Abstract

abnormal uterine shed blood ( AUB ) is a common and debilitating condition with high direct and indirect costs. AUB frequently co-exists with fibroids, but the kinship between the two remains incompletely understand and in many women the recognition of fibroids may be incidental expense to a menstrual shed blood complaint. A structured approach for establishing the causal agent using the Fédération International de Gynécologie et d’Obstétrique ( FIGO ) PALM-COEIN ( P olyp, A denomyosis, L eiomyoma, M alignancy ( and hyperplasia ), C oagulopathy, O vulatory disorders, E ndometrial, I atrogenic and N ot otherwise classified ) classification system will facilitate accurate diagnosis and inform treatment options. Office hysteroscopy and increasing sophisticated imagination will assist provision of robust evidence for the underlying induce. Increased handiness of medical options has expanded the choice for women and many will no retentive need to recourse to potentially complicated operating room. treatment must remain personalize and encompass the impact of pressure symptoms, desire for retentiveness of fertility and contraceptive needs, angstrom good as address the management of AUB in order to achieve improved quality of life. Keywords:

abnormal uterine bleeding (AUB), fibroids, FIGO PALM-COEIN classification of AUB

Background

abnormal uterine bleed ( AUB ) is a significant clinical entity. AUB and its submarine group, fleshy menstrual bleeding ( HMB ), are coarse conditions affecting 14–25 % of women of generative age [ 1 ], [ 2 ] and may have a significant impingement on their physical, social, aroused and substantial quality of life [ 3 ]. In the UK, over 800,000 women seek aid for AUB per annum [ 3 ]. Along with the conduct impact on the charwoman and her family, there are meaning costs to both economy and health avail. A united states analyze reported fiscal losses of > $ 2000 per patient per annum due to work absence and base management costs [ 4 ]. AUB is the fourth most common reason for referral to UK gynecological services [ 5 ]. A late national audited account in England and Wales ( RCOG HMB audit ) reported that at 1-year mail referral, lone a third of women ( including those managed with operating room ) were ‘ meet ’ ( or better ) at the view of stream menstrual symptoms continuing, as presently experienced, for the next 5 years [ 6 ]. While there may be relief from HMB during pregnancy and lactation, and an end to the problem at menopause, women affected will tend to suffer the adverse impacts of AUB over what should be the flower years of their lives. Fibroids ( leiomyoma ) represent the most common tumor of women ; by the age of 50, about 70 % of white women and > 80 % of black women will have developed at least one fibroid tumor [ 7 ]. Fibroids are associated with subfertility, miscarriage, preterm labor and obstruction of labor. In accession, they may cause discomfort and pressure symptoms, typically urinary. In rare circumstances, at larger sizes, they may cause compression of the nephritic tract and pelvic vasculature leading to mar nephritic function and venous thromboembolism, respectively. conversely, many women with fibroids will be wholly asymptomatic [ 8 ]. however, many women most normally present to gynecological services with AUB and associated iron-deficiency anemia. For women with uterine fibroids, everyday life is much disrupted and fibroids remain a run indication for hysterectomy [ 9 ], [ 10 ]. button-down estimates of annual direct treatment costs and collateral costs from lost work hours as a result of fibroids are $ 4.1–9.4 billion and $ 1.55–17.2 billion, respectively [ 11 ]. The mechanism, however, linking AUB and fibroids remain incompletely sympathize. As women increasingly defer pregnancy, richness preservation is critical and newer medical options offer actual effective relief for both AUB and early symptoms associated with fibroids. This review addresses the causes of AUB and set about to judgment and general principles of management of the pre-menopausal womanhood with fibroids .

Definitions

AUB was redefined by Fédération International de Gynécologie et d’Obstétrique ( FIGO ) in 2009 by the FIGO Menstrual Disorders Group ( FMDG ) [ 12 ], ∗ [ 13 ]. This was in order to standardise definitions, terminology and the underlying categories of etiology. It was hoped that this would facilitate comfort of investigation and comparison of similar patient populations and thereby aid inquiry and improve evidence-based care ; this would besides be a practical creature for assessing contributing aetiologies. Chronic AUB was defined as ‘ bleed from the uterine principal that is abnormal in bulk, regularity and/or time that has been present for the majority of the final 6 months ’ [ 13 ]. Values outwith the bear 5–95th percentiles indicated abnormality ( ) .

