No evidence of clinical efficacy of oxomemazine in cough, according to a systematic review.

PURPOSE: Cough is a prevalent symptom driving patients to seek medical attention in general practice. Despite its widespread use, the clinical efficacy of oxomemazine, the second most reimbursed molecule in France for symptomatic cough treatment, remains uncertain. This study aims to systematically evaluate the clinical efficacy of oxomemazine in cough. METHODS: A systematic literature review with meta-analysis of randomized controlled trials (RCTs) was conducted according to the Rebuild the Evidence Base (REB) protocol. Clinical trials comparing the efficacy of oxomemazine versus placebo or active comparator in cough were searched for. Trials with insufficient data were excluded. Searches were conducted across major databases (Medline, Cochrane Central Register of Controlled Trials, and Embase) and trial registries (World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov). RCTs comparing oxomemazine versus placebo or active comparators in cough were sought. Risk of bias was assessed using the Cochrane Collaboration's RoB2 tool. The protocol was preregistered on PROSPERO under the number CRD42022345496 (15). This study received no funding. RESULTS: No RCTs were at low risk of bias. Therefore, no meta-analysis was conducted, in accordance to the pre-specified protocol. CONCLUSIONS: This systematic review highlights the lack of evidence regarding the efficacy of oxomemazine in cough treatment and underscores the need for further well-designed clinical trials to inform its clinical utility in primary care settings.

Experiencing and enduring patient distress: the distress of palliative care patients and its emotional impact on physicians in training.

BACKGROUND: The extreme vulnerability experienced by patients in palliative care may result in significant distress. These patients require appropriate care while not pathologizing their natural distress. Given the challenges of caring for people experiencing significant distress, it is important to understand what professionals in training may feel when caring for patients in palliative care. Therefore, the aim of this study was to explore how professionals in training feel when confronted with the distress of patients undergoing palliative care. METHODS: A qualitative study employing interpretative phenomenological analysis was conducted. In 2022, 11 physicians in training were interviewed about their experiences with distressed patients due to palliative care. The interviews were conducted via video conference. The students participated in the national palliative care cross-training and were in their final year of residency training. RESULTS: The interviews revealed the following five themes: feelings of powerlessness, duty to act, difficulty in building a relationship, feeling insecure about oneself, and creating a space for listening and relating. All participants felt powerless in front of their patient's distress. Numerous defense mechanisms were identified that made the relationship with the patient difficult. Four participants described being able to create a space for listening and relating to their patients. CONCLUSIONS: A minority of students could establish a quality relationship with their distressed patients. Two concepts, interprofessional education and the patient-centered approach, were identified and could be developed in training.

A Rebuild the Evidence-Base-reading of cholinesterase inhibitors' effect on all-cause mortality in patients with dementia.

We propose a new reading of the results of a solid systematic review published in 2022 in Neurology by Truong et al. comparing cholinesterase inhibitors (ChEIs) treatment to placebo or no treatment on all-cause mortality in patients with any type of dementia. Leaving ethical considerations aside, we tested if another method of interpretation of the results of the systematic review would yield different results. We applied the "Rebuild the Evidence Base" method to the data extracted from the meta-analysis and found that the positive result of the meta-analysis (P = .01) and the lack of heterogeneity did not weigh enough in the balance against the strictly exploratory nature of all the results of the individual randomized controlled trials included and the suspected publication bias. There was a lack of evidence of effect of ChEI treatment on overall mortality in patients with dementia.

The roles of French community pharmacists in palliative home care.

BACKGROUND: The World Health Organization identifies pharmacists as a key resource in palliative care. However, the roles of these professionals in end-of-life care at home remain poorly understood, and community pharmacists themselves sometimes struggle to recognize their true role in this care. The aim of our study was to analyze community pharmacists' representations of their roles in palliative care at home in France. METHODS: The methodology was qualitative and based on semi-structured interviews with community pharmacists (n = 26). The analysis of the interviews was carried out using a qualitative content approach with thematic and lexical analysis. RESULTS: Three main elements of the community pharmacist's role were identified: drug expertise, care management, and psychosocial support for patients and their families. CONCLUSIONS: This study highlights a wide variety of roles adopted by French community pharmacists in palliative care at home. Some of these roles, which are in line with WHO recommendations on palliative care, have been little described to date. These roles of community pharmacists in home-based palliative care could be better recognized, and the players better integrated into end-of-life care systems at home, in order to improve such care. TRIAL REGISTRATION: This work was carried out within the framework of a call for projects from the Fondation de France and has received the approval of the University Clermont Auvergne Research Ethics Committee (no. IRB00011540-2021-60).

