Identification of genetic variants affecting reproduction traits in Vrindavani cattle.

Genome-wide association studies (GWAS) are one of the best ways to look into the connection between single-nucleotide polymorphisms (SNPs) and the phenotypic performance. This study aimed to identify the genetic variants that significantly affect the important reproduction traits in Vrindavani cattle using genome-wide SNP chip array data. In this study, 96 randomly chosen Vrindavani cows were genotyped using the Illumina Bovine50K BeadChip platform. A linear regression model of the genome-wide association study was fitted in the PLINK program between genome-wide SNP markers and reproduction traits, including age at first calving (AFC), inter-calving period (ICP), dry days (DD), and service period (SP) across the first three lactations. Information on different QTLs and genes, overlapping or adjacent to genomic coordinates of significant SNPs, was also mined from relevant databases in order to identify the biological pathways associated with reproductive traits in bovine. The Bonferroni correction resulted in total 39 SNP markers present on different chromosomes being identified that significantly affected the variation in AFC (6 SNPs), ICP (7 SNPs), DD (9 SNPs), and SP (17 SNPs). Novel potential candidate genes associated with reproductive traits that were identified using the GWAS methodology included UMPS, ITGB5, ADAM2, UPK1B, TEX55, bta-mir-708, TMPO, TDRD5, MAPRE2, PTER, AP3B1, DPP8, PLAT, TXN2, NDUFAF1, TGFA, DTNA, RSU1, KCNQ1, ADAM32, and CHST8. The significant SNPs and genes associated with the reproductive traits and the enriched genes may be exploited as candidate biomarkers in animal improvement programs, especially for improved reproduction performance in bovines.

The association between discordant umbilical arterial resistance in growth-restricted fetuses and adverse outcomes.

BACKGROUND: Assessing the umbilical artery pulsatility index via Doppler measurements plays a crucial role in evaluating fetal growth impairment. OBJECTIVE: This study aimed to investigate perinatal outcomes associated with discordant pulsatility indices of umbilical arteries in fetuses with growth restriction. STUDY DESIGN: In this retrospective cohort study, all singleton pregnancies were included if their estimated fetal weight and/or abdominal circumference fell below the 10th percentile for gestational age (2017-2022). Eligible cases included singleton pregnancies with concurrent sampling of both umbilical arteries within 14 days of birth at the ultrasound evaluation closest to delivery. The exclusion criteria included births before 22 weeks of gestation, evidence of absent or reverse end-diastolic flow in either umbilical artery, and known fetal genetic or structural anomalies. The study compared cases with discordant umbilical artery pulsatility index values (defined as 1 umbilical artery pulsatility index at ≤95th percentile and the other umbilical artery pulsatility index at >95th percentile for gestational age) to pregnancies where both umbilical artery pulsatility indices had normal pulsatility index values and those with both umbilical arteries displaying abnormal pulsatility index values. The primary outcome assessed was the occurrence of composite adverse neonatal outcomes. Multivariable logistic regressions were performed, adjusting for relevant covariates. RESULTS: The study encompassed 1014 patients, including 194 patients (19.1%) with discordant umbilical artery pulsatility index values among those who had both umbilical arteries sampled close to delivery, 671 patients (66.2%) with both umbilical arteries having normal pulsatility index values, and 149 patients (14.7%) with both umbilical arteries exhibiting abnormal values. Pregnancies with discordant umbilical artery pulsatility index values displayed compromised sonographic parameters compared with those with both umbilical arteries showing normal pulsatility index values. Similarly, the number of abnormal umbilical artery pulsatility index values was associated with adverse perinatal outcomes in a dose-response manner. Cases with 1 abnormal (discordant) umbilical artery pulsatility index value showed favorable sonographic parameters and perinatal outcomes compared with cases with both abnormal umbilical artery pulsatility index values, and cases with both abnormal umbilical artery pulsatility index values showed worse sonographic parameters and perinatal outcomes compared with cases with discordant UA PI values. Multivariate analysis revealed that discordant umbilical artery pulsatility indices were significantly and independently associated with composite adverse perinatal outcomes, with an adjusted odds ratio of 1.75 (95% confidence interval, 1.24-2.47; P = .002). CONCLUSION: Evaluating the resistance indices of both umbilical arteries may provide useful data and assist in assessing adverse perinatal outcomes among fetuses with growth restriction.

Allele mining in gene encoding fc fragment of IgG receptor, transporter, alpha (FCGRT) and association of nucleotide variants with passive transfer of immunity in neonatal buffalo calves.

