How Long Does It Take For Tmj Splint To Work

• Journal List
• Oncotarget
• v.7(51); 2016 December 20
• PMC5356643

Oncotarget. 2016 Dec twenty; 7(51): 84043–84053.

Efficacy of splint therapy for the management of temporomandibular disorders: a meta-assay

Chao Zhang

^ane Center for Evidence-Based Medicine and Clinical Research, Taihe Hospital, Hubei Academy of Medicine, Southward Renmin Road, Shiyan, Cathay

Jun-Yi Wu

¹ Center for Evidence-Based Medicine and Clinical Research, Taihe Hospital, Hubei University of Medicine, Due south Renmin Route, Shiyan, China

² Schoolhouse of Stomatology, Hubei University of Medicine, Shiyan, Mainland china

Dong-Lai Deng

³ The State Fundamental Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine, Ministry building of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, Cathay

Bing-Yang He

ⁱⁱⁱ The State Cardinal Laboratory Breeding Base of operations of Basic Science of Stomatology & Fundamental Laboratory of Oral Biomedicine, Ministry of Education, Schoolhouse & Hospital of Stomatology, Wuhan University, Wuhan, China

Yuan Tao

^one Center for Evidence-Based Medicine and Clinical Research, Taihe Hospital, Hubei University of Medicine, South Renmin Road, Shiyan, China

Yu-Ming Niu

¹ Heart for Evidence-Based Medicine and Clinical Research, Taihe Hospital, Hubei University of Medicine, South Renmin Route, Shiyan, China

⁴ Section of Stomatology, Taihe Hospital, Hubei Academy of Medicine, Shiyan, Communist china

Mo-Hong Deng

^v The Land Key Laboratory Convenance Base of Basic Science of Stomatology & Fundamental Laboratory of Oral Biomedicine, Ministry of Education, Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Wuhan University, Wuhan, People's republic of china

Received 2016 Aug 24; Accepted 2016 Oct 24.

Abstruse

Temporomandibular disorders (TMD) are a group of clinical issues affecting temporomandibular articulation (TMJ), myofascial muscles and other related structures. Splint therapy is the well-nigh commonly used arroyo to treatment of TMD, but its effectiveness is remains unclear. We therefore conducted a meta-analysis to evaluate the effectiveness of splint therapy for TMD in adults. The electronic databases PubMed, EMBASE, Cochrane Library, and ClinicalTrials.gov were searched for reports published up to March 31, 2016. Xiii eligible studies involving 538 patients were identified. The results indicated that splint therapy increased maximal rima oris opening (MMO) for patients with a MMO <45mm and reduced pain intensity measured using the visual analogue scale (VAS) for patients with TMD without specific description (TMDSD). Splint therapy as well reduced the frequency of painful episodes for patients with TMJ clicking. No publication bias was observed, as adamant with Egger's test for all outcomes. On the basis of this show, nosotros recommend the utilize of splints for the treatment and command of TMD in adults.

Keywords: temporomandibular disorders, splint, maximal mouth opening, visual counterpart scales of pain, meta-analysis

INTRODUCTION

Temporomandibular disorders (TMD) are a group of clinical problems affecting the temporomandibular joint (TMJ), myofascial muscles and other related structures [1]. In that location is currently no unified standard for the classification of TMD, but research diagnostic criteria for temporomandibular disorders (RDC/TMD) are the nearly usually practical criteria [two]. The main signs and symptoms involve TMJ pain and clicking, myofascial or oral masticatory muscle pain, and aberrant jaw motion [3].TMD constitute a major public health problem, every bit they are a main source of chronic oral facial pain, interfering with daily activities [iv]. These disorders are also unremarkably associated with other symptoms affecting the caput and cervix region, including headache, ear-related symptoms, cervical spine dysfunction, and contradistinct caput and cervical posture [five, half dozen]. Notably, signs of TMD are detected in about 60-lxx% of the full general population, yet only about one in four people with signs are actually aware of any symptoms [7]. The etiologies of TMD are not still clear, but contributing factors include occlusal abnormalities, psychological stress, orthodontic treatment, microtrauma, poor health and nutrition, articulation laxity and exogenous estrogen [8, 9].

