Effectiveness of local exercise therapy versus spinal manual therapy in patients with patellofemoral pain syndrome: medium term follow-up results of a randomized controlled trial.

BACKGROUND: Increasing evidence has shown benefits of spinal manipulations in patients with patellofemoral pain syndrome (PFPS). There is scarcity regarding medium term effects of spinal manual therapy on outcome measures in PFPS patients. Therefore, the aim of the present study was to compare the effectiveness of local exercise therapy and spinal manual therapy for knee pain, function and maximum voluntary peak force (MVPF) velocity of the quadriceps in PFPS patients. METHODS: Forty-three patients with PFPS were randomly assigned to a local exercise or spinal manual therapy group. The local exercise group received six sessions (one session per week) of supervised training of the knee-and hip muscles with mobilization of the patellofemoral joint. The spinal manual therapy group received six interventions (one intervention per week) of high velocity low thrust manipulations at the thoracolumbar region, sacroiliac joint, and/or hip. All patients were also asked to do home exercises. Maximum, minimum and current pain were measured using the visual analogue scale. Function was assessed with the anterior knee pain scale (AKPS) and MPFV was recorded using a Biodex System 3 dynamometer. Patients were assessed before intervention, after 6 weeks of intervention and after 6 weeks of follow-up. Between-group differences at assessments were analysed by way of analysis of covariance with Bonferroni correction. RESULTS: Pain and functionality improved more following spinal manipulative therapy than local exercise therapy. After 6 weeks of intervention the between-group difference (local versus spinal) for maximal pain was 23.4 mm [95% CI: 9.3, 37.6; effect size (ES): 1.04] and - 12.4 [95% CI: - 20.2, - 4.7; ES: 1.00] for the AKPS. At 6 weeks of follow-up the between-group difference for maximal pain was 18.7 mm [95% CI: 1.4, 36.0; ES: 0.68] and - 11.5 [95% CI: - 19.9, - 3.3; ES: - 0.87] for the AKPS. CONCLUSIONS: This study suggests that spinal manual therapy is more effective than local exercise therapy in improving pain and function in patients with PFPS in the medium term. We suggest for future research to investigate whether combining local exercise therapy and spinal manual therapy is more effective than either single intervention on its own. This clinical trial study was approved by the Medical Ethics Committee METC Z under registration number NL57207.096. and registered retrospectively in ClinicalTrials.gov PRS with registration ID number NCT04748692 on the 10th of February 2021.

Thin-Section CT Features of Idiopathic Pulmonary Fibrosis Correlated with Micro-CT and Histologic Analysis.

Purpose To elucidate the underlying lung changes responsible for the computed tomographic (CT) features of idiopathic pulmonary fibrosis (IPF) and to gain insight into the way IPF proceeds through the lungs and progresses over time. Materials and Methods Micro-CT studies of tissue cores obtained from explant lungs were examined and were correlated 1:1 with a CT study obtained immediately before transplantation. Samples for histologic analysis were obtained from selected cores. Results In areas with no or minimal abnormalities on CT images, small areas of increased attenuation located in or near the interlobular septa can be seen on micro-CT studies. In more involved lung areas, the number of opacities increases and opacities enlarge and approach each other along the interlobular septa, causing a fine reticular pattern on CT images. Simultaneously, air-containing structures in and around these opacities arise, corresponding with small cysts on CT images. Honeycombing is caused by a progressive increase in the number and size of these cystic structures and tissue opacities that gradually extend toward the centrilobular region and finally replace the entire lobule. At histologic analysis, the small islands of increased attenuation very likely correspond with fibroblastic foci. Near these fibroblastic foci, an abnormal adjacency of alveolar walls was seen, suggesting alveolar collapse. In later stages, normal lung tissue is replaced by a large amount of young collagen, as seen in patients with advanced fibrosis. Conclusion Fibrosis and cyst formation in patients with IPF seem to start at the periphery of the pulmonary lobule and progressively extend toward the core of this anatomic lung unit. Evidence was found that alveolar collapse might already be present in an early stage when there is only little pulmonary fibrosis. © RSNA, 2016.

