SMT-738: a novel small-molecule inhibitor of bacterial lipoprotein transport targeting Enterobacteriaceae.

Carbapenem-resistant Enterobacteriaceae (CREs) are described by the Centers for Disease Control as an urgent threat, and there is a critical need for new therapeutic agents able to treat infections caused by these pathogens. Herein, we describe the microbiological profile, the mechanism f action, and the in vitro safety as well as the pharmacokinetic (PK)/PD profile of SMT-738, a small molecule belonging to a new chemical class. SMT-738 is active against Enterobacterales [including multi-drug-resistant Escherichia coli with 90% of isolates having a minimum inhibitory concentration (MIC90) of 1 µg/mL and Klebsiella pneumoniae 2 µg/mL] and inactive against a broad panel of Gram-negative and Gram-positive pathogens. SMT-738 displays rapid bactericidal activity (2-4 h) and has a low propensity for resistance development (less than ~10-9). Characterization of resistant mutants following exposure to SMT-738 identified mutations within the lipoprotein transport complex (LolCDE), a clinically unexploited and essential bacterial molecular target in Gram-negative bacteria. SMT-738 has a promising in vitro toxicology profile. Furthermore, PK studies demonstrated that when dosed intravenously, SMT-738 maintained exposure levels across infection sites (bloodstream/urinary tract/lung). Proof-of-concept studies across multiple murine in vivo infection models (bloodstream/pneumonia/urinary tract) demonstrated that SMT-738 significantly reduced the bacterial burden compared to baseline and vehicle control. SMT-738 represents a promising novel drug candidate being developed to address clinically challenging serious life-threatening infections caused by highly resistant Enterobacteriaceae including CRE.

Inferential properties with a novel two parameter Poisson generalized Lindley distribution with regression and application to INAR(1) process.

Based on the well-known Poisson (P) distribution and the new generalized Lindley distribution (NGLD) developed by using gamma (α,θ) and gamma (α-1,θ) distributions, a new compound two-parameter Poisson generalized Lindley (TPPGL) distribution is proposed in this paper and thereon systematically explores the mathematical properties. Closed form expressions are assembled for such properties including the probability generating function, moments, skewness, kurtosis, etc. The likelihood-based method is used for estimating the parameters followed by a broad Monte Carlo simulation study. To further motivate the proposed model, a count regression model and a first order integer valued autoregressive process are constructed based on the novel TPPGL distribution. The empirical importance of the proposed models is confirmed through application to four real datasets.

Radiology of Castleman disease: the pivotal role of imaging in diagnosis, staging, and response assessment of this rare entity.

Castleman Disease (CD) is a rare entity that typically presents as an enhancing nodal mass in the mediastinum or head and neck region on computed tomography (CT). It may manifest as unicentric or multicentric regions of lymph node enlargement. A key clinical issue in the context of CD is delayed diagnosis, which contributes adversely to patient outcome, given that accurate diagnosis facilitates earlier treatment of this curable disease. This article will address relevant imaging aspects, with reference to typical and atypical imaging features of CD, illustrated using examples from our specialist centre; the imaging journey for patients with CD; and will provide practical pointers to radiologists in differentiating CD from other benign and malignant causes of enhancing lymphadenopathy, including lymphoma and neoplastic adenopathy. We will also review current classification tools and staging challenges with reference to World Health Organization guidelines, International Working Group guidelines as well as the Lugano classification. Finally, we will discuss the potential role of additional imaging techniques in CD, highlighting novel imaging methods and expanded utilities from our specialist centre.

A randomised controlled trial of a novel tramadol chewable tablet: pharmacokinetics and tolerability in children.

Tramadol is a bitter atypical opioid analgesic drug and is prescribed to treat postoperative pain in children. However, in many countries there is no licensed paediatric tramadol formulation available. We have formulated a novel chewable chocolate-based drug delivery system for the administration of tramadol to children. This pilot, single-centre, open-label, randomised clinical study assessed the taste tolerability and comparative population pharmacokinetics of the novel tramadol chewable tablet against a compounded tramadol hydrochloride oral liquid, at a dose of 1 mg.kg-1 . A 5-point facial hedonic scale was used by the children, parents and nurses to assess tolerability. One hundred and forty-one children aged 3-16 years were given tramadol 30 min before general anaesthesia. Blood samples were taken following the induction of anaesthesia and for up to 5 h following tramadol administration. Tramadol and its active metabolite O-desmethyltramadol were analysed using reversed-phase high-performance liquid chromatography. A population pharmacokinetic model was built using non-linear mixed effects modelling. The relative bioavailability for the tablet was 1.25 times higher (95%CI 1.16-1.35) than for tramadol hydrochloride oral liquid, while the absorption rate constant for the tablet was significantly lower (1.97 h-1 vs. 3.34 h-1 , p < 0.001). Larger inter-individual variability in absorption rates were observed with the liquid tramadol. The tramadol chewable tablet was more acceptable in taste to children when assessed by the children, parents and nurses (all p < 0.001). We conclude that the novel tramadol chewable tablet has favourable acceptability and more reliable relative bioavailability in children compared with tramadol hydrochloride oral liquid.