The main treatment options for TMD include occlusal therapy [10], psychotherapy [xi], physical therapy [12], medication [thirteen], manual therapy [14], and surgery [xv]. In practice, the occlusal splint is a removable appliance, usually fabricated of resin and almost often designed to cover all of the occlusal and incisal surfaces of the teeth in the upper or lower jaw. Occlusal splint therapy is most unremarkably used clinical approach considering of its ease of use, low price, and broad indications. A previous meta-assay addressed the effectiveness of splint therapy for TMD, but why it is effectiveremains unclear [xvi]. To further explore the clinical effectiveness of splint therapy in the management of TMD in adults, we performed the present meta-analysis to elucidate the functional properties of splint therapy by comparison the clinical effects reported in all relevant randomized controlled trials (RCTs) [17].

RESULTS

Literature search result

We identified 2062 publications in the electronic databases (Figure ​ i). Employing the selection criteria summarized in Materials and methods department, we obtained quantitative data for our meta-assay after reading all titles, abstracts and full texts. Thirteen eligible studies [10, eighteen-27] from xi publications were included in our final analysis.

Summary of trial identification and pick

Study characteristics

The 13 eligible studies included a total of 538 patients. The alter in maximal mouth opening (MMO) was determined for 122 patients from five studies [x, xviii, 20, 23], and the initial telescopic of MMO was categorized to three levels: less than 37 mm, 37 mm to 45 mm, and greater than 45 mm. The modify in the corporeality of pain experienced, equally reported using the visual analogue scale (VAS), was assessed in 285 patients from 6 studies [19-22, 25]. Iii types of disorder were assessed: TMD without specific clarification (TMDSD) [21, 22, 25], osteoarthritis [xx], and TMJ clicking [19]. The rate of healing from TMJ clicking was recorded in 170 patients from 4 studies [19, 26, 27]. The frequency of hurting relief was evaluated in 112 patients from ii studies [22, 24]. There were v studies [18, 20, 22, 23, 25] missing standard deviations (SD), which were estimated from the P-values. Tabular array ​ ii describes the clinical characteristics of patients in all thirteen studies.

Tabular array 2

Characteristics of the included studies

Study	Year	Region	Age (mean±SD)	Gender (female %)	Sample	Diagnostic criteria	Classification of diseases	History (month)	Intervention group	Command group	Course (month)	Follow-upwardly (month)
Conti PC[xviii]	2012	Brazil	38.09/38.fourteen	80.9%/100%	17/nine	RDC/TMD	TMD	NA	splint	Self-intendance	NA	3
Madani Every bit[19]	2011	Iran	27.20±12.43/22.43±vi.02	75%/92.86%	xx/14	RDC/TMD	TMJ clicking	6	Splint	Concrete	4/five	NA
Alpaslan C a[20]	2008	Turkey	29.8±xi.1/28.9±11.three	NA	22/14	Clinical examination	Osteoarthritis	eighteen	Difficult splint	Arthrocentesis	NA	half dozen
Alpaslan C b[20]	2008	Turkey	31.6±10.v/28.9±11.iii	NA	9/14	Clinical examination	Osteoarthritis	18	Soft splint	Arthrocentesis	NA	6
Al Quran FA[21]	2006	Jardon	31.8/36	NA	38/38	Clinical examination	TMD	NA	Splint	Control appliance	NA	three
Ekberg E[22]	2003	Sweden	31/28	83.33%/90%	thirty/30	RDC/TMD	TMD	half dozen	Stabilization splint	Control appliance	2.5	NA
Maloney M[23]	2002	USA	NA	NA	10/7	RDC/TMD	TMD	NA	splint	Command appliance	NA	NA
Ekberg E[24]	1998	Sweden	xiii-76/xv-72	86.67%/96.67%	30/30	Clinical examination	TMD	36	splint	Control apparatus	two.v	2.5
Wright EF[ten]	1995	USA	34/31	NA	ten/10	NA	TMD	NA	Soft splint	No handling	1.5	NA
Turk DC[25]	1993	U.s.a.	35.9±9.1/33.1±8	75%/eighty%	30/20	NA	TMD	two	splint	BF/SM	1.5	six
Lundh H[26]	1988	Sweden	NA	NA	21/22	NA	the inductive disc displacement	NA	Flat splint	Untreated controls	six	6
Lundh H a[27]	1985	Sweden	NA	NA	24/23	NA	TMJ clicking	NA	Anterior repositioning splint	Command apparatus	NA	NA
Lundh H b[27]	1985	Sweden	NA	NA	23/23	NA	TMJ clicking	NA	Flat splint	Control apparatus	NA	NA

Abbreviations: RDC/TMD: research diagnostic criteria for temporomandibular disorders; TMD: temporomandibular disorders; TMJ: temporomandibular joint; BF/SM: Biofeedback-assisted relaxation and stress management; NA: Not bachelor.