Table 1

Clinical Parameter Descriptive term Normal limits (5–95th percentiles)
Frequency of menses (days) Frequent
Normal
Infrequent
<24
24–38
>38
Regularity of menses, cycle to cycle (Variation in days over 12 months) Absent
Regular
Irregular
No bleeding
Variation ± 2–20 days
Variation >20 days
Duration of flow (days) Prolonged
Normal
Shortened
>8.0
4.5–8.0
<4.5
Volume of monthly blood loss (mL) Heavy
Normal
Light
>80
5–80
<5

Open in a separate window With attentiveness to volume, however, both the Royal College of Obstetricians and Gynaecologists ( RCOG ) and american College of Obstetricians and Gynecologists ( ACOG ) prefer the patient-centred definition of HMB, ‘ excessive menstrual blood loss which interferes with a womanhood ‘s physical, social, emotional and/or material timbre of animation ’ [ 3 ], as an indication for probe and treatment options. As such, objective measurements of volume are normally the conserve of inquiry studies and surrogates such a pictorial blood-loss judgment chart ( PBAC ) scores are not recommended in routine clinical drill .

Contribution of fibroids (leiomyoma) to AUB

The kinship between AUB and fibroids remains incompletely understand. The obvious paradox is that many women have fibroids but besides have wholly normal bleed patterns. Fibroids are besides highly prevailing in women presenting with AUB. previous postulate theories include an increased endometrial coat sphere and the presence of delicate and congested vasculature in the perimyoma environment [ 15 ]. The increase in vascular menstruate observed along with these enlarged vessels can overcome platelet action [ 16 ]. There is increasing cognition regarding the complex cellular and molecular changes found in affiliation with fibroids, with shock on angiogenesis, alteration in vasoactive substrates and increase factors vitamin a well as alteration in curdling [ 16 ]. The effect of fibroids on endometrial function is immediately thought to represent a field change within the uterine cavity quite than limited to regions overlying the myoma ( mho ). Some of these changes may have an impingement on endometrial receptiveness and implantation arsenic good as AUB [ 17 ], ∗ [ 18 ]. Matrix metalloproteinase ( MMP ) 2 and 11 levels are increased in fibroids ( with MMP 1 and 3 unaltered ) [ 19 ], [ 20 ], but the shock on endometrial run is ill-defined. expression of vascular endothelial increase factor ( VEGF ), basic fibroblast growth divisor ( bFGF ), heparin-binding cuticular growth factor, platelet-derived increase factor ( PDGF ), parathyroid gland hormone-related protein ( PTHrP ) and prolactin is altered in women with fibroids [ 16 ]. VEGF, bFGF, PDGF and PTHrP all have potential angiogenic effects but their specific function within the endometrium in women with fibroids has however to be determined [ 17 ]. There is revision of plasminogen modulators and this may impact on endometrial hemostasis and repair [ 16 ]. Transforming emergence factor beta ( TGF-β ) is produced in overindulgence in the endometrium in women with fibroids and is associated with reduce levels of plasminogen activator inhibitor-1 ( PAI-1 ), thrombomodulin and antithrombin III, both in vivo and in endometrial stromal cells treated in vitro with TGF-β [ 18 ]. This may represent a putative mechanism for some cases of AUB observed in the context of fibroids and may in the future offer a electric potential therapeutic target. In women with fibroids, alterations in the blood plasma levels of circulating interleukin ( IL ) -13, IL-17 and IL-10 have been reported [ 21 ]. Whether these variations affect immune routine and inflammation implicated in endometrial breakdown and haunt remains unknown. With esteem to the location of fibroids, it was previously thought that those women with SM fibroids, particularly with those distorting the cavity, were more likely to present with HMB [ 15 ]. There is current consider that women with significant cavity distortion represent extra remedy challenges .

SEE ALSO  E major - Wikipedia

Other causes of AUB

The PALM-COEIN classification system accepts that women may have more than one fundamental etiology and besides that often in the lawsuit of structural abnormalities, many women may in fact be asymptomatic .