Gut microbiota of animals living in polluted environments are a potential resource of anticancer molecules.

Cancer is a prominent cause of morbidity and mortality worldwide, in spite of advances in therapeutic interventions and supportive care. In 2018 alone, there were 18·1 million new cancer cases and 9·6 million deaths indicating the need for novel anticancer agents. Plant-based products have often been linked with protective effects against communicable and non-communicable diseases. Recently, we have shown that animals such as crocodiles thrive in polluted environments and are often exposed to carcinogenic agents, but still benefit from prolonged lifespan. The protective mechanisms shielding them from cancer could be attributed to the immune system, and/or it is possible that their gut microbiota produce anticancer molecules. In support, several lines of evidence suggest that gut microbiota plays a critical role in the physiology of its host. Here, we reviewed the available literature to assess whether the gut microbiota of animals thriving in polluted environment possess anticancer molecules.

Gut microbiome and human health under the space environment.

The gut microbiome is well recognized to have a pivotal role in regulation of the health and behaviour of the host, affecting digestion, metabolism, immunity, and has been linked to changes in bones, muscles and the brain, to name a few. However, the impact of microgravity environment on gut bacteria is not well understood. In space environments, astronauts face several health issues including stress, high iron diet, radiation and being in a closed system during extended space missions. Herein, we discuss the role of gut bacteria in the space environment, in relation to factors such as microgravity, radiation and diet. Gut bacteria may exact their effects by synthesis of molecules, their absorption, and through physiological effects on the host. Moreover we deliberate the role of these challenges in the dysbiosis of the human microbiota and possible dysregulation of the immune system.

Current and future best practice in imaging, staging, and response assessment for Non-Hodgkin's lymphomas: the Specialist Integrated Haematological Malignancy Imaging Reporting (SIHMIR) paradigm shift.

Non-Hodgkin's lymphoma (NHL) encompasses over 40 different haematological malignancies, including low and high-grade neoplasms, such as follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) respectively. A key clinical issue in the context of NHL is delayed and inaccurate diagnosis, which contributes adversely to patient morbidity and mortality. This article will address relevant imaging aspects, with particular reference to advancements in NHL imaging, including computed tomography (CT), integrated positron-emission tomography (PET)-CT, and magnetic resonance imaging (MRI). We provide multiparametric (anato-functional) imaging display items, including histological correlation. We will also introduce our original concept of "Specialist Integrated Haematological Malignancy Imaging Reporting" (SIHMIR), a paradigm shift in lymphoma radiology.

Examining the role of mother-child interactions and DNA methylation of the oxytocin receptor gene in understanding child controlling attachment behaviors.

This study examined mother-child interactions and DNA methylation of the oxytocin receptor (OXTR) gene in the child, in relation with controlling-attachment behaviors at early preschool age. Maternal interactive behaviors were coded using the Emotional Availability Scales, and child attachment behaviors were assessed with the Separation-Reunion procedure and coded with the Preschool Attachment Rating Scales. DNA methylation data were captured from exon 3 of the OXTR. Results indicated that lower maternal sensitivity was associated with more controlling-caregiving behaviors, and that less maternal structuring was associated with more controlling-punitive behaviors. Hypomethylation of the OXTR gene was associated with greater maternal structuring behaviors, and with more child controlling-caregiving behaviors. The moderating role of the OXTR gene was examined in the association between interactive behaviors and child controlling behaviors, but no interaction effect was found. These results suggest that maternal interactive behaviors and OXTR methylation are independently associated with child controlling attachment.

Patient and Public Involvement (PPI) in evidence synthesis: how the PatMed study approached embedding audience responses into the expression of a meta-ethnography.

