Features from the photoplethysmogram and the electrocardiogram for estimating changes in blood pressure.

There is a growing emphasis being placed on the potential for cuffless blood pressure (BP) estimation through modelling of morphological features from the photoplethysmogram (PPG) and electrocardiogram (ECG). However, the appropriate features and models to use remain unclear. We investigated the best features available from the PPG and ECG for BP estimation using both linear and non-linear machine learning models. We conducted a clinical study in which changes in BP ([Formula: see text]BP) were induced by an infusion of phenylephrine in 30 healthy volunteers (53.8% female, 28.0 (9.0) years old). We extracted a large and diverse set of features from both the PPG and the ECG and assessed their individual importance for estimating [Formula: see text]BP through Shapley additive explanation values and a ranking coefficient. We trained, tuned, and evaluated linear (ordinary least squares, OLS) and non-linear (random forest, RF) machine learning models to estimate [Formula: see text]BP in a nested leave-one-subject-out cross-validation framework. We reported the results as correlation coefficient ([Formula: see text]), root mean squared error (RMSE), and mean absolute error (MAE). The non-linear RF model significantly ([Formula: see text]) outperformed the linear OLS model using both the PPG and the ECG signals across all performance metrics. Estimating [Formula: see text]SBP using the PPG alone ([Formula: see text] = 0.86 (0.23), RMSE = 5.66 (4.76) mmHg, MAE = 4.86 (4.29) mmHg) performed significantly better than using the ECG alone ([Formula: see text] = 0.69 (0.45), RMSE = 6.79 (4.76) mmHg, MAE = 5.28 (4.57) mmHg), all [Formula: see text]. The highest ranking features from the PPG largely modelled increasing reflected wave interference driven by changes in arterial stiffness. This finding was supported by changes observed in the PPG waveform in response to the phenylephrine infusion. However, a large number of features were required for accurate BP estimation, highlighting the high complexity of the problem. We conclude that the PPG alone may be further explored as a potential single source, cuffless, blood pressure estimator. The use of the ECG alone is not justified. Non-linear models may perform better as they are able to incorporate interactions between feature values and demographics. However, demographics may not adequately account for the unique and individualised relationship between the extracted features and BP.

Diagnosing hypertension in primary care: a retrospective cohort study to investigate the importance of night-time blood pressure assessment.

BACKGROUND: Ambulatory blood-pressure monitoring (ABPM) has become less frequent in primary care since the COVID-19 pandemic, with home blood-pressure monitoring (HBPM) often the preferred alternative; however, HBPM cannot measure night-time blood pressure (BP), and patients whose night-time BP does not dip, or rises (reverse dipping), have poorer cardiovascular outcomes. AIM: To investigate the importance of measuring night-time BP when assessing individuals for hypertension. DESIGN AND SETTING: Retrospective cohort study of two patient populations - namely, hospital patients admitted to four UK acute hospitals located in Oxfordshire, and participants of the BP in different ethnic groups (BP-Eth) study, who were recruited from 28 UK general practices in the West Midlands. METHOD: Using BP data collected for the two cohorts, three systolic BP phenotypes (dipper, non-dipper, and reverse dipper) were studied. RESULTS: Among the hospital cohort, 48.9% (n = 10 610/21 716) patients were 'reverse dippers', with an average day-night systolic BP difference of +8.0 mmHg. Among the community (BP-Eth) cohort, 10.8% (n = 63/585) of patients were reverse dippers, with an average day-night systolic BP difference of +8.5 mmHg. Non-dipper and reverse-dipper phenotypes both had lower daytime systolic BP and higher night-time systolic BP than the dipper phenotype. Average daytime systolic BP was lowest in the reverse-dipping phenotype (this was 6.5 mmHg and 6.8 mmHg lower than for the dipper phenotype in the hospital and community cohorts, respectively), thereby placing them at risk of undiagnosed, or masked, hypertension. CONCLUSION: Not measuring night-time BP puts all groups, other than dippers, at risk of failure to identify hypertension. As a result of this study, it is recommended that GPs should offer ABPM to all patients aged ≥60 years as a minimum when assessing for hypertension.

Classifying nocturnal blood pressure patterns using photoplethysmogram features.

