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\begin{document}

\title{Effectiveness of Treatments for Disc Displacement Without Reduction of
the Temporomandibular Joint -- An Overview of the current Evidence}



\author[1]{Carolina Chaves Gama Aires}%
\author[1]{Lívia Mirelle Barbosa}%
\author[1]{Davi da Silva Barbirato}%
\author[1]{José Rodrigues Laureano Filho}%
\author[1]{Sandra Lúcia Dantas de Moraes}%
\author[2]{Eduardo Piza Pellizzer}%
\author[1]{Belmiro Cavalcanti do Egito Vasconcelos}%
\affil[1]{Universidade de Pernambuco - Campus Santo Amaro}%
\affil[2]{Universidade Estadual Paulista Julio de Mesquita Filho - Campus de Aracatuba}%


\vspace{-1em}



  
  \date{May 27, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
\textbf{Purpose:} Thus, this overview aimed to answer the focused
question: ``What is the evidence from systematic reviews on the
treatment of patients with DDwoR of the TMJ?''. \textbf{Methods:} This
overview was register on the Open Science Framework under osf.io/74cej.
This study was performed according to The Joanna Briggs Institute
Reviewers' Manual 2014: Methodology for JBI Umbrella Reviews and
Cochrane Handbook for Systematic Reviews of Interventions Version 6.2,
using the following electronic databases: MEDLINE\textbar{}PubMed, Web
of Science, Cochrane Library, Embase, Scopus and LILACS\textbar{}VHL,
and other sources. Eligible articles were systematically reviewed and
assessed for bias using preset criteria. The quality of evidence and the
possibility of biased results from the included studies were
independently assessed by two researchers using AMSTAR 2, OQAQ, CASP and
ROBIS tools. \textbf{Results:} Five systematic reviews with
meta-analyses and one qualitative review were included in this overview.
Differences in pain control and improvement in mandibular function were
observed between the treatments studied, especially for open surgery.
However, the comparative effectiveness of conservative and invasive
treatments for DDwoR remains uncertain due to the low methodological
quality of the secondary studies analyzed in this overview and the risk
of bias of the primary studies reported by the authors.
\textbf{Conclusions:} Currently, it is not possible to guarantee the
superiority of different DDwoR treatments to guide professionals and
patients. This overview clarified the reason for the lack of consensus
on which treatment is most effective for DDwoR and identified the low
quality of evidence on the subject.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Temporomandibular joint disorder (TMD) comprises a set of
musculoskeletal disorders that affect the temporomandibular joint (TMJ),
masticatory muscles and facial structures. Among the types of TMD, there
are internal derangements (ID), including articular disc displacement
without reduction (DDwoR).\textsuperscript{1} In DDwoR, the articular
disc is displaced anteriorly to the condyle and does not return to its
normal position during mandibular kinetics. Macro and microtraumas
represent the main causes of this condition, in which pain and
restriction of mandibular movements are the most frequent
symptoms.\textsuperscript{1,2}

The absence of treatment or failure in therapeutic management results in
chronic displacement of the disc, leading to its deformation and
perforation, and to the rupture of the fibrocartilage that covers the
mandibular condyle and the articular fossa. Degeneration of joint
structures by DDwoR is associated with osteoarthritis of the
TMJ.\textsuperscript{3,4} The treatment of this condition consists of
conservative and surgical procedures, represented by manipulation,
medication, modification of habits, physiotherapy and splint therapy,
followed by arthrocentesis, arthroscopy and open joint surgery as a
second-step therapy, respectively.\textsuperscript{1,5,6}

There are systematic reviews (SRs) comparing the effects of different
treatments, conservative and invasive, in the treatment of
DDwoR;\textsuperscript{7-12} however, there is no consensus on which
treatment is most effective and the quality of evidence on this issue
has not yet been established. Therefore, this overview aimed to
summarize the comparative effectiveness between different DDwoR
treatments and assess the quality of evidence from secondary studies
through different validated scales.

\textbf{Materials and methods}

This study was performed according to The Joanna Briggs Institute
Reviewers' Manual 2014: Methodology for JBI Umbrella Reviews and
Cochrane Handbook for Systematic Reviews of Interventions Version
6.2.\textsuperscript{13} The review protocol was registered at The Open
Science Framework under osf.io/74cej.