BACKGROUND: Patient and public involvement (PPI) has become enshrined as an important pillar of health services empirical research, including PPI roles during stages of research development and analysis and co-design approaches. Whilst user participation has been central to qualitative evidence synthesis (QES) for decades, as seen in the Cochrane consumer network and guidelines, meta-ethnography has been slow to incorporate user participation and published examples of this occurring within meta-ethnography are sparse. In this paper, drawing upon our own experience of conducting a meta-ethnography, we focus on what it means in practice to 'express a synthesis' (stage 7). We suggest the methodological importance of 'expression' in Noblit and Hare's seven stage process (Noblit, GW and Hare, RD. Meta-ethnography: synthesizing qualitative studies, 1988) has been overlooked, and in particular, opportunities for PPI user participation within it. METHODS: Meta-ethnography comprises a seven-stage process of evidence synthesis. Noblit and Hare describe the final 7th stage of the meta-ethnography process as 'expression of synthesis', emphasizing co-construction of findings with the audience. In a previous study we conducted a meta-ethnography exploring patient and student experience of medical education within primary care contexts. We subsequently presented and discussed initial meta-ethnography findings with PPI (students and patients) in focus groups and interviews. We transcribed patient and student PPI interpretations of synthesis findings. As a research team, we then translated these into our existing meta-ethnography findings. RESULTS: We describe, with examples, the process of involving PPI in stage 7 of meta-ethnography and discuss three methodological implications of incorporating PPI within an interpretative approach to QES: (1) we reflect on the construct hierarchy of user participants' interpretations and consider whether incorporating these additional 1st order, 2nd level constructs implies an additional logic of 3rd order 2nd level constructs of the QES team; (2) we discuss the link between PPI user participation and what Noblit and Hare may have meant by ideas of 'expression' and 'audience' as integral to stage 7; and (3) we link PPI user participation to Noblit and Hare's underlying theory of social explanation, i.e. how expression of the synthesis is underpinned by ideas of translation and that the synthesis must be 'translated in the audience's (user participants) particular language'. CONCLUSIONS: The paper aims to complement recent attempts in the literature to refine and improve guidance on conducting a meta-ethnography, highlighting opportunities for PPI user participation in the processes of interpretation, translation and expression. We discuss the implications of user participation in meta-ethnography on ideas of 'generalisability'.

Impact of new definitions of pre-eclampsia on incidence and performance of first-trimester screening.

OBJECTIVE: The traditional definition of pre-eclampsia (PE) is based on the development of hypertension and proteinuria. This has been revised recently to include cases without proteinuria but with evidence of renal, hepatic or hematological dysfunction. The aim of this study was to examine the impact of new definitions of PE on, first, the incidence and severity of the disease and, second, the performance of the competing-risks model for first-trimester assessment of risk for PE. METHODS: This was a retrospective study of 66 964 singleton pregnancies that were classified as having PE, gestational hypertension (GH) or no PE or GH, according to the traditional criteria of the International Society for the Study of Hypertension in Pregnancy (ISSHP-old), which defines PE as the presence of both hypertension and proteinuria. We reviewed the records of pregnancies with GH, and those cases with high creatinine or liver enzymes or low platelet count were reclassified as having PE, according to the new criteria of ISSHP (ISSHP-new) and the new criteria of the American College of Obstetricians and Gynecologists (ACOG). The groups of PE according to the traditional and new criteria were compared for, first, gestational age at delivery, birth-weight percentile and incidence of a small-for-gestational-age (SGA) neonate with birth weight < 10th percentile and perinatal death, and, second, the predictive performance for preterm PE of the competing-risks model based on the combination of maternal risk factors, uterine artery pulsatility index, mean arterial pressure and serum placental growth factor at 11-13 weeks' gestation (triple test). RESULTS: According to ISSHP-old, 1870 (2.8%) cases had PE, 2182 (3.3%) had GH and 62 912 (94.0%) had no PE or GH. The incidence of PE according to ACOG was 3.0% (2029/66 964) and ISSHP-new was 3.4% (2301/66 964). Median gestational age at delivery in the extra cases of PE according to ACOG (difference, 1.3 weeks; 95% CI, 0.71-1.71 weeks) and in the extra cases of PE according to ISSHP-new (difference, 1.5 weeks; 95% CI, 1.29-1.71 weeks) was higher than in cases with PE according to ISSHP-old (38.4 weeks). The incidence of a SGA neonate in the extra cases of PE according to ACOG (relative risk, 0.57; 95% CI, 0.42-0.79) and in the extra cases of PE according to ISSHP-new (relative risk, 0.52; 95% CI, 0.42-0.65) was lower than in the cases of PE according to ISSHP-old (33.64%). In first-trimester screening for preterm PE by the triple test, the detection rate, at a 10% false-positive rate, was 75.9% (95% CI, 70.8-80.6%) for ISSHP-old, 74.3% (95% CI, 69.2-79.0%) for ACOG and 74.0% (95% CI, 68.9-78.6%) for ISSHP-new. CONCLUSIONS: The new definitions of PE resulted in, first, an increase in pregnancies classified as having PE but the additional cases had milder disease, and, second, a non-significant decrease in the performance of first-trimester screening for PE. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Pituitary metastases: presentation and outcomes from a pituitary center over the last decade.