Quality of the included studies

The risk of bias in the included studies was strictly evaluated. Details of methodological approach are presented in Table ​ 3.

Table 3

Gamble of bias in the included studies

Study	Yr	Random sequence generation	Allocation concealment	Blinding of participants and personnel	Blinding of outcome assessment	Incomplete upshot data	Selective reporting	Other bias
Conti PC[18]	2012	unclear	high	high	high	depression	low	unclear
Madani Equally[xix]	2011	unclear	high	loftier	high	depression	low	high
Alpaslan C a[20]	2008	unclear	high	high	high	low	low	high
Alpaslan C b[20]	2008	unclear	high	high	high	low	depression	high
Al Quran FA[21]	2006	high	high	loftier	high	low	depression	high
Ekberg E[22]	2003	low	low	high	low	depression	low	unclear
Maloney G[23]	2002	unclear	high	high	loftier	low	low	high
Ekberg E[24]	1998	depression	low	high	low	low	low	unclear
Wright EF[10]	1995	low	high	high	high	low	low	unclear
Turk DC[25]	1993	unclear	high	loftier	high	low	low	high
Lundh H[26]	1988	unclear	high	high	high	low	low	loftier
Lundh H a[27]	1985	unclear	high	loftier	high	depression	low	high
Lundh H b[27]	1985	unclear	loftier	loftier	high	low	depression	high

Results of private event variables

Changes in MMO

Comparison of the splint therapy and control groups revealed a significant difference in the change of MMO (Figure ​ ii) (MD = 5.39, 95% CI [3.96, 6.81], I² = 48.9%, P = 0.098]). Moreover, subgroup analysis showed that for patients with an initial MMO < 37mm (Dr. = 6.21, 95% CI [4.50, seven.92], I² = 34.0%, P = 0.220) or an initial MMO = 37-45mm (MD = v.20, 95% CI [i.71, 8.69], I² = Not available (NA), P = NA), splint therapy led to a significant increase in MMO every bit compared to control. No significant difference in the change in MMO was detected for the subgroups with MMO > 45mm (MD = 1.57, 95% CI [-2.22, 5.36], I² = NA, P = NA). In addition, for the MMO < 37mm group, meta-regression showed there was no pregnant difference between the command and splint therapy groups after adjusting for differences in baseline and possible misreckoning factors (Tabular array ​ 4).

Table 4

Meta-regression results for the chief outcomes: VAS for pain and MMO <37 mm

Misreckoning factors	MMO <37mm			VAS of pain
	Number of study	Coef 95%CI	P	Number of report	Coef 95%CI	P
Historic period	three	0.468(-i.941, 2.878)	0.703	6	-0.027 (-0.215, 0.162)	0.782
Gender	3	NA	NA	half dozen	0.103 (-0.027, 0.234)	0.12
Region ( Ref=Europe)	0	NA	NA	ane	NA	NA
N America	1	NA	NA	one	-0.300( -ii.969, 2.369)	0.826
Other	two	-5.791(-12.409, 0.826)	0.086	4	0.517 (-ii.146, iii.179)	0.704
Diagnostic criteria (Ref=Clinical test)	2	NA	NA	three	NA	NA
RDC	i	5.791(-0.826, 12.409)	0.086	2	-0.193 (-1.664, 1.279)	0.797
Other	0	NA	NA	i	-0.834 (-1.853, 0.185)	0.109
Nomenclature of diseases (Ref=Osteoarthritis)	2	NA	NA	2	NA	NA
TMD	1	5.791(-0.826, 12.409)	0.086	3	0.615 (-2.130, 3.360)	0.66
TMJ clicking	0	NA	NA	1	0.935 (-two.196, 4.066)	0.558
Form	three	NA	NA	6	-0.061 (-0.319, 0.197)	0.643
Follow-up	iii	-3.217(-6.894, 0.459)	0.086	6	-0.318 (-0.659, 0.024)	0.069
Sample	3	-0.377(-0.0820, 0.067)	0.096	six	0.019 (-0.014, 0.052)	0.25
Publish yr	3	-0.965(-2.068, 0.138)	0.086	half dozen	0.053 (-0.015, 0.122)	0.131
Sources of SD(Ref=Reported SD)	one	NA	NA	2	NA	NA
Approximate the SD from P value	2	2.733(-10.521, 15.988)	0.686	iv	-0.883 (-1.828, 0.062)	0.067

