High-Risk Genotypes Associated with Poor Response to Controlled Ovarian Stimulation in Indian Women.

Background: Infertility is a global burden and has become exceedingly common in the preceding years; controlled ovarian stimulation (COS) is a pre-requisite for couples opting to conceive via in vitro fertilisation (IVF). Based on the number of oocytes retrieved upon COS, a patient may be classified as a good responder or poor responder. The genetic aspect of response to COS has not been elucidated in the Indian population. Aims: This study aimed to establish a genomic basis for COS in IVF in the Indian population and to understand its predictive value. Settings and Design: The patient samples were collected at both Hegde Fertility Centre and GeneTech laboratory. The test was carried out at GeneTech, a diagnostic research laboratory based in Hyderabad, India. Patients with infertility without any history of polycystic ovary syndrome and hypogonadotropic hypogonadism were included in the study. Detailed clinical, medical and family history was obtained from patients. The controls had no history of secondary infertility or pregnancy losses. Materials and Methods: A total of 312 females were included in the study comprising 212 women with infertility and 100 controls. Next-generation sequencing technology was employed to sequence multiple genes associated with response to COS. Statistical Analysis Used: Statistical analysis using odds ratio was carried out to understand the significance of the results obtained. Results: Strong association of c.146G>T of AMH, c.622-6C>T of AMHR2, c.453-397T>C and c.975G>C of ESR1, c.2039G>A of FSHR and c.161+4491T>C of LHCGR with infertility and response to COS was established. Further, combined risk analysis was carried out to establish a predictive risk factor for patients with a combination of the genotypes of interest and biochemical parameters commonly considered during IVF procedures. Conclusion: This study has enabled the identification of potential markers pertaining to response to COS in the Indian population.

Placental Transfusion Strategies in Preterm Infants in Low- and Middle-Income Countries: A Systematic Review and Network Meta-Analysis.

INTRODUCTION: Placental transfusion strategies in preterm newborns have not been evaluated in low- and middle-income countries (LMICs). The objective of this systematic review was to compare placental transfusion strategies in preterm newborns in LMICs, including delayed cord clamping (DCC) for various time intervals, DCC until cord pulsations stop, umbilical cord milking, and immediate cord clamping (ICC). METHODS: Medline, Embase, CINAHL, and CENTRAL were searched from inception. Observational studies and randomized controlled trials (RCTs) were included. Two authors independently extracted data for Bayesian random-effects network meta-analysis (NMA) if more than 3 interventions reported an outcome or a pairwise meta-analysis was utilized. RESULTS: Among newborns <34 weeks of gestation, NMA of 9 RCTs could not rule out benefit or harm for survival from DCC 30-60 s compared to ICC: relative risk (RR) (95% credible interval) 0.96 (0.78-1.12), moderate certainty, or any included strategy compared to each other (low to very low certainty). Among late preterm newborns, DCC 120 s might be associated with improved survival: RR (95% confidence interval) 1.11 (1.01-1.22), very low certainty. We could not detect differences in the risk of intraventricular hemorrhage grade > II and bronchopulmonary dysplasia for any included intervention (low to very low certainty). DCC 60 s and 120 s might improve the hematocrit level among all preterm newborns (very low certainty), and DCC 45 s may decrease the risk of receipt of inotropes among newborns <34 weeks of gestation (low certainty). CONCLUSIONS: In LMICs, DCC for 60 s and 120 s might improve hematocrit level in preterm newborns, and DCC for 45 s may decrease the risk of receipt of inotropes in newborns <34 weeks, with no conclusive effect on survival.

Lin-7 targets the Kir 2.3 channel on the basolateral membrane via a L27 domain interaction with CASK.

Polarized expression of the Kir 2.3 channel in renal epithelial cells is influenced by the opposing activities of two different PDZ proteins. Mammalian Lin-7 (mLin-7) directly interacts with Kir 2.3 to coordinate basolateral membrane expression, whereas the tax interacting protein 1 (TIP-1), composed of a single PDZ domain, competes for interaction with mLin-7 and drives Kir 2.3 into the endocytic pathway. Here we show that the basolateral targeting function of mLin-7 depends on its L27 domain, which directs interaction with a cognate L27 domain in the basolateral membrane-anchoring protein, calcium/calmodulin-dependent serine protein kinase (CASK). In MDCK cells, the expression of an mLin-7 mutant that lacks the L27 domain displaced Kir 2.3 from the mLin-7/CASK complex and caused the channel to accumulate into large intracellular vesicles that partially colocalized with Rab-11. Conversely, transplantation of the mLin-7 L27 domain to TIP-1 conferred CASK interaction and basolateral targeting of Kir 2.3. Expression of the CASK L27 domain redistributed endogenous mLin-7 to an intracellular compartment and caused Kir 2.3 to accumulate in subapical endosomes. Taken together, these data support a model whereby mLin-7 acts as a PDZ-to-L27 adapter, mediating indirect association of Kir 2.3 with a basolateral membrane scaffold and thereby stabilizing Kir 2.3 at the basolateral membrane.