An extensive literature search was performed among seven electronic
databases for articles published up to February 5, 2022: MEDLINE/PubMed,
Web of Science, Cochrane Library, Embase, Scopus, LILACS and BBO. Other
sources were consulted through Google Scholar and System for Information
on Grey Literature in Europe (SIGLE) through OpenGrey databases. The
protocol registration databases included PROSPERO and Open Science
Framework -- OSF. Hand-searches were also performed in specialized
periodicals (Step 1): \emph{Journal of Oral and Maxillofacial Surgery;
International Journal of Oral and Maxillofacial Surgery; Journal of
Cranio-Maxillo-Facial Surgery; British Journal of Oral and Maxillofacial
Surgery; Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology;
Journal of Dentistry, Medicine and Medical Sciences; and Journal of Oral
Rehabilitation;} and in reference lists of selected articles (Step 2).
To keep the search strategy updated, alerts were established for each
database.

This overview aimed to answer the focused question: ``What is the
quality of evidence of secondary studies on the treatment of DDwoR of
the TMJ?'' The terms and keywords of the search strategy (Table 1) were
defined to identify SRs based on the elements of the PICO question:

\begin{itemize}
\tightlist
\item
  Population (P) = patients with DDwoR of the TMJ
\item
  Intervention/Comparison (I/C) = types of non-invasive treatment,
  minimally invasive treatment and open surgery of the TMJ
\item
  Outcomes (O) = pain and mandibular function
\end{itemize}

We included SRs and meta-analyses on the comparison of different types
of treatment for DDwoR of the TMJ. Systematic reviews based on animal
studies and data from observational studies, and that did not report the
eligibility criteria or quality assessment of the primary studies were
excluded. Unavailability of the full paper was described in the PRISMA
flow diagram. There was no restriction of studies by date and language
of publication.

The selection process was conducted in two phases: Phase 1, two
researchers (L.M.B. and D.S.B.) independently assessed all titles and
abstracts, applying the including process (blind process); and Phase 2,
the same two reviewers independently applied the exclusion criteria to
the remaining studies, based on reading the full text. Inter-reviewer
reliability in the study selection process was determined by the Cohen \selectlanguage{greek}κ
\selectlanguage{english}test, assuming an acceptable threshold value of
0.80.\textsuperscript{14} The disagreement at any stage was resolved by
discussion, and a third reviewer (B.C.E.V.) will be consulted (consensus
meeting). The final decision/selection was always based on the full text
of the publication.

Data was independently extracted by two blinded reviewers (L.M.B. and
D.S.B) using a standardized sheet, as recommended by the Cochrane
Handbook for Systematic Reviews of Interventions Version
6.2,\textsuperscript{13} ordered in the PICO sequence: authors, year of
publication, country where trials were performed, trial design,
objectives, patient population characteristics, number of participants
randomly assigned to each treatment group, clinical setting, detail of
interventions in each group, details of comparators in each group,
outcomes, measured outcomes (including assessment methods), results,
duration of follow-up, number of withdrawals, and source of funding.
When there were unclear or missed information, lack of data or when the
full text was not available, weekly attempts were made for up to five
weeks to contact the authors. The accuracy of extracted data was
confirmed by another author (M.C.M.B.). The synthesis of qualitative
results followed the SWiM reporting guideline.\textsuperscript{15}

The quality of evidence and the possibility of biased results (bias)
from the included systematic reviews and meta-analyses were
independently assessed by two researchers (L.M.B. and D.S.B.) using the
tools: ''A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR
2)'',\textsuperscript{16} ''Overview Quality Assessment Questionnaire
(OQAQ)''\textsuperscript{17} and ''Critical Appraisal Skills Programme
(CASP)''.\textsuperscript{18} The risk of bias in SRs was assessed using
the ``Risk of Bias in Systematic Reviews'' (ROBIS)
tool.\textsuperscript{19}

\textbf{Results}

The study selection process is described in the flowchart in Figure 1.
Initial screening retrieved 44 studies in MEDLINE\textbar{}PubMed, 82 in
Web of Science, 10 in Cochrane Library, 38 in Embase, 150 in Scopus and
two in LILACS\textbar{}VHL. Searching other sources and manual-searching
did not add any studies to this overview. After excluding duplicate
records, 314 articles were analyzed in the title and abstract reading.
Seven articles were selected to read the full text and apply the
exclusion criteria. Of these, a systematic review was excluded as it
included patients with disc displacement with reduction in the analysis.
The level of agreement between reviewers was almost perfect (\selectlanguage{greek}κ \selectlanguage{english}[?] \selectlanguage{english}0.81)
for all databases consulted.