Pediatric pharmaceutical interventions in self-medication: a descriptive study in community pharmacies.

BACKGROUND: The practice of self-medication is common but not without risk, especially for vulnerable populations such as the pediatric population. Community pharmacists have an important role of vigilance in dispensing drugs available without a medical prescription, with the possibility of carrying out a Pharmaceutical Intervention (PI) if necessary. The aim of our study was to characterize the Pediatric Pharmaceutical Interventions (PPIs) in self-medication carried out during a spontaneous request for a drug at the community pharmacy. METHODS: We conducted a descriptive study in 139 pharmacies in the Auvergne-Rhône-Alpes region (France). Data were collected from students under the supervision of internship masters in the pharmacy, using the validated GIPAMED (GrId for PhArmaceutical Self-MEDication interventions) notification grid, the first week of each month, from February to May for five years (2017 to 2021). Collected data were entered on a secure university platform. RESULTS: Of the 3,552 PIs collected, 8,3% (n = 286) were PPIs. Of these PPIs, 35% (n = 100) was generated by requests for optional prescription drugs contraindicated by the pathophysiological condition, 28.3% for drugs requiring a prescription and 20.6% for over the counter drugs not indicated by the symptomatology. Finally, 10% of requests required a referral for a medical consultation. Four Anatomical Therapeutic Chemical (ATC) classes accounted for more than 90% of the requests: respiratory system (39.5%), alimentary tract and metabolism (19.2%), nervous system (11.5%), and musculoskeletal system (10.8%). The most common drugs generating PPIs were: ibuprofen, oxomemazine and combination camphor/essential oils, mainly due to age-related or weight-related contraindication. Paracetamol also generated PPIs frequently, mainly due to problems with drug compliance and more precise infra-therapeutic doses. When these PPIs were dispensed, the pharmacist's proposed solutions were accepted in 94.8% (n = 271) of the cases. CONCLUSIONS: The community pharmacist has an important role in providing information about medicines and their correct use to patients. Our research shows that this attention benefits vulnerable populations, such as children, even for drugs that are widely used (e.g. paracetamol and non-steroidal anti-inflammatory drugs) or active substances for which there are age-related or weight-related contraindications (e.g. antitussives, camphor combinations).

Prescription-free consultation: A cross-sectional study in general practice.

PURPOSE: In 2005, 10% of consultations in France ended without a prescription. In 2019, a review of the literature found 30 to 70% of prescription-free consultations in Northern Europe and 10 to 22% in Southern Europe and underlined the scarcity of quantitative data. Different factors contribute to this heterogeneity, such as product availability and status, modes of management, distribution channels, clinical practice recommendations, public policies targeting certain classes, etc. The main objective of our study was to quantify the rate of prescription-free consultations in general practice in France in 2021. The secondary objective was to characterize prescription-free consultations and analyze their determinants. METHODS: This was a quantitative observational study conducted using self-questionnaires among patients in medical practices in Auvergne. RESULTS: Out of 540 questionnaires, the rate of prescription-free consultations was 24% (95% CI [20.11-27.41]). Prescription-free consultations were for prevention, administrative problems, and gestures. The limiting factors are "feeling a need for a medication" (OR=0,006), "not knowing if a medication is needed" (OR=0.11) and "consultations for acute reasons" (OR=0.33). CONCLUSION: Acute consultations limit prescription-free consultations. General practitioners (GPs) probably overestimate patients' expectation of drug prescription. The French GP must be supported in their decision to not prescribe drugs. This is a long-term investment of time, to educate patients and avoid new consultations for acute reasons. A tool to help doctors manage non-prescription during acute consultations will be created in a future study in France.

Prescription-free consultation in France and Europe: Rates' evolution, physicians' and patients' perceptions from 2005 to 2019, a systematic review.

