Multi-criteria decision making to validate performance of RBC-based formulae to screen [Formula: see text]-thalassemia trait in heterogeneous haemoglobinopathies.

BACKGROUND: India has the most significant number of children with thalassemia major worldwide, and about 10,000-15,000 children with the disease are born yearly. Scaling up e-health initiatives in rural areas using a cost-effective digital tool to provide healthcare access for all sections of people remains a challenge for government or semi-governmental institutions and agencies. METHODS: We compared the performance of a recently developed formula SCS[Formula: see text] and its web application SUSOKA with 42 discrimination formulae presently available in the literature. 6,388 samples were collected from the Postgraduate Institute of Medical Education and Research, Chandigarh, in North-Western India. Performances of the formulae were evaluated by eight different measures: sensitivity, specificity, Youden's Index, AUC-ROC, accuracy, positive predictive value, negative predictive value, and false omission rate. Three multi-criteria decision-making (MCDM) methods, TOPSIS, COPRAS, and SECA, were implemented to rank formulae by ensuring a trade-off among the eight measures. RESULTS: MCDM methods revealed that the Shine & Lal and SCS[Formula: see text] were the best-performing formulae. Further, a modification of the SCS[Formula: see text] formula was proposed, and validation was conducted with a data set containing 939 samples collected from Nil Ratan Sircar (NRS) Medical College and Hospital, Kolkata, in Eastern India. Our two-step approach emphasized the necessity of a molecular diagnosis for a lower number of the population. SCS[Formula: see text] along with the condition MCV[Formula: see text] 80 fl was recommended for a higher heterogeneous population set. It was found that SCS[Formula: see text] can classify all BTT samples with 100% sensitivity when MCV[Formula: see text] 80 fl. CONCLUSIONS: We addressed the issue of how to integrate the higher-ranked formulae in mass screening to ensure higher performance through the MCDM approach. In real-life practice, it is sufficient for a screening algorithm to flag a particular sample as requiring or not requiring further specific confirmatory testing. Implementing discriminate functions in routine screening programs allows early identification; consequently, the cost will decrease, and the turnaround time in everyday workflows will also increase. Our proposed two-step procedure expedites such a process. It is concluded that for mass screening of BTT in a heterogeneous set of data, SCS[Formula: see text] and its web application SUSOKA can provide 100% sensitivity when MCV[Formula: see text] 80 fl.

Incidence of Interstitial Alveolar Syndrome on Point-of-Care Lung Ultrasonography in Pre-eclamptic Women With Severe Features: A Prospective Observational Study.

BACKGROUND: Lung interstitial edema is a clinically silent pathology that develops before overt pulmonary edema among pre-eclamptic women with severe features. Point-of-care lung ultrasonography (LUS) has been suggested as an accessible bedside tool that may identify lung interstitial edema before developing clinical signs and symptoms. Thus, we planned to use bedside LUS as a diagnostic tool in admitted pre-eclamptic women with severe features, with the aim of identifying alveolar-interstitial fluid, seen as B-lines. Our primary objective was to assess the incidence of interstitial alveolar syndrome on lung ultrasonography. METHODS: We conducted a prospective, single-center, observational study on parturients with pre-eclampsia with severe features over a period of 15 months. LUS in 4 intercostal spaces (ICS) was performed on all eligible patients. The number of single or confluent B-lines in each space was recorded by an independent observer. A scoring system was used to grade the lung fluid content based on the number of single and confluent B-lines per ICS, with scores ranging from 0 to 32 (low, 0-10; moderate, 11-20; and high, 21+). The incidence of B-lines at admission and before and after delivery was calculated. In addition, bedside 2D echocardiography was performed to assess left ventricular systolic and diastolic function. Any correlation between presence of B-lines on LUS and blood pressure, clinical symptoms, or echocardiography findings was assessed. RESULTS: Seventy patients were enrolled in the study. On LUS, B-lines were seen in 64.3% patients at admission (45/70 vs 25/70 without B-lines; P = .02), 65.7% patients before delivery (46/70 vs 24/70 without B-lines; P = .01), and 58.6% patients 24 hours postpartum (41/70 versus 29/70 without B-lines; P = .15). Nearly all patients (94.3%) exhibited low to moderate severity of pulmonary fluid burden at admission. Echocardiography revealed diastolic dysfunction in 47.1% (n = 33/70) patients with associated B-lines in the majority (n = 32/33). The total B-line score and E/e' ratio among patients with diastolic dysfunction was found to be strongly correlated (r = 0.848; P < .001). All pre-eclamptic women with presence of breathlessness (11/11; 100%) and facial puffiness (16/16; 100%) on admission had B-lines on LUS. CONCLUSIONS: We conclude that ultrasonographic pulmonary interstitial syndrome is present in more than half of the women with pre-eclampsia with severe features and correlates with diastolic dysfunction, high blood pressure records, and acute-onset breathlessness.