Polyps (AUB-P)

endometrial polyps are epithelial proliferations arising from the endometrial stroma and glands. The majority are asymptomatic. The contribution of polyps to AUB varies widely ranging from 3.7 % to 65 % [ 22 ], [ 23 ], but it is widely accepted [ 24 ]. The incidence of polyps as with fibroids increases with historic period and both pathologies may frequently co-exist, or suspected polyps visualised on transvaginal ultrasound scan ( TV-USS ) may be mistaken for SM fibroids and vice-versa [ 25 ] .

Adenomyosis (AUB-A)

The relationship between endometriosis and AUB remains ill-defined [ 26 ], peculiarly with attentiveness to wide-eyed variations in histopathological diagnosis reflecting variations in criteria used and besides improved radiological diagnosis. typically, endometriosis is associated with increasing senesce and may co-exist with fibroids. furthermore, endometriosis may be both focal and diffuse and it may be harder to establish diagnosis if fibroids are besides present [ 27 ] .

Malignancy (AUB-M)

endometrial cancer is the most common gynecological malignancy in the western worldly concern. Historically, endometrial cancer has rarely occurred in premenopausal women ; however, with increasing fleshiness and rising prevalence of the metabolic syndrome, the endocrine-driven subset of endometrial malignity has markedly increased in frequency. Between 1992–1994 and 2009–2011, the european age-standardised rates of uterine cancer in the UK have increased by 48 % [ 28 ]. With the reclassification by the WHO from hyperplasia to endometrial intraepithelial neoplasia ( EIN ), the current preponderance of premalignant disease is obscure. The evaluation of the endometrium may be affected by aberration of the uterine cavity by fibroids, and as such, the co-existing pathology may delay diagnosis. The diagnosis of cervical cancer should be considered, particularly with persistent intermenstrual bleeding, and rarely ovarian cancer may present with AUB. Uterine sarcoma have been reported as rare ( 3–7/100,000 in the USA ) [ 29 ] but possibly a induce of AUB-M. A holocene meta-analysis reported that leiomyosarcoma are unexpectedly diagnosed following operating room for predict ‘ benign ’ myoma in 2.94 per 1000 women ( one in 340 women ) [ 30 ], [ 31 ]. Race is the merely commonalty between leiomyosarcoma and leiomyoma with black women having an approximately double increased hazard [ 29 ]. The gamble of development of leiomyosarcoma is reported to increase with age with < 1 case per 500 among women aged under 30 years to one in 98 among women in the age range 75–79 years [ 30 ], [ 31 ]. early risk factors for uterine leiomyosarcoma include the long-run manipulation of estrogen antagonist [ 32 ], previous pelvic radiation therapy [ 33 ] and rare familial disorders such as ancestral leiomyomatosis and nephritic cell carcinoma ( HLRCC ) [ 34 ]. interestingly, the previously held see was that a quickly enlarging uterus would raise the suspicion for malignity. This is now no long held to be true as benign fibroids can grow quickly and sarcomas develop lento [ 35 ], [ 36 ]. however, more objective investigations are still lacking. Both ultrasound scan ( USS ) and magnetic plangency visualize ( MRI ) do not as even have robust criteria to accurately predict differentiation between leiomyoma and leiomyosarcoma [ 37 ]. The miss of a robust pre-surgical predictor/biomarker has recently altered surgical practice because morcellation of an unsuspected leiomyosarcoma increases dissemination [ 38 ]. If malignancy or premalignancy is found along with AUB categorization, the pathology should be described and staged utilising the appropriate WHO/FIGO systems [ 39 ] .

Coagulopathy (AUB-C)

Coagulopathies are reported to affect 13 % [ 40 ] of the women presenting with HMB. The majority of these women suffer from Von Willebrand disease [ 40 ]. systemic disorders of hemostasis may be identified in 90 % of women using a structure history [ 41 ], ∗ [ 42 ] ( ) .

Table 2

Criteria
1. Heavy bleeding since the menarche
2. One of the following:

  • • Postpartum bleeding
  • • Surgical-related bleed
  • • Bleeding associated with dental employment
3. Two or more of the following:

  • • Bruising 1–2 times/month
  • • nosebleed 1–2 times per/month
  • • frequent gum bleed
  • • kin history of bleeding problems

Open in a separate window If 1, 2 or 3 ( visit ) is ascertained, it indicates positive riddle, and far referral for appropriate probe should be considered. Anticoagulant and antiplatelet therapy so far has been considered as a region of ‘ AUB-C ’ ( preferably than AUB-I ). compression caused by a large fibroid tumor uterus may lead to venous thromboembolism ( VTE ). Bleeding previously deemed as AUB-L may be exacerbated by subsequent anticoagulation and presents extra management challenges .