Circadian rhythms in blood pressure (BP) may in some cases be indicative of an increased risk of adverse cardiovascular events. However, current methods for assessing these rhythms can be disruptive to sleep, work, and daily activities. Features of the photoplethysmogram (PPG), which can be non-invasively and unobtrusively recorded, have been suggested as surrogate measures of BP. This work investigates the presence of a circadian rhythm in these features and evaluates their potential to classify nocturnal BP patterns. 742 patients who were discharged home from the ICU were selected from the MIMIC-III database. Our results show that a number of PPG features exhibit a clear and observable circadian rhythm. Of the 19 features evaluated, the circadian rhythms of 5 features outperformed heart rate (HR) in terms of correlation with the circadian rhythm of SBP ( ). We also present evidence that a metric combining the PPG features significantly improves BP phenotype classification accuracy. Clinical Relevance-This work suggests that a combined metric of PPG features may be able to accurately assess an individual's circadian rhythm of BP.

The Use of Wearable Pulse Oximeters in the Prompt Detection of Hypoxemia and During Movement: Diagnostic Accuracy Study.

BACKGROUND: Commercially available wearable (ambulatory) pulse oximeters have been recommended as a method for managing patients at risk of physiological deterioration, such as active patients with COVID-19 disease receiving care in hospital isolation rooms; however, their reliability in usual hospital settings is not known. OBJECTIVE: We report the performance of wearable pulse oximeters in a simulated clinical setting when challenged by motion and low levels of arterial blood oxygen saturation (SaO2). METHODS: The performance of 1 wrist-worn (Wavelet) and 3 finger-worn (CheckMe O2+, AP-20, and WristOx2 3150) wearable, wireless transmission-mode pulse oximeters was evaluated. For this, 7 motion tasks were performed: at rest, sit-to-stand, tapping, rubbing, drinking, turning pages, and using a tablet. Hypoxia exposure followed, in which inspired gases were adjusted to achieve decreasing SaO2 levels at 100%, 95%, 90%, 87%, 85%, 83%, and 80%. Peripheral oxygen saturation (SpO2) estimates were compared with simultaneous SaO2 samples to calculate the root-mean-square error (RMSE). The area under the receiver operating characteristic curve was used to analyze the detection of hypoxemia (ie, SaO2<90%). RESULTS: SpO2 estimates matching 215 SaO2 samples in both study phases, from 33 participants, were analyzed. Tapping, rubbing, turning pages, and using a tablet degraded SpO2 estimation (RMSE>4% for at least 1 device). All finger-worn pulse oximeters detected hypoxemia, with an overall sensitivity of ≥0.87 and specificity of ≥0.80, comparable to that of the Philips MX450 pulse oximeter. CONCLUSIONS: The SpO2 accuracy of wearable finger-worn pulse oximeters was within that required by the International Organization for Standardization guidelines. Performance was degraded by motion, but all pulse oximeters could detect hypoxemia. Our findings support the use of wearable, wireless transmission-mode pulse oximeters to detect the onset of clinical deterioration in hospital settings. TRIAL REGISTRATION: ISRCTN Registry 61535692; http://www.isrctn.com/ISRCTN61535692. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1136/bmjopen-2019-034404.

Non-contact physiological monitoring of post-operative patients in the intensive care unit.

Prolonged non-contact camera-based monitoring in critically ill patients presents unique challenges, but may facilitate safe recovery. A study was designed to evaluate the feasibility of introducing a non-contact video camera monitoring system into an acute clinical setting. We assessed the accuracy and robustness of the video camera-derived estimates of the vital signs against the electronically-recorded reference values in both day and night environments. We demonstrated non-contact monitoring of heart rate and respiratory rate for extended periods of time in 15 post-operative patients. Across day and night, heart rate was estimated for up to 53.2% (103.0 h) of the total valid camera data with a mean absolute error (MAE) of 2.5 beats/min in comparison to two reference sensors. We obtained respiratory rate estimates for 63.1% (119.8 h) of the total valid camera data with a MAE of 2.4 breaths/min against the reference value computed from the chest impedance pneumogram. Non-contact estimates detected relevant changes in the vital-sign values between routine clinical observations. Pivotal respiratory events in a post-operative patient could be identified from the analysis of video-derived respiratory information. Continuous vital-sign monitoring supported by non-contact video camera estimates could be used to track early signs of physiological deterioration during post-operative care.