The site and nature of airway obstruction after lung transplantation.

RATIONALE: The chronic rejection of lung allografts is attributable to progressive small airway obstruction. OBJECTIVES: To determine precisely the site and nature of this type of airway obstruction. METHODS: Lungs from patients with rejected lung allografts treated by a second transplant (n = 7) were compared with unused donor (control) lungs (n = 7) using multidetector computed tomography (MDCT) to determine the percentage of visible airways obstructed in each airway generation, micro-computed tomography (microCT) to visualize the site of obstruction, and histology to determine the nature of this obstruction. MEASUREMENTS AND MAIN RESULTS: The number of airways visible with MDCT was not different between rejected and control lungs. However, 10 ± 7% of observed airways greater than 2 mm in diameter, 50 ± 22% of airways between 1 and 2 mm in diameter, and 73 ± 10% of airways less than 1 mm in diameter were obstructed in the rejected lungs. MicroCT confirmed that the mean lumen diameter of obstructed airways was 647 ± 317 µm but showed no difference in either total number and cross-sectional area of the terminal bronchioles or in alveolar dimensions (mean linear intercept) between groups (P > 0.05). In addition, microCT demonstrated that only segments of the airways are obstructed. Histology confirmed a constrictive form of bronchiolitis caused by expansion of microvascular-rich granulation tissue in some locations and collagen-rich scar tissue in others. CONCLUSIONS: Chronic lung allograft rejection is associated with a progressive form of constrictive bronchiolitis that targets conducting airways while sparing larger airways as well as terminal bronchioles and the alveolar surface.

The impact of being overweight or obese on 12 month clinical recovery in patients following lumbar microdiscectomy for radiculopathy.

BACKGROUND CONTEXT: The proportion of patients who undergo lumbar microdiscectomy due to lumbar radiculopathy who are also overweight or obese is high. However, whether high body mass index (BMI) affects clinical outcomes is not well-studied. PURPOSE: To investigate the difference in the clinical course between normal weight, overweight, and obese patients with radiculopathy who underwent lumbar microdiscectomy followed by physical therapy and to evaluate whether high BMI is associated with poor recovery. STUDY DESIGN/SETTING: A prospective cohort study with a 12-month follow-up was conducted in a multidisciplinary clinic. PATIENT SAMPLE: We included 583 patients (median [IQR] age: 45 [35-52] years; 41% female) with clinical signs and symptoms of lumbar radiculopathy, consistent with magnetic resonance imaging findings, who underwent microdiscectomy followed by postoperative physical therapy. OUTCOME MEASURES: Outcomes were leg pain and back pain intensity measured with a visual analogue scale, disability measured with the Roland Morris Disability Questionnaire at 3 and 12-month follow-ups, and complications. METHODS: Patients were classified as being normal weight (46.9%), overweight (38.4%), or obese (14.7%). A linear mixed-effects model was used to assess the difference in the clinical course of pain and disability between the three BMI categories. The association between BMI and outcomes was evaluated using univariable and multivariable logistic regression analyses. RESULTS: All three patient groups experienced a significant improvement in leg pain, back pain, and disability over 3 and 12-month follow-up. Patients who were overweight, obese, or normal weight experienced comparable leg pain (p=.14) and disability (p=.06) over the clinical course (p=.14); however, obese patients experienced higher back pain (MD=-6.81 [95%CI: -13.50 to -0.14]; p=.03). The difference in back pain scores was not clinically relevant. CONCLUSIONS: In the first year following lumbar microdiscectomy, patients demonstrated clinical improvements and complications that were unrelated to their preoperative BMI.

Variability in recovery following microdiscectomy and postoperative physiotherapy for lumbar radiculopathy: A latent class trajectory analysis.

