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Chronic Opioid Therapy: A Scoping Literature Review on Evolving Clinical and Scientific Definitions.The Journal of Pain Mar 2021The management of chronic noncancer pain (CNCP) with chronic opioid therapy (COT) is controversial. There is a lack of consensus on how COT is defined resulting in...
The management of chronic noncancer pain (CNCP) with chronic opioid therapy (COT) is controversial. There is a lack of consensus on how COT is defined resulting in unclear clinical guidance. This scoping review identifies and evaluates evolving COT definitions throughout the published clinical and scientific literature. Databases searched included PubMed, Embase, and Web of Science. A total of 227 studies were identified from 8,866 studies published between January 2000 and July 2019. COT definitions were classified by pain population of application and specific dosage/duration definition parameters, with results reported according to PRISMA-ScR. Approximately half of studies defined COT as "days' supply duration >90 days" and 9.3% defined as ">120 days' supply," with other days' supply cut-off points (>30, >60, or >70) each appearing in <5% of total studies. COT was defined by number of prescriptions in 63 studies, with 16.3% and 11.0% using number of initiations or refills, respectively. Few studies explicitly distinguished acute treatment and COT. Episode duration/dosage criteria was used in 90 studies, with 7.5% by Morphine Milligram Equivalents + days' supply and 32.2% by other "episode" combination definitions. COT definitions were applied in musculoskeletal CNCP (60.8%) most often, and typically in adults aged 18 to 64 (69.6%). The usage of ">90 days' supply" COT definitions increased from 3.2 publications/year before 2016 to 20.7 publications/year after 2016. An increasing proportion of studies define COT as ">90 days' supply." The most recent literature trends toward shorter duration criteria, suggesting that contemporary COT definitions are increasingly conservative. PERSPECTIVE: This study summarized the most common, current definition criteria for chronic opioid therapy (COT) and recommends adoption of consistent definition criteria to be utilized in practice and research. The most recent literature trends toward shorter duration criteria overall, suggesting that COT definition criteria are increasingly stringent.
Topics: Analgesics, Opioid; Chronic Pain; Drug Prescriptions; Humans; Practice Patterns, Physicians'
PubMed: 33031943
DOI: 10.1016/j.jpain.2020.09.002 -
Diagnostics (Basel, Switzerland) Jan 2024. This paper aims to estimate asymptomatic hip osteonecrosis prevalence in SLE patients using MRI examination and to determine the prevalence among higher risk... (Review)
Review
. This paper aims to estimate asymptomatic hip osteonecrosis prevalence in SLE patients using MRI examination and to determine the prevalence among higher risk subpopulations. . PubMed, Embase, Cochrane, and SCOPUS were searched from inception to May 9th, 2023. Studies on patients who were clinically diagnosed with systemic lupus erythematosus without reported symptoms attributable to hip osteonecrosis were included. Two independent reviewers extracted data and assessed the risk of bias. Data collected from each study include the study year, the number of hips screened, the number of hips with osteonecrosis, demographics, laboratory data, medications, follow-up time, radiological protocols, and MRI-based osteonecrosis detection and grading criteria. . Eleven eligible studies including 503 participants (15-35 years old; 74-100% female) with SLE were identified. Significant risk of bias was determined in one study. The overall prevalence of osteonecrosis of the hip was found to be 14% (184/1006 hip joints, 95% confidence interval: 7-22%, number needed to scan: 7.1). SLE patients who received corticosteroid treatment had a higher prevalence of asymptomatic hip osteonecrosis (18%) compared to non-corticosteroid users (0%, -value < 0.01). Additionally, meta-regression results revealed that daily corticosteroid dose was associated with increased prevalence of asymptomatic osteonecrosis (0.5%/milligram, -value < 0.01). . The high prevalence of asymptomatic hip osteonecrosis in SLE patients raises concerns about the timeliness of interventions. The limitations of this study include a relatively low number of identified studies; and one study lacked full-text availability.
PubMed: 38337795
DOI: 10.3390/diagnostics14030279 -
BMC Geriatrics Oct 2019Older surgical patients are at high risk of developing postoperative delirium. Non-pharmacological strategies are recommended for delirium prevention, but no... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Older surgical patients are at high risk of developing postoperative delirium. Non-pharmacological strategies are recommended for delirium prevention, but no pharmacological agents have compelling evidence to decrease the incidence of delirium. The purpose of this study was to assess whether perioperative melatonin decreases the incidence of delirium in older adults undergoing surgical procedures.
