Adapting, restarting, and terminating a randomised control trial for people with cystic fibrosis: Reflections on the impact of the COVID-19 pandemic upon research in a clinical population.

Background: Habitual physical activity (PA) and exercise form a cornerstone of the management of cystic fibrosis (CF), a genetically inherited pulmonary and digestive condition - whereby telehealth platforms have been proposed as a mechanism to engage remotely people with CF in PA and exercise. Methods: To test this, in early 2020, the 'ActivOnline: Physical Activity in Cystic Fibrosis Trial' (ActiOn PACT) randomised control trial was established to examine whether an online intervention was effective at increasing PA in adolescents and adults with CF. Results: The emergence of the COVID-19 pandemic in 2020 forced this trial to be paused and modified, with the adoption of online recruitment and remote assessment of outcome measures. Despite such adaptations in accord with frameworks developed by the National Institute for Health Research, this trial failed to recruit and was subsequently terminated. Conclusions: This article details the authors reflections upon the proposed reasons for lack of recruitment, including improved technology and medications for people with CF, and contextualises this finding in relation to the wider issue of non-reporting of trial results in clinical research.

Process evaluation of school-based high-intensity interval training interventions for children and adolescents: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Several systematic reviews have been published to investigate the effectiveness of high-intensity interval training (HIIT) in schools. However, there has been limited attention given to understanding the functioning of the intervention processes, which is of paramount importance for interpreting and translating the intervention effectiveness. The aim of this systematic review is to determine the extent to which process evaluation is measured in school-based HIIT interventions and to explore the effects of process evaluation and intervention characteristics on cardiorespiratory fitness (CRF), body composition, muscular strength, and blood pressure. METHODS: A comprehensive search was conducted in SPORT Discus (EBSCOhost), Web of Science, Scopus, Medline (Ovid) and Cochrane Central Register of Controlled Trials. The extent to which process evaluation is measured was narratively reported, alongside with the guidance of process evaluation of complex interventions by UK Medical Research Council. Meta-analyses and meta-regressions were conducted to determine the effects of process evaluation and intervention characteristics to the intervention outcomes. RESULTS: The literature search identified 77 studies reporting on 45 school-based HIIT interventions. In total, five interventions reported process evaluation in a section or in a separate study, and only one intervention adopted a process evaluation framework. On average, 6 out of 12 process evaluation measures were reported in all interventions. Subgroup analyses did not indicate any beneficial treatment effects for studies with process evaluation group, whereas all pooled data and studies without process evaluation group showed significant improvement for CRF and body composition. CONCLUSION: Process evaluation is frequently omitted in the literature of school-based HIIT in children and adolescents. Although reporting of process evaluation measures may not directly associate with better intervention outcomes, it allows accurate interpretation of intervention outcomes, thereby enhancing the generalisability and dissemination of the interventions.

The effect of the Mid-Day Meal programme on the longitudinal physical growth from childhood to adolescence in India.

The study aims to examine the effect of the world's largest school-feeding programme, the Mid-Day Meal (MDM) programme, on the changes in the underweight prevalence among school-children in India. Data from the Indian Human Development Survey (IHDS) Rounds 1 (2004-05) and 2 (2011-12) were utilized. The sample included individual-level information of children aged 6 to 9 years in IHDS-1 who then turned 13 to 16 years in IHDS-2. The sample was categorised into four groups based on their MDM consumption history (Group 1: no MDM support in IHDS-1 and IHDS-2, Group 2: MDM support in IHDS-1, Group 3: MDM support in IHDS-2, Group 4: persistent MDM support in IHDS-1 and IHDS-2). The dependent variable was underweight status as defined by the World Health Organisation Child Growth Standards Body Mass Index for age (BMI Z-score) < -2 SD of the median. Bivariate analysis was used to examine the prevalence of underweight and establish associations between underweight status and socio-demographic characteristics. Logistic regression was performed to assess the strength of the association of socio-demographic characteristics and MDM consumption patterns with underweight across poor and non-poor asset groups. The findings suggest that early and persistent MDM support among respondents reduced the likelihood of low BMI Z-scores compared to those without MDM support. Respondents from the poor asset group who received MDM support in at least one of the two survey rounds had higher odds of being underweight in comparison with those who did not receive MDM support at all. Girls and adolescents residing in the Eastern region of India were less likely to be underweight. The study shows that the MDM programme was effective in reducing the rate of underweight among school children. However, continuous programme upscaling with a special focus on children from poor households will significantly benefit India's school-aged children.