Six articles were included in this overview, five systematic reviews
with meta-analyses\textsuperscript{7-10,12} and a qualitative
review.\textsuperscript{11} Two articles included only randomized
controlled trials (RCTs),\textsuperscript{9,11} two articles included
RCTs and quasi-randomized clinical trials
(q-RCTs)\textsuperscript{8-10,12} and one article included RCTs, q-RCTs
and case series in the analyses.\textsuperscript{7} Only three articles
described the male: female proportion of the sample, with females being
predominant in the three articles.\textsuperscript{8,9,11} As for the
diagnosis of DDwoR, different criteria were reported in the articles:
Wilkes staging,\textsuperscript{8,10} American Association of Orofacial
Pain (AAOP),\textsuperscript{10} Research diagnostic criteria for
temporomandibular disorders (RDC/TMD) \textsuperscript{10}, Diagnostic
criteria for temporomandibular disorders
(DC/TMD),\textsuperscript{11,12} and Magnetic Resonance Imaging
(MRI).\textsuperscript{9,11} One study did not describe the diagnostic
criteria for participants.\textsuperscript{7} No secondary studies
described the duration of TMD or whether previous treatment for this
condition was performed (Table 2).

This overview showed that systematic reviews have confirmed
methodological heterogeneity in the clinical studies. Furthermore, the
meta-analyses showed statistical
heterogeneity.\textsuperscript{7-10,12}In general, the studies
investigated the following comparisons: comparison between different
non-invasive modalities;\textsuperscript{8-10} non-invasive versus
minimally invasive modalities;\textsuperscript{10,12} non-invasive
versus invasive modalities;\textsuperscript{8-10} minimally invasive
versus invasive modalities;\textsuperscript{7,10} and comparison between
invasive modalities.\textsuperscript{7-10} Outcomes reported in
secondary studies were: improvement assessed by the
patient\textsuperscript{7}; reduction of pain\textsuperscript{8};
frequency, intensity and duration of pain events\textsuperscript{9};
symptom remission\textsuperscript{9}; mandibular function; TMJ pain
intensity\textsuperscript{10-12}; and maximum mouth opening
(MMO)\textsuperscript{7,8,10-12}(Table 2).

Follow-up time for patients varied between studies between 10 minutes
(only one primary study) and 60 months. Most of the articles included
assessed the risk of bias within studies using the Cochrane's tool; none
of the primary studies had a low risk of bias in all
domains.\textsuperscript{8-10,12} One article used the PEDro scale and
noted that only 5:10 primary studies showed high methodological quality
with scores ranging from 7 to 8 points.\textsuperscript{11} One article
did not report the risk of bias analysis of the included studies (Table
2).\textsuperscript{7}

Tables 3 and 4 (Table 3 and 4) present descriptive data and results of
pairwise comparisons of different treatment modalities for DDwoR
reported by secondary studies included in this overview.

Comparisons such as ``rehabilitation'' vs ``medical
management'',\textsuperscript{8} ``physical medicine'' vs ``palliative
care'',\textsuperscript{8} ``physical medicine'' vs
``controls'',\textsuperscript{8-10} ``palliative care'' vs
``physiotherapy'' vs ``no treatment'',\textsuperscript{9} revealed the
absence of significant difference in the improvement of
pain\textsuperscript{8-10} and/or mandibular
function.\textsuperscript{8} Comparing ``mandibular manipulation'' vs
``no treatment'', pain improvement and MMO were significantly greater in
patients who received mandibular manipulation.\textsuperscript{10} ``Jaw
exercises'' vs ``education'' showed no significant difference in pain
and MMO improvement.\textsuperscript{10} Comparing ``self-management''
(self-exercises + self care/medication) vs ``no treatment'',
``self-care'' represented a significant improvement in pain and MMO
compared to ``no treatment''.\textsuperscript{10}

