

Pulmonary Mycobacterium abscessus: a canary in the cystic fibrosis coalmine.

We present a case of pulmonary nontuberculous mycobacterial infection (PNTM) with M. abscessus. After exclusion of genetic immune disorders known to cause NTM susceptibility, we found compound heterozygosity of two mutations, F508del and R117H in CFTR. The combination of F508del with a hypomorphic CFTR mutation can cause a mild Cystic Fibrosis (CF) phenotype with delayed CF symptoms in adulthood. Although the patient was continuously treated for her lung infection by different physicians for more than twenty years, the diagnosis CF had been missed. The forme fruste of CF should be considered in the analysis of host factors predisposing for PNTM.

Diagnosis and mortality prediction in pulmonary hypertension: the value of the electrocardiogram-derived ventricular gradient.

PURPOSE: The aim of this study was to investigate the use of the electrocardiogram-derived ventricular gradient, projected on the x-axis (VGx), for detection of pulmonary hypertension (PH) and for prediction of all-cause mortality in PH patients. METHODS: In patients referred for PH screening (n = 216), the VGx was calculated semiautomatically from the electrocardiogram and was defined as abnormal when less than 24 mV · ms. The VGx of PH patients was compared with the VGx of patients without PH. The association between a reduced VGx and mortality was investigated in PH patients. RESULTS: Patients with PH (n = 117) had a significantly reduced VGx: 14 ± 27 vs 45 ± 23 mV · ms, P < .001. Furthermore, a severely reduced VGx (<0 mV · ms) was associated with increased mortality in PH patients: hazard ratio, 1.025 (95% confidence interval, 1.006-1.045; P = .012) per mV·ms VGx decrease. CONCLUSION: Reduced VGx is associated with the presence of PH and, more importantly, within PH patients, a severely reduced VGx predicts mortality.

Head-and-neck paragangliomas are associated with sleep-related complaints, especially in the presence of carotid body tumors.

OBJECTIVES: The carotid body functions as a chemoreceptor. We hypothesized that head-and-neck paragangliomas (HNP) may disturb the function of these peripheral chemoreceptors and play a role in sleep-disordered breathing. DESIGN: This is a case-control study. SETTING: This study was conducted in a tertiary referral center. PARTICIPANTS AND MAIN OUTCOME MEASURES: We assessed fatigue, sleep, and exercise capacity in 74 HNP patients using three questionnaires (Epworth Sleepiness Scale, St. George Respiratory Questionnaire, and a standard clinical sleep assessment questionnaire). Outcomes were compared to those of age- and sex-matched controls. RESULTS AND CONCLUSIONS: Activity, disturbance of psychosocial function, and total score were worse compared to controls (15.4 ± 18.5 vs. 7.2 ± 9.9, P = 0.007; 5.3 ± 10.5 vs. 1.2 ± 2.6, P = 0.008; and 10.4 ± 12.9 vs. 5.0 ± 4.8, P = 0.006, respectively). Patients reported more daytime fatigue, concentration difficulties, and depression (51% vs. 24%, P = 0.006; 31% vs. 10%, P = 0.010; and 19% vs. 2%, P = 0.012). Waking up was reported to be less refreshing in HNP patients (53% vs. 73%, P = 0.038). Dysphonia was a predictor of symptoms, activity, disturbance of psychosocial function, and total scores. Remarkably, the presence of a carotid body tumor was an independent predictor of increased daytime sleepiness (ß = 0.287, P = 0.029). In conclusion, patients with HNP have remarkable sleep-related complaints. Especially the presence of carotid body tumors appears to be associated with increased daytime somnolence.

Illness perceptions and quality of life in Japanese and Dutch patients with non-small-cell lung cancer.

This study examined quality of life (QOL) and illness perceptions in Dutch and Japanese patients with non-small-cell lung cancer, thereby extending the body of knowledge on cultural differences and psychosocial aspects of this illness. 24 Dutch and 22 Japanese patients with non-small-cell lung cancer filled out questionnaires on three occasions: immediately before chemotherapy, 1 week later, and 8 weeks after the initial chemotherapy. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) assessed QOL, and the Brief Illness Perception Questionnaire (B-IPQ) illness perceptions. Scores on several QOL measures indicated (a) major impact of first chemotherapy sessions, and (b) some tendency to returning to baseline measures at 8 weeks. Differences between Japanese and Dutch samples were found on five EORTC QLQ-C30 dimensions: global health status, emotional functioning, social functioning, constipation, and financial difficulties, with the Dutch patients reporting more favorable scores. Regarding illness perceptions, Japanese patients had higher means on perceived treatment control and personal control, expressing a higher sense of belief in the success of medical treatment than Dutch patients. In both Japanese and Dutch patients, impact of chemotherapy on QOL was evident. Some differences in illness perceptions and QOL between the two samples were observed, with implications for integral medical management. Both samples reported illness perceptions that reflect the major consequences of non-small-cell lung cancer. Incorporating symptom reports, illness perceptions, and QOL into medical management may have positive consequences for patients with non-small-cell lung cancer.

