-
Lasers in Medical Science Feb 2023The aim of this study is to compare needling (RF-needling, meso-needling, micro-needling) and ablative fractional lasers (CO, erbium-YAG) in the treatment of atrophic... (Review)
Review
A systematic review of the comparison between needling (RF-needling, meso-needling, and micro-needling) and ablative fractional lasers (CO, erbium YAG) in the treatment of atrophic and hypertrophic scars.
The aim of this study is to compare needling (RF-needling, meso-needling, micro-needling) and ablative fractional lasers (CO, erbium-YAG) in the treatment of atrophic and hypertrophic scars in a systematic review. The database was searched, and 10 articles were selected that were relevant in terms of content, topic, and purpose and met the inclusion criteria. Of all the articles reviewed in this study, there were 2 randomized split-face trials (20%), 1 controlled nonrandomized trial (10%), 1 controlled randomized phase III clinical trial (10%), 1 prospective trial (10%), 1 prospective nonrandomized open-label trial (10%), and 1 randomized comparative trial (10%), with the type of study not reported in 3 articles. We used Endnote X8 to review the articles and extract data. After review, the studies were analyzed and categorized. No statistically significant difference was found between the two methods, laser and micro-needling, in the treatment of atrophic and hypertrophic scars in 60% of the articles studied, and both showed significant improvement (70% or more improvement to complete response). Significant improvement was noted in 20% of the studies reviewed for the laser and micro-needling treatment methods. The results of this study show that needling and ablative fractional lasers are tolerable and safe procedures with no significant difference in the treatment of skin scars in sixty percent of the studies.
Topics: Humans; Acne Vulgaris; Atrophy; Carbon Dioxide; Cicatrix; Cicatrix, Hypertrophic; Erbium; Lasers, Gas; Lasers, Solid-State; Prospective Studies; Randomized Controlled Trials as Topic; Skin; Treatment Outcome; Clinical Trials as Topic
PubMed: 36749436
DOI: 10.1007/s10103-022-03694-x -
International Journal of Cardiology Jun 2017There is a growing interest in the intersection of heart failure (HF) and frailty; however, estimates of the prevalence of frailty in HF vary widely. The purpose of this... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
There is a growing interest in the intersection of heart failure (HF) and frailty; however, estimates of the prevalence of frailty in HF vary widely. The purpose of this paper was to quantitatively synthesize published literature on the prevalence of frailty in HF and to examine the relationship between study characteristics (i.e. age and functional class) and the prevalence of frailty in HF.
METHODS
The prevalence of frailty in HF, divided into Physical Frailty and Multidimensional Frailty measures, was synthesized across published studies using a random-effects meta-analysis of proportions approach. Meta-regression was performed to examine the influence of age and functional class (at the level of the study) on the prevalence of frailty.
RESULTS
A total of 26 studies involving 6896 patients with HF were included in this meta-analysis. Despite considerable differences across studies, the overall estimated prevalence of frailty in HF was 44.5% (95% confidence interval, 36.2%-52.8%; z=10.54; p<0.001). The prevalence was slightly lower among studies using Physical Frailty measures (42.9%, z=9.05; p<0.001) and slightly higher among studies using Multidimensional Frailty measures (47.4%, z=5.66; p<0.001). There were no significant relationships between study age or functional class and prevalence of frailty.
CONCLUSIONS
Frailty affects almost half of patients with HF and is not necessarily a function of age or functional classification. Future work should focus on standardizing the measurement of frailty and on broadening the view of frailty beyond a strictly geriatric syndrome in HF.
Topics: Clinical Trials as Topic; Frailty; Heart Failure; Prevalence
PubMed: 28215466
DOI: 10.1016/j.ijcard.2017.01.153 -
British Journal of Sports Medicine Apr 2017To examine the effects of stepping interventions on fall risk factors and fall incidence in older people. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To examine the effects of stepping interventions on fall risk factors and fall incidence in older people.
DATA SOURCE
Electronic databases (PubMed, EMBASE, CINAHL, Cochrane, CENTRAL) and reference lists of included articles from inception to March 2015.
STUDY SELECTION
Randomised (RCT) or clinical controlled trials (CCT) of volitional and reactive stepping interventions that included older (minimum age 60) people providing data on falls or fall risk factors.