Validation and Calibration for Embedding Rating of Perceived Exertion Into High-Intensity Interval Exercise in Adolescents: A Lab-Based Study.

PURPOSE: Rating of perceived exertion (RPE) is a convenient and cost-effective tool that can be used to monitor high-intensity interval exercise (HIIE). However, no methodological study has demonstrated the validity of RPE in this context. Therefore, the aim of this study was to validate and calibrate RPE for monitoring HIIE in adolescents. METHODS: RPE, heart rate (HR), and oxygen uptake (V˙O2) data were retrospectively extracted from 3 lab-based crossover studies, with a pooled sample size of 45 adolescents, performing either cycling-based or running-based HIIE sessions. Within-participant correlations were calculated for RPE-HR and RPE-V˙O2, and receiver operator characteristic curve analysis was used to establish RPE cut points. RESULTS: The results showed that RPE-HR demonstrated acceptable criterion validity (r = .53-.74, P < .01), while RPE-V˙O2 had poor validity (r = .40-.48, P < .01), except for HIIE at 100% peak power (r = .59, P < .01). RPE cut points of 4 and 5 were established in corresponding to HR/V˙O2 based thresholds. CONCLUSION: RPE has some utility in evaluating intensity during lab-based running or cycling HIIE in adolescents. Future studies should expand the validation and calibration of RPE for prescribing and monitoring HIIE in children and adolescents in field-based contexts.

The Role of Speckle-Tracking Echocardiography in Predicting Mortality and Morbidity in Patients With Congenital Heart Disease: A Systematic Review and Meta-analysis.

BACKGROUND: Speckle-tracking echocardiography (STE) is now routinely included in cardiac evaluations, but its role in predicting mortality and morbidity in congenital heart disease (CHD) is not well described. We conducted a systematic review to evaluate the prognostic value of STE in patients with CHD. METHODS: The EMBASE, Medline, Web of Science, Scopus, and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched from inception to January 2023 for terms related to all CHD, STE, and prognosis. Meta-analysis of association of right ventricle and left ventricle strain (RV Sl and LV Sl, respectively) with major adverse cardiovascular events (MACEs) was performed in atrial switch transposition of the great arteries (asTGA)/congenitally corrected TGA (ccTGA), tetralogy of Fallot (ToF), and congenital aortic stenosis (cAS)/bicuspid aortic valve (BAV). P-value combination analysis was additionally performed for all CHD groups. RESULTS: A total of 33 studies (30 cohorts, n = 8,619 patients, children, and adults) were included. Meta-analysis showed the following parameters as being associated with MACE: RV Sl in asTGA/ccTGA (hazard ratio [HR] = 1.1/%; CI, [1.03; 1.18]), RV Sl and LV Sl in ToF (HR = 1.14/%; CI, [1.03; 1.26] and HR = 1.14/%; CI, [1.08; 1.2], respectively), and LV Sl in cAS/BAV (HR = 1.19/%; CI, [1.15; 1.23]). The RV Sl and strain rate were associated with outcomes also in single ventricle/hypoplastic left heart syndrome (at all palliation stages except before Norwood stage 1) and LV Sl in Ebstein's anomaly. CONCLUSIONS: This systematic review and meta-analysis showed that biventricular strain and strain rate were associated with outcomes in a variety of CHD, highlighting the need for updated recommendations on the use of STE in the current guidelines, specific to disease types.

Parental recommendations and exercise attitudes in congenital hearts.

