Risk factors and outcome of antenatally diagnosed congenital diaphragmatic hernia following in-utero transfer in a busy public-sector tertiary care center in North India.

We analyzed the risk factors and outcomes of antenatally diagnosed congenital diaphragmatic hernia (CDH) from a tertiary-care children's hospital following in-utero transfer. A total of 41 antenatally detected cases of CDH were included; 30 were live-born and 11 were still-born. The primary outcome was postnatal survival. The secondary outcome was the probable factor affecting survival. No medical termination of the pregnancy was done. The mean gestational age at diagnosis was 23 weeks. The diagnostic accuracy of antenatal ultrasonography was 40/41 (97.5%). Lung-to-head ratio (LHR) was <1 in 20 cases (survived 2), LHR was >1 in 10 cases (survived 8), and LHR was not recorded in 11 cases (survived 4). Overall survival was 14/41 (34.1%). Survival in fetuses with polyhydramnios was 0% (n=3; survived 0), associated anomalies were 33.3% (n=3; survived 1), and liver herniation was 22.2% (n=9; survived 2). Postnatally, significant risk factors included a low Apgar score, the need for ventilation, and neonatal intensive care unit (NICU) management. Survival in live-born cases was 14/30 (46.6%) and in operated cases was 14/19 (73.6%). We concluded that antenatal ultrasound had a high accuracy rate for detecting CDH. Antenatal risk factors affecting outcomes were low LHR, maternal polyhydramnios, liver herniation, and associated malformations. Postnatal risk factors included a low Apgar score, NICU admission, and a need for ventilation. The overall survival rate, as well as the survival rates for live-borns and those undergoing surgery, were 34.1%, 46.6%, and 73.6%, respectively. This data will guide clinicians in counseling the families of antenatally diagnosed CDH.

Relative prevalence and outcome of fetal posterior fossa abnormality.

AIM: To find out the relative incidence and outcome of posterior fossa abnormality (PFA) in terms of survival at birth until 2 years of age. METHODS: We conducted a prospective study; all fetuses diagnosed with posterior fossa abnormality were followed-up. The outcome was observed with respect to survival, the presence of associated anomalies, the existence of developmental delay after a telephonic interview. RESULTS: Out of 2703 children with congenital anomalies, 921 (34.1%) had a central nervous system defect; 76 cases of PFA were fully followed. Dandy-Walker malformation (DWM) was present in 50% (38/76), mega cisterna magna 18.4% (14/76), Blake pouch cyst 13.2% (10/76), vermian hypoplasia (VH) 13.2% (10/76) and arachnoid cyst 5.2% (4/76). The diagnosis was possible before 20 weeks in only 12 (15.8%) cases. The mean gestational age at delivery was 34.7 ± 6.7 weeks. Associated anomalies were seen in 35/76 (46.1%) cases. A total of 35/76 (46.1%) survived after 2 years; there was developmental delay in 9.2% of cases. CONCLUSION: There is a large variation in the outcome of PFA depending upon the type of anomaly. Associated anomalies are common in VH and DWM, making their prognosis worse.

Lung Volume Head Ratio: A Potential Parameter for Prediction of Respiratory Distress in Newborn.

OBJECTIVE: This study aimed to evaluate the role of fetal lung biometry profile including fetal lung volume head ratio (LVHR) in predicting the occurrence of respiratory distress (RD) in early preterm newborn. STUDY DESIGN: Prospective analytical cohort study was done to evaluate the clinical value of fetal sonographic measures, such as the total lung area (TLA), total lung volume (TLV), TLA head ratio (TLHR), LVHR, in pregnant women between 30 to 34 weeks' gestation who were expected to deliver within the next 72 hours. The cases with RD were compared with controls who had normal outcome. RESULT: A total of 30 (27.4%) out of 110 patients, who underwent early preterm delivery, with RD rest 80 (72.6%) were controls. The TLA was 694.1 ± 373.1 mm2 in cases whereas 1,149.0 ± 506 0.7 mm2 in controls with significant difference between the two groups (p < 0.001). Similarly the lung volume (p < 0.001) and the LVHR were significantly less (p < 0.001) in cases compared with controls. The TLV was a better parameter (sensitivity, 73.7% and specificity, 86.4%) compared with TLA (sensitivity, 68.4% and specificity, 81.5%). Among the lung head ratios, LVHR had the best sensitivity of 95.5%, specificity: 80.3%, positive predictive value (PPV): 58.3%, and negative predictive value (NPV): 97.0% at the cut-off of 46.5. CONCLUSION: RD was observed in nearly one-third of the preterm infants born between 30 and 34 weeks of gestation and could be predicted accurately in over 9 out of 10 cases using the novel parameter TLVR. KEY POINTS: · Preterm newborn.. · Fetal lung volume.. · Respiratory distress..