RESULTS
Meta-analyses of seven RCTs (n=660) showed that the stepping interventions significantly reduced the rate of falls (rate ratio=0.48, 95% CI 0.36 to 0.65, p<0.0001, I=0%) and the proportion of fallers (risk ratio=0.51, 95% CI 0.38 to 0.68, p<0.0001, I=0%). Subgroup analyses stratified by reactive and volitional stepping interventions revealed a similar efficacy for rate of falls and proportion of fallers. A meta-analysis of two RCTs (n=62) showed that stepping interventions significantly reduced laboratory-induced falls, and meta-analysis findings of up to five RCTs and CCTs (n=36-416) revealed that stepping interventions significantly improved simple and choice stepping reaction time, single leg stance, timed up and go performance (p<0.05), but not measures of strength.
CONCLUSIONS
The findings indicate that both reactive and volitional stepping interventions reduce falls among older adults by approximately 50%. This clinically significant reduction may be due to improvements in reaction time, gait, balance and balance recovery but not in strength. Further high-quality studies aimed at maximising the effectiveness and feasibility of stepping interventions are required.
SYSTEMATIC REVIEWS REGISTRATION NUMBER
CRD42015017357.
Topics: Accidental Falls; Aged; Controlled Clinical Trials as Topic; Gait; Humans; Middle Aged; Physical Therapy Modalities; Postural Balance; Randomized Controlled Trials as Topic; Reaction Time
PubMed: 26746905
DOI: 10.1136/bjsports-2015-095452 -
The Cochrane Database of Systematic... Sep 2015Ultrasonography (performed by means of a four-quadrant, focused assessment of sonography for trauma (FAST)) is regarded as a key instrument for the initial assessment of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Ultrasonography (performed by means of a four-quadrant, focused assessment of sonography for trauma (FAST)) is regarded as a key instrument for the initial assessment of patients with suspected blunt abdominal and thoraco-abdominal trauma in the emergency department setting. FAST has a high specificity but low sensitivity in detecting and excluding visceral injuries. Proponents of FAST argue that ultrasound-based clinical pathways enhance the speed of primary trauma assessment, reduce the number of unnecessary multi-detector computed tomography (MDCT) scans, and enable quicker triage to surgical and non-surgical care. Given the proven accuracy, increasing availability of, and indication for, MDCT among patients with blunt abdominal and multiple injuries, we aimed to compile the best available evidence of the use of FAST-based assessment compared with other primary trauma assessment protocols.
OBJECTIVES
To assess the effects of diagnostic algorithms using ultrasonography including in FAST examinations in the emergency department in relation to the early, late, and overall mortality of patients with suspected blunt abdominal trauma.
SEARCH METHODS
The most recent search was run on 30th June 2015. We searched the Cochrane Injuries Group Specialised Register, The Cochrane Library, MEDLINE (OvidSP), EMBASE (OvidSP), ISI Web of Science (SCI-EXPANDED, SSCI, CPCI-S, and CPSI-SSH), clinical trials registers, and screened reference lists. Trial authors were contacted for further information and individual patient data.
SELECTION CRITERIA
We included randomised controlled trials (RCTs). Participants were patients with blunt torso, abdominal, or multiple trauma undergoing diagnostic investigations for abdominal organ injury. The intervention was diagnostic algorithms comprising emergency ultrasonography (US). The control was diagnostic algorithms without US examinations (for example, primary computed tomography (CT) or diagnostic peritoneal lavage (DPL)). Outcomes were mortality, use of CT or invasive procedures (DPL, laparoscopy, laparotomy), and cost-effectiveness.
DATA COLLECTION AND ANALYSIS
Two authors (DS and CG) independently selected trials for inclusion, assessed methodological quality, and extracted data. Methodological quality was assessed using the Cochrane Collaboration risk of bias tool. Where possible, data were pooled and relative risks (RRs), risk differences (RDs), and weighted mean differences, each with 95% confidence intervals (CIs), were calculated by fixed-effect or random-effects models as appropriate.
