Highlighting nuances of blue light phototherapy: Mechanisms and safety considerations

The efficacy of blue light therapy in dermatology relies on numerous clinical studies. The safety remains a topic of controversy, where potentially deleterious effects were derived from in vitro rather than in vivo experiments. The objectives of this work were (1) to highlight the nuances behind “colors” of blue light, light propagation in tissue and the plurality of modes of action; and (2) to rigorously analyze studies on humans reporting both clinical and histological data from skin biopsies with focus on DNA damage, proliferation, apoptosis, oxidative stress, impact on collagen, elastin, immune cells, and pigmentation. We conclude that blue light therapy is safe for human skin. It induces intriguing skin pigmentation, in part mediated by photoreceptor Opsin-3, which might have a photoprotective effect against ultraviolet irradiation. Future research needs to unravel photochemical reactions and the most effective and safe parameters of blue light in dermatology.     

Positive effects of low-dose photodynamic therapy with aminolevulinic acid or its methyl ester in skin rejuvenation and wound healing: An update

In dermatology, photodynamic therapy (PDT) is widely used in skin tumors, infections, etc., because of the killing effect triggered by toxic reactive oxygen species (ROS). However, the ROS concentration is determined by various photosensitizer concentrations and formulations, as well as various irradiation parameters. Low-dose PDT leads to sufficiently low ROS level, which results in biological effects that are the exact opposite of the killing potency. Therefore, in recent years, low-dose PDT has been exploited in improving aging and wound. Low-dose ALA/MAL PDT might improve aging through promoting the proliferation of fibroblasts, blocking DNA damage, counteracting oxidative stress, inhibiting melanogenesis, and remodeling lymphatic vessels in aged skin. Promoting fibroblasts and epidermal stem cells proliferation and migration, promoting granulation tissue formation and angiogenesis and regulating the inflammatory process might be the mechanisms of low-dose ALA/MAL PDT in wound healing. Nevertheless, the positive effects of low-dose PDT have not been thoroughly investigated in dermatology, and high-quality studies are still needed to fill the relevant vacancy.     

Integrated photoacoustic and hyperspectral dual‐modality microscopy for co‐imaging of melanoma and cutaneous squamous cell carcinoma in vivo

Skin carcinoma such as melanoma (MM) and cutaneous squamous cell carcinoma (cSCC) are considered as the highest mortality and the most aggressive skin cancers in dermatology. In view that early diagnosis and treatment can greatly improve the survival rate and life quality of the patients, developing noninvasive and effective evaluation methods is of great significance for the detection and identification of early stage cutaneous cancers. In this article, we propose a hybrid photoacoustic and hyperspectral dual‐modality microscopy to evaluate and differentiate skin carcinoma by structural and multiphysiological parameters. The proposed system's imaging abilities are verified by mimic phantoms and normal mice experiments. Furthermore, in vivo characterization and evaluation results of MM and cSCC mice are obtained successfully, which prove this novel method could be used as a reliable and useful method for skin cancer detection in early stages.     

Optoacoustic monitoring of water content in tissue phantoms and human skin

Skin water content monitoring is important for diagnostics and management of edema, dehydration, and other skin conditions as well as for cosmetic applications. Because optoacoustic (OA) technique has high (optical) contrast and (ultrasound) resolution and significant probing depth, it may be suitable for accurate, noninvasive water content monitoring in the skin. In this work we studied OA response from skin tissue phantoms and human wrist skin in the wavelength range from 1370 nm to 1650 nm using a novel, tunable OPO OA system. We identified optimal wavelengths for OA water content monitoring in different skin layers. The results of our study suggest that the OA technique may become a valuable, quantitative tool for accurate, high-resolution water content monitoring in the skin and other tissues and may find wide applications in dermatology, cosmetology, and tissue trauma management.     

Depth-dependent in vivo human skin backscattering spectra extraction from full-field optical coherence tomography

With homemade active crystalline fibers, we generated bright and broadband light sources for full-field optical coherence tomography, offering deep penetration into skin tissues with cellular resolution at a high frame rate. Extraction of backscattered spectra from the tissue has potential applications in biomedicine. The hysteresis nonlinearity of the piezoelectric transducer actuating the Mirau interferometer has been greatly reduced by a feedforward compensation approach. The linearized hysteresis response enables us to extract depth-dependent spectra accurately. To validate, the complex dispersion of a fused silica plate was characterized with 2% error. Further validation on an in vitro setting, the backscattered spectra from indocyanine green pigment and nonpigmented microspheres were obtained and verified. For in vivo skin measurement, the backscattered spectra show depth-dependent spectral shift and bandwidth variation due to the complex skin anatomy and pigment absorption. Such a high-speed spectra acquisition of in vivo deep tissue backscattering could lead to disease diagnosis in clinical settings.     

