-
Association of arterial stiffness and neuropathy in diabetes: a systematic review and meta-analysis.BMJ Open Diabetes Research & Care Feb 2023Evidence is still emerging on the relationships of arterial stiffness with cardiac autonomic neuropathy (CAN) and peripheral neuropathy (PN). To our knowledge no... (Meta-Analysis)
Meta-Analysis
Evidence is still emerging on the relationships of arterial stiffness with cardiac autonomic neuropathy (CAN) and peripheral neuropathy (PN). To our knowledge no systematic reviews or meta-analyses of these associations have been published. The purpose of our review was to assess the association of arterial stiffness with each type of neuropathy. Medline and Embase were systematically searched for observational studies of arterial stiffness and neuropathy.The systematic review of 60 studies (25 for CAN and 37 for PN), 59 including people with diabetes, showed arterial stiffness overall was higher in people with neuropathy than people without neuropathy. Forty-three studies were included in the meta-analysis. For CAN (19 studies), arterial stiffness was increased in people with neuropathy compared with without, as measured by pulse wave velocity (PWV) (mean difference: 1.32 m/s, 95% CI 0.82 to 1.81, p<0.00001), pulse pressure (PP) (mean difference: 6.25 mmHg, 95% CI 4.51 to 7.99, p<0.00001) or augmentation index (mean difference: 5.52%, 95% CI 3.46 to 7.58, p<0.0001). For PN (26 studies), arterial stiffness was increased in people with neuropathy compared with those without, as measured by PWV (mean difference: 1.22 m/s, 95% CI 0.87 to 1.58, p<0.00001) or PP (mean difference: 4.59 mmHg, 95% CI 2.96 to 6.22, p<0.00001). Only two cohort studies were located so the temporality of the association between arterial stiffness and neuropathy remains unclear. Increased arterial stiffness is associated with CAN and PN.PROSPERO registration number: CRD42019129563.
Topics: Humans; Vascular Stiffness; Pulse Wave Analysis; Diabetes Mellitus; Peripheral Nervous System Diseases; Blood Pressure
PubMed: 36746528
DOI: 10.1136/bmjdrc-2022-003140 -
Neuromodulation : Journal of the... Oct 2023Chronic headache remains a major cause of disability and pain worldwide. Although the literature has extensively described pharmacologic options for headache treatment... (Review)
Review
OBJECTIVES
Chronic headache remains a major cause of disability and pain worldwide. Although the literature has extensively described pharmacologic options for headache treatment and prophylaxis, there remains a paucity of data on the efficacy of neuromodulation interventions for treatment of headache unresponsive to conventional pharmacologic therapy. The primary aim of this review was to appraise the literature for the efficacy of cervical spinal cord stimulation (cSCS) in treating any intractable chronic headache, including migraine headaches (with or without aura), cluster headache, tension headache, and other types of headaches.
MATERIALS AND METHODS
In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, we performed a systematic review by identifying studies in PubMed, Embase (Scopus), Web of Science, and Cochrane Central Register of Controlled Trials that assessed cSCS to treat chronic headache. Data were synthesized qualitatively, with primary outcomes of headache intensity and frequency. The secondary outcome was adverse effects.
RESULTS
In total, 16 studies comprising 107 patients met the inclusion criteria. Findings were presented based on type of headache, which included migraine headache with or without aura, cluster headache, trigeminal neuropathy, occipital neuralgia, posttraumatic headache, cervicogenic headache, short-lasting unilateral neuralgiform headache with autonomic symptoms, and poststroke facial pain. Per the Grading of Recommendations, Assessment, Development and Evaluations criteria, there was very low-quality evidence that cSCS is associated with a decrease in migraine headache frequency, migraine headache intensity, and trigeminal neuropathy intensity. Placement for cSCS leads ranged from C1 to C4.
CONCLUSIONS
Our review suggests promising data from observational studies that cSCS may be helpful in decreasing frequency and intensity of chronic intractable headache. Future well-powered, randomized controlled trials are needed.