Quality of life in long-term survivors of acute pulmonary embolism.

BACKGROUND: To our knowledge, studies evaluating the quality of life (QoL) in patients with a history of acute pulmonary embolism (PE) are not available, even though QoL is a key outcome component of medical care and a predictor of disease-specific prognosis. METHODS: As part of a large follow-up study, the Short Form 36 (SF-36) was presented to consecutive patients who had survived one or more episodes of acute PE. The results of all nine subscales of the SF-36 were compared with sex- and age-adjusted Dutch population norms. Single and multivariate analyses were performed to identify independent determinants of the QoL in our study population. RESULTS: The SF-36 was completed by 392 patients. Except for the health change subscale, patients had substantially lower QoL than population norms on all eight remaining subscales. After multivariate analysis, the time interval between the last thromboembolic episode and study inclusion was inversely related to QoL, and significant determinants of poor QoL were prior PE, age, obesity, active malignancy, and cardiopulmonary comorbid conditions. Regression models that included all identified significant determinants proved to be quite modest predictors for QoL in the individual patient. Awareness of illness, coping mechanisms, and self-management behavior might be additional important indicators of QoL in our study population but require further investigation. CONCLUSION: We identified several PE- and non-PE-related determinants of QoL in patients with a history of acute PE, which is impaired compared with sex- and age-adjusted population norms. QoL after acute PE should be studied more extensively and added as a standard measure to outcome studies.

Partial sleep restriction decreases insulin sensitivity in type 1 diabetes.

OBJECTIVE: Sleep restriction results in decreased insulin sensitivity and glucose tolerance in healthy subjects. We hypothesized that sleep duration is also a determinant of insulin sensitivity in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: We studied seven patients (three men, four women) with type 1 diabetes: mean age 44 +/- 7 years, BMI 23.5 +/- 0.9 kg/m(2), and A1C 7.6 +/- 0.3%. They were studied once after a night of normal sleep duration and once after a night of only 4 h of sleep. Sleep characteristics were assessed by polysomnography. Insulin sensitivity was measured by hyperinsulinemic euglycemic clamp studies with an infusion of [6,6-(2)H(2)]glucose. RESULTS Sleep duration was shorter in the night with sleep restriction than in the unrestricted night (469 +/- 8.5 vs. 222 +/- 7.1 min, P = 0.02). Sleep restriction did not affect basal levels of glucose, nonesterified fatty acids (NEFAs), or endogenous glucose production. Endogenous glucose production during the hyperinsulinemic clamp was not altered during the night of sleep restriction compared with the night of unrestricted sleep (6.2 +/- 0.8 vs. 6.9 +/- 0.6 micromol x kg lean body mass(-1) x min(-1), NS). In contrast, sleep restriction decreased the glucose disposal rate during the clamp (25.5 +/- 2.6 vs. 22.0 +/- 2.1 micromol x kg lean body mass(-1) x min(-1), P = 0.04), reflecting decreased peripheral insulin sensitivity. Accordingly, sleep restriction decreased the rate of glucose infusion by approximately 21% (P = 0.04). Sleep restriction did not alter plasma NEFA levels during the clamp (143 +/- 29 vs. 133 +/- 29 micromol/l, NS). CONCLUSIONS: Partial sleep deprivation during a single night induces peripheral insulin resistance in these seven patients with type 1 diabetes. Therefore, sleep duration is a determinant of insulin sensitivity in patients with type 1 diabetes.

A single night of partial sleep deprivation induces insulin resistance in multiple metabolic pathways in healthy subjects.

