A Pilot Observational Study Evaluating the Diagnostic Capacity of Rotational Thromboelastometry in Periprosthetic Joint Infections.

BACKGROUND: Periprosthetic joint infections (PJIs) are associated with altered hemostatic dynamics; therefore, coagulation laboratory methods such as rotational thromboelastometry (ROTEM) may be valuable in their diagnosis. The aim of this study was to evaluate the diagnostic role of ROTEM in PJI. METHODS: A diagnostic study was conducted including 65 patients who underwent revision total hip arthroplasty or total knee arthroplasty due to PJI (30 patients) or aseptic loosening (35 patients). Preoperative laboratory evaluation included conventional coagulation studies, inflammatory markers, and ROTEM analysis. These parameters were compared between patients with PJI and patients with aseptic loosening. RESULTS: Several ROTEM parameters differed in the patients with PJI, indicating a higher coagulation potential associated with PJI. Specifically, the development of PJI was associated with higher EXTEM maximum clot firmness (MCF) (odds ratio [OR], 1.12 [95% confidence interval (CI), 1.04 to 1.20]; p = 0.001). Among the ROTEM parameters, EXTEM MCF was found to have the highest diagnostic accuracy for PJI (area under the receiver operating characteristic curve, 0.850; sensitivity, 76.6%; specificity, 91.4%), which was comparable with C-reactive protein (CRP) (p = 0.22) and erythrocyte sedimentation rate (ESR) (p = 0.65), but higher than D-dimer (p = 0.037). Moreover, the combined diagnostic accuracy of elevated EXTEM MCF and CRP was improved compared with CRP alone (p = 0.019). CONCLUSIONS: Our results indicate that ROTEM analysis might be helpful for the detection of the hemostatic derangements that are associated with the development of PJI. However, because of the small size of this pilot study, further research is needed to investigate the value of incorporating viscoelastic studies in diagnostic scores for PJI. LEVEL OF EVIDENCE: Diagnostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Asthma and Tobacco Smoking.

Asthma is a prevalent chronic pulmonary condition with significant morbidity and mortality. Tobacco smoking is implicated in asthma pathophysiology, diagnosis, prognosis and treatment. Smokers display increased prevalence and incidence of asthma, but a causal association cannot be claimed using existing evidence. Second-hand smoking and passive exposure to tobacco in utero and early life have also been linked with asthma development. Currently, approximately one-fourth of asthma patients are smokers. Regular smokers with asthma might display accelerated lung function decline and non-reversible airflow limitation, making their distinction from chronic obstructive pulmonary disease patients challenging. Asthma patients who smoke typically have uncontrolled disease, as shown by increased symptoms, more exacerbations and impaired quality of life. On the other hand, smoking cessation improves lung function and asthma severity. Thus, asthma patients and their caregivers should be actively questioned about their smoking status at each medical encounter, and smoking cessation ought to be strongly encouraged both for patients with asthma and their close contacts. Smokers with asthma should be provided with comprehensive smoking cessation interventions on top of other anti-asthma medications.

Conducting umbrella reviews.

In this article, Lazaros Belbasis and colleagues explain the rationale for umbrella reviews and the key steps involved in conducting an umbrella review, using a working example.

Prognostic factors for adverse outcomes in patients with COVID-19: a field-wide systematic review and meta-analysis.