PURPOSE: Highlight and characterize manifestations, diagnostic/management approaches and outcomes in a contemporary cohort of patients with pituitary metastases (PM) from a large European pituitary center-over 10 years. METHODS: Retrospective review of PM cases between 1/2009 and 12/2018. Clinical, laboratory, imaging data at PM detection and during follow-up were analysed. RESULTS: 18 cases were identified (14 females; median age at diagnosis 61.5 years). Most common primary malignancies were lung (39%) and breast (32%). Most frequent presenting manifestation was visual dysfunction (50%). Gonadotrophin, ACTH, TSH deficiency were diagnosed in 85%, 67%, 46% of cases, respectively; diabetes insipidus (DI) was present in 17%. 33% of cases were detected during investigation for symptoms unrelated to PM. PM management included radiotherapy (44%), transsphenoidal surgery (17%), transsphenoidal surgery and radiotherapy (6%) or monitoring only (33%). One-year survival was 49% with median survival from PM detection 11 months (range 2-47). CONCLUSIONS: In our contemporary series, clinical presentation of PM has evolved; we found increased prevalence of anterior hypopituitarism, decreased rates of DI and longer survival compared with older literature. Increased availability of diagnostic imaging, improvements in screening and recognition of pituitary disease and longer survival of patients with metastatic cancer may be contributing factors.

[Possibilities of application of modern training methods (project activities) in training health care organizers on the example of a military medical educational organization].

The efficiency of health care and the quality of medical care can be improved by implementing modern management methods and technologies. It requires modern and high-quality training of medical management personnel. Qualified personnel are the key factor in the organization and transformation of the health system. Human resources ultimately ensure the efficiency and effectiveness of the entire health sector. Requirements to economic management methods are changing and increasing, and specialists with skills in managing medical organizations at different levels of the healthcare system are becoming in demand. At the level of the constituent entities of the Russian Federation, the role of medical personnel who possess strategic methods of healthcare management is increasing. Available training programs in leading higher educational institutions of medical profile do not fully fulfill these tasks due to limited time, a large volume of lecture material, and frequent changes in the conditions and tasks of health care. These problems can be solved by optimizing training programs for retraining and advanced training of health care organizers, introducing active training methods such as business games, case methods, and project activities into the curriculum. The paper describes the system of training students for training courses in the field of healthcare and public health through planning and implementation, project management in the context of military educational organizations of the Ministry of Defense of the Russian Federation, the statistical analysis of the training effectiveness, the factors that influence the success of development programs.

Routine ultrasound at 32 vs 36 weeks' gestation: prediction of small-for-gestational-age neonates.

OBJECTIVE: To evaluate and compare the performance of routine ultrasonographic estimated fetal weight (EFW) and fetal abdominal circumference (AC) at 31 + 0 to 33 + 6 and 35 + 0 to 36 + 6 weeks' gestation in the prediction of a small-for-gestational-age (SGA) neonate. METHODS: This was a prospective study of 21 989 singleton pregnancies undergoing routine ultrasound examination at 31 + 0 to 33 + 6 weeks' gestation and 45 847 undergoing routine ultrasound examination at 35 + 0 to 36 + 6 weeks' gestation. In each case, the estimated fetal weight (EFW) from measurements of fetal head circumference, AC and femur length was calculated using the Hadlock formula and expressed as a percentile according to The Fetal Medicine Foundation fetal and neonatal population weight charts. The same charts were used for defining a SGA neonate with birth weight < 10th and < 3rd percentiles. For each gestational-age window, the screen-positive and detection rates, at different EFW percentile cut-offs between the 10th and 50th percentiles, were calculated for prediction of delivery of a SGA neonate with birth weight < 10th and < 3rd percentiles within 2 weeks and at any stage after assessment. The areas under the receiver-operating characteristics curves (AUC) in screening for a SGA neonate by EFW and AC at 31 + 0 to 33 + 6 and at 35 + 0 to 36 + 6 weeks' gestation were compared. RESULTS: First, the AUCs in screening by EFW for a SGA neonate with birth weight < 10th and < 3rd percentiles delivered within 2 weeks and at any stage after screening at 35 + 0 to 36 + 6 weeks' gestation were significantly higher than those at 31 + 0 to 33 + 6 weeks (P < 0.001). Second, at both 35 + 0 to 36 + 6 and 31 + 0 to 33 + 6 weeks' gestation, the predictive performance for a SGA neonate with birth weight < 10th and < 3rd percentiles born at any stage after screening was significantly higher using EFW Z-score than AC Z-score. Similarly, at 35 + 0 to 36 + 6 weeks, but not at 31 + 0 to 33 + 6 weeks, the predictive performance for a SGA neonate with birth weight < 10th and < 3rd percentiles born within 2 weeks after screening was significantly higher using EFW Z-score than AC Z-score. Third, screening by EFW < 10th percentile at 35 + 0 to 36 + 6 weeks' gestation predicted 70% and 84% of neonates with birth weight < 10th and < 3rd percentiles, respectively, born within 2 weeks after assessment, and the respective values for a neonate born at any stage after assessment were 46% and 65%. Fourth, prediction of > 85% of SGA neonates with birth weight < 10th percentile born at any stage after screening at 35 + 0 to 36 + 6 weeks' gestation requires use of EFW < 40th percentile. Screening at this percentile cut-off predicted 95% and 99% of neonates with birth weight < 10th and < 3rd percentiles, respectively, born within 2 weeks after assessment, and the respective values for a neonate born at any stage after assessment were 87% and 94%. CONCLUSIONS: The predictive performance for a SGA neonate of routine ultrasonographic examination during the third trimester is higher if, first, the scan is carried out at 35 + 0 to 36 + 6 weeks' gestation than at 31 + 0 to 33 + 6 weeks, second, the method of screening is EFW than fetal AC, third, the outcome measure is birth weight < 3rd than < 10th percentile, and, fourth, if delivery occurs within 2 weeks than at any stage after assessment. Prediction of a SGA neonate by EFW < 10th percentile is modest and prediction of > 85% of cases at 35 + 0 to 36 + 6 weeks' gestation necessitates use of EFW < 40th percentile. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Prediction of large-for-gestational-age neonate by routine third-trimester ultrasound.