BACKGROUND: Neonatal Fc receptors (FcRn) mediate the transcytosis of IgG present in colostrum across absorptive gut epithelium of newborn calves. FcRn receptor is a heterodimer composed of two polypeptides encoded by FCGRT (Fc fragment of IgG Receptor Transporter neonatal) and B2M (Beta 2 microglobulin) genes. Polymorphism in FCGRT gene may have a bearing on absorption of colostral immunoglobulins by neonatal buffalo calves, thereby affecting their immune status and susceptibility to diseases. The primary aim of our study was to mine alleles and single nucleotide polymorphs in the FCGRT gene and determine their association with the levels of IgG in serum of neonatal buffalo calves. METHODS AND RESULTS: On the basis of serum IgG levels estimated by indirect ELISA in 80 newborn calves, 20 calves each with highest and lowest IgG concentration were selected to study polymorphism in the FCGRT gene. The exonic regions of this gene were amplified in nine fragments which were subjected to PCR-SSCP to detect variations followed by the sequencing of variants to locate the SNPs. A total of nine SNPs (7 in introns and 2 in exons) were detected in four polymorphic fragments. Association study based on Odds ratios (ORs) with 95% Confidence Interval (CIs) established that the SNP G40T in fragment 3 has a significant (P < 0.05) bearing on IgG level in serum of neonatal buffalo calves. CONCLUSION: Genetic variation in FCGRT gene in buffalo calves was found to be associated with their serum IgG levels in neonatal stage which may have implications in calf survival and growth vis-à-vis inadequate transfer of passive immunity.

Comparison of circulating maternal placenta growth factor levels and sonographic evaluation of patients with abnormal first trimester screening analytes.

OBJECTIVE: To evaluate the role of mid-trimester placental growth factor (PlGF) in patients with abnormal circulating levels of first-trimester biomarkers. METHODS: Retrospective cohort study including singleton pregnancies complicated by abnormal first-trimester biomarkers (2017-2020). Pregnancies complicated with chromosomal/structural anomalies were excluded. All patients had ultrasound imaging including uterine artery Doppler combined with measurement of maternal circulating PlGF. Sonographic findings, maternal and perinatal outcomes, and placental histopathology were compared between pregnancies with normal and low (<10th percentile for gestational age) PlGF levels. The diagnostic accuracy of PlGF for the prediction of specific placental-mediated complications was compared with the uterine artery Doppler assessment and additional sonographic findings. RESULTS: Seventy-one pregnancies were assessed, of which 35 (49.3%) had low PlGF levels. Maternal sociodemographic characteristics, nulliparity, and aspirin consumption were comparable. In comparison with patients with normal PlGF levels, individuals with low PlGF levels had a higher rate of fetal growth restriction (EFW <3rd centile; 42.9% vs. 8.3%, p = 0.001), preterm-preeclampsia (22.9% vs. 0%, p = 0.002), preterm delivery <34 weeks (54.3% vs. 8.3%, p < 0.001) and maternal vascular malperfusion placental pathology (72.7% vs. 21.7%, p < 0.001) following delivery. Adjusting for uterine artery Doppler and fetal biometry status, mid-trimester low PlGF remained significantly associated with these placental-mediated complications. The predictive capacity of PlGF outperformed ultrasound imaging with only minimal diagnostic improvement when ultrasound information was combined with PlGF status. CONCLUSION: In pregnancies with unexplained abnormal first-trimester biomarkers, mid-trimester PlGF outperformed a comprehensive ultrasound assessment in the identification of a subset of patients destined to develop placental dysfunction. This blood test may be an alternative initial approach in this context, especially where access to specialist care is more geographically challenging.

Diagnostic utility of serial circulating placental growth factor levels and uterine artery Doppler waveforms in diagnosing underlying placental diseases in pregnancies at high risk of placental dysfunction.

