The Effect of a Short Duration, High Intensity Exercise Intervention on Gait Biomechanics in Patients With COPD: Findings From a Pilot Study

Previous work has shown that patients with chronic obstructive pulmonary disease (COPD) demonstrate changes in their gait biomechanics as compared to controls. This pilot study was designed to explore the possibility that biomechanical alterations present in COPD patients might be amenable to treatment by exercise training of skeletal muscle. This study investigated the effect of a 6-week exercise intervention on gait biomechanics in patients with COPD under both a rest and a non-rested condition. Seven patients with COPD underwent a supervised cardio-respiratory and strength training protocol 2-3 times per week for 6-weeks for a total of 16-sessions. Spatiotemporal, kinematic and kinetic gait variables were collected prior to and post intervention. All patients demonstrated significant improvements in strength following the intervention. The knee joint biomechanics demonstrated a significant main effect for intervention and for condition. Step width demonstrated a significant interaction as it decreased from pre- to post-intervention under the rest condition and increased under the non-rested condition. It does appear that being pushed (non-rested) has a strong influence at the knee joint. The quadriceps muscles, the primary knee extensors, have been shown to demonstrate muscular abnormalities in patients with COPD and the intervention may have influenced gait patterns through an effect on this skeletal muscle structure and function. Additionally, the intervention influenced step width closer to a more healthy value. Patients with COPD are more likely to fall and step width is a risk factor for falling suggesting the intervention may address fall risk. Whether a longer duration intervention would have more profound effects remains to be tested

Walking abnormalities are associated with COPD: An investigation of the NHANES III dataset

Research on the peripheral effects of COPD has focused on physiological and structural changes. However, different from muscular weakness or decreased physical activity, mechanical abnormalities of the muscular system, e.g. walking, have yet to be investigated. Our purpose was to utilize the National Health and Nutritional Examination Survey (NHANES) dataset to determine whether walking abnormalities are associated with COPD severity. To determine if walking abnormalities were independently associated with COPD severity, our analysis aimed to investigate the association of physical activity levels with COPD severity and with walking abnormalities. The NHANES III dataset that contains data for 31,000 persons that were collected from 1988 to 1994, was used to explore the association of COPD severity on gross walking abnormalities, i.e. limp, shuffle, etc. Logistic regression models were created using FEV1/FVC ratio, age, gender, BMI, and smoking status as predictors of walking abnormalities and physical activity in persons aged 40 to 90 years old. Results demonstrated a significant correlation between the presence of walking abnormalities and severe COPD (odds ratio: 1.97; 95% CI: 1.1 to 3.5). This suggests that disease severity can contribute to mechanical outcomes of patients with COPD. In addition, decreased physical activity levels were significantly associated with all COPD severity levels with the exception of mild COPD. The association between altered gait and COPD status may be due to the presence of physical inactivity that is present in patients with COPD. Future research directions should include investigating more closely the mechanical outcomes of persons with COPD

The Melanocortin-4 Receptor Integrates Circadian Light Cues and Metabolism

The melanocortin system directs diverse physiological functions from coat color to body weight homoeostasis. A commonality among melanocortin-mediated processes is that many animals modulate similar processes on a circannual basis in response to longer, summer days, suggesting an underlying link between circadian biology and the melanocortin system. Despite key neuroanatomical substrates shared by both circadian and melanocortin-signaling pathways, little is known about the relationship between the two. Here we identify a link between circadian disruption and the control of glucose homeostasis mediated through the melanocortin-4 receptor (Mc4r). Mc4r-deficient mice exhibit exaggerated circadian fluctuations in baseline blood glucose and glucose tolerance. Interestingly, exposure to lighting conditions that disrupt circadian rhythms improve their glucose tolerance. This improvement occurs through an increase in glucose clearance by skeletal muscle and is food intake and body weight independent. Restoring Mc4r expression to the paraventricular nucleus prevents the improvement in glucose tolerance, supporting a role for the paraventricular nucleus in the integration of circadian light cues and metabolism. Altogether these data suggest that Mc4r signaling plays a protective role in minimizing glucose fluctuations due to circadian rhythms and environmental light cues and demonstrate a previously undiscovered connection between circadian biology and glucose metabolism mediated through the melanocortin system