Comparing ''self-care'' (self-care + self-care/non-steroidal
anti-inflammatory drugs) vs ''splint'': although there was a greater
reduction in pain intensity in the ''self-care'' group in the short
term, the difference was not statistically
significant.\textsuperscript{10}For MMO, ''self-care'' was more
effective than ''splint''.\textsuperscript{10} Comparing
''immobilization'' vs ''information and pain medication as needed'',
pain reduction was less frequent in the ''immobilization'' group in the
long-term.\textsuperscript{10}

The number of patients with [?] 50 \% pain reduction was significantly
higher in the ''splint'' group compared to the ''transcutaneous
electrical nerve stimulation (TENS)'' group; however, there was no
statistically significant difference between both interventions for
MMO.\textsuperscript{10}

''Combination therapy'' (splint plus exercise +
self-care/medication/education) compared to ''Education'' (only) or
''self-care'' (self-care/medication/education \selectlanguage{ngerman}± self-care) showed no
significant difference in pain improvement and
MMO.\textsuperscript{10}''Manual therapy and exercise interventions'' vs
''splints'' showed no significant difference for pain improvement;
however, the improvement in MMO was significantly greater for ''manual
therapy and exercise interventions''.\textsuperscript{11}

There was no statistically significant difference in the effects of
''combination of splint plus jaw exercises'' compared to ''splint'' for
short-term pain. For MMO, however, there was a statistically significant
difference in favor of combined treatment.\textsuperscript{10}

Comparing ''active pulsed electromagnetic fields (PEMF)'' vs
''placebo'', there was no significant difference in pain improvement and
MMO. ''Active iontophoresis'' (by dexamethasone + lidocaine) showed
short-term improvement in pain and MMO compared with the ''placebo''
group, but the differences were not statistically
significant.\textsuperscript{10}

In the ''arthrocentesis'' vs ''arthrography only'' and
''arthrocentesis'' vs ''auriculotemporal nerve block'' comparisons,
there was no significant difference in the effects for pain and MMO.
''Arthrocentesis'' showed significant short-term pain improvement
compared to ''combination therapy'' (splint plus
self-care/self-exercise); there was no significant difference between
interventions for MMO\textsuperscript{10}. Another review observed that
arthrocentesis showed a significant difference in terms of increased
mouth opening and reduced pain level in relation to the stabilization
splint\textsuperscript{12}.

In the ``rehabilitation'' vs ``arthroscopic
surgery\textsuperscript{''}and ``rehabilitation'' vs ``arthroplasty''
comparisons, there was no significant difference in the effects for pain
and MMO.\textsuperscript{8} There was no significant difference in pain
control comparing ''arthroscopic surgery'' vs ''self-management''
(self-care/medication/education), ''arthroscopic surgery'' vs
''combination of splint plus exercises'' {[}+
self-care/medication/education + cognitive behavioral therapy (CBT){]}
and ''open surgery'' vs ''self-management''
(self-care/medication/education). Comparing ''open surgery'' vs
''combination of splint plus exercises'' (+
self-care/medication/education + CBT), ''open surgery'' demonstrated a
significant improvement in pain control in the short term, but not in
the long term.\textsuperscript{10}

There was no ``improvement'' assessed by the
patient,\textsuperscript{7}pain reduction and MMO\textsuperscript{10}
improvement when comparing ''arthrocentesis'' vs ''arthroscopy''.
Comparing ''open surgery'' vs ''arthroscopy'', one of the secondary
studies did not report a significant difference for the ''improvement
assessed by the patient'' (meta-analysis through indirect
comparisons).\textsuperscript{7} Meta-analyses from the other study
showed an overall improvement in open surgery and a significant
reduction in long-term pain intensity. Sensitivity analysis excluding a
primary study without imaging diagnosis showed no significant difference
between surgical procedures.\textsuperscript{10}

Figures 2 and 3 show the results of the methodological analysis of the
articles included, according to AMSTAR 2. These data suggest
methodological weaknesses in the studies, added to the limitations of
the primary studies related to heterogeneity. In the overall confidence
rating, all articles included had a critically low confidence level.
According to the OQAQ methodological quality analysis (figure 4), only
three articles had a positive response for all
domains.\textsuperscript{10-12} In the quality analysis using the CASP,
only two articles showed a positive response for all
domains.\textsuperscript{10,12} Regarding the assessment of the risk of
bias of the systematic reviews, after answering the focused questions
(Figure 5), none study presented a low risk of bias in all domains of
the instrument (Figure 6).