BACKGROUND: Placental pathology assessment following delivery in pregnancies complicated by preeclampsia, fetal growth restriction, abruption, and stillbirth reveals a range of underlying diseases. The most common pathology is maternal vascular malperfusion, characterized by high-resistance uterine artery Doppler waveforms and abnormal expression of circulating maternal angiogenic growth factors. Rare placental diseases (massive perivillous fibrinoid deposition and chronic histiocytic intervillositis) are reported to have high recurrence risks, but their associations with uterine artery Doppler waveforms and angiogenic growth factors are presently ill-defined. OBJECTIVE: To characterize the patterns of serial placental growth factor measurements and uterine artery Doppler waveform assessments in pregnancies that develop specific types of placental pathology to gain insight into their relationships with the timing of disease onset and pregnancy outcomes. STUDY DESIGN: A retrospective cohort study conducted between January 2017 and November 2021 included all singleton pregnancies with at least 1 measurement of maternal circulating placental growth factor between 16 and 36 weeks' gestation, delivery at our institution, and placental pathology analysis demonstrating diagnostic features of maternal vascular malperfusion, fetal vascular malperfusion, villitis of unknown etiology, chronic histiocytic intervillositis, or massive perivillous fibrinoid deposition. Profiles of circulating placental growth factor as gestational age advanced were compared between these placental pathologies. Maternal and perinatal outcomes were recorded. RESULTS: A total of 337 pregnancies from 329 individuals met our inclusion criteria. These comprised placental pathology diagnoses of maternal vascular malperfusion (n=109), fetal vascular malperfusion (n=87), villitis of unknown etiology (n=96), chronic histiocytic intervillositis (n=16), and massive perivillous fibrinoid deposition (n=29). Among patients who developed maternal vascular malperfusion, placental growth factor levels gradually declined as pregnancy progressed (placental growth factor <10th percentile at 16-20 weeks' gestation in 42.9%; 20-24 weeks in 61.9%; 24-28 weeks in 77%; and 28-32 weeks in 81.4%) accompanied by mean uterine artery Doppler pulsatility index >95th percentile in 71.6% cases. Patients who developed either fetal vascular malperfusion or villitis of unknown etiology mostly exhibited normal circulating placental growth factor values in association with normal uterine artery Doppler waveforms (mean [standard deviation] pulsatility index values: fetal vascular malperfusion, 1.14 [0.49]; villitis of unknown etiology, 1.13 [0.45]). Patients who developed either chronic histiocytic intervillositis or massive perivillous fibrinoid deposition exhibited persistently low placental growth factor levels from the early second trimester (placental growth factor <10th centile at 16-20 weeks' gestation in 80% and 77.8%, respectively; 20-24 weeks in 88.9% and 63.6%; 24-28 weeks in 85.7% and 75%), all in combination with normal uterine artery Doppler waveforms (mean pulsatility index >95th centile: chronic histiocytic intervillositis, 25%; massive perivillous fibrinoid deposition, 37.9%). Preeclampsia developed in 83 of 337 (24.6%) patients and was most common in those developing maternal vascular malperfusion (54/109, 49.5%) followed by chronic histiocytic intervillositis (7/16, 43.8%). There were 29 stillbirths in the cohort (maternal vascular malperfusion, n=10 [9.2%]; fetal vascular malperfusion, n=5 [5.7%]; villitis of unknown etiology, n=1 [1.0%]; chronic histiocytic intervillositis, n=7 [43.8%]; massive perivillous fibrinoid deposition, n=6 [20.7%]). Most patients experiencing stillbirth exhibited normal uterine artery Doppler waveforms (21/29, 72.4%) and had nonmaternal vascular malperfusion pathologies (19/29, 65.5%). By contrast, 28 of 29 (96.5%) patients experiencing stillbirth had ≥1 low placental growth factor values before fetal death. CONCLUSION: Serial circulating maternal placental growth factor tests, in combination with uterine artery Doppler waveform assessments in the second trimester, may indicate the likely underlying type of placental pathology mediating severe adverse perinatal events. This approach has the potential to test disease-specific therapeutic strategies to improve clinical outcomes. Serial placental growth factor testing, compared with uterine artery Doppler studies, identifies a greater proportion of patients destined to have a poor perinatal outcome because diseases other than maternal vascular malperfusion are characterized by normal uteroplacental circulation.

Circulating maternal placental growth factor responses to low-molecular-weight heparin in pregnant patients at risk of placental dysfunction.