MAIN RESULTS
We identified four studies meeting our inclusion criteria. Overall, trials were of poor to moderate methodological quality. Few trial authors responded to our written inquiries seeking to resolve controversial issues and to obtain individual patient data. Strong heterogeneity amongst the trials prompted discussion between the review authors as to whether the data should or should not be pooled; we decided in favour of a quantitative synthesis to provide a rough impression about the effect sizes achievable with US-based triage algorithms. We pooled mortality data from three trials involving 1254 patients; the RR in favour of the FAST arm was 1.00 (95% CI 0.50 to 2.00). FAST-based pathways reduced the number of CT scans (random-effects model RD -0.52, 95% CI -0.83 to -0.21), but the meaning of this result was unclear.
AUTHORS' CONCLUSIONS
The experimental evidence justifying FAST-based clinical pathways in diagnosing patients with suspected abdominal or multiple blunt trauma remains poor. Because of strong heterogeneity between the trial results, the quantitative information provided by this review may only be used in an exploratory fashion. It is unlikely that FAST will ever be investigated by means of a confirmatory, large-scale RCT in the future. Thus, this Cochrane Review may be regarded as a review which provides the best available evidence for clinical practice guidelines and management recommendations. It can only be concluded from the few head-to-head studies that negative US scans are likely to reduce the incidence of MDCT scans which, given the low sensitivity of FAST (or reliability of negative results), may adversely affect the diagnostic yield of the trauma survey. At best, US has no negative impact on mortality or morbidity. Assuming that major blunt abdominal or multiple trauma is associated with 15% mortality and a CT-based diagnostic work-up is considered the current standard of care, 874, 3495, or 21,838 patients are needed per intervention group to demonstrate non-inferiority of FAST to CT-based algorithms with non-inferiority margins of 5%, 2.5%, and 1%, power of 90%, and a type-I error alpha of 5%.
Topics: Abdominal Injuries; Algorithms; Emergencies; Humans; Randomized Controlled Trials as Topic; Ultrasonography; Wounds, Nonpenetrating
PubMed: 26368505
DOI: 10.1002/14651858.CD004446.pub4 -
BMJ (Clinical Research Ed.) Mar 2020To systematically examine the design, reporting standards, risk of bias, and claims of studies comparing the performance of diagnostic deep learning algorithms for...
OBJECTIVE
To systematically examine the design, reporting standards, risk of bias, and claims of studies comparing the performance of diagnostic deep learning algorithms for medical imaging with that of expert clinicians.
DESIGN
Systematic review.
DATA SOURCES
Medline, Embase, Cochrane Central Register of Controlled Trials, and the World Health Organization trial registry from 2010 to June 2019.
ELIGIBILITY CRITERIA FOR SELECTING STUDIES
Randomised trial registrations and non-randomised studies comparing the performance of a deep learning algorithm in medical imaging with a contemporary group of one or more expert clinicians. Medical imaging has seen a growing interest in deep learning research. The main distinguishing feature of convolutional neural networks (CNNs) in deep learning is that when CNNs are fed with raw data, they develop their own representations needed for pattern recognition. The algorithm learns for itself the features of an image that are important for classification rather than being told by humans which features to use. The selected studies aimed to use medical imaging for predicting absolute risk of existing disease or classification into diagnostic groups (eg, disease or non-disease). For example, raw chest radiographs tagged with a label such as pneumothorax or no pneumothorax and the CNN learning which pixel patterns suggest pneumothorax.
REVIEW METHODS
Adherence to reporting standards was assessed by using CONSORT (consolidated standards of reporting trials) for randomised studies and TRIPOD (transparent reporting of a multivariable prediction model for individual prognosis or diagnosis) for non-randomised studies. Risk of bias was assessed by using the Cochrane risk of bias tool for randomised studies and PROBAST (prediction model risk of bias assessment tool) for non-randomised studies.
RESULTS
Only 10 records were found for deep learning randomised clinical trials, two of which have been published (with low risk of bias, except for lack of blinding, and high adherence to reporting standards) and eight are ongoing. Of 81 non-randomised clinical trials identified, only nine were prospective and just six were tested in a real world clinical setting. The median number of experts in the comparator group was only four (interquartile range 2-9). Full access to all datasets and code was severely limited (unavailable in 95% and 93% of studies, respectively). The overall risk of bias was high in 58 of 81 studies and adherence to reporting standards was suboptimal (<50% adherence for 12 of 29 TRIPOD items). 61 of 81 studies stated in their abstract that performance of artificial intelligence was at least comparable to (or better than) that of clinicians. Only 31 of 81 studies (38%) stated that further prospective studies or trials were required.