OBJECTIVES: The clinical course of lumbar radiculopathy following microdiscectomy and post-operative physiotherapy varies substantially. No prior studies assessed this variability by deriving outcome trajectories. The primary aims of this study were to evaluate the variability in long-term recovery after lumbar microdiscectomy followed by post-operative physiotherapy and to identify outcome trajectories. The secondary aim was to assess whether demographic, clinical characteristics and patient-reported outcome measures routinely collected at baseline could predict poor outcome trajectories. METHODS: We conducted a prospective cohort study with a 24-month follow-up. We included 479 patients with clinical signs and symptoms of lumbar radiculopathy confirmed by Magnetic Resonance Imaging findings, who underwent microdiscectomy and post-operative physiotherapy. Outcomes were leg pain and back pain measured with Visual Analogue Scales, and disability measured with the Roland-Morris Disability Questionnaire. Descriptive statistics were performed to present the average and the individual clinical course. A latent class trajectory analysis was conducted to identify leg pain, back pain, and disability outcome trajectories. The best number of clusters was determined using the Bayesian Information Criterion, Akaike's information criteria, entropy, and overall interpretability. Prediction models for poor outcome trajectories were assessed using multivariable logistic regression analyses. RESULTS: Several outcome trajectories were identified. Most patients were assigned to the 'large improvement' trajectory (leg pain: 79.3%; back pain: 70.2%; disability: 59.5% of patients). Smaller proportions of patients were assigned to the 'moderate improvement' trajectory (leg pain: 7.9%; back pain: 10.6%; disability: 20.7% of patients), the 'minimal improvement' trajectory (leg pain: 4.9%, back pain: 6.7%, disability: 16.3% of patients) and the 'relapse' trajectory (leg pain: 7.9%; back pain: 12.5%; disability: 3.5%). Approximately one-third of patients (32.6%) belonged to one or more than one poor outcome trajectory. Patients with previous treatment (prior back surgery, injection therapy, and medication use) and those who had higher baseline pain and disability scores were more likely to belong to the poor outcome trajectories in comparison to the large improvement trajectories in back pain, leg pain and disability, and the moderate improvement trajectory in disability. The explained variance (Nagelkerke R2) of the prediction models ranged from 0.06 to 0.13 and the discriminative ability (Area Under the Curve) from 0.66 to 0.73. CONCLUSION: The clinical course of lumbar radiculopathy varied following microdiscectomy and post-operative physiotherapy, and several outcome trajectories could be identified. Although most patients were allocated to favorable trajectories, one in three patients was assigned to one or more poor outcome trajectories following microdiscectomy and post-operative physiotherapy for lumbar radiculopathy. Routinely gathered data were unable to predict the poor outcome trajectories accurately. Prior to surgery, clinicians should discuss the high variability and the distinctive subgroups that are present in the clinical course with their patients.

A Clinical Journey Mobile Health App for Perioperative Patients: Cross-sectional Study.

BACKGROUND: Mobile eHealth apps are important tools in personal health care management. The Patient Journey app was developed to inform patients with musculoskeletal disorders during their perioperative period. The app contains timely information, video exercises, and functional tasks. Although the Patient Journey app and other health apps are widely used, little research is available on how patients appreciate these apps. OBJECTIVE: The primary aim of this study was to evaluate the user-friendliness of the Patient Journey app in terms of its usability and the attitudes of users toward the app. The secondary aim was to evaluate positive and negative user experiences. METHODS: A web-based questionnaire was sent to 2114 patients scheduled for surgery for a musculoskeletal disorder. Primary outcomes were usability (measured with the System Usability Scale) and user attitudes regarding the Patient Journey app (assessed with the second part of the eHealth Impact Questionnaire). The secondary outcomes were evaluated with multiple choice questions and open-ended questions, which were analyzed via inductive thematic content analyses. RESULTS: Of the 940 patients who responded, 526 used the Patient Journey app. The usability of the app was high (System Usability Scale: median 85.0, IQR 72.5-92.5), and users had a positive attitude toward the Information and Presentation provided via the app (eHealth Impact Questionnaire: median 78.0, IQR 68.8-84.4). The app did not adequately improve the users' confidence in discussing health with others (eHealth Impact Questionnaire: median 63.9, IQR 50.0-75.0) or motivation to manage health (eHealth Impact Questionnaire: median 61.1, IQR 55.6-72.2). Three core themes emerged regarding positive and negative user experiences: (1) content and information, (2) expectations and experiences, and (3) technical performance. Users experienced timely information and instructions positively and found that the app prepared and guided them optimally through the perioperative period. Negative user experiences were overly optimistic information, scarcely presented information about pain (medication), lack of reference data, insufficient information regarding clinical course deviations and complications, and lack of interaction with clinicians. CONCLUSIONS: The Patient Journey app is a usable, informative, and presentable tool to inform patients with musculoskeletal disorders during their perioperative period. The qualitative analyses identified aspects that can further improve the user experiences of the app.

