[go: up one dir, main page]

WO2023085447A1 - Procédé pour prédire le pronostic d'un patient possédant une uvéite antérieure hypertensive - Google Patents

Procédé pour prédire le pronostic d'un patient possédant une uvéite antérieure hypertensive Download PDF

Info

Publication number
WO2023085447A1
WO2023085447A1 PCT/KR2021/016264 KR2021016264W WO2023085447A1 WO 2023085447 A1 WO2023085447 A1 WO 2023085447A1 KR 2021016264 W KR2021016264 W KR 2021016264W WO 2023085447 A1 WO2023085447 A1 WO 2023085447A1
Authority
WO
WIPO (PCT)
Prior art keywords
anterior uveitis
patients
virus
anterior
pcr
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR2021/016264
Other languages
English (en)
Korean (ko)
Inventor
김성재
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gyeongsang National University Hospital
Original Assignee
Gyeongsang National University Hospital
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gyeongsang National University Hospital filed Critical Gyeongsang National University Hospital
Priority to PCT/KR2021/016264 priority Critical patent/WO2023085447A1/fr
Publication of WO2023085447A1 publication Critical patent/WO2023085447A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B3/00—Apparatus for testing the eyes; Instruments for examining the eyes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B3/00—Apparatus for testing the eyes; Instruments for examining the eyes
    • A61B3/10—Objective types, i.e. instruments for examining the eyes independent of the patients' perceptions or reactions
    • A61B3/12—Objective types, i.e. instruments for examining the eyes independent of the patients' perceptions or reactions for looking at the eye fundus, e.g. ophthalmoscopes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/70—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving virus or bacteriophage