OBJECTIVES: First, to evaluate and compare the performance of routine ultrasonographic estimated fetal weight (EFW) and fetal abdominal circumference (AC) at 31 + 0 to 33 + 6 and 35 + 0 to 36 + 6 weeks' gestation in the prediction of a large-for-gestational-age (LGA) neonate born at ≥ 37 weeks' gestation. Second, to assess the additive value of fetal growth velocity between 32 and 36 weeks' gestation to the performance of EFW at 35 + 0 to 36 + 6 weeks' gestation for prediction of a LGA neonate. Third, to define the predictive performance for a LGA neonate of different EFW cut-offs on routine ultrasound examination at 35 + 0 to 36 + 6 weeks' gestation. Fourth, to propose a two-stage strategy for identifying pregnancies with a LGA fetus that may benefit from iatrogenic delivery during the 38th gestational week. METHODS: This was a retrospective study. First, data from 21 989 singleton pregnancies that had undergone routine ultrasound examination at 31 + 0 to 33 + 6 weeks' gestation and 45 847 that had undergone routine ultrasound examination at 35 + 0 to 36 + 6 weeks were used to compare the predictive performance of EFW and AC for a LGA neonate with birth weight > 90th and > 97th percentiles born at ≥ 37 weeks' gestation. Second, data from 14 497 singleton pregnancies that had undergone routine ultrasound examination at 35 + 0 to 36 + 6 weeks' gestation and had a previous scan at 30 + 0 to 34 + 6 weeks were used to determine, through multivariable logistic regression analysis, whether addition of growth velocity, defined as the difference in EFW Z-score or AC Z-score between the early and late third-trimester scans divided by the time interval between the scans, improved the performance of EFW at 35 + 0 to 36 + 6 weeks in the prediction of delivery of a LGA neonate at ≥ 37 weeks' gestation. Third, in the database of the 45 847 pregnancies that had undergone routine ultrasound examination at 35 + 0 to 36 + 6 weeks' gestation, the screen-positive and detection rates for a LGA neonate born at ≥ 37 weeks' gestation and ≤ 10 days after the initial scan were calculated for different EFW percentile cut-offs between the 50th and 90th percentiles. RESULTS: First, the areas under the receiver-operating characteristics curves (AUC) of screening for a LGA neonate were significantly higher using EFW Z-score than AC Z-score and at 35 + 0 to 36 + 6 than at 31 + 0 to 33 + 6 weeks' gestation (P < 0.001 for all). Second, the performance of screening for a LGA neonate achieved by EFW Z-score at 35 + 0 to 36 + 6 weeks was not significantly improved by addition of EFW growth velocity or AC growth velocity. Third, in screening by EFW > 90th percentile at 35 + 0 to 36 + 6 weeks' gestation, the predictive performance for a LGA neonate born at ≥ 37 weeks' gestation was modest (65% and 46% for neonates with birth weight > 97th and > 90th percentiles, respectively, at a screen-positive rate of 10%), but the performance was better for prediction of a LGA neonate born ≤ 10 days after the scan (84% and 71% for neonates with birth weight > 97th and > 90th percentiles, respectively, at a screen-positive rate of 11%). Fourth, screening by EFW > 70th percentile at 35 + 0 to 36 + 6 weeks' gestation predicted 91% and 82% of LGA neonates with birth weight > 97th and > 90th percentiles, respectively, born at ≥ 37 weeks' gestation, at a screen-positive rate of 32%, and the respective values of screening by EFW > 85th percentile for prediction of a LGA neonate born ≤ 10 days after the scan were 88%, 81% and 15%. On the basis of these results, it was proposed that routine fetal biometry at 36 weeks' gestation is a screening rather than diagnostic test for fetal macrosomia and that EFW > 70th percentile should be used to identify pregnancies in need of another scan at 38 weeks, at which those with EFW > 85th percentile should be considered for iatrogenic delivery during the 38th week. CONCLUSIONS: First, the predictive performance for a LGA neonate by routine ultrasonographic examination during the third trimester is higher if the scan is carried out at 36 than at 32 weeks, the method of screening is EFW than fetal AC, the outcome measure is birth weight > 97th than > 90th percentile and if delivery occurs within 10 days than at any stage after assessment. Second, prediction of a LGA neonate by EFW > 90th percentile is modest and this study presents a two-stage strategy for maximizing the prenatal prediction of a LGA neonate. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Maternal and neonatal complications of fetal macrosomia: cohort study.