The presence of a circadian rhythm in pulse arrival time and its application for classifying blood pressure night-time dip.

Circadian rhythms of blood pressure (BP) have key diagnostic significance in the assessment of hypertension. The night-time dip or rise in BP (10-20% decrease or increase compared to daytime BP), for example, has been shown to be a strong indicator for cardiovascular disease. However, current methods for assessing the circadian rhythms of BP can be disruptive to sleep, work, and daily activities. Pulse arrival time (PAT) has been suggested as a surrogate measure of BP. This work investigates the presence of a circadian rhythm in PAT and evaluates its application to classify nocturnal BP dip or rise. 769 patients who were discharged home from the ICU were selected from the MIMIC database. Our results show a clear and observable circadian rhythm of PAT that is strongly inversely correlated with BP (r = -0.89). The ratios between nocturnal and diurnal changes in PAT accurately classifies an individual as a nocturnal BP dipper (AUC = 0.72) or a riser (AUC = 0.71).Clinical Relevance-This work shows that you can accurately assess an individuals's circadian rhythm of BP using PAT.

Pulse arrival time as a surrogate of blood pressure.

Various models have been proposed for the estimation of blood pressure (BP) from pulse transit time (PTT). PTT is defined as the time delay of the pressure wave, produced by left ventricular contraction, measured between a proximal and a distal site along the arterial tree. Most researchers, when they measure the time difference between the peak of the R-wave in the electrocardiogram signal (corresponding to left ventricular depolarisation) and a fiducial point in the photoplethysmogram waveform (as measured by a pulse oximeter attached to the fingertip), describe this erroneously as the PTT. In fact, this is the pulse arrival time (PAT), which includes not only PTT, but also the time delay between the electrical depolarisation of the heart's left ventricle and the opening of the aortic valve, known as pre-ejection period (PEP). PEP has been suggested to present a significant limitation to BP estimation using PAT. This work investigates the impact of PEP on PAT, leading to a discussion on the best models for BP estimation using PAT or PTT. We conducted a clinical study involving 30 healthy volunteers (53.3% female, 30.9 ± 9.35 years old, with a body mass index of 22.7 ± 3.2 kg/m[Formula: see text]). Each session lasted on average 27.9 ± 0.6 min and BP was varied by an infusion of phenylephrine (a medication that causes venous and arterial vasoconstriction). We introduced new processing steps for the analysis of PAT and PEP signals. Various population-based models (Poon, Gesche and Fung) and a posteriori models (inverse linear, inverse squared and logarithm) for estimation of BP from PTT or PAT were evaluated. Across the cohort, PEP was found to increase by 5.5 ms ± 4.5 ms from its baseline value. Variations in PTT were significantly larger in amplitude, - 16.8 ms ± 7.5 ms. We suggest, therefore, that for infusions of phenylephrine, the contribution of PEP on PAT can be neglected. All population-based models produced large BP estimation errors, suggesting that they are insufficient for modelling the complex pathways relating changes in PTT or PAT to changes in BP. Although PAT is inversely correlated with systolic blood pressure (SBP), the gradient of this relationship varies significantly from individual to individual, from - 2946 to - 470.64 mmHg/s in our dataset. For the a posteriori inverse squared model, the root mean squared errors (RMSE) for systolic and diastolic blood pressure (DBP) estimation from PAT were 5.49 mmHg and 3.82 mmHg, respectively. The RMSEs for SBP and DBP estimation by PTT were 4.51 mmHg and 3.53 mmHg, respectively. These models take into account individual calibration curves required for accurate blood pressure estimation. The best performing population-based model (Poon) reported error values around double that of the a posteriori inverse squared model, and so the use of population-based models is not justified.

A Chest Patch for Continuous Vital Sign Monitoring: Clinical Validation Study During Movement and Controlled Hypoxia.

