Validity and responsiveness of the Daily- and Clinical visit-PROactive Physical Activity in COPD (D-PPAC and C-PPAC) instruments.

BACKGROUND: The Daily-PROactive and Clinical visit-PROactive Physical Activity (D-PPAC and C-PPAC) instruments in chronic obstructive pulmonary disease (COPD) combines questionnaire with activity monitor data to measure patients' experience of physical activity. Their amount, difficulty and total scores range from 0 (worst) to 100 (best) but require further psychometric evaluation. OBJECTIVE: To test reliability, validity and responsiveness, and to define minimal important difference (MID), of the D-PPAC and C-PPAC instruments, in a large population of patients with stable COPD from diverse severities, settings and countries. METHODS: We used data from seven randomised controlled trials to evaluate D-PPAC and C-PPAC internal consistency and construct validity by sex, age groups, COPD severity, country and language as well as responsiveness to interventions, ability to detect change and MID. RESULTS: We included 1324 patients (mean (SD) age 66 (8) years, forced expiratory volume in 1 s 55 (17)% predicted). Scores covered almost the full range from 0 to 100, showed strong internal consistency after stratification and correlated as a priori hypothesised with dyspnoea, health-related quality of life and exercise capacity. Difficulty scores improved after pharmacological treatment and pulmonary rehabilitation, while amount scores improved after behavioural physical activity interventions. All scores were responsive to changes in self-reported physical activity experience (both worsening and improvement) and to the occurrence of COPD exacerbations during follow-up. The MID was estimated to 6 for amount and difficulty scores and 4 for total score. CONCLUSIONS: The D-PPAC and C-PPAC instruments are reliable and valid across diverse COPD populations and responsive to pharmacological and non-pharmacological interventions and changes in clinically relevant variables.

ERS statement on respiratory muscle testing at rest and during exercise.

Assessing respiratory mechanics and muscle function is critical for both clinical practice and research purposes. Several methodological developments over the past two decades have enhanced our understanding of respiratory muscle function and responses to interventions across the spectrum of health and disease. They are especially useful in diagnosing, phenotyping and assessing treatment efficacy in patients with respiratory symptoms and neuromuscular diseases. Considerable research has been undertaken over the past 17 years, since the publication of the previous American Thoracic Society (ATS)/European Respiratory Society (ERS) statement on respiratory muscle testing in 2002. Key advances have been made in the field of mechanics of breathing, respiratory muscle neurophysiology (electromyography, electroencephalography and transcranial magnetic stimulation) and on respiratory muscle imaging (ultrasound, optoelectronic plethysmography and structured light plethysmography). Accordingly, this ERS task force reviewed the field of respiratory muscle testing in health and disease, with particular reference to data obtained since the previous ATS/ERS statement. It summarises the most recent scientific and methodological developments regarding respiratory mechanics and respiratory muscle assessment by addressing the validity, precision, reproducibility, prognostic value and responsiveness to interventions of various methods. A particular emphasis is placed on assessment during exercise, which is a useful condition to stress the respiratory system.

2D-DIGE proteomic analysis of vastus lateralis from COPD patients with low and normal fat free mass index and healthy controls.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with several extra-pulmonary effects of which skeletal muscle wasting is one of the most common and contributes to reduced quality of life, increased morbidity and mortality. The molecular mechanisms leading to muscle wasting are not fully understood. Proteomic analysis of human skeletal muscle is a useful approach for gaining insight into the molecular basis for normal and pathophysiological conditions. METHODS: To identify proteins involved in the process of muscle wasting in COPD, we searched differentially expressed proteins in the vastus lateralis of COPD patients with low fat free mass index (FFMI), as a surrogate of muscle mass (COPDL, n = 10) (FEV1 33 ± 4.3% predicted, FFMI 15 ± 0.2 Kg.m-2), in comparison to patients with COPD and normal FFMI (COPDN, n = 8) and a group of age, smoking history, and sex matched healthy controls (C, n = 9) using two-dimensional fluorescence difference in gel electrophoresis (2D-DIGE) technology, combined with mass spectrometry (MS). The effect of silencing DOT1L protein expression on markers of cell arrest was analyzed in skeletal muscle satellite cells (HSkMSCs) in vitro and assessed by qPCR and Western blotting. RESULTS: A subset of 7 proteins was differentially expressed in COPDL compared to both COPDN and C. We found an increased expression of proteins associated with muscle homeostasis and protection against oxidative stress, and a decreased expression of structural muscle proteins and proteins involved in myofibrillogenesis, cell proliferation, cell cycle arrest and energy production. Among these was a decreased expression of the histone methyltransferase DOT1L. In addition, silencing of the DOT1L gene in human skeletal muscle satellite cells in vitro was significantly related to up regulation of p21 WAF1/Cip1/CDKN1A, a marker of cell arrest and ageing. CONCLUSIONS: 2D-DIGE coupled with MS identified differences in the expression of several proteins in the wasted vastus lateralis that are relevant to the disease process. Down regulation of DOT1L in the vastus lateralis of COPDL patients may mediate the muscle wasting process through up regulation of markers of cell arrest and senescence.

