A comprehensive molecular study identified 12 complementation groups with 56 novel FANC gene variants in Indian Fanconi anemia subjects.

Fanconi anemia (FA) is a rare autosomal or X-linked genetic disorder characterized by chromosomal breakages, congenital abnormalities, bone marrow failure (BMF), and cancer. There has been a discovery of 22 FANC genes known to be involved in the FA pathway. This wide number of pathway components makes molecular diagnosis challenging for FA. We present here the most comprehensive molecular diagnosis of FA subjects from India. We observed a high frequency (4.42 ± 1.5 breaks/metaphase) of chromosomal breakages in 181 FA subjects. The major clinical abnormalities observed were skin pigmentation (70.2%), short stature (46.4%), and skeletal abnormalities (43.1%), along with a few minor clinical abnormalities. The combination of Sanger sequencing and Next Generation Sequencing could molecularly characterize 164 (90.6%) FA patients and identified 12 different complementation groups [FANCA (56.10%), FANCG (16.46%), FANCL (12.80%), FANCD2 (4.88%), FANCJ (2.44%), FANCE (1.22%), FANCF (1.22%), FANCI (1.22%), FANCN (1.22%), FANCC (1.22%), FANCD1 (0.61%) and FANCB (0.61%)]. A total of 56 novel variants were identified in our cohort, including a hotspot variant: a deletion of exon 27 in the FANCA gene and a nonsense variant at c.787 C>T in the FANCG gene. Our comprehensive molecular findings can aid in the stratification of molecular investigation in the diagnosis and management of FA patients.

A founder variant in the South Asian population leads to a high prevalence of FANCL Fanconi anemia cases in India.

Fanconi anemia (FA) is a rare genetic disorder characterized by bone marrow failure, predisposition to cancer, and congenital abnormalities. FA is caused by pathogenic variants in any of 22 genes involved in the DNA repair pathway responsible for removing interstrand crosslinks. FANCL, an E3 ubiquitin ligase, is an integral component of the pathway, but patients affected by disease-causing FANCL variants are rare, with only nine cases reported worldwide. We report here a FANCL founder variant, anticipated to be synonymous, c.1092G>A;p.K364=, but demonstrated to induce aberrant splicing, c.1021_1092del;p.W341_K364del, that accounts for the onset of FA in 13 cases from South Asia, 12 from India and one from Pakistan. We comprehensively illustrate the pathogenic nature of the variant, provide evidence for a founder effect, and propose including this variant in genetic screening of suspected FA patients in India and Pakistan, as well as those with ancestry from these regions of South Asia.

Screening and management of preinvasive lesions of the cervix: Good clinical practice recommendations from the Federation of Obstetrics and Gynaecologic Societies of India (FOGSI).

In India, there are marked variations in resources for cervical cancer screening. For the first time, resource-stratified screening guidelines have been developed that will be suitable for low middle-income countries with similar diversities. The current article describes the process and outcomes of these resource stratified guidelines for screening and treatment of preinvasive lesions of cervix. Evidence from literature was collated and various guidelines were reviewed by an expert panel. Based on the level of evidence, guidelines were developed for screening by human papillomavirus (HPV) testing, cytology and visual inspection after application of acetic acid (VIA), and management of screen positive lesions in different resource settings. Expert opinion was used for certain country-specific situations. The healthcare system was stratified into two resource settings - good or limited. The mode of screening and treatment for each was described. HPV testing is the preferred method for cervical cancer screening. VIA by trained providers is especially suitable for low resource settings until an affordable HPV test becomes available. Healthcare providers can choose the most appropriate screening and treatment modality. A single visit approach is encouraged and treatment may be offered based on colposcopy diagnosis ('see and treat') or even on the basis of HPV test or VIA results ('screen and treat'), if compliance cannot be ensured. The Federation of Obsterician and Gynaecologists of India Good Clinical Practice Recommendations (FOGSI) GCPR are appropriately designed for countries with varied resource situations to ensure an acceptable cervical cancer prevention strategy.

INTDOSKIT: An R-Code for Calculation of Dose Coefficients and Studying Their Uncertainties.

ABSTRACT: An R-code, which allows the calculation of the time dependent activity distribution based on ICRP reference models, the number of decays in a commitment period, and the dose coefficients for tissues and organs of the human body, has been developed. R Language was chosen due to its powerful mathematical and statistical modeling features, as well as its graphical capabilities. The developed set of functions and constants (called "INTDOSKIT") can be sourced in R-scripts that define or import the models and calculations to be performed. The code has been tested on models of several radionuclides and was successfully validated against reference data taken from ICRP OIR Data Viewer software. Furthermore, the code has been tested and verified on the modeling of the radioactivity of decay chains using data of the 233Ra model presented by Höllriegl and colleagues. The results of calculations with INTDOSKIT demonstrated that the code is able to reproduce the ICRP bioassay data and dose coefficients. Deviations are a few percent only and are due mainly to rounding in the original data. Lastly, the code is able to handle uncertainty and sensitivity studies as demonstrated by the results in a pilot study of injection of 241Am, which estimated geometric standard deviations (GSD) for dose coefficients ranging between 1.25 (bone-surface) and 1.66 (testes); these results are consistent with those obtained from similar studies done by other researchers who reported GSD values ranging from 1.13 to 1.73.

Study of Caesarean Section Births in a Tertiary Care Hospital in Mumbai Using Robson Classification System.