\textbf{Discussion}

This overview summarized data and key results from five systematic
reviews that investigated the effects of different DDwoR treatments and
assessed the quality of evidence from these reviews. The analysis of
general data revealed heterogeneity between studies. Despite the
significant number of primary studies on the subject, the significant
variation in pairwise comparisons within each study compromises
evidence-based clinical/surgical decision-making for the treatment of
DDwoR. Different outcome evaluation criteria and follow-up times were
also observed. These characteristics also compromised the grouping of
studies for meta-analyses in systematic reviews.

Among the reviews that performed
meta-analyses,\textsuperscript{7-10,12}one included only one
RCT\textsuperscript{9} and three included two to four
RCTs.\textsuperscript{8,10,12} In a third systematic review, 15 studies
were considered in the meta-analysis,\textsuperscript{7} based on
indirect comparisons, including comparison between prospective
uncontrolled studies and RCTs. These authors constructed a different
artificial, untreated control group, which represents a bias and
compromises the degree of confidence of the results, since the
comparative analyzes were not based on real samples and did not consider
eligibility criteria, random allocation, collection and blind analysis
of the data.

Despite the number of primary studies on the subject, this overview
revealed a significant variation in comparisons related to the treatment
of DDwoR in RCTs. Comparison between different non-invasive
modalities,\textsuperscript{8-10} non-invasive versus minimally
invasive,\textsuperscript{10,12} non-invasive versus
invasive,\textsuperscript{8-10} minimally invasive versus
invasive\textsuperscript{7,10} and comparison between invasive
modalities\textsuperscript{7-10} were observed.

The systematic reviews included primarily compared the effects of
non-invasive treatments for DDwoR. This can be explained by the fact
that this modality is considered, by consensus, as the first therapeutic
option for DDwoR. In addition, the significant number of non-invasive
options applied alone or in combination in the treatment of DDwoR also
contributes to a greater number of publications and favors the carrying
out of secondary studies on the subject.

The signs and symptoms associated with DI are caused by the loss of
intra-articular tissue structure and function, compromising the
biomechanics of the biomechanical temporomandibular joint. The cause of
this tissue failure is most often joint overload, leading to tissue
failure and an inflammatory/degenerative arthropathy of the
temporomandibular joint.\textsuperscript{20}

It is not possible to state which is the best non-invasive treatment
method, as in most reported results no significant difference was
detected in pain control and improvement in MMO between groups. This
finding may be related to the self-limited natural course of DDwoR.
Significant improvement in clinical symptoms of closed lock is expected
in 75 \% of patients over a 2.5-year follow-up. The reduction in pain
and mouth opening restriction is probably associated with the active
adaptation to the new structural situation of the
TMJ.\textsuperscript{20,21} Even so, the therapeutic approach to DDwoR
is necessary due to the expected benefits of pain and functional
limitations, in addition to preventing osteoarthritis as an evolution of
the internal TMJ disorder. The persistence of these clinical symptoms
and the evolution of joint TMD lead to the need for TMJ invasive
therapeutic approaches.

In this context, the minimally invasive modalities, represented by
arthrocentesis, represent the first step in the treatment of ID, after
the failure of the non-invasive approach. This technique had mild and
pain-restricted benefits, only in the short term, compared to the
non-invasive combined treatment. Despite limitations for clinical
decision-making associated with heterogeneity between studies, the data
summarized in this overview suggest a small benefit of arthrocentesis in
the treatment of DDwoR, restricted to clinical symptoms and only in the
short term, compared to non-invasive therapeutic modalities.

Arthroscopic surgery and arthroplasty did not show significant
differences in pain control and MMO compared to non-invasive
modalities,\textsuperscript{8-10} and arthrocentesis and arthroscopy did
not differ for improvement assessed by the patient, pain reduction and
MMO.\textsuperscript{7,10} Open surgery showed short-term improvement in
pain control compared to non-invasive treatment, significant overall
improvement and long-term improvement in pain intensity, compared to
arthroscopy.\textsuperscript{10}

The optimal treatment for DDwoR should not be considered universal
protocol, but a personalized approach. Each patient must be assessed and
treated individually considering the severity of symptoms and functional
limitations associated with TMD, prioritizing the non-invasive treatment
model, followed by minimally invasive and invasive/open surgery
modalities. Bronstein and Merrill\textsuperscript{21} reported higher
success rates for arthroscopic treatment of ID in early stages than in
advanced stages. Zhang et al.\textsuperscript{22} reported that
arthroscopic disc repositioning was not appropriate for Wilkes stage IV
or V, suggesting a limitation of the technique for more complex cases.