Detecting mouse squamous cell carcinoma from submicron full-field optical coherence tomography images by deep learning

The standard medical practice for cancer diagnosis requires histopathology, which is an invasive and time-consuming procedure. Optical coherence tomography (OCT) is an alternative that is relatively fast, noninvasive, and able to capture three-dimensional structures of epithelial tissue. Unlike most previous OCT systems, which cannot capture crucial cellular-level information for squamous cell carcinoma (SCC) diagnosis, the full-field OCT (FF-OCT) technology used in this paper is able to produce images at sub-micron resolution and thereby facilitates the development of a deep learning algorithm for SCC detection. Experimental results show that the SCC detection algorithm can achieve a classification accuracy of 80% for mouse skin. Using the sub-micron FF-OCT imaging system, the proposed SCC detection algorithm has the potential for in-vivo applications.     

Contrast‐enhanced optical coherence tomography for melanoma detection: An in vitro study

Optical coherence tomography (OCT), with a high‐spatial resolution (<10 microns), intermediate penetration depth (~1.5 mm) and volumetric imaging capability is a great candidate to be used as a diagnostic‐assistant modality in dermatology. At this time, the accuracy of OCT for melanoma detection is lower than anticipated. In this letter, we studied for the first time, the use of a novel contrast agent consist of ultra‐small nanoparticles conjugated to a melanoma biomarker to improve the accuracy of OCT for differentiation of melanoma cells from nonmelanoma cells, in vitro. We call this approach SMall nanoparticle Aggregation‐enhanced Radiomics of Tumor (SMART)‐OCT imaging. This initial proof of concept study is the first step toward the broad utilization of this method for high accuracy all types of tumor detection applications.     

Remote photoplethysmography with consumer smartphone reveals temporal differences between glabrous and nonglabrous skin: Pilot in vivo study

Photoplethysmography (PPG) is a noninvasive optical technology, with applications including vital sign extraction and patient monitoring. The PPG acquisition skin type may be of importance. Skin is either nonglabrous (~90%) or glabrous (~10%). Clinical PPG collection is typically from glabrous (fingerpad), while proliferating wearables collecting PPG, which may perform critical functions like arrythmia detection, often acquire from atypical sites. Glabrous skin has significant differences from nonglabrous, including microcirculation, yet comparisons between their PPG signals have not been well reported. Using a smartphone-based remote/contactless PPG, a pilot dataset was collected from the hands (palmar/dorsal) of five healthy volunteers. The data shows statistically significant lead time (52 ± 36 ms) of glabrous over nonglabrous. Further, a trend of glabrous amplitude increase over nonglabrous (31%) was found. Although our study has a small number of participants, these results further the characterization of PPG skin differences, and can be used to inform development of PPG-based devices.     

Comparative analysis of intrinsic skin aging between Caucasian and Asian subjects by slide‐free in vivo harmonic generation microscopy

Phenotypical and functional differences in the intrinsic skin aging process of individuals between Caucasians and Asians have generated considerable interest in dermatology and cosmetic industry. Most of the studies focused on the stratum corneum, and in some other studies inter‐individual differences overwhelms the racial difference. None of the studies comparatively analyzes the difference from the histopathological point of view. Here we report our harmonic generation microscopy study to analyze the difference of intrinsic aging between Caucasian and Asian skin from a histopathological point of view. As a result, the cellular and nuclear areas of basal cells in Caucasian subjects were found to increase at the same rate as the Asian subjects, ideal for scoring age. The maximum thickness of the viable epidermis, the dermal papilla (DP) volume per unit area and the depth of the DP zone in Caucasians were found to decrease at faster rates than those in Asians.     