INTRODUCTION: The individual prognostic factors for coronavirus disease 2019 (COVID-19) are unclear. For this reason, we aimed to present a state-of-the-art systematic review and meta-analysis on the prognostic factors for adverse outcomes in COVID-19 patients. METHODS: We systematically reviewed PubMed from 1 January 2020 to 26 July 2020 to identify non-overlapping studies examining the association of any prognostic factor with any adverse outcome in patients with COVID-19. Random-effects meta-analysis was performed, and between-study heterogeneity was quantified using I2 statistic. Presence of small-study effects was assessed by applying the Egger's regression test. RESULTS: We identified 428 eligible articles, which were used in a total of 263 meta-analyses examining the association of 91 unique prognostic factors with 11 outcomes. Angiotensin-converting enzyme inhibitors, obstructive sleep apnoea, pharyngalgia, history of venous thromboembolism, sex, coronary heart disease, cancer, chronic liver disease, COPD, dementia, any immunosuppressive medication, peripheral arterial disease, rheumatological disease and smoking were associated with at least one outcome and had >1000 events, p<0.005, I2<50%, 95% prediction interval excluding the null value, and absence of small-study effects in the respective meta-analysis. The risk of bias assessment using the Quality in Prognosis Studies tool indicated high risk of bias in 302 out of 428 articles for study participation, 389 articles for adjustment for other prognostic factors and 396 articles for statistical analysis and reporting. CONCLUSIONS: Our findings could be used for prognostic model building and guide patient selection for randomised clinical trials.

Tobacco Smoking and Risk for Pulmonary Fibrosis: A Prospective Cohort Study From the UK Biobank.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease of unknown origin. A limited number of small studies show an effect of tobacco smoking on risk of IPF, but second-hand smoking has not been examined. RESEARCH QUESTION: Are smoking-related exposures associated with risk of IPF and does interaction between them exist? STUDY DESIGN AND METHODS: We designed a prospective cohort study using UK Biobank data, including 437,453 nonrelated men and women of White ethnic background (40-69 years of age at baseline). We assessed the effect of tobacco smoking-related exposures on risk for IPF using Cox regression adjusted for age, sex, Townsend deprivation index, and home area population density. We also examined potential additive and multiplicative interaction between these exposures. Multiple imputation with chained equations was used to address missing data. RESULTS: We identified 802 incident IPF cases. We showed an association between smoking status (hazard ratio [HR], 2.12; 95% CI, 1.81-2.47), and maternal smoking (HR, 1.38; 95% CI, 1.18-1.62) with risk of IPF. In ever smokers, a dose-response relationship was observed between pack-years of smoking and risk of IPF (HR per 1-pack-year increase, 1.013; 95% CI, 1.009-1.016). Furthermore, an additive and multiplicative interaction was observed between maternal smoking and smoking status, with a relative excess risk due to interaction of 1.00 (95% CI, 0.45-1.54) and a ratio of HRs of 1.50 (95% CI, 1.05-2.14). INTERPRETATION: Active and maternal tobacco smoking have an independent detrimental effect on risk of IPF and work synergistically. Also, intensity of smoking presents a dose-response association with IPF, strengthening the hypothesis for a potentially causal association.

Early-Life Factors and Risk of Multiple Sclerosis: An MR-EWAS.

BACKGROUND: Although several risk factors are associated with multiple sclerosis (MS) in adulthood, evidence for risk factors acting from birth to adolescence is scarce. METHODS: We conceived a 2-step study design, where signals from an Environment-Wide Association Study are prioritized for follow-up in a Mendelian Randomization study (MR-EWAS), to examine the association of early-life factors with risk of MS. The EWAS was conducted in UK Biobank, where we agnostically selected all the available risk factors acting from the perinatal period until the adolescence, including perinatal factors, anthropometric characteristics during childhood, male and female sexual factors, and skin phenotypic characteristics. We prioritized statistically significant risk factors to perform a 2-sample MR study using publicly available summary-level genetic data. We also calculated the power of the 2-step MR-EWAS approach under several scenarios and compared it against a 1-step hypothesis-free MR approach to detect risk factors of MS. RESULTS: In the EWAS, an increase per 1 year in age at menarche was associated with a lower risk of MS (OR = 0.93; 95% CI: 0.90-0.96) and a plumper than average body size at the age of 10 was associated with a higher risk of MS (OR = 1.42; 95% CI: 1.24-1.61). Individuals getting very tanned or moderately tanned were at higher risk of MS compared with individuals that never tan or get mildly to occasionally tanned (OR = 0.86; 95% CI: 0.79-0.94). The MR analysis supported the association of age at menarche and childhood body mass index (BMI) without presence of pleiotropic effects. In the multivariable MR analysis, the association of age at menarche was not statistically significant after adjusting for childhood BMI. The MR analysis for ease of tanning did not reveal a statistically significant association. In multiple scenarios, the power of MR-EWAS approach was larger than the power of a hypothesis-free MR approach. CONCLUSIONS: We introduced the MR-EWAS, a 2-step approach that is more powerful compared with the hypothesis-free MR approach under certain scenarios, to test potential causal signals. Our comprehensive assessment of early-life risk factors of MS highlighted a potential causal role of early menarche and elevated childhood BMI for risk of MS.