BACKGROUND: In 2005, the rate of prescription-free consultations in Europe varied widely: 57% in the Netherlands, 28% in Germany, 17% in Spain and 10% in France. OBJECTIVES: To assess the number of prescription-free consultations in European countries since 2005 and to analyse the perceptions of patients and general practitioners (GPs). METHODS: This was a systematic review of the literature from 2005 to 2019, including both quantitative and qualitative studies on prescription-free consultations. RESULTS: Of 13,380 studies, 28 were included. The rates of prescription-free consultations were 30% in Belgium, 41% in Slovenia, 47% in the UK and 22% in France, according to the most recent figures. Swedish GPs estimated their prescription-free consultation rate at 70%. The only significant factor that decreased the number of prescription-free consultations was laboratory visits. According to the qualitative data, the main constraint was lack of time; the main facilitating factor was a shared medical decision. CONCLUSION: Medical visits decreased the number of prescription-free consultations. According to qualitative studies, the main barrier was lack of time. The countries with the highest drug consumption levels were those with the lowest number of prescription-free consultations. Achieving prescription-free consultations to combat overmedication and for the quality of care and the environment is a priority. To understand and analyse consultations without prescriptions, a quantitative observational study was launched in France in 2020.

Applying Landscape Ecology in Local Planning, Some Experiences.

Landscape ecology is repeatedly described as an applied science that can help reduce the negative effects of land-use and land-use changes on biodiversity. However, the extent to which landscape ecology is in fact contributing to planning and design processes is questioned. The aim of this paper is to investigate if and how landscape ecology can be integrated in a planning and design process, and to uncover possible problems that, e.g., landscape architects and planners, may face in such processes. Our conclusion, based on a case study from Asker municipality, Norway, is that such a landscape ecological approach has a lot to offer. However, it is difficult to exploit the potential fully for different reasons, e.g., biodiversity information tends to be specialized, and not easily used by planners and designers, and landscape ecological principles need an adaptation process to be applicable in a real-world situation. We conclude that for the situation to improve, landscape ecologists need to ease this process. In addition, we recommend collaboration across disciplinary boundaries, preferably with a common design concept as a foundation.

Patients' acceptance of less blood pressure measurement in consultation: a cross-sectional study in general practice.

PURPOSE: Blood pressure (BP) is measured at almost every general practitioner (GP) consultation in the region of Auvergne, France. A 2018 qualitative study shows that GPs measure BP to satisfy patients, whereas patients declare themselves indifferent to the absence of the measurement. The objective was to validate the results of a qualitative study, to quantitatively assess patient satisfaction when BP is not measured, and to study the factors associated with the degree of patient satisfaction. METHODS: This was a quantitative observational study conducted using self-questionnaires among patients in medical practices in Auvergne. RESULTS: Four hundred and ninety-two questionnaires were evaluated in 20 medical practices. Sixty percent of patients had indifferent or favorable feelings in the absence of BP measurement. In bivariate analysis, young age, male sex, absence of pathology, and low frequency of visits were associated with indifferent or favorable feelings in the absence of BP measurement. In multivariable analysis, a history of hypertension and psychiatric history were associated with unfavorable feelings. The intraclass correlation coefficient for practice-related variability was 5.6%. Patients' susceptibility to having particularly favorable or unfavorable feelings could be related to their GP (physician effect). CONCLUSION: The hypothesis put forward in the qualitative study is confirmed: the majority of patients are in favor of or indifferent to the absence of BP measurement in general practice. General practice could be more efficient by measuring BP less frequently and better.

Project rebuild the evidence base (REB): A method to interpret randomised clinical trials and their meta-analysis to present solid benefit-risk assessments to patients.

Evidence-based medicine is the cornerstone of shared-decision making in healthcare today. The public deserves clear, transparent and trust-worthy information on drug efficacy. Yet today, many drugs are prescribed and used without solid evidence of efficacy. Clinical trials and randomised clinical trials (RCTs) are the best method to evaluate drug efficacy and side effects. In a shared medical decision-making approach, general practitioners need drug assessment based on patient-important outcomes. The aim of project rebuild the evidence base (REB) is to bridge the gap between the data needed in clinical practice and the data available from clinical research. The drugs will be assessed on clinical patient important outcomes and for a population. Using the Cochrane tools, we propose to analyse for each population and outcome: 1) a meta-analysis based on RCTs with a low risk of bias overall; 2) an evaluation of results of confirmatory RCTs; 3) a statistical analysis of heterrogeneity between RCTs and 4) an analysis of publication bias. Depending on the results of these analyses, the evidence will be categorized in 4 different levels: firm evidence, evidence (to be confirmed), signal or absence of evidence. Project REB proposes a method for reading and interpreting RCTs and their meta-analysis to produce quality data for general practitioners to focus on risk-benefit assessment in the interest of patients. If this data does not exist, it could enable clinical research to better its aim.

