Summary
Neurodegenerative diseases, the leading cause of morbidity and disability, are gaining increased attention as they impose a considerable socioeconomic impact, due in part to the ageing ...community. Neuronal damage is a pathological hallmark of Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, Huntington's disease, spinocerebellar ataxia and multiple sclerosis, although such damage is also observed following neurotropic viral infections, stroke, genetic white matter diseases and paraneoplastic disorders. Despite the different aetiologies, for example, infections, genetic mutations, trauma and protein aggregations, neuronal damage is frequently associated with chronic activation of an innate immune response in the CNS. The growing awareness that the immune system is inextricably involved in shaping the brain during development as well as mediating damage, but also regeneration and repair, has stimulated therapeutic approaches to modulate the immune system in neurodegenerative diseases. Here, we review the current understanding of how astrocytes and microglia, as well as neurons and oligodendrocytes, shape the neuroimmune response during development, and how aberrant responses that arise due to genetic or environmental triggers may predispose the CNS to neurodegenerative diseases. We discuss the known interactions between the peripheral immune system and the brain, and review the current concepts on how immune cells enter and leave the CNS. A better understanding of neuroimmune interactions during development and disease will be key to further manipulating these responses and the development of effective therapies to improve quality of life, and reduce the impact of neuroinflammatory and degenerative diseases.
Here, we review the current understanding of how astrocytes and microglia, as well as neurons and oligodendrocytes, shape the neuroimmune response during development, and how aberrant responses that arise due to genetic or environmental triggers may predispose the CNS to neurodegenerative diseases. We discuss the known interactions between the peripheral immune system and the brain, and review the current concepts on how immune cells enter and leave the CNS. A better understanding of neuroimmune interactions during development and disease will be key to further manipulating these responses and the development of effective therapies to improve quality of life, and reduce the impact of neuroinflammatory and degenerative diseases.
Background
Self management interventions help patients with chronic obstructive pulmonary disease (COPD) acquire and practise the skills they need to carry out disease‐specific medical regimens, ...guide changes in health behaviour and provide emotional support to enable patients to control their disease. Since the first update of this review in 2007, several studies have been published. The results of the second update are reported here.
Objectives
1. To evaluate whether self management interventions in COPD lead to improved health outcomes.
2. To evaluate whether self management interventions in COPD lead to reduced healthcare utilisation.
Search methods
We searched the Cochrane Airways Group Specialised Register of trials (current to August 2011).
Selection criteria
Controlled trials (randomised and non‐randomised) published after 1994, assessing the efficacy of self management interventions for individuals with COPD, were included. Interventions with fewer than two contact moments between study participants and healthcare providers were excluded.
Data collection and analysis
Two review authors independently assessed trial quality and extracted data. Investigators were contacted to ask for additional information. When appropriate, study results were pooled using a random‐effects model. The primary outcomes of the review were health‐related quality of life (HRQoL) and number of hospital admissions.
Main results
Twenty‐nine studies were included. Twenty‐three studies on 3189 participants compared self management versus usual care; six studies on 499 participants compared different components of self management on a head‐to‐head basis. Although we included non‐randomised controlled clinical trials as well as RCTs in this review, we restricted the primary analysis to RCTs only and reported these trials in the .
In the 23 studies with a usual care control group, follow‐up time ranged from two to 24 months. The content of the interventions was diverse. A statistically relevant effect of self management on HRQoL was found (St George's Respiratory Questionnaire (SGRQ) total score, mean difference (MD) ‐3.51, 95% confidence interval (CI) ‐5.37 to ‐1.65, 10 studies, 1413 participants, moderate‐quality evidence). Self management also led to a lower probability of respiratory‐related hospitalisations (odds ratio (OR) 0.57, 95% CI 0.43 to 0.75, nine studies, 1749 participants, moderate‐quality evidence) and all cause hospitalisations (OR 0.60; 95% CI 0.40 to 0.89, 6 studies, 1365 participants, moderate‐quality evidence). Over one year of follow‐up, eight (95% CI 5 to 14) participants with a high baseline risk of respiratory‐related hospital admission needed to be treated to prevent one participant with at least one hospital admission, and 20 (95% CI 15 to 35) participants with a low baseline risk of hospitalisation needed to be treated to prevent one participant with at least one respiratory‐related hospital admission.