Environmental factors and risk of multiple sclerosis: Findings from meta-analyses and Mendelian randomization studies.

Multiple sclerosis (MS) is a chronic demyelinating disease that is associated with permanent disability and low quality of life. Development of MS is attributed to a combination of genetic and environmental factors. Genome-wide association studies revealed more than 200 variants that are associated with risk of MS. An umbrella review showed that smoking, history of infectious mononucleosis, and anti-Epstein-Barr virus nuclear antigen (anti-EBNA) immunoglobulin G (IgG) seropositivity are credible risk factors of MS. In the present narrative review, we updated our published umbrella review, showing that body mass index in childhood and adolescence and anti-viral capsid antigen (anti-VCA) IgG seropositivity are additional credible risk factors of MS. In addition, we discuss the findings from Mendelian randomization studies, which present evidence for a potential causal role of serum vitamin D and adulthood body mass index on risk of MS. Finally, we discuss the potential limitations of meta-analyses, umbrella reviews, and Mendelian randomization studies in the search for risk factors of MS.

Prognostic models for outcome prediction in patients with chronic obstructive pulmonary disease: systematic review and critical appraisal.

OBJECTIVE: To map and assess prognostic models for outcome prediction in patients with chronic obstructive pulmonary disease (COPD). DESIGN: Systematic review. DATA SOURCES: PubMed until November 2018 and hand searched references from eligible articles. ELIGIBILITY CRITERIA FOR STUDY SELECTION: Studies developing, validating, or updating a prediction model in COPD patients and focusing on any potential clinical outcome. RESULTS: The systematic search yielded 228 eligible articles, describing the development of 408 prognostic models, the external validation of 38 models, and the validation of 20 prognostic models derived for diseases other than COPD. The 408 prognostic models were developed in three clinical settings: outpatients (n=239; 59%), patients admitted to hospital (n=155; 38%), and patients attending the emergency department (n=14; 3%). Among the 408 prognostic models, the most prevalent endpoints were mortality (n=209; 51%), risk for acute exacerbation of COPD (n=42; 10%), and risk for readmission after the index hospital admission (n=36; 9%). Overall, the most commonly used predictors were age (n=166; 41%), forced expiratory volume in one second (n=85; 21%), sex (n=74; 18%), body mass index (n=66; 16%), and smoking (n=65; 16%). Of the 408 prognostic models, 100 (25%) were internally validated and 91 (23%) examined the calibration of the developed model. For 286 (70%) models a model presentation was not available, and only 56 (14%) models were presented through the full equation. Model discrimination using the C statistic was available for 311 (76%) models. 38 models were externally validated, but in only 12 of these was the validation performed by a fully independent team. Only seven prognostic models with an overall low risk of bias according to PROBAST were identified. These models were ADO, B-AE-D, B-AE-D-C, extended ADO, updated ADO, updated BODE, and a model developed by Bertens et al. A meta-analysis of C statistics was performed for 12 prognostic models, and the summary estimates ranged from 0.611 to 0.769. CONCLUSIONS: This study constitutes a detailed mapping and assessment of the prognostic models for outcome prediction in COPD patients. The findings indicate several methodological pitfalls in their development and a low rate of external validation. Future research should focus on the improvement of existing models through update and external validation, as well as the assessment of the safety, clinical effectiveness, and cost effectiveness of the application of these prognostic models in clinical practice through impact studies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017069247.