Effectiveness of Smartphone Devices in Promoting Physical Activity and Exercise in Patients with Chronic Obstructive Pulmonary Disease: A Systematic Review.

The objectives of this systematic review were to analyse existing evidence on the efficacy of smartphone devices in promoting physical activity (PA) in patients with chronic obstructive pulmonary disease (COPD) and to identify the validity and precision of their measurements. A systematic review was undertaken across nine electronic databases: WOS Core Collection, PubMed, CINAHL, AMED, Academic Search Complete, Cochrane Central Register of Controlled Trials, SciELO, LILACS and ScienceDirect. Randomized and non-randomized controlled clinical trials were identified. To obtain additional eligible articles, the reference lists of the selected studies were also checked. Eligibility criteria and risk of bias were assessed by two independent authors. A total of eight articles met eligibility criteria. The studies were focused on promoting PA (n  =  5) and the precision of device measurements (n = 3). The effectiveness of smartphones in increasing PA level (steps/day) at short and long term is very limited. Mobile-based exercise programs reported improvements in exercise capacity (i.e. incremental Shuttle-Walk-Test) at short and long term (18.3% and 21%, respectively). The precision of device measurements was good-to-excellent (r = 0.69-0.99); however, these data should be interpreted with caution due to methodological limitations of studies. The effectiveness of smartphone devices in promoting PA levels in patients with COPD is scarce. Further high-quality studies are needed to evaluate the effectiveness of smartphone devices in promoting PA levels. Registration number: CRD42016050048.

Interventions to modify physical activity in patients with COPD: a systematic review.

The broad range of interventions to increase physical activity (PA) in patients with chronic obstructive pulmonary disease (COPD) has not been systematically assessed. We aimed to perform a systematic review of the interventional studies that have assessed PA as an outcome in patients with COPD.A systematic search in five different databases (Medline, Embase, PsycINFO, CINAHL and Web of Science) was performed in March 2015. Two independent reviewers analysed the studies against the inclusion criteria (COPD defined by spirometry; prospective, randomised/nonrandomised studies, cohort and experimental studies with interventions using PA as an outcome), extracted the data and assessed the quality of evidence.60 studies were included. Seven intervention groups were identified. PA counselling increased PA levels in COPD, especially when combined with coaching. 13 studies showed positive effects of pulmonary rehabilitation (PR) on PA, while seven studies showed no changes. All three PR programmes >12 weeks in duration increased PA. Overall, the quality of evidence was graded as very low.Interventions focusing specifically on increasing PA, and longer PR programmes, may have greater impacts on PA in COPD. Well-designed clinical trials with objective assessment of PA in COPD patients are needed.

Circulating desmosine levels do not predict emphysema progression but are associated with cardiovascular risk and mortality in COPD.