Home blood pressure monitoring and adherence in patients with hypertension on primary prevention treatment: a survey of 1026 patients in general medicine in the Auvergne region.

BACKGROUND: Home blood pressure monitoring (HBPM) could improve blood pressure control through therapeutic adherence. The main objective of this study was to determine the link between HBPM used by hypertensive patients treated in primary care and their medication adherence. METHODS: Cross-sectional comparative study conducted in the Auvergne region from June to November 2016. Patients were recruited by general practitioners (GPs) selected at random. Adherence was evaluated according to the Girerd score. RESULTS: From a sample of eighty-two GPs including 1026 patients, 45% of patients reported owning an HBPM device. Among these, 18% knew the rule of 3 (3 measurements in the morning and 3 in the evening for 3 days) recommended by the French State Health Authority. There was no difference in adherence between patients using HBPM and those who did not. Patients with HBPM using the rule of 3 reported better adherence than patients without the device (p = 0.06), and those who did not perform self-measurements according to the rule of 3 (p = 0.01). Patients who used HBPM according to the rule of 3 were older (p = 0.006) and less smokers (p = 0.001) than the others. Their GPs were more often GP teachers (p < 0.001) who practiced in rural areas (p = 0.001). CONCLUSION: The statistical link between medication adherence and HBPM for patients who apply the rule of 3, emphasizes the importance of the GP educating the patient on the proper use of HBPM.

"I Can't Go Far": Perceptions and Experiences of Heart Failure Patients Regarding Physical Activity: A Qualitative Study Using Semistructured Face-to-Face Interviews.

BACKGROUND: Participation in regular physical activity (RPA) is beneficial to the quality of life and life expectancy of patients with chronic heart failure (CHF). However, it is inadequate in many patients. AIMS: To determine the factors that influence the practice of RPA in patients with CHF managed in general practice. METHOD: This was a qualitative study using semistructured, individual face-to-face interviews. Patients with CHF (New York Heart Association Stages 1-3) capable of participating in RPA were enrolled by their general practitioner. A longitudinal and transversal inductive thematic analysis was performed by two researchers. RESULTS: Five themes emerged from the 19 interviews that were conducted. Poor knowledge of the disease and the benefits of participating in RPA, as well as the lack of motivation or enjoyment, in particular due to the absence of previous participation, were considered significant obstacles. Fear associated with CHF or other comorbidities was also an obstacle. Attendance at a rehabilitation center, family and social circles, and having a pet all appeared to be beneficial. Family and friends were important for motivating the patient to participate in an activity but could also be an obstacle when they were overprotective. CONCLUSION: This study helps highlight the difficulties for patients with CHF associated with participation in RPA. Despite the obstacles, there are enabling factors on which the general practitioner may rely to motivate their patients.

Risk stratification in heart failure decompensation in the community: HEFESTOS score.