Topics: Humans; Cluster Headache; Spinal Cord Stimulation; Headache; Headache Disorders; Migraine Disorders; Post-Traumatic Headache; Neuralgia; Epilepsy; Trigeminal Nerve Diseases
PubMed: 36513586
DOI: 10.1016/j.neurom.2022.10.060 -
Muscle & Nerve Apr 2023Small-fiber neuropathy (SFN) is a disorder that exclusively affects the small nerve fibers, sparing the large nerve fibers. Thinly myelinated Aδ-fibers and unmyelinated... (Review)
Review
Small-fiber neuropathy (SFN) is a disorder that exclusively affects the small nerve fibers, sparing the large nerve fibers. Thinly myelinated Aδ-fibers and unmyelinated C-fibers are damaged, leading to development of neuropathic pain, thermal dysfunction, sensory symptoms, and autonomic disturbances. Although many SFNs are secondary and due to immunological causes or metabolic disturbances, the etiology is unknown in up to half of the patients. Over the years, this proportion of "idiopathic SFN" has decreased, as familial and genetic causes have been discovered, thus shifting a proportion of once "idiopathic" cases to the genetic category. After the discovery of SCN9A-gene variants in 2012, SCN10A and SCN11A variants have been found to be pathogenic in SFN. With improved accessibility of SFN diagnostic tools and genetic tests, many non-SCN variants and genetically inherited systemic diseases involving the small nerve fibers have also been described, but only scattered throughout the literature. There are 80 SCN variants described as causing SFN, 8 genes causing hereditary sensory autonomic neuropathies (HSAN) described with pure SFN, and at least 7 genes involved in genetically inherited systemic diseases associated with SFN. This systematic review aims to consolidate and provide an updated overview on the genetic variants of SFN to date---SCN genes and beyond. Awareness of these genetic causes of SFN is imperative for providing treatment directions, prognostication, and management of expectations for patients and their health-care providers.
Topics: Humans; Small Fiber Neuropathy; Neuralgia; Nerve Fibers, Unmyelinated; Genetic Testing; Causality; NAV1.7 Voltage-Gated Sodium Channel
PubMed: 36448457
DOI: 10.1002/mus.27752 -
Orphanet Journal of Rare Diseases Sep 2022Hereditary transthyretin amyloidosis (hATTR) is a progressive and fatal disease with heterogenous clinical presentations, limited diagnosis and poor prognosis. This...
BACKGROUND
Hereditary transthyretin amyloidosis (hATTR) is a progressive and fatal disease with heterogenous clinical presentations, limited diagnosis and poor prognosis. This retrospective analysis study aimed to report the genotypes and phenotypes of herediary transthyretin amyloidosis (hATTR) in Chinese through a systematic review of published literature.
METHODS
The systematic review included structured searches of peer-reviewed literature published from 2007 to 2020 of following online reference databases: PubMed, Web of Science and the literature database in China. Extracted data included sample size, personal information (sex, age, natural course, family history), mutation type, clinical milestones and reason of death.
RESULTS
We described 126 Chinese patients with hereditary transthyretin amyloidosis identified through a systematic review of 30 studies. The most common genotype in the Chinese population was Gly83Arg (25, 19.8%), which most likely presented visual and neurological abnormalities without reported death. The second and third most common genotypes were Val30Met (20, 15.9%) and Val30Ala (10, 7.9%). Peripheral neurological manifestations (91, 72%) were dominant in 126 patients. The followed manifestation was autonomic neurological abnormalities (73, 58%). Half of the cases were reported to have visual disorders, and nearly one-third of the cases presented cardiac abnormalities. Among all 126 reported patients, 46.03% were classified as neurological type, 30.16% as mixed type and only 2.38% as cardiac type. In addition. Chinese patients were mostly early onset, with age of onset at 41.8 (SD: 8.9) years, and the median time from onset to death was 7.5 [IQR: 5.3] years. Patients with cardiac involvement had a shorter survival duration (log Rank (Mantel-Cox), χ = 26.885, P < 0.001).
CONCLUSIONS
This study focused on 126 Chinese hATTR patients obtained from a literature review. A total of 26 kinds of TTR mutations were found and the most common one was Gly83Arg. As for phenotype, 46.03% were classified as neurological type, 30.16% as mixed type and only 2.38% as cardiac type. Chinese hATTR patients were mostly early onset (AO 41.8 years), and the median time from onset to death was 7.5 years.