Elastin degradation is a key feature of emphysema and may have a role in the pathogenesis of atherosclerosis associated with chronic obstructive pulmonary disease (COPD). Circulating desmosine is a specific biomarker of elastin degradation. We investigated the association between plasma desmosine (pDES) and emphysema severity/progression, coronary artery calcium score (CACS) and mortality.pDES was measured in 1177 COPD patients and 110 healthy control subjects from two independent cohorts. Emphysema was assessed on chest computed tomography scans. Aortic arterial stiffness was measured as the aortic-femoral pulse wave velocity.pDES was elevated in patients with cardiovascular disease (p<0.005) and correlated with age (rho=0.39, p<0.0005), CACS (rho=0.19, p<0.0005) modified Medical Research Council dyspnoea score (rho=0.15, p<0.0005), 6-min walking distance (rho=-0.17, p<0.0005) and body mass index, airflow obstruction, dyspnoea, exercise capacity index (rho=0.10, p<0.01), but not with emphysema, emphysema progression or forced expiratory volume in 1 s decline. pDES predicted all-cause mortality independently of several confounding factors (p<0.005). In an independent cohort of 186 patients with COPD and 110 control subjects, pDES levels were higher in COPD patients with cardiovascular disease and correlated with arterial stiffness (p<0.05).In COPD, excess elastin degradation relates to cardiovascular comorbidities, atherosclerosis, arterial stiffness, systemic inflammation and mortality, but not to emphysema or emphysema progression. pDES is a good biomarker of cardiovascular risk and mortality in COPD.

The PROactive instruments to measure physical activity in patients with chronic obstructive pulmonary disease.

No current patient-centred instrument captures all dimensions of physical activity in chronic obstructive pulmonary disease (COPD). Our objective was item reduction and initial validation of two instruments to measure physical activity in COPD.Physical activity was assessed in a 6-week, randomised, two-way cross-over, multicentre study using PROactive draft questionnaires (daily and clinical visit versions) and two activity monitors. Item reduction followed an iterative process including classical and Rasch model analyses, and input from patients and clinical experts.236 COPD patients from five European centres were included. Results indicated the concept of physical activity in COPD had two domains, labelled "amount" and "difficulty". After item reduction, the daily PROactive instrument comprised nine items and the clinical visit contained 14. Both demonstrated good model fit (person separation index >0.7). Confirmatory factor analysis supported the bidimensional structure. Both instruments had good internal consistency (Cronbach's α>0.8), test-retest reliability (intraclass correlation coefficient ≥0.9) and exhibited moderate-to-high correlations (r>0.6) with related constructs and very low correlations (r<0.3) with unrelated constructs, providing evidence for construct validity.Daily and clinical visit "PROactive physical activity in COPD" instruments are hybrid tools combining a short patient-reported outcome questionnaire and two activity monitor variables which provide simple, valid and reliable measures of physical activity in COPD patients.

Genome-wide mRNA expression profiling in vastus lateralis of COPD patients with low and normal fat free mass index and healthy controls.

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) has significant systemic effects beyond the lungs amongst which muscle wasting is a prominent contributor to exercise limitation and an independent predictor of morbidity and mortality. The molecular mechanisms leading to skeletal muscle dysfunction/wasting are not fully understood and are likely to be multi-factorial. The need to develop therapeutic strategies aimed at improving skeletal muscle dysfunction/wasting requires a better understanding of the molecular mechanisms responsible for these abnormalities. Microarrays are powerful tools that allow the investigation of the expression of thousands of genes, virtually the whole genome, simultaneously. We aim at identifying genes and molecular pathways involved in skeletal muscle wasting in COPD. METHODS: We assessed and compared the vastus lateralis transcriptome of COPD patients with low fat free mass index (FFMI) as a surrogate of muscle mass (COPDL) (FEV1 30 ± 3.6%pred, FFMI 15 ± 0.2 Kg.m(-2)) with patients with COPD and normal FFMI (COPDN) (FEV1 44 ± 5.8%pred, FFMI 19 ± 0.5 Kg.m(-2)) and a group of age and sex matched healthy controls (C) (FEV1 95 ± 3.9%pred, FFMI 20 ± 0.8 Kg.m(-2)) using Agilent Human Whole Genome 4x44K microarrays. The altered expression of several of these genes was confirmed by real time TaqMan PCR. Protein levels of P21 were assessed by immunoblotting. RESULTS: A subset of 42 genes was differentially expressed in COPDL in comparison to both COPDN and C (PFP < 0.05; -1.5 ≥ FC ≥ 1.5). The altered expression of several of these genes was confirmed by real time TaqMan PCR and correlated with different functional and structural muscle parameters. Five of these genes (CDKN1A, GADD45A, PMP22, BEX2, CGREF1, CYR61), were associated with cell cycle arrest and growth regulation and had been previously identified in studies relating muscle wasting and ageing. Protein levels of CDKN1A, a recognized marker of premature ageing/cell cycle arrest, were also found to be increased in COPDL. CONCLUSIONS: This study provides evidence of differentially expressed genes in peripheral muscle in COPD patients corresponding to relevant biological processes associated with skeletal muscle wasting and provides potential targets for future therapeutic interventions to prevent loss of muscle function and mass in COPD.