Spectrum of fetal limb anomalies.

PURPOSE: Antenatal detection of limb anomalies is not uncommon, and pregnancies are usually terminated in view of the expected physical handicap. The aim of this retrospective observational study is to delineate the spectrum of fetal limb anomalies and provide evidence in support of complete postnatal evaluation in establishing recurrence risk. METHODS: We present 54 cases of limb malformations detected antenatally and discuss the spectrum of abnormalities, the utility of fetal autopsy, and genetic testing to establish recurrence risk in subsequent pregnancies. RESULTS: 16/54 cases were isolated radial ray anomalies. There were five cases of amniotic band syndrome, five limb body wall complex cases, three VACTERL (vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities) associations, one case of sirenomelia, two cases of limb pelvis hypoplasia, and one case of OEIS (Omphalocele Exstrophy Imperforate anus and spinal defects). Four fetuses with non-isolated radial ray anomaly had trisomy 18. One case with bilateral radial ray defect had a mutation in the FANC-E gene confirming fanconi anemia. Twelve cases were unclassified. CONCLUSION: Autopsy is the most important investigation in fetuses with limb anomalies. We suggest chromosomal microarray (CMA) as a first-tier test after autopsy. However, in cases of bilaterally symmetrical limb anomalies, in case of previous similarly affected child, or history of consanguinity, whole exome sequencing (WES) can be offered as the primary investigation, followed by CMA if WES is normal.

Patient Satisfaction after Antenatal Joint Fetal Medicine and Pediatric Surgery Counseling.

AIMS AND OBJECTIVES: The aim of this study was to find out the level of satisfaction among couples receiving antenatal counseling provided jointly by fetal medicine specialists and pediatric surgeons. MATERIALS AND METHODS: This was a questionnaire-based observational study. A total of 110 consecutive couples who were antenatally diagnosed with fetal structural anomaly and received counseling by fetal medicine specialist and pediatric surgeon together, were given a validated patient satisfaction questionnaire (PSQ-18) after delivery to assess their level of satisfaction regarding the antenatal care they received. RESULTS: A total of 120 couple responded to the questionnaire, mean gestational age at delivery was 33.8 ± 7.14 weeks. In PSQ, 75.8% gave high scores for general satisfaction, maximum subjects provided high scores for interpersonal manner (IM) (77.5%) and communication (77.5%), and the least number gave high scores for time spent with the doctor (50.8%) and accessibility (42.5%). The technical quality (TQ) subscale was significantly high for the stillbirth/abortion group compared to live birth (P = 0.020). Significantly high scores for TQ (P = 0.037) and IM (P = 0.023) were obtained in the <20 weeks group. CONCLUSION: The joint counseling provided good interaction opportunity to the couple but still fell short of their expectations regarding time spent with the doctor and their accessibility.

Reference centile charts of first-trimester aneuploidy screening & Doppler parameters for Indian population.

BACKGROUND & OBJECTIVES: The risk estimation for foetal aneuploidies in the first trimester of pregnancy uses reference curves based on western data. The objective of this study was to construct the reference curves of first-trimester foetal aneuploidy screening parameters for the Indian women. METHODS: : Cross-sectional data were obtained from 1204 singleton pregnancies between the crown-rump length (CRL) of 40-84 mm. Linear regression models were constructed; the mean, median and standard deviation were derived as a function of CRL. RESULTS: The mean value of CRL was 61.3 mm. The regression analysis showed a significant correlation between all variables and CRL (P< 0.001). There was a positive correlation of CRL with nuchal translucency (NT) (y=0.010x+0.629, R2=0.116) and pregnancy-associated plasma protein-A (PAPP-A) (y=0.107x-1.079, R2=0.173), whereas inverse correlation was seen with free ß-human chorionic gonadotropin (ß-hCG) (y=-0.409x+75.025, R2=0.018) and Doppler parameters pulsatility index (PI) (y=-0.008x+1.924 R2=0.053). The centile charts of NT, PAPP-A, free ß-hCG and uterine artery (Ut A) Doppler PI were constructed. INTERPRETATION & CONCLUSIONS: The reference centile charts of first trimester aneuploidy screening along with Doppler parameters were derived in Indian pregnant women. These centile charts may be used as a reference for clinical use in Indian population.