SEE ALSO  Peridot (เพอริดอท)

Ovulatory (AUB-O)

Anovulatory cycles may contribute to AUB by unopposed estrogen effects on the endometrium causing marked proliferation and thickening resulting in HMB along with an adapted frequency of menstruation. This is observed at the extremes of generative historic period ; however, impingement on the HPO bloc along with endocrinopathies is besides present. The latter include polycystic ovarian syndrome ( PCOS ), hyperprolactinaemia, hypothyroidism ampere well as factors such as fleshiness, anorexia, weight loss, mental stress and extreme exert. typically, women in this group have menstrual cycles that fall out with 38 days or have a variation of > 21 days. Drugs that affect dopamine levels, with their attendant effects on the HPO axis, besides presently fall under this category preferably than AUB-I. In women with fibroids, the co-existing ovulatory dysfunction may exacerbate menstrual loss. The FIGO AUB categorization system is a dynamic system with feedback and contemporary debate inform future revisions [ 13 ]. The position of drug therapies affecting AUB is presently under review with regard to whether anticoagulant/antiplatelet therapies and drugs affecting the HPO axis may be better placed in ‘ AUB-I ’.

Endometrial (AUB-E)

AUB that occurs in the context of a structurally normal uterus with regular menstrual cycles without attest of coagulopathy is likely to have an underlie endometrial induce. endometrial serve in the context of menstruation and its disorders is still not amply sympathize and remains an area of active scientific inquiry, peculiarly the complexities of the sequence of events triggered by progesterone withdrawal ( due to demise of the principal luteum in the absence of pregnancy ). Hypoxia, excitement, hemostasis and angiogenesis all play all-important roles in the shed and subsequent scarless haunt of the functional upper level of the endometrium. Perturbation of local glucocorticoid metamorphosis, aberrant prostaglandin deduction and excessive plasminogen ( resulting in premature clot lysis ) have all been implicated in AUB [ 43 ]. AUB-E may be implicated in many women with AUB, but a lack of clinically available specific tests or biomarkers means that practical testing for such disorders is not however feasible. As such, diagnosis depends on careful history consider and excommunication of early contributors. The high prevalence of electric potential endometrial dysfunction means that it is highly likely that those with AUB-L will much have an chemical element of AUB-E contributing to increased/aberrant menstrual blood loss with its attendant implication for therapy .

Iatrogenic (AUB-I)

iatrogenic causes of AUB include exogenous therapy than may lead to unscheduled endometrial bleed. This is typically associated with continuous estrogen or progestin therapy ( systemic or intrauterine pitch routes ) or those interventions that act on ovarian steroid hormone free such as gonadotropin-releasing hormone ( GnRH ) agonists and aromatase inhibitors. selective estrogen receptor modulators ( SERMs ) and more rarely selective progesterone receptor modulators ( SPRMs ) may cause AUB through conduct action on the endometrium. The manipulation of an intrauterine device ( IUD ) may cause a low-grade metritis which may besides contribute to AUB .

Not otherwise classified (AUB-N)

It is inevitable that there will be pathologies that are either rare or ill defined that do not easily fit within the categories described earlier. Examples include arteriovenous malformations, endometrial pseudoaneurysms, myometrial hypertrophy and chronic metritis ( not precipitated by an IUD ). All of these can co-exist with AUB-L. The planned regular review of the FIGO PALM-COEIN classification system every 3–5 years through FIGO [ 13 ] will allow reappraisal, in particular, of this class. Further areas considered for future sub-classification include AUB-P and AUB-A .