Successive treatment attempts by different therapeutic modalities, in a
gradual hierarchical sequence of complexity/invasiveness, should
represent delay in the remission of clinical signs and symptoms of TMD
associated with DDwoR and greater morbidity in more complex/severe
cases. However, invasive procedures, such as open surgery, must be
carefully indicated considering the possible
pitfalls.\textsuperscript{23}

Despite the limitations of this study and the impossibility of
establishing the most effective evidence-based treatment for DDwoR, all
treatments benefit patients and had slightly different effects from each
other, except for open surgery which resulted in overall improvement and
a significant reduction in long-term pain intensity. Invasive procedures
should not be the first choice in the treatment of DDwoR, however, the
literature suggests that open surgery should be considered a possibility
for the most severe cases.

\textbf{Conclusion}

There is a lack of evidence on the effectiveness of different treatments
for DDwoR. Although this overview showed differences in pain control and
improvement in mandibular function between the treatments studied,
especially for open surgery, it is not possible to state the best
treatment, indication, predictability and limitations of each one per
DDwoR profile. The comparative effectiveness of conservative and
invasive treatments for DDwoR remains uncertain due to the low
methodological quality of the secondary studies analyzed in this
overview and the risk of bias of the primary studies reported by the
authors. In this sense, new RCTs and repeated comparisons between types
of treatment for DDwoR in different populations and TMD profiles are
needed to guide professionals and patients among clinical and surgical
options to better treat internal derangements.

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\textbf{Compliance with Ethical Standards}

\emph{Conflict of Interest}

The authors declare no conflict of interest.

\emph{Ethical Approva} l

Not required.

\emph{Informed consent}

Not applicable.

\textbf{Figures legends}

Figure 1: PRISMA flow diagram for new systematic reviews which included
searches of databases, registers, and other sources of the screening
process.

Figure 2: Quality analysis of Systematic Reviews according to AMSTAR 2

Legend: D1. Did the research questions and inclusion criteria for the
review include the components of PICO? YES or NO.''; D2. Did the report
of the review contain an explicit statement that the review methods were
established prior to the conduct of the review and did the report
justify any significant deviations from the protocol? YES, PARTIAL YES
or NO.; D3. Did the review authors explain their selection of the study
designs for inclusion in the review? YES or NO.; D4. Did the review
authors use a comprehensive literature search strategy? YES, PARTIAL YES
or NO.; D5. Did the review authors perform study selection in duplicate?
YES or NO.; D6\textbf{. Did the review authors perform data extraction
in duplicate?} YES or NO.; D7. Did the review authors provide a list of
excluded studies and justify the exclusions? YES, PARTIAL YES or NO.;
D8. Did the review authors describe the included studies in adequate
detail? YES, PARTIAL YES or NO.; D9. Did the review authors use a
satisfactory technique for assessing the risk of bias (RoB) in
individual studies that were included in the review? YES, PARTIAL YES or
NO.; D10. Did the review authors report on the sources of funding for
the studies included in the review? YES or NO.; D11. If meta-analysis
was performed did the review authors use appropriate methods for
statistical combination of results? Yes, No or No meta-analysis
conducted.; D12. If meta-analysis was performed, did the review authors
assess the potential impact of RoB in individual studies on the results
of the meta-analysis or other evidence synthesis? Yes, No or No
meta-analysis conducted.; D13. Did the review authors account for RoB in
individual studies when interpreting/ discussing the results of the
review? Yes, No or No meta-analysis conducted.; D14. Did the review
authors provide a satisfactory explanation for, and discussion of, any
heterogeneity observed in the results of the review? YES or NO.; D15. If
they performed quantitative synthesis did the review authors carry out
an adequate investigation of publication bias (small study bias) and
discuss its likely impact on the results of the review? Yes, No or No
meta-analysis conducted.; D16. Did the review authors report any
potential sources of conflict of interest, including any funding they
received for conducting the review? YES or NO. Y= Yes, N= No, N/MA= No
meta-analysis conducted.

