Bleeding Risk With Combination Intrapleural Fibrinolytic and Enzyme Therapy in Pleural Infection: An International, Multicenter, Retrospective Cohort Study.

BACKGROUND: Combination intrapleural fibrinolytic and enzyme therapy (IET) has been established as a therapeutic option in pleural infection. Despite demonstrated efficacy, studies specifically designed and adequately powered to address complications are sparse. The safety profile, the effects of concurrent therapeutic anticoagulation, and the nature and extent of nonbleeding complications remain poorly defined. RESEARCH QUESTION: What is the bleeding complication risk associated with IET use in pleural infection? STUDY DESIGN AND METHODS: This was a multicenter, retrospective observational study conducted in 24 centers across the United States and the United Kingdom. Protocolized data collection for 1,851 patients treated with at least one dose of combination IET for pleural infection between January 2012 and May 2019 was undertaken. The primary outcome was the overall incidence of pleural bleeding defined using pre hoc criteria. RESULTS: Overall, pleural bleeding occurred in 76 of 1,833 patients (4.1%; 95% CI, 3.0%-5.0%). Using a half-dose regimen (tissue plasminogen activator, 5 mg) did not change this risk significantly (6/172 [3.5%]; P = .68). Therapeutic anticoagulation alongside IET was associated with increased bleeding rates (19/197 [9.6%]) compared with temporarily withholding anticoagulation before administration of IET (3/118 [2.6%]; P = .017). As well as systemic anticoagulation, increasing RAPID score, elevated serum urea, and platelets of < 100 × 109/L were associated with a significant increase in bleeding risk. However, only RAPID score and use of systemic anticoagulation were independently predictive. Apart from pain, non-bleeding complications were rare. INTERPRETATION: IET use in pleural infection confers a low overall bleeding risk. Increased rates of pleural bleeding are associated with concurrent use of anticoagulation but can be mitigated by withholding anticoagulation before IET. Concomitant administration of IET and therapeutic anticoagulation should be avoided. Parameters related to higher IET-related bleeding have been identified that may lead to altered risk thresholds for treatment.

Pleural Effusions in the Critically Ill and "At-Bleeding-Risk" Population.

Thoracentesis is a common bedside procedure, which has a low risk of complications when performed with thoracic ultrasound and by experienced operators. In critically ill or mechanically ventilated patients, or in patients with bleeding risks due to medications or other coagulopathies, the complication rate remains low. Drainage of pleural effusion in the intensive care unit has diagnostic and therapeutic utility, and perceived bleeding risks should be one part of an individualized and comprehensive risk-benefit analysis.

Tuberculosis and Biologic Therapies: Anti-Tumor Necrosis Factor-α and Beyond.

Biologic drugs have revolutionized the treatment of certain hematologic, autoimmune, and malignant diseases, but they may place patients at risk for reactivation or acquisition of tuberculosis. This risk is highest with the tumor necrosis factor-alpha (TNF-α) inhibitors. Amongst this class of drugs, the monoclonal antibodies (infliximab, adalimumab, golimumab) and antibody fragment (certolizumab) carry an increased risk compared to the soluble receptor fusion molecule, etanercept. Treatment of latent TB is critical to decrease the risk of reactivation. Data continues to emerge regarding tuberculosis risk associated with novel biologics targeting cytokines involved in tuberculosis control.

Medical and Surgical Management of Empyema.

Infection of the pleural space is an ancient and common clinical problem, the incidence which is on the rise. Advances in therapy now present clinicians of varying disciplines with an array of therapeutic options ranging from thoracentesis and chest tube drainage (with or without intrapleural fibrinolytic therapies) to video-assisted thoracic surgery (VATS) or thoracotomy. A framework is provided to guide decision making, which involves weighing multiple factors (clinical history and presentation, imaging characteristics, comorbidities); multidisciplinary collaboration and active management are needed as the clinical course over a few days determines subsequent refinement. The initial choice of antibiotics depends on whether the empyema is community-acquired or nosocomial, and clinicians must recognize that culture results often do not reflect the full disease process. Antibiotics alone are rarely successful and can be justified only in specific circumstances. Early drainage with or without intrapleural fibrinolytics is usually required. This is successful in most patients; however, when surgical decortication is needed, clear benefit and low physiologic impact are more likely with early intervention, expeditious escalation of interventions, and care at a center experienced with VATS.