Clinical use of biomarkers of survival in pulmonary fibrosis.

BACKGROUND: Biologic predictors or biomarkers of survival in pulmonary fibrosis with a worse prognosis, more specifically in idiopathic pulmonary fibrosis would help the clinician in deciding whether or not to treat since treatment carries a potential risk for adverse events. These decisions are made easier if accurate and objective measurements of the patients' clinical status can predict the risk of progression to death. METHOD: A literature review is given on different biomarkers of survival in interstitial lung disease, mainly in IPF, since this disease has the worst prognosis. CONCLUSION: Serum biomarkers, and markers measured by medical imaging as HRCT, pertechnegas, DTPA en FDG-PET are not ready for clinical use to predict mortality in different forms of ILD. A baseline FVC, a change of FVC of more than 10%, and change in 6MWD are clinically helpful predictors of survival.

Baseline Patient Characteristics Commonly Captured Before Surgery Do Not Accurately Predict Long-Term Outcomes of Lumbar Microdiscectomy Followed by Physiotherapy.

STUDY DESIGN: Prospective cohort study. OBJECTIVE: To develop and internally validate prognostic models based on commonly collected preoperative data for good and poor outcomes of lumbar microdiscectomy followed by physiotherapy. SUMMARY OF BACKGROUND DATA: Lumbar microdiscectomy followed by physiotherapy is a common intervention for lumbar radiculopathy. Postoperatively, a considerable percentage of people continues to experience pain and disability. Prognostic models for recovery are scarce. METHODS: We included 298 patients with lumbar radiculopathy who underwent microdiscectomy followed by physiotherapy. Primary outcomes were recovery and secondary outcomes were pain and disability at 12 months follow-up. Potential prognostic factors were selected from sociodemographic and biomedical data commonly captured preoperatively. The association between baseline characteristics and outcomes was evaluated using multivariable logistic regression analyses. RESULTS: At 12 months follow-up, 75.8% of the participants met the criterion for recovery. Variables in the model for good recovery included: younger age, leg pain greater than back pain, high level of disability, and a disc herniation at another level than L3-L4. The model for poor recovery included: lower educational level, prior back surgery, and disc herniation at L3-L4. Following internal validation, the explained variance (Nagelkerke R) and area under the curve for both models were poor (≤0.02 and ≤0.60, respectively). The discriminative ability of the models for disability and pain were also poor. CONCLUSION: The outcome of microdiscectomy followed by postoperative physiotherapy cannot be predicted accurately by commonly captured preoperative sociodemographic and biomedical factors. The potential value of other biomedical, personal, and external factors should be further investigated. LEVEL OF EVIDENCE: 3.

Small airways pathology in idiopathic pulmonary fibrosis: a retrospective cohort study.