Topics: Amyloid Neuropathies, Familial; Humans; Phenotype; Prealbumin; Retrospective Studies
PubMed: 36056432
DOI: 10.1186/s13023-022-02481-9 -
Diabetes & Metabolism Journal Nov 2022In addition to the metabolic effects in diabetes, glucagon-like peptide 1 receptor (GLP-1R) agonists lead to a small but substantial increase in heart rate (HR).... (Meta-Analysis)
Meta-Analysis
BACKGROUND
In addition to the metabolic effects in diabetes, glucagon-like peptide 1 receptor (GLP-1R) agonists lead to a small but substantial increase in heart rate (HR). However, the GLP-1R actions on the autonomic nervous system (ANS) in diabetes remain debated. Therefore, this meta-analysis evaluates the effect of GLP-1R agonist on measures of ANS function in diabetes.
METHODS
According to the Cochrane Collaboration and Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, we conducted a meta-analysis considering clinical trials in which the autonomic function was evaluated in diabetic subjects chronically treated with GLP-1R agonists. The outcomes were the change of ANS function measured by heart rate variability (HRV) and cardiac autonomic reflex tests (CARTs).
RESULTS
In the studies enrolled, HR significantly increased after treatment (P<0.001), whereas low frequency/high frequency ratio did not differ (P=0.410); no changes in other measures of HRV were detected. Considering CARTs, only the 30:15 value derived from lying-to-standing test was significantly lower after treatment (P=0.002), but only two studies reported this measurement. No differences in other CARTs outcome were observed.
CONCLUSION
The meta-analysis confirms the HR increase but seems to exclude an alteration of the sympatho-vagal balance due to chronic treatment with GLP-1R agonists in diabetes, considering the available measures of ANS function.
Topics: Humans; Autonomic Nervous System; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor
PubMed: 35410110
DOI: 10.4093/dmj.2021.0314 -
Acta Diabetologica Mar 2022We aimed to estimate the prevalence of Diabetic peripheral neuropathy (DPN) and Cardiac autonomic neuropathy (CAN) in youth with type 1 diabetes; identify key risk... (Review)
Review
A systematic review of the prevalence, risk factors and screening tools for autonomic and diabetic peripheral neuropathy in children, adolescents and young adults with type 1 diabetes.
AIMS
We aimed to estimate the prevalence of Diabetic peripheral neuropathy (DPN) and Cardiac autonomic neuropathy (CAN) in youth with type 1 diabetes; identify key risk factors; identify the most useful tests for the diagnostic evaluation of DPN and CAN; identify key treatment options for DPN and CAN.
METHODS
A systematic search was performed including studies published in the last 15 years. PICO framework was used in the selection process and evidence was assessed using the GRADE system.
RESULTS
A total of 758 studies were identified and a final number of 49 studies were included in this systematic review. According to moderate-high level quality studies, the prevalence of probable DPN, ranged between 13.5 and 62%; subclinical DPN between 22 and 88%; confirmed DPN between 2.6 and 11%. The Michigan Neuropathy Screening Instrument was the tool with higher sensitivity and specificity for detecting DPN, which needs to be confirmed by nerve conduction velocity. The prevalence of CAN was 4-39%. Specific treatment options for DPN or CAN in patients younger than 25 years are not available. Key risk factors for DPN and CAN are hyperglycemia/HbA1c, age, diabetes duration, the presence of other microvascular complications, waist/height ratio, lipid profile and blood pressure. For CAN, additional risk factors were cigarette smoking, BMI and total daily insulin.
CONCLUSIONS
Prevalence of neuropathy in youth with type 1 diabetes varies depending on different screening methods and characteristics of the study populations. However, the assessed studies confirmed a relatively high prevalence of subclinical neuropathy, reiterating the importance of early identification of risk factors to prevent this complication.