Determinants and outcomes of physical activity in patients with COPD: a systematic review.

BACKGROUND: The relationship between physical activity, disease severity, health status and prognosis in patients with COPD has not been systematically assessed. Our aim was to identify and summarise studies assessing associations between physical activity and its determinants and/or outcomes in patients with COPD and to develop a conceptual model for physical activity in COPD. METHODS: We conducted a systematic search of four databases (Medline, Embase, CINAHL and Psychinfo) prior to November 2012. Teams of two reviewers independently selected articles, extracted data and used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) to assess quality of evidence. RESULTS: 86 studies were included: 59 were focused on determinants, 23 on outcomes and 4 on both. Hyperinflation, exercise capacity, dyspnoea, previous exacerbations, gas exchange, systemic inflammation, quality of life and self-efficacy were consistently related to physical activity, but often based on cross-sectional studies and low-quality evidence. Results from studies of pharmacological and non-pharmacological treatments were inconsistent and the quality of evidence was low to very low. As outcomes, COPD exacerbations and mortality were consistently associated with low levels of physical activity based on moderate quality evidence. Physical activity was associated with other outcomes such as dyspnoea, health-related quality of life, exercise capacity and FEV1 but based on cross-sectional studies and low to very low quality evidence. CONCLUSIONS: Physical activity level in COPD is consistently associated with mortality and exacerbations, but there is poor evidence about determinants of physical activity, including the impact of treatment.

Ageing and the border between health and disease.

Ageing is associated with a progressive degeneration of the tissues, which has a negative impact on the structure and function of vital organs and is among the most important known risk factors for most chronic diseases. Since the proportion of the world's population aged >60 years will double in the next four decades, this will be accompanied by an increased incidence of chronic age-related diseases that will place a huge burden on healthcare resources. There is increasing evidence that many chronic inflammatory diseases represent an acceleration of the ageing process. Chronic pulmonary diseases represents an important component of the increasingly prevalent multiple chronic debilitating diseases, which are a major cause of morbidity and mortality, particularly in the elderly. The lungs age and it has been suggested that chronic obstructive pulmonary disease (COPD) is a condition of accelerated lung ageing and that ageing may provide a mechanistic link between COPD and many of its extrapulmonary effects and comorbidities. In this article we will describe the physiological changes and mechanisms of ageing, with particular focus on the pulmonary effects of ageing and how these may be relevant to the development of COPD and its major extrapulmonary manifestations.

Real-world walking cadence in people with COPD.

Introduction: The clinical validity of real-world walking cadence in people with COPD is unsettled. Our objective was to assess the levels, variability and association with clinically relevant COPD characteristics and outcomes of real-world walking cadence. Methods: We assessed walking cadence (steps per minute during walking bouts longer than 10 s) from 7 days' accelerometer data in 593 individuals with COPD from five European countries, and clinical and functional characteristics from validated questionnaires and standardised tests. Severe exacerbations during a 12-month follow-up were recorded from patient reports and medical registries. Results: Participants were mostly male (80%) and had mean±sd age of 68±8 years, post-bronchodilator forced expiratory volume in 1 s (FEV1) of 57±19% predicted and walked 6880±3926 steps·day-1. Mean walking cadence was 88±9 steps·min-1, followed a normal distribution and was highly stable within-person (intraclass correlation coefficient 0.92, 95% CI 0.90-0.93). After adjusting for age, sex, height and number of walking bouts in fractional polynomial or linear regressions, walking cadence was positively associated with FEV1, 6-min walk distance, physical activity (steps·day-1, time in moderate-to-vigorous physical activity, vector magnitude units, walking time, intensity during locomotion), physical activity experience and health-related quality of life and negatively associated with breathlessness and depression (all p<0.05). These associations remained after further adjustment for daily steps. In negative binomial regression adjusted for multiple confounders, walking cadence related to lower number of severe exacerbations during follow-up (incidence rate ratio 0.94 per step·min-1, 95% CI 0.91-0.99, p=0.009). Conclusions: Higher real-world walking cadence is associated with better COPD status and lower severe exacerbations risk, which makes it attractive as a future prognostic marker and clinical outcome.