Biallelic NLRP7 variants in patients with recurrent hydatidiform mole: A review and expert consensus.

Hydatidiform mole (HM) is an abnormal human pregnancy characterized by excessive growth of placental trophoblasts and abnormal early embryonic development. Following a first such abnormal pregnancy, the risk for women of successive molar pregnancies significantly increases. To date variants in seven maternal-effect genes have been shown to cause recurrent HMs (RHM). NLRP7 is the major causative gene for RHM and codes for NOD-like receptor (NLR) family pyrin domain containing 7, which belongs to a family of proteins involved in inflammatory disorders. Since its identification, all NLRP7 variants have been recorded in Infevers, an online registry dedicated to autoinflammatory diseases (https://infevers.umai-montpellier.fr/web/). Here, we reviewed published and unpublished recessive NLRP7 variants associated with RHM, scored their pathogenicity according to the American College of Medical Genetics classification, and recapitulated all functional studies at the level of both the patients and the conceptions. We also provided data on further variant analyses of 32 patients and genotypes of 36 additional molar pregnancies. This comprehensive review integrates published and unpublished data on NLRP7 and aims at guiding geneticists and clinicians in variant interpretation, genetic counseling, and management of patients with this rare condition.

Cervical cytology in the detection of uterine clear cell carcinoma: Diagnostic predictors from a case-control study.

INTRODUCTION: Uterine clear cell adenocarcinoma (CCC) is a rare, aggressive malignancy with poor prognosis. The present study aimed to identify and describe its characteristic morphological features in cervical cytology. METHODS: This was a 3-year retrospective case-control study. Cases included cervical samples of histopathologically proven endometrial and cervical CCC. Controls included cervical samples of histopathologically proven endometrial serous carcinoma (n = 15), endometrioid adenocarcinoma (n = 20), and endocervical adenocarcinoma (n = 15). Twenty-eight cytomorphological features were evaluated; the strength of association was determined by odds ratio (OR) and Cramer's V, and the diagnostic accuracy of statistically significant features was assessed. RESULTS: Cases consisted of histopathologically proven 25 (34.7%) endometrial and 13 (18.0%) cervical CCC. Corresponding cervical samples were available for a total of 14 (36.8%) patients, of which 13 (92.8%) were positive for epithelial cell abnormality. On univariate analysis, three cytomorphological variables were significant predictors of uterine CCC: presence of dense cytoplasm (OR = 88; V = 0.72), deep nuclear membrane irregularities (OR = 17.5; V = 0.55), and coarse chromatin (OR = 21.3; V = 0.46). Dense cytoplasm had the highest positive predictive value (92%) and high specificity (97.8%), whereas coarse chromatin had the highest sensitivity (92.3%) and negative predictive value (96.7%). CONCLUSIONS: The presence of dense cytoplasm and deep nuclear membrane irregularities in the tumour cells were strong predictors, and coarse chromatin a moderate predictor, of uterine CCC compared to its close cytological mimics.

Socio-behavioural determinants of maternal near miss: a prospective case control study from a tertiary care centre of India.