Gait mechanics in patients with chronic obstructive pulmonary disease

Background Chronic obstructive pulmonary disease (COPD) is characterized by the frequent association of disease outside the lung. The objective of this study was to determine the presence of biomechanical gait abnormalities in COPD patients compared to healthy controls while well rested and without rest. Methods Patients with COPD (N = 17) and aged-matched, healthy controls (N = 21) walked at their self-selected pace down a 10-meter walkway while biomechanical gait variables were collected. A one-minute rest was given between each of the five collected trials to prevent tiredness (REST condition). Patients with COPD then walked at a self-selected pace on a treadmill until the onset of self-reported breathlessness or leg tiredness. Subjects immediately underwent gait analysis with no rest between each of the five collected trials (NO REST condition). Statistical models with and without covariates age, gender, and smoking history were used. Results After adjusting for covariates, COPD patients demonstrated more ankle power absorption in mid-stance (P = 0.006) than controls during both conditions. Both groups during NO REST demonstrated increased gait speed (P = 0.04), stride length (P = 0.03), and peak hip flexion (P = 0.04) with decreased plantarflexion moment (P = 0.04) and increased knee power absorption (P = 0.04) as compared to REST. A significant interaction revealed that peak ankle dorsiflexion moment was maintained from REST to NO REST for COPD but increased for controls (P \u3c 0.01). Stratifying by disease severity did not alter these findings, except that step width decreased in NO REST as compared to REST (P = 0.01). Standardized effect sizes of significant effects varied from 0.5 to 0.98. Conclusions Patients with COPD appear to demonstrate biomechanical gait changes at the ankle as compared to healthy controls. This was seen not only in increased peak ankle power absorption during no rest but was also demonstrated by a lack of increase in peak ankle dorsiflexion moment from the REST to the NO REST condition as compared to the healthy controls. Furthermore, a wider step width has been associated with fall risk and this could account for the increased incidence of falls in patients with COPD

Pneumococcal Colonisation Rates in Patients Admitted to a UK Hospital with Lower Respiratory Tract Infection - a prospective case-control study

BACKGROUND Current diagnostic tests are ineffective at identifying the aetiological pathogen in hospitalised adults with lower respiratory tract infection (LRTI). The association of pneumococcal colonisation with disease has been suggested as a means to increase diagnostic precision. We compared pneumococcal colonisation rate and density of nasal pneumococcal colonisation by a) classical culture and b) quantitative real time lytA Polymerase Chain Reaction (qPCR) in patients admitted to hospital in the UK with LRTI compared to control patients. METHODS 826 patients were screened for inclusion in this prospective case-control study. 38 patients were recruited, 19 with confirmed LRTI and 19 controls with another diagnosis. Nasal wash (NW) was collected at the time of recruitment. RESULTS Pneumococcal colonisation was detected in 1 LRTI patient and 3 controls (p=0.6) by classical culture. Using qPCR pneumococcal colonisation was detected in 10 LRTI patients and 8 controls (p=0.5). Antibiotic usage prior to sampling was significantly higher in the LRTI than control group 19 v. 3 (p8000 copies/ml on qPCR pneumococcal colonisation was found in 3 LRTI patients and 4 controls (p > 0.05). CONCLUSIONS We conclude that neither prevalence nor density of nasal pneumococcal colonisation (by culture and qPCR) can be used as a method of microbiological diagnosis in hospitalised adults with LRTI in the UK. A community based study recruiting patients prior to antibiotic therapy may be a useful future step

CHCHD4 confers metabolic vulnerabilities to tumour cells through its control of the mitochondrial respiratory chain.

BACKGROUND: Tumour cells rely on glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) to survive. Thus, mitochondrial OXPHOS has become an increasingly attractive area for therapeutic exploitation in cancer. However, mitochondria are required for intracellular oxygenation and normal physiological processes, and it remains unclear which mitochondrial molecular mechanisms might provide therapeutic benefit. Previously, we discovered that coiled-coil-helix-coiled-coil-helix domain-containing protein 4 (CHCHD4) is critical for regulating intracellular oxygenation and required for the cellular response to hypoxia (low oxygenation) in tumour cells through molecular mechanisms that we do not yet fully understand. Overexpression of CHCHD4 in human cancers correlates with increased tumour progression and poor patient survival. RESULTS: Here, we show that elevated CHCHD4 expression provides a proliferative and metabolic advantage to tumour cells in normoxia and hypoxia. Using stable isotope labelling with amino acids in cell culture (SILAC) and analysis of the whole mitochondrial proteome, we show that CHCHD4 dynamically affects the expression of a broad range of mitochondrial respiratory chain subunits from complex I-V, including multiple subunits of complex I (CI) required for complex assembly that are essential for cell survival. We found that loss of CHCHD4 protects tumour cells from respiratory chain inhibition at CI, while elevated CHCHD4 expression in tumour cells leads to significantly increased sensitivity to CI inhibition, in part through the production of mitochondrial reactive oxygen species (ROS). CONCLUSIONS: Our study highlights an important role for CHCHD4 in regulating tumour cell metabolism and reveals that CHCHD4 confers metabolic vulnerabilities to tumour cells through its control of the mitochondrial respiratory chain and CI biology

CHCHD4 regulates tumour proliferation and EMT-related phenotypes, through respiratory chain-mediated metabolism