BACKGROUND: The standard of care in general wards includes periodic manual measurements, with the data entered into track-and-trigger charts, either on paper or electronically. Wearable devices may support health care staff, improve patient safety, and promote early deterioration detection in the interval between periodic measurements. However, regulatory standards for ambulatory cardiac monitors estimating heart rate (HR) and respiratory rate (RR) do not specify performance criteria during patient movement or clinical conditions in which the patient's oxygen saturation varies. Therefore, further validation is required before clinical implementation and deployment of any wearable system that provides continuous vital sign measurements. OBJECTIVE: The objective of this study is to determine the agreement between a chest-worn patch (VitalPatch) and a gold standard reference device for HR and RR measurements during movement and gradual desaturation (modeling a hypoxic episode) in a controlled environment. METHODS: After the VitalPatch and gold standard devices (Philips MX450) were applied, participants performed different movements in seven consecutive stages: at rest, sit-to-stand, tapping, rubbing, drinking, turning pages, and using a tablet. Hypoxia was then induced, and the participants' oxygen saturation gradually reduced to 80% in a controlled environment. The primary outcome measure was accuracy, defined as the mean absolute error (MAE) of the VitalPatch estimates when compared with HR and RR gold standards (3-lead electrocardiography and capnography, respectively). We defined these as clinically acceptable if the rates were within 5 beats per minute for HR and 3 respirations per minute (rpm) for RR. RESULTS: Complete data sets were acquired for 29 participants. In the movement phase, the HR estimates were within prespecified limits for all movements. For RR, estimates were also within the acceptable range, with the exception of the sit-to-stand and turning page movements, showing an MAE of 3.05 (95% CI 2.48-3.58) rpm and 3.45 (95% CI 2.71-4.11) rpm, respectively. For the hypoxia phase, both HR and RR estimates were within limits, with an overall MAE of 0.72 (95% CI 0.66-0.78) beats per minute and 1.89 (95% CI 1.75-2.03) rpm, respectively. There were no significant differences in the accuracy of HR and RR estimations between normoxia (≥90%), mild (89.9%-85%), and severe hypoxia (<85%). CONCLUSIONS: The VitalPatch was highly accurate throughout both the movement and hypoxia phases of the study, except for RR estimation during the two types of movements. This study demonstrated that VitalPatch can be safely tested in clinical environments to support earlier detection of cardiorespiratory deterioration. TRIAL REGISTRATION: ISRCTN Registry ISRCTN61535692; https://www.isrctn.com/ISRCTN61535692.

Day-to-day progression of vital-sign circadian rhythms in the intensive care unit.

BACKGROUND: Disrupted vital-sign circadian rhythms in the intensive care unit (ICU) are associated with complications such as immune system disruption, delirium and increased patient mortality. However, the prevalence and extent of this disruption is not well understood. Tools for its detection are currently limited. METHODS: This paper evaluated and compared vital-sign circadian rhythms in systolic blood pressure, heart rate, respiratory rate and temperature. Comparisons were made between the cohort of patients who recovered from the ICU and those who did not, across three large, publicly available clinical databases. This comparison included a qualitative assessment of rhythm profiles, as well as quantitative metrics such as peak-nadir excursions and correlation to a demographically matched 'recovered' profile. RESULTS: Circadian rhythms were present at the cohort level in all vital signs throughout an ICU stay. Peak-nadir excursions and correlation to a 'recovered' profile were typically greater throughout an ICU stay in the cohort of patients who recovered, compared to the cohort of patients who did not. CONCLUSIONS: These results suggest that vital-sign circadian rhythms are typically present at the cohort level throughout an ICU stay and that quantitative assessment of these rhythms may provide information of prognostic use in the ICU.

Non-Contact Assessment of Peripheral Artery Haemodynamics Using Infrared Video Thermography.

Skin temperature has long been used as a natural indicator of vascular diseases in the extremities. Considerable correlation between oscillations in skin surface temperature and oscillations of skin blood flow has previously been demonstrated. We hypothesised that the impairment of blood flow in stenotic (subcutaneous) peripheral arteries would influence cutaneous temperature such that, by measuring gradients in the temperature distribution over skin surfaces, one may be able to diagnose or quantify the progression of vascular conditions in whose pathogenesis a reduction in subcutaneous blood perfusion plays a critical role (e.g. peripheral artery disease). As proof of principle, this study investigates the local changes in the skin temperature of healthy humans (15 male, [Formula: see text] years old, BMI [Formula: see text] kg/m 2) undergoing two physical challenges designed to vary their haemodynamic status. Skin temperature was measured in four central regions (forehead, neck, chest, and left shoulder) and four peripheral regions (left upper arm, forearm, wrist, and hand) using an infrared thermal camera. We compare inter-region patterns. Median temperature over the peripheral regions decreased from baseline after both challenges (maximum decrease: [Formula: see text] °C at 60 s after exercise; [Formula: see text] and [Formula: see text] °C at 180 s of cold-water immersion; [Formula: see text]). Median temperature over the central regions showed no significant changes. Our results show that the non-contact measurement of perfusion-related changes in peripheral temperature from infrared video data is feasible. Further research will be directed towards the thermographic study of patients with symptomatic peripheral vascular disease.