Topics: Adolescent; Child; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Humans; Prevalence; Risk Factors; Young Adult
PubMed: 35089443
DOI: 10.1007/s00592-022-01850-x -
BMJ Open Diabetes Research & Care Jan 2022Continuous glucose monitoring (CGM)-derived time in range (TIR) correlates with hemoglobin A1c (A1c) among patients with type 2 diabetes mellitus (T2DM); however, there...
Continuous glucose monitoring (CGM)-derived time in range (TIR) correlates with hemoglobin A1c (A1c) among patients with type 2 diabetes mellitus (T2DM); however, there is a paucity of data evaluating its association with microvascular complications. We conducted this systematic review to examine the association between TIR and microvascular complications of diabetic retinopathy (DR), diabetic nephropathy (DN), and diabetic peripheral neuropathy (DPN). We conducted a comprehensive literature search on PubMed, Scopus, and Web of Science online databases following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Full-text original articles that evaluated the association between CGM-derived TIR and risk of microvascular complications and were published between 2010 and June 2021 were included in our systematic review. The quality of the included studies was evaluated using the National Heart, Lung, and Blood Institute Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. Data were analyzed using qualitative synthesis. Eleven studies on a total of 13 987 patients were included in the systematic review. The median sample size, baseline A1c, and diabetes duration were 466 patients (range: 105-5901), 8.2% (SD 0.5%), and 11.3 years (1.0), respectively. Majority of the studies were conducted in Asia (10 out of 11). Four studies evaluated the relationship between CGM-derived TIR and DR and CGM-derived TIR and DN, while seven studies evaluated the relationship between CGM-derived TIR and DPN. A 10% increase in TIR was associated with a reduction in albuminuria, severity of DR, and prevalence of DPN and cardiac autonomic neuropathy. In addition, an association was observed between urinary albumin to creatinine ratio but not with estimated glomerular filtration rate. This review summarizes recent evidence supporting an association between CGM-derived TIR and microvascular complications among patients with T2DM. A larger-scale multicenter investigation that includes more diverse participants is warranted to further validate the utility of TIR as a predictor of diabetic microvascular complications.
Topics: Blood Glucose; Blood Glucose Self-Monitoring; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans
PubMed: 34980591
DOI: 10.1136/bmjdrc-2021-002573 -
BMJ Open Diabetes Research & Care Dec 2021We aimed to determine the prognostic association between cardiac autonomic neuropathy (CAN) and cardiovascular disease events (CVE) and mortality in type 1 and type 2... (Meta-Analysis)
Meta-Analysis Review
We aimed to determine the prognostic association between cardiac autonomic neuropathy (CAN) and cardiovascular disease events (CVE) and mortality in type 1 and type 2 diabetes through a systematic review and meta-analysis. This systematic review and meta-analysis was registered with PROSPERO (CRD42020216305) and was conducted with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodological criteria. CAN was defined on the basis of 1 (early/possible CAN) or ≥2 (definite CAN) positive autonomic function tests as per the Toronto Consensus guidelines. Studies included those with prospective CVE or mortality data. Methodological variables/risk of bias were assessed using ROBINS-I (Risk Of Bias In Non-randomized Studies - of Interventions) and RoB-2 (Risk-Of-Bias tool for randomized trials) appraisal tools. Electronic database searches yielded 18 467 articles; 84 articles were screened full-text, 26 articles fulfilled the inclusion criteria for quantitative synthesis. Sixteen studies from patients with (n=2875) and without (n=11 722) CAN demonstrated a pooled relative risk (RR) of 3.16 (95%CI 2.42 to 4.13; p<0.0001) of future CVE in favour of CAN. Nineteen studies provided all-cause mortality data from patients with (n=3679) and without (n=12 420) CAN, with a pooled RR of 3.17 (95%CI 2.11 to 4.78; p<0.0001) in favour of CAN. The risk of both future CVE and mortality was higher in type 1 compared with type 2 diabetes and with a definite CAN (vs possible CAN) diagnosis. Three studies were considered to have risk of serious bias. This study confirms the significant association between CAN and CVE and all-cause mortality. The implementation of population-based CAN screening will identify a subgroup with disproportionately higher cardiovascular and mortality risk that will allow for earlier targeted intervention.
Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Humans; Mass Screening; Prognosis
PubMed: 34969689
DOI: 10.1136/bmjdrc-2021-002480 -
The Cochrane Database of Systematic... Dec 2021Implanted spinal neuromodulation (SNMD) techniques are used in the treatment of refractory chronic pain. They involve the implantation of electrodes around the spinal... (Review)
Review
BACKGROUND
Implanted spinal neuromodulation (SNMD) techniques are used in the treatment of refractory chronic pain. They involve the implantation of electrodes around the spinal cord (spinal cord stimulation (SCS)) or dorsal root ganglion (dorsal root ganglion stimulation (DRGS)), and a pulse generator unit under the skin. Electrical stimulation is then used with the aim of reducing pain intensity.
OBJECTIVES
To evaluate the efficacy, effectiveness, adverse events, and cost-effectiveness of implanted spinal neuromodulation interventions for people with chronic pain.
SEARCH METHODS
We searched CENTRAL, MEDLINE Ovid, Embase Ovid, Web of Science (ISI), Health Technology Assessments, ClinicalTrials.gov and World Health Organization International Clinical Trials Registry from inception to September 2021 without language restrictions, searched the reference lists of included studies and contacted experts in the field.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) comparing SNMD interventions with placebo (sham) stimulation, no treatment or usual care; or comparing SNMD interventions + another treatment versus that treatment alone. We included participants ≥ 18 years old with non-cancer and non-ischaemic pain of longer than three months duration. Primary outcomes were pain intensity and adverse events. Secondary outcomes were disability, analgesic medication use, health-related quality of life (HRQoL) and health economic outcomes.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened database searches to determine inclusion, extracted data and evaluated risk of bias for prespecified results using the Risk of Bias 2.0 tool. Outcomes were evaluated at short- (≤ one month), medium- four to eight months) and long-term (≥12 months). Where possible we conducted meta-analyses. We used the GRADE system to assess the certainty of evidence.
MAIN RESULTS
We included 15 unique published studies that randomised 908 participants, and 20 unique ongoing studies. All studies evaluated SCS. We found no eligible published studies of DRGS and no studies comparing SCS with no treatment or usual care. We rated all results evaluated as being at high risk of bias overall. For all comparisons and outcomes where we found evidence, we graded the certainty of the evidence as low or very low, downgraded due to limitations of studies, imprecision and in some cases, inconsistency. Active stimulation versus placebo SCS versus placebo (sham) Results were only available at short-term follow-up for this comparison. Pain intensity Six studies (N = 164) demonstrated a small effect in favour of SCS at short-term follow-up (0 to 100 scale, higher scores = worse pain, mean difference (MD) -8.73, 95% confidence interval (CI) -15.67 to -1.78, very low certainty). The point estimate falls below our predetermined threshold for a clinically important effect (≥10 points). No studies reported the proportion of participants experiencing 30% or 50% pain relief for this comparison. Adverse events (AEs) The quality and inconsistency of adverse event reporting in these studies precluded formal analysis. Active stimulation + other intervention versus other intervention alone SCS + other intervention versus other intervention alone (open-label studies) Pain intensity Mean difference Three studies (N = 303) demonstrated a potentially clinically important mean difference in favour of SCS of -37.41 at short term (95% CI -46.39 to -28.42, very low certainty), and medium-term follow-up (5 studies, 635 participants, MD -31.22 95% CI -47.34 to -15.10 low-certainty), and no clear evidence for an effect of SCS at long-term follow-up (1 study, 44 participants, MD -7 (95% CI -24.76 to 10.76, very low-certainty). Proportion of participants reporting ≥50% pain relief We found an effect in favour of SCS at short-term (2 studies, N = 249, RR 15.90, 95% CI 6.70 to 37.74, I 0% ; risk difference (RD) 0.65 (95% CI 0.57 to 0.74, very low certainty), medium term (5 studies, N = 597, RR 7.08, 95 %CI 3.40 to 14.71, I = 43%; RD 