Postpneumonectomy-like syndrome due to bronchial carcinoid: a unique case report.

BACKGROUND: Postpneumonectomy-like syndrome is a rare condition resulting from unilateral lung disease with severe lung volume loss leading to excessive mediastinal shift and herniation of the healthy lung into the contralateral hemithorax, mimicking the mediastinal shift observed in postpneumonectomy syndrome after pneumonectomy. We report a unique case of postpneumonectomy-like syndrome caused by an atypical bronchial carcinoid completely occluding the left main bronchus. CASE PRESENTATION: A 25-year-old woman presented with symptoms of chronic exertional dyspnea and productive cough. Imaging studies showed complete left lung atelectasis due to a mass occluding the left main bronchus, as well as extreme mediastinal deviation and substantial herniation of the right lung into the left hemithorax. Bronchoscopic biopsy of the tumor and subsequent left pneumonectomy with concurrent lymph node dissection revealed an atypical carcinoid. Sixteen months after surgery the patient has been asymptomatic with repeat imaging studies showing no change in mediastinal shifting. CONCLUSION: Bronchial carcinoids are notorious for causing bronchial obstruction. The present case represents an extreme complication of centrally located bronchial carcinoid, resulting in postpneumonectomy-like syndrome with severe mediastinal shift and herniation of the healthy lung into the diseased hemithorax.

Introduction to Epidemiological Studies.

The basic epidemiological study designs are cross-sectional, case-control, and cohort studies. Cross-sectional studies provide a snapshot of a population by determining both exposures and outcomes at one time point. Cohort studies identify the study groups based on the exposure and, then, the researchers follow up study participants to measure outcomes. Case-control studies identify the study groups based on the outcome, and the researchers retrospectively collect the exposure of interest. The present chapter discusses the basic concepts, the advantages, and disadvantages of epidemiological study designs and their systematic biases, including selection bias, information bias, and confounding.

Risk factors for type 2 diabetes mellitus: An exposure-wide umbrella review of meta-analyses.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a global epidemic associated with increased health expenditure, and low quality of life. Many non-genetic risk factors have been suggested, but their overall epidemiological credibility has not been assessed. METHODS: We searched PubMed to capture all meta-analyses and Mendelian randomization studies for risk factors of T2DM. For each association, we estimated the summary effect size, its 95% confidence and prediction interval, and the I2 metric. We examined the presence of small-study effects and excess significance bias. We assessed the epidemiological credibility through a set of predefined criteria. RESULTS: We captured 86 eligible papers (142 associations) covering a wide range of biomarkers, medical conditions, and dietary, lifestyle, environmental and psychosocial factors. Adiposity, low hip circumference, serum biomarkers (increased level of alanine aminotransferase, gamma-glutamyl transferase, uric acid and C-reactive protein, and decreased level of adiponectin and vitamin D), an unhealthy dietary pattern (increased consumption of processed meat and sugar-sweetened beverages, decreased intake of whole grains, coffee and heme iron, and low adherence to a healthy dietary pattern), low level of education and conscientiousness, decreased physical activity, high sedentary time and duration of television watching, low alcohol drinking, smoking, air pollution, and some medical conditions (high systolic blood pressure, late menarche age, gestational diabetes, metabolic syndrome, preterm birth) presented robust evidence for increased risk of T2DM. CONCLUSIONS: A healthy lifestyle pattern could lead to decreased risk for T2DM. Future randomized clinical trials should focus on identifying efficient strategies to modify harmful daily habits and predisposing dietary patterns.

Systematic evaluation of the associations between environmental risk factors and dementia: An umbrella review of systematic reviews and meta-analyses.