Assessment of the patient presenting with AUB and fibroids

As described earlier, all of the other causes of AUB may co-exist with fibroids. As such, it is all-important when a patient with known or suspected fibroids presents with AUB, she is appropriately assessed for the presence of early aetiologies. Misdiagnosis will have an impact on treatment options and efficacy, and in the event of undiagnosed coagulopathy, render surgical intervention disproportionately hazardous. As separate of structured history, factors such as co-morbidities, polypharmacy, soundbox multitude index ( BMI ), previous surgery and most crucially richness desire and impact of press symptoms must be assessed as these importantly affect treatment access. A structure border on is shown in .An external file that holds a picture, illustration, etc.
Object name is gr3.jpgOpen in a separate window An accurate menstrual history and associated symptoms will identify a likely AUB-O causal agent. As described early, a structure screen for coagulopathies will identify 90 % of those women with disorders of systemic hemostasis ( ). History will besides identify contributors to AUB-I. combine history and examination will suggest possible AUB-P/-A/-L and should be confirmed with subsequent visualize. TV-USS remains the most acceptable and validated first-line probe. The increasing function of saline solution infusion sonography ( SIS ) and selected hysteroscopy will improve sensitivity and specificity for diagnosis of polyps and SM fibroids ∗ [ 37 ], ∗ [ 44 ]. The optimum mode of imaging for suspected endometriosis has even to be established [ 45 ]. Furthermore, women with fibroids may have them confused for focal endometriosis and vice-versa using conventional imaging [ 27 ]. The increased use of one-stop clinics with access to outpatient hysteroscopy improves affected role gratification and facilitates timely probe and management [ 46 ]. MRI plays a role in selected patients with AUB and fibroids, besides in the assessment of suitability for uterine artery embolisation ( UAE ). As previously discussed, it is relatively poor people at providing reassurance of the absence of sarcomatous deepen .

Endometrial sampling

In the UK, NICE recommend endometrial sampling in women with dogged inter-menstrual bleed or aged ≥45 years with treatment failure [ 3 ]. This has been highlighted in the RCOG guidelines with an exception of reducing the senesce of sampling in the context of treatment failure to 40 [ 47 ]. With the mark increase in endometrial cancer, the authors would encourage all gynaecologists to continue to excise their clinical judgment for those women aged < 40 years with HMB who have gamble factors for premalignant change such as fleshiness and PCOS. Endometrial sampling may be more challenging if fibroids distort the cavity, and access to concurrent outpatient hysteroscopy can facilitate timely exclusion of endometrial pathology .

Approach to management

management of AUB-L should address richness desire, affect of coerce symptoms, co-morbidities, and any other AUB contributors. treatment should be individualised. No one-size-fits-all approaches are available with involve to initial and subsequent treatment options, and there is a relative dearth of large robust clinical trials providing neck and neck data preferably to placebo. In those with other underlying AUB causes co-existing with fibroids, targeted discussion of these may ameliorate bleed, and in the absence of pressure symptoms or sub-mucosal myoma-related sterility, all the treatments may be required. specific treatments for early causes are shown in .

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Table 3

AUB Sub-classification Specific treatment
Polyp Resection
Adenomyosis Surgery: hysterectomy; adenomyomectomy (not frequently performed)
Malignancy Surgery +/− adjuvant treatment
High-dose progestogens (if surgery not possible)
Palliation (including radiotherapy)
Coagulopathy Tranexamic acid
DDVAP
Ovulation Lifestyle modification
Cabergoline (if hyperprolactinaemia)
Levothyroxine (if hypothyroid)
Endometrial Specific therapies await further delineation of underlying mechanisms
Iatrogenic Refer to FSRH CEU guidance on problematic bleeding with hormonal contraception [56]
Not otherwise classified Antibiotics for endometritis
Embolisation of AV malformation