Introduction: Robson ten-group classification system is recommended by WHO (World health organization) as a global standard for assessment and monitoring caesarean section (CS) rates. This classification is simple and robust. It is prospective, easily reproducible and clinically relevant. Methodology: We conducted a prospective observational study of CS births at a tertiary care institute. Caesarean births in a tertiary care hospital were classified using Robson classification system as recommended by WHO. The study was conducted for period of 6 months duration. The ethics committee of the institute approved this study. We enrolled 4771 consecutive women who delivered during this study period. We included patients who had vaginal delivery as well as those who had delivery by CS. Both live births and stillbirths (of at least 500-g birth weight or at least 22 weeks gestation (according to WHO recommendations) were included in this study. Results: During this study period, we had 4771 deliveries, out of which 2231 pregnant women (46.76%) were delivered by CS as compared to 2540 vaginal deliveries. Women with previous CS (term with single cephalic pregnancy) were included in Robson group 5. Group 5 had the highest CS rate (13.41%). Robson group 5, 1 and 10 were the largest contributors to the high CS rates at our institute. Conclusion: In our study, 4771 deliveries were conducted during this study period (6 months). Out of 4771 deliveries, CS was done in 2231 pregnant women (46.76%). 2540 women had vaginal deliveries. Group 5 (13.41%) which comprised of women with previous CS had the highest CS rate followed by group 1 and group 10. The second largest contribution was from Group 1 with CS rate of 9.01%. Robson Group 1 included nulliparous term women with single cephalic pregnancy in spontaneous labour. Group 10 was the third largest contributor to the overall CS. Group 10 included women who delivered preterm (single cephalic presentation). Group 10 contributed to 8.09% of overall CS rate. We should make every effort to provide CS for women requiring this procedure, rather than work towards achieving a specific rate for CS.

Impact of the Coronavirus Infection in Pregnancy: A Preliminary Study of 141 Patients.

BACKGROUND: The novel coronavirus disease (COVID-19) is the most challenging health crisis that we are facing today. Against the backdrop of this pandemic, it becomes imperative to study the effects of this infection on pregnancy and its outcome. Hence, the present study was undertaken to evaluate the effects of COVID-19 infection on the maternal morbidity and mortality, the course of labour as well as the neonatal outcome. MATERIALS AND METHODS: A total of 977 pregnant women were included in the study, from 1st April to 15th May 2020 at a tertiary care hospital. There were 141 women who tested COVID positive and remaining 836 patients were included in the COVID negative group. Findings were compared in both the groups. RESULTS: The incidence of COVID positive pregnant women was found to be 14.43%. More patients delivered by LSCS in the COVID positive and the COVID negative group (50%) as compared to COVID negative group (47%), (p > 0.05). Low APGAR score (0-3) was observed in 2(1.52%) neonates of COVID positive mothers and in 15 (1.91%) neonates of COVID negative mothers. Overall most of the babies were healthy. Out of all babies tested, 3 were detected positive initially which were retested on day 5 and were found to be negative. CONCLUSION: There is no significant effect of COVID infection on maternal and foetal outcome in pregnancy and there is no evidence of vertical transmission of the COVID-19 infection but long-term follow-up of these babies is recommended.

An Observational Study to Evaluate the Maternal and Foetal Outcomes in Pregnancies Complicated with Jaundice.

BACKGROUND: Incidence of jaundice in pregnancy, including underlying chronic liver diseases, is 3-5%. However, the maternal mortality rate in some conditions can be as high as 18% in acute fatty liver of pregnancy and 22% in hepatitis E in pregnancy. OBJECTIVES: This is an observational study of the demographics, obstetrical profile, aetiology, maternal morbidity, mortality and neonatal outcomes in pregnancies complicated with jaundice. MATERIALS AND METHODS: This is an observational study conducted in Department of Obstetrics and Gynaecology of a tertiary care hospital, situated amidst the biggest urban slum in Mumbai spanning over 1 year from January 2016 to December 2016. All registered, unregistered and transferred patients with abnormal liver function tests excluding patients with chronic liver diseases were included in this study. RESULTS: Most of the cases of jaundice in pregnancy were seen in primigravida (51%) and age group of 20-30 years (58%). Fifty-three percentage of cases were referred or transferred from periphery hospitals. Hepatitis E was the most common cause (42%) of jaundice in pregnancy. Complications like disseminated intravenous coagulopathy, postpartum haemorrhage, hepatic encephalopathy and hepatoportal hypertension were seen in 65% of cases. Maternal mortality rate and perinatal mortality rate were as high as 40 and 37%, respectively, in our study. CONCLUSION: Incidence of jaundice in pregnancy, mainly due to viral hepatitis, is very high in lower socio-economic, densely populated urban slums. Special efforts should be made to counsel and educate the mothers about initial symptoms and preventive measures for viral hepatitis. Patients along with the relatives should be informed about the severe features of pre-eclampsia to combat these preventable causes of maternal mortality.

Natural Killer Cell Degranulation Defect: A Cause for Impaired NK-Cell Cytotoxicity and Hyperinflammation in Fanconi Anemia Patients.

Fanconi anemia (FA) is a rare inherited syndrome characterized by progressive bone marrow failure (BMF), abnormal skin pigmentation, short stature, and increased cancer risk. BMF in FA is multifactorial and largely results from the death of hematopoietic stem cells due to genomic instability. Also, inflammatory pathology in FA has been previously reported, however the mechanism is still not clear. In literature, decreased NK-cell count and/or impaired NK-cell activity, along with other immunological abnormalities have been described in FA-patients (1). However, to the best of our knowledge, this is the first report showing a defective degranulation mechanism leading to abnormal NK-cell cytotoxicity in FA-patients, which may explain the development of a hyperinflammatory response in these patients. This may predispose some patients to develop Hemophagocytic lymphohistiocytosis (HLH) which manifests with prolonged fever, progressive cytopenias and organomegaly. Early diagnosis and initiation of immunosuppressive therapy in these patients will help to better manage these patients. We also propose FA genes to be listed as a cause of familial HLH.