The circadian clock protein REVERBα inhibits pulmonary fibrosis development.

Pulmonary inflammatory responses lie under circadian control; however, the importance of circadian mechanisms in the underlying fibrotic phenotype is not understood. Here, we identify a striking change to these mechanisms resulting in a gain of amplitude and lack of synchrony within pulmonary fibrotic tissue. These changes result from an infiltration of mesenchymal cells, an important cell type in the pathogenesis of pulmonary fibrosis. Mutation of the core clock protein REVERBα in these cells exacerbated the development of bleomycin-induced fibrosis, whereas mutation of REVERBα in club or myeloid cells had no effect on the bleomycin phenotype. Knockdown of REVERBα revealed regulation of the little-understood transcription factor TBPL1. Both REVERBα and TBPL1 altered integrinß1 focal-adhesion formation, resulting in increased myofibroblast activation. The translational importance of our findings was established through analysis of 2 human cohorts. In the UK Biobank, circadian strain markers (sleep length, chronotype, and shift work) are associated with pulmonary fibrosis, making them risk factors. In a separate cohort, REVERBα expression was increased in human idiopathic pulmonary fibrosis (IPF) lung tissue. Pharmacological targeting of REVERBα inhibited myofibroblast activation in IPF fibroblasts and collagen secretion in organotypic cultures from IPF patients, thus suggesting that targeting of REVERBα could be a viable therapeutic approach.

Circadian asthma airway responses are gated by REV-ERBα.

BACKGROUND: The circadian clock powerfully regulates inflammation and the clock protein REV-ERBα is known to play a key role as a repressor of the inflammatory response. Asthma is an inflammatory disease of the airways with a strong time of day rhythm. Airway hyper-responsiveness (AHR) is a dominant feature of asthma; however, it is not known if this is under clock control. OBJECTIVES: To determine if allergy-mediated AHR is gated by the clock protein REV-ERBα. METHODS: After exposure to the intra-nasal house dust mite (HDM) allergen challenge model at either dawn or dusk, AHR to methacholine was measured invasively in mice. MAIN RESULTS: Wild-type (WT) mice show markedly different time of day AHR responses (maximal at dusk/start of the active phase), both in vivo and ex vivo, in precision cut lung slices. Time of day effects on AHR were abolished in mice lacking the clock gene Rev-erbα, indicating that such effects on asthma response are likely to be mediated via the circadian clock. We suggest that muscarinic receptors one (Chrm 1) and three (Chrm 3) may play a role in this pathway. CONCLUSIONS: We identify a novel circuit regulating a core process in asthma, potentially involving circadian control of muscarinic receptor expression, in a REV-ERBα dependent fashion. CLINICAL IMPLICATION: These insights suggest the importance of considering the timing of drug administration in clinic trials and in clinical practice (chronotherapy).

Optical spectral transmission to assess inflammation in hand and wrist joints of rheumatoid arthritis patients.

Objective: To develop an optical spectral transmission (OST) model to measure joint inflammation, and thus disease activity, as well as to evaluate (patho-)physiological findings that could lead to misclassification of inflammation. Methods: Forty-six RA patients were included in this cross-sectional study, where US scores, duplicate OST measurements and 28-joint DAS (DAS28) were acquired. With US as a reference standard, the diagnostic performance of OST in detecting inflammation at the joint level was evaluated using receiver operating characteristic (ROC) curve analyses. At the patient level, correlations with US were analysed for DAS28 and OST, and at joint level for OST and tender and swollen joint counts (TJC and SJC, respectively). Joint pathology potentially influencing misclassification by OST [erosions, osteophytes, tendon (sheath) inflammation (ab)normal vasculature and chondrocalcinosis] was evaluated for significance in a multivariate nominal logistic regression model. Results: Diagnostic performance of OST was good for MCP [area under the ROC curve (AUC-ROC) 0.88], PIP (AUC-ROC 0.83) and wrist (AUC-ROC 0.74) joints and for all joints together (AUC-ROC 0.85). At the patient level, DAS28 correlated very poorly (ρ = 0.06) and OST moderately (ρ = 0.54) with US. At the joint level, US correlation with OST was strong (ρ = 0.64), with SJC it was weak (ρ = 0.30) and with TJC it was very weak (ρ = -0.02). Misclassification of inflammation by OST was relatively rare (17%). Dorsal erosions [odds ratio (OR) 4.0], osteophytes (OR 2.1) and extensor tendinitis (OR 4.6) increased the risk of underestimating inflammation of MCP and PIP joints and osteophytes (OR 3.0) also increased the risk of overestimating inflammation. Conclusion: OST is a sensitive, specific and objective technique to assess joints inflammation of the hands and wrists of RA patients, even though bone and tendon pathology increases the risk of misclassification.