Definitions

  • Anterior uveitis is the most common type of uveitis and occurs in acute, recurrent and chronic forms.
  • Anterior uveitis has infectious causes such as bacteria, fungi, and viruses, as well as various non-infectious causes such as immune mediators or impostor syndrome.
  • intraocular pressure anterior uveitis is associated with mild inflammation of the anterior chamber with elevated intraocular pressure (IOP).
  • Herpes virus is known to be the main cause of ocular hypertension anterior uveitis (AU), and in recent years, herpes simplex virus (HSV), varicella zoster virus (VZV), and cytomegalovirus have been virus (CMV) has been reported.
  • CMV or rubella virus was recently identified as the cause of hypertensive AU previously diagnosed as Posner-Schlossmann syndrome (PSS) and Fuchs uveitis syndrome (FUS). Although identification of the cause is very important for the treatment of ocular hypertension anterior uveitis, there are few long-term and systematic studies on the spread, cause, clinical progression, and visual outcome of ocular hypertension anterior uveitis (AU).
  • An object of the present invention is to provide a method for predicting the prognosis of patients with ocular hypertension anterior uveitis.
  • the virus is one or more selected from the group consisting of herpes simplex virus, varicella-zoster virus, cytomegalovirus and Epstein-Barr virus, and predicting the prognosis of patients with ocular hypertension anterior uveitis.
  • the present invention provides a method for predicting the prognosis of patients with ocular hypertension anterior uveitis.
  • the present invention provides a method for predicting the reduction rate and recurrence rate of the number of corneal endothelial cells in a patient by analyzing the type of corneal deposit in the anterior segment of a patient with ocular hypertension anterior uveitis and detecting a virus in the aqueous humor of the patient.
  • a-c indicate coin-type KPs (white arrows) positive for cytomegalovirus in multiplex PCR.
  • d shows diffuse small-to-medium pigmented KP in herpes simplex virus-positive patients.
  • e represents the KP of the diffuse medium-large lamb fat type of a patient who tested positive for varicella zoster virus in a multiplex PCR test.
  • f shows diffuse corneal edema and multiple microscopic KPs in an Epstein Barr virus-positive patient.
  • Figure 2 shows the results of multivariate analysis on multipolymerase chain reaction positivity in patients with ocular hypertension anterior uveitis.
  • PCR stands for polymerase chain reaction
  • KP keratoprecipitate
  • OR odds ratio
  • CI confidence interval
  • BCVA best corrected visual acuity
  • IOP intraocular pressure
  • ECC endothelial cell count
  • CCT central corneal thickness.
  • Figure 4 shows the results of multivariate analysis of Final BCVA (logMAR) in hypertensive anterior uveitis patients.
  • the present invention relates to a method for predicting the prognosis of patients with ocular hypertension anterior uveitis.
  • high intraocular pressure anterior uveitis refers to anterior uveitis involving an intraocular pressure of 25 mmHg or greater.
  • viral infectious ocular hypertension anterior uveitis is mistakenly identified as non-infectious ocular hypertension anterior uveitis and only steroid treatment is performed, it may cause steroid glaucoma or viral proliferation, and patients with ocular hypertension anterior uveitis may already have complications of glaucoma. In many cases, the initial treatment period may be missed or vision loss or vision loss may occur due to recurrence. Therefore, by quickly identifying the cause of ocular hypertension anterior uveitis and predicting the resulting prognosis (number of corneal endothelial cells, risk of recurrence) through the method of the present invention, appropriate and rapid treatment can be accompanied.
  • the present invention comprises the steps of collecting an anterior segment image of an ocular hypertension anterior uveitis patient through an image collection unit; Analyzing the type of corneal deposit through the anterior segment image; And it provides a method for predicting the prognosis of an ocular hypertension anterior uveitis patient comprising the step of detecting a virus in the aqueous humor collected from an ocular hypertension anterior uveitis patient.
  • the type of corneal deposit can be analyzed through the collected anterior segment images.
  • the types of corneal deposits may be, for example, coin-shaped corneal deposits, mutton-fat corneal deposits, fine corneal deposits, and pigmented corneal deposits (FIG. 1).
  • the virus to be detected in the aqueous humor of patients with ocular hypertension anterior uveitis may be at least one selected from the group consisting of herpes simplex virus, varicella-zoster virus, cytomegalovirus and Epstein-Barr virus.
  • a method of detecting the virus in the aqueous humor of patients with ocular hypertension anterior uveitis may be to perform multiplex PCR, but is not limited thereto.
  • multiplex polymerase chain reaction can be used interchangeably, and multiplex primer pairs are used simultaneously to target multiple target genes in the same reaction. It means a method of amplification in liquid.
  • the sample concentration, the concentration of dNTP, and a suitable temperature are not particularly limited, and the reaction is performed at a sample concentration, dNTP concentration and suitable temperature, etc. that are obvious to those skilled in the art. can be performed.
  • initial denaturation at 92 ° C to 96 ° C for 10 to 20 minutes or 10 to 15 minutes
  • denaturation at 92 ° C to 96 ° C for 30 seconds 58
  • One cycle may be constituted by annealing at 68° C. to 68° C. for 60 seconds to 120 seconds and extension at 68° C. to 76° C. for 10 seconds to 50 seconds, and repeating the cycle two or more times.
  • final extension may be performed at 68° C. to 76° C. for 5 to 15 minutes.
  • the initial corneal endothelial cell count of patients in whom at least one virus selected from the group consisting of herpes simplex virus, varicella-zoster virus, cytomegalovirus, and Epstein-Barr virus was detected in the aqueous humor of patients with ocular hypertension anterior uveitis was not detected.
  • the number of corneal endothelial cells in patients with detected virus may decrease more rapidly.
  • the initial corneal endothelial cell number of a patient in which the virus is detected is 1900.0/mm 3 or less, and the reduction rate of the corneal endothelial cell number is 25% or more.
  • early corneal endothelial cells are detected according to whether herpes simplex virus, varicella-zoster virus, cytomegalovirus or Epstein-Barr virus is detected through polypolymerase chain reaction (polypolymerase chain reaction positive)
  • the reduction in the number of endothelial cells in the cornea of patients with the virus was about 29%, and the reduction in the number of endothelial cells in the patients in which the virus was not detected was about 5%.