METHODS
A systematic search using PubMed/Medline, Embase, PsycINFO, CINAHL, and references of identified articles published in English between January 1990 and October 2017 was performed. Two independent reviewers screened titles and abstracts, and then extracted data following a full-text review of included articles with consensus generation and bias assessment. Studies reporting outcomes for melatonin or ramelteon use to prevent delirium in postoperative hospitalized patients (mean age ≥ 50 years) were eligible for inclusion. Data were pooled using a fixed-effects model to generate a forest plot and obtain a summary odds ratio for the outcome of interest (delirium incidence). Cochran's Q and I values were used to investigate heterogeneity.
RESULTS
Of 335 records screened, 6 studies were selected for the qualitative analysis and 6 were included in the meta-analysis (n = 1155). The mean age of patients in included studies ranged from 59 to 84 years. Patients in intervention groups typically received melatonin or ramelteon at daily doses of two to eight milligrams around cardiothoracic, orthopedic, or hepatic surgeries for one to nine days, starting on the evening before or the day of surgery. The incidence of delirium ranged from 0 to 30% in the intervention groups versus 4-33% in the comparator groups, and was significantly reduced in the melatonin group, with a summary effect of the meta-analysis yielding an odds ratio of 0.63 (95% CI 0.46 to 0.87; 0.006; I = 72.1%). A one study removed analysis reduced overall odds ratio to 0.310 (95% CI 0.19 to 0.50), while reducing heterogeneity (Cochran's Q = 0.798, I = 0.000).
CONCLUSION
Perioperative melatonin reduced the incidence of delirium in older adults in the included studies. While optimal dosing remains an unanswered question, the potential benefit of melatonin and melatonin receptor agonists may make them a reasonable option to use for delirium prevention in older adults undergoing surgical procedures.
Topics: Aged; Aged, 80 and over; Central Nervous System Depressants; Delirium; Humans; Incidence; Melatonin; Middle Aged; Postoperative Cognitive Complications; Randomized Controlled Trials as Topic
PubMed: 31619178
DOI: 10.1186/s12877-019-1297-6 -
Heliyon Aug 2021Controversy still exists regarding the analgesic efficacy of transverse abdominis plane (TAP) block versus ilioinguinal or iliohypogastric (IL/IH) nerve block for...
BACKGROUND
Controversy still exists regarding the analgesic efficacy of transverse abdominis plane (TAP) block versus ilioinguinal or iliohypogastric (IL/IH) nerve block for postoperative pain management following cesarean section. This meta-analysis aimed to perform relatively credible pooled results on the efficacy of the TAP versus IL/IH nerve block for postoperative pain management after cesarean section.
METHODS
Databases such as: PubMed/MEDLINE, Google scholar, and google were systematically searched. studies compared the analgesic efficacy of TAP versus IL/IH nerve block for postoperative pain management following cesarean section were included. Data were extracted by three reviewers independently by using Microsoft Excel and then exported to STATA™ 16 version statistical software for analysis. We used a random-effects model meta-analysis and the mean difference of analgesic efficacy with a 95 % confidence interval was reported based on Preferred Reporting Items for systematic reviews and meta-analysis (PRISMA).
RESULTS
Five studies with a total of 390 (196 in TAP and 194 in IL/IH) study participants were included in this meta-analysis. No statistically significant difference was observed between the TAP and IL/IH groups in time to first rescue analgesic request, total postoperative analgesic consumption in milligrams of intravenous tramadol equivalence, and post pain severity score at different points of time both rest and movement.
CONCLUSION
This meta-analysis revealed that both approaches have similar postoperative analgesic efficacy following cesarean section. we recommend that the clinician may consider either approach for post-cesarean section pain management.
PubMed: 34430749
DOI: 10.1016/j.heliyon.2021.e07774 -
Drugs Oct 2020Deprescribing, the process of reducing or discontinuing unnecessary or harmful medicines is an essential part of clinical practice.
BACKGROUND
Deprescribing, the process of reducing or discontinuing unnecessary or harmful medicines is an essential part of clinical practice.