Stability of mid-shaft clavicle fractures after plate fixation versus intramedullary repair and after hardware removal.

PURPOSE: Operative treatment for middle-third clavicle fractures has been increasing as recent data has demonstrated growing patient dissatisfaction and functional deficits after non-operative management. A controlled biomechanical comparison of the characteristics of locked intramedullary (IM) fixation versus superior pre-contoured plating for fracture repair and hardware removal is warranted. Therefore, the purpose of the present study was to investigate potential differences between these devices in a biomechanical model. METHODS: Thirty fourth-generation composite clavicles were randomized to one of five groups with 6 specimens each and tested in a random order. The groups tested were intact, repair with plate, repair with IM device, plate removal, and IM device removal. The lateral end of the clavicles was loaded to failure at a rate of 60 mm/min in a cantilever bending setup. Failure mechanism, energy (J), and torque (Nm) at the site of failure were recorded. RESULTS: Failure torque of the intact clavicle (mean ± standard deviation) was 36.5 ± 7.3 Nm. Failure torques of the IM repair (21.5 ± 9.0 Nm) and plate repair (18.2 ± 1.6 Nm) were not significantly different (n.s.) but were significantly less than the intact group (P < 0.05). Failure torque following IM device removal (30.2 ± 6.5 Nm) was significantly greater than plate removal (12.9 ± 2.0 Nm) (P < 0.05). No significant differences were observed between the intact and IM device removal groups (n.s.). CONCLUSION: The results of the current study demonstrate that IM and plate devices provide similar repair strength for middle-third clavicle fractures. However, testing of the hardware removal groups found the IM device removal group to be significantly stronger than the plate removal group.

Shape conveyed by visual-to-auditory sensory substitution activates the lateral occipital complex.

The lateral-occipital tactile-visual area (LOtv) is activated when objects are recognized by vision or touch. We report here that the LOtv is also activated in sighted and blind humans who recognize objects by extracting shape information from visual-to-auditory sensory substitution soundscapes. Recognizing objects by their typical sounds or learning to associate specific soundscapes with specific objects do not activate this region. This suggests that LOtv is driven by the presence of shape information.

Visual experiences in the blind induced by an auditory sensory substitution device.

In this report, the phenomenology of two blind users of a sensory substitution device - "The vOICe" - that converts visual images to auditory signals is described. The users both report detailed visual phenomenology that developed within months of immersive use and has continued to evolve over a period of years. This visual phenomenology, although triggered through use of The vOICe, is likely to depend not only on online visualization of the auditory signal but also on the users' previous (albeit distant) experience of veridical vision (e.g. knowledge of shapes and visual perspective). Once established, the sensory substitution mapping between the auditory and visual domains is not confined to when the device is worn and, thus, may constitute an example of acquired synaesthesia.

The clinical value of routinely obtained postoperative chest radiographs in post-anaesthesia care unit patients seems poor-a prospective observational study.

BACKGROUND: The clinical value of routinely obtained postoperative chest radiographs (CXRs) in post-anaesthesia care unit (PACU) patients is largely unknown. METHODS: To determine the diagnostic efficacy and treatment impact of postoperative routinely obtained CXRs in a university hospital PACU. Observational study collecting the expectations of attending physicians, the findings on routinely obtained CXRs and actions based on the findings on these CXRs in postoperative PACU patients. A 22-bed PACU in a university hospital in the Netherlands. Patients admitted to the PACU during a 9-month period. The analysis was restricted to CXRs routinely obtained during the first PACU admission, i.e., CXRs obtained during later admissions were excluded. Diagnostic efficacy, defined as the percentage of CXRs showing any unexpected major abnormality; treatment impact, defined as the percentage of CXRs showing an unexpected major abnormality that triggered a predefined change in therapy. RESULTS: The analysis included 294 postoperative CXRs. Of them 94 showed a new and unexpected predefined major abnormality (diagnostic efficacy of 35%). Of these 94 CXRs, only 10 triggered an intervention (treatment impact of 4%). CONCLUSIONS: The diagnostic efficacy of routinely obtained postoperative CXRs in PACU patients is fair; the treatment impact seems low if we assume that all CXRs that showed an abnormality but were not followed by an intervention and did not require an intervention. Future research should focus on the safety and cost-effectiveness of abrogating routine postoperative CXRs.

Multisensory perceptual learning and sensory substitution.