Study protocol for an exploratory interventional study investigating the feasibility of video-based non-contact physiological monitoring in healthy volunteers by Mapping Of Lower Limb skIn pErfusion (MOLLIE).

INTRODUCTION: Skin perfusion varies in response to changes in the circulatory status. Blood flow to skin is reduced during haemodynamic collapse secondary to peripheral vasoconstriction, whereas increased skin perfusion is frequently observed when haemodynamics improve with resuscitation. These changes in perfusion may be monitored using non-contact image-based methods. Previous camera-derived physiological measurements have focused on accurate vital signs monitoring and extraction of physiological signals from environmental noise. One of the biggest challenges of camera-derived monitoring is artefacts from motion, which limits our understanding of what parameters may be derived from skin. In this study, we use phenylephrine and glyceryl trinitrate (GTN) to cause vasoconstriction and vasodilation in stationary healthy volunteers to describe directional changes in skin perfusion pattern. METHODS AND ANALYSIS: We aim to recruit 30 healthy volunteers who will undergo protocolised infusions of phenylephrine and GTN, followed by the monitored and timed release of a thigh tourniquet. The experimental timeline will be identical for all participants. Measurements of traditionally used haemodynamic markers (heart rate, blood pressure and stroke volume) and camera-derived measurements will be taken concurrently throughout the experimental period. The parameters of interest from the image data are skin colour and pattern, skin surface temperature, pulsatile signal detected at the skin surface and skin perfusion index. ETHICS AND DISSEMINATION: This study was reviewed and approved by the Oxford University Research and Ethics Committee and Clinical Trials and Research Governance teams (R63796/RE001). The results of this study will be presented at scientific conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN10417167.

Protocol for a prospective, controlled, cross-sectional, diagnostic accuracy study to evaluate the specificity and sensitivity of ambulatory monitoring systems in the prompt detection of hypoxia and during movement.

INTRODUCTION: Automated continuous ambulatory monitoring may provide an alternative to intermittent manual vital signs monitoring. This has the potential to improve frequency of measurements, timely escalation of care and patient safety. However, a major barrier to the implementation of these wearable devices in the ward environment is their uncertain reliability, efficiency and data fidelity. The purpose of this study is to test performance of selected devices in a simulated clinical setting including during movement and low levels of peripheral oxygen saturation. METHODS AND ANALYSIS: This is a single centre, prospective, controlled, cross-sectional, diagnostic accuracy study to determine the specificity and sensitivity of currently available ambulatory vital signs monitoring equipment in the detection of hypoxia and the effect of movement on data acquisition. We will recruit up to 45 healthy volunteers who will attend a single study visit; starting with a movement phase and followed by the hypoxia exposure phase where we will gradually decrease saturation levels down to 80%. We will simultaneously test one chest patch, one wrist worn only and three wrist worn with finger probe devices against 'clinical standard 'and 'gold standard' references. We will measure peripheral oxygen saturations, pulse rate, heart rate and respiratory rate continuously and arterial blood gases intermittently throughout the study. ETHICS AND DISSEMINATION: This study has received ethical approval by the East of Scotland Research Ethics Service REC 2 (19/ES/0008). The results will be broadly distributed through conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: ISRCTN61535692 registered on 10/06/2019.

Risk factors for new-onset atrial fibrillation on the general adult ICU: A systematic review.