CONCLUSIONS
Few prospective deep learning studies and randomised trials exist in medical imaging. Most non-randomised trials are not prospective, are at high risk of bias, and deviate from existing reporting standards. Data and code availability are lacking in most studies, and human comparator groups are often small. Future studies should diminish risk of bias, enhance real world clinical relevance, improve reporting and transparency, and appropriately temper conclusions.
STUDY REGISTRATION
PROSPERO CRD42019123605.
Topics: Algorithms; Bias; Deep Learning; Diagnostic Imaging; Humans; Image Processing, Computer-Assisted; Physicians; Randomized Controlled Trials as Topic; Research Design
PubMed: 32213531
DOI: 10.1136/bmj.m689 -
Revista Latino-americana de Enfermagem Jun 2017to learn about the effects of the use of therapeutic massage in children with cancer. (Review)
Review
OBJECTIVE:
to learn about the effects of the use of therapeutic massage in children with cancer.
METHOD:
systematic review of controlled clinical trials The search was conducted in November 2014 in the following databases: Pubmed, CSIC, Dialnet, Scopus, Cochrane and PEDro. Inclusion criteria were: clinical trials, published in English or Spanish, analyzing the effects of massage on the different stages and types of childhood cancer (between 1 and 18 years old).
RESULTS:
of 1007 articles found, 7 met the inclusion criteria. Their authors use different massage techniques (Swedish massage, effleurage, petrissage, frictions, pressures), obtaining benefits in the symptoms present during the illness (decrease of pain, nausea, stress, anxiety and increase of white blood cells and neutrophils).
CONCLUSION:
therapeutic massage improves the symptoms of children with cancer, but there is a need for more research that may support the effects attributed to it.
OBJETIVO:
conocer los efectos del uso del masaje terapéutico en niños con cáncer.
MÉTODO:
revisión sistemática de ensayos clínicos controlados la búsqueda se llevó a cabo en noviembre de 2014 en las bases de datos científicas: Pubmed, CSIC, Dialnet, Scopus, Cochrane y PEDro. Los criterios de inclusión han sido: ensayos clínicos, publicados en inglés o español, en los que se analizaran los efectos del masaje en las diferentes etapas y tipos de cáncer infantil (entre 1 y 18 años).
RESULTADOS:
de 1007 artículos localizados, 7 cumplieron los criterios de inclusión. Sus autores utilizan diferentes técnicas de masaje (masaje sueco, effleurage, petrissage, fricciones, presiones), obteniendo beneficios en los síntomas presentes durante la enfermedad (disminución del dolor, náuseas, estrés, ansiedad y aumento de glóbulos blancos y neutrófilos).
CONCLUSIÓN:
el masaje terapéutico mejora los síntomas de los niños con cáncer, que respalden los efectos que se le atribuyen.
OBJETIVO:
conhecer os efeitos do uso da massagem terapêutica em crianças com câncer.
MÉTODO:
revisão sistemática de ensaios clínicos controlados. A pesquisa foi realizada em novembro de 2014 em bases de dados científicas: Pubmed, CSIC, Dialnet, Scopus, Cochrane and PEDro. Os critérios de inclusão foram: ensaios clínicos, publicados em inglês ou espanhol, analisando os efeitos da massagem nas diferentes fases e tipos de câncer infantil (entre 1 e 18 anos).
RESULTADOS:
de 1007 artigos encontrados, 7 preencheram os critérios de inclusão. Os autores utilizam diferentes técnicas de massagem (massagem sueca, effleurage, petrissage, fricções, pressões), obtendo benefícios nos sintomas presentes durante a doença (diminuição da dor, náusea, estresse, ansiedade e aumento de glóbulos brancos e neutrófilos).
CONCLUSÃO:
a massagem terapêutica melhora os sintomas das crianças com câncer, mas são necessárias mais pesquisas que apoiem os efeitos atribuídos a ela.
Topics: Adolescent; Child; Child, Preschool; Controlled Clinical Trials as Topic; Humans; Infant; Massage; Neoplasms; Treatment Outcome
PubMed: 28614430
DOI: 10.1590/1518-8345.1774.2903 -
Alimentary Pharmacology & Therapeutics Aug 2018Fibrotic stricture is a common complication of Crohn's disease (CD) affecting approximately half of all patients. No specific anti-fibrotic therapies are available;...