Abbreviations: VAS: Visual counterpart scales, MMO: Maximal oral fissure opening, RDC: Research diagnostic criteria, TMD: Temporomandibular disorders, TMJ: Temporomandibular joint, SD: Standard difference, CI: Confidence interval, Coef: Coefficient, Ref: Reference, NA: Not available.

Forest plot of the changes in MMO

Change in pain level (VAS)

Comparison of the splint therapy and command groups also revealed a meaning difference in the changes in level of perceived pain, as adamant using the VAS (Figure ​ 3) (Medico = 2.02, 95% CI [1.55, 2.49], I² = 0%, P = 0.558). Subgroup analysis showed that patients with TMDSD in the splint therapy group experienced a meaning decrease in hurting as compared to control (Md = 2.00, 95% CI [i.50, 2.51], Iⁱⁱ = 34.5%, P = 0.217). This was as well the instance for patients with TMJ clicking (MD = 2.35, 95% CI [0.89, three.81], I² = NA, P = NA), only non for patients with osteoarthritis (Physician = i.41, 95% CI [-one.16, 3.97], I^two = 0%, P = 0.494). On the other hand, meta-regression revealed no meaning differences in the change in VAS for pain later adjusting for baseline and possible confounding factors (Table ​ 4).

Forest plot of the changes in VAS for hurting

Rate of healing from TMJ clicking

Comparing of the splint therapy and command groups using a stock-still-effects model showed that there was no significant difference in the rates of healing from TMJ clicking between the two groups (Figure ​ iv) (RR = one.17, 95% CI [0.69, i.98], I² = 0.0%, P = 0.701).

Forest plot of the rate of healing of TMJ clicking

Frequency of pain relief

Comparison of the splint therapy and control groups using a stock-still-effects model showed that splint therapy significantly reduced the frequency of painful episodes in patients with TMJ clicking (Effigy ​ 5) (RR = ane.90, 95% CI [1.19, 3.02], I² = 0.0%, P = 0.442).

Forest plot of the frequency of pain relief

Publication Bias

The result of Egger's test showed there was no significant difference between both the modify in MMO (Bias = -i.915 [-4.50, 0.67], P = 0.100) and the change in the VAS for pain (Bias = -0.072 [-2.xiii, 1.98], P = 0.927).

DISCUSSION

In this meta-analysis, nosotros evaluated 13 clinical trials that included TMD patients older than 18 years of historic period. We constitute that patients with an initial MMO less than 45mm showed a statistically significant change with splint therapy, whereas patients with an initial MMO greater than 45mm did not. Furthermore, subgroup analysis confirmed that splint therapy was most effective with patients exhibiting a limited ability to open up their mouths. Information technology also appears splint therapy provides significant pain relief to patients with TMDSD and TMJ clicking, merely splint therapy did not reduce the hurting in patients with osteoarthritis. We speculate that this is because osteoarthritis occurs after impairment to the tissue has already occurred, whereas TMDSD and TMJ clicking occur in the early stage of the disease, when the splint is more able to exert a beneficial effect. In addition, although we constitute that splint therapy had no significant beneficial effect on the symptoms of TMJ clicking, the meta-assay showed that splint therapy reduced the frequency of TMJ pain.