One of the most exciting recent findings in neuroscience has been the capacity for neural plasticity in adult humans and animals. Studies of perceptual learning have provided key insights into the mechanisms of neural plasticity and the changes in functional neuroanatomy that it affords. Key questions in this field of research concern how practice of a task leads to specific or general improvement. Although much of this work has been carried out with a focus on a single sensory modality, primarily visual, there is increasing interest in multisensory perceptual learning. Here we will examine how advances in perceptual learning research both inform and can be informed by the development and advancement of sensory substitution devices for blind persons. To allow 'sight' to occur in the absence of visual input through the eyes, visual information can be transformed by a sensory substitution device into a representation that can be processed as sound or touch, and thus give one the potential to 'see' through the ears or tongue. Investigations of auditory, visual and multisensory perceptual learning can have key benefits for the advancement of sensory substitution, and the study of sensory deprivation and sensory substitution likewise will further the understanding of perceptual learning in general and the reverse hierarchy theory in particular. It also has significant importance for the developing understanding of the brain in metamodal terms, where functional brain areas might be best defined by the computations they carry out rather than by their sensory-specific processing role.

How well do you see what you hear? The acuity of visual-to-auditory sensory substitution.

Sensory substitution devices (SSDs) aim to compensate for the loss of a sensory modality, typically vision, by converting information from the lost modality into stimuli in a remaining modality. "The vOICe" is a visual-to-auditory SSD which encodes images taken by a camera worn by the user into "soundscapes" such that experienced users can extract information about their surroundings. Here we investigated how much detail was resolvable during the early induction stages by testing the acuity of blindfolded sighted, naïve vOICe users. Initial performance was well above chance. Participants who took the test twice as a form of minimal training showed a marked improvement on the second test. Acuity was slightly but not significantly impaired when participants wore a camera and judged letter orientations "live". A positive correlation was found between participants' musical training and their acuity. The relationship between auditory expertise via musical training and the lack of a relationship with visual imagery, suggests that early use of a SSD draws primarily on the mechanisms of the sensory modality being used rather than the one being substituted. If vision is lost, audition represents the sensory channel of highest bandwidth of those remaining. The level of acuity found here, and the fact it was achieved with very little experience in sensory substitution by naïve users is promising.

Femoral cortical suspension devices for soft tissue anterior cruciate ligament reconstruction: a comparative biomechanical study.

BACKGROUND: Optimization of anterior cruciate ligament (ACL) fixation is desired to improve graft healing. New soft tissue cortical suspension devices for femoral tunnel fixation should be biomechanically evaluated. HYPOTHESIS: All femoral fixation devices would prevent a clinically significant amount of displacement and support loads significantly larger than in situ forces experienced by the ACL during early rehabilitation. STUDY DESIGN: Controlled laboratory study. METHODS: Four cortical soft tissue ACL graft suspension devices were tested under cyclic and pull-to-failure loading conditions in both an isolated device-only setup and as a complete bone-device-tendon construct in porcine femurs using a tensile testing machine. RESULTS: There were significant differences in the ultimate failure loads among the devices. The highest ultimate failure loads when tested as a construct were observed for the XO Button (1748 N), followed by the Endobutton CL (1456 N), ToggleLoc with ZipLoop (1334 N), and TightRope RT (859 N). Cyclic displacement after 1000 cycles during isolated device testing was less than 1 mm for all devices. Cyclic displacements after 1000 cycles in the porcine construct were 1.88 mm, 2.74 mm, 3.34 mm, and 1.82 mm for the Endobutton, TightRope, ToggleLoc, and XO Button, respectively; all were significantly different from each other except when the Endobutton was compared with the XO Button. The ToggleLoc exceeded the 3.0-mm displacement threshold defined as a clinical failure. The most displacement occurred during the first cycle, especially for the adjustable-length loop devices. Stiffness reapproximated the native ACL stiffness for all constructs. CONCLUSION: The Endobutton, TightRope, and XO Button have the necessary biomechanical properties with regard to ultimate failure strength, displacement, and stiffness for initial fixation of soft tissue grafts in the femoral tunnel for ACL reconstruction. The ToggleLoc had sufficient ultimate failure strength but crossed our 3.0-mm clinical failure threshold for cyclic displacement. Although this study was not designed to compare fixed and adjustable-length loop devices, it was noted that both fixed-loop devices allowed less cyclic displacement and initial displacement. CLINICAL RELEVANCE: Adjustable-length loop devices may need to be retensioned after cycling the knee and fixing the tibial side to account for the increased initial displacement seen with these devices.

Functional recruitment of visual cortex for sound encoded object identification in the blind.

Individuals using a visual-to-auditory sensory substitution device (SSD) called 'The vOICe' can identify objects in their environment through images encoded by sound. We have shown that identifying objects with this SSD is associated with activation of occipital visual areas. Here, we show that repetitive transcranial magnetic stimulation (rTMS) delivered to a specific area of occipital cortex (identified by functional MRI) profoundly impairs a blind user's ability to identify objects. rTMS delivered to the same site had no effect on a visual imagery task. The task and site-specific disruptive effect of rTMS in this individual suggests that the cross-modal recruitment of occipital visual areas is functional in nature and critical to the patient's ability to process and decode the image sounds using this SSD.