Ultrasonography and autopsy correlation of fetal hypoplastic left heart syndrome.

Hypoplastic left heart syndrome (HLHS) represents a spectrum of abnormalities which marks the underdevelopment of left side cardiac structures. We present the ultrasound and autopsy correlation of two cases with HLHS with core pathology as isolated mitral atresia in one and aortic atresia in another. In both the cases after diagnostic confirmation on ultrasound (US), the couple opted for termination of pregnancy and consented for autopsy. The correlation of US and autopsy images of HLHS, facilitated our understanding of pathology behind the image obtained on US. The autopsy not only confirmed the antenatal diagnosis, but also added new findings.

Approach to the diagnosis of skeletal dysplasias: Experience at a center with limited resources.

PURPOSE: A fetus with skeletal disorder poses diagnostic challenges in a resource-poor setting with limited management options. The objective of the study was to develop a step-by-step approach for the diagnosis of skeletal dysplasia in light of the limited resources available. METHODS: An algorithmic approach was used. The assessment for lethality was the first step, followed by the evaluation for fractures. In cases without evidence of fracture, severe constriction of thorax or associated polydactyly were searched for. In cases without severe thoracic constriction, the severity of micromelia was evaluated. After delivery, fetal examination was done to ascertain the etiology. RESULTS: During the 6-year period, 41 cases with shortened long bones were fully evaluated. Lethality was suspected in 30 cases. Fracture and beading were present in eight cases, and severe thoracic constriction with polydactyly was observed in seven cases. Mild micromelia was seen in 19 cases and severe micromelia in 7 cases. Among lethal skeletal dysplasias, thanatophoric dysplasia was most common (six cases). Among nonlethal skeletal dysplasias, achondroplasia was seen in eight cases. CONCLUSIONS: Lethality of skeletal dysplasia could be predicted on prenatal ultrasound with 100% accuracy. The step-by-step approach was helpful to characterize skeletal dysplasias. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 44:529-539, 2016.

Clinical applications and implications of common and founder mutations in Indian subpopulations.

South Asian Indians represent a sixth of the world's population and are a racially, geographically, and genetically diverse people. Their unique anthropological structure, prevailing caste system, and ancient religious practices have all impacted the genetic composition of most of the current-day Indian population. With the evolving socio-religious and economic activities of the subsects and castes, endogamous and consanguineous marriages became a commonplace. Consequently, the frequency of founder mutations and the burden of heritable genetic disorders rose significantly. Specifically, the incidence of certain autosomal-recessive disorders is relatively high in select Indian subpopulations and communities that share common recent ancestry. Although today clinical genetics and molecular diagnostic services are making inroads in India, the high costs associated with the technology and the tests often keep patients from an exact molecular diagnosis, making more customized and tailored tests, such as those interrogating the most common and founder mutations or those that cater to select sects within the population, highly attractive. These tests offer a quick first-hand affordable diagnostic and carrier screening tool. Here, we provide a comprehensive catalog of known common mutations and founder mutations in the Indian population and discuss them from a molecular, clinical, and historical perspective.

Endodermal sinus tumor of vagina posing a diagnostic challenge and managed by chemotherapy and novel posterior sagittal surgical approach: lessons learned.

Vaginal germ cell tumor (GCT) is a rare gynecological malignancy with no more than 100 reported cases in the international medical literature. It is an unusual, but an important, cause of premenarchal vaginal bleeding in a child. This article describes a 2-year-old child with vaginal GCT, initially misdiagnosed as rhabdomyosarcoma (on imprint smear cytology) and then as clear cell adenocarcinoma. The authors highlight the salient differentiating clinical, radiological and histological features to prevent misdiagnosis in future. The report emphasizes the need for increased awareness and screening for vaginal GCT by estimation of serum α-fetoprotein levels, in all patients with premenarchal vaginal bleeds, to prevent inadvertent operative interventions.