OBJECTIVE: To estimate the risks of maternal and neonatal complications in pregnancies with macrosomia. METHODS: This was a retrospective cohort study conducted at a large maternity unit in the UK between January 2009 and December 2016. The incidence of maternal and neonatal complications in pregnancies with macrosomia, defined as birth weight (BW) > 4000 g, and in those with severe macrosomia, defined as BW > 4500 g, was compared with that in pregnancies with normal BW (2500-4000 g). Regression analysis was performed to determine odds ratios (ORs) for complications in macrosomic pregnancies compared to those with normal BW. RESULTS: The study population of 35 548 pregnancies included 4522 (12.7%) with macrosomia, of which 643 (1.8%) had severe macrosomia, and 31 026 (87.3%) with normal BW. In the macrosomia group, the adjusted OR was 3.1 (95% CI, 2.6-3.6) for Cesarean section for failure to progress, 2.4 (95% CI, 2.0-3.0) for severe postpartum hemorrhage, 2.3 (95% CI, 1.9-2.8) for obstetric anal sphincter injury, 10.4 (95% CI, 8.6-12.6) for shoulder dystocia, 28.5 (95% CI, 8.9-90.7) for obstetric brachial plexus injury, 32.3 (95% CI, 3.8-278.2) for birth fractures and 4.4 (95% CI, 2.2-8.8) for hypoxic-ischemic encephalopathy. The respective values in pregnancies with severe macrosomia were 4.3 (95% CI, 3.1-6.1), 2.9 (95% CI, 1.9-4.4), 3.1 (95% CI, 1.9-5.1), 28.7 (95% CI, 20.8-39.8), 73.9 (95% CI, 15.1-363.2), 87.2 (95% CI, 7.7-985.0) and 13.8 (95% CI, 5.2-36.8). CONCLUSION: Macrosomia is associated with serious adverse perinatal outcomes. This study provides accurate estimates of risks to aid in pregnancy management. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Complicaciones maternas y neonatales de la macrosomía fetal: estudio de cohorte OBJETIVO: Estimar los riesgos de complicaciones maternas y neonatales en embarazos con macrosomía. METHODS: Este fue un estudio de cohorte retrospectivo realizado en una unidad de maternidad de gran tamaño en el Reino Unido entre enero de 2009 y diciembre de 2016. La incidencia de complicaciones maternas y neonatales en los embarazos con macrosomía, definida como peso al nacer (PN) >4000 g, y en los embarazos con macrosomía grave, definida como PN >4500 g, se comparó con la de los embarazos con PN normal (2500-4000 g). Se realizó un análisis de regresión para determinar las razones de momios (RM) para las complicaciones en los embarazos macrosómicos en comparación con los que tenían un PN normal. RESULTADOS: La población estudiada de 35 548 embarazos incluyó 4522 (12,7%) casos con macrosomía, 643 (1,8%) con macrosomía grave y 31 026 (87,3%) con PN normal. En el grupo de macrosomía, la RM ajustada fue de 3,1 (IC 95%: 2,6-3,6) para la cesárea por no progresar, 2,4 (IC 95%: 2,0-3,0) para hemorragia posparto grave, 2,3 (IC 95%: 1,9-2,8) para la lesión obstétrica del esfínter anal, 10.4 (IC 95%, 8.6-12.6) para la distocia de hombro, 28.5 (IC 95%, 8.9-90.7) para la lesión obstétrica del plexo braquial, 32.3 (IC 95%, 3.8-278.2) para las fracturas de nacimiento y 4.4 (IC 95%, 2.2-8.8) para la encefalopatía hipóxica-isquémica. Los valores respectivos en los embarazos con macrosomía grave fueron 4,3 (IC 95%: 3,1-6,1), 2,9 (IC 95%: 1,9-4,4), 3,1 (IC 95%: 1,9-5,1), 28,7 (IC 95%: 20,8-39,8), 73,9 (IC 95%: 15,1-363,2), 87,2 (IC 95%: 7,7-985,0) y 13,8 (IC 95%: 5,2-36,8). CONCLUSIÓN: La macrosomía se asocia con resultados perinatales adversos graves. Este estudio proporciona estimaciones precisas de los riesgos para ayudar en el cuidado del embarazo.