OBJECTIVE
To evaluate the efficacy of interventions designed to deprescribe opioid analgesics for pain relief in patients with chronic non-cancer pain.
METHODS
We searched electronic databases, including clinical trial registries, from database inception to 13th January 2020 without restrictions, and conducted citation tracking. Our systematic review included randomised controlled trials (RCTs) evaluating interventions reducing the prescription, or use of opioid analgesics in patients with chronic pain versus control. Inventions could be aimed at the patient, clinician, or both. We excluded trials enrolling patients with cancer or illicit drug use. Two authors independently screened and extracted data. Outcome follow-up timepoints were short (≤ 3 months), intermediate (> 3 but < 12 months) or long (≥ 12 months) term. Primary outcome was the reduction in opioid dose [morphine milligram equivalent (MME) mg/day]. Methodological quality was assessed using the Cochrane Risk of Bias Tool.
RESULTS
We included ten patient-focused RCT interventions (n = 835; median 37 participants) and 2 testing clinician-focused interventions (n = 291 clinicians); none at low risk of bias. Patient-focused interventions did not reduce opioid dose in the intermediate term [e.g. dose reduction protocol, mean difference (MD) - 19.9 MME, 95% CI - 107.5 to 67.7], nor did they increase the number of participants who ceased their dose, or increase the risk of serious adverse events or adverse events. One clinician intervention of education plus decision tools versus decision tools alone reduced the number of opioid prescriptions (risk difference (RD) - 0.1, 95% CI - 0.2 to - 0.1), dose (MD - 5.3 MME, 95% CI - 6.2 to - 4.5) and use (RD - 0.1, 95% CI - 0.1 to - 0.0) in the long term.
LIMITATIONS
Study heterogeneity prevented meta-analysis.
CONCLUSION
The small number of studies and heterogeneity prevented firm conclusions to recommend any one opioid-analgesic-deprescribing strategy in patients with chronic pain.
SYSTEMATIC REVIEW REGISTRATION NUMBER
PROSPERO CRD42017068422.
Topics: Analgesics, Opioid; Buprenorphine; Chronic Pain; Clinical Decision-Making; Deprescriptions; Drug Prescriptions; Humans; Mindfulness; Narcotic Antagonists; Opioid Epidemic; Pain Management; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 32737739
DOI: 10.1007/s40265-020-01368-y -
The Clinical Journal of Pain Feb 2022The aim was to examine research on the impact of spinal cord stimulation (SCS) on the reduction of preimplantation opioid dose and what preimplantation opioid dose is...
OBJECTIVE
The aim was to examine research on the impact of spinal cord stimulation (SCS) on the reduction of preimplantation opioid dose and what preimplantation opioid dose is associated with a reduction or discontinuation of opioid use postimplantation.
METHODS
Systematic review of literature from PubMed, Web of Science, and Ovid Medline search of "opioid" and "pain" and "spinal cord stimulator." Inclusion criteria included original research providing data on SCS preimplantation opioid dosing and 12 months postimplantation opioid dosing or that correlated specific preimplantation opioid dose or opioid dose cutoff with significantly increased likelihood of opioid use discontinuation at 12 months postimplantation.
RESULTS
Systematic review of the literature yielded 17 studies providing data on pre-SCS and post-SCS implantation dose and 4 providing data on the preimplantation opioid dose that significantly increased likelihood of opioid use discontinuation at 12 months postimplantation. Data from included studies indicated that SCS is an effective tool in reducing opioid dose from preimplantation levels at 12 months postimplantation. Data preliminarily supports the assertion that initiation of SCS at a preimplantation opioid dose of ≤20 to ≤42.5 morphine milligram equivalents increases the likelihood of postimplantation elimination of opioid use.
DISCUSSION
SCS is an effective treatment for many types of chronic pain and can reduce or eliminate chronic opioid use. Preimplantation opioid dose may impact discontinuation of opioid use postimplantation and the effectiveness of SCS in the relief of chronic pain. More research is needed to support and strengthen clinical recommendations for initiation of SCS use at lower daily opioid dose.