There are many types of splints for the treatment or control of TMD. These include the stabilization splint, soft splint, apartment splint, and pivot splint [xi]. Although the mechanisms of activity of splints are not fully understood, Aleksandra et al [28] found that plasma levels of calcitonin gene related peptide (CGRP) were increased in TMD patients treated with an occlusal splint. CGRP is a strong neuropeptide idea to play an essential function in stretching and relaxing musculus, neurogenic vasodilatation and maintaining the functional integrity of peripheral tissues [29]. We therefore suggest that the increased CGRP reflects the decreased activity muscles responsible for MMO. In improver, Glaroset al [30] proposed that splints decrease pain by preventing molar contact and reducing muscle tension. Seligman et al [31] suggested that part occlusal relationships reflect the balance of working occlusal contacts, length and symmetry of retruded contact position-intercuspal position (RCP-ICP) slides, occlusal guidance patterns, parafunction, and dental compunction. All these interacting factors play of import roles during splint therapy, which explains in part why combination therapies are more effective for the treatment of TMD [32].

To our knowledge, 4 meta-analyses examining effectiveness of splint therapy have been published [11, 33-35]. Ii of those studies [11, 34] indicated that splints reduce pain in patients with TMD. Ebrahim et al [34] included 11 studies involving 455 patients. 2 outcomes, VAS for hurting and the incidence of continued pain, were described without subgroup analysis. Friction et al [11] simply included the rate of hurting reduction among 50 patients self-reporting pain, and Al-Ani et al [35] but included pain every bit an outcome. MMO was not examined in any of those studies. In the present meta-analysis, we included thirteen studies and used two main outcomes (VAS for pain and MMO) and ii secondary outcomes (rate of healing from TMJ clicking and frequency of pain) [36]. Moreover, comprehensive subgroup analyses were conducted based on the range of initial MMO and subclasses of VAS for pain. The clinical heterogeneity was relieved, and the results were largely consistent with the experience in clinical practice [37].

There are several limitations to this study that should be addressed. Start, just a few clinical trials met the inclusion and exclusion criteria. Consequently, more clinical studies will exist required to confirm our results [38]. Second, some of the clinical trials had missing information on basic characteristics, possibly falsely increasing heterogeneity due to failure to perform a meta-regression for confounding factors [39, twoscore]. Although we estimated the missing SD from P-values, this can lead to errors [41]. Finally, although all included studies were randomized controlled trials or parallel-grouping design clinical trials, we could non implement consummate allocation darkening, blinding the participants and personnel to the outcome assessment [42, 43].

CONCLUSIONS

This report examined the effectiveness of splint therapy in TMD patients in a meta-analysis of published results. Our results bespeak that splint therapy effectively reduces pain levels in TMDSD patients, and reduces the frequency of hurting inpatients with TMJ clicking. Additionally, splint therapy increased mouth opening ability in patients with initial MMO < 45mm. On the ground of this evidence, we recommend the employ of splints for the treatment and command of TMD in adults.

MATERIALS AND METHODS

This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) argument [44]. No ethical issues were involved in this written report, and all collected data were based on published studies.

Literature search strategy

We conducted a search of iv electronic databases, PubMed, EMBASE, the Cochrane Key Register of Controlled Trials and Clinical Trails.gov, up to March 31, 2016 for eligible randomized or parallel-grouping design clinical trials that evaluated the effectiveness of splint therapy in patients suffering from the TMD. The electronic search and the PICO (population, intervention, comparator, outcomes) strategy are shown in Table ​ 1.

Table 1

Search strategy and picots criteria for the systematic review

PICOS criteria
Population	ane)MeSH term: (temporomandibular joint disorders) OR (temporomandibular joint disc) OR (temporomandibular joint) OR (temporomandibular disorders) 2)Text word: (temporomandibular joint dis*) OR (dis*, temporomandibular) OR (disc*, temporomandibular joint) OR (joint dis*, temporomandibular) OR (TMJ disorders) OR (disorder, TMJ) OR (disorders, TMJ) OR (TMJ dis*) OR (temporomandibular disorder*) OR TMD
Intervention	iii) MeSH term: splints OR (occlusal splints) 4) Text give-and-take: splint* OR (splints, occlusal) OR (occlusal splint*) OR (splint, occlusal)
Intervention	5) MeSH term: placebos 6) Text word: placebo* OR (no treatment) OR (sham splint*)
Outcomes	7) MeSH term:pain OR (pain measurement) 8) Text word: (maximal oral fissure opening) OR (MMO) OR pain OR (pain measurement) OR (visual counterpart scales of pain) OR (VAS of hurting) OR (healing from TMJ clicking) OR (pain relief)
Study blueprint	nine) MeSH term: randomized controlled trials AND controlled clinical trials
Search combination	ane AND 2 AND 3 AND iv AND 5 AND 6 AND 7 AND 8 AND 9
Language	English
Electronic database	Electronic database Medline/PubMed, EMBASE, Cochrane Fundamental Register of Controlled Trials (Fundamental) and Clinical Trails.gov
Focused question	Is using splint therapy helpful to better clinical outcomes in the direction of temporomandibular disorders(TMD)?

