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PROSPERO ONLINE SUBMISSION FORM - FINAL VERSION FOR SC
URL: https://www.crd.york.ac.uk/PROSPERO/
Date prepared: 2026-05-14
Status: READY FOR SUBMISSION pending [NEEDS SERGIO INPUT] items
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INSTRUCTIONS FOR SERGIO:
1. Create a PROSPERO account at https://www.crd.york.ac.uk/PROSPERO/
2. Click "Register a new review" and select "Standard review" / "Overview of reviews".
3. Copy each FIELD value below into the matching online form box.
4. Replace every [NEEDS SERGIO INPUT: ...] tag before submitting.
5. Attach the two supplementary documents listed at the END of this file.
6. Click "Submit" - PROSPERO returns an ID within ~2-4 weeks.

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FIELD 1: REVIEW TITLE [max 200 characters]
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Axillary Management After Neoadjuvant Chemotherapy in Node-Positive Breast Cancer: An Umbrella Review of 23 Systematic Reviews and Meta-Analyses (2006-2026)

[character count: 174]

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FIELD 2: ORIGINAL LANGUAGE TITLE [if applicable]
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N/A (English)

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FIELD 3: ANTICIPATED OR ACTUAL START DATE
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01/06/2026

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FIELD 4: ANTICIPATED COMPLETION DATE
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15/12/2026

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FIELD 5: STAGE OF REVIEW AT TIME OF SUBMISSION
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[X] Preliminary searches - Started, Completed
[X] Piloting of the study selection process - Started, Completed
[X] Formal screening of search results against eligibility criteria - Started, Completed
[X] Data extraction - Started, Pilot completed (23 SRs included; 10 excluded with PICOS rationale)
[ ] Risk of bias (quality) assessment - Not yet started
[ ] Data analysis - Not yet started

Notes: Preliminary searches AND pilot data extraction completed. Final included set: 23 systematic reviews and meta-analyses (13 ELIGIBLE + 10 BORDERLINE per AMSTAR-2 stratification). 10 candidate reviews excluded after full-text assessment with PICOS-based rationale documented in Supplementary File S4.

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FIELD 6: NAMED CONTACT
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Name: Dr Sergio Cervera, MD
Email: [NEEDS SERGIO INPUT: institutional email, e.g. sergio.cervera@hospital.es]
Postal address: [NEEDS SERGIO INPUT: full institutional postal address including department, hospital, street, postcode, city, country]
Telephone: [NEEDS SERGIO INPUT: international format, e.g. +34 9XX XXX XXX - PROSPERO requires a working phone number]
ORCID iD: [NEEDS SERGIO INPUT: 0000-0000-0000-0000 - obtain free at https://orcid.org if none]

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FIELD 7: NAMED CONTACT EMAIL
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[NEEDS SERGIO INPUT: same institutional email as Field 6]

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FIELD 8: ORGANISATIONAL AFFILIATION OF THE REVIEW
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Independent academic project (Cervera SC, Duque DD). No institutional sponsor; no external funding.

[NEEDS SERGIO INPUT: if you would like to list your hospital/department as the host institution rather than declare independent, replace this line with the affiliation. PROSPERO accepts either.]

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FIELD 9: REVIEW TEAM MEMBERS AND THEIR ORGANISATIONAL AFFILIATIONS
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1. Dr Sergio Cervera, MD - Principal Investigator; Breast Surgical Oncology
   Affiliation: [NEEDS SERGIO INPUT: full institution name and city/country]
   Role (CRediT): Conceptualization, Methodology, Investigation, Supervision, Writing - review and editing.

2. Dr David Duque, MD - Data Lead; Plastic and Reconstructive Surgery / Methodology and Digital Tools
   Affiliation: Independent (Spain)
   Role (CRediT): Data curation, Software, Visualization, Writing - original draft, Project administration.

3. [NEEDS SERGIO INPUT: BIOSTATISTICIAN - to be recruited]
   Suggested profile: PhD biostatistician or epidemiologist with prior meta-analysis or network meta-analysis experience in oncology.
   Suggested sourcing: epidemiology / preventive medicine department of Sergio's institution; or international colleagues from the cited SRs (see Mocellin 2015 PMID 26439659 / Cao 2021 PMID 33970373 author lists).
   Role (CRediT): Formal analysis, Methodology, Validation, Writing - review and editing.

4. [NEEDS SERGIO INPUT: SENIOR BREAST SURGEON CO-AUTHOR - to be recruited]
   Suggested profile: senior breast surgical oncologist with prior umbrella review or systematic review experience; preferably contributor to NCCN, ESMO, AGO, EUSOMA or EUBREAST guideline panels.
   Role (CRediT): Conceptualization, Investigation, Validation, Writing - review and editing, Supervision.