BACKGROUND: Patients at high risk of severe preeclampsia and fetal growth restriction have low circulating levels of placental growth factor and features of maternal vascular malperfusion placental pathology at delivery. Multimodal screening and commencement of aspirin prophylaxis at 11 to 13 weeks' gestation markedly reduces the risk of preterm delivery with preeclampsia. However, the additional role of low-molecular-weight heparin and mechanisms of action remain uncertain. Because low-molecular-weight heparin augments the production and release of placental growth factor in vitro by both placental villi and vascular endothelium, it may be effective to suppress the risk of severe preeclampsia in a niche group of high-risk patients with low circulating placental growth factor in the early second trimester. OBJECTIVE: This study aimed to define a gestational age-specific reference range for placental growth factor and to test the hypothesis that prophylactic low-molecular-weight heparin administered in the early second trimester may restore deficient circulating placental growth factor levels and thereby prolong pregnancy. STUDY DESIGN: Centile curves for circulating placental growth factor levels from 12 to 36 weeks' gestation were derived using quantile regression of combined data from a published cohort of 4207 unselected nulliparous patients in Cambridge, United Kingdom, at 4 sampling time points (12, 20, 28, and 36 weeks' gestation) and the White majority (n=531) of a healthy nulliparous cohort in Toronto, Canada, at 16 weeks' gestation using the same test platform. Within a specialty high-risk clinic in Toronto, a niche group of 7 patients with a circulating placental growth factor at the <10th centile in the early second trimester received daily prophylactic low-molecular-weight heparin (enoxaparin; 40 mg subcutaneously) and were followed up until delivery (group 1). Their baseline characteristics, delivery details, and placental pathologies were compared with 5 similar patients who did not receive low-molecular-weight heparin during the observation period (group 2) and further with 21 patients who delivered with severe preeclampsia (group 3) in the same institution. RESULTS: A gestational age-specific reference range for placental growth factor levels at weekly intervals between 12 and 36 weeks was established for White women with singleton pregnancies. Within group 1, 5 of 7 patients demonstrated a sustained increase in circulating placental growth factor levels, whereas placental growth factor levels did not increase in group 2 or group 3 patients who did not receive low-molecular-weight heparin. Group 1 patients receiving low-molecular-weight heparin therapy exhibited a later gestation at delivery, relative to groups 2 and 3 (36 weeks [33-37] vs 23 weeks [22-26] and 28 weeks [27-31], respectively), and consequently had higher birthweights (1.93 kg [1.1-2.7] vs 0.32 kg [0.19-0.39] and 0.73 kg [0.52-1.03], respectively). The incidence of stillbirth was lowest in group 1 (14% [1 of 7]), relative to groups 2 and 3 (80% [4 of 5] and 29% [6 of 21], respectively). Maternal vascular malperfusion was the most common placental pathology found in association with abnormal uterine artery Doppler. CONCLUSION: In patients at high risk of a serious adverse pregnancy outcome owing to placental disease, the addition of low-molecular-weight heparin to aspirin prophylaxis in the early second trimester may restore deficient circulating placental growth factor to mediate an improved perinatal outcome. These data support the implementation of a multicenter pilot randomized control trial where patients are recruited primarily based on the assessment of placental function in the early second trimester.

Detection of nucleotide variants in FCGRT (Fc fragment of IgG, receptor, transporter, alpha) gene and their influence on colostral IgG concentration in Indian water buffalo (Bubalus bubalis).

BACKGROUND: The neonatal Fc receptors (FcRn) mediate the transfer of immunoglobulin G (IgG) molecules from a dam's circulation to the colostrum produced by it immediately after parturition. In ruminants, the calves born are agammaglobulinemic therefore, ingestion of colostrum with high concentration of IgG imparts passive immunity to the newborn. The FcRn molecule is a heterodimer, coded by FCGRT (Fc fragment of IgG Receptor Transporter neonatal) and B2M (Beta 2 microglobulin) genes. Present study attempted to identify single nucleotide polymorphisms (SNPs) in the FCGRT gene in 40 buffaloes of Murrah breed and evaluated the association of these nucleotide variations and haplotypes with IgG concentration in their colostrum. METHODS AND RESULTS: Animals producing colostrum with high IgG and low IgG levels were identified by indirect ELISA and selected. SNPs were detected in the FCGRT gene sequence of selected animals by amplifying it in nine fragments covering all exons (with flanking introns) followed by PCR-single strand conformational polymorphism (PCR-SSCP). A total of nine SNPs were observed of which seven were present in flanking introns and two in exon 4 of the gene. The SNP A75G was non-synonymous and produced an amino acid change from isoleucine to valine. The exonic SNPs and corresponding haplotypes were found to be significantly (P < 0.01 and 0.05 respectively) associated with colostral IgG concentration based on Odds ratios at 95% confidence interval. CONCLUSION: Polymorphism in FCGRT gene is found to be associated with IgG concentration in colostrum and identification of females with desirable variations may prevent failure of passive transfer in neonatal ruminants.

Perinatal outcomes in women living with HIV-1 and receiving antiretroviral therapy-a systematic review and meta-analysis.