BACKGROUND: Children and young people with CHD benefit from regular physical activity. Parents are reported as facilitators and barriers to their children's physical activity. The aim of this study was to explore parental factors, child factors, and their clinical experience on physical activity participation in young people with CHD. METHODS: An online questionnaire was co-developed with parents (n = 3) who have children with CHD. The survey was then distributed in the United Kingdom by social media and CHD networks, between October 2021 and February 2022. Data were analysed using mixed methods. RESULTS: Eighty-three parents/guardians responded (94% mothers). Young people with CHD were 7.3 ± 5.0 years old (range 0-20 years; 53% female) and 84% performed activity. Parental participation in activity (X2(1) = 6.9, P < 0.05) and perceiving activity as important for their child were positively associated with activity (Fisher's Exact, P < 0.05). Some parents (∼15%) were unsure of the safety of activity, and most (∼70%) were unsure where to access further information about activity. Fifty-two parents (72%) had never received activity advice in clinic, and of the 20 who received advice, 10 said it was inconsistent. Qualitative analysis produced the theme "Knowledge is power and comfort." Parents described not knowing what activity was appropriate or the impact of it on their child. CONCLUSION: Parental participation and attitudes towards activity potentially influence their child's activity. A large proportion of young people performed activity despite a lack and inconsistency of activity advice offered by CHD clinics. Young people with CHD would benefit from activity advice with their families in clinics.

Cardiopulmonary Exercise Testing Provides Prognostic Information in Advanced Cystic Fibrosis Lung Disease.

Rationale: Cardiopulmonary exercise testing (CPET) provides prognostic information in cystic fibrosis (CF); however, its prognostic value for patients with advanced CF lung disease is unknown. Objectives: To determine the prognostic value of CPET on the risk of death or lung transplant (LTX) within 2 years. Methods: We retrospectively collected data from 20 CF centers in Asia, Australia, Europe, and North America on patients with a forced expiratory volume in 1 second (FEV1) ⩽ 40% predicted who performed a cycle ergometer CPET between January 2008 and December 2017. Time to death/LTX was analyzed using mixed Cox proportional hazards regression. Conditional inference trees were modeled to identify subgroups with increased risk of death/LTX. Results: In total, 174 patients (FEV1, 30.9% ± 5.8% predicted) were included. Forty-four patients (25.5%) died or underwent LTX. Cox regression analysis adjusted for age, sex, and FEV1 revealed percentage predicted peak oxygen uptake ([Formula: see text]o2peak) and peak work rate (Wpeak) as significant predictors of death/LTX: adjusted hazard ratios per each additional 10% predicted were 0.60 (95% confidence interval, 0.43-0.90; P = 0.008) and 0.60 (0.48-0.82; P < 0.001). Tree-structured regression models, including a set of 11 prognostic factors for survival, identified Wpeak to be most strongly associated with 2-year risk of death/LTX. Probability of death/LTX was 45.2% for those with a Wpeak ⩽ 49.2% predicted versus 10.9% for those with a Wpeak > 49.2% predicted (P < 0.001). Conclusions: CPET provides prognostic information in advanced CF lung disease, and Wpeak appears to be a promising marker for LTX referral and candidate selection.

The discovery of a data-driven causal diagram of sport participation in children and adolescents with heart disease: a pilot study.

The interventions aimed at improving the levels of physical activity (PA) in children and adolescents diagnosed with heart disease did not produce the expected outcomes. Safe participation in sport activities proposed based on actual recommendations could be a solution to promote PA in this population. The aims of this study were to discover a causal diagram of sport participation in children and youth with heart disease and establish the factors that affect and are affected thereof through the use of questionnaires. Furthermore, the study aims to qualitatively assess the reliability of the constructed diagram in comparison with existing medical knowledge. The Greedy Fast Causal Inference method was employed to conduct a data-driven search of the directed acyclic graph that represents the causal relationships within the provided observational data. This causal discovery was performed using the Tetrad software. The analysis involved a cohort of 121 Caucasian patients (50 females) diagnosed with heart disease. The age range of the patients included in the study was 8-17 years. The study findings indicate that the participants engaged in sports presented significantly higher values of health-related quality of life (QoL) and motives for participating in physical and leisure activities. Age appears to be a cause of sport participation. Sport participation appears to be a cause of participation in physical education classes, which in turn appears to be a cause of higher enjoyment. Higher enjoyment appears to be a cause of other motives for participating in physical and leisure activities, as well as a higher score in terms of physical health. The causal diagram provided a graphical representation of the causal relationship between sport participation and better QoL with potential confounders for children and adolescents with heart disease that nearly coincided with the existing literature. Clinical trials should be designed to validate clinical utility of the presented causal diagram.

The utility of the reperfusion rate of tissue oxygen saturation as a measure of vascular endothelial function in adolescents: reliability, validity and sensitivity.