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FIELD 10: FUNDING SOURCES / SPONSORS
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None. No external funding has been received. The review is investigator-initiated and self-funded by the authors. No commercial sponsorship has been solicited or accepted.

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FIELD 11: CONFLICTS OF INTEREST
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D.D. (David Duque) developed the companion clinical prediction tool available at https://ganglio.cicatra.com. The tool is freely accessible without registration, contains no advertising, generates no revenue, and shares no user data with third parties. D.D. holds no equity, patents, royalties, consultancy, speaker, or advisory-board ties to manufacturers of axillary localization devices (clip, radioactive seed, magnetic seed, radar reflector, superparamagnetic iron oxide) or related diagnostic imaging providers.

S.C. (Sergio Cervera) declares no conflicts of interest.

The biostatistician and senior breast surgeon co-authors will declare their own COIs upon recruitment; any disclosure will be appended to this PROSPERO record by amendment.

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FIELD 12: COLLABORATORS
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The team is open to international collaboration, particularly contributors from breast surgical units that participated in TAD/MARI/RISAS validation cohorts and methodologists experienced in JBI umbrella-review methodology. Interested collaborators should contact the corresponding author.

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FIELD 13: REVIEW QUESTION [max 500 chars per question]
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In adult women with biopsy-proven node-positive (cN+) breast cancer who undergo neoadjuvant chemotherapy (NAC), what is the diagnostic accuracy and oncologic safety of de-escalated axillary surgical strategies (SLNB, MLNB, TAD, MARI, RISAS) compared with completion axillary lymph node dissection (ALND), considering nodal pathologic complete response (ypN0), false-negative rate, identification rate, locoregional and axillary recurrence, overall and disease-free survival, and lymphedema?

[character count: 491]

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FIELD 14: SEARCHES
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Databases: PubMed/MEDLINE, EMBASE (via Elsevier), Cochrane Database of Systematic Reviews (Cochrane Library), Epistemonikos.

Date range: 2006-01-01 to 2026-04-30. The search will be re-run within 30 days of manuscript submission.

Languages: English, Spanish, French.

Search building blocks combine: (i) breast cancer terms; (ii) neoadjuvant therapy terms; (iii) axillary surgery terms (sentinel, TAD, MARI, RISAS, MLNB, ALND, ypN0, clip, seed, magseed); (iv) systematic-review/meta-analysis publication-type filter and title/abstract terms.

Hand-search: reference lists of all included reviews; reference lists of NCCN, ESMO, ASCO, St Gallen, AGO, EUSOMA, EUBREAST guidelines (2020-2026); table of contents of Annals of Surgical Oncology, British Journal of Surgery, JAMA Surgery, The Breast, European Journal of Surgical Oncology (2024-Q4 to 2026-Q2).

Grey literature: PROSPERO registry, ESMO and SABCS abstracts (2024-2026).

Full database queries are detailed in the supplementary file 'search_strategy_pilot.md'.

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FIELD 15: URL TO SEARCH STRATEGY [if pre-deposited]
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https://ganglio.cicatra.com/protocol/search_strategy (to be activated upon registration)

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FIELD 16: CONDITION OR DOMAIN BEING STUDIED
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Invasive breast cancer with documented axillary lymph node involvement at diagnosis (cN+) treated with neoadjuvant systemic chemotherapy with intent to downstage the axilla and offer surgical de-escalation. The clinical domain spans surgical oncology, radiation oncology, medical oncology, and diagnostic imaging.

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FIELD 17: PARTICIPANTS / POPULATION
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Inclusion: adult women aged 18 years or older with histologically confirmed invasive breast cancer (any subtype: HR+/HER2-, HR+/HER2+, HR-/HER2+, triple-negative); biopsy- or cytology-confirmed clinically node-positive (cN1, cN2, cN3) status documented prior to NAC by ultrasound-guided fine-needle aspiration or core-needle biopsy; treatment with at least one cycle of neoadjuvant systemic chemotherapy (anthracycline-based, taxane-based, platinum-containing, dual HER2 blockade, or chemo-immunotherapy regimens); surgical axillary staging after completion of NAC.

Exclusion: reviews restricted to clinically node-negative (cN0) only; recurrent or metastatic disease; male breast cancer when reported as a separable subgroup (mixed-sex cohorts retained if at least 95% female); ductal/lobular carcinoma in situ only; reviews of neoadjuvant endocrine therapy only without comparison or pooling with NAC.