Using the Analytical Target Profile to Drive the Analytical Method Lifecycle.

Quality by design (ICH-Topic Q8) requires a prospective summary of the desired quality characteristics of a drug product. This is known as the Quality Target Product Profile (QTPP), which forms the basis for the design and development of the product. An analogous term has been established for analytical procedures called the Analytical Target Profile (ATP). The ATP, in a similar fashion to the QTPP, prospectively summarizes the requirements associated with a measurement on a quality attribute which needs to be met by an analytical procedure. Criteria defined in the ATP relate to the maximum uncertainty associated with the reportable result that is required to maintain acceptable confidence in the quality decision made from the result. The ATP is used to define and assess the fitness of an analytical procedure in the development phase and during all changes across the analytical lifecycle. One or more analytical procedures can meet the requirements of an ATP. The ATP can be applied to any quality attribute across any pharmaceutical modality where an analytical procedure is used to generate a reportable result, and this paper provides examples from three of these modalities: small molecules, oligonucleotides, and vaccines. Some key performance characteristics will be discussed for each ATP, namely specificity, accuracy, and precision, taking into account the expected range of the analyte. The combination of accuracy and precision into a combined uncertainty characteristic is also discussed as a more holistic approach. The use of the ATP concept will help focus attention on the properties of a method which impact quality decisions rather than method descriptions and may enable greater regulatory flexibility across the lifecycle using established conditions based on method performance criteria as proposed in the Step 2 version of ICHQ12. The revision of ICHQ2(R1) and development of the new ICHQ14 guideline (Analytical Procedure Development) will provide a golden opportunity to harmonize the definition of new QbD concepts such as the ATP.

Restrictive Spirometry Pattern, Cardiac Structure and Function, and Incident Heart Failure in African Americans. The Jackson Heart Study.

RATIONALE: Although chronic obstructive pulmonary disease has been related to heart failure, the relationship between the restrictive spirometry pattern (forced vital capacity [FVC] < 80% predicted with preserved forced expiratory volume in 1 second [FEV1]/FVC ratio) and heart failure is poorly understood. OBJECTIVES: To determine whether having a restrictive spirometry pattern is associated with incident heart failure hospitalization. METHODS: Community-dwelling African Americans from the Jackson Heart Study (total n = 5,306; analyzed n = 4,210 with spirometry and heart failure outcome data) were grouped by restrictive spirometry (FEV1/FVC ≥ 0.70, FVC < 80%; n = 840), airflow obstruction (FEV1/FVC < 0.70; n = 341), and normal spirometry (FEV1/FVC ≥ 0.70, FVC ≥ 80%; n = 3,029) at the time of baseline examination in 2000-2004. We assessed relationships of echocardiographic parameters and biomarkers with spirometry patterns using regression models. Incident heart failure was defined as an adjudicated hospitalization for heart failure after January 1, 2005 in subjects with no self-reported heart failure history. We used multivariable-adjusted Poisson regression models and Cox proportional hazards models, with death treated as a competing risk in the Cox models, to test associations between spirometry patterns and incident heart failure. We also modeled the association of FVC% predicted with heart failure hospitalization risk using a restricted cubic spline after excluding subjects with airflow obstruction. RESULTS: At the time of baseline spirometry, participants with restrictive spirometry had a median age of 57.2 years (interquartile range, 47.8-64.1); 38.1% were male. Compared with normal spirometry, restrictive spirometry was associated with a higher transmitral early (E) wave velocity to atrial (A) wave velocity ratio, higher pulmonary artery systolic pressure, and higher endothelin levels. After a median follow-up time of 8.0 years, 8.0% of subjects with restrictive spirometry (n = 67) had developed incident heart failure, compared with 3.8% of those with normal spirometry (n = 115) and 10.6% of those with airflow obstruction (n = 36). After risk adjustment, both a restrictive pattern (hazard ratio [HR], 1.5; 95% confidence interval [CI], 1.1-2.0) and airflow obstruction (HR, 1.7; 95% CI, 1.1-2.5) were associated with increased rates of incident heart failure hospitalization compared with normal spirometry. Using flexible modeling, the lowest hazards of heart failure hospitalization were observed around FVC 90-100%, with lower FVC% values associated with an increased incidence of heart failure. CONCLUSIONS: Both a restrictive pattern on spirometry and airflow obstruction identify African Americans with impaired lung health at risk for heart failure.