  • the recurrence rate when one or more viruses selected from the group consisting of herpes simplex virus, varicella-zoster virus, cytomegalovirus, and Epstein-Barr virus is detected in the aqueous humor of patients with ocular hypertension anterior uveitis is The recurrence rate is high compared to , and the probability of recurrence more than 4 times is significantly high.
  • the recurrence rate when a virus is detected is 70% or more, and the recurrence rate 4 or more times is 20% or more.
  • the recurrence rate is different depending on whether herpes simplex virus, varicella-zoster virus, cytomegalovirus or Epstein-Barr virus is detected through polypolymerase chain reaction (polypolymerase chain reaction positive) , and the recurrence rate of patients in which the virus was detected was higher (about 71.4% of patients in whom the virus was detected had recurrence of ocular hypertension anterior uveitis (20 out of 28 eyes), and about 21.4% (6 out of 28 eyes) About 38.3% of patients in whom no virus was detected had recurrences of ocular hypertension anterior uveitis (23 out of 60 eyes), and about 3.3% (2 out of 60 eyes) had 4 or more relapses (Table 1). 4).
  • the presumptive diagnosis was classified into viral endothelitis, FUS-like anterior uveitis, and granulomatous anterior uveitis according to the phenotype of the clinical features of prepuncture anterior uveitis based on the "Phenotypes of viral AU" previously reported by Chan and Chee in 2019. .
  • CCT central corneal thickness
  • ECC endothelial cell count
  • tonometry using Goldmann applanation tonometry
  • dilated fundus examination .
  • a Pentacam (Oculus Inc., Dutenhofen, Japan) was used for the CCT test, and a Topcon SP2000P reflector microscope (Topcon, Tokyo, Japan) and a CellChek XL reflector microscope (Konan, Irvine, CA, USA) were used for the ECC test. Goldmann applanation tonometry was used.
  • early glaucoma was defined as -5.00 dB or more (mean deviation MD)
  • intermediate glaucoma was defined as -5.01 to -12.00 dB (mean deviation MD)
  • late glaucoma was defined as visual impairment corresponding to -12.00 dB or less.
  • the extracted nucleic acid (5 ⁇ L) was mixed with the reagents of the Seeplex Meningitis-V1 ACE Detection kit (10 ⁇ MV1 ACE PM 2 ⁇ L, 8-MOP solution 3 ⁇ L, 2 ⁇ multiplex master mix 10 ⁇ L), and PCR was performed using Veriti 96 according to the manufacturer's instructions. -well thermal cycler (Applied Biosystems, Waltham, Mass.). PCR was performed under the following conditions. (1) predenaturation at 94°C for 15 min, (2) denaturation at 94°C for 30 sec, (3) annealing at 63°C for 90 sec, (4) 40 cycle extension at 72°C for 90 sec, (5) Additional extension at 72°C for 10 min. Identical dose amplification products were analyzed using 2% agarose gel electrophoresis with 0.5 mg/mL ethidium bromide staining.
  • 2% topical ganciclovir eye drops using intravenous ganciclovir were administered 6 times a day for patients with CMV-positive anterior uveitis during the first month, followed by 2-3 It was administered 4 times a day for 6 months, then gradually reduced to 2-3 times a day for up to 6 months.
  • Patients who tested positive for HSV1, VZV, or EBV ocular hypertension anterior uveitis received oral acyclovir 800 mg three times a day for 4–6 weeks followed by 400–800 mg daily for 4 months.
  • topical acyclovir ointment (Herpesid, Samil Co.
  • oral acyclovir 400 mg/day 3 times (for 6 to 8 weeks) and topical acyclovir ointment 4 times a day for 6 weeks are administered, and the dose is gradually reduced to 2 to 3 times/day for up to 4 months. .
  • Continuous variables are presented as means ( ⁇ standard deviation, SD) and interquartile ranges, and categorical variables as numbers (percentage).
  • Continuous variables between PCR positive and negative groups were compared using the Mann-Whitney U test, and differences in categorical variables were evaluated using Fisher's exact test.
  • logistic analysis was performed to obtain the risk odds ratio (95% confidence interval; CI) of PCR positivity, recurrence, and final best corrected visual acuity (BCVA). A P-value ⁇ 0.05 was considered statistically significant.
  • Statistical analysis was performed using R software version 2.2.1 (R Project for Statistical Computing, Vienna, Austria).
  • Tables 1 and 2 Detailed demographic and clinical characteristics of the included patients are shown in Tables 1 and 2.
  • the mean follow-up period of the patients was 33.5 months.
  • the mean age of the patients was 61.0 ⁇ 14.3 years, and 66 patients (75%) were male.
  • Fifty patients (66.8%) were diagnosed with glaucoma or hyperocular hypertension and took one or more antiglaucoma drugs, and 86.4% and 51.1% of patients received steroid and antiviral treatment, respectively, before visiting the hospital.
  • There was a statistically significant difference between PCR-positive and negative groups according to presumptive diagnosis (P 0.042) (Table 1).
  • Table 1 shows the demographic characteristics of patients with ocular hypertension anterior uveitis.
  • AU anterior uveitis
  • FUS Fuchs uveitis syndrome
  • IQR interquartile range
  • PCR polymerase chain reaction
  • SD standard deviation
  • Table 2 shows the clinical characteristics of patients with ocular hypertension anterior uveitis (BCVA (best corrected visual acuity) is the best corrected visual acuity
  • CCT central corneal thickness
  • ECC endothelial cell count
  • KP corneal deposit
  • IOP intraocular pressure
  • IQR interquartile range
  • MAR minimum angle of resolution
  • PCR polymerase chain reaction
  • P-values were calculated between the PCR negative and positive groups using the Mann-Whitney U test for continuous variables and Fisher's exact test for categorical variables.
  • PCR was positive in 20 eyes with the presumptive diagnosis of viral endothelitis, 6 eyes with the presumptive diagnosis of FUS, and 2 eyes with the presumptive diagnosis of granulomatous anterior uveitis (Table 3).
  • Table 3 shows multiple PCR results in hypertensive anterior uveitis (AU is anterior uveitis, CMV is cytomegalovirus, EBV is Epstein-Barr virus, FUS is Fuchs uveitis syndrome, HSV is herpes simplex virus, PCR is polymerase chain reaction, VZV is varicella -zoster virus).
  • Table 5 shows the comparison of BCVA, IOP, ECC and CCT between PCR negative and PCR positive groups in ocular hypertension anterior uveitis (BCVA is best corrected visual acuity, CCT is central corneal thickness, ECC is endothelial cell count, IOP is intraocular pressure, IQR stands for interquartile range, MAR stands for minimum angle of resolution, and PCR stands for polymerase chain reaction).
  • Table 6 is a table of complications and complications of surgery in patients with ocular hypertension anterior uveitis (PCR stands for polymerase chain reaction and PKP stands for penetrating keratoplasty).