Topics: Analgesics, Opioid; Chronic Pain; Humans; Neuralgia; Opioid-Related Disorders; Pain Management; Spinal Cord; Spinal Cord Stimulation; Treatment Outcome
PubMed: 35132028
DOI: 10.1097/AJP.0000000000001021 -
The Cochrane Database of Systematic... Jun 2024Persistent visceral pain is an unpleasant sensation coming from one or more organs within the body. Visceral pain is a common symptom in those with advanced cancer.... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Persistent visceral pain is an unpleasant sensation coming from one or more organs within the body. Visceral pain is a common symptom in those with advanced cancer. Interventional procedures, such as neurolytic sympathetic nerve blocks, have been suggested as additional treatments that may play a part in optimising pain management for individuals with this condition.
OBJECTIVES
To evaluate the benefits and harms of neurolytic sympathetic nerve blocks for persistent visceral pain in adults with inoperable abdominopelvic cancer compared to standard care or placebo and comparing single blocks to combination blocks.
SEARCH METHODS
We searched the following databases without language restrictions on 19 October 2022 and ran a top-up search on 31 October 2023: CENTRAL; MEDLINE via Ovid; Embase via Ovid; LILACS. We searched trial registers without language restrictions on 2 November 2022: ClinicalTrials.gov; WHO International Clinical Trials Registry Platform (ICTRP). We searched grey literature, checked reference lists of reviews and retrieved articles for additional studies, and performed citation searches on key articles. We also contacted experts in the field for unpublished and ongoing trials. Our trial protocol was preregistered in the Cochrane Database of Systematic Reviews on 21 October 2022.
SELECTION CRITERIA
We searched for randomised controlled trials (RCTs) comparing any sympathetic nerve block targeting sites commonly used to treat abdominal pelvic pain from inoperable malignancies in adults to standard care or placebo.
DATA COLLECTION AND ANALYSIS
We independently selected trials based on predefined inclusion criteria, resolving any differences via adjudication with a third review author. We used a random-effects model as some heterogeneity was expected between the studies due to differences in the interventions being assessed and malignancy types included in the study population. We chose three primary outcomes and four secondary outcomes of interest. We sought consumer input to refine our review outcomes and assessed extracted data using Cochrane's risk of bias 2 tool (RoB 2). We assessed the certainty of evidence using the GRADE system.
MAIN RESULTS
We included 17 studies with 1025 participants in this review. Fifteen studies with a total of 951 participants contributed to the quantitative analysis. Single block versus standard care Primary outcomes No included studies reported our primary outcome, 'Proportion of participants reporting no worse than mild pain after treatment at 14 days'. The evidence is very uncertain about the effect of sympathetic nerve blocks on reducing pain to no worse than mild pain at 14 days when compared to standard care due to insufficient data (very low-certainty evidence). Sympathetic nerve blocks may provide small to 'little to no' improvement in quality of life (QOL) scores at 14 days after treatment when compared to standard care, but the evidence is very uncertain (standardised mean difference (SMD) -0.73, 95% confidence interval (CI) -1.70 to 0.25; I² = 87%; 4 studies, 150 participants; very low-certainty evidence). The evidence is very uncertain about the risk of serious adverse events as defined in our review as only one study contributed data to this outcome. Sympathetic nerve blocks may have an 'increased risk' to 'no additional risk' of harm compared with standard care (very low-certainty evidence). Secondary outcomes Sympathetic nerve blocks showed a small to 'little to no' effect on participant-reported pain scores at 14 days using a 0 to 10 visual analogue scale (VAS) for pain compared with standard care, but the evidence is very uncertain (mean difference (MD) -0.44, 95% CI -0.98 to 0.11; I² = 56%; 5 studies, 214 participants; very low-certainty evidence). There may be a 'moderate to large' to 'little to no' reduction in daily consumption of opioids postprocedure at 14 days with sympathetic nerve blocks compared with standard care, but the evidence is very uncertain (change in daily consumption of opioids at 14 days as oral milligrams morphine equivalent (MME): MD -41.63 mg, 95% CI -78.54 mg to -4.72 mg; I² = 90%; 4 studies, 130 participants; very low-certainty evidence). The evidence is very uncertain about the effect of sympathetic nerve blocks on participant satisfaction with procedure at 0 to 7 days and time to need for retreatment or treatment effect failure (or both) due to insufficient data. Combination block versus single block Primary outcomes There is no evidence about the effect of combination sympathetic nerve blocks compared with single sympathetic nerve blocks on the proportion of participants reporting no worse than mild pain after treatment at 14 days because no studies reported this outcome. There may be a small to 'little to no' effect on QOL score at 14 days after treatment, but the evidence is very uncertain (very low-certainty evidence). The evidence is very uncertain about the risk of serious adverse events with combination sympathetic nerve blocks compared with single sympathetic nerve blocks due to limited reporting in the included studies (very low-certainty evidence). Secondary outcomes The evidence is very uncertain about the effect of combination sympathetic nerve blocks compared with single sympathetic nerve blocks on participant-reported pain score and change in daily consumption of opioids postprocedure, at 14 days. There may be a small to 'little to no' effect, but the evidence is very uncertain (very low-certainty evidence). There is no evidence about the effect on participant satisfaction with procedure at 0 to 7 days and time to need for retreatment or treatment effect failure (or both) due to these outcomes not being measured by the studies. Risk of bias The risk of bias was predominately high for most outcomes in most studies due to significant concerns regarding adequate blinding. Very few studies were deemed as low risk across all domains for any outcome.