0.43, 95% CI 0.14 to 0.73, low-certainty evidence), and long term (1 study, N = 87, RR 15.15, 95% CI 2.11 to 108.91 ; RD 0.35, 95% CI 0.2 to 0.49, very low certainty) follow-up. Adverse events (AEs) Device related No studies specifically reported device-related adverse events at short-term follow-up. At medium-term follow-up, the incidence of lead failure/displacement (3 studies N = 330) ranged from 0.9 to 14% (RD 0.04, 95% CI -0.04 to 0.11, I 64%, very low certainty). The incidence of infection (4 studies, N = 548) ranged from 3 to 7% (RD 0.04, 95%CI 0.01, 0.07, I 0%, very low certainty). The incidence of reoperation/reimplantation (4 studies, N =5 48) ranged from 2% to 31% (RD 0.11, 95% CI 0.02 to 0.21, I 86%, very low certainty). One study (N = 44) reported a 55% incidence of lead failure/displacement (RD 0.55, 95% CI 0.35, 0 to 75, very low certainty), and a 94% incidence of reoperation/reimplantation (RD 0.94, 95% CI 0.80 to 1.07, very low certainty) at five-year follow-up. No studies provided data on infection rates at long-term follow-up. We found reports of some serious adverse events as a result of the intervention. These included autonomic neuropathy, prolonged hospitalisation, prolonged monoparesis, pulmonary oedema, wound infection, device extrusion and one death resulting from subdural haematoma. Other No studies reported the incidence of other adverse events at short-term follow-up. We found no clear evidence of a difference in otherAEs at medium-term (2 studies, N = 278, RD -0.05, 95% CI -0.16 to 0.06, I 0%) or long term (1 study, N = 100, RD -0.17, 95% CI -0.37 to 0.02) follow-up. Very limited evidence suggested that SCS increases healthcare costs. It was not clear whether SCS was cost-effective.
AUTHORS' CONCLUSIONS
We found very low-certainty evidence that SCS may not provide clinically important benefits on pain intensity compared to placebo stimulation. We found low- to very low-certainty evidence that SNMD interventions may provide clinically important benefits for pain intensity when added to conventional medical management or physical therapy. SCS is associated with complications including infection, electrode lead failure/migration and a need for reoperation/re-implantation. The level of certainty regarding the size of those risks is very low. SNMD may lead to serious adverse events, including death. We found no evidence to support or refute the use of DRGS for chronic pain.
Topics: Adolescent; Adult; Bias; Chronic Pain; Humans; Pain Measurement; Quality of Life; Wound Infection
PubMed: 34854473
DOI: 10.1002/14651858.CD013756.pub2 -
Journal of Diabetes and Its... Nov 2021To estimate the prevalence of neuropathy in adolescents with type 1 diabetes. (Review)
Review
AIMS
To estimate the prevalence of neuropathy in adolescents with type 1 diabetes.
METHODS
Systematic collection of published studies exploring the prevalence of large fibre neuropathy (LFN), small fibre neuropathy (SFN), and autonomic neuropathy in adolescents with type 1 diabetes. Following prospective registration (Prospero CRD42020206093), PubMed, EMBASE, and Cochrane Library were searched for studies from 2000 to 2020. PICO framework was used in the selection process (Population: adolescents aged 10-19 years with type 1 diabetes; Intervention: diagnostic methods for neuropathy; Comparison: reference data; Outcome: data on prevalence or comparison). Data were extracted concerning study quality based on available data and established methods for determining and diagnosing various neuropathy types.
RESULTS
From 2,017 initial citations, 27 studies (7589 participants) fulfilled eligibility criteria. The study population (47% males) had a diabetes duration between 4.0 and 10.6 years, and HbA1c level between 7.3 and 10.8%, 56-95 mmol/mol. The prevalence of LFN, based on nerve conduction studies, was 10-57%. Based on other tests for neuropathy, the prevalence of LFN and SFN was 12-62%, and that of cardiac autonomic neuropathy was 12-75%.
CONCLUSION
The described prevalence of neuropathy in adolescents with type 1 diabetes varied, which can be methodological due to different screening methods and classifications of neuropathy.
Topics: Adolescent; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Female; Humans; Male; Peripheral Nervous System Diseases; Prevalence; Prospective Studies
PubMed: 34429229
DOI: 10.1016/j.jdiacomp.2021.108027