Figure 3: Rating overall confidence in the results of the review
according to AMSTAR2.

Figure 4: Quality analysis of Systematic Reviews according to OQAQ.

Legend: D1. Were the search methods reported? D2. Was the search
comprehensive? D3. Were the inclusion criteria reported? D4. Was
selection bias avoided? D5. Were the validity criteria reported? D6. Was
validity assessed appropriately? D7. Were the methods used to combine
studies reported? D8. Were the findings combined appropriately? D9. Were
the conclusions supported by the reported data? D10. What was the
overall scientific quality of the overview? Y= YES, N= NO, CT= Can't
Tell.

Figure 5: Quality analysis of Systematic Reviews according to CASP.

Legend: D1. Did the review address a clearly focused question? D2. Did
the authors look for the right type of papers? D3. ``Do you think all
the important, relevant studies were included? D4. Did the review's
authors do enough to assess quality of the included studies? D5. If the
results of the review have been combined, was it reasonable to do so?
D6. What are the overall results of the review? D7. How precise are the
results? D8. Can the results be applied to the local population? D9.
Were all important outcomes considered? D10. Are the benefits worth the
harms and costs? Y= YES, N= NO, CT= Can't Tell.

Figure 6. Identifying concerns with the review process according to
ROBIS 2 tool domains. Domain 1: study eligibility criteria; Domain 2:
identification and selection of studies; Domain 3: data collection and
study appraisal; Domain 4: synthesis and findings.

Legend: D1.1 Did the review adhere to pre-defined objectives and
eligibility criteria? Y/PY/PN/N/NI.; D1.2 Were the eligibility criteria
appropriate for the review question? Y/PY/PN/N/NI.; D1.3 Were
eligibility criteria unambiguous? Y/PY/PN/N/NI; D1.4 Were any
restrictions in eligibility criteria based on study characteristics
appropriate (e.g. date, sample size, study quality, outcomes measured)?
Y/PY/PN/N/NI; D1.5 Were any restrictions in eligibility criteria based
on sources of information appropriate (e.g. publication status or
format, language, availability of data)? Y/PY/PN/N/NI; D2.1 Did the
search include an appropriate range of databases/electronic sources for
published and unpublished reports? Y/PY/PN/N/NI; D2.2 Were methods
additional to database searching used to identify relevant reports?
Y/PY/PN/N/NI; D2.3 Were the terms and structure of the search strategy
likely to retrieve as many eligible studies as possible? Y/PY/PN/N/NI;
D2.4 Were restrictions based on date, publication format, or language
appropriate? Y/PY/PN/N/NI; D2.5 Were efforts made to minimise error in
selection of studies? Y/PY/PN/N/NI; D3.1 Were efforts made to minimise
error in data collection? Y/PY/PN/N/NI; D3.2 Were sufficient study
characteristics available for both review authors and readers to be able
to interpret the results? Y/PY/PN/N/NI; D3.3 Were all relevant study
results collected for use in the synthesis? Y/PY/PN/N/NI D3.4 Was risk
of bias (or methodological quality) formally assessed using appropriate
criteria? Y/PY/PN/N/NI; D3.5 Were efforts made to minimise error in risk
of bias assessment? Y/PY/PN/N/NI; D4.1 Did the synthesis include all
studies that it should? Y/PY/PN/N/NI 4.2 Were all pre-defined analyses
reported or departures explained? Y/PY/PN/N/NI; D4.3 Was the synthesis
appropriate given the nature and similarity in the research questions,
study designs and outcomes across included studies? Y/PY/PN/N/NI; D4.4
Was between-study variation (heterogeneity) minimal or addressed in the
synthesis? Y/PY/PN/N/NI; D4.5 Were the findings robust, e.g. as
demonstrated through funnel plot or sensitivity analyses? Y/PY/PN/N/NI;
D4.6 Were biases in primary studies minimal or addressed in the
synthesis? Y=YES, PY=PROBABLY YES, PN=PROBABLY NO, N=NO, NI=NO
INFORMATION

Figure 7: Bias risk classification according to ROBIS 2 domains.

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