INTRODUCTION: Dementia is a heterogeneous neurodegenerative disease, whose etiology results from a complex interplay between environmental and genetic factors. METHODS: We searched PubMed to identify meta-analyses of observational studies that examined associations between nongenetic factors and dementia. We estimated the summary effect size using random-effects and fixed-effects model, the 95% CI, and the 95% prediction interval. We assessed the between-study heterogeneity (I-square), evidence of small-study effects, and excess significance. RESULTS: A total of 76 unique associations were examined. By applying standardized criteria, seven associations presented convincing evidence. These associations pertained to benzodiazepines use, depression at any age, late-life depression, and frequency of social contacts for all types of dementia; late-life depression for Alzheimer's disease; and type 2 diabetes mellitus for vascular dementia and Alzheimer's disease. DISCUSSION: Several risk factors present substantial evidence for association with dementia and should be assessed as potential targets for interventions, but these associations may not necessarily be causal.

Environmental Risk Factors and Amyotrophic Lateral Sclerosis: An Umbrella Review and Critical Assessment of Current Evidence from Systematic Reviews and Meta-Analyses of Observational Studies.

BACKGROUND: The pathogenesis of amyotrophic lateral sclerosis (ALS) involves both environmental and genetic factors. Our study aimed at summarising the environmental risk factors for ALS, assessing the evidence for diverse biases, and pinpointing risk factors with high epidemiological credibility. METHODS: We searched PubMed from inception to August 20, 2015, to identify systematic reviews and meta-analyses of observational studies examining associations between environmental factors and ALS. For each meta-analysis, we estimated the summary effect size by the use of random-effects and fixed-effects models, the 95% CI, the 95% prediction interval (PI), and the between-study heterogeneity. We assessed the evidence of small-study effects and excess significance bias. RESULTS: Sixteen unique meta-analyses of different risk factors and ALS were considered. Of them, 5 were statistically significant at p < 0.001 under the random-effects model. Only one factor presented robust evidence for a convincing association. This association pertained to chronic occupational exposure to lead (random-effects OR 1.81, 95% CI 1.39-2.35). CONCLUSIONS: A small number of published meta-analyses on environmental factors and risk of ALS was identified, a phenomenon that could be attributed to the challenges in studying a rare neurological disease. More observational studies with adequate sample size and study design are needed to clarify the environmental component of ALS pathogenesis.

Environmental risk factors and Parkinson's disease: An umbrella review of meta-analyses.

BACKGROUND: Parkinson's disease is a neurological disorder with complex pathogenesis implicating both environmental and genetic factors. We aimed to summarise the environmental risk factors that have been studied for potential association with Parkinson's disease, assess the presence of diverse biases, and identify the risk factors with the strongest support. METHODS: We searched PubMed from inception to September 18, 2015, to identify systematic reviews and meta-analyses of observational studies that examined associations between environmental factors and Parkinson's disease. For each meta-analysis we estimated the summary effect size by random-effects and fixed-effects models, the 95% confidence interval and the 95% prediction interval. We estimated the between-study heterogeneity expressed by I(2), evidence of small-study effects and evidence of excess significance bias. RESULTS: Overall, 75 unique meta-analyses on different risk factors for Parkinson's disease were examined, covering diverse biomarkers, dietary factors, drugs, medical history or comorbid diseases, exposure to toxic environmental agents and habits. 21 of 75 meta-analyses had results that were significant at p < 0.001 by random-effects. Evidence for an association was convincing (more than 1000 cases, p < 10(-6) by random-effects, not large heterogeneity, 95% prediction interval excluding the null value and absence of hints for small-study effects and excess significance bias) for constipation, and physical activity. CONCLUSION: Many environmental factors have substantial evidence of association with Parkinson's disease, but several, perhaps most, of them may reflect reverse causation, residual confounding, information bias, sponsor conflicts or other caveats.

Environmental risk factors and multiple sclerosis: an umbrella review of systematic reviews and meta-analyses.

