{"paper_id":"fd42e010-756a-41b9-a581-93790f18dc7e","body_text":"MEDICAL SCIENCE l REPORT \nMedical Science, 26, ms106e2083 (2022)                                                                                                                                            1 of 7 \n \nImaging of adenomyosis of \nuterus: What radiologist needs \nto know? \n \nAvinash Dhok1*, Kajal Mitra2 \n  \n \nABSTRACT \nBackground: Adenomyosis of uterus is difficult to diagnose clinically because \nof nonspecific symptoms and signs. Accurate diagnosis can be achieved with \nimaging. Objective: To study imaging findings of adenomyosis of uterus by \nEVUS and MRI with histopathological correlation and to evaluate accuracy of \nEVUS and MRI in diagnosis of adenomyosis. Material & Methods:  Prospective \nstudy of 50 patients in age group of 30 -59 years, presenting clinically with \nmenorrhagia, dysmenorrhea, pelvic discomfort, low backache and uterine \nenlargement underwent EVUS and MRI. Imaging findings were correlated \nwith histopathology reports from biopsy and operated cases. Results: \nAdenomyosis of uterus was confirmed in 41 patients, 38 patients were \ndiagnosed correctly on magnetic resonance imaging. MRI showed 2 false \npositive and 3 false negative diagnosis. EVUS correctly diagnosed 33 patients. \nIt showed 4 false positives and 8 false negatives . Sensitivity of MRI was \n92.68% and specificity was 81.82%. EVUS showed sensitivity of 80.49% \n(p<0.001) and specificity of 69.23% (p=0.41). Conclusion: EVUS and MRI are \nextremely accurate methods of diagnosing uterine adenomyosis. MRI is more \nprecise than EVUS. \n \nKeywords: Uterine Adenomyosis, Endovaginal ultrasonography, Magnetic \nResonance Imaging, Uterine Enlargement, Uterine junctional zone. \n \n \n1. INTRODUCTION \nAdenomyosis of uterus is an important gynecological pathology. On \nhistopathological examination t here are heterotopias of endometrial glands \nand adjacent stromal tissue into surrounding myometrium along with \nhyperplasia of smooth muscles. There are no specific symptoms or signs on \nclinical examination, making it difficult to diagnose adenomyosis of ut erus \nclinically. Role of EVUS & MRI in diagnosing cases with clinically highly \nsuspicious adenomyosis of uterus can be established as follows: Firstly, the \naccurate diagnosis can be done with diagnostic imaging, whereas, uterus \npreserving treatment can be done in mild and uncomplicated adenomyosis. \nHowever, total hysterectomy is the management of choice for severe \nadenomyosis. Secondly, diagnostic imaging is important to measure the \ndegree of involvement of myometrium. Measurement of extent of myometrial \ninvasion is crucial for planning the management, because endometrial \nMedical Science \n  pISSN 2321–7359; eISSN 2321–7367 \n \n \n \n \n \n \n \n \n \nTo Cite: \nAvinash Dhok, Kajal Mitra. Imaging of adenomyosis of uterus: What \nradiologist needs to know?. Medical Science, 2022, 26, ms106e2083.  \ndoi: https://doi.org/10.54905/disssi/v26i121/ms106e2083  \n \nAuthors’ Affiliation: \n1Professor, Department of Radiodiagnosis, NKP Salve Institute of \nMedical Sciences and Research Centre, Digdoh hills, Nagpur 440019, \nMaharashtra, India; Email: nkpsimsradio@gmail.com \n2Professor, Department of Radiodiagnosis, NKP Salve Institute of \nMedical Sciences and Research Centre, Digdoh hills, Nagpur 440019, \nMaharashtra, India; Email id:mitrakajal@gmail.com \n \n*Corresponding Author  \nProfessor, Department of Radiodiagnosis, NKP Salve Institute of Medical \nSciences and Research Centre, Digdoh hills,  \nNagpur 440019, Maharashtra, India  \nEmail: nkpsimsradio@gmail.com \n \nPeer-Review History \nReceived: 27 January 2022 \nReviewed & Revised: 31/January/2022 to 10/March/2022 \nAccepted: 11 March 2022 \nPublished: 22 March 2022 \n \nPeer-review Method \nExternal peer-review was done through double-blind method. \n \nURL: https://www.discoveryjournals.org/medicalscience \n \n \n \nThis work is licensed under a Creative Commons Attribution 4.0 \nInternational License. \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n  \nCopyright © 2022 Discovery Scientific Society.  \n \nDISCOVERY \nSCIENTIFIC SOCIETY \n \n\nMEDICAL SCIENCE l REPORT \nMedical Science, 26, ms106e2083 (2022)                                                                                                                                            2 of 7 \nablation therapy is highly effective in superficially invasive adenomyosis than in extensive adenomyosis. Thirdly, diagnostic  \nimaging is useful for follow up of disease progression in cases  who are undergoing medical line of treatment (Reinhold et al., 1999). \nAdenomyosis of uterus can be sometimes complicated by presence of fibroids, making it difficult to  diagnose accurately by \nultrasonography alone.  \nThe line of management and prognosis of pathology is separate. Most of the clinicians more often choose medical management \nfor adenomyosis alone, whereas, surgical management for  adenomyosis with leiomyoma, especially if the  uterus is bulky (Hanafi, \n2013). Di agnostic imaging findings revealed by EVUS and MRI are correlated very closely to those demonstrated on \nhistopathological diagnosis. Previous studies on diagnosis of adenomyosis by EVUS have noted sensitivity, specificity and \ndiagnostic accuracy of 80-86%, 50-96% and 68-86% respectively (Brosens et al., 1995; Fedele et al., 1992; Reinhold et al., 1995) . Many \nstudies also found Magnetic Resonance Imaging more accurate in diagnosing adenomyosis showing sensitivity of 86 -100% and \nspecificity of 84-100% with diagnostic accuracy of 85-90% (Reinhold et al., 1996). \nAim of our prospective study is to demonstrate imaging characteristics of adenomyosis of uterus and to differentiate findings of \nuterine adenomyosis by EVUS & MRI with histopathological correlation from biopsy and operated cases and to evaluate the \nsensitivity, specificity, predictivity and accuracy of imaging modalities.  \n \n2. MATERIAL & METHODS \nOur prospective, observational diagnostic study was conducted from February 2020 to February 2021 on 50 female patients of \ncentral India after approval by Institutional Ethics Committee (No. NKPSIMS & RC&LMH/IEC/5/2020). Patients of 30 -59 years age \ngroup, presenting with complaints of menorrhagia, dysmenorrhea, pelvic discomfort, backache & uterine enlargement on clinical  \nexamination were included. Patients, clinically suspected of uterine adenomyosis w ere examined by EVUS and MRI. \nHistopathological correlation was obtained from biopsy and operated cases. EVUS was performed on high end Ultrasonography \nmachine with high frequency EVUS probe (5 -8MHz) to obtain high resolution quality uterine images for bet ter demonstration of \nadenomyosis. The real time EVUS Ultrasonographic findings of adenomyosis were studied, as the findings may not be properly \nseen on static images. The normal uterine parenchyma shows different zones with varying Echo pattern.  \nThe endometrial heterotopia in uterine adenomyosis arises from stratum basal layer of endometrium, which is a thin layer and \ndifficult to demonstrate separately at ultrasonography.  In adenomyosis the different uterine parenchymal zones show altered Echo \npattern & distorted appearance. On EVUS, adenomyosis shows heterogeneous hypoechoic areas in myometrium. The hypoechoic \nareas represent hyperplasia of smooth muscles of myometrium at histopathological analysis. The heterogeneous areas correspond \nto small echogenic foci of heterotrophic endometrial tissue with hypoechoic smooth muscle surrounding it. The presence of ecstatic \nglands or small foci of hemorrhages within the endometrial heterotopic component results in formation of small cysts in \nmyometrium (frequently less than 5 mm in size) (Reinhold et al., 1999) . Additional EVUS features of adenomyosis are abnormality \nof uterine contour, ill-defined demarcation of abnormal and normal myometrial tissue and an oval or elliptical t ype of myometrial \nabnormality. \nAt least two of the following five criteria on EVUS are essential to diagnose adenomyosis of uterus. a) No distinction of \nendometrium-myometrium junction. b) Anterior and posterior wall myometrial asymmetry. c) Striations at sub endometrial -\nmyometrial junction. d) Presence of cysts and fibrosis in myometrium. e) Heterogeneity of myometrial parenchyma (Fedele et al., \n1992; Reinhold et al., 1995; Reinhold et al., 1996; Bazot et al., 2001; Bazot et al., 2002) . 