INTRODUCTION: Antiretroviral therapy-naïve pregnant women living with HIV are at an increased risk for adverse pregnancy outcomes. It remains controversial whether this risk persists with antiretroviral therapy. We conducted a systematic review and meta-analysis to evaluate whether pregnant women living with HIV and receiving antiretroviral therapy antenatally, are at an increased risk of adverse outcomes compared with HIV-negative controls. MATERIAL AND METHODS: We searched MEDLINE, Embase, International Pharmaceutical Abstracts, EBM Reviews, PubMed (non-MEDLINE records), EBSCO CINAHL Complete, Clarivate Web of Science, African Index Medicus, LILACS and Google Scholar for all observational studies comparing pregnant women living with HIV on antiretroviral therapy with HIV-negative controls from 1 January 1994 to 10 August 2021 with no language or geographic restrictions. Perinatal outcomes included preterm birth (PTB), low birthweight, small-for-gestational age and preeclampsia. Using a random-effects model we pooled raw data to generate odds ratio (OR) with 95% confidence intervals (CI) for each outcome. Sub-analyses for high and low resource countries and time of antiretroviral therapy initiation were performed. This systematic review and meta-analysis is registered with PROSPERO, number CRD42020182722. RESULTS: Of the 7900 citations identified, 27 were eligible for analysis (12 636 pregnant women living with HIV on antiretroviral therapy and 7 812 115 HIV-negative controls). ORs (95% CI) of PTB (1.88 [1.63-2.17]), small-for-gestational age (1.60 [1.18-2.17]) and low birthweight (2.15 [1.58-2.92]) were significantly higher in pregnant women living with HIV than in HIV-negative women, while the risk of preeclampsia (0.86 [0.57-1.30]) was comparable. The risk of PTB and low birthweight was higher in both high resource and low resource countries, while the risk of small-for-gestational age was higher only in the former. Preconceptional antiretroviral therapy was associated with a higher risk of PTB compared with antenatal initiation. CONCLUSIONS: Pregnant women living with HIV on antiretroviral therapy have an increased risk of PTB, low birthweight and small-for-gestational age in high resource countries, as well as PTB and low birthweight in low income countries compared with HIV-negative controls.

Fetal Meconium Peritonitis - Prenatal Findings and Postnatal Outcome: A Case Series, Systematic Review, and Meta-Analysis.

PURPOSE: To describe the postnatal outcome of fetal meconium peritonitis and identify prenatal predictors of neonatal surgery. METHODS: We retrospectively reviewed all fetuses with ultrasound findings suspicious for meconium peritonitis at a single center over a 10-year period. A systematic review and meta-analysis were then performed pooling our results with previous studies assessing prenatally diagnosed meconium peritonitis and postnatal outcome. Prenatal sonographic findings were analyzed to identify predictors for postnatal surgery. RESULTS: 34 cases suggestive of meconium peritonitis were diagnosed at our center. These were pooled with cases from 14 other studies yielding a total of 244 cases. Postnatal abdominal surgery was required in two thirds of case (66.5 %). The strongest predictor of neonatal surgery was meconium pseudocyst (OR [95 % CI] 6.75 [2.53-18.01]), followed by bowel dilation (OR [95 % CI] 4.17 [1.93-9.05]) and ascites (OR [95 % CI] 2.57 [1.07-5.24]). The most common cause of intestinal perforation and meconium peritonitis, found in 52.2 % of the cases, was small bowel atresia. Cystic fibrosis was diagnosed in 9.8 % of cases. Short-term neonatal outcomes were favorable, with a post-operative mortality rate of 8.1 % and a survival rate of 100 % in neonates not requiring surgery. CONCLUSION: Meconium pseudocysts, bowel dilation, and ascites are prenatal predictors of neonatal surgery in cases of meconium peritonitis. Fetuses with these findings should be delivered in centers with pediatric surgery services. Though the prognosis is favorable, cystic fibrosis complicates postnatal outcomes.

Selective fetal reduction in complicated monochorionic twin pregnancies: A comparison of techniques.