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FIELD 18: INTERVENTION(S) / EXPOSURE(S)
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Targeted axillary dissection (TAD); sentinel lymph node biopsy (SLNB) with single or dual tracer (radioisotope, blue dye, indocyanine green, superparamagnetic iron oxide); marked lymph node biopsy (MLNB); MARI procedure; RISAS protocol; marker technologies including metallic clip, 125I seed, magnetic seed (Magseed, Sirius Pintuition), radar reflector (LOCalizer, SAVI SCOUT), carbon-ink tattoo, hookwire.

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FIELD 19: COMPARATOR(S) / CONTROL
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Completion axillary lymph node dissection (ALND) as reference standard for diagnostic accuracy outcomes (FNR, IR, NPV); completion ALND vs no further axillary surgery (with or without regional nodal irradiation) for oncologic outcomes (recurrence, OS, DFS, lymphedema).

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FIELD 20: TYPES OF STUDY TO BE INCLUDED
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Systematic reviews with or without meta-analysis; network meta-analyses; pooled patient-level analyses described as systematic reviews. Required SR criteria: explicit research question, at least one bibliographic database with reproducible query, explicit eligibility criteria, structured selection process. Quality threshold for primary synthesis: AMSTAR-2 overall confidence "moderate" or "high"; "low" / "critically low" reviews reported in transparency table and used only in sensitivity analyses.

Final included set after pilot screening (2026-05): 23 SRs (13 ELIGIBLE primary tier + 10 BORDERLINE secondary tier). 10 reviews excluded with PICOS-based rationale documented in Supplementary File S4.

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FIELD 21: CONTEXT
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International multi-setting evidence base, spanning academic and community breast units in Europe, North America, Asia-Pacific, and Latin America. The review is conducted in the context of evolving international guidelines (NCCN, ESMO, ASCO, St Gallen, AGO 2020-2026) that increasingly endorse axillary surgical de-escalation in selected cN+ to ycN0 patients while leaving optimal technique unsettled.

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FIELD 22: MAIN OUTCOME(S)
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1. Axillary pathologic complete response rate (ypN0) - proportion of patients with no residual disease on final axillary pathology after NAC, by molecular subtype, by initial cN stage, and overall.

2. False-negative rate (FNR) of SLNB, TAD, MLNB, MARI, and RISAS using completion ALND as the reference standard.

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FIELD 23: ADDITIONAL OUTCOME(S)
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Identification rate (IR) of marked node and sentinel nodes; number of nodes retrieved; locoregional recurrence and isolated axillary recurrence at 3, 5, 10 years; overall survival (OS); disease-free survival (DFS); distant disease-free survival; lymphedema incidence and severity; predictors of ypN0 (subtype, initial cN stage, tumour grade, Ki-67, regimen including pembrolizumab); patient-reported outcomes when available.

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FIELD 24: DATA EXTRACTION (SELECTION AND CODING)
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Title/abstract screening: dual independent screening by Sergio Cervera and David Duque (Rayyan or equivalent); inter-rater agreement reported (Cohen's kappa). Full-text screening: dual independent against eligibility criteria; reasons for exclusion documented (see Supplementary File S4 for the 10 reviews excluded after full-text assessment). Discrepancy resolution: consensus discussion; persistent disagreements adjudicated by the third reviewer (biostatistician).

Data extraction: independent dual extraction onto a piloted standardized form covering bibliographic metadata, PICOS domains, search characteristics, included primary studies, pooled estimates with 95% CIs, heterogeneity statistics, risk-of-bias methods used, AMSTAR-2 score, authors' conclusions.

Overlap of primary studies: corrected covered area (CCA) computed for each outcome to quantify review overlap.

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FIELD 25: RISK OF BIAS (QUALITY) ASSESSMENT
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AMSTAR-2 (16 items) for every included systematic review, performed independently by two reviewers; overall confidence rated as high, moderate, low, or critically low according to the 7 critical-domain logic.

ROBIS used in sensitivity analysis on a stratified random sample to test concordance with AMSTAR-2.

GRADE used to rate the certainty of evidence per outcome at the umbrella-review level (high, moderate, low, very low).

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FIELD 26: STRATEGY FOR DATA SYNTHESIS
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Umbrella review per JBI methodology and reported per PRIOR. No re-pooling of primary-study data (deliberate methodological choice given substantial overlap of primary studies among the 23 included reviews).