BACKGROUND
Fibrotic stricture is a common complication of Crohn's disease (CD) affecting approximately half of all patients. No specific anti-fibrotic therapies are available; however, several therapies are currently under evaluation. Drug development for the indication of stricturing CD is hampered by a lack of standardised definitions, diagnostic modalities, clinical trial eligibility criteria, endpoints and treatment targets in stricturing CD.
AIM
To standardise definitions, diagnosis and treatment targets for anti-fibrotic stricture therapies in Chron's disease.
METHODS
An interdisciplinary expert panel consisting of 15 gastroenterologists and radiologists was assembled. Using modified RAND/University of California Los Angeles appropriateness methodology, 109 candidate items derived from systematic review and expert opinion focusing on small intestinal strictures were anonymously rated as inappropriate, uncertain or appropriate. Survey results were discussed as a group before a second and third round of voting.
RESULTS
Fibrotic strictures are defined by the combination of luminal narrowing, wall thickening and pre-stenotic dilation. Definitions of anastomotic (at site of prior intestinal resection with anastomosis) and naïve small bowel strictures were similar; however, there was uncertainty regarding wall thickness in anastomotic strictures. Magnetic resonance imaging is considered the optimal technique to define fibrotic strictures and assess response to therapy. Symptomatic strictures are defined by abdominal distension, cramping, dietary restrictions, nausea, vomiting, abdominal pain and post-prandial abdominal pain. Need for intervention (endoscopic balloon dilation or surgery) within 24-48 weeks is considered the appropriate endpoint in pharmacological trials.
CONCLUSIONS
Consensus criteria for diagnosis and response to therapy in stricturing Crohn's disease should inform both clinical practice and trial design.
Topics: Catheterization; Clinical Trials as Topic; Colon; Consensus; Constriction, Pathologic; Crohn Disease; Dilatation; Endoscopy; Expert Testimony; Fibrosis; Humans; Intestinal Obstruction; Intestine, Small; Practice Guidelines as Topic; Reference Standards
PubMed: 29920726
DOI: 10.1111/apt.14853 -
Orthodontics & Craniofacial Research Nov 2018The aim of this review was to evaluate available evidence on the effect of early orthodontic management and myofunctional treatment in the developing dentition children,... (Meta-Analysis)
Meta-Analysis
Effect of orthodontic management and orofacial muscle training protocols on the correction of myofunctional and myoskeletal problems in developing dentition. A systematic review and meta-analysis.
The aim of this review was to evaluate available evidence on the effect of early orthodontic management and myofunctional treatment in the developing dentition children, on anterior open bite correction, as well as on normalization of patterns of mouth breathing, swallowing and tongue resting position and pressure. Electronic searches in MEDLINE, Cochrane and LILACS, without language restrictions were conducted. Additionally, unpublished literature was identified. Randomized controlled trials, or controlled clinical trials, comparing interventions applied to manage anterior open bite and other muscle functions such as breathing/swallowing pattern and tongue resting position and pressure, were considered. Quality assessment was based on the Cochrane Risk of Bias tool. Random effects meta-analyses were conducted to assess treatment effects. From the 265 initial search results, 15 articles were included in the review. Eight were randomized controlled trials (RCTs) and 7 were controlled clinical trials. Treatment outcomes comprised skeletal and dentoalveolar changes recorded cephalometrically, mouth posture and lip closure normalization, improvement of tongue resting position/pressure and modification of swallowing pattern. Quantitative synthesis was possible for only 2 of the included RCTs. There was no evidence to support bonded lingual spurs over banded fixed appliances for the correction of anterior open bite in mixed dentition children presenting nonnutritive oral habits at the onset of treatment (SMD: -0.03; 95%CI: -.81, 0.74; P = 0.94). Although early orthodontic management and myofunctional treatment in the deciduous and mixed dentition children appears to be a promising approach, the quality of the existing evidence is questionable.