Validity of physical activity monitors during daily life in patients with COPD.

Symptoms during physical activity and physical inactivity are hallmarks of chronic obstructive pulmonary disease (COPD). Our aim was to evaluate the validity and usability of six activity monitors in patients with COPD against the doubly labelled water (DLW) indirect calorimetry method. 80 COPD patients (mean ± sd age 68 ± 6 years and forced expiratory volume in 1 s 57 ± 19% predicted) recruited in four centres each wore simultaneously three or four out of six commercially available monitors validated in chronic conditions for 14 consecutive days. A priori validity criteria were defined. These included the ability to explain total energy expenditure (TEE) variance through multiple regression analysis, using TEE as the dependent variable with total body water (TBW) plus several physical activity monitor outputs as independent variables; and correlation with activity energy expenditure (AEE) measured by DLW. The Actigraph GT3X (Actigraph LLC, Pensacola, FL, USA), and DynaPort MoveMonitor (McRoberts BV, The Hague, the Netherlands) best explained the majority of the TEE variance not explained by TBW (53% and 70%, respectively) and showed the most significant correlations with AEE (r=0.71, p<0.001 and r=0.70, p<0.0001, respectively). The results of this study should guide users in choosing valid activity monitors for research or for clinical use in patients with chronic diseases such as COPD.

Improving physical activity in COPD: towards a new paradigm.

Chronic obstructive pulmonary disease (COPD) is a debilitating disease affecting patients in daily life, both physically and emotionally. Symptoms such as dyspnea and muscle fatigue, lead to exercise intolerance, which, together with behavioral issues, trigger physical inactivity, a key feature of COPD. Physical inactivity is associated with adverse clinical outcomes, including hospitalization and all-cause mortality. Increasing activity levels is crucial for effective management strategies and could lead to improved long-term outcomes. In this review we summarize objective and subjective instruments for evaluating physical activity and focus on interventions such as pulmonary rehabilitation or bronchodilators aimed at increasing activity levels. To date, only limited evidence exists to support the effectiveness of these interventions. We suggest that a multimodal approach comprising pulmonary rehabilitation, pharmacotherapy, and counselling programs aimed at addressing emotional and behavioural aspects of COPD may be an effective way to increase physical activity and improve health status in the long term.

Pulmonary rehabilitation and physical interventions.

Pulmonary rehabilitation has established a status of evidence-based therapy for patients with symptomatic COPD in the stable phase and after acute exacerbations. Rehabilitation should have the possibility of including different disciplines and be offered in several formats and lines of healthcare. This review focusses on the cornerstone intervention, exercise training, and how training interventions can be adapted to the limitations of patients. These adaptations may lead to altered cardiovascular or muscular training effects and/or may improve movement efficiency. Optimising pharmacotherapy (not the focus of this review) and oxygen supplements, whole-body low- and high-intensity training or interval training, and resistance (or neuromuscular electrical stimulation) training are important training modalities for these patients in order to accommodate cardiovascular and ventilatory impairments. Inspiratory muscle training and whole-body vibration may also be worthwhile interventions in selected patients. Patients with stable but symptomatic COPD, those who have suffered exacerbations and patients waiting for or who have received lung volume reduction or lung transplantation are good candidates. The future surely holds promise to further personalise exercise training interventions and to tailor the format of rehabilitation to the individual patient's needs and preferences.

A retrospective study of crossover ambulatory oxygen walk testing in patients with fibrotic lung disease.