Introduction: The near-infrared spectroscopy (NIRS)-derived reperfusion rate of tissue oxygen saturation (slope 2 StO2) may provide a surrogate measure of vascular function, however, this has yet to be examined in a paediatric population. This study investigated in adolescents: 1) the between-day reliability of NIRS-derived measurements; 2) the relationship between slope 2 StO2 and macro- (flow-mediated dilation, FMD) and microvascular (peak reactive hyperaemia, PRH) function; and 3) the effect of high-intensity interval exercise (HIIE) on slope 2 StO2, FMD, and PRH. Methods: Nineteen boys (13.3 ± 0.5 y) visited the laboratory on two occasions, separated by ∼ 1 week. On visit 1, participants underwent simultaneous assessment of brachial artery FMD and slope 2 StO2 and PRH on the internal face of the forearm. On visit 2, participants completed a bout of HIIE with slope 2 StO2, FMD and PRH measured pre-, immediately post- and 1.5 h post-exercise. Results: Slope 2 StO2 showed no mean bias (p = 0.18) and an intraclass correlation coefficient of 0.67 (p = 0.003) between visits. No significant correlation between slope 2 StO2 and FMD or PRH was observed on visit 1 (r = -0.04, p = 0.89 and r = -0.30, p = 0.23, respectively) or visit 2 pre-exercise (r = -0.28, p = 0.25 and r = -0.31, p = 0.20, respectively). Compared to pre-exercise, FMD decreased immediately post-exercise (p < 0.001) and then increased 1.5 h post-exercise (p < 0.001). No significant change was detected for slope 2 StO2 (p = 0.30) or PRH (p = 0.55) following HIIE. Conclusion: In adolescents, slope 2 StO2 can be measured reliably, however, it is not correlated with FMD or PRH and does not follow the acute time course of changes in FMD post-exercise. Hence, the use of slope 2 StO2 as a surrogate measure of vascular function in youth must be refuted.

Exploring the role of socioeconomic status and psychological characteristics on talent development in an English soccer academy.

Social factors and psychological characteristics can influence participation and development in talent pathways. However, the interaction between these two factors is relatively unknown. The aim of this study was to investigate the implications of socioeconomic status and psychological characteristics in English academy soccer players (n=58; aged 11 to 16 years). To assess socioeconomic status, participants' home postcodes were coded according to each individual's social classification and credit rating, applying the UK General Registrar Classification system and CameoTM geodemographic database, respectively. Participants also completed the six factor Psychological Characteristics for Developing Excellence Questionnaire (PCDEQ). A classification of 'higher-potentials' (n=19) and 'lower-potentials' (n=19) were applied through coach potential rankings. Data were standardised using z-scores to eliminate age bias and data were analysed using independent sample t-tests. Results showed that higher-potentials derived from families with significantly lower social classifications (p=0.014) and reported higher levels for PCDEQ Factor 3 (coping with performance and developmental pressures) (p=0.007) compared to lower-potentials. This study can be used to support the impetus for researchers and practitioners to consider the role of social factors and psychological characteristics when developing sporting talent. For example, facilitating player-centred development within an academy and, where necessary, providing individuals with additional support.

Citizen Science to improve healthy and active living among adolescents in four European countries: a protocol of the cluster randomised controlled trial of the Science Engagement to Empower aDolescentS (SEEDS) project.

INTRODUCTION: Improving healthy lifestyles of adolescents is challenging. Citizen Science is a way to engage them in the design and delivery of interventions, and may also increase their interest in science, technology, engineering and mathematics (STEM). The Science Engagement to Empower aDolescentS (SEEDS) project aims to use an equity-lens, and engage and empower boys and girls from deprived areas by designing and cocreating interventions to promote healthy lifestyles, and to seed interest in STEM. METHODS AND ANALYSIS: SEEDS is a cluster randomised controlled trial in four countries (Greece, the Netherlands, Spain and the UK). Each country will recruit six to eight high schools from lower socioeconomic neighbourhoods. Adolescents aged 13-15 years are the target population. High schools will be randomised into intervention or control group. Each country will select 15 adolescents from intervention schools called ambassadors, who will be involved throughout the project.In each country, focus groups with ambassadors and stakeholders will focus on physical activity, snacking behaviour and STEM. The input from focus groups will be used to shape Makeathon events, cocreation events where adolescents and stakeholders will develop the interventions. The resultant intervention will be implemented in the intervention schools during 6 months. In total, we aim to recruit 720 adolescents who will complete questionnaires related to healthy lifestyles and STEM outcomes at baseline (November 2021) and after the 6 months (June 2022). ETHICS AND DISSEMINATION: The four countries obtained approval from their corresponding Ethics Committees (Greece: Bioethics Committee of Harokopio University; the Netherlands: The Medical Research Ethics Committee of the Erasmus Medical Center; Spain: The Drug Research Ethics Committee of the Pere Virgili Health Research Institute; UK: Sport and Health Sciences Ethics Committee of the University of Exeter). Informed consent will be collected from adolescents and their parents in line with General Data Protection Regulation legislation. The findings will be disseminated by conference presentations, publications in scientific peer-reviewed journals and during (local) stakeholders and public events. Lessons learnt and the main results will also be used to provide policy recommendations. TRIAL REGISTRATION NUMBER: NCT05002049.