BACKGROUND: Subsequent nights with partial sleep restriction result in impaired glucose tolerance, but the effects on insulin sensitivity have not been characterized. OBJECTIVE: The aim of this study was to evaluate the effect of a single night of partial sleep restriction on parameters of insulin sensitivity. RESEARCH DESIGN AND METHODS: Nine healthy subjects (five men, four women) were studied once after a night of normal sleep duration (sleep allowed from 2300 to 0730 h), and once after a night of 4 h of sleep (sleep allowed from 0100 to 0500 h). Sleep characteristics were assessed by polysomnography. Insulin sensitivity was measured by hyperinsulinemic euglycemic clamp studies (from 1130 to 1430 h) with infusion of [6,6-(2)H(2)]glucose. RESULTS: Sleep duration was shorter in the night with sleep restriction than in the unrestricted night (226 +/- 11 vs. 454 +/- 9 min; P< 0.0001). Sleep restriction did not affect basal levels of glucose, nonesterified fatty acids, insulin, or endogenous glucose production. Sleep restriction resulted in increased endogenous glucose production during the hyperinsulinemic clamp study compared to the unrestricted night (4.4 +/- 0.3 vs. 3.6 +/- 0.2 micromol x kg lean body mass(-1) x min(-1); P = 0.017), indicating hepatic insulin resistance. In addition, sleep restriction decreased the glucose disposal rate during the clamp (32.5 +/- 3.6 vs. 40.7 +/- 5.1 micromol x kg lean body mass(-1) x min(-1); P = 0009), reflecting decreased peripheral insulin sensitivity. Accordingly, sleep restriction decreased the rate of glucose infusion by approximately 25% (P = 0.001). Sleep restriction increased plasma nonesterified fatty acid levels during the clamp study (68 +/- 5 vs. 57 +/- 4 micromol/liter; P = 0.005). CONCLUSIONS: Partial sleep deprivation during only a single night induces insulin resistance in multiple metabolic pathways in healthy subjects. This physiological observation may be of relevance for variations in glucoregulation in patients with type 1 and type 2 diabetes.

Prospective cardiopulmonary screening program to detect chronic thromboembolic pulmonary hypertension in patients after acute pulmonary embolism.

BACKGROUND: Chronic thromboembolic pulmonary hypertension after pulmonary embolism is associated with high morbidity and mortality. Understanding the incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism is important for evaluating the need for screening but is also a subject of debate because of different inclusion criteria among previous studies. We determined the incidence of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism and the utility of a screening program for this disease. DESIGN AND METHODS: We conducted a cohort screening study in an unselected series of consecutive patients (n=866) diagnosed with acute pulmonary embolism between January 2001 and July 2007. All patients who had not been previously diagnosed with pulmonary hypertension (PH) and had survived until study inclusion were invited for echocardiography. Patients with echocardiographic suspicion of PH underwent complete work-up for chronic thromboembolic pulmonary hypertension, including ventilation-perfusion scintigraphy and right heart catheterization. RESULTS: After an average follow-up of 34 months of all 866 patients, PH was diagnosed in 19 patients by routine clinical care and in 10 by our screening program; 4 patients had chronic thromboembolic pulmonary hypertension, all diagnosed by routine clinical care. The cumulative incidence of chronic thromboembolic pulmonary hypertension after all cause pulmonary embolism was 0.57% (95% confidence interval [CI] 0.02-1.2%) and after unprovoked pulmonary embolism 1.5% (95% CI 0.08-3.1%). CONCLUSIONS: Because of the low incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism and the very low yield of the echocardiography based screening program, wide scale implementation of prolonged follow-up including echocardiography of all patients with pulmonary embolism to detect chronic thromboembolic pulmonary hypertension does not seem to be warranted.

Patient outcomes after acute pulmonary embolism. A pooled survival analysis of different adverse events.