No statistically significant effect of self management on mortality (OR 0.79, 95% CI 0.58 to 1.07, 8 studies, 2134 participants, very low‐quality evidence) was detected. Also, dyspnoea measured by the (modified) Medical Research Council Scale ((m)MRC) was reduced in individuals who participated in self management (MD ‐0.83, 95% CI ‐1.36 to ‐0.30, 3 studies, 119 participants, low‐quality evidence). The difference in exercise capacity as measured by the six‐minute walking test was not statistically significant (MD 33.69 m, 95% CI ‐9.12 to 76.50, 6 studies, 570 participants, very low‐quality evidence). Subgroup analyses depending on the use of an exercise programme as part of the intervention revealed no statistically significant differences between studies with and without exercise programmes in our primary outcomes of HRQoL and respiratory‐related hospital admissions.
We were unable to pool head‐to‐head trials because of heterogeneity among interventions and controls; thus results are presented narratively within the review.
Authors' conclusions
Self management interventions in patients with COPD are associated with improved health‐related quality of life as measured by the SGRQ, a reduction in respiratory‐related and all cause hospital admissions, and improvement in dyspnoea as measured by the (m)MRC. No statistically significant differences were found in other outcome parameters. However, heterogeneity among interventions, study populations, follow‐up time and outcome measures makes it difficult to formulate clear recommendations regarding the most effective form and content of self management in COPD.
Background
Chronic Obstructive Pulmonary Disease (COPD) self‐management interventions should be structured but personalised and often multi‐component, with goals of motivating, engaging and ...supporting the patients to positively adapt their behaviour(s) and develop skills to better manage disease. Exacerbation action plans are considered to be a key component of COPD self‐management interventions. Studies assessing these interventions show contradictory results. In this Cochrane Review, we compared the effectiveness of COPD self‐management interventions that include action plans for acute exacerbations of COPD (AECOPD) with usual care.
Objectives
To evaluate the efficacy of COPD‐specific self‐management interventions that include an action plan for exacerbations of COPD compared with usual care in terms of health‐related quality of life, respiratory‐related hospital admissions and other health outcomes.
Search methods
We searched the Cochrane Airways Group Specialised Register of trials, trials registries, and the reference lists of included studies to May 2016.
Selection criteria
We included randomised controlled trials evaluating a self‐management intervention for people with COPD published since 1995. To be eligible for inclusion, the self‐management intervention included a written action plan for AECOPD and an iterative process between participant and healthcare provider(s) in which feedback was provided. We excluded disease management programmes classified as pulmonary rehabilitation or exercise classes offered in a hospital, at a rehabilitation centre, or in a community‐based setting to avoid overlap with pulmonary rehabilitation as much as possible.
Data collection and analysis
Two review authors independently assessed trial quality and extracted data. We resolved disagreements by reaching consensus or by involving a third review author. Study authors were contacted to obtain additional information and missing outcome data where possible. When appropriate, study results were pooled using a random‐effects modelling meta‐analysis. The primary outcomes of the review were health‐related quality of life (HRQoL) and number of respiratory‐related hospital admissions.
Main results
We included 22 studies that involved 3,854 participants with COPD. The studies compared the effectiveness of COPD self‐management interventions that included an action plan for AECOPD with usual care. The follow‐up time ranged from two to 24 months and the content of the interventions was diverse.