16 channel 1.5 Tesla MRI machine with \ndedicated pelvic multicoil array was used for performing MRI. High resolution thin section MRI images obtained with pelvic \nmulticoil array were sufficient to diagnose adenomyosis. On MRI, the zone wise anatomy of ute rus was optimally demonstrated on \nT2-weighted sequences in sagittal plane. In females of child bearing age, different zones of uterus can be demonstrated on T2 -\nweighted image. On MRI adenomyosis was seen as hypointense lesions on T2 weighted image with foc al or generalized widening \nof junctional zone.  \nHypointense lesions represented hyperplasia of smooth muscles along with endometrial heterotopia. 12 mm and more \nmaximum junction zone thickness confirmed adenomyosis, whereas, 8 mm and below junction zone th ickness, ruled out \nadenomyosis. If maximum thickness of junction zone was between 8and 12 mm, other features, like focal thickening of junctiona l \nzone, ill -defined peripheral margins or small hyperintense lesions on T1 and/or T2 sequences were required to confirm \nadenomyosis. \nTo differentiate adenomyosis from leiomyoma was frequently difficult. On EVUS, features that favored adenomyosis were, ill \ndemarcated borders, minimum mass effect, an oval or ellipse shape, no significant vessels near the borders, abse nce of calcification, \nwhorled appearance, linear striations and hyperechoic nodules. On MRI, hyperintense linear foci were typical for adenomyosis.  \n\nMEDICAL SCIENCE l REPORT \nMedical Science, 26, ms106e2083 (2022)                                                                                                                                            3 of 7 \nPatients diagnosed as adenomyosis on EVUS and MRI underwent surgery or biopsy. Histopathological evaluation was done. The \nhistopathological diagnosis of post -surgery/ post biopsy tissue was noted. Statistical tests like specificity, sensitivity positive and \nnegative predictivity values and total accuracy was determined for EVUS and MRI in correlation with final histopathological \ndiagnosis. Statistically significant P value considered was p<0.005 \n \n3. RESULTS \nOur study included 50 females with clinical impression of adenomyosis and age ranging from 30 -59 years. No significant difference \nwas observed in patient grav idity of uterus, parity, height, weight, mean age in diagnosis groups. Adenomyosis was proved in 41 \nwomen. MRI correctly diagnosed 38 out of 41 patients. 3 pseudo -negative and 2 pseudo -positive diagnosis were observed with \nMRI. Sensitivity of 92.68% in dia gnosing adenomyosis was observed on MRI. MRI showed specificity of 81.82%, positive \npredictivity value of 95% and negative predictivity value of 75% with total accuracy of 90.38%. Patients positively diagnosed  as \nadenomyosis on MRI were 5.10 times more pos sibility of having adenomyosis. On the other side, patients not diagnosed as \nadenomyosis on MRI had 0.09 times less likely possibility of having adenomyosis. On MRI, the patients having adenomyosis \nshowed 14.5 mm mean thickness of junctional zone thickness , whereas, patients without adenomyosis showed 7.2 mm mean \njunctional zone thickness (p<.001). The optimal value of junctional zone thickness for confirmation of adenomyosis on MRI was \n12mm or more (table 1). \nWith EVUS, 33 out of 41 patients were correctly  diagnosed as adenomyosis. 8 pseudo -negative and 4 pseudo-positive diagnosis \nobserved. The commonest cause of pseudo negative diagnosis with EVUS was misdiagnosis of adenomyosis as leiomyoma. \nSensitivity of EVUS to diagnose adenomyosis was found to be 80.4 9 % (p< .001) and specificity was 69.23 % (p=.41). The positive \nand negative predictivity value respectively was 89.19% and 52.94 % with total accuracy of 77.78%. Patients positively diagno sed as \nadenomyosis with EVUS had 2.62 time more possibility to have  adenomyosis, whereas, cases not diagnosed as adenomyosis with \nEVUS had 0.28 times less possibility to have adenomyosis (table 2). This shows that, EVUS was more sensitive and less specifi c, \nwhich may be likely due to interference in diagnosing adenomyosis in cases with other uterine pathologies.  \nMRI was found significantly better (p<.002) than EVUS to detect adenomyosis. 33 cases were found true positive at EVUS, out o f \nwhich 24 cases (73%) showed inhomogeneous myometrial echo texture and low attenuation areas without small cystic lesions. 