Near miss occurs in far greater numbers than maternal deaths and allows a more robust quantification on risk factors and determinants of life-threatening complications. A 'Three delay model' has been proposed in identification of causes of near miss and maternal deaths. There may be delay in seeking and obtaining health care: delay in recognising danger signs and deciding to reach source of care, delay in reaching appropriate source of care and delay in obtaining appropriate and adequate treatments. We compared various delays between near miss cases (n = 100) and controls (n = 200). Women who fulfilled criteria of near miss were taken as cases. Women who had obstetrical complications like near miss but were managed successfully and did not reach near miss state were labelled as controls. Near miss were then compared with maternal death. For normally distributed measurable data, outcome was compared using Student's t-test, for non-normally distributed/ordinal data, outcome was compared using Mann-Whitney's test. For categorical/classified data, association with outcome was analysed using Chi-Square test/Fisher's exact test.Delay in all three levels was seen among the groups. Lack of knowledge, non-availability of decision maker, and concern of cost of transport were main contributors of these delays.Impact StatementWhat is already known on this subject? Nonavailability of healthcare and low socio-economic status strongly correlate with maternal morbidity and mortality.What do the results of this study add? Lack of knowledge, non-availability of the decision maker, and concern of cost of transport were the main contributors of delay in seeking medical care. Majority of the cases of near miss were attributed to poor utilisation of health resources, ignorance and lack of emergency obstetric care at the primary level.What are the implications of these findings for clinical practice and/or further research? Patient and attendant education to ensure follow-up visits, recognise danger signs and report without undue delay, compliance to dietary modifications, medications given needs to be addressed at every visit to reduce the impact of socio-behavioural determinants on maternal near miss and mortality which are preventable in majority of cases.

Comparison of intracervical Foley catheter combined with a single dose of vaginal misoprostol tablet or intracervical dinoprostone gel for cervical ripening: a randomised study.

We compared two combined methods for cervical ripening before induction of labour (IOL) Women (n = 150) were randomised into Foley's-misoprostol (n = 75) and Foley's-dinoprostone (n = 75) groups. A single dose of vaginal misoprostol tablet (25 µg) or intracervical dinoprostone gel (0.5 mg) were used alongwith intracervical Foley's. The primary outcome was induction-delivery interval (IDI) and secondary outcomes were change in Bishop's score, oxytocin requirement, caesarean section (CS) rate, chorioamnionitis and neonatal outcome. The mean parity, gestation and indications for IOL were similar in the two groups. The IDI (19 h 37 min and 19 h 20 min; p = .683), cervical ripening time, oxytocin requirement, CS rate (18.7 and 25.4%, p = .322) and neonatal outcome were similar. Hyperstimulation developed in 2.7% women with Foley's-misoprostol and in 1.3% with Foley's-dinoprostone (p = .55). No woman had chorioamnionitis. Thus, these two combined methods of cervical ripening and IOL were observed to be similarly efficacious. A low incidence of hyperstimulation and no chorioamnionitis may be attributed to using a single dose of prostaglandins. Misoprostol may be substituted for dinoprostone in resource limited countries.Impact statementWhat is already known on this subject? Combined methods for cervical ripening (intracervical Foley's plus prostaglandins) before induction of labour (IOL) may be similarly or more efficacious than individual methods. Most studies comparing various combined methods have used repeated doses of prostaglandins. A combined method using repetitive doses of prostaglandins may increase the risk of hyperstimulation and also of infection consequent to repeated vaginal examination to administer prostaglandins. These two concerns may be offset by combining a single dose of prostaglandin with intracervical Foley's catheter.What do the results of this study add? Two combined methods for cervical ripening using a single dose of vaginal misoprostol (25 µg) or intracervical dinoprostone gel (0.5 mg) co-administered with intracervical Foley's catheter were found to be similarly efficacious. The IDI (19 h 37 min and 19 h 20 min; p = .683), cervical ripening time, oxytocin requirement, CS rate (18.7 and 25.4%, p = .322) and neonatal outcome were similar. The incidence of hyperstimulation was low (2.7 and 1.3% with Foley's-misoprostol and Foley's-dinoprostone, respectively) and no woman had chorioamnionitis.What are the implications of these findings for clinical practice and/or further research? Combined methods for cervical ripening using a single dose of prostaglandins (misoprostol or dinoprostone) were observed to be similarly efficacious. Misoprostol is a cheaper alternative to dinoprostone and may be utilised in resource limited countries. These methods may be compared with each other in more number of women in order to identify which combined method is more efficient and safe. Clinical Trials Registry of India: CTRI/2017/12/010738.

Causative Mutations and Mechanism of Androgenetic Hydatidiform Moles.