RATIONALE: There is a lack of information on the long-term prognosis of patients with acute pulmonary embolism (PE). OBJECTIVES: To assess the long-term risk for adverse events after PE. METHODS: Consecutive patients diagnosed with PE between January 2001 and July 2007, and patients in whom PE was ruled out from a previous study were followed until July 2008 for the occurrence of adverse clinical events: mortality, symptomatic recurrent venous thromboembolism, cancer, arterial cardiovascular events and chronic thromboembolic pulmonary hypertension. Hazard ratios (HR) for all endpoints and a combined endpoint were calculated and adjusted for potential confounders. MEASUREMENTS AND MAIN RESULTS: Three hundred eight patients with unprovoked, 558 with provoked, and 334 without PE were studied with a median follow-up period of 3.3 years. Patients with unprovoked PE had a lower overall risk for mortality than patients with provoked PE (HR, 0.59; 95% confidence interval [CI], 0.43-0.82), but a higher risk for nonmalignancy-related mortality (HR, 1.8; 95% CI, 1.3-2.5), recurrent venous thromboembolism (HR, 2.1; 95% CI, 1.3-3.1), cancer (HR, 4.4; 95% CI, 2.0-10), cardiovascular events (HR, 2.6; 95% CI, 1.5-3.8) and chronic thromboembolic pulmonary hypertension (1.5 vs. 0%). The risk for the combined endpoint did not differ between both groups (HR, 0.98; 95% CI, 0.82-1.1). Patients without PE had similar risks for malignancy and cardiovascular events than patients with provoked PE, but lower risks for the remaining outcomes. The fraction of both patients with provoked and unprovoked PE without events after 1 year was only 70% and decreased to fewer than 60% after 2 years and fewer than 50% after 4 years, whereas this latter was 84% for the control patients. CONCLUSIONS: The clinical course of acute PE is complicated by high rates of serious adverse events, which occur in half of the patients within 4 years.

MVA.85A boosting of BCG and an attenuated, phoP deficient M. tuberculosis vaccine both show protective efficacy against tuberculosis in rhesus macaques.

BACKGROUND: Continuous high global tuberculosis (TB) mortality rates and variable vaccine efficacy of Mycobacterium bovis Bacille Calmette-Guérin (BCG) motivate the search for better vaccine regimes. Relevant models are required to downselect the most promising vaccines entering clinical efficacy testing and to identify correlates of protection. METHODS AND FINDINGS: Here, we evaluated immunogenicity and protection against Mycobacterium tuberculosis in rhesus monkeys with two novel strategies: BCG boosted by modified vaccinia virus Ankara expressing antigen 85A (MVA.85A), and attenuated M. tuberculosis with a disrupted phoP gene (SO2) as a single-dose vaccine. Both strategies were well tolerated, and immunogenic as evidenced by induction of specific IFNgamma responses. Antigen 85A-specific IFNgamma secretion was specifically increased by MVA.85A boosting. Importantly, both MVA.85A and SO2 treatment significantly reduced pathology and chest X-ray scores upon infectious challenge with M. tuberculosis Erdman strain. MVA.85A and SO2 treatment also showed reduced average lung bacterial counts (1.0 and 1.2 log respectively, compared with 0.4 log for BCG) and significant protective effect by reduction in C-reactive protein levels, body weight loss, and decrease of erythrocyte-associated hematologic parameters (MCV, MCH, Hb, Ht) as markers of inflammatory infection, all relative to non-vaccinated controls. Lymphocyte stimulation revealed Ag85A-induced IFNgamma levels post-infection as the strongest immunocorrelate for protection (spearman's rho: -0.60). CONCLUSIONS: Both the BCG/MVA.85A prime-boost regime and the novel live attenuated, phoP deficient TB vaccine candidate SO2 showed significant protective efficacy by various parameters in rhesus macaques. Considering the phylogenetic relationship between macaque and man and the similarity in manifestations of TB disease, these data support further development of these primary and combination TB vaccine candidates.

EBUS-TBNA for the clarification of PET positive intra-thoracic lymph nodes-an international multi-centre experience.

INTRODUCTION: To determine the sensitivity and accuracy of endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) for clarification of the nature of fluorodeoxyglucose-positron emission tomography (FDG) positive hilar and/or mediastinal lymph nodes in patients with (suspected) lung cancer. METHODS: All consecutive patients who had undergone EBUS-TBNA alone for assessment of abnormal FDG-uptake in hilar and/or mediastinal lymph nodes between January 2005 and August 2007 were reviewed. RESULTS: One-hundred-nine patients underwent EBUS-TBNA of 127 positron emission tomography positive lymph nodes. Hilar (station 10 or 11) nodes (N1 or N3) were aspirated in 26 patients and mediastinal (stations 2, 4, 7) nodes (N2 or N3) in 90 patients. In 7 patients both hilar and mediastinal nodes were sampled. There were no procedure-related complications. Malignancy was detected in 77 (71%) cases. Thirty-two patients were tumor negative by EBUS-TBNA; subsequent surgical biopsy in 19 showed malignancy in 7. In four cases the false negative result was due to sampling error and in three cases due to detection error. In 13 cases surgical staging was not performed although long term follow-up in 3 showed no evidence of malignancy. The sensitivity and accuracy of EBUS-TBNA for malignancy in patients with reference pathology was 91% and 92%, respectively. The negative predictive value was 60%. If the 10 cases for which confirmatory surgical staging was not performed are assumed to be false negative results, overall sensitivity and accuracy were 82% and 84%, respectively. CONCLUSIONS: EBUS-TBNA offers an effective accurate, minimally invasive strategy for evaluating FDG avid hilar and mediastinal lymph nodes. However, negative findings should be confirmed by surgical staging.