BACKGROUND: The cause of multiple sclerosis is believed to involve environmental exposure and genetic susceptibility. We aimed to summarise the environmental risk factors that have been studied in relation to onset of multiple sclerosis, assess whether there is evidence for diverse biases in this literature, and identify risk factors without evidence of biases. METHODS: We searched PubMed from inception to Nov 22, 2014, to identify systematic reviews and meta-analyses of observational studies that examined associations between environmental factors and multiple sclerosis. For each meta-analysis we estimated the summary effect size by use of random-effects and fixed-effects models, the 95% CI, and the 95% prediction interval. We estimated the between-study heterogeneity expressed by I(2) (defined as large for I(2)≥50%), evidence of small-study effects (ie, large studies had significantly more conservative results than smaller studies), and evidence of excess significance bias (ie, more studies than expected with significant results). FINDINGS: Overall, 44 unique meta-analyses including 416 primary studies of different risk factors and multiple sclerosis were examined, covering a wide range of risk factors: vaccinations, comorbid diseases, surgeries, traumatic events and accidents, exposure to environmental agents, and biochemical, infectious, and musculoskeletal biomarkers. 23 of 44 meta-analyses had results that were significant at p values less than 0·05 and 11 at p values less than 0·001 under the random-effects model. Only three of the 11 significant meta-analyses (p<0·001) included more than 1000 cases, had 95% prediction intervals excluding the null value, and were not suggestive of large heterogeneity (I(2)<50%), small-study effects (p for Egger's test >0·10), or excess significance (p>0·05). These were IgG seropositivity to Epstein-Barr virus nuclear antigen (EBNA) (random effects odds ratio [OR] 4·46, 95% CI 3·26-6·09; p for effect size=1·5 × 10(-19); I(2)=43%), infectious mononucleosis (2·17, 1·97-2·39; p=3·1 × 10(-50); I(2)=0%), and smoking (1·52, 1·39-1·66; p=1·7 × 10(-18;)I(2)=0%). INTERPRETATION: Many studies on environmental factors associated with multiple sclerosis have caveats casting doubts on their validity. Data from more and better-designed studies are needed to establish robust evidence. A biomarker of Epstein-Barr virus (anti-EBNA IgG seropositivity), infectious mononucleosis, and smoking showed the strongest consistent evidence of an association. FUNDING: None.

The association between bullying-related behaviours and subjective health complaints in late adolescence: cross-sectional study in Greece.

BACKGROUND: Bullying is quite prevalent in the school setting and has been associated with several subjective health complaints such as headache, backache, abdominal pain, dizziness, fatigue and sleep problems. The aim of the present study was to investigate the association between bullying and subjective health complaints in a sample of Greek adolescents taking into account the presence of psychiatric morbidity. METHODS: A stratified random sample of 2427 adolescents aged 16-18 years old and attending senior high schools were randomly selected for a computerized interview. Subjective health complaints were assessed using a symptom checklist used in the context of a previous World Health Organization study and relevant sections of the revised Clinical Interview Schedule (CIS-R). The latter was also used for the assessment of psychiatric morbidity. Bullying was assessed with the revised Olweus bully/victim questionnaire. A series of logistic regression models were used to investigate the association between bullying and subjective health complaints. RESULTS: Victims of bullying were more likely to report backache (Odds Ratio [OR] = 1.92, 95% CI: 1.01-3.67), dizziness (OR = 2.83, 95% CI: 1.11-7.22) and fatigue (OR = 0.41, 95% CI: 0.19-0.86), independently of the presence of psychiatric morbidity. In addition bullying perpetrators were more likely to report backache (OR = 3.49, 95% CI: 1.49-8.18). It is worth noting that sleep problems and abdominal pain were also associated with being bullied and fatigue with bullying perpetration but these associations were all attenuated after adjustment for psychiatric morbidity. CONCLUSIONS: Strong associations between bullying in schools and subjective health complaints among a sample of Greek students aged 16-18 years have been observed. The exact nature of these associations should be investigated in future longitudinal studies.