Androgenetic complete hydatidiform moles are human pregnancies with no embryos and affect 1 in every 1,400 pregnancies. They have mostly androgenetic monospermic genomes with all the chromosomes originating from a haploid sperm and no maternal chromosomes. Androgenetic complete hydatidiform moles were described in 1977, but how they occur has remained an open question. We identified bi-allelic deleterious mutations in MEI1, TOP6BL/C11orf80, and REC114, with roles in meiotic double-strand breaks formation in women with recurrent androgenetic complete hydatidiform moles. We investigated the occurrence of androgenesis in Mei1-deficient female mice and discovered that 8% of their oocytes lose all their chromosomes by extruding them with the spindles into the first polar body. We demonstrate that Mei1-/- oocytes are capable of fertilization and 5% produce androgenetic zygotes. Thus, we uncover a meiotic abnormality in mammals and a mechanism for the genesis of androgenetic zygotes that is the extrusion of all maternal chromosomes and their spindles into the first polar body.

Novel pathogenic variants in NLRP7, NLRP5, and PADI6 in patients with recurrent hydatidiform moles and reproductive failure.

Recurrent hydatidiform moles (RHMs) are human pregnancies with abnormal embryonic development and hyperproliferating trophoblast. Biallelic mutations in NLRP7 and KHDC3L, members of the subcortical maternal complex (SCMC), explain the etiology of RHMs in only 60% of patients. Here we report the identification of seven functional variants in a recessive state in three SCMC members, five in NLRP7, one in NLRP5, and one in PADI6. In NLRP5, we report the first patient with RHMs and biallelic mutations. In PADI6, the patient had four molar pregnancies, two of which had fetuses with various abnormalities including placental mesenchymal dysplasia and intra-uterine growth restriction, which are features of Beckwith-Wiedemann syndrome and Silver Russell syndrome, respectively. Our findings corroborate recent studies and highlight the common oocyte origin of all these conditions and the continuous spectrum of abnormalities associated with deficiencies in the SCMC genes.

Different dietary combinations of folic acid and vitamin B12 in parental diet results in epigenetic reprogramming of IGF2R and KCNQ1OT1 in placenta and fetal tissues in mice.

Genomic imprinting is important for mammalian development and its dysregulation can cause various developmental defects and diseases. The study evaluated the effects of different dietary combinations of folic acid and B12 on epigenetic regulation of IGF2R and KCNQ1OT1 ncRNA in C57BL/6 mice model. Female mice were fed diets with nine combinations of folic acid and B12 for 4 weeks. They were mated and off-springs born (F1) were continued on the same diet for 6 weeks postweaning and were allowed to mate. The placenta and fetal (F2) tissues were collected at day 20 of gestation. Dietary deficiency of folate (BNFD and BOFD) and B12 (BDFN) with either state of other vitamin or combined deficiency of both vitamins (BDFD) in comparison to BNFN, were overall responsible for reduced expression of IGF2R in the placenta (F1) and the fetal liver (F2) whereas a combination of folate deficiency with different levels of B12 revealed sex-specific differences in kidney and brain. The alterations in the expression of IGF2R caused by folate-deficient conditions (BNFD and BOFD) and both deficient condition (BDFD) was found to be associated with an increase in suppressive histone modifications. Over-supplementation of either folate or B12 or both vitamins in comparison to BNFN, led to increase in expression of IGF2R and KCNQ1OT1 in the placenta and fetal tissues. The increase in the expression of IGF2R caused by folate over-supplementation (BNFO) was associated with decreased DNA methylation in fetal tissues. KCNQ1OT1 noncoding RNA (ncRNA), however, showed upregulation under deficient conditions of folate and B12 only in female fetal tissues which correlated well with hypomethylation observed under these conditions. An epigenetic reprograming of IGF2R and KCNQ1OT1 ncRNA in the offspring was evident upon different dietary combinations of folic acid and B12 in the mice.

ALDH1 & CD133 in invasive cervical carcinoma & their association with the outcome of chemoradiation therapy.