AUTHORS' CONCLUSIONS
There is limited evidence to support or refute the use of sympathetic nerve blocks for persistent abdominopelvic pain due to inoperable malignancy. We are very uncertain about the effect of combination sympathetic nerve blocks compared with single sympathetic nerve blocks. The certainty of the evidence is very low and these findings should be interpreted with caution.
Topics: Humans; Randomized Controlled Trials as Topic; Autonomic Nerve Block; Adult; Bias; Pelvic Neoplasms; Abdominal Neoplasms; Cancer Pain; Abdominal Pain; Pain Management; Nerve Block; Quality of Life
PubMed: 38842054
DOI: 10.1002/14651858.CD015229.pub2 -
British Journal of Anaesthesia Feb 2018The optimal local-anaesthetic (LA) dose for transversus-abdominis-plane (TAP) block is unclear. In this meta-analysis, we aimed to determine whether TAP blocks for... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The optimal local-anaesthetic (LA) dose for transversus-abdominis-plane (TAP) block is unclear. In this meta-analysis, we aimed to determine whether TAP blocks for Caesarean delivery (CD) with low-dose (LD) LA demonstrated non-inferiority in terms of analgesic efficacy, compared with high-dose (HD) LA.
METHODS
A literature search was performed for randomised controlled trials examining the analgesic efficacy of TAP blocks vs control after CD. The different dosing used in these studies was classified as HD or LD (bupivacaine equivalents >50 or ≤50 mg per block side, respectively). The pooled results of each dose group vs control were indirectly compared using the Q test. The primary outcome was 24 h opioid consumption. Secondary outcomes included 6 and 24 h postoperative pain scores, time to first analgesia, 6 h opioid consumption, opioid-related side-effects, and maternal satisfaction.
RESULTS
Fourteen studies consisting of 770 women (389 TAP and 381 control) were included. Compared with controls, the 24 h opioid consumption (milligram morphine equivalents) was lower in HD [mean difference (MD) 95% confidence interval (CI) -22.41 (-38.56, -6.26); P=0.007; I=93%] and LD [MD 95% CI -16.29 (-29.74, -2.84); P=0.02; I=98%] TAP groups. However, no differences were demonstrated between the HD and LD groups (P=0.57). There were also no differences between the HD and LD groups for the 6 h opioid consumption, time to first analgesia, 6 and 24 h pain scores, postoperative nausea and vomiting, pruritus, and maternal satisfaction.
CONCLUSIONS
Low-dose TAP blocks for Caesarean delivery provide analgesia and opioid-sparing effects comparable with the high-dose blocks. This suggests that lower doses can be used to reduce local anaesthetic toxicity risk without compromising the analgesic efficacy.
Topics: Abdominal Muscles; Abdominal Wall; Adult; Analgesia, Obstetrical; Anesthetics, Local; Cesarean Section; Female; Humans; Nerve Block; Pain, Postoperative; Pregnancy; Randomized Controlled Trials as Topic
PubMed: 29406174
DOI: 10.1016/j.bja.2017.11.084 -
Annals of Internal Medicine Nov 2020Opioids are frequently prescribed for acute musculoskeletal injuries and may result in long-term use and consequent harms. (Meta-Analysis)
Meta-Analysis
Predictors of Prolonged Opioid Use After Initial Prescription for Acute Musculoskeletal Injuries in Adults : A Systematic Review and Meta-analysis of Observational Studies.