EBUS-TBNA for the diagnosis of central parenchymal lung lesions not visible at routine bronchoscopy.

BACKGROUND: Obtaining a tissue diagnosis of malignancy is challenging in patients with suspected lung cancer presenting with centrally located intrapulmonary masses. OBJECTIVE: (1) To evaluate the yield of endobronchial ultrasound with real-time guided transbronchial needle aspiration (EBUS-TBNA) for diagnosing centrally located lesions after a non-diagnostic conventional bronchoscopy. (2) To assess the impact of EBUS-TBNA on patient management for this indication. STUDY DESIGN AND PATIENTS: A retrospective analysis of a series of patients with a central parenchymal lung lesion suspected to be lung cancer who had been referred to three university hospitals for EBUS-TBNA to obtain a tissue diagnosis was undertaken. If EBUS-TBNA did not result in a formal pathological diagnosis of malignancy, patients were subsequently referred for a transthoracic needle aspiration biopsy or a surgical diagnostic procedure. RESULTS: Sixty patients were investigated with EBUS-TBNA. The majority (82%) had a prior (non-diagnostic) flexible bronchoscopy. EBUS-TBNA was performed in an out-patient setting in 97%. With ultrasound, the primary lung lesion was observed in all cases. EBUS-TBNA confirmed lung cancer in 46 (77%). A final reference pathology diagnosis was available in 59 (98%) cases. The sensitivity of EBUS-TBNA for diagnosing lung cancer was 82% (95% confidence intervals (CI) 69-91%) with a negative predictive value of 23% (95%CI 5-53%). Based on the EBUS-TBNA findings, transthoracic needle aspiration biopsy or a surgical diagnostic procedure was cancelled in 47% and 30% of patients, respectively. No serious procedure-related complications were reported. CONCLUSION: EBUS-TBNA is a sensitive tool for the diagnosis of centrally located primary lung cancer not visible at conventional bronchoscopy. Therefore, EBUS-TBNA can impact on patient management in this setting. However, the low negative predictive value indicates that a negative EBUS-TBNA result should be confirmed by other methods. IMPLICATION: EBUS-TBNA can be considered as a diagnostic test in patients with a centrally located lung lesion after a previous non-diagnostic conventional bronchoscopy.

Screening for small-cell lung cancer: a follow-up study of patients with Lambert-Eaton myasthenic syndrome.

PURPOSE: A small-cell lung carcinoma (SCLC) is found in 50% of patients with Lambert-Eaton myasthenic syndrome (LEMS). We evaluated screening to optimize screening strategy for SCLC. It is important to detect these tumors early in newly diagnosed patients with LEMS to offer optimal patient treatment. PATIENTS AND METHODS: A large nationwide cohort study of consecutive patients in the Netherlands, seen between 1990 and 2007, were screened for the presence of a tumor using chest x-ray, computed tomography of the thorax (CT-thorax), [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET), bronchoscopy, and/or mediastinoscopy. RESULTS: SCLC was found in 54 patients, and in 46 patients, no tumor was found during a median follow-up of 8 years (range, 3 to 26 years). All patients with SCLC had a positive smoking history and 86% were still smoking at diagnosis. SCLC was found in 92% of these patients within 3 months and in 96% within a year. At first screening, CT-thorax detected an SCLC in 45 patients (83%), whereas chest x-ray found the tumor in only 23 patients (51%). An SCLC was found during secondary screening in another nine patients (median, 3 months; range, 1 to 41 months). In six patients, a lung tumor was found by CT-thorax or FDG-PET, and in three patients, extrapulmonary metastases were found, initially without identifiable tumor mass on CT-thorax. CONCLUSION: In almost all patients (96%), the SCLC was found within 1 year of diagnosis. CT-thorax scans detected most of the tumors (93%) and was far more sensitive than chest x-ray (51%). FDG-PET may have additive value in selected cases. We propose a screening protocol based on CT-thorax and FDG-PET.