The Vital Capacity Is Vital: Epidemiology and Clinical Significance of the Restrictive Spirometry Pattern.

Epidemiologic research has revealed a substantial portion of the general population with abnormal spirometry results that are characterized by decreased FEV1 and FVC but a preserved FEV1/FVC ratio. This restrictive spirometry pattern (RSP) is inconsistently defined in the literature and not well addressed by current guidelines; there is an accumulating body of evidence, however, that RSP is prevalent to a similar degree as airflow obstruction. Genetic and other risk factors for RSP, such as inhalational injuries and early life exposures, continue to be actively described. Although it seems that RSP is closely associated with the metabolic syndrome, diabetes, and systemic inflammation, it is not a simple marker of obesity. RSP is associated with adverse cardiovascular outcomes, as well as mortality, and it may be an underappreciated cause of functional impairments and respiratory symptoms. Improvement in outcomes in this population will require that clinicians have an appreciation for the significance of this spirometry pattern; additional research into the clinical and radiologic phenotype of these subjects is also needed. This article provides an overview of the recent developments in our understanding of this prevalent and highly morbid spirometry pattern.

Metronidazole-induced encephalopathy after prolonged metronidazole course for treatment of C. difficile colitis.

A 65-year-old woman with a diagnosis of Clostridium difficile colitis undergoing prolonged treatment with metronidazole was admitted to hospital for altered mentation, slurred speech and weakness. She was diagnosed with metronidazole-induced encephalopathy, confirmed with brain MRI and improved when the offending agent was removed. This case report highlights encephalopathy as a complication of prolonged metronidazole treatment, which has become more common in clinical practice for the treatment of C. difficile infection.

Prognostic indicators for upper tract urothelial carcinoma after radical nephroureterectomy: the impact of lymphovascular invasion.

UNLABELLED: What's known on the subject? and What does the study add? In an array of urological and non-urological malignancies, lymphovascular invasion (LVI) is a pathological feature known to be associated with adverse outcomes for recurrence and survival. For some cancers, LVI has therefore been incorporated into American Joint Committee on Cancer TNM staging algorithms. This study presents an analysis of the impact of LVI in upper urinary tract urothelial carcinoma (UTUC) treated at our institution over a 20-year period. In addition to known associations with features of aggressive disease and overall survival, we were able to show that LVI-positive status upsets the TNM staging for UTUC. Namely, patients with superficial stage and LVI-positive disease have overall survival outcomes similar to those of patients with muscle-invasive LVI-negative carcinoma. Such evidence may support the addition of LVI to future TNM staging algorithms for UTUC. OBJECTIVE: To assess the impact of lymphovascular invasion (LVI) on the prognosis of patients with upper urinary tract urothelial cell carcinoma (UTUC) treated with radical nephroureterectomy (RNU). PATIENTS AND METHODS: The Columbia University Medical Center Urologic Oncology database was queried and 211 patients undergoing RNU for UTUC between 1990 and 2010 were identified. These cases were retrospectively reviewed, and the prognostic significance of relevant clinical and pathological variables was analysed using log-rank tests and Cox proportional hazards regression models. Actuarial survival curves were calculated using the Kaplan-Meier method. RESULTS: LVI was observed in 68 patients (32.2%). The proportion of LVI increased with advancing stage, high grade, positive margin status, concomitant carcinoma in situ, and lymph node metastases. The 5- and 10-year overall survival rates were 74.7% and 53.1% in the absence of LVI, and 35.7% and 28.6% in the presence of LVI, respectively. In multivariate analysis, age, race and LVI were independent predictors of overall survival. CONCLUSIONS: The presence of LVI on pathological review of RNU specimens was associated with worse overall survival in patients with UTUC. LVI status should be included in the pathological report for RNU specimens to help guide postoperative therapeutic options. With confirmation from large international studies, inclusion of LVI in the tumour-node-metastasis staging system for UTUC should be considered.