BACKGROUND
Opioids are frequently prescribed for acute musculoskeletal injuries and may result in long-term use and consequent harms.
PURPOSE
To explore factors associated with persistent opioid use after its prescription for acute musculoskeletal injury.
DATA SOURCES
Searches of multiple electronic databases, without language restrictions, from inception to 6 January 2020, and reference lists of selected articles.
STUDY SELECTION
Observational studies of adults with opioid prescriptions for outpatient acute musculoskeletal injuries, in an adjusted model, that explored risk factors for prolonged use.
DATA EXTRACTION
6 reviewers, working in pairs, independently extracted data, rated the quality of studies, and evaluated the certainty of evidence.
DATA SYNTHESIS
14 cohorts with 13 263 393 participants were included. The overall prevalence of prolonged opioid use after musculoskeletal injury for high-risk populations (that is, patients receiving workers' compensation benefits, Veterans Affairs claimants, or patients with high rates of concurrent substance use disorder) was 27% (95% CI, 18% to 37%). The prevalence among low-risk populations was 6% (CI, 4% to 8%; for interaction < 0.001). Moderate-certainty evidence showed increased odds of persistent opioid use with older age (absolute risk increase [ARI] for every 10-year increase, 1.1% [CI, 0.7% to 1.5%]) and physical comorbidity (ARI, 0.9% [CI, 0.1% to 1.7%]). Low-certainty evidence suggested increased risk for persistent opioid use with past or current substance use disorder (ARI, 10.5% [CI, 4.2% to 19.8%]), prescriptions lasting more than 7 days (median ARI, 4.5%), and higher morphine milligram equivalents per day.
LIMITATION
Sparse, heterogeneous data with suboptimal adjustment for potential confounders.
CONCLUSION
Avoiding prescribing opioids for acute musculoskeletal injuries to patients with past or current substance use disorder, and restricting duration to 7 days or less and using lower doses when they are prescribed, are potentially important targets to reduce rates of persistent opioid use.
PRIMARY FUNDING SOURCE
National Safety Council. (PROSPERO: CRD42018104968).
Topics: Adult; Age Distribution; Analgesics, Opioid; Comorbidity; Drug Administration Schedule; Humans; Musculoskeletal System; Observational Studies as Topic; Opioid-Related Disorders; Prevalence; Risk Factors; Substance-Related Disorders
PubMed: 32805130
DOI: 10.7326/M19-3600 -
Journal of Hematology Apr 2021While pain is the hallmark of sickle cell disease (SCD), healthcare personnel are often ill-equipped to adequately treat patients who present in vaso-occlusive crisis...
BACKGROUND
While pain is the hallmark of sickle cell disease (SCD), healthcare personnel are often ill-equipped to adequately treat patients who present in vaso-occlusive crisis (VOC). Although symptom severity varies from individual to individual, SCD is characterized by intervallic pain as a result of oxygen deprivation in tissues and organs. Regardless of pain severity, SCD patients are often viewed as drug seekers by healthcare personnel who have concerns regarding patients' dependence on opioids which may lead to addiction. The objective was to assess the types and amount of opioids used to treat VOC in comparison to Centers for Disease Control opioid prescription guidelines.
METHODS
Literature search was conducted using CINAHL, PubMed, the Cochrane Library, Web of Science and hand search. Data were analyzed from 1999 to 2018. Randomized trials, observational, and case studies involved hospitalized adults with SCD who were prescribed opioids to treat VOC. Quality assessment was conducted using Downs and Black checklist. Meta-analysis was not conducted.
RESULTS
Five studies were conducted in the USA, Arabia and the Netherlands, and the USA and Canada were included. Participants were treated with either morphine or morphine milligram equivalent (MME). No study used the same method of opioid administration.
CONCLUSIONS
Patients with SCD who are hospitalized secondary to VOC mostly received opioids for pain well within the Centers for Disease Control and Prevention prescription guidelines. No uniform method exists. Additional research is warranted.
PubMed: 34007365
DOI: 10.14740/jh828