BACKGROUND: The observation that patients with idiopathic pulmonary fibrosis (IPF) can have higher than normal expiratory flow rates at low lung volumes led to the conclusion that the airways are spared in IPF. This study aimed to re-examine the hypothesis that airways are spared in IPF using a multiresolution imaging protocol that combines multidetector CT (MDCT), with micro-CT and histology. METHODS: This was a retrospective cohort study comparing explanted lungs from patients with severe IPF treated by lung transplantation with a cohort of unused donor (control) lungs. The donor control lungs had no known lung disease, comorbidities, or structural lung injury, and were deemed appropriate for transplantation on review of the clinical files. The diagnosis of IPF in the lungs from patients was established by a multidisciplinary consensus committee according to existing guidelines, and was confirmed by video-assisted thoracic surgical biopsy or by pathological examination of the contralateral lung. The control and IPF groups were matched for age, sex, height, and bodyweight. Samples of lung tissue were compared using the multiresolution imaging approach: a cascade of clinical MDCT, micro-CT, and histological imaging. We did two experiments: in experiment 1, all the lungs were randomly sampled; in experiment 2, samples were selected from regions of minimal and established fibrosis. The patients and donors were recruited from the Katholieke Universiteit Leuven (Leuven, Belgium) and the University of Pennsylvania Hospital (Philadelphia, PA, USA). The study took place at the Katholieke Universiteit Leuven, and the University of British Columbia (Vancouver, BC, Canada). FINDINGS: Between Oct 5, 2009, and July 22, 2016, explanted lungs from patients with severe IPF (n=11), were compared with a cohort of unused donor (control) lungs (n=10), providing 240 samples of lung tissue for comparison using the multiresolution imaging approach. The MDCT specimen scans show that the number of visible airways located between the ninth generation (control 69 [SD 22] versus patients with IPF 105 [33], p=0·0023) and 14th generation (control 9 [6] versus patients with IPF 49 [28], p<0·0001) of airway branching are increased in patients with IPF, which we show by micro-CT is due to thickening of their walls and distortion of their lumens. The micro-CT analysis showed that compared with healthy (control) lung anatomy (mean 5·6 terminal bronchioles per mL [SD 1·6]), minimal fibrosis in IPF tissue was associated with a 57% loss of the terminal bronchioles (mean 2·4 terminal bronchioles per mL [SD 1·0]; p<0·0001), the appearance of fibroblastic foci, and infiltration of the tissue by inflammatory immune cells capable of forming lymphoid follicles. Established fibrosis in IPF tissue had a similar reduction (66%) in the number of terminal bronchioles (mean 1·9 terminal bronchioles per mL [SD 1·4]; p<0·0001) and was dominated by increased airspace size, Ashcroft fibrosis score, and volume fractions of tissue and collagen. INTERPRETATION: Small airways disease is a feature of IPF, with significant loss of terminal bronchioles occuring within regions of minimal fibrosis. On the basis of these findings, we postulate that the small airways could become a potential therapeutic target in IPF. FUNDING: Katholieke Universiteit Leuven, US National Institutes of Health, BC Lung Association, and Genentech.

Multiplex protein profiling of bronchoalveolar lavage in idiopathic pulmonary fibrosis and hypersensitivity pneumonitis.

CONTEXT: Idiopathic pulmonary fibrosis (IPF) and chronic hypersensitivity pneumonitis (HP) are diffuse parenchymal lung diseases characterized by a mixture of inflammation and fibrosis, leading to lung destruction and finally death. AIMS: The aim of this study was to compare different pathophysiological mechanisms, such as angiogenesis, coagulation, fibrosis, tissue repair, inflammation, epithelial damage, oxidative stress, and matrix remodeling, in both disorders using bronchoalveolar lavage (BAL). METHODS: at diagnosis, patients underwent bronchoscopy with BAL and were divided into three groups: Control (n = 10), HP (n = 11), and IPF (n = 11), based on multidisciplinary approach (clinical examination, radiology, and histology): Multiplex searchlight technology was used to analyze 25 proteins representative for different pathophysiological processes: Eotaxin, basic fibroblast growth factor (FGFb), fibronectin, hepatocyte growth factor (HGF), interleukine (IL)-8, IL-12p40, IL-17, IL-23, monocyte chemotactic protein (MCP-1), macrophage-derived chemokine (MDC), myeloperoxidase (MPO), matrix metalloproteinase (MMP)-8, MMP-9, active plasminogen activating inhibitor 1 (PAI-1), pulmonary activation regulated chemokine (PARC), placental growth factor (PlGF), protein-C, receptor for advanced glycation end products (RAGE), regulated on activation normal T cells expressed and secreted (RANTES), surfactant protein-C (SP-C), transforming growth factor-ß1 (TGF-ß1), tissue inhibitor of metalloproteinase-1 (TIMP-1), tissue factor, thymic stromal lymphopoietin (TSLP), and vascular endothelial growth factor (VEGF). RESULTS: All patients suffered from decreased pulmonary function and abnormal BAL cell differential compared with control. Protein levels were increased in both IPF and HP for MMP-8 (P = 0.022), MMP-9 (P = 0.0020), MCP-1 (P = 0.0006), MDC (P = 0.0048), IL-8 (P = 0.013), MPO (P = 0.019), and protein-C (P = 0.0087), whereas VEGF was decreased (P = 0.0003) compared with control. HGF was upregulated in HP (P = 0.0089) and active PAI-1 was upregulated (P = 0.019) in IPF compared with control. Differences in expression between IPF and HP were observed for IL-12p40 (P = 0.0093) and TGF-ß1 (P = 0.0045). CONCLUSIONS: Using BAL, we demonstrated not only expected similarities but also important differences in both disorders, many related to the innate immunity. These findings provide new clues for further research in both disorders.