The use of 2-D speckle tracking echocardiography in differentiating healthy adolescent athletes with right ventricular outflow tract dilation from patients with arrhythmogenic cardiomyopathy.

AIMS: Echocardiographic assessment of adolescent athletes for arrhythmogenic cardiomyopathy (ACM) can be challenging owing to right ventricular (RV) exercise-related remodelling, particularly RV outflow tract (RVOT) dilation. The aim of this study is to evaluate the role of RV 2-D speckle tracking echocardiography (STE) in comparing healthy adolescent athletes with and without RVOT dilation to patients with ACM. METHODS AND RESULTS: A total of 391 adolescent athletes, mean age 14.5 ± 1.7 years, evaluated at three sports academies between 2014 and 2019 were included, and compared to previously reported ACM patients (n = 38 definite and n = 39 borderline). Peak systolic RV free wall (RVFW-Sl), global and segmental strain (Sl), and corresponding strain rates (SRl) were calculated. The participants meeting the major modified Task Force Criteria (mTFC) for RVOT dilation were defined as mTFC+ (n = 58, 14.8%), and the rest as mTFC- (n = 333, 85.2%). Mean RVFW-Sl was -27.6 ± 3.4% overall, -28.2 ± 4.1% in the mTFC+ group and - 27.5 ± 3.3% in the mTFC- group. mTFC+ athletes had normal RV-FW-Sl when compared to definite (-29% vs -19%, p < 0.001) and borderline ACM (-29% vs -21%, p < 0.001) cohorts. In addition, all mean global and regional Sl and SRl values were no worse in the mTFC+ group compared to the mTFC- (p values range < 0.0001 to 0.1, inferiority margin of 2% and 0.1 s-1 respectively). CONCLUSIONS: In athletes with RVOT dilation meeting the major mTFC, STE evaluation of the RV can demostrate normal function and differentiate physiological remodelling from pathological changes found in ACM, improving screening in grey-area cases.

The effect of 4 weeks of high-intensity interval training and 2 weeks of detraining on cardiovascular disease risk factors in male adolescents.

NEW FINDINGS: What is the central question of this study? What is the effect of 4 weeks of high-intensity interval training (HIIT) and 2 weeks of detraining on vascular function and traditional cardiovascular disease (CVD) risk factors in male adolescents? What is the main finding and its importance? Four weeks of HIIT improved macrovascular function in adolescents. However, this training period did not measurably change microvascular function, body composition or blood biomarkers. Following 2 weeks of detraining, the improvement in flow-mediated dilatation (FMD) was lost. This highlights the importance of the continuation of regular exercise for the primary prevention of CVD. ABSTRACT: High-intensity interval training (HIIT) represents an effective method to improve cardiometabolic health in adolescents. This study aimed to investigate the effect of 4 weeks of HIIT followed by 2 weeks of detraining on vascular function and traditional cardiovascular disease (CVD) risk factors in adolescent boys. Nineteen male adolescents (13.3 ± 0.5 years) were randomly allocated to either a training (TRAIN, n = 10) or control (CON, n = 9) group. Participants in TRAIN completed 4 weeks of HIIT running with three sessions per week. Macro- (flow-mediated dilatation, FMD) and microvascular (peak reactive hyperaemia, PRH) function, body composition (fat mass, fat free mass, body fat percentage) and blood biomarkers (glucose, insulin, total cholesterol, high- and low-density lipoprotein, triacylglycerol) were assessed pre-, 48 h post- and 2 weeks post-training for TRAIN and at equivalent time points for CON. Following training, FMD was significantly greater in TRAIN compared to CON (9.88 ± 2.40% and 8.64 ± 2.70%, respectively; P = 0.036) but this difference was lost 2 weeks after training cessation (8.22 ± 2.47% and 8.61 ± 1.99%, respectively; P = 0.062). No differences were detected between groups for PRH (P = 0.821), body composition (all P > 0.14) or blood biomarkers (all P > 0.18). In conclusion, 4 weeks of HIIT improved macrovascular function; however, this training period did not measurably change microvascular function, body composition or blood biomarkers. The reversal of the FMD improvement 2 weeks post-training highlights the importance of the continuation of regular exercise for the primary prevention of CVD.