AIMS: Because evidence regarding risk stratification predicting prognosis of patients with heart failure (HF) decompensation attended in primary care is lacking, we developed and externally validated a model to forecast death/hospitalization during the first 30 days after an episode of decompensation. The predictive model is based on variables easily obtained in primary care settings. METHODS AND RESULTS: HEFESTOS is a multinational study consisting of a derivation cohort of HF patients recruited in 14 primary healthcare centres in Barcelona and a validation cohort from primary healthcare in 9 other European countries. The derivation and validation cohorts included 561 and 250 patients, respectively. Percentages of women in the derivation and validation cohorts were 56.3% and 47.6% (P = 0.026), respectively. Mean age was 82.2 years (SD 8.03) in the derivation cohort, and 79.3 years (SD 10.3) in the validation one (P = 0.001). HF with preserved ejection fraction represented 72.1% in the derivation cohort and 58.8% in the validation one (P = 0.004). Mortality/hospitalization during the first 30 days after a decompensation episode was 30.5% and 26% (P = 0.225) for the derivation and validation cohorts, respectively. Multivariable logistic regression models were performed to develop a score of risk. The identified predictors were worsening of dyspnoea [odds ratio (OR): 2.5; P = 0.001], orthopnoea (OR: 2.16; P = 0.01), paroxysmal nocturnal dyspnoea (OR: 2.25; P = 0.01), crackles (OR: 2.35; P = 0.01), New York Heart Association functional class III/IV (OR: 2.11; P = 0.001), oxygen saturation ≤ 90% (OR: 4.98; P < 0.001), heart rate > 100 b.p.m. (OR: 2.72; P = 0.002), and previous hospitalization due to HF (OR: 2.45; P < 0.001). The model showed an area under the curve (AUC) of 0.807, 95% confidence interval (CI): [0.770; 0.845] in the derivation cohort and AUC 0.73, 95% CI: [0.660; 0.808] in the validation one. No significant differences between both cohorts were observed (P = 0.08). Regarding probability of hospitalization/death, three risk groups were defined: low <5%, medium 5-20%, and high >20%. Outcome incidence was 2.7% for the low-risk group, 12.8% for medium risk, and 46.2% for high risk in the derivation cohort, and 9.1%, 12.9%, and 39.6% in the validation one. CONCLUSIONS: The HEFESTOS score, based on variables easily accessible in a community setting and validated in an external European cohort, properly predicted the risk of death/hospitalization during the first 30 days after an HF decompensation episode.

Talking about premature ejaculation in primary care: the GET UP cluster randomised controlled trial.

BACKGROUND: Premature ejaculation (PE) is the most common sexual dysfunction in males. A previous qualitative study identified six communication strategies described by GPs to tackle this topic during consultations. AIM: To determine whether these six strategies are more effective than usual care for promoting discussion about PE between patients and their GPs. DESIGN AND SETTING: Cluster randomised controlled trial, stratified in four French regions, with an intervention group (GPs who received a training session on the six communication strategies) and a control group (routine medical care). Participants were males aged 18-80 years consulting for a sexual, urogenital, or psychological reason. METHOD: The efficacy of the training session in communication skills, compared with usual care, was evaluated by determining the percentage of patients who discussed PE with their GP (primary outcome). The percentage of enrolled patients with PE was calculated using a cut-off score >9 of the premature ejaculation diagnostic tool (PEDT) completed by the enrolled patients at Week 4 after the consultation. The quality-of-life changes were evaluated as the SF-12 scale score difference between baseline and Week 4 post-consultation. RESULTS: In total, 130 patients were included by 32 GPs (n = 16 in the intervention and n = 16 in the control group). The percentage of patients who discussed PE was higher in the intervention group than in the control group (42.0% versus 4.9%, absolute difference = 37.1%; 95% confidence intervals [CI] = 24% to 50%, P<0.001). CONCLUSION: Training GPs in communication strategies about PE improves its detection.

Benefits and adverse effects of sacubitril/valsartan in patients with chronic heart failure: A systematic review and meta-analysis.

This review aims to assess the benefits and adverse effects of sacubitril/valsartan in heart failure, with a focus on important patient outcomes. A systematic review was conducted of double-blind randomized controlled trials (RCTs) comparing sacubitril/valsartan versus a reference drug, in heart failure patients with reduced (HFrEF) and preserved (HFpEF) ejection fraction, published in French or English. Searches were undertaken of Medline, Cochrane Central, and Embase. The primary outcomes were all-cause mortality and adverse events. From 2 082 articles analyzed, 5 were included. For all-cause mortality, the absolute numbers for HFrEF (2 RCTs, 4627 patients) were 16% on sacubitril/valsartan and 18% on enalapril, with a risk ratio (RR) of 0.85 [CI = 0.78, 0.93], and 13% vs 14% in with HFpEF (2 RCTs, 5097 patients), with no statistical difference. Under the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, the evidence for HFrEF patients was of moderate quality. For HFrEF patients, an increased risk of symptomatic hypotension and angioedema (low quality of evidence) was shown. There was no statistical difference for the risk of hyperkalemia or worsening renal function. There was a protective RR (0.50 [0.34, 0.75]) for worsening renal function for patients with HFpEF, with a high quality of evidence despite similar absolute numbers (1.4% vs. 2.8%). To keep in mind for shared decision-making, sacubitril/valsartan reduces all-cause mortality in HFrEF patients but for HFpEF further data are needed. Take into consideration the small number of studies to date to assess the risks.