OBJECTIVE: To compare perinatal outcomes associated with three methods of selective reduction in complicated monochorionic (MC) twin pregnancies: bipolar cord coagulation (BC), fetoscopic or ultrasound guided laser cord occlusion and radiofrequency ablation (RFA). METHODS: Retrospective cohort study of complicated MC twin pregnancies undergoing selective fetal reduction at a tertiary fetal center over a 20-year period. Obstetric and perinatal outcomes were compared. RESULTS: 105 procedures met inclusion criteria: 74 RFAs, 17 lasers and 14 BCs. Procedure duration was significantly shorter for RFA (27.4 ± 15.8 minutes) compared to BC (91.7 ± 38.7 minutes) and laser (83.4 ± 40.4 minutes), P < .0001). The incidence of preterm prelabor rupture of membranes (PPROM) and co-twin demise did not differ between groups, however preterm delivery <34 weeks occurred less frequently following RFA (29.7%), compared to laser (64.7%) or BC (42.9%) (P = .02); delivery <37 weeks was also less frequent following RFA (45.9%), compared to laser (76.5%) or BC (78.6%)(P = .01). The difference in preterm birth<34 weeks between RFA and laser was maintained after adjusting for cord occlusion indication and amnionicity (OR 3.96, 95% CI 1.27-12.31). CONCLUSIONS: In our experience, RFA procedures were simpler, faster and associated with a lower risk of preterm delivery <34 and <37 weeks, compared to laser or BC.

Stillbirth Following Normal Ultrasound Findings and Maternal Placental Growth Factor Levels.

BACKGROUND: Attempts to reduce the current rate of antepartum stillbirth in the late third trimester have largely focused on the accurate identification of fetal growth restriction. Universal ultrasound significantly increases detection, especially when combined with maternal angiogenic growth factors, but this screening strategy is not well suited to identify umbilical cord pathology. While this poses unique challenges to pregnancy care, the recurrence risk of cord obstruction is low in comparison with many intrinsic placental diseases. CASE: A 30-year-old woman with normal uterine artery Doppler waveforms, fetal growth ultrasounds, and circulating placental growth factor experienced an unexpected third-trimester stillbirth. Placental pathology demonstrated fetal vascular malperfusion and cord hyper-coiling. CONCLUSION: Despite normal placental function, the otherwise healthy fetus is at risk of antepartum stillbirth due to cord-related pathology.

Reducing the Number of Opioids Consumed After Discharge Following Elective Cesarean Delivery: A Randomized Controlled Trial.

OBJECTIVE: To reduce opioids consumed after discharge from hospital after elective cesarean delivery by 50%. METHODS: This was a 2-week parallel group non-blinded randomized controlled trial at Mount Sinai Hospital. Eligible women undergoing elective cesarean delivery were assigned by random number generation to receive the hospital's standard post-cesarean opioid prescription of 20 1-mg hydromorphone tablets or a prescription for 10 1-mg hydromorphone tablets if opioids were required in hospital or no hydromorphone if no opioids were required in hospital. Patients completed a study questionnaire at 2 weeks postpartum detailing outcome measures. The primary outcome was the amount of opioid consumed after discharge. RESULTS: A total of 40 women were randomly assigned to a study group and 37 were included in the data analysis; 17 patients were in the control group and 20 in the experimental group. The median number of tablets consumed did not differ between groups (P = 0.407). The median number of excess tablets prescribed was 20 (range 2-18) in the control group and 0 (range 0-10) in the experimental group (P < 0.001). CONCLUSIONS: The current standard discharge practice of giving 20 1-mg hydromorphone tablets to all patients post-discharge after cesarean delivery contributes to a substantial excess of opioids in the community. These opioids can be diverted for unintended or accidental usage, and exacerbate larger societal issues of opioid misuse and addiction. Decreasing the number of opioids prescribed with tailored discharge prescriptions based on in-hospital opioid use provides nearly all patients with adequate pain control.

Targets (Metabolic Mediators) of Therapeutic Importance in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC), an extremely aggressive invasive cancer, is the fourth most common cause of cancer-related death in the United States. The higher mortality in PDAC is often attributed to the inability to detect it until it has reached advanced stages. The major challenge in tackling PDAC is due to its elusive pathology, minimal effectiveness, and resistance to existing therapeutics. The aggressiveness of PDAC is due to the capacity of tumor cells to alter their metabolism, utilize the diverse available fuel sources to adapt and grow in a hypoxic and harsh environment. Therapeutic resistance is due to the presence of thick stroma with poor angiogenesis, thus making drug delivery to tumor cells difficult. Investigating the metabolic mediators and enzymes involved in metabolic reprogramming may lead to the identification of novel therapeutic targets. The metabolic mediators of glucose, glutamine, lipids, nucleotides, amino acids and mitochondrial metabolism have emerged as novel therapeutic targets. Additionally, the role of autophagy, macropinocytosis, lysosomal transport, recycling, amino acid transport, lipid transport, and the role of reactive oxygen species has also been discussed. The role of various pro-inflammatory cytokines and immune cells in the pathogenesis of PDAC and the metabolites involved in the signaling pathways as therapeutic targets have been previously discussed. This review focuses on the therapeutic potential of metabolic mediators in PDAC along with stemness due to metabolic alterations and their therapeutic importance.

