Recent advances in chronic obstructive pulmonary disease pathogenesis: from disease mechanisms to precision medicine

Chronic obstructive pulmonary disease (COPD) is a devastating lung disease with a high personal and societal burden. Exposure to toxic particles and gases, including cigarette smoke, is the main risk factor for COPD. Together with smoking cessation, current treatment strategies of COPD aim to improve symptoms and prevent exacerbations, but there is no disease-modifying treatment. The biggest drawback of today's COPD treatment regimen is the ‘one size fits all’ pharmacological intervention, mainly based on disease severity and symptoms and not the individual's disease pathology. To halt the worrying increase in the burden of COPD, disease management needs to be advanced with a focus on personalized treatment. The main pathological feature of COPD includes a chronic and abnormal inflammatory response within the lungs, which results in airway and alveolar changes in the lung as reflected by (small) airways disease and emphysema. Here we discuss recent developments related to the abnormal inflammatory response, ECM and age-related changes, structural changes in the small airways and the role of sex-related differences, which are all relevant to explain the individual differences in the disease pathology of COPD and improve disease endotyping. Furthermore, we will discuss the most recent developments of new treatment strategies using biologicals to target specific pathological features or disease endotypes of COPD. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Foot and ankle joint movements inside orthoses for children with spastic CP

We compared the ankle joint and foot segment kinematics of pediatric cerebral palsy (CP) participants walking with and without orthoses. A six segment foot model (6SF) was used to track foot motion. Holes were cut in the study orthoses so that electromagnetic markers could be directly placed on the skin. The Hinged Ankle Foot Orthoses (HAFO) allowed a significant increase in ankle dorsiflexion as compared to the barefoot condition during gait, but significantly constrained sagittal forefoot motion and forefoot sagittal range of motion (ROM) (p < 0.01), which may be detrimental. The Solid Ankle Foot Orthoses (SAFO) constrained forefoot ROM as compared to barefoot gait (p < 0.01). The 6SF model did not confirm that the SAFO can control excessive plantarflexion for those with severe plantarflexor spasticity. The supramalleolar orthosis (SMO) significantly (p < 0.01) constrained forefoot ROM as compared to barefoot gait at the beginning and end of the stance phase, which could be detrimental. The SMO had no effects observed in the coronal plane. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:531–536, 2014.     

Correspondence between neurophysiological and clinical measurements of chemotherapy‐induced peripheral neuropathy: secondary analysis of data from the CI‐PeriNomS study

Chemotherapy‐induced peripheral neuropathy (CIPN) lacks standardized clinical measurement. The objective of the current secondary analysis was to examine data from the CIPN Outcomes Standardization (CI‐PeriNomS) study for associations between clinical examinations and neurophysiological abnormalities. Logistic regression estimated the strength of associations of vibration, pin, and monofilament examinations with lower limb sensory and motor amplitudes. Examinations were classified as normal (0), moderately abnormal (1), or severely abnormal (2). Among 218 participants, those with class 1 upper extremity (UE) and classes 1 or 2 lower extremity (LE) monofilament abnormality were 2.79 (95% confidence interval [CI]: 1.28–6.07), 3.49 (95%CI: 1.61–7.55), and 4.42 (95%CI: 1.35–14.46) times more likely to have abnormal sural nerve amplitudes, respectively, compared to individuals with normal examinations. Likewise, those with class 2 UE and classes 1 or 2 LE vibration abnormality were 8.65 (95%CI: 1.81–41.42), 2.54 (95%CI: 1.19–5.41), and 7.47 (95%CI: 2.49–22.40) times more likely to have abnormal sural nerve amplitudes, respectively, compared to participants with normal examinations. Abnormalities in vibration and monofilament examinations are associated with abnormal sural nerve amplitudes and are useful in identifying CIPN.     

Functional Electrical Stimulation to Dorsiflexors and Plantar Flexors During Gait to Improve Walking in Adults With Chronic Hemiplegia

Embrey DG, Holtz SL, Alon G, Brandsma BA, McCoy SW. Functional electrical stimulation to dorsiflexors and plantar flexors during gait to improve walking in adults with chronic hemiplegia.

Objective

To determine whether functional electrical stimulation (FES) timed to activate the dorsiflexors and plantar flexors during gait improves the walking of adults with hemiplegia.

Design

Randomized crossover trial.

Setting

Outpatient rehabilitation clinic.

Participants

Adults with hemiplegia (N=28) with a mean age ± SD of 60±10.9 years and 4.9±3.8 years postincident.