Landscapes

  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Organic Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Ophthalmology & Optometry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medical Informatics (AREA)
  • Public Health (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Immunology (AREA)
  • Zoology (AREA)
  • Biomedical Technology (AREA)
  • Wood Science & Technology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Surgery (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Analytical Chemistry (AREA)
  • Virology (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne un procédé permettant de prédire le pronostic d'une uvéite antérieure hypertensive, comprenant les étapes suivantes : collecte d'images du segment antérieur d'un patient possédant une uvéite antérieure par le biais d'une partie de collecte d'images; analyse des types de dépôts cornéens à l'aide des images du segment antérieur; et détection de virus dans l'humeur aqueuse du patient possédant une uvéite antérieure. La cause de l'uvéite antérieure est diagnostiquée et un pronostic en fonction de la cause est établi, afin qu'un traitement approprié soit présenté en parallèle et que la perte de la vue causée par des complications telles que celles du glaucome accompagné d'une uvéite antérieure puisse être évitée.
PCT/KR2021/016264 2021-11-09 2021-11-09 Procédé pour prédire le pronostic d'un patient possédant une uvéite antérieure hypertensive Ceased WO2023085447A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/KR2021/016264 WO2023085447A1 (fr) 2021-11-09 2021-11-09 Procédé pour prédire le pronostic d'un patient possédant une uvéite antérieure hypertensive

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/KR2021/016264 WO2023085447A1 (fr) 2021-11-09 2021-11-09 Procédé pour prédire le pronostic d'un patient possédant une uvéite antérieure hypertensive

Publications (1)

Publication Number Publication Date
WO2023085447A1 true WO2023085447A1 (fr) 2023-05-19

Family

ID=86335933

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2021/016264 Ceased WO2023085447A1 (fr) 2021-11-09 2021-11-09 Procédé pour prédire le pronostic d'un patient possédant une uvéite antérieure hypertensive

Country Status (1)

Country Link
WO (1) WO2023085447A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130100404A1 (en) * 2011-04-25 2013-04-25 Carl Zeiss Meditec, Inc. Automated detection of uveitis using optical coherence tomography
KR20190140301A (ko) * 2018-06-11 2019-12-19 사회복지법인 삼성생명공익재단 전안부 질환 진단 시스템 및 이를 이용한 진단 방법
KR20210073388A (ko) * 2019-12-10 2021-06-18 사회복지법인 삼성생명공익재단 전안부 이미지를 이용한 각막 병변 분석 시스템 및 방법 그리고 컴퓨터로 판독 가능한 기록 매체