7 \ncases (21%) showed low attenuation areas with small cystic lesions and 2 cases (6%) showed inhomogeneous areas in the \nmyometrium. The mean length, an antero-posterior and transverse dimension were more in uterus with adenomyosis, than without \nadenomyosis, but was not found significant statistically. In adenomyosis, the mean posterior wall myometrial thickness was \nsignificantly more than mean anterior myometrial thickness (25.2 mm compared to 21.2 mm, p<0.02). So, we can  consider that, an \nill-defined inhomogeneous area in myometrium can be basis for adenomyosis (figure 1, 2 and 3). \n \nTable 1 EVUS statistics (n=50) \nStatistic Value 95% Cl \nSensitivity  80.49% 65.13% to 91.18% \nSpecificity  69.23% 38.57% to 90.91% \nPositive predictive value 89.19% 78.26 to 94.98% \nNegative predictive value 52.94% 35.39% to 69.79% \nPositive Likelihood Ratio 2.62 1.14 to 5.99 \nNegative Likelihood Ratio 0.28 0.14 to 0.58 \nTotal Accuracy  77.78%  64.40% to 87.96% \n \nTable 2 Magnetic Resonance Imaging statistics (n=50). \nStatistic Value 95% Cl \nSensitivity  92.68% 80.08% to 98.46% \nSpecificity  81.82% 48.22% to 97.72% \nPositive predictive value 95% 84.39% to 98.52% \nNegative predictive value 75% 49.35% to 90.23% \nPositive Likelihood Ratio 5.10 1.45 to 17.91 \nNegative Likelihood Ratio 0.09 0.03 to 0.28 \nTotal Accuracy  90.38%  78.97% to 96.80% \n\nMEDICAL SCIENCE l REPORT \nMedical Science, 26, ms106e2083 (2022)                                                                                                                                            4 of 7 \n \n \nFigure 1 shows Uterine Adenomyosis on T2 weighted MR image in sagittal plane with increased thickness of anterior uterine wall \n(Red arrow) as compared to posterior uterine wall (purple arrow)   \n \n \n \nFigure 2 shows Uterine Adenomyosis on T2 weighted MR image in sagittal plane with increased number of cystic spaces (red \narrow) and disruption of endo-myometrial junction (purple arrow) \n \n \n \nFigure 3 shows asymmetry of uterine wall with endometrial heterotropia in Uterine Adenomyosis on EVUS  \n \n\n\nMEDICAL SCIENCE l REPORT \nMedical Science, 26, ms106e2083 (2022)                                                                                                                                            5 of 7 \n4. DISCUSSION \nIn our study 50 females, in age group ra nging from 30 to 59 years were studied with clinically suspected uterine adenomyosis. 41 \npatients were proved to be uterine adenomyosis. Accurate diagnosis was made on MRI in 38 cases out of 41 cases. 3 false negat ive \nand 2 false positive diagnosis were ob served on MRI. On MRI, mean thickness of uterine junctional zone was 14.5 mm (p<.001) in \npatients having adenomyosis. In cases with no adenomyosis, the mean uterine junctional zone thickness was 7.2mm (p<.001). The  \noptimum uterine junctional zone thickness  for confirmation of adenomyosis with MRI was 12mm or more. The MRI sensitivity in \ndetection of adenomyosis was 92.68% (p<.001), specificity 81.82% and 95% positive predictivity value with 75% negative \npredictivity value. Total accuracy of 90.38% was noted . With EVUS, adenomyosis was accurately diagnosed in 33 cases out of 41 \ncases. 8 pseudo -negative and 4 pseudo -positive diagnosis occurred. The sensitivity of EVUS for adenomyosis was 80.49 % and \nspecificity of 69.23%. Positive predictivity noted was 89.19% and negative predictivity was 52.94 % with total accuracy of 77.78%. \nThe detectivity rate of adenomyosis reported by earlier studies had wide range which ranged from 8 -85% (Hanafi, 2013; Brosens \net al., 1995; Fedele et al., 1992; Reinhold et al., 1996; As cher et al., 1994; Reinhold et al., 1995; Bazot et al., 2001; Atzori et al., 1996). \nThe justification for these long ranges of values could be different histological evaluation parameters for demonstration of \nadenomyosis, the handling & processing of patho logic specimens and total sampling specimen blocks prepared. The various \nsample sizes, the modalities used for detection of adenomyosis, and variable exclusion and inclusion criteria used could also  be \nattributed to long range of detectivity rate of adenomyosis.  \nOur study showed sensitivity of 80.49% and specificity of 69.23 % on EVUS for adenomyosis, but p value failed to reach the \nlevel of significance for specificity, proving that EVUS was sensitive but not specific enough as a diagnostic modality for d iagnosing \nadenomyosis. In our study, the sensitivity correlated with previous studies, but the specificity was different from previous studies. \nThis might be due to other uterine pathologies, especially uterine leiomyoma compromising the accuracy of EVUS for adenomyosis. \nAscher et al., (1994) studied 20 females with clinical suspicion of adenomyosis.17 cases were having adenomyosis. Accurate \ndiagnosis was done on MRI in 15 cases out of 17 cases. With EVUS, adenomyosis was correctly diagnosed in 9 cases out of 17 cases. \n8 false negative diagnoses occurred. The most frequent cases of false negative diagnosis with EVUS were misinterpretation of \nadenomyosis with leiomyoma. They concluded that MRI is significantly better (p<.002) than EVUS in the diagnosing of \nadenomyosis.  \nTogashi et al., (1989) evaluated 93 females with clinically enlarged uterus on palpation and suspected for adenomyosis or \nleiomyoma. The MRI findings were consistent with operative and histopathological diagnosis. In 71 cases they found that, t he \nuterus was enlarged due to leiomyoma whereas, in 16 cases the uterus was enlarged due to adenomyosis. Remaining 6 subjects ha d \nboth lesions simultaneously. On T2 weighted MRI sequence, adenomyosis showed ill -defined inhomogeneous, predominantly \nhypointense, areas with hyperintense tiny spots within it. In 92 out of 93 females the cause of enlarged uterus was accurately \ndemonstrated by MRI. They found that, MRI was almost completely accurate in differentiating leiomyoma from adenomyosis in \ncases having uterine enlargement. Reinhold et al., (1996) studied 119 patients who were undergoing hysterectomy. In 28 out of 119 \ncases, adenomyosis was confirmed as a reason of uterine enlargement. On EVUS the sensitivity was 89% and positive predictivit y \nvalue 71% and negative predictivity value 96%, whereas for Magnetic Resonance Imaging the sensitivity was also 89%, positive \npredictivity value 65% and negative predictivity value 95%. The difference in sensitivity and specificity of EVUS and MRI was  \nstatistically not significant.  \nTogashi et al., (1989) also found that, making a diagnosis of adenomyosis preoperatively was a difficult task and in most of the \ncases histopathological examination was essential to confirm the diagnosis. Many authors also believed that it was  difficult to \ndifferentiate adenomyosis from leiomyoma. However Magnetic Resonance Imaging was found highly accurate in demonstrating \nuterus abnormalities. In their study spin echo images with long transverse relaxation time demonstrated optimum details of  zonal \nanatomy of uterus. They concluded that MRI was highly sensitive not only in the diagnosi s adenomyosis but also in differentiating \nadenomyosis from leiomyoma. Magnetic Resonance Imaging played a crucial role in differentiating these lesions preoperat ively \nand was also useful in offering appropriate management. \nReinhold et al., (1998) reviewed imaging appearances of adenomyosis. They also evaluated the limitations and role of presentl y \navailable non-invasive imaging modalities and procedures including EVUS and MRI, in correctly diagnosing adenomyosis. They \nfound that, the EVUS appearance of adenomyosis is actually due to hyperplasia of uterine smooth muscles associated with \nendometrial heterotopia and seen as hypoechoic areas on EVUS and hypointense are as on MRI. The endometrial heterotopia also \nhelps in producing the imaging picture of adenomyosis. Due to availability of high -resolution machines, the frequency of detecting \nchanges of adenomyosis has improved.  \n\nMEDICAL SCIENCE l REPORT \nMedical Science, 26, ms106e2083 (2022)                                                                                                                                            6 of 7 \nIn the study of Atri et al., (2000) the ade nomyosis prevalence was relatively more in premenopausal period. The study noted \n81% sensitivity, 71% specificity, 90% positive predictivity, 54% negative predictivity and 74% accuracy on EVUS for detection  of \nadenomyosis. However, the predictivity was dep endent on prevalence. The hyperechoic areas represented specks of glands in \nendometrium and low echogenicity areas represented hyperplasia of myometrial muscles. They concluded that, myometrial \nasymmetry in thickness, echogenic nodules in subendometrial ti ssue and linear striations showed highest specificity and positive \npredictivity in case of adenomyosis.  \nKepkep et al., (2007) observed in their study that, uteri with adenomyosis were frequently seen with leiomyoma and \nendometrial hyperplasia. The sensiti vity reported was 80.8%, specificity was 61.4%, positive predictivity was 55.3% and negative \npredictivity was 84.4%. The specificity reported by them was lower as compared to studies by other authors. The different sel ection \ncriteria for the diagnosing ade nomyosis could be the factor responsible for different specificity and accuracy values on EVUS. In \ntheir study, linear striations in the subendometrial area showed highest specificity and positive predictive value and they \nconsidered this finding the most specific for diagnosis, although it’s detection on Ultrasonography was uncommon. Their study \nsubjects were restricted only to women considered for hysterectomy and there was no exclusion of cases with large and multipl e \nleiomyomas which distorted the shape  of uterus. These were the limitations of their study. Their study results suggested that, for \nuterine adenomyosis, inhomogeneous myometrial echotexture had higher sensitivity, whereas, a bulky uterus with globular shape , \nsmall cysts in the myometrium and linear subendometrial striations showed high specificity and positive predictive value. \nDueholm et al., (2002) reported that MRI was better than EVUS in the identification of uterine adenomyosis. MRI and EVUS \nwere highly accurate in diagnosing adenomyosis.  MRI accuracy was not dependent on uterine size and volume. MRI was better \nthan EVUS in evaluating myometrial infiltration by sub endometrial cells. They considered histopathological diagnosis as gold  \nstandard in adenomyosis. Hirai et al., (1995) assessed various findings to differentiate malignancy from adenomyosis. They \nobserved that, abnormal glands present in the endometrial basal layer were responsible for development of adenomyosis and \ncancers of endometrium sometimes may resemble adenomyosis, because  both conditions are in continuity with endometrium. \nAdenomyosis showed either no contour or thin irregular contour. They introduced new scoring system which differentiated normal \nuterus, leiomyomas and adenomyosis. Their new system of scoring showed 91% s ensitivity, 96% specificity and 94 overall \naccuracies in diagnosing adenomyosis. \n \n5. CONCLUSION \nAdenomyosis of uterus mainly occurs due to excessive growth of endometrial tissue which infiltrates in surrounding myometrium . \nEVUS and MRI are highly effective  in adenomyosis. MRI is more accurate (p<0.02) compared to EVUS. On MRI, 12 mm or more \nthickness of uterine junctional zone strongly favors adenomyosis, whereas, 8 mm or less thickness of uterine junctional zone almost \nrules out adenomyosis. In uterine ade nomyosis, EVUS is valuable, easily available, non -invasive modality. EVUS is more sensitive \nbut less specific in adenomyosis. MRI is more indicated in indeterminate cases of EVUS and where uterus conserving treatment is \nconsidered. \n \nAbbreviations  \nEndovaginal Ultrasonography (EVUS), Magnetic Resonance Imaging (MRI) \n \nAcknowledgement \nWe are indebted to the participants for making this research possible and to all physicians, faculty and junior residents, Dr . Aisha \nLakhani, Dr. Yash Jakhotia of radiolo gy department and staff of NKP Salve Institute of Medical Sciences and Research centre, \nDigdoh hills, Nagpur 440019, Maharashtra, India. \n \nAuthors Contribution \nAll authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took \npart in drafting the article or revising it critically for important intellectual content; gave final approval of the version  to be \npublished; and agree to be accountable for all aspects of the work.  \n \nEthical Approval \nThe study was approved by Medical Ethics Committee of NKP Salve Institute of Medical Sciences and Research Centre with the \nletter number: (NKPSIMS &RC & LMH/IEC/5). \n\nMEDICAL SCIENCE l REPORT \nMedical Science, 26, ms106e2083 (2022)                                                                                                                                            7 of 7 \n \nFunding \nThis study has not received any external funding. \n \nConflicts of interest \nThe authors declare that there are no conflicts of interests. \n \nData and materials availability \nAll data associated with this study are present in the paper. \n \nREFERENCES AND NOTES \n1. 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