BACKGROUND: Fibrotic interstitial lung disease (ILD) comprises a group of lung conditions that are often progressive, debilitating, and life-shortening. Ambulatory oxygen therapy (AOT) is regularly prescribed to manage symptoms in patients with fibrotic ILD. In our institution, the decision to prescribe portable oxygen is made on the basis of oxygen improving exercise capacity, measured with the single-blinded, crossover ambulatory oxygen walk test (AOWT). This study aimed to investigate the characteristics and survival rates of patients with fibrotic ILD who have either positive or negative results on the AOWT. METHODS: This retrospective cohort study compared the data from 99 patients with fibrotic ILD who underwent the AOWT. These patients were classified into two groups based on whether they showed improvement in the AOWT with supplemental oxygen (positive group) or no improvement (negative group). Patient demographics for both groups were compared to determine any significant differences. A multivariate Cox proportional hazards model was used to analyze the survival rates of the two groups. RESULTS: Out of the 99 patients, 71 were in the positive group. We compared the measured characteristics between the positive and negative groups and found no significant difference, wherein the adjusted hazard ratio was 1.33 (95% confidence interval 0.69-2.60, P = 0.40). CONCLUSIONS: The AOWT can be used to rationalize AOT, but there was no significant difference in baseline characteristics or survival rates between patients whose performance was improved or not in the AOWT.

Effectiveness of home-based pulmonary rehabilitation: systematic review and meta-analysis.

INTRODUCTION: Despite proven effectiveness for people with chronic respiratory diseases, practical barriers to attending centre-based pulmonary rehabilitation (centre-PR) limit accessibility. We aimed to review the clinical effectiveness, components and completion rates of home-based pulmonary rehabilitation (home-PR) compared to centre-PR or usual care. METHODS AND ANALYSIS: Using Cochrane methodology, we searched (January 1990 to August 2021) six electronic databases using a PICOS (population, intervention, comparison, outcome, study type) search strategy, assessed Cochrane risk of bias, performed meta-analysis and narrative synthesis to answer our objectives and used the Grading of Recommendations, Assessment, Development and Evaluations framework to rate certainty of evidence. RESULTS: We identified 16 studies (1800 COPD patients; 11 countries). The effects of home-PR on exercise capacity and/or health-related quality of life (HRQoL) were compared to either centre-PR (n=7) or usual care (n=8); one study used both comparators. Compared to usual care, home-PR significantly improved exercise capacity (standardised mean difference (SMD) 0.88, 95% CI 0.32-1.44; p=0.002) and HRQoL (SMD -0.62, 95% CI -0.88--0.36; p<0.001). Compared to centre-PR, home-PR showed no significant difference in exercise capacity (SMD -0.10, 95% CI -0.25-0.05; p=0.21) or HRQoL (SMD 0.01, 95% CI -0.15-0.17; p=0.87). CONCLUSION: Home-PR is as effective as centre-PR in improving functional exercise capacity and quality of life compared to usual care, and is an option to enable access to pulmonary rehabilitation.

Clinical effectiveness and components of Home-pulmonary rehabilitation for people with chronic respiratory diseases: a systematic review protocol.

INTRODUCTION: Chronic respiratory diseases (CRDs) are common and disabling conditions that can result in social isolation and economic hardship for patients and their families. Pulmonary rehabilitation (PR) improves functional exercise capacity and health-related quality of life (HRQoL) but practical barriers to attending centre-based sessions or the need for infection control limits accessibility. Home-PR offers a potential solution that may improve access. We aim to systematically review the clinical effectiveness, completion rates and components of Home-PR for people with CRDs compared with Centre-PR or Usual care. METHODS AND ANALYSIS: We will search PubMed, CINAHL, Cochrane, EMBASE, PeDRO and PsycInfo from January 1990 to date using a PICOS search strategy (Population: adults with CRDs; Intervention: Home-PR; Comparator: Centre-PR/Usual care; Outcomes: functional exercise capacity and HRQoL; Setting: any setting). The strategy is to search for 'Chronic Respiratory Disease' AND 'Pulmonary Rehabilitation' AND 'Home-PR', and identify relevant randomised controlled trials and controlled clinical trials. Six reviewers working in pairs will independently screen articles for eligibility and extract data from those fulfilling the inclusion criteria. We will use the Cochrane risk-of-bias tool and Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate the quality of evidence. We will perform meta-analysis or narrative synthesis as appropriate to answer our three research questions: (1) what is the effectiveness of Home-PR compared with Centre-PR or Usual care? (2) what components are used in effective Home-PR studies? and (3) what is the completion rate of Home-PR compared with Centre-PR? ETHICS AND DISSEMINATION: Research ethics approval is not required since the study will review only published data. The findings will be disseminated through publication in a peer-reviewed journal and presentation in conferences. PROSPERO REGISTRATION NUMBER: CRD42020220137.