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130100404A1 (en) * 2011-04-25 2013-04-25 Carl Zeiss Meditec, Inc. Automated detection of uveitis using optical coherence tomography
KR20190140301A (ko) * 2018-06-11 2019-12-19 사회복지법인 삼성생명공익재단 전안부 질환 진단 시스템 및 이를 이용한 진단 방법
KR20210073388A (ko) * 2019-12-10 2021-06-18 사회복지법인 삼성생명공익재단 전안부 이미지를 이용한 각막 병변 분석 시스템 및 방법 그리고 컴퓨터로 판독 가능한 기록 매체

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KIM JIN-HO, LEE JI-YOUNG, CHOI JIN-A: "Comparison of Clinical Characteristics between Patients with Cytomegalovirus Positive and Negative Hypertensive Uveitis", JOURNAL OF THE KOREAN OPHTHALMOLOGICAL SOCIETY, KR, vol. 61, no. 3, 1 January 2020 (2020-01-01), KR , pages 258 - 266, XP093066421, ISSN: 0378-6471, DOI: 10.3341/jkos.2020.61.3.258 *
YOO WOONG-SUN, KIM GYU-NAM, CHUNG INYOUNG, CHO MIN-CHUL, HAN YONG SEOP, KANG SANG SOO, YUN SEUNG PIL, SEO SEONG-WOOK, KIM SEONG-JA: "Clinical characteristics and prognostic factors in hypertensive anterior uveitis diagnosed with polymerase chain reaction", SCIENTIFIC REPORTS, vol. 11, no. 1, 23 April 2021 (2021-04-23), pages 8814, XP093066419, DOI: 10.1038/s41598-021-87931-3 *

Similar Documents

Publication Publication Date Title
Babu et al. Viral anterior uveitis
Anwar et al. The diagnostic utility of anterior chamber paracentesis with polymerase chain reaction in anterior uveitis
Fox et al. Detection of herpesvirus DNA in vitreous and aqueous specimens by the polymerase chain reaction
Moshfeghi et al. Diagnostic approaches to severe, atypical toxoplasmosis mimicking acute retinal necrosis
Pleyer et al. Current aspects on the management of viral uveitis in immunocompetent individuals
Hwang et al. The validity of clinical feature profiles for cytomegaloviral anterior segment infection
Kakimaru-Hasegawa et al. Clinical application of real-time polymerase chain reaction for diagnosis of herpetic diseases of the anterior segment of the eye
Murata et al. The characteristics of Posner-Schlossman syndrome: A comparison in the surgical outcome between: cytomegalovirus:-positive and: cytomegalovirus:-negative patients
Su et al. Topical ganciclovir treatment in patients with cytomegalovirus endotheliitis receiving penetrating keratoplasty
Cao et al. Digital droplet polymerase chain reaction analysis of common viruses in the aqueous humour of patients with Posner‐Schlossman syndrome in Chinese population
Musa et al. Herpes simplex keratitis: A brief clinical overview
Teo et al. Intermediate uveitis: a review
Suzuki et al. A case of Epstein-Barr virus acute retinal necrosis successfully treated with foscarnet
Stavrou et al. Detection of varicella-zoster virus DNA in ocular samples from patients with uveitis but no cutaneous eruption
Lorenzo et al. The prevalence of autoimmune diseases in patients with primary open-angle glaucoma undergoing ophthalmic surgeries
Chen et al. Comparative analysis of cytomegalovirus retinitis and microvascular retinopathy in patients with acquired immunodeficiency syndrome
Yoo et al. Clinical characteristics and prognostic factors in hypertensive anterior uveitis diagnosed with polymerase chain reaction
WO2023085447A1 (fr) Procédé pour prédire le pronostic d'un patient possédant une uvéite antérieure hypertensive
Mori et al. Clinical features of glaucoma associated with cytomegalovirus corneal endotheliitis
CN112080586B (zh) 感染性眼病病原体固相多重联排pcr检测试剂盒及检测方法
Al Somali et al. Concomitant varicella zoster virus and cytomegalovirus corneal endotheliitis in an immunocompetent patient
García et al. Persistent and Severe Mpox Keratitis Despite Systemic and Topical Treatment
Rangel et al. Acute retinal necrosis: experience in a reference center in Santander–Colombia
Kim et al. Clinical results and utility of herpesviruses multiplex polymerase chain reaction: Assessment of aqueous humor samples from patients with corneal endotheliitis and high intraocular pressure
Cai et al. Investigation of the infection route of HIV-associated cytomegalovirus retinitis

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21964157

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 21964157

Country of ref document: EP

Kind code of ref document: A1