Maternal and neonatal complications of fetal macrosomia: systematic review and meta-analysis.

OBJECTIVE: To determine accurate estimates of risks of maternal and neonatal complications in pregnancies with fetal macrosomia by performing a systematic review of the literature and meta-analysis. METHODS: A search of MEDLINE, EMBASE, CINAHL and The Cochrane Library was performed to identify relevant studies reporting on maternal and/or neonatal complications in pregnancies with macrosomia having a birth weight (BW) > 4000 g and/or those with birth weight > 4500 g. Prospective and retrospective cohort and population-based studies that provided data regarding both cases and controls were included. Maternal outcomes assessed were emergency Cesarean section (CS), postpartum hemorrhage (PPH) and obstetric anal sphincter injury (OASIS). Neonatal outcomes assessed were shoulder dystocia, obstetric brachial plexus injury (OBPI) and birth fractures. Meta-analysis using a random-effects model was used to estimate weighted pooled estimates of summary statistics (odds ratio (OR) and 95% CI) for each complication, according to birth weight. Heterogeneity between studies was estimated using Cochran's Q, I2 statistic and funnel plots. RESULTS: Seventeen studies reporting data on maternal and/or neonatal complications in pregnancy with macrosomia were included. In pregnancies with macrosomia having a BW > 4000 g, there was an increased risk of the maternal complications: emergency CS, PPH and OASIS, which had OR (95% CI) of 1.98 (1.80-2.18), 2.05 (1.90-2.22) and 1.91 (1.56-2.33), respectively. The corresponding values for pregnancies with BW > 4500 g were: 2.55 (2.33-2.78), 3.15 (2.14-4.63) and 2.56 (1.97-3.32). Similarly, in pregnancies with a BW > 4000 g, there was an increased risk of the neonatal complications: shoulder dystocia, OBPI and birth fractures, which had OR (95% CI) of 9.54 (6.76-13.46), 11.03 (7.06-17.23) and 6.43 (3.67-11.28), respectively. The corresponding values for pregnancies with a BW > 4500 g were: 15.64 (11.31-21.64), 19.87 (12.19-32.40) and 8.16 (2.75-24.23). CONCLUSION: Macrosomia is associated with serious maternal and neonatal adverse outcomes. This study provides accurate estimates of these risks, which can be used for decisions on pregnancy management. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Complicaciones maternas y neonatales de la macrosomía fetal: revisión sistemática y metaanálisis OBJETIVO: Determinar estimaciones precisas de los riesgos de complicaciones maternas y neonatales en embarazos con macrosomía fetal mediante la realización de una revisión sistemática de la literatura y un metaanálisis. MÉTODOS: Se realizó una búsqueda en MEDLINE, EMBASE, CINAHL y The Cochrane Library para identificar estudios relevantes que informaron sobre complicaciones maternas y/o neonatales en embarazos con macrosomía con un peso al nacer (PN) >4000 g y/o aquellos con un peso al nacer >4500 g. Se incluyeron estudios de cohortes prospectivos y retrospectivos y estudios basados en la población que proporcionaron datos con respecto a los casos y controles. Las medidas maternas de resultados evaluadas fueron la cesárea de urgencia (CU), la hemorragia posparto (HPP) y la lesión obstétrica del esfínter anal (LOEA). Los resultados neonatales evaluados fueron distocia de hombro, lesión obstétrica del plexo braquial (LOPB) y fracturas de nacimiento. Se utilizó un metaanálisis con un modelo de efectos aleatorios para estimar las estimaciones agrupadas ponderadas de los estadísticos resumen (razones de momios [RM] y IC del 95%) para cada complicación, según el peso al nacer. La heterogeneidad entre estudios se estimó mediante la prueba estadística Q de Cochran, la prueba estadística I2 y gráficos de embudo. RESULTADOS: Se incluyeron 17 estudios que reportaron datos sobre las complicaciones maternas y/o neonatales en embarazos con macrosomía. En aquellos con un PN >4000 g, hubo un mayor riesgo de complicaciones maternas: CU, HPP y LOEA de urgencia, que tuvieron una RM (IC 95%) de 1,98 (1,80-2,18), 2,05 (1,90-2,22) y 1,91 (1,56-2,33), respectivamente. Los valores correspondientes para los embarazos con PN >4500 g fueron: 2,55 (2,33-2,78), 3,15 (2,14-4,63) y 2,56 (1,97-3,32). De manera similar, en los embarazos con un PN >4000 g, hubo un mayor riesgo de complicaciones neonatales: distocia de hombro, LOEA y fracturas de nacimiento, que tuvieron una RM (IC 95%) de 9,54 (6,76-13,46), 11,03 (7,06-17,23) y 6,43 (3,67-11,28), respectivamente. Los valores correspondientes para los embarazos con un PN >4500 g fueron: 15,64 (11,31-21,64), 19,87 (12,19-32,40) y 8,16 (2,75-24,23). CONCLUSIÓN: La macrosomía se asocia con resultados adversos maternos y neonatales graves. Este estudio proporciona estimaciones precisas de estos riesgos, que pueden utilizarse para tomar decisiones sobre el cuidado del embarazo.

