Effects of psychosocial factors on monitoring treatment effect in newly diagnosed rheumatoid arthritis patients over time: response data from the tREACH study

Objectives: To investigate whether, apart from effects of patient- and disease-related factors, p

Rational clinical examination of the critically ill patient

In this thesis the evidence of clinical examination of the cardiovascular system was evaluated in critically ill patients. Current guidelines advocate the use of clinical examination to diagnose circulatory shock. Shock is a life-threatening condition wherein the blood circulation and cardiac output is insufficient to provide sufficient oxygen to vital organs. Previous studies showed that physicians may be insufficiently capable of estimating cardiac output solely based on the clinical examination; their diagnostic accuracy was comparable to a flip of a coin. These studies were, however, conducted more than 20 years ago and of low methodologic quality.During this PhD-thesis an observational study of high methodologic quality was conducted to educate physicians on the diagnostic and prognostic value of clinical examination. A study-design with pre-specified hypotheses was published and guidelines for statistical analysis plans were written to promote transparency in observational studies. The first main observation was that clinical signs are important warning signals that a patient deteriorates but cannot reliably indicate what the cardiac output is, and what the underlying cause is. Second, it was observed that clinical examination performs reasonably for distinguishing 90-day survivors from non-survivors, but that this ability was similar to established prognostic scores. This PhD-thesis also investigated if dopamine, a drug used to increase cardiac output, was beneficial in critically ill patients with cardiac dysfunction. In a systematic review we observed that the evidence for using dopamine was sparse and of low quality, which implicates that contemporary use of dopamine can neither be recommended nor refuted

Serodiagnosis of Mycobacterium abscessus complex infection in cystic fibrosis

Early signs of pulmonary disease with Mycobacterium abscessus complex (MABSC) can be missed in patients with cystic fibrosis (CF). A serological method could help stratify patients according to risk. The objective of this study was to test the diagnostic accuracy of a novel method for investigating IgG activity against MABSC. A prospective study of all patients attending the Copenhagen CF Centre was conducted by culturing for MABSC during a 22-month period and then screening patients with an anti-MABSC IgG ELISA. Culture-positive patients had stored serum examined for antibody kinetics before and after culture conversion. 307 patients had 3480 respiratory samples cultured and were then tested with the anti-MABSC IgG ELISA. Patients with MABSC pulmonary disease had median anti-MABSC IgG levels six-fold higher than patients with no history of infection (434 versus 64 ELISA units; p<0.001). The test sensitivity was 95% (95% CI 74–99%) and the specificity was 73% (95% CI 67–78%). A diagnostic algorithm was constructed to stratify patients according to risk. The test accurately identified patients with pulmonary disease caused by MABSC and was suited to be used as a complement to mycobacterial culture

Xpert MTB/RIF Assay Shows Faster Clearance of Mycobacterium tuberculosis DNA with Higher Levels of Rifapentine Exposure.

The Xpert MTB/RIF assay is both sensitive and specific as a diagnostic test. Xpert also reports quantitative output in cycle threshold (CT) values, which may provide a dynamic measure of sputum bacillary burden when used longitudinally. We evaluated the relationship between Xpert CT trajectory and drug exposure during tuberculosis (TB) treatment to assess the potential utility of Xpert CT for treatment monitoring. We obtained serial sputum samples from patients with smear-positive pulmonary TB who were consecutively enrolled at 10 international clinical trial sites participating in study 29X, a CDC-sponsored Tuberculosis Trials Consortium study evaluating the tolerability, safety, and antimicrobial activity of rifapentine at daily doses of up to 20 mg/kg of body weight. Xpert was performed at weeks 0, 2, 4, 6, 8, and 12. Longitudinal CT data were modeled using a nonlinear mixed effects model in relation to rifapentine exposure (area under the concentration-time curve [AUC]). The rate of change of CT was higher in subjects receiving rifapentine than in subjects receiving standard-dose rifampin. Moreover, rifapentine exposure, but not assigned dose, was significantly associated with rate of change in CT (P = 0.02). The estimated increase in CT slope for every additional 100 μg · h/ml of rifapentine drug exposure (as measured by AUC) was 0.11 CT/week (95% confidence interval [CI], 0.05 to 0.17). Increasing rifapentine exposure is associated with a higher rate of change of Xpert CT, indicating faster clearance of Mycobacterium tuberculosis DNA. These data suggest that the quantitative outputs of the Xpert MTB/RIF assay may be useful as a dynamic measure of TB treatment response

Exploring CSF neurofilament light as a biomarker for MS in clinical practice; a retrospective registry-based study

BACKGROUND: Neurofilament light (NFL) has been increasingly recognized for prognostic and therapeutic decisions. OBJECTIVE: To validate the utility of cerebrospinal fluid NFL (cNFL) as a biomarker in clinical practice of relapsing-remitting multiple sclerosis (RRMS). METHODS: RRMS patients (n = 757) who had cNFL analyzed as part of the diagnostic work-up in a single academic multiple sclerosis (MS) center, 2001–2018, were retrospectively identified. cNFL concentrations were determined with two different immunoassays and the ratio of means between them was used for normalization. RESULTS: RRMS with relapse had 4.4 times higher median cNFL concentration (1134 [interquartile range (IQR) 499–2744] ng/L) than those without relapse (264 [125–537] ng/L, p < 0.001) and patients with gadolinium-enhancing lesions had 3.3 times higher median NFL (1414 [606.8–3210] ng/L) than those without (426 [IQR 221–851] ng/L, p < 0.001). The sensitivity and specificity of cNFL to detect disease activity was 75% and 98.5%, respectively. High cNFL at MS onset predicted progression to Expanded Disability Status Scale (EDSS) ⩾ 3 (p < 0.001, hazard ratios (HR) = 1.89, 95% CI = 1.44–2.65) and conversion to secondary progressive MS (SPMS, p = 0.001, HR = 2.5, 95% CI = 1.4–4.2). CONCLUSIONS: cNFL is a robust and reliable biomarker of disease activity, treatment response, and prediction of disability and conversion from RRMS to SPMS. Our data suggest that cNFL should be included in the assessment of patients at MS-onset