Background & objectives: Chemoradiation is the standard therapy for locally advanced invasive cervical cancer and response to treatment determines the outcome. Cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) play a role in response to treatment and hence the aim of this study was to evaluate if their levels in pre-treatment biopsies by immunohistochemistry (IHC) could predict response to treatment and outcome. Methods: The study comprised 60 patients with FIGO Stage IIB/III invasive cervical carcinoma treated by chemoradiation. They were divided into two groups based on their clinical outcome: group 1, 30 patients who had no evidence of disease at 48 month follow up and group 2, 30 patients who had disease relapse within 6-12 months of treatment completion. IHC was performed for CSC markers (ALDH1, CD133, Nanog and Oct-4), EMT markers (E-cadherin and vimentin) and squamocolumnar junction (KRT7) markers and H-scores determined. Intergroup comparison was performed. The expression of these markers was also evaluated in histological sections of cervical pre-cancer (CIN1 and CIN3) in comparison to normal cervix. Results: Cervical Intraepithelial Neoplasia grade 3 (CIN3) showed high expression of ALDH1 and KRT7 as compared to normal cervical epithelium. Aldehyde dehydrogenase 1 (ALDH1) and CD133 were overexpressed in 70 and 24 per cent cervical carcinoma cases whereas E-cadherin showed reduced expression in invasive carcinoma as compared to normal controls. ALDH1 overexpression was significantly associated with disease relapse in invasive cervical carcinoma treated by chemoradiation (P<0.01). Interpretation & Conclusions: Determination of ALDH1 levels in pre-treatment cervical biopsies of invasive cervical carcinoma may be useful for prediction of response to chemoradiation, with high levels predicting for a poor response.

Detection of co-infection of Gardnerella vaginalis and Atopobium vaginae using qualitative PCR: A better predictor of bacterial vaginosis.

The present study aimed to determine the utility of detection of co-infection of Gardnerella vaginalis and Atopobium vaginae using qualitative PCR for diagnosing bacterial vaginosis (BV). Vaginal samples (n = 385) categorized as positive (n = 108) or negative (n = 208) for bacterial vaginosis based on the Nugent scoring system, were analyzed for the presence of G. vaginalis and A. vaginae by conventional PCR. We compared the sensitivity, specificity, positive predictive value, negative predictive value and odds ratio for the detection of each bacterium alone with the combination of the two bacteria for diagnosing BV. The detection of co-infection of the two bacteria demonstrated a sensitivity of 96%, a specificity of 82.9%, a positive predictive value of 68.5%, a negative predictive value of 98.2% with an odds ratio of 116 (CI -32 - 409). In our study, we found a high sensitivity, specificity, negative predictive value and odds ratio for the detection of co-infection of A. vaginae and G. vaginalis for the diagnosis of BV.

Second trimester medical abortion in a primigravida with lupus nephritis and rapidly progressive renal failure: challenges and outcome.

In the second trimester, medical abortion is preferred as it is less invasive, and the surgical method carries more risk. There is a paucity of published literature on medical abortion in women with renal failure requiring haemodialysis. We came across a woman who presented with rapidly progressive renal failure at 18 weeks of gestation and required therapeutic abortion. We are reporting the challenges, outcomes, and precautions to be taken while performing a medical abortion in such a case.

Insulin growth factor-1 pathway in cervical carcinoma cancer stem cells.

Cancer stem cells (CSC) drive tumour progression and are implicated in relapse and resistance to conventional cancer therapies. Identification of differentially expressed genes by gene expression (GEP) profiling may help identify the differentially activated signalling pathways in cancer stem cells as opposed to bulk tumour cells which will provide new insights into cancer stem cell biology and aid in identification of novel therapeutic targets. Our study focused on the inhibition of CSC from cervical cancer cell lines by targeting insulin-like growth factor (IGF), which was identified by differential GEP. Targeted inhibition of IGF-1 by JB-1 trifluoroacetate (inhibitor of IGF) was carried out in SiHa, RSBS-14 and RSBS-43 cervical cancer derived cell lines. Effect of cisplatin was also evaluated. Inhibition of IGF-1 signalling was confirmed by demonstration of reduction in p-Akt levels. The cell biological effects of IGF-1 inhibition included an increase in G2M/S fraction, increased apoptosis and decreased invasive ability. JB-1 and cisplatin showed synergism. However, transcript levels of stemness and EMT markers showed variable levels following IGF inhibition. Overall, this proof-of-concept study has shown that IGF-1 is an attractive target for inhibition of CSC in invasive cervical cancer.