Analysis of relation between skin elasticity and the entropy of skin image using near‐infrared and visible light sources

Skin elasticity has been regarded as one of the main indicators of skin condition. Current measurement devices for skin elasticity are mostly expensive for home‐use and should contact the skin surface. As a first step to develop improved methods, we focus on the relation between skin elasticity and the entropy of skin images. Reduced skin elasticity causes wrinkles. It spreads frequency components and increases their randomness in the frequency domain. The randomness is quantified as entropy, which is a measure of the disorder of a system in physics. Therefore, skin elasticity is expected to have a negative relation with entropy. This tendency can be improved by applying penetration depth characteristics according to the wavelength of light. From cheeks and forehead of 12 Korean adults, skin images are acquired with three different light sources (470 nm, 870 nm and broadband light) and skin elasticity is measured. The root mean square error between the measured data and the fitted model is “0.27” (870 nm), “0.49” (broadband light) and “1.42” (470 nm). Furthermore, the results are analyzed by classifying by sex, age and measurement area. This study demonstrates the possibility of developing noncontact home‐use devices to measure skin elasticity in the future.     

Exploring the utility of Deep Red Anthraquinone 5 for digital staining of ex vivo confocal micrographs of optically sectioned skin

We investigated the utility of the fluorescent dye Deep Red Anthraquinone 5 (DRAQ5) for digital staining of optically sectioned skin in comparison to acridine orange (AO). Eight fresh-frozen thawed Mohs discard tissue specimens were stained with AO and DRAQ5, and imaged using an ex vivo confocal microscope at three wavelengths (488 nm and 638 nm for fluorescence, 785 nm for reflectance). Images were overlaid (AO + Reflectance, DRAQ5 + Reflectance), digitally stained, and evaluated by three investigators for perceived image quality (PIQ) and histopathological feature identification. In addition to nuclear staining, AO seemed to stain dermal fibers in a subset of cases in digitally stained images, while DRAQ5 staining was more specific to nuclei. Blinded evaluation showed substantial agreement, favoring DRAQ5 for PIQ (82%, Cl 75%-90%, Gwet's AC 0.74) and for visualization of histopathological features in (81%, Cl 73%-89%, Gwet's AC 0.67), supporting its use in digital staining of multimodal confocal micrographs of skin.     

Efficacy and safety of convalescent plasma for severe COVID-19 based on evidence in other severe respiratory viral infections: a systematic review and meta-analysis

BACKGROUND:The safety and efficacy of convalescent plasma in severe coronavirus disease 2019 (COVID-19) remain uncertain. To support a guideline on COVID-19 management, we conducted a systematic review and meta-analysis of convalescent plasma in COVID-19 and other severe respiratory viral infections.METHODS:In March 2020, we searched international and Chinese biomedical literature databases, clinical trial registries and prepublication sources for randomized controlled trials (RCTs) and nonrandomized studies comparing patients receiving and not receiving convalescent plasma. We included patients with acute coronavirus, influenza and Ebola virus infections. We conducted a meta-analysis using random-effects models and assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.RESULTS:Of 1099 unique records, 6 studies were eligible, and none of these included patients with COVID-19. One nonrandomized study (n = 40) on convalescent plasma in severe acute respiratory syndrome coronavirus (SARS-CoV) provided uninformative results regarding mortality (relative risk [RR] 0.10, 95% confidence interval [CI] CI 0.01 to 1.70). Pooled estimates from 4 RCTs on influenza (n = 572) showed no convincing effects on deaths (4 RCTs, RR 0.94, 95% CI 0.49 to 1.81), complete recovery (2 RCTs, odds ratio 1.04, 95% CI 0.69 to 1.64) or length of stay (3 RCTs, mean difference −1.62, 95% CI −3.82 to 0.58, d). The quality of evidence was very low for all efficacy outcomes. Convalescent plasma caused few or no serious adverse events in influenza RCTs (RR 0.85, 95% CI 0.56 to 1.29, low-quality evidence).INTERPRETATION:Studies of non-COVID-19 severe respiratory viral infections provide indirect, very low-quality evidence that raises the possibility that convalescent plasma has minimal or no benefit in the treatment of COVID-19 and low-quality evidence that it does not cause serious adverse events.