Abstract: Background: Mitochondrial oxidative phosphorylation (OXPHOS) via the respiratory chain is required for the maintenance of tumour cell proliferation and regulation of epithelial to mesenchymal transition (EMT)-related phenotypes through mechanisms that are not fully understood. The essential mitochondrial import protein coiled-coil helix coiled-coil helix domain-containing protein 4 (CHCHD4) controls respiratory chain complex activity and oxygen consumption, and regulates the growth of tumours in vivo. In this study, we interrogate the importance of CHCHD4-regulated mitochondrial metabolism for tumour cell proliferation and EMT-related phenotypes, and elucidate key pathways involved. Results: Using in silico analyses of 967 tumour cell lines, and tumours from different cancer patient cohorts, we show that CHCHD4 expression positively correlates with OXPHOS and proliferative pathways including the mTORC1 signalling pathway. We show that CHCHD4 expression significantly correlates with the doubling time of a range of tumour cell lines, and that CHCHD4-mediated tumour cell growth and mTORC1 signalling is coupled to respiratory chain complex I (CI) activity. Using global metabolomics analysis, we show that CHCHD4 regulates amino acid metabolism, and that CHCHD4-mediated tumour cell growth is dependent on glutamine. We show that CHCHD4-mediated tumour cell growth is linked to CI-regulated mTORC1 signalling and amino acid metabolism. Finally, we show that CHCHD4 expression in tumours is inversely correlated with EMT-related gene expression, and that increased CHCHD4 expression in tumour cells modulates EMT-related phenotypes. Conclusions: CHCHD4 drives tumour cell growth and activates mTORC1 signalling through its control of respiratory chain mediated metabolism and complex I biology, and also regulates EMT-related phenotypes of tumour cells

Can machine-learning improve cardiovascular risk prediction using routine clinical data

BackgroundCurrent approaches to predict cardiovascular risk fail to identify many people who would benefit from preventive treatment, while others receive unnecessary intervention. Machine-learning offers opportunity to improve accuracy by exploiting complex interactions between risk factors. We assessed whether machine-learning can improve cardiovascular risk prediction.MethodsProspective cohort study using routine clinical data of 378,256 patients from UK family practices, free from cardiovascular disease at outset. Four machine-learning algorithms (random forest, logistic regression, gradient boosting machines, neural networks) were compared to an established algorithm (American College of Cardiology guidelines) to predict first cardiovascular event over 10-years. Predictive accuracy was assessed by area under the ‘receiver operating curve’ (AUC); and sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) to predict 7.5% cardiovascular risk (threshold for initiating statins).Findings24,970 incident cardiovascular events (6.6%) occurred. Compared to the established risk prediction algorithm (AUC 0.728, 95% CI 0.723–0.735), machine-learning algorithms improved prediction: random forest +1.7% (AUC 0.745, 95% CI 0.739–0.750), logistic regression +3.2% (AUC 0.760, 95% CI 0.755–0.766), gradient boosting +3.3% (AUC 0.761, 95% CI 0.755–0.766), neural networks +3.6% (AUC 0.764, 95% CI 0.759–0.769). The 78 highest achieving (neural networks) algorithm predicted 4,998/7,404 cases (sensitivity79 67.5%, PPV 18.4%) and 53,458/75,585 non-cases (specificity 70.7%, NPV 95.7%), correctly predicting 355 (+7.6%) more patients who developed cardiovascular disease compared to the established algorithm.ConclusionsMachine-learning significantly improves accuracy of cardiovascular risk prediction, increasing the number of patients identified who could benefit from preventive treatment, while avoiding unnecessary treatment of others

Community Education on MTM Services

Background: Medication nonadherence, defined as “the number of doses not taken or taken incorrectly that jeopardizes the patient’s therapeutic outcome,” is a major health problem with about 43% of the general population nonadherent to their medications. Medication nonadherence accounts for an estimated 125,000 deaths per year in the US, 33-69% of medication-related hospital readmissions, and an estimated $100 to$300 billion in direct and indirect medical costs. Medication therapy management (MTM), defined as “a distinct service or group of services that optimize therapeutic outcomes for individual patients,” has been found to reduce medication nonadherence. However, many individuals eligible for MTM services are not aware of the resource available to them and do not believe the service will be beneficial to them. Objectives: A pre post observational study design will be used to determine the effects of two types of educational interventions on MTM of patient’s perceptions of MTM and enrollment in MTM services. Methodology: Participants will be divided into two intervention groups. All participants will complete a pre survey to assess current perceptions of MTM services. One group will attend a community educational event on MTM, and the second group will receive an educational brochure in the mail. All participants will complete a post survey to reassess perceptions of MTM after the educational intervention. In addition, all participants will be tracked to determine future enrollment in an MTM service. Analysis: Descriptive tests and paired t-tests/Wilcoxon Signed Rank tests will be run on data acquired from pre and post surveys. Unpaired t-tests/Mann Whitney and chi-square tests will be run to compare data between intervention groups. Descriptive tests will be run on data acquired from tracking enrollment