Interventions

Intervention “A” included 3 months of wearing the FES system, which activated automatically during walking for 6 to 8h/d, 7d/wk, plus walking 1h/d, 6d/wk. Intervention “B” included 3 months of walking 1h/d, 6d/wk without FES. Of the 28 patients who completed the study, 15 were randomly assigned to group A-B, 13 to group B-A. Crossover occurred at 3 months.

Main Outcome Measures

Variables were measured at pretreatment, 3 months, and 6 months. Three primary outcomes were selected a priori and included 2 functional variables, the 6-minute walk test and the Emory Functional Ambulatory Profile, and 1 participation variable, the Stroke Impact Scale. Secondary impairment measures included muscle strength and spasticity. Assessments were done without electrical stimulation.

Results

In phase 1, patients who received treatment A (A-B group) showed improvement compared with patients who received treatment B (B-A group) on the 6-minute walk test (P=.02), Emory Functional Ambulatory Profile (P=.08), and Stroke Impact Scale (P=.03). In phase 2, the A-B group maintained improvement in all 3 primary outcomes even without FES. Both groups improved significantly on all primary outcome measures, comparing 6-month to initial measures (P≤.05).

Conclusions

An FES system that stimulates dorsiflexors and plantar flexors similar to the timing of typical adult gait, combined with daily walking, can improve the walking ability of adults with hemiplegia.     

Electronic momentary assessment in chronic pain I: psychological pain responses as predictors of pain intensity

OBJECTIVES AND METHODS: Electronic momentary assessment was employed to substantiate the relevance of psychological functioning in chronic pain. More than 7,100 electronic diaries from 80 patients with varying IASP classified types of chronic pain served to investigate to what extent fear-avoidance, cognitive and spousal solicitous and punishing pain responses explained fluctuations in pain intensity and whether patients with pre-chronic, recently chronic and persistently chronic pain differed in this regard. RESULTS: Psychological pain responses explained 40% of the total variance in pain intensity: almost 24% concerned pain variance that occurred between the CPD patients and 16% pertained to pain variance due to momentary differences within these patients. Separately tested fear-avoidance and cognitive responses each explained about 28% of the total pain variance, while spousal responses explained 9%. Catastrophizing emerged as the strongest pain predictor, followed by pain-related fear and bodily vigilance. Results did not differ with the duration of chronicity. DISCUSSION: Exaggerated negative interpretations of pain, and fear that movement will induce or increase pain strongly predicted CPD pain intensity. Spousal responses-assessed only when the spouse was with the patient who at that moment was in actual pain-may more strongly affect immobility due to pain than pain intensity per se (see part II of the study). The findings substantiate the importance of catastrophizing, fear and vigilance identified primarily in low back pain and extend this to other forms of chronic pain. The compelling evidence of momentary within-patients differences underscores that these must be accounted for in chronic pain research and practice.     

CSF protein profiling using Multiplex Immuno-assay

Objective The diagnosis of leptomeningeal metastases (LM) is based on clinical symptoms, magnetic resonance imaging (MRI) of brain and spine and cytological analysis of cerebrospinal fluid (CSF). The clinical picture of LM is highly variable and both cytological CSF analysis and contrast-enhanced MRI are limited in sensitivity. More sensitive tools are needed to diagnose LM. We measured a profile of proteins involved in adhesion and inflammation in the CSF of LM and control patients and determined their potential diagnostic value for LM. Patients and methods Using Multiplex Immuno-Assay (MIA), the CSF concentrations of nine soluble adhesion molecules, cyto- and chemokines were measured in patients with cytologically proven LM (n=57) and control patients with a systemic malignancy (n=20), aseptic/viral meningitis (n=11) or other (non-)neurological diseases (n=19). Results We found high CSF levels of soluble Vascular Cell Adhesion Molecule-1 (sVCAM-1), soluble Intercellular Adhesion Molecule-1 (sICAM-1), Interleukin-8 (IL-8), Pulmonary and Activation Regulated Chemokine (PARC), Interleukin-18 (IL-18) and Interferon-γ inducible protein (IP-10) in patients with LM. The CSF protein profile in LM patients differed significantly from the profile found in control patients. Multivariate logistic regression and ROC analysis showed that the MIA-measured CSF protein profile has an additive discriminating value for LM above standard CSF parameters. A combination of total protein, glucose, IL-8, PARC and IP-10 CSF levels proved to be most discriminative between LM and non-LM patients. Conclusion Our results warrant a prospective study to determine whether a CSF protein profile, including IL-8, PARC and IP-10 has diagnostic value compared with CSF cytology, the golden standard for LM. Received in revised form: 2 November 2005