Chronic rejection pathology after orthotopic lung transplantation in mice: the development of a murine BOS model and its drawbacks.

Almost all animal models for chronic rejection (CR) after lung transplantation (LTx) fail to resemble the human situation. It was our attempt to develop a representative model of CR in mice. Orthotopic LTx was performed in allografts receiving daily immunosuppression with steroids and cyclosporine. Controls included isografts and mice only undergoing thoracotomy (SHAM). Allografts were sacrificed 2, 4, 6, 8, 10 or 12 weeks after LTx. Pulmonary function was measured repeatedly in the 12w allografts, isografts and SHAM mice. Histologically, all allografts demonstrated acute rejection (AR) around the blood vessels and airways two weeks after LTx. This decreased to 50-75% up to 10 weeks and was absent after 12 weeks. Obliterative bronchiolitis (OB) lesions were observed in 25-50% of the mice from 4-12 weeks. Isografts and lungs of SHAM mice were normal after 12 weeks. Pulmonary function measurements showed a decline in FEV(0.1), TLC and compliance in the allografts postoperatively (2 weeks) with a slow recovery over time. After this initial decline, lung function of allografts increased more than in isografts and SHAM mice indicating that pulmonary function measurement is not a good tool to diagnose CR in a mouse. We conclude that a true model for CR, with clear OB lesions in about one third of the animals, but without a decline in lung function, is possible. This model is an important step forward in the development of an ideal model for CR which will open new perspectives in unraveling CR pathogenesis and exploring new treatment options.

Azithromycin decreases MMP-9 expression in the airways of lung transplant recipients.

The neomacrolide antibiotic azithromycin is known to have an anti-inflammatory effect and is increasingly being used in the treatment of chronic inflammatory pulmonary diseases. We investigated whether azithromycin influenced matrix remodeling. Matrix metalloproteinase (MMP)-9 protein levels were measured by ELISA in bronchoalveolar lavaga fluid in 10 stable patients and in 10 lung transplant patients suffering from nCLAD/NRAD. MMP-9 was measured via ELISA before and after 3 to 6 months of azithromycin therapy. We further elaborated on the role of MMP-9 by performing gelatin-zymography and gelatinolytic activity assays. Differential and total cell counts on BAL were performed in all cases. The nCLAD/NRAD patients showed higher airway neutrophilia (p<0.0001), ELISA MMP-9 (p<0.0001), zymography proMMP-9 (p<0.0001), activated MMP-9 (p=0.0003) and gelatinolytic activity (p=0.0002) compared to the control group. Airway neutrophilia in the nCLAD/NRAD group significantly decreased after 3-6 months of treatment with azithromycin (p=0.0020). This was associated with a decrease in ELISA MMP-9 levels (p=0.0059), in activated MMP-9 shown on zymography (p=0.016) and in gelatinolytic activity (p=0.031). Remarkably, proMMP-9 levels were not altered by azithromycin. Although azithromycin significantly reduced ELISA MMP-9 levels and gelatinolytic activity in transplant patients, these levels remained higher compared to control patients (p=0.0011 and p=0.043). Neutrophil counts, activated MMP-9 and gelatinolytic activity levels in nCLAD/NRAD decreased after azithromycin treatment, but some remained elevated compared to control patients. This illustrates that treatment with azithromycin did not completely restore chronic inflammation in the airways and suggested that preventive therapy may yield added value to curative therapy.