Materno-fetal outcome with PlGF above or below cutoff during second half of pregnancy in high-risk women.

OBJECTIVE: To evaluate the materno-fetal outcome of high-risk women using placental growth factor (PlGF). METHODS: This prospective cohort study was performed at a tertiary care hospital from September 2019 to April 2022. Women having clinically major or minor high risk factors of pre-eclampsia were included after consent. The placental growth factor (PlGF) was evaluated among high-risk women at 20-22, 28-30, and 34-36 weeks of gestation. They were followed throughout pregnancy until delivery. Materno-fetal outcome was evaluated based on PlGF levels at three different time points. The gestational age specific cutoff was derived. Those with levels below cutoff were taken as cases and those with values above cutoff were considered as controls. The odds of having complications if the PlGF was below cutoff were determined. RESULTS: Out of 287 high-risk women, 46 (16%) had pre-eclampsia (PE). The derived cutoff of PlGF was 224, 211, and 176 pg/mL at 20-22, 28-30, and 34-36 weeks, respectively. With PlGF below the cutoff at 20-22 weeks the odds of having HELLP syndrome was 15.8, with low PlGF at 28-30 weeks the odds for developing early onset PE was 11.3. Low PlGF was also significantly associated with preterm delivery (P < 0.001) and early onset FGR (P < 0.001). The sensitivity (91.7%) and specificity (78.5%) of PlGF for PE prediction was highest at 28-30 weeks. CONCLUSION: Low PlGF at 28-30 weeks was associated with high likelihood of developing early onset PE, and the PlGF cutoff should be gestational age specific.

Postnatal outcome of congenital anomalies in low resource setting.

OBJECTIVE: This study aimed to determine the postnatal outcome of congenital malformations in a tertiary care hospital of India. MATERIAL AND METHODS: This was a prospective study of all women with prenatally detected major congenital malformations. Postnatal follow-up of live born babies was carried out for 1 year. RESULTS: There were 574 cases with major congenital anomalies, 523 of which were fully followed. Only 69 women (13.6%) had the initial scan before 20 weeks of gestation. Craniospinal defects were the most common (42.7%), followed by genitourinary anomalies (28%). There was no live birth in cases such as anencephaly, iniencephaly, bilateral renal agenesis, gastroschisis, and cystic hygroma. Survival at 1 year was less than 25% in spina bifida, bilateral cystic kidneys, complex cardiac disease, and non-immune hydrops fetalis. In cases with mild hydrocephalus or unilateral and mild renal disease, the survival was over 75%. CONCLUSION: In India, the majority of congenital anomalies present late in gestation. Although fetal outcome is invariably poor for severe defects, existing legislation in the country leaves pregnancy continuation as the only option.

Revisiting destructive operations to prevent second stage caesarean section in COVID times: A case series.

Destructive operations diminish the bulk of the foetus for facilitating vaginal delivery. Procedures such as craniotomy or decapitation can be carried out to deliver a dead baby in appropriately selected cases. Ours is a retrospective case series at a single tertiary facility during the first wave of the COVID pandemic. From July 2020 to January 2021, six destructive operations (five craniotomies and one decapitation) were performed in women who had arrest of descent in the second stage of labour but had intrapartum foetal demise. The average operative time was 30 minutes with a mean hospital stay of 4.3 days, which was significantly less than CS, and with much less morbidity. None of these women had significant post-partum haemorrhage or sepsis. Destructive procedures should be considered for better obstetric future of the patient, and a lesser burden on the health facility. What was practiced in COVID times should be extended beyond.

Antenatal risk stratification for preeclampsia with sFlt-1/PlGF ratio: Which is the best time to test?