Synthesis structured by intervention (SLNB, TAD, MARI/RISAS, MLNB) and within each intervention by outcome (ypN0, FNR, IR, recurrence, survival, lymphedema). For each outcome: tabulate every published pooled estimate with 95% CI, I-squared, and number of contributing primary studies; identify convergence and divergence; attribute divergence to plausible methodological reasons; visualise with forest-style summary plots showing each review's pooled estimate side-by-side; provide meta-bias assessment per outcome.

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FIELD 27: ANALYSIS OF SUBGROUPS OR SUBSETS
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Pre-specified subgroup analyses (where review-level data permit):
- By molecular subtype: HR-/HER2+, HR+/HER2+, triple-negative, HR+/HER2-, luminal A vs luminal B (Samiei 2021 stratification);
- By initial cN stage: cN1 vs cN2-cN3;
- By NAC era: pre-2018 conventional regimens vs post-2018 era including dual HER2 blockade and chemo-immunotherapy (KEYNOTE-522 era);
- By geography of underlying primary studies;
- By marker technology: clip vs radioactive seed vs magnetic/radar marker vs SPIO;
- By AMSTAR-2 tier: ELIGIBLE (n=13) vs BORDERLINE (n=10) sensitivity analysis.

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FIELD 28: TYPE AND METHOD OF REVIEW
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Umbrella review (overview of systematic reviews) following the JBI Manual for Evidence Synthesis (Aromataris 2024 update) and reported per the PRIOR statement (Pollock 2022).

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FIELD 29: LANGUAGE
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English, Spanish, French (full-text reading and extraction by team members fluent in all three).

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FIELD 30: COUNTRY
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[NEEDS SERGIO INPUT: country of corresponding author's institution, e.g. "Spain" or "International project. Review team based in Spain."]

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FIELD 31: OTHER REGISTRATION DETAILS
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N/A. First registration of this work. No related Cochrane title currently registered on this exact topic; an Epistemonikos LOVE search will be re-run before final registration submission to confirm.

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FIELD 32: REFERENCE AND/OR URL FOR PUBLISHED PROTOCOL
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Full protocol manuscript deposited at https://ganglio.cicatra.com/protocol upon registration. PROSPERO ID will be added to the manuscript title page once issued.

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FIELD 33: DISSEMINATION PLANS
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Open-access peer-reviewed journal submission, in order of preference: British Journal of Surgery, ESMO Open, European Journal of Surgical Oncology, The Breast, Annals of Surgical Oncology. Companion interactive web tool at https://ganglio.cicatra.com (probability calculator integrating subtype-specific ypN0 estimates and AMSTAR-2 weighted recommendations). Conference presentations targeted at ESSO and EUBREAST annual meetings. Plain-language summary in Spanish and English aimed at patient associations.

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FIELD 34: KEYWORDS [comma separated]
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breast cancer; node-positive breast cancer; neoadjuvant chemotherapy; sentinel lymph node biopsy; targeted axillary dissection; TAD; MARI; RISAS; ypN0; axillary lymph node dissection; de-escalation; umbrella review; meta-analysis; AMSTAR-2

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FIELD 35: DETAILS OF ANY EXISTING REVIEW OF THE SAME TOPIC BY THE SAME AUTHORS
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None. This is the first systematic-review-level project on this topic by the named authors. Members of the team have authored individual primary studies and clinical commentaries on related topics, but no prior systematic review or umbrella review on cN+ to ypN0 axillary management.

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FIELD 36: CURRENT REVIEW STATUS
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Ongoing - data extraction phase (pilot completed; AMSTAR-2 and GRADE pending).

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FIELD 37: ANY ADDITIONAL INFORMATION
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Pilot search yielded 33 systematic reviews and meta-analyses (2006-2026). After full-text assessment: 23 reviews INCLUDED (13 ELIGIBLE primary tier + 10 BORDERLINE secondary tier per AMSTAR-2 prelim) and 10 reviews EXCLUDED with PICOS-based rationale (Supplementary File S4). Seminal reviews calibrated for AMSTAR-2 inter-rater reliability include Samiei 2021 (PMID 33881478), Swarnkar 2021 (PMID 33810544), and de Wild 2024 (PMID 38531689). The review will produce an interactive companion tool at https://ganglio.cicatra.com.

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ATTACHMENTS TO UPLOAD WITH SUBMISSION
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- Supplementary File S1: search_strategy_pilot.md (full database queries, located in this same folder)
- Supplementary File S2: PROSPERO_protocol.md (full long-form protocol, located in this same folder)

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END OF FORM - submit at https://www.crd.york.ac.uk/PROSPERO/
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