Management of pregnant laboring women during COVID-19 pandemic.

Since its first outbreak in December 2019 in Wuhan, China, coronavirus disease 2019 (COVID-19) has become a global public health threat. In the midst of this rapidly evolving pandemic condition, the unique needs of pregnant women should be kept in mind while making treatment policies and preparing response plans. Management of COVID-19 parturients requires a multidisciplinary approach consisting of a team of anesthesiologists, obstetricians, neonatologists, nursing staff, critical care experts, infectious disease, and infection control experts. Labor rooms as well as operating rooms should be in a separate wing isolated from the main wing of the hospital. In the operating room, dedicated equipment and drugs for both neuraxial labor analgesia and cesarean delivery, as well as personal protective equipment, should be readily available. The entire staff must be specifically trained in the procedures of donning, doffing, and in the standard latest guidelines for disposal of biomedical waste of such areas. All protocols for the management of both COVID-19 suspects as well as confirmed patients should be in place. Further, simulation-based rehearsal of the procedures commonly carried out in the labor room and the operation theaters should be ensured.

Temporal expression of genes involved in folate metabolism and transport during placental development, preeclampsia and neural tube defects.

Folate is an essential micronutrient during pregnancy. The differential expression of genes related to folate transport and metabolism during the advancing gestation and pregnancy complications is not well established. Hence, we studied the gene expression of folate metabolism and transport proteins in the placenta with advancing gestation, preeclampsia and neural tube defects (NTD). The expression of folate transporters and enzymes involved in folate metabolism in the placenta with advancing gestation and pregnancy-related disorders were studied by 2-step RT-PCR. Folate levels were estimated by microbiological assay using Lactobacillus casei. Significant changes in levels of placental folate metabolizing enzymes were found in both physiological and pathological pregnancies during advancing gestation. Expression of methyltetrahydrofolate reductase (MTHFR) (p < 0.001) and cystathionine-ß-synthase (CBS) (p < 0.001) was decreased while that of methionine synthase (MS) (p < 0.001) was increased with advancing gestation. A much-reduced expression of MTHFR (p < 0.01) and an abnormally high expression of methionine synthase reductase (p < 0.001) were observed in the NTD group. In NTDs, there was an adaptive up-regulation of folate transporters mainly reduced folate carrier (p < 0.001) and folate receptor alpha (p < 0.001). MTHFR expression showed a strong positive correlation (r = 0.96, p < 0.01) with folate levels in placenta. Pregnant women with preeclampsia had low expression of MS (p < 0.01) in association with low folate levels. Placental folate metabolizing enzymes exhibited a differential pattern during advancing gestation. Deficient folate status in association with alteration in expression of enzymes involved in folate metabolism might be associated with pregnancy complications such as preeclampsia and NTDs.

Applicability of WHO Maternal Severity Score (MSS) and Maternal Severity Index (MSI) Model to predict the maternal outcome in near miss obstetric patients: a prospective observational study.

OBJECTIVE: To assess the applicability of WHO Maternal Severity Score (MSS) and Maternal Severity Index (MSI) Model in near miss (NM) obstetric patients METHODS: It was a prospective observational study conducted at a tertiary health care center from July 2015 to Feb 2016. All patients fulfilling one or more WHO NM criteria were included. MSS and MSI were calculated for all NM patients on admission. They were then followed up till the final outcome (NM or death). Each NM parameter, system-wise MSS, total MSS and MSI were then associated with the final outcome. RESULTS: Of 4822 patients, 1739 had potentially life-threatening conditions of which 174 were identified as NM. The average MSS and MSI of patients who remained NM was 4.41 and 11.67%, respectively, and those who died was 9.47 and 58.16%, respectively. Both were found to be significantly associated with the outcome (p < 0.001). MSI had good accuracy for maternal death prediction in women with markers of organ dysfunction (AUROC - 0.838 [95% CI 0.766-0.910]). However, of 25 NM criteria, only 17 NM criteria and 3 system dysfunctions (cardiovascular, respiratory and neurological) were found to associate significantly with the outcome. CONCLUSION: MSS and MSI act as good prognostic tools to assess the severity of maternal complications and estimate the probability of death in NM patients. As all NM parameters are not equally predictive of severity of maternal morbidity, different scores per NM parameter and system should be assigned while calculating MSS for better prognostication.