Over 12 months, there was a statistically significant beneficial effect of self‐management interventions with action plans on HRQoL, as measured by the St. George's Respiratory Questionnaire (SGRQ) total score, where a lower score represents better HRQoL. We found a mean difference from usual care of ‐2.69 points (95% CI ‐4.49 to ‐0.90; 1,582 participants; 10 studies; high‐quality evidence). Intervention participants were at a statistically significant lower risk for at least one respiratory‐related hospital admission compared with participants who received usual care (OR 0.69, 95% CI 0.51 to 0.94; 3,157 participants; 14 studies; moderate‐quality evidence). The number needed to treat to prevent one respiratory‐related hospital admission over one year was 12 (95% CI 7 to 69) for participants with high baseline risk and 17 (95% CI 11 to 93) for participants with low baseline risk (based on the seven studies with the highest and lowest baseline risk respectively).
There was no statistically significant difference in the probability of at least one all‐cause hospital admission in the self‐management intervention group compared to the usual care group (OR 0.74, 95% CI 0.54 to 1.03; 2467 participants; 14 studies; moderate‐quality evidence). Furthermore, we observed no statistically significant difference in the number of all‐cause hospitalisation days, emergency department visits, General Practitioner visits, and dyspnoea scores as measured by the (modified) Medical Research Council questionnaire for self‐management intervention participants compared to usual care participants. There was no statistically significant effect observed from self‐management on the number of COPD exacerbations and no difference in all‐cause mortality observed (RD 0.0019, 95% CI ‐0.0225 to 0.0263; 3296 participants; 16 studies; moderate‐quality evidence). Exploratory analysis showed a very small, but significantly higher respiratory‐related mortality rate in the self‐management intervention group compared to the usual care group (RD 0.028, 95% CI 0.0049 to 0.0511; 1219 participants; 7 studies; very low‐quality evidence).
Subgroup analyses showed significant improvements in HRQoL in self‐management interventions with a smoking cessation programme (MD ‐4.98, 95% CI ‐7.17 to ‐2.78) compared to studies without a smoking cessation programme (MD ‐1.33, 95% CI ‐2.94 to 0.27, test for subgroup differences: Chi² = 6.89, df = 1, P = 0.009, I² = 85.5%). The number of behavioural change techniques clusters integrated in the self‐management intervention, the duration of the intervention and adaptation of maintenance medication as part of the action plan did not affect HRQoL. Subgroup analyses did not detect any potential variables to explain differences in respiratory‐related hospital admissions among studies.
Authors' conclusions
Self‐management interventions that include a COPD exacerbation action plan are associated with improvements in HRQoL, as measured with the SGRQ, and lower probability of respiratory‐related hospital admissions. No excess all‐cause mortality risk was observed, but exploratory analysis showed a small, but significantly higher respiratory‐related mortality rate for self‐management compared to usual care.
For future studies, we would like to urge only using action plans together with self‐management interventions that meet the requirements of the most recent COPD self‐management intervention definition. To increase transparency, future study authors should provide more detailed information regarding interventions provided. This would help inform further subgroup analyses and increase the ability to provide stronger recommendations regarding effective self‐management interventions that include action plans for AECOPD. For safety reasons, COPD self‐management action plans should take into account comorbidities when used in the wider population of people with COPD who have comorbidities. Although we were unable to evaluate this strategy in this review, it can be expected to further increase the safety of self‐management interventions. We also advise to involve Data and Safety Monitoring Boards for future COPD self‐management studies.
Background
Self‐management interventions help people with chronic obstructive pulmonary disease (COPD) to acquire and practise the skills they need to carry out disease‐specific medical regimens, ...guide changes in health behaviour and provide emotional support to enable them to control their disease. Since the 2014 update of this review, several studies have been published.
Objectives
Primary objectives
To evaluate the effectiveness of COPD self‐management interventions compared to usual care in terms of health‐related quality of life (HRQoL) and respiratory‐related hospital admissions. To evaluate the safety of COPD self‐management interventions compared to usual care in terms of respiratory‐related mortality and all‐cause mortality.
Secondary objectives
To evaluate the effectiveness of COPD self‐management interventions compared to usual care in terms of other health outcomes and healthcare utilisation. To evaluate effective characteristics of COPD self‐management interventions.