OBJECTIVE: To find out the predictive value of sFlt-1/PlGF ratio for antenatal risk stratification (ARS) of women at high risk of preeclampsia (PE). METHODS: Antenatal women at high risk of PE underwent sFlt-1/PlGF ratio at 20-22, 28-30 and 34-36 weeks and were followed till delivery. Those who developed PE were cases those who had normal outcome were controls, the cases and controls were compared. RESULTS: Hypertension in pregnancy was seen in 116/287 (40.4 %), 46/287(16.0 %) had PE and 21(7.3 %) had early onset PE. Mean arterial pressure at 20-22 weeks was the high in those who developed early onset PE (109.08 ± 9.74 mmHg). The sFlt-1/PlGF ratio of 38 or more at 20-22 weeks resulted in either PE or adverse fetal outcome in all cases. Whereas, the ratio of less than 38 ruled out PE in all cases up to 29 + 6 weeks. At 28-30 weeks, the ratio less than 38 predicted no PE up to 34 weeks and no complication up to 29+6 weeks. The sensitivity for the detection at later gestation further decreased as the gestation advanced however the specificity was above 98 % at all gestations. The positive predictive value of the test increased with the advancing gestation, the negative predictive value was 93 % or higher at all gestations. CONCLUSION: The usefulness of sFlt-1/PlGF ratio ≥38 for risk stratification was validated in the study, the testing at 28-30 weeks appeared to be the best time to test for PE prediction in high risk women.

Impact of Action Taken in Response to Stillbirth Audit: A Success Story.

Objectives: Study the impact of intra-facility interventions on the modifiable factors causing stillbirths (SB), using point-of-care quality improvement (POCQI) methodology. Material and Methods: Stillbirth data during the 9 months pre-intervention period were reviewed to identify the common preventable causes. Two interventions, namely, ultrasound at 34-36 weeks gestation and intrapartum monitoring on a common customized labor chart for all health-care providers, were done. Post-intervention data were collected to observe the impact of the interventions. Results: The stillbirth rate reduced from 212/5940 deliveries (35.7/1000) in the pre-intervention period to 165/5993 deliveries (27.7/1000) in the post-intervention period (p = 0.011). The intra-facility failure to identify FGR significantly reduced in the post-intervention group (p = 0.033), leading to 63% (RR 0.37) reduction in its risk. Using a common customized labor chart led to a significant decline in the inadequate monitoring as a provider-related cause of stillbirth (p < 0.001) leading to its 42% decline as contributor to modifiable cause of SB (RR 0.48). Conclusion: Reviewing the perinatal death surveillance response (PDSR) data, identifying gaps in care, and using improvement methodology for instituting corrective measures play an important role in reducing intramural stillbirths.

Perceiving placental ultrasound image texture evolution during pregnancy with normal and adverse outcome through machine learning prism.

INTRODUCTION: The objective was to perform placental ultrasound image texture (UPIA) in first (T1), second(T2) and third(T3) trimesters of pregnancy using machine learning( ML). METHODS: In this prospective observational study the 2D placental ultrasound (US) images from 11-14 weeks, 20-24 weeks, and 28-32 weeks were taken. The image data was divided into training, validating, and testing subsets in the ratio of 80%, 10%, and 10%. Three different ML techniques, deep learning, transfer learning, and vision transformer were used for UPIA. RESULTS: Out of 1008 cases included in the study, 59.5% (600/1008) had a normal outcome. The image texture classification was compared between T1&T2, T2 &T3 and T1&T3 pairs. Using Inception v3 model, to classify T1& T2 images, gave the accuracy, Cohen Kappa score of 83.3%, 0.662 respectively. The image classification between T1&T3 achieved best results using EfficientNetB0 model, having the accuracy, Cohen Kappa score, sensitivity and specificity of 87.5%, 0.749, 83.4%, and 88.9% respectively. Comparison of placental image texture among cases with materno-fetal adverse outcome and controls was done using Efficient Net B0. The F1 score, was found to be 0.824 , 0.820, and 0.892 in T1, T2 and T3 respectively. The sensitivity and specificity of the model was 77.4% at 80.2% at T1 but increased to 81.0% and 93.9% at T2 &T3 respectively. DISCUSSION: The study presents a novel technique to classify placental ultrasound image texture using ML models and could differentiate first and third-trimester normal placenta and normal and adverse pregnancy outcome images with good accuracy.

Prenatal sonographic evaluation and postnatal outcome of renal anomalies.

