Examining the educational impact of the mini-CEX: a randomised controlled study.

BACKGROUND: The purpose of this study is to evaluate the mini-Clinical Evaluation Exercise (mini-CEX) as a formative assessment tool among undergraduate medical students, in terms of student perceptions, effects on direct observation and feedback, and educational impact. METHODS: Cluster randomised study of 38 fifth-year medical students during a 16-week clinical placement. Hospitals were randomised to provide a minimum of 8 mini-CEXs per student (intervention arm) or continue with ad-hoc feedback (control arm). After finishing their clinical placement, students completed an Objective Structured Clinical Examination (OSCE), a written test and a survey. RESULTS: All participants in the intervention group completed the pre-planned number of assessments, and 60% found them to be useful during their clinical placement. Overall, there were no statistically significant differences between groups in reported quantity or quality of direct observation and feedback. Observed mean scores were marginally higher on the OSCE and written test in the intervention group, but not statistically significant. CONCLUSIONS: There is considerable potential in assessing medical students during clinical placements and routine practice, but the educational impact of formative assessments remains mostly unknown. This study contributes with a robust study design, and may serve as a basis for future research.

Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization.

Inhalation of silica crystals causes inflammation in the alveolar space. Prolonged exposure to silica can lead to the development of silicosis, an irreversible, fibrotic pulmonary disease. The mechanisms by which silica and other crystals activate immune cells are not well understood. Here we demonstrate that silica and aluminum salt crystals activated inflammasomes formed by the cytoplasmic receptor NALP3. NALP3 activation required phagocytosis of crystals, and this uptake subsequently led to lysosomal damage and rupture. 'Sterile' lysosomal damage (without crystals) also induced NALP3 activation, and inhibition of either phagosomal acidification or cathepsin B activity impaired NALP3 activation. Our results indicate that the NALP3 inflammasome senses lysosomal damage as an endogenous 'danger' signal.

The Rab11a GTPase controls Toll-like receptor 4-induced activation of interferon regulatory factor-3 on phagosomes.

Toll-like receptor 4 (TLR4) is indispensable for recognition of Gram-negative bacteria. We described a trafficking pathway for TLR4 from the endocytic recycling compartment (ERC) to E. coli phagosomes. We found a prominent colocalization between TLR4 and the small GTPase Rab11a in the ERC, and Rab11a was involved in the recruitment of TLR4 to phagosomes in a process requiring TLR4 signaling. Also, Toll-receptor-associated molecule (TRAM) and interferon regulatory factor-3 (IRF3) localized to E. coli phagosomes and internalization of E. coli was required for a robust interferon-ß induction. Suppression of Rab11a reduced TLR4 in the ERC and on phagosomes leading to inhibition of the IRF3 signaling pathway induced by E. coli, whereas activation of the transcription factor NF-κB was unaffected. Moreover, Rab11a silencing reduced the amount of TRAM on phagosomes. Thus, Rab11a is an important regulator of TLR4 and TRAM transport to E. coli phagosomes thereby controlling IRF3 activation from this compartment.

Reconstituted High-Density Lipoprotein Attenuates Cholesterol Crystal-Induced Inflammatory Responses by Reducing Complement Activation.

Chronic inflammation of the arterial wall is a key element in the development of atherosclerosis, and cholesterol crystals (CC) that accumulate in plaques are associated with initiation and progression of the disease. We recently revealed a link between the complement system and CC-induced inflammasome caspase-1 activation, showing that the complement system is a key trigger in CC-induced inflammation. HDL exhibits cardioprotective and anti-inflammatory properties thought to explain its inverse correlation to cardiovascular risk. In this study, we sought to determine the effect of reconstituted HDL (rHDL) on CC-induced inflammation in a human whole blood model. rHDL bound to CC and inhibited the CC-induced complement activation as measured by soluble terminal C5b-9 formation and C3c deposition on the CC surface. rHDL attenuated the amount of CC-induced complement receptor 3 (CD11b/CD18) expression on monocytes and granulocytes, as well as reactive oxygen species generation. Moreover, addition of CC to whole blood resulted in release of proinflammatory cytokines that were inhibited by rHDL. Our results support and extend the notion that CC are potent triggers of inflammation, and that rHDL may have a beneficial role in controlling the CC-induced inflammatory responses by inhibiting complement deposition on the crystals.

Cholesterol crystals induce complement-dependent inflammasome activation and cytokine release.

Inflammation is associated with development of atherosclerosis, and cholesterol crystals (CC) have long been recognized as a hallmark of atherosclerotic lesions. CC appear early in the atheroma development and trigger inflammation by NLRP3 inflammasome activation. In this study we hypothesized whether CC employ the complement system to activate inflammasome/caspase-1, leading to release of mature IL-1ß, and whether complement activation regulates CC-induced cytokine production. In this study we describe that CC activated both the classical and alternative complement pathways, and C1q was found to be crucial for the activation. CC employed C5a in the release of a number of cytokines in whole blood, including IL-1ß and TNF. CC induced minimal amounts of cytokines in C5-deficient whole blood, until reconstituted with C5. Furthermore, C5a and TNF in combination acted as a potent primer for CC-induced IL-1ß release by increasing IL-1ß transcripts. CC-induced complement activation resulted in upregulation of complement receptor 3 (CD11b/CD18), leading to phagocytosis of CC. Also, CC mounted a complement-dependent production of reactive oxygen species and active caspase-1. We conclude that CC employ the complement system to induce cytokines and activate the inflammasome/caspase-1 by regulating several cellular responses in human monocytes. In light of this, complement inhibition might be an interesting therapeutic approach for treatment of atherosclerosis.

Long-term changes in lung function after Roux-en-Y gastric bypass in patients with severe obesity.

Obesity can decrease the lung function. The proposed mechanisms of reduced lung function in persons with obesity have been altered mechanical properties in the lung and chest wall, airway narrowing and increased respiratory resistance. The aim of this current study was to analyse the long-term results after gastric bypass surgery in patients with reduced lung function. The bariatric surgery observation study invited patients to a follow up 10 years after gastric bypass surgery. We compared the spirometry results before surgery to the spirometry 10 years after surgery. Thirty percent of 198 participants had reduced lung function before surgery. There was no significant relation between body mass index before surgery and lung function. Seventy-three percent of the participants with reduced lung function had normal lung function 10 years after surgery. There was no significant relation between the degree of weight loss and the improvement in lung function. Most participants with reduced lung function had normal lung function 10 years after gastric bypass surgery. There was no significant correlation between weight loss and improvement in lung function.