Search methods
We searched the Cochrane Airways Trials Register, CENTRAL, MEDLINE, EMBASE, trials registries and the reference lists of included studies up until January 2020.
Selection criteria
Randomised controlled trials (RCTs) and cluster‐randomised trials (CRTs) published since 1995. To be eligible for inclusion, self‐management interventions had to include at least two intervention components and include an iterative process between participant and healthcare provider(s) in which goals were formulated and feedback was given on self‐management actions by the participant.
Data collection and analysis
Two review authors independently selected studies for inclusion, assessed trial quality and extracted data. We resolved disagreements by reaching consensus or by involving a third review author. We contacted study authors to obtain additional information and missing outcome data where possible. Primary outcomes were health‐related quality of life (HRQoL), number of respiratory‐related hospital admissions, respiratory‐related mortality, and all‐cause mortality. When appropriate, we pooled study results using random‐effects modelling meta‐analyses.
Main results
We included 27 studies involving 6008 participants with COPD. The follow‐up time ranged from two‐and‐a‐half to 24 months and the content of the interventions was diverse. Participants' mean age ranged from 57 to 74 years, and the proportion of male participants ranged from 33% to 98%. The post‐bronchodilator forced expiratory volume in one second (FEV1) to forced vital capacity (FVC) ratio of participants ranged from 33.6% to 57.0%. The FEV1/FVC ratio is a measure used to diagnose COPD and to determine the severity of the disease. Studies were conducted on four different continents (Europe (n = 15), North America (n = 8), Asia (n = 1), and Oceania (n = 4); with one study conducted in both Europe and Oceania).
Self‐management interventions likely improve HRQoL, as measured by the St. George’s Respiratory Questionnaire (SGRQ) total score (lower score represents better HRQoL) with a mean difference (MD) from usual care of ‐2.86 points (95% confidence interval (CI) ‐4.87 to ‐0.85; 14 studies, 2778 participants; low‐quality evidence). The pooled MD of ‐2.86 did not reach the SGRQ minimal clinically important difference (MCID) of four points. Self‐management intervention participants were also at a slightly lower risk for at least one respiratory‐related hospital admission (odds ratio (OR) 0.75, 95% CI 0.57 to 0.98; 15 studies, 3263 participants; very low‐quality evidence). The number needed to treat to prevent one respiratory‐related hospital admission over a mean of 9.75 months' follow‐up was 15 (95% CI 8 to 399) for participants with high baseline risk and 26 (95% CI 15 to 677) for participants with low baseline risk. No differences were observed in respiratory‐related mortality (risk difference (RD) 0.01, 95% CI ‐0.02 to 0.04; 8 studies, 1572 participants ; low‐quality evidence) and all‐cause mortality (RD ‐0.01, 95% CI ‐0.03 to 0.01; 24 studies, 5719 participants; low‐quality evidence).
We graded the evidence to be of ‘moderate’ to ‘very low’ quality according to GRADE. All studies had a substantial risk of bias, because of lack of blinding of participants and personnel to the interventions, which is inherently impossible in a self‐management intervention. In addition, risk of bias was noticeably increased because of insufficient information regarding a) non‐protocol interventions, and b) analyses to estimate the effect of adhering to interventions. Consequently, the highest GRADE evidence score that could be obtained by studies was ‘moderate’.
Authors' conclusions
Self‐management interventions for people with COPD are associated with improvements in HRQoL, as measured with the SGRQ, and a lower probability of respiratory‐related hospital admissions. No excess respiratory‐related and all‐cause mortality risks were observed, which strengthens the view that COPD self‐management interventions are unlikely to cause harm. By using stricter inclusion criteria, we decreased heterogeneity in studies, but also reduced the number of included studies and therefore our capacity to conduct subgroup analyses. Data were therefore still insufficient to reach clear conclusions about effective (intervention) characteristics of COPD self‐management interventions. As tailoring of COPD self‐management interventions to individuals is desirable, heterogeneity is and will likely remain present in self‐management interventions.