Trial of labor versus elective repeat cesarean delivery in twin pregnancies after a previous cesarean delivery-A systematic review and meta-analysis.

OBJECTIVE: To perform a systematic review of success rates of trial of labor after cesarean (TOLAC) and maternal and neonatal outcomes in twin pregnancy versus elective repeat cesarean delivery (ERCD). METHODS: We searched MEDLINE, EMBASE, and Web of Science from data inception to May 2018 with no language or regional restrictions, to identify all studies that compared twin TOLAC and ERCD for maternal and/or neonatal outcomes. The Newcastle-Ottawa Scale was used to assess the methodological quality of the included studies. We assessed the pooled relative risk and mean difference using a random-effects model. The pooled event rates for successful VBAC, cesarean delivery for twin B after vaginal delivery of twin A, and uterine rupture were determined. RESULTS: Of the 841 citations identified, 10 were eligible for analysis (2336 TOLAC cases and 5763 ERCD cases). The pooled event rates for successful VBAC and uterine rupture during TOLAC were 72.2% (95% CI 59.7%-83.2%) and 0.87% (95% CI 0.51%-1.31%), respectively. TOLAC was associated with a significantly higher risk of neonatal death (RR 3.02 [95% CI 1.07-8.54]) with no significant differences in mean gestational age at birth, NICU admission rates, or 5-minute Apgar <7. Although the risk for maternal infectious morbidity was significantly lower with TOLAC (RR 0.48 [95% CI 0.25-0.90]), risks of uterine dehiscence, blood transfusions, and hysterectomy were comparable. CONCLUSIONS: Twin TOLAC is associated with a relatively high rate of successful vaginal delivery and a low risk of uterine rupture. The finding of higher neonatal mortality rates may be influenced by prematurity, but requires further investigation.

Cellular and molecular targets for the immunotherapy of hepatocellular carcinoma.

Liver cancer is the sixth most common cancer worldwide and 3rd most common cause of cancer-related death. Hepatocellular carcinoma (HCC) represents more than 90% of primary liver cancer and is a major public health problem. Due to the advanced stages of HCC at the time of diagnosis, utilizing the conventional treatment for solid tumors frequently ends with treatment failure, recurrence, or poor survival. HCC is highly refractory to chemotherapy and other systemic treatments, and locoregional therapies or selective internal radiation therapies are largely palliative. Considering how the pathogenesis of HCC often induces an immunosuppressed state which is further amplified by post-treatment recurrence and reactivation, immunostimulation provides a potential novel approach for the treatment of HCC. Immune response(s) of the body may be potentiated by immunomodulation of various effector cells such as B-cells, T-cells, Treg cells, natural killer cells, dendritic cells, cytotoxic T-lymphocytes, and other antigen-presenting cells; cellular components such as genes and microRNA; and molecules such as proteins, proteoglycans, surface receptors, chemokines, and cytokines. Targeting these effectors individually has helped in the development of newer therapeutic approaches; however, combinational therapies targeting multi-faceted biomarkers have yielded better results. Still, there is a need for further research to develop novel therapeutic strategies which may act as either complementary or an alternative treatment to the standard therapy protocols of HCC. This review focuses on potential cellular and molecular targets, as well as the role of virotherapy and combinational therapy in the treatment of HCC.

The miRNA Mirage: How Close Are We to Finding a Non-Invasive Diagnostic Biomarker in Endometriosis? A Systematic Review.