Abbreviations:TMJ, temporomandibular articulation; TMD, temporomandibular disorders; Key, Cochrane Central Register of Controlled Trials

Selection criteria

All studies were selected in accordance with the post-obit inclusion criteria: i) RCTs; 2) included just TMD patients older than 18 years; three) compared the effectiveness of splint therapy using controls receiving no treatment or placebo; 4) included only patients who should accept been diagnosed with TMD (due east.one thousand., osteoarthritis, TMJ clicking or inductive disc displacement with or without reduction); 5) included patients who had non been administered a TMD treatment prior to the study; and 6) investigated one of the following outcomes: i) changes in MMO without support, ii) changes in VAS for pain, three) charge per unit of healing from TMJ clicking or 4) change in the frequency of pain from more than once a week to less than once a week. The main outcomes in this written report were defined every bit a change of MMO and change in VAS for hurting. The secondary outcomes were the charge per unit of healing from TMJ clicking and the change in the frequency of hurting.

Exclusion criteria

Studies were excluded based on the following criteria: 1) pain at rest was used as the hurting score; 2) the report was a duplicate; 3) the information could not be extracted or obtained through contact with the author; and 4) too picayune information to calculate the missing SD.

Data extraction

The relevant data, including study pattern, patient characteristics, interventions, comparisons, and outcomes, were independently extracted and entered into a database by two investigators. When relevant inquiry information was missing, especially written report design or effect information, we contacted the original authors for clarification. The post-obit information was extracted from each study: publication year, region, age, gender, sample, diagnostic criteria, classification of diseases, history, intervention and command groups, course, follow-upwardly, and outcomes. Disagreements between the ii investigators on data extraction or quality assessment were resolved by give-and-take. If the dispute persisted, other senior investigators were consulted to reach consensus.

Quality assessment of included studies

Two investigators independently evaluated the methodological quality of eligible trials using the Cochrane collaboration tool [38] for assessing hazard of bias (random sequence generation, resource allotment concealment, blinding of participants and personnel, blinding of upshot assessment, incomplete issue data, selective reporting and other sources of bias).

Statistical analysis

To describe the principal outcomes based on continuous data, we used weighted mean differences (MD) [38], and 95% confidence intervals (CI). For the secondary outcomes, based on dichotomous information, we used relative gamble (RR) [38, 45] and 95% CI. All the consequence information were candy using STATA 14.0 software. All missing SD were estimated from P-values [41]. We performed a statistical test for heterogeneity [37] and adopted I² > 50% and P≥0.one as show for heterogeneity [38]. If the data were homogeneous nether a stock-still-effects model, the initial telescopic of the MMO and illness classification were identified as central sources of heterogeneity in the chief outcomes [37]. Heterogeneity was so dealt with using subgroups based on these modifiers. If the information were even so heterogeneous, nosotros introduced a random-furnishings model [37]. In addition, the baseline and possible misreckoning factors, including historic period, gender, region, diagnostic criteria, nomenclature of diseases, course, follow-upward, sample, publish year, and sources of SD, were detected using meta-regression [46]. Finally, the Egger'south test was employed to address quantitative detection bias [47].

Footnotes

CONFLICTS OF Interest

The authors declare no disharmonize of interest.

Contributed by

Writer contributors

CZ and MHD had full access to all of the information in the written report, and took responsibleness for the integrity of the data and the accuracy of the information analysis. JYW, YMN, and CZ designed the study. MHD and YT developed and tested the data collection forms. JYW, YMN, and DLD acquired the data. CZ and BYH conducted the analysis and interpreted the information. JYW and YMN drafted the manuscript. All authors critically revised the manuscript. MHD and CZ are guarantors.

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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356643/

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