For future studies, we would urge using only COPD self‐management interventions that include iterative interactions between participants and healthcare professionals who are competent using behavioural change techniques (BCTs) to elicit participants' motivation, confidence and competence to positively adapt their health behaviour(s) and develop skills to better manage their disease. In addition, to inform further subgroup and meta‐regression analyses and to provide stronger conclusions regarding effective COPD self‐management interventions, there is a need for more homogeneity in outcome measures. More attention should be paid to behavioural outcome measures and to providing more detailed, uniform and transparently reported data on self‐management intervention components and BCTs. Assessment of outcomes over the long term is also recommended to capture changes in people's behaviour. Finally, information regarding non‐protocol interventions as well as analyses to estimate the effect of adhering to interventions should be included to increase the quality of evidence.
Summary
Communication between the immune system and the central nervous system (CNS) is exemplified by cross‐talk between glia and neurons shown to be essential for maintaining homeostasis. While ...microglia are actively modulated by neurons in the healthy brain, little is known about the cross‐talk between oligodendrocytes and microglia. Oligodendrocytes, the myelin‐forming cells in the CNS, are essential for the propagation of action potentials along axons, and additionally serve to support neurons by producing neurotrophic factors. In demyelinating diseases such as multiple sclerosis, oligodendrocytes are thought to be the victims. Here, we review evidence that oligodendrocytes also have strong immune functions, express a wide variety of innate immune receptors, and produce and respond to chemokines and cytokines that modulate immune responses in the CNS. We also review evidence that during stress events in the brain, oligodendrocytes can trigger a cascade of protective and regenerative responses, in addition to responses that elicit progressive neurodegeneration. Knowledge of the cross‐talk between microglia and oligodendrocytes may continue to uncover novel pathways of immune regulation in the brain that could be further exploited to control neuroinflammation and degeneration.
Background: Comorbidities are known to complicate disease management in patients with Chronic Obstructive Pulmonary Disease (COPD). This is partly due to lack of insight into the interplay of acute ...exacerbations of COPD (AECOPD) and comorbid flare-ups. This study aimed to explore patterns of AECOPDs and comorbid flare-ups. Methods: Data of increased symptoms were extracted from a 12-month daily symptom follow-up database including patients with COPD and comorbidities (chronic heart failure (CHF), anxiety, depression) and transformed to visualizations of AECOPDs and comorbid flare-up patterns over time. Patterns were subsequently categorized using an inductive approach, based on both predominance (ie, which occurs most often) of AECOPDs or comorbid flare-ups, and their simultaneous (ie, simultaneous start in greater than or equal to 50%) occurrence. Results: We included 48 COPD patients (68 + or - 9 years; comorbid CHF: 52%, anxiety: 40%, depression: 38%). In 25 patients with AECOPDs and CHF flare-ups, the following patterns were identified: AECOPDs predominant (n = 14), CHF flare-ups predominant (n = 5), AECOPDs nor CHF flare-ups predominant (n = 6). Of the 24 patients with AECOPDs and anxiety and/or depression flare-ups, anxiety and depression flare-ups occurred simultaneously in 15 patients. In 9 of these 24 patients, anxiety or depression flare-ups were observed independently from each other. In 31 of the included 48 patients, AECOPDs and comorbid flare-ups occurred mostly simultaneously. Conclusion: Patients with COPD and common comorbidities show a variety of patterns of AECOPDs and comorbid flare-ups. Some patients, however, show repetitive patterns that could potentially be used to improve personalized disease management, if recognized. Keywords: chronic obstructive pulmonary disease, heart failure, anxiety, depression, personalized medicine, disease monitoring
Summary
Neurodegeneration, the progressive dysfunction and loss of neurons in the central nervous system (CNS), is the major cause of cognitive and motor dysfunction. While neuronal degeneration is ...well‐known in Alzheimer's and Parkinson's diseases, it is also observed in neurotrophic infections, traumatic brain and spinal cord injury, stroke, neoplastic disorders, prion diseases, multiple sclerosis and amyotrophic lateral sclerosis, as well as neuropsychiatric disorders and genetic disorders. A common link between these diseases is chronic activation of innate immune responses including those mediated by microglia, the resident CNS macrophages. Such activation can trigger neurotoxic pathways leading to progressive degeneration. Yet, microglia are also crucial for controlling inflammatory processes, and repair and regeneration. The adaptive immune response is implicated in neurodegenerative diseases contributing to tissue damage, but also plays important roles in resolving inflammation and mediating neuroprotection and repair. The growing awareness that the immune system is inextricably involved in mediating damage as well as regeneration and repair in neurodegenerative disorders, has prompted novel approaches to modulate the immune system, although it remains whether these approaches can be used in humans. Additional factors in humans include ageing and exposure to environmental factors such as systemic infections that provide additional clues that may be human specific and therefore difficult to translate from animal models. Nevertheless, a better understanding of how immune responses are involved in neuronal damage and regeneration, as reviewed here, will be essential to develop effective therapies to improve quality of life, and mitigate the personal, economic and social impact of these diseases.