Coronavirus disease 2019 (COVID-19) has been diagnosed in nearly 3 million individuals around the globe, of whom around 0.2 million have died.¹ Many patients with COVID-19 develop severe acute respiratory illness requiring admission to intensive care units (ICU) and often mechanical ventilation.² The case fatality rate in COVID-19 may be as high as 2.3% overall² and from 10% to 40% among severely affected individuals. ^3,4 There is an urgent need for effective therapies.Emerging epidemiologic and clinical data show both similarities and differences between severe COVID-19 and severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS).⁵ Similarly, treatment strategies for severe influenza infections tested during the H1N1 pandemic and H5N1 and H7N9 outbreaks could inform the care of patients with severe COVID-19.⁶Of the treatment options proposed for COVID-19,⁷ convalescent plasma has evidence suggesting a mortality benefit for Ebola virus infection.⁸ This intervention has also been tested in other severe acute viral respiratory infections.^6,9,10 “Convalescent plasma” refers to plasma obtained from individuals recently recovered from a viral illness, which is expected to contain the highest levels of polyclonal antibodies directed against the virus.¹¹ Similarly, “hyperimmune plasma” is collected from donors exhibiting high titres of neutralizing antibodies, independent of time elapsed since viral illness. Authors have used the terms interchangeably, and because viral neutralization is only one of the postulated mechanisms by which antibodies exert their antiviral effect, the importance of the distinction between the 2 products remains unclear (Figure 1).Open in a separate windowFigure 1:Potential mechanisms of action of anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in coronavirus disease 2019 (COVID-19). This figure illustrates the normal entry of SARS-CoV-2 in a host cell, in which membrane fusion is mediated by the interaction between the SARS-CoV-2 spike glycoprotein (red) and the angiotensin-converting enzyme 2 (ACE2) receptor (green) on the host cell, either through the cytoplasmic or endosomal route. Antibodies directed against the receptor-binding domain (RBD) of the spike protein can interfere with its interaction with the ACE2 receptor and prevent viral entry in the host cell (panel A). Antibodies directed against epitopes outside the RBD can also exert antiviral functions through other mechanisms (panels B, C and D). The relative importance of these various functions in rescuing patients from an active SARS-CoV-2 infection is unknown. Importantly, neutralization assays generally used to qualify hyperimmune products measure only 1 of the 4 mechanisms depicted here and do not necessarily correlate with the others.Clinicians have typically administered convalescent plasma to patients with viral infections whose condition deteriorated despite supportive care.⁶ Although the primary postulated mechanism of action of convalescent plasma is reduction in viremia (passive immunity),¹² an increase in host immune response (active immunity) has also been proposed.¹³ We describe in Figure 1 the possible mechanisms by which convalescent plasma inhibits severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).Systematic summaries of the available evidence regarding safety and effectiveness can inform the use of convalescent plasma in patients with COVID-19. We therefore conducted a systematic review to summarize the evidence for convalescent plasma to support a guideline on COVID-19 management.¹⁴ Because we anticipated a paucity of direct evidence addressing the use of convalescent plasma in COVID-19, we summarized the available evidence addressing convalescent plasma in the treatment of SARS, MERS and influenza, including H1N1, H7N9 and H5N1, as well as addressing possible adverse effects in patients with Ebola disease.     

Effects of plasma jet,dielectric barrier discharge,photodynamic therapy and sodium hypochlorite on infected curved root canals

The aim of this investigation was to evaluate the effects of 2 different cold atmospheric plasma (CAP) sources, photodynamic therapy and sodium hypochlorite (NaOCl), on infected root canals. Therefore, 50 standardized curved human root canals were infected with Enterococcus faecalis and assigned to 5 groups—negative control (NC), plasma jet (CAP I), dielectric barrier discharge (CAP II), photodynamic therapy (PDT) and NaOCl + passive ultrasonic irrigation—for 30 s. Colony forming units (CFUs) were determined. NaOCl was significantly more effective at reducing CFUs than all test groups (P < .0001 [Mann‐Whitney U test]) in both parts of the root canal. CFUs in PDT were significantly lower than those in CAP II (P = .015), and those in CAP I were lower than those in CAP II (P = .05). Among all other groups and in the apical parts, no significant differences were found (P > .05).      

A comparative analysis of different biofluids using Raman spectroscopy to determine disease activity in ANCA-associated vasculitis

Identifying persistent or relapsing disease in anti-neutrophil cytoplasmic autoantibody- associated vasculitis (AAV) remains a clinical challenge with an unmet need for a reliable biomarker of multisystem disease. In this study, we confirm for the first time that Raman spectroscopy offers a novel cost-effective candidate biomarker to discriminate active disease from remission in AAV with excellent accuracy. Spectrochemical interrogation of plasma and serum samples demonstrated equal ability to discriminate disease activity with good group separation on PC1 direction and a high degree of accuracy on validation testing using blind predictive modelling: F-score 80% for plasma (specificity 93.3%, sensitivity 70%, AUC 0.95) and 80% for serum (specificity 80%, sensitivity 80%, AUC 0.92). Similar findings were seen on analysis of paired remission samples following successful remission-induction therapy. A larger study with longitudinal data is required to validate these findings with the potential to aid patient care.     