Topics: Humans; Cephalometry; Controlled Clinical Trials as Topic; Databases, Factual; Deglutition; Dentition, Mixed; Facial Muscles; Malocclusion; Mouth Breathing; Myofunctional Therapy; Open Bite; Orthodontic Appliances, Fixed; Orthodontic Appliances, Functional; Randomized Controlled Trials as Topic; Tongue; Tooth, Deciduous; Treatment Outcome
PubMed: 30152171
DOI: 10.1111/ocr.12240 -
JAMA Oncology Apr 2021Older adults with cancer are at risk of overtreatment or undertreatment when decision-making is based solely on chronological age. Although a geriatric assessment is...
IMPORTANCE
Older adults with cancer are at risk of overtreatment or undertreatment when decision-making is based solely on chronological age. Although a geriatric assessment is recommended to inform care, the time and expertise required limit its feasibility for all patients. Screening tools offer the potential to identify those who will benefit most from a geriatric assessment. Consensus about the optimal tool to use is lacking.
OBJECTIVE
To appraise the evidence on screening tools used for older adults with cancer and identify an optimal screening tool for older adults with cancer who may benefit from geriatric assessment.
EVIDENCE REVIEW
Systematic review of 4 databases (MEDLINE, Embase, CINAHL [Cumulative Index to Nursing and Allied Health Literature], and PubMed) with narrative synthesis from January 1, 2000, to March 14, 2019. Studies reporting on the diagnostic accuracy and use of validated screening tools to identify older adults with cancer who need a geriatric assessment were eligible for inclusion. Data were analyzed from March 14, 2019, to March 23, 2020.
FINDINGS
Seventeen unique studies were included, reporting on the use of 12 screening tools. Most studies were prospective cohort studies (n = 11) with only 1 randomized clinical trial. Not all studies reported time taken to administer the screening tools. The Geriatric-8 (G8) (n = 12) and the Vulnerable Elders Survey-13 (VES-13) (n = 9) were the most frequently evaluated screening tools. The G8 scored better in sensitivity and the VES-13 in specificity. Other screening tools evaluated include the Groningen Frailty Index, abbreviated comprehensive geriatric assessment, and Physical Performance Test in 2 studies each. All other screening tools were evaluated in 1 study each.
CONCLUSIONS AND RELEVANCE
To date, the G8 and VES-13 have the most evidence to recommend their use to inform the need for geriatric assessment. When choosing a screening tool, clinicians will need to weigh the tradeoffs between sensitivity and specificity. Future research needs to further validate or improve current screening tools and explore other factors that can influence their use, such as ease of use and resourcing.
Topics: Aged; Early Detection of Cancer; Geriatric Assessment; Humans; Mass Screening; Neoplasms; Prospective Studies; Randomized Controlled Trials as Topic
PubMed: 33443547
DOI: 10.1001/jamaoncol.2020.6736 -
Neuroscience and Biobehavioral Reviews Apr 2019The current meta-analysis aimed to quantify the effectiveness of hypnosis for reducing pain and identify factors that influence efficacy. Six major databases were... (Meta-Analysis)
Meta-Analysis
The current meta-analysis aimed to quantify the effectiveness of hypnosis for reducing pain and identify factors that influence efficacy. Six major databases were systematically searched for trials comparing hypnotic inductions with no-intervention control conditions on pain ratings, threshold and tolerance using experimentally-evoked pain models in healthy participants. Eighty-five eligible studies (primarily crossover trials) were identified, consisting of 3632 participants (hypnosis nö=ö2892, control nö=ö2646). Random effects meta-analysis found analgesic effects of hypnosis for all pain outcomes (gö=ö0.54-0.76, p's<.001). Efficacy was strongly influenced by hypnotic suggestibility and use of direct analgesic suggestion. Specifically, optimal pain relief was obtained for hypnosis with direct analgesic suggestion administered to high and medium suggestibles, who respectively demonstrated 42% (pö<ö.001) and 29% (pö<ö.001) clinically meaningful reductions in pain. Minimal benefits were found for low suggestibles. These findings suggest that hypnotic intervention can deliver meaningful pain relief for most people and therefore may be an effective and safe alternative to pharmaceutical intervention. High quality clinical data is, however, needed to establish generalisability in chronic pain populations.
Topics: Chronic Disease; Clinical Trials as Topic; Humans; Hypnosis; Pain; Pain Management; Treatment Outcome
PubMed: 30790634
DOI: 10.1016/j.neubiorev.2019.02.013