Background
Improved treatment options for people with haemophilia (PWH) have increased the possibilities for sports participation, but the risk of sports‐induced bleeding (SIB) is still considered ...considerable by many.
Aim
To assess sports associated injury‐ and bleeding risk in PWH and to assess clotting levels associated with safe sports participation.
Methods
Sports injuries and SIBs were prospectively collected for 12 months in PWH aged 6–49 without inhibitors playing sports at least once weekly. Injuries were compared according to factor levels, severity, joint health, sports risk category and sports intensity. Factor activity at the time of injury was estimated using a pharmacokinetic model.
Results
125 participants aged 6–49 (41 children, 90% haemophilia A; 48% severe, 95% severe on prophylaxis) were included. Sports injuries were reported by 51 participants (41%). Most participants (62%) reported no bleeds at all and only 16% reported SIBs. SIBs were associated with factor levels at time of injury (OR: 0.93/%factor level (CI 0.88–0.99); p = .02), but not with haemophilia severity (OR: 0.62 (CI 0.20–1.89); p = .40), joint health, sports risk category or sports intensity. PWH with factor levels <10% during sports injury had a bleeding risk of 41% versus 20% in those with higher (>10%) factor levels.
Conclusion
The results of this study emphasize the importance of clotting factor levels in prevention of bleeds. This information is vital for patient counselling and tailoring prophylactic treatment with clotting factors and non‐replacement therapy.
Microglial nodules in the normal-appearing white matter have been suggested as the earliest stage(s) of multiple sclerosis (MS) lesion formation. Such nodules are characterized by an absence of ...leukocyte infiltration, astrogliosis or demyelination, and may develop into active demyelinating MS lesions. Although the etiology of MS is still not known, inflammation and autoimmunity are considered to be the central components of this disease. Previous studies provide evidence that Wallerian degeneration, occurring as a consequence of structural damage in MS lesions, might be responsible for observed pathological abnormalities in connected normal-appearing white matter. As innate immune cells, microglia/macrophages are the first to react to even minor pathological changes in the CNS. Biopsy tissue from 27 MS patients and autopsy and biopsy tissue from 22 normal and pathological controls were analyzed to determine the incidence of microglial nodules. We assessed MS periplaque white matter tissue from early disease stages to determine whether microglial nodules are associated with altered axons. With immunohistochemical methods, the spatial relation of the two phenomena was visualized using HLA-DR antibody for MHC II expression by activated microglia/macrophages and by applying antibodies against damaged axons, i.e., SMI32 (non-phosphorylated neurofilaments) and amyloid precursor protein as well as neuropeptide Y receptor Y1, which marks axons undergoing Wallerian degeneration. Our data demonstrate that the occurrence of microglial nodules is not specific to MS and is associated with degenerating as well as damaged axons in early MS. In addition, we show that early MS microglial nodules exhibit both pro- and antiinflammatory phenotypes.
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