Diffuse reflectance spectroscopy as a monitoring tool for gastric mucosal devitalization treatments with argon plasma coagulation

Electrosurgery with argon plasma coagulation is a widespread technique used in various medical fields for applications which range from hemostasis to devitalization processes. Developing tools which provide feedback concerning tissue condition during these surgeries is fundamental for improving the safety and success of this treatment. We present here a method based on diffuse reflectance spectroscopy to monitor gastric mucosal devitalization treatments. The analysis of the diffusely reflected spectra of the tissue allows us to differentiate between ablation states by using linear discriminant analysis (LDA) as a classification algorithm. An ex vivo pilot study on several swine stomachs showed promising results, with 97.8% of correctly classified ablation states on a new unseen stomach, encouraging further tests with human tissue.     

Simple and cheap preparation of fluorescence paper sensor based in carbon dot for visual detection of chloramphenicol

Carbon dots (CDs) are nanometer-scale particles produced from carbon sources that exhibit fluorescence emission. The present work presents the synthesis and characterization of CDs, as well as the sensing studies for the determination of chloramphenicol (CAP). CAP is an antibiotic used in human medicine and agriculture, and its indiscriminate use and inappropriate disposal have caused damage to human health and the environment. The carbonaceous precursor used in the synthesis of CDs was 3,4-diaminobenzoic acid (3,4-DABA) through the hydrothermal method via domestic microwave irradiation. The first synthesis procedure was carried out in the presence of water/ethanol (a-CDs) and the second in the presence of 1 mol/L sodium hydroxide/ethanol (b-CDs). The CDs were initially characterized in terms of spectroscopic properties in the ultraviolet and visible region (UV-visible), Fourier-transform infrared (FTIR) spectra, Raman spectroscopy, and fluorescence emission spectroscopy. Sensing studies for the antibiotic C were performed by fluorescence suppression in the presence of a- and b-CDs, as well as the precursor 3,4-DABA. The a- and b-CDs presented similar values of linear range 0.00080–0.0050 mg/ml and limit of detection (LOD) = 0.00030 mg/ml (0.30 ppm) for CAP. Then, a- and b-CDs were embedded in Whatman and Mellita® filter paper, and CAP sensing was evaluated through UV light excitation.     

Production of endothelial progenitor cells from skin fibroblasts by direct reprogramming for clinical usages

Endothelial progenitor cells (EPCs) play an important role in angiogenesis. However, they exist in limited numbers in the human body. This study was aimed to produce EPCs, for autologous transplantation, using direct reprogramming of skin fibroblasts under GMP-compliant conditions. Fibroblasts were collected and cultured from the skin in DMEM/F12 medium supplemented with 5% activated platelet-rich plasma and 1% antibiotic-antimycotic solution. They were then transfected with mRNA ETV2 and incubated in culture medium under hypoxia (5% oxygen) for 14 d. Phenotype analysis of transfected cells confirmed that single-factor ETV2 transfection successfully reprogrammed dermal fibroblasts into functional EPCs. Our results showed that ETV2 mRNA combined with hypoxia can give rise to functional EPCs. The cells exhibited functional phenotypes similar to endothelial cells derived from umbilical cord vein; they expressed CD31 and VEGFR2, and formed capillary-like structures in vitro. Moreover, these EPCs could significantly improve hindlimb ischemia in mouse models. Although the direct conversion efficacy was low (3.12 ± 0.98%), altogether our study demonstrates that functional EPCs can be produced from fibroblasts and can be used in clinical applications.     

Dependence of laser-induced optical breakdown on skin type during 1064 nm picosecond laser treatment

The current study aims to evaluate the dependence of laser-induced optical breakdown (LIOB) on skin types by using 1064 nm picosecond laser with micro-lens arrays (MLA) and diffractive optical elements (DOE). Both black and white skin tissues were examined to comparatively assess the LIOB effects in the skin in terms of laser-induced vacuolization. The black skin irradiated at 3.0 J/cm² demonstrated that MLA yielded a deeper distribution (180-400 μm) of laser-induced vacuoles with a size of 67 μm, compared to DOE (180-280 μm; 40 μm in size). However, the white skin presented that MLA created larger vacuoles (134 μm in size) in a smaller number at deeper distributions (125-700 μm) than MLA with the black skin. DOE generated no laser-induced vacuolization in the white skin. The white skin tissue with inherent higher scattering could be responsible for deeper vacuolization after the picosecond laser treatment. Further investigations are expected to determine the optimal treatment conditions for various skin types.     