Comparison of intracervical Foley catheter used alone or combined with a single dose of dinoprostone gel for cervical ripening: a randomised study.

Prostaglandins and intracervical catheters are similarly effective for cervical ripening and for an induction of labour (IOL). Studies comparing the combined use with either method alone have administered repetitive doses of prostaglandins vaginally, which may increase the risk of tachysystole and chorioamnionitis. These disadvantages may be offset by co-administering a single dose of prostaglandin. Women (n = 110) planned for IOL, ≥37 weeks of gestation and with a Bishop Score of ≤6 were randomised into two groups: intracervical Foley catheter alone or combined with dinoprostone gel (0.5 mg) for 12 hours followed by oxytocin. The primary outcome was the IDI and the others were: change in Bishop Score, caesarean section (CS) requirement, any complications and neonatal outcome. The baseline Bishop was ≤4 in all and >80% were nulliparous. The post-ripening Bishop was significantly higher (6.67 vs. 5.98; p = .045) and the IDI was significantly lower in the combined group (16 hours and 16 minutes vs. 20 hours 44 minutes, p = .002). The CS rate was similar (29.1 vs. 25.5%; p = .669). No woman had hyperstimulation or chorioamnionitis and the neonatal outcomes were similar. Thus, co-administering one dose of an intracervical PGE2 gel with Foley was superior to Foley alone for cervical ripening and IOL. Impact statement What is already known on this subject? Prostaglandins and intracervical balloon catheters used individually are similarly effective for ripening an unfavourable cervix prior to the induction of labour (IOL). A few studies which have compared their found it to result in a shorter cervical ripening time and induction delivery interval (IDI) as compared to prostaglandins alone, though chorioamnionitis was a concern. When compared to balloon catheter used alone, combined use was either similarly or more effective. The studies comparing combined use with either method used alone have administered repetitive doses of prostaglandins vaginally, which may increase the risk of tachysystole, and possibly of chorioamnionitis. Co-administering a single dose of prostaglandin with a balloon catheter may offset these disadvantages. What do the results of this study add? A combined method for cervical ripening using a single dose of intracervical dinoprostone gel (PGE2, 0.5 mg) coadministered with an intracervical Foley catheter was superior to Foley catheter alone. The combined method improved the Bishop score after 12 hours and reduced the IDI significantly compared to the Foley catheter alone; while the caesarean rate and neonatal outcomes were similar. No woman had chorioamnionits or hyperstimulation. What are the implications of these findings for clinical practice and/or further research? The combined methods for cervical ripening should be compared to individual methods in more women, and the combinations may explore the use of other single use prostaglandins like the dinoprostone vaginal insert or misoprostol tablets.

Quality of recovery and analgesia after total abdominal hysterectomy under general anesthesia: A randomized controlled trial of TAP block vs epidural analgesia vs parenteral medications.

BACKGROUND AND AIMS: Parenteral analgesics and epidural analgesia are two standard options to treat postoperative pain after total abdominal hysterectomy (TAH). Fascial plane blocks such as transversus abdominis plane (TAP) block have gained popularity recently. However, effect of these analgesic regimens on quality of postoperative recovery (QoR) has not been studied. Hence we aimed to assess and compare the QoR with three different postoperative analgesic regimens---parenteral analgesia, epidural analgesia, and TAP block in patients undergoing TAH under general anesthesia. MATERIAL AND METHODS: Sixty female patients undergoing TAH were randomized into three groups of 20 each for postoperative analgesia. Epidural group received boluses of 0.125% bupivacaine for 24 h, parenteral group received injection diclofenac and injection tramadol alternately every 6 h for 24 h, and TAP group received bilateral TAP block with 0.25% bupivacaine at end of operation. QoR was assessed postoperatively by 40-item questionnaire-QOR-40 and pain was assessed by numerical rating scale (NRS). RESULTS: QOR-40 score was comparable across the three groups at 24, 48, and 72 h postoperatively. TAP block prolonged the time to first rescue analgesic (P = 0.02) and reduced the total 24-h postoperative morphine consumption by 2.4 (95% CI: 1.0, 3.8) mg (P = 0.002) and 7.8 (95% CI: 6.4, 9.1) mg (P < 0.001) when compared with epidural and parenteral groups, respectively. CONCLUSION: The QoR after abdominal hysterectomy is similar with either intravenous analgesics or epidural analgesia or TAP block when used with rescue analgesia to manage postoperative pain. TAP block provides superior analgesia and reduces 24-h morphine consumption when compared with parenteral and epidural analgesia.