Dielectric Properties of Ovine Heart at Microwave Frequencies.

Accurate knowledge of the dielectric properties of biological tissues is important in dosimetry studies and for medical diagnostic, monitoring and therapeutic technologies. In particular, the dielectric properties of the heart are used in numerical simulations of radiofrequency and microwave heart ablation. In one recent study, it was demonstrated that the dielectric properties of different components of the heart can vary considerably, contrary to previous literature that treated the heart as a homogeneous organ with measurements that ignored the anatomical location. Therefore, in this study, we record and report the dielectric properties of the heart as a heterogeneous organ. We measured the dielectric properties at different locations inside and outside of the heart over the 500 MHz to 20 GHz frequency range. Different parts of the heart were identified based on the anatomy of the heart and their function; they include the epicardium, endocardium, myocardium, exterior and interior surfaces of atrial appendage, and the luminal surface of the great vessels. The measured dielectric properties for each part of the heart are reported at both a single frequency (2.4 GHz), which is of interest in microwave medical applications, and as parameters of a broadband Debye model. The results show that in terms of dielectric properties, different parts of the heart should not be considered the same, with more than 25% difference in dielectric properties between some parts. The specific Debye models and single frequency dielectric properties from this study can be used to develop more detailed models of the heart to be used in electromagnetic modeling.

A Simulation-Based Methodology of Developing 3D Printed Anthropomorphic Phantoms for Microwave Imaging Systems.

This work is devoted to the development and manufacturing of realistic benchmark phantoms to evaluate the performance of microwave imaging devices. The 3D (3 dimensional) printed phantoms contain several cavities, designed to be filled with liquid solutions that mimic biological tissues in terms of complex permittivity over a wide frequency range. Numerical versions (stereolithography (STL) format files) of these phantoms were used to perform simulations to investigate experimental parameters. The purpose of this paper is two-fold. First, a general methodology for the development of a biological phantom is presented. Second, this approach is applied to the particular case of the experimental device developed by the Department of Electronics and Telecommunications at Politecnico di Torino (POLITO) that currently uses a homogeneous version of the head phantom considered in this paper. Numerical versions of the introduced inhomogeneous head phantoms were used to evaluate the effect of various parameters related to their development, such as the permittivity of the equivalent biological tissue, coupling medium, thickness and nature of the phantom walls, and number of compartments. To shed light on the effects of blood circulation on the recognition of a randomly shaped stroke, a numerical brain model including blood vessels was considered.

Benefits and adverse effects of ACE inhibitors in patients with heart failure with reduced ejection fraction: a systematic review and meta-analysis.

PURPOSE: Angiotensin-converting enzyme (ACE) inhibitors are part of first-line treatment for reduced ejection fraction heart failure (HFrEF). The aim was to assess the benefits and adverse effects of ACE inhibitors in HFrEF with a focus on important patient outcomes. METHODS: A systematic review of double-blind randomized clinical trials (RCTs) and comparison of ACE inhibitors versus placebo, in HFrEF patients published in French or English. Searches were undertaken of Medline, Cochrane Central, and Embase. The primary outcomes were all-cause mortality and adverse events. RESULTS: From 636 articles analysed, 11 were included (13,882 patients). For all-cause mortality (5 RCTs, 9277 patients), the number needed to treat (NNT) to avoid one death at 6 months was 50 (33-107). The NNT to prevent one death at 12 months (6 RCTs, 13,016 patients) was 63 (35-314). Under the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, the evidence was of moderate quality. The number needed to harm was 12 (10-15) for cough, 20 (14-31) for hypotension, 23 (17-36) for dizziness, 31 (23-47) for hyperkalaemia, and 49 (30-121) for increased creatinine levels. The quality of evidence was moderate for these criteria except for cough (low quality of evidence). CONCLUSION: This review focuses on clinical elements necessary in a shared decision-making process. In practice, general practitioners will be able to use these data to discuss ACE inhibitor treatment with HFrEF patients. This study was registered in the PROSPERO registry under the reference number CRD42018096930.