Open in a separate window otherwise, treatment should be tailored depending on the impact of associate symptoms, birthrate requirements and cavity distortion ( ). It should be remembered that a conservative approach ( incorporating oral iron replacement if indicated ) may be an entirely acceptable treatment approach path, particularly in the peri-menopausal phase with amenorrhea and regression of fibroid tumor size at hand .An external file that holds a picture, illustration, etc.
Object name is gr4.jpgOpen in a separate window In AUB, in the absence of press symptoms, medical discussion may be more appropriate, peculiarly when fertility preservation is required. Tranexamic acidic and NSAIDs ( e.g. mefenamic acerb ) remain the only amply non-contraceptive checkup options [ 3 ]. Whilst the risk of expulsion of a levonorgestrel-releasing intrauterine arrangement ( LNG–IUS ) is without doubt higher in the context of fibroids, there is still evidence for efficacy [ 48 ] although cavity distortion may preclude the function of LNG–IUS. The current Cochrane review for the SPRMs is limited to mifepristone [ 49 ] and a future review incorporating other members of the SPRM class is afoot. GnRH analogues are effective in reducing both size of fibroids and amelioration of bleeding, but their side effects and shock on cram concentration limit their longer-term utility, and rebound of symptoms is rapid on cessation [ 50 ]. GnRH agonists frequently are beneficial as a short-run treatment anterior to IVF or operating room, but given the findings in the PEARL II study, there is dependable tell that the SPRM ulipristal acetate rayon ( UPA ) is better tolerated in those women pre-surgery without loss of efficacy [ 51 ]. There is no robust evidence for alternative therapies such as acupuncture or herbal remedies for the treatment of fibroids [ 52 ], [ 53 ]. With see to interventional radiological ( uterine artery embolisation, UAE ) and surgical options, the anticipated outputs of the FEMME study [ 54 ] will hopefully provide robust evidence for affect on symptoms and other qualitative measures between myomectomy and UAE. MR-guided focussed ultrasound ( MRgFUS ) is not a widely available proficiency. Its role in the management of symptomatic fibroids remains to be established. Hysterectomy is a authoritative treatment, and in the context of management options for HMB, it remains as a therapeutic choice with the highest patient satisfaction and cost-effectiveness for > 5 years [ 55 ]. Hysterectomy, however, is often a challenging operation in women with high electric potential blood losses and risk of ureteric injury due to anatomic distortion in the pelvis. With increasing fleshiness, the complexity of surgery is compounded. Whilst alternative treatment strategies are under development, a cohort of women whose richness plans are complete and for whom definitive surgery, that is, hysterectomy, becomes the most appropriate management will remain .

Conclusions

AUB is a common and enfeeble discipline with high conduct and indirect costs. Symptoms of AUB frequently co-exist with fibroids, but the relationship between AUB and fibroids remains incompletely sympathize. In many women, fibroids may be an incidental innocent bystander in the underlie etiology of a menstrual run complaint. A structure approach to establishing the campaign using the FIGO PALM-COEIN categorization system will facilitate accurate diagnosis and inform discussion options. The categorization organization, however, hush lacks effective biomarkers for ‘ AUB-E ’. Office hysteroscopy and the increasingly sophisticate visualize will assist provision of robust testify for the fundamental campaign. The increase handiness of medical options has expanded the choice for women. Many will no long need to recourse to potentially complicated operating room. treatment must remain personalize and encompass the impact of pressure symptoms, desire for retentiveness of birthrate and contraceptive needs, arsenic well as address the management of their AUB in order to achieve better quality of life sentence .

  • • A structure approach for using the PALM-COEIN model should be developed to ensure that important contributors apart from fibroids are not missed .
  • • In finical, coagulopathies should be verbally screened for in all patients presenting with AUB, given their high prevalence in this population and implications for management .
  • • In view of the rapid increase in endometrial cancer, clinical sagacity regarding endometrial sampling should be considered in younger women with AUB with risk factors for EIN and malignancy .
  • • treatment should be individualised encompassing impact of press symptoms, desire for retention of birthrate, contraceptive needs and impact of symptoms on choice of biography .
  • • Imaging for fibroids, in detail, modality for diagnosis of endometriosis and for discriminating between fibroids and leiomyosarcoma .
  • • Increased attest root for long-run medical treatments for management of AUB in the context of fibroids, with particular stress on quality of liveliness .
  • • Improved evidence for interventional treatments for AUB in the context of fibroids .

Conflict of interest statement

LW has no conflict of interest. HODC has clinical research digest for testing ground consumables and staff from Bayer Pharma AG and provides consultancy advice ( but with no personal remuneration ) for Bayer Pharma AG, PregLem SA, Gedeon Richter, Vifor Pharma UK Ltd, AbbVie Inc .

Acknowledgements

We are most grateful to Mrs Sheila Milne for her avail with manuscript readiness and Mr Ronnie Grant for graphic aid. We thank Professors Mac Munro ( USA ), Alistair Williams ( UK ), Dr Jane Walker and Dr Alison Murray for provision of several of the images in. HC has concession hold from the Medical Research Council ( MR/J003011/1 and G1002033 ) and NIHR ( 12/206/52 ). LW is supported by the Medical Research Council ( MR/J003011/1 and G1002033 ) .

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