The genetics of recurrent hydatidiform moles: new insights and lessons from a comprehensive analysis of 113 patients.

Hydatidiform mole is an aberrant human pregnancy characterized by early embryonic arrest and excessive trophoblastic proliferation. Recurrent hydatidiform moles are defined by the occurrence of at least two hydatidiform moles in the same patient. Fifty to eighty percent of patients with recurrent hydatidiform moles have biallelic pathogenic variants in NLRP7 or KHDC3L. However, in the remaining patients, the genotypic types of the moles are unknown. We characterized 80 new hydatidiform mole tissues, 57 of which were from patients with no mutations in the known genes, and we reviewed the genotypes of a total of 123 molar tissues. We also reviewed mutation analysis in 113 patients with recurrent hydatidiform moles. While all hydatidiform moles from patients with biallelic NLRP7 or KHDC3L mutations are diploid biparental, we demonstrate that those from patients without mutations are highly heterogeneous and only a small minority of them are diploid biparental (8%). The other mechanisms that were found to recur in patients without mutations are diploid androgenetic monospermic (24%) and triploid dispermic (32%); the remaining hydatidiform moles were misdiagnosed as moles due to errors in the analyses and/or their unusual mechanisms. We compared three parameters of genetic susceptibility in patients with and without mutations and show that patients without mutations are mostly from non-familial cases, have fewer reproductive losses, and more live births. Our data demonstrate that patients with recurrent hydatidiform moles and no mutations in the known genes are, in general, different from those with mutations; they have a milder genetic susceptibility and/or a multifactorial etiology underlying their recurrent hydatidiform moles. Categorizing these patients according to the genotypic types of their recurrent hydatidiform moles may facilitate the identification of novel genes for this entity.

Significance of CD133 positive cells in four novel HPV-16 positive cervical cancer-derived cell lines and biopsies of invasive cervical cancer.

BACKGROUND: Cervical cancer is a major cause of cancer-related mortality in women in the developing world. Cancer Stem cells (CSC) have been implicated in treatment resistance and metastases development; hence understanding their significance is important. METHODS: Primary culture from tissue biopsies of invasive cervical cancer and serial passaging was performed for establishing cell lines. Variable Number Tandem Repeat (VNTR) assay was performed for comparison of cell lines with their parental tissue. Tumorsphere and Aldefluor assays enabled isolation of cancer stem cells (CSC); immunofluorescence and flow cytometry were performed for their surface phenotypic expression in cell lines and in 28 tissue samples. Quantitative real-time PCR for stemness and epithelial-mesenchymal transition (EMT) markers, MTT cytotoxicity assay, cell cycle analysis and cell kinetic studies were performed. RESULTS: Four low-passage novel cell lines designated RSBS-9, - 14 and - 23 from squamous cell carcinoma and RSBS-43 from adenocarcinoma of the uterine cervix were established. All were HPV16+. VNTR assay confirmed their uniqueness and derivation from respective parental tissue. CSC isolated from these cell lines showed CD133+ phenotype. In tissue samples of untreated invasive cervical cancer, CD133+ CSCs ranged from 1.3-23% of the total population which increased 2.8-fold in radiation-resistant cases. Comparison of CD133+ with CD133- bulk population cells revealed increased tumorsphere formation and upregulation of stemness and epithelial-mesenchymal transition (EMT) markers with no significant difference in cisplatin sensitivity. CONCLUSION: Low-passage cell lines developed would serve as models for studying tumor biology. Cancer Stem Cells in cervical cancer display CD133+ phenotype and are increased in relapsed cases and hence should be targeted for achieving remission.