Systematic review and meta-analysis: Associations of vitamin D with pulmonary function in children and young people with cystic fibrosis.

BACKGROUND: Increasing evidence suggests that vitamin D is associated with pulmonary health, which may benefit children and young people diagnosed with Cystic Fibrosis (cypCF). Therefore, the aim of this systematic review was to evaluate primary research to establish associations between 25OHD and pulmonary health in cypCF. METHODS: Electronic databases were searched with keywords related to CF, vitamin D, children/young people and pulmonary function. Included studies were cypCF (aged ≤21 years) treated in a paediatric setting. The primary outcome was lung function [forced expiratory volume in 1 s (FEV1% predicted)] and secondary outcomes were rate of pulmonary exacerbations, 25OHD status and growth. Evidence was appraised for risk of bias using the CASP tool, and quality using the EPHPP tool. A Meta-analysis was performed. RESULTS: Twenty-one studies were included with mixed quality ratings and heterogeneity of reported outcomes. The Meta-analysis including 5 studies showed a significantly higher FEV1% predicted in the 25OHD sufficiency compared to the deficiency group [FEV1% predicted mean difference (95% CI) was 7.71 (1.69-13.74) %; p = 0.01]. The mean ± SD FEV1% predicted for the sufficient (≥75 nmol/L) vs. deficient (<50 nmol/L) group was 94.7 ± 31.9% vs. 86.9 ± 13.2%; I2 = 0%; χ2 = 0.5; df = 4). Five studies (5/21) found significantly higher rate of pulmonary exacerbations in those who were 25OHD deficient when compared to the sufficient group and negative associations between 25OHD and FEV% predicted. The effects of vitamin D supplementation dosages on 25OHD status (10/21) varied across studies and no study (12/21) showed associations between 25OHD concentration and growth. CONCLUSION: This systematic review suggests that 25OHD concentration is positively associated with lung function and a concentration of >75 nmol/L is associated with reduced frequency of pulmonary exacerbations, which may slow lung function decline in cypCF. Future randomised clinical trials and mechanistic studies are warranted.

Expert guidelines on exercise and physical activity for people with cystic fibrosis.

Research has shown that there is a lack of confidence and understanding in how to use exercise for managing cystic fibrosis. This editorial discusses the key points of a consensus statement that highlights what is and is not known about the relationship between cystic fibrosis and exercise.

Heart Rate Variability in Individuals with Down Syndrome: A Scoping Review with Methodological Considerations.

Individuals with Down syndrome (DS) present similar heart rate variability (HRV) parameters at rest but different responses to selected movement maneuvers in comparison to individuals without DS, which indicates reduced vagal regulation. The present study undertakes a scoping review of research on HRV in individuals with DS, with special attention paid to the compliance of the studies with standards and methodological paper guidelines for HRV assessment and interpretation. A review was performed using PubMed, Web of Science and CINAHL databases to search for English language publications from 1996 to 2020 with the MESH terms "heart rate variability" and "down syndrome", with the additional inclusion criteria of including only human participants and empirical investigations. From 74 studies, 15 were included in the review. None of the reviewed studies met the recommendations laid out by the standards and guidelines for providing the acquisition of RR intervals and necessary details on HRV analysis. Since authors publishing papers on this research topic do not adhere to the prescribed standards and guidelines when constructing the methodology, results of the research papers on the topic are not directly comparable. Authors need to design the study methodology more robustly by following the aforementioned standards, guidelines and recommendations.