BACKGROUND: Endometriosis is a common disorder of the reproductive age group, characterised by the presence of ectopic endometrial tissue. The disease not only causes enormous suffering to the affected women, but also brings a tremendous medical and economic burden to bear on society. There is a long lag phase between the onset and diagnosis of the disease, mainly due to its non-specific symptoms and the lack of a non-invasive test. Endometriosis can only be diagnosed invasively by laparoscopy. A specific, non-invasive test to diagnose endometriosis is an unmet clinical need. The recent discovery of microRNAs (miRNAs) as modulators of gene expression, and their stability and specificity, make them an attractive candidate biomarker. Various studies on miRNAs in endometriosis have identified their cardinal role in the pathogenesis of the disease, and have proposed them as potential biomarkers in endometriosis. Rationale/Objectives: The aims of this review were to study the role of circulatory miRNAs in endometriosis, and bring to light whether circulatory miRNAs could be potential non-invasive biomarkers to diagnose the disease. SEARCH METHODS: Three databases, PubMed, EMBASE, and BIOSIS were searched, using a combination of Mesh or Emtree headings and free-text terms, to identify literature relating to circulating miRNAs in endometriosis published from 1996 to 31 December 2017. Only peer-reviewed, full-text original research articles in English were included in the current review. The studies meeting the inclusion criteria were critically assessed and checked using the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies) tool. The dysregulated miRNAs were assessed regarding the concordance between the various studies and their role in the disease. OUTCOMES: Nine studies were critically analysed, and 42 different miRNAs were found to be dysregulated in them, with only one common miRNA (miR-20a) differentially expressed in more than one study. miR-17-5p/20a, miR-200, miR-199a, miR-143, and miR-145 were explored for their pivotal role in the aetiopathogenesis of endometriosis. Wider implications: It is emerging that miRNAs play a central role in the pathogenesis of endometriosis and have the potential of being promising biomarkers. Circulating miRNAs as a non-invasive diagnostic tool may shorten the delay in the diagnosis of the disease, thus alleviating the suffering of women and reducing the burden on health care systems. However, despite numerous studies on circulating miRNAs in endometriosis, no single miRNA or any panel of them seems to meet the criteria of a diagnostic biomarker. The disagreement between the various studies upholds the demand of larger, well-controlled systematic validation studies with uniformity in the research approaches and involving diverse populations.

Toxoplasma gondii Toc75 Functions in Import of Stromal but not Peripheral Apicoplast Proteins.

Apicomplexa are unicellular parasites causing important human and animal diseases, including malaria and toxoplasmosis. Most of these pathogens possess a relict but essential plastid, the apicoplast. The apicoplast was acquired by secondary endosymbiosis between a red alga and a flagellated eukaryotic protist. As a result the apicoplast is surrounded by four membranes. This complex structure necessitates a system of transport signals and translocons allowing nuclear encoded proteins to find their way to specific apicoplast sub-compartments. Previous studies identified translocons traversing two of the four apicoplast membranes. Here we provide functional support for the role of an apicomplexan Toc75 homolog in apicoplast protein transport. We identify two apicomplexan genes encoding Toc75 and Sam50, both members of the Omp85 protein family. We localize the respective proteins to the apicoplast and the mitochondrion of Toxoplasma and Plasmodium. We show that the Toxoplasma Toc75 is essential for parasite growth and that its depletion results in a rapid defect in the import of apicoplast stromal proteins while the import of proteins of the outer compartments is affected only as the secondary consequence of organelle loss. These observations along with the homology to Toc75 suggest a potential role in transport through the second innermost membrane.

Relevance of mouse models of cardiac fibrosis and hypertrophy in cardiac research.

Heart disease causing cardiac cell death due to ischemia-reperfusion injury is a major cause of morbidity and mortality in the United States. Coronary heart disease and cardiomyopathies are the major cause for congestive heart failure, and thrombosis of the coronary arteries is the most common cause of myocardial infarction. Cardiac injury is followed by post-injury cardiac remodeling or fibrosis. Cardiac fibrosis is characterized by net accumulation of extracellular matrix proteins in the cardiac interstitium and results in both systolic and diastolic dysfunctions. It has been suggested by both experimental and clinical evidence that fibrotic changes in the heart are reversible. Hence, it is vital to understand the mechanism involved in the initiation, progression, and resolution of cardiac fibrosis to design anti-fibrotic treatment modalities. Animal models are of great importance for cardiovascular research studies. With the developing research field, the choice of selecting an animal model for the proposed research study is crucial for its outcome and translational purpose. Compared to large animal models for cardiac research, the mouse model is preferred by many investigators because of genetic manipulations and easier handling. This critical review is focused to provide insight to young researchers about the various mouse models, advantages and disadvantages, and their use in research pertaining to cardiac fibrosis and hypertrophy.

Complete recovery following hyperbaric oxygen therapy in idiopathic sudden sensorineural hearing loss--a report of two cases.

Idiopathic sudden sensorineural hearing loss (ISSHL), a common otologic emergency, presents mostly as an abrupt onset unilateral hearing loss, aural fullness, often with vertigo and tinnitus, usually upon awakening in the morning. Its etiopathogenesis is multifactorial, so a number of different therapeutic regimens are in practice, hyperbaric oxygen (HBO2) therapy being an effective yet underutilized one. Not all cases recover completely even after treatment. Here we describe two cases of ISSHL, diagnosed on the basis of clinical examination and pure-tone audiometry, who had a complete recovery following administration of HBO2 therapy in addition to medical treatment. These cases are reported to highlight the effectiveness of this modality in a physician's armamentarium.