Photoacoustic imaging of in vivo hemodynamic responses to sodium nitroprusside

The in vivo hemodynamic impact of sodium nitroprusside (SNP), a widely used antihypertensive agent, has not been well studied. Here, we applied functional optical-resolution photoacoustic microscopy (OR-PAM) to study the hemodynamic responses to SNP in mice in vivo. As expected, after the application of SNP, the systemic blood pressure (BP) was reduced by 53%. The OR-PAM results show that SNP induced an arterial vasodilation of 24% and 23% in the brain and skin, respectively. A weaker venous vasodilation of 9% and 5% was also observed in the brain and skin, respectively. The results show two different types of blood oxygenation response. In mice with decreased blood oxygenation, the arterial and venous oxygenation was respectively reduced by 6% and 13% in the brain, as well as by 7% and 18% in the skin. In mice with increased blood oxygenation, arterial and venous oxygenation was raised by 4% and 22% in the brain, as well as by 1% and 9% in the skin. We observed venous change clearly lagged the arterial change in the skin, but not in the brain. Our results collectively show a correlation among SNP induced changes in systemic BP, vessel size and blood oxygenation.     

Comparative effect of physical exercise versus statins on improving arterial stiffness in patients with high cardiometabolic risk: A network meta-analysis

BackgroundThe comparative analysis of the effect of several doses of statins against different intensities of physical exercise on arterial stiffness (a measure of cardiovascular risk) could shed light for clinicians on which method is most effective in preventing cardiovascular disease (CVD) and be used to inform shared decision-making between doctors and patients. This study was aimed at analyzing the effect, in high cardiometabolic risk patients, of different statins doses and exercise intensities on arterial stiffness (a measure of cardiovascular risk) by integrating all available direct and indirect evidence in network meta-analyses.Methods and findingsWe systematically searched MEDLINE, Embase, SPORTDiscus, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Web of Science databases from their inception to February 28, 2020; for unpublished trials, we also searched ClinicalTrials.gov. We searched for studies concerning the effect of statins or physical exercise on arterial stiffness, measured by pulse wave velocity (PWV). For methodological quality assessment, Cochrane Collaboration’s tool for assessing risk of bias (RoB2) was used. A network geometry graph was used to assess the strength of the evidence. Comparative evaluation of the interventions effect was performed by conducting a standard pairwise meta-analysis and a network meta-analysis (NMA) for direct and indirect comparisons between interventions and control/nonintervention. A total of 22 studies were included in the analyses (18 randomized controlled trials (RCTs) and 4 nonrandomized experimental studies), including 1,307 patients with high cardiometabolic risk from Asia (3 studies), Oceania (2 studies), Europe (10 studies), North America (5 studies), and South America (2 studies). The overall risk of bias assessed with RoB2 was high in all included studies. For standard pairwise meta-analysis and NMA, high-intensity exercise versus control (mean difference (MD) −0.56; 95% CI: −1.01, −0.11; p = 0.015 and −0.62; 95% CI: −1.20, −0.04; p = 0.038, respectively) and moderate statin dose versus control (MD −0.80, 95% CI: −1.59, −0.01; p = 0.048 and −0.73, 95% CI: −1.30, −0.15; p = 0.014, respectively) showed significant MDs. When nonrandomized experimental studies were excluded, the effect on high-intensity exercise versus control and moderate statin dose versus was slightly modified. The main limitation of this study was that the magnitude of the effect of the exercise interventions could be underestimated due to regression toward the mean bias because the baseline cardiometabolic risk profile of patients in the physical exercise intervention trials was healthier than those in the statins ones; consequently, more modest improvements in physical exercise interventions compared to statins interventions can be expected. Additionally, we might consider as limitations the small study sizes, the heterogeneous patient groups, the focus on a proxy endpoint (PWV), and the high risk of bias.ConclusionsIn this NMA, we found that although many patients could benefit from statins for reducing CVD risk, our results support that, considering the beneficial effects of high-intensity exercise on arterial stiffness, it would be worthwhile to refocus our attention on this type of exercise as an effective tool for the prevention of CVD.Systematic review registrationPROSPERO CRD42019123120.

In this network meta-analysis, Iván Cavero-Redondo and colleagues synthesise findings on statins vs. exercise for alleviating arterial stiffness.