OBJECTIVE: To determine the prognosis of antenatally detected renal anomalies by sonographic evaluation. MATERIALS AND METHODS: This was a follow-up study of all antenatally detected renal anomalies from January 2008 to Dec 2009 referred to fetal medicine clinic. Prenatal evaluation was done and cases were divided into four groups depending upon their prenatal sonographic findings. Post natal follow-up was done up to one year in cases of live babies. Autopsy was carried out in still born fetus after consent. RESULTS: The renal anomaly was detected in 55 cases, which were fully followed. The prognosis was said to be poor for group I cases with gross extra renal anomaly along with the renal anomaly, and for group II in which there was organic renal pathology with loss of renal function suggested by non-visualization of bladder and almost absent liquor. Prognosis was guarded and depended upon the gestational age of presentation in group III, which had obstructive uropathy; prognosis was good in group IV cases, which were mild, unilateral or which presented late. CONCLUSION: Prenatal sonographic evaluation gives reasonably accurate picture of the prognosis and can be very helpful in counseling the parents regarding prognosis and help in deciding the timing and route of delivery.

Prenatal Ultrasound Markers: A Comparative Study for Prediction of Respiratory Distress in Early Preterm Newborns.

Purpose of Study: This study aimed to compare the prenatal ultrasound parameters- fetal lung biometry and pulmonary artery Doppler in preterm newborns for prediction of respiratory distress (RD). Methods: A prospective analytic study was conducted in Department of Obstetrics and Gynecology in collaboration with Department of Neonatalogy. Fetal ultrasound and Doppler parameters were evaluated in women predisposed to have preterm delivery at or before 34 weeks. The neonates were followed for occurrence of RD. Result: Out of 100 study population, neonates who developed RD were taken as cases (n = 36) and rest were grouped as controls (n = 64). The gestational age at delivery, mean birth weight and Apgar score were significantly less in cases than controls. All the fetal lung biometric parameters were significantly less in cases than controls (p value < 0.001). The fetal lung volume had highest sensitivity (72.22%) and negative predictive value (83%). The right lung area had highest specificity (89%) and positive predictive value (72%). Among the Doppler parameters, the At/Et ratio showed high degree of accuracy (68%). The sensitivity and specificity were 55.56% and 75%, respectively. The positive and negative predictive values were 72% and 60%, respectively. Conclusions: Both fetal lung biometry and pulmonary artery Doppler offer an excellent noninvasive approach for assessment of fetal lung maturity, clinically assessed by RD. On comparison of all the ultrasound parameters, fetal lung volume and At/Et ratio showed highest degree of accuracy in prediction of RD.

Ultrasound placental image texture analysis using artificial intelligence to predict hypertension in pregnancy.

BACKGROUND: The placental pathological changes in hypertensive disorders of pregnancy (HDP) starts early in pregnancy, the deep convolutional neural networks (CNN) can identify these changes before its clinical manifestation. OBJECTIVE: To compare the placental quantitative ultrasound image texture of women with HDP to those with the normal outcome. METHODS: The cases were enrolled in the first trimester of pregnancy, good quality images of the placenta were taken serially in the first, second, and third trimester of pregnancy. The women were followed till delivery, those with normal outcomes were controls, and those with HDP were cases. The images were processed and classified using validated deep learning tools. RESULTS: Total of 429 cases were fully followed till delivery, 58 of them had HDP (13.5%). In the first trimester, there was a significant difference in the placental length (p = .033), uterine artery PI (p = .019), biomarkers PAPP-A (p = .001) PlGF (p = .013) and placental image texture (p = .001) between the cases and controls. In the second trimester the uterine artery PI, serum PAPP-A (p = .010) and PlGF (p = .005) levels were significantly low among women who developed hypertension later on pregnancy. The image texture disparity between the two groups was highly significant (p < .001). The model "resnext 101_32x8d" had Cohen kappa score of 0.413 (moderate) and the accuracy score of 0.710 (good). In the first trimester the best sensitivity and specificity was observed for abnormal placental image texture (70.6% and 76.6%, respectively) followed by PlGF (64% and 50%, respectively), in the second trimester the abnormal image texture had the highest sensitivity and specificity (60.4% and 73.3%, respectively) followed by uterine artery PI (58.6% and 54.7%, respectively). Similarly in the third trimester, uterine artery PI had sensitivity and specificity of 60.3% and specificity of 50.7%, whereas the abnormal image texture had sensitivity and specificity of 83.5%. CONCLUSION: Ultrasound placental analysis using artificial intelligence (UPAAI) is a promising technique, would open avenues for more research in this field.