PURPOSE: This study was performed to systematically review the available evidence for the risk factors for new-onset atrial fibrillation (NOAF) on the general adult intensive care unit (ICU) and provide a semi-quantitative evidence synthesis. METHODS: We searched the MEDLINE, EMBASE, Cochrane Database of Systematic Reviews and the CENTRAL databases from 1970 to 2018. We included studies of adults based in general ICUs that evaluated potential risk factors for NOAF. We excluded studies involving patients with a history of atrial fibrillation (AF). We semi-qualitatively evaluated the strength of evidence for each identified variable. RESULTS: We screened 1447 studies. Seventeen studies were included in the final analysis. We identified strong evidence for age, male sex, preceding cardiovascular disease, acute renal failure, acute respiratory failure, APACHE score and the use of vasopressors as risk factors for the development of NOAF on the ICU. Modifiable risk factors had not been studied in detail. CONCLUSIONS: We provide the first systematic review with evidence synthesis of risk factors for NOAF on the general adult ICU. Evidence for modifiable risk factors was limited. Further research is therefore required and may contribute towards the evidence-based prevention and management of this important condition.

Non-invasive stroke volume estimation by transthoracic electrical bioimpedance versus Doppler echocardiography in healthy volunteers.

Thoracic electrical bioimpedance (TEB) and transthoracic echocardiography (TTE) are non-invasive methods to estimate stroke volume (SV) and cardiac output (CO). Thoracic electrical bioimpedance is not in widespread clinical use with reports of inaccurate cardiac output estimation compared to invasive monitors, particularly in non-healthy populations. We explore its use as a trend monitor by comparing it against thoracic echocardiography in fifteen healthy volunteers undergoing two physical challenges designed to vary cardiac output. Of all paired values, 54.6% showed gross trend agreement and only 1.9% showed direct disagreement between the two monitors. Our results show thoracic bioimpedance may have a role as a non-invasive cardiac output trend monitor in healthy volunteer studies.

Risk factors for new-onset atrial fibrillation on the general adult ICU: protocol for a systematic review.

INTRODUCTION: Atrial fibrillation (AF) is a common arrhythmia in the critical care environment. New-onset AF is associated with increased mortality and intensive care unit (ICU) length of stay. Observational studies have identified several epidemiological and disease severity-related factors associated with developing new-onset AF on the ICU. However, there are limited data on the modifiable risk factors in the general adult ICU population.We describe a protocol for a systematic review of modifiable and non-modifiable risk factors for new-onset AF in the general adult ICU population. The results of this review will aid the development of risk prediction tools and inform future research into AF prevention on the ICU. METHODS AND ANALYSIS: Medical Literature Analysis and Retrieval System Online, Excerpta Medica database and the Cochrane Library, including Cochrane Database of Systematic Reviews and the Cochrane Central Register of Controlled Trials will be searched for studies that assess the association of patient variables, investigation results, interventions and diagnoses associated with subsequent new-onset AF on the ICU.Only studies involving adult patients admitted to non-service-specific ICUs will be included. We will extract data relating to the statistical association between reversible and non-reversible factors and AF, the quality of the studies and the generalisability of the results. This systematic review will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. ETHICS AND DISSEMINATION: This proposed systematic review will be based on published data, and therefore ethical approval is not required. The findings of this study will be disseminated through publication in a peer reviewed journal and will be presented at conferences. PROSPERO REGISTRATION NUMBER: CRD42017074221.

Availability and performance of image/video-based vital signs monitoring methods: a systematic review protocol.

BACKGROUND: For many vital signs, monitoring methods require contact with the patient and/or are invasive in nature. There is increasing interest in developing still and video image-guided monitoring methods that are non-contact and non-invasive. We will undertake a systematic review of still and video image-based monitoring methods. METHODS: We will perform searches in multiple databases which include MEDLINE, Embase, CINAHL, Cochrane library, IEEE Xplore and ACM Digital Library. We will use OpenGrey and Google searches to access unpublished or commercial data. We will not use language or publication date restrictions. The primary goal is to summarise current image-based vital signs monitoring methods, limited to heart rate, respiratory rate, oxygen saturations and blood pressure. Of particular interest will be the effectiveness of image-based methods compared to reference devices. Other outcomes of interest include the quality of the method comparison studies with respect to published reporting guidelines, any limitations of non-contact non-invasive technology and application in different populations. DISCUSSION: To the best of our knowledge, this is the first systematic review of image-based non-contact methods of vital signs monitoring. Synthesis of currently available technology will facilitate future research in this highly topical area. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016029167.