Effects of cross-fostering and developmental exposure to mixtures of environmental contaminants on hepatic gene expression in prepubertal 21 days old and adult male Sprague-Dawley rats.

The notion that adverse health effects produced by exposure to environmental contaminants (EC) may be modulated by the presence of non-chemical stressors is gaining attention. Previously, our lab demonstrated that cross-fostering (adoption of a litter at birth) acted as a non-chemical stressor that amplified the influence of developmental exposure to EC on the glucocorticoid stress-response in adult rats. Using liver from the same rats, the aim of the current study was to investigate whether cross-fostering might also modulate EC-induced alterations in hepatic gene expression profiles. During pregnancy and nursing, Sprague-Dawley dams were fed cookies laced with corn oil (control, C) or a chemical mixture (M) composed of polychlorinated biphenyls (PCB), organochlorine pesticides (OCP), and methylmercury (MeHg), at 1 mg/kg/day. This mixture simulated the contaminant profile reported in maternal human blood. At birth, some control and M treated litters were cross-fostered to form two additional groups with different biological/nursing mothers (CC and MM). The hepatic transcriptome was analyzed by DNA microarray in male offspring at postnatal days 21 and 78-86. Mixture exposure altered the expression of detoxification and energy metabolism genes in both age groups, but with different sets of genes affected at day 21 and 78-86. Cross-fostering modulated the effects of M on gene expression pattern (MM vs M), as well as expression of energy metabolism genes between control groups (CC vs C). In conclusion, while describing short and long-term effects of developmental exposure to EC on hepatic transcriptomes, these cross-fostering results further support the consideration of non-chemical stressors in EC risk assessments.

Stakeholder perspectives on public-private partnership in health service delivery in Sindh province of Pakistan: a qualitative study.

OBJECTIVE: The objective of this study was to explore the perspectives of stakeholders on public-private partnership (PPP) in healthcare service delivery in Sindh province of Pakistan including the reasons for adopting such policies and the barriers for its implementation. STUDY DESIGN: This was a qualitative primary study. METHODS: Semistructured in-depth interviews were conducted with 13 stakeholders, including officials from provincial government and district administration (legislators, district managers, deputy commissioners and assistant commissioners) and representatives from private sector organisations with direct or indirect role in implementation of PPP policy, selected using purposive sampling methods. Data were analysed using a thematic approach. RESULTS: Participants had very limited in-depth understanding about the concept of PPP. They considered multifaceted corruption in the health system and the success of existing PPP initiatives as the main reasons for the PPP policy adoption. Resistance from healthcare staff was perceived as the main barrier for implementation of PPP. There was a common perception that better monitoring capacity in the private sector management can be a cause of concern for public sector employees who may have become used to less efficient working. A common theme found in the narratives was the possible apprehensions from healthcare staff about the loss of their jobs. CONCLUSION: Our findings indicated lack of effective engagement with key stakeholders and the resistance from healthcare staff as the key barriers for PPP implementation in Sindh, Pakistan. These findings provide useful insights for the successful implementation of such initiatives in Pakistan as well as in other similar settings.

Suppresive plants as weed management tool: Managing Parthenium hysterophorus under simulated grazing in Australian grasslands.

Parthenium hysterophorus L. is among one of the most problematic invasive grassland weeds in Australia, and in many other countries around the world. It can reduce pasture and livestock production, natural community biodiversity, and negatively affect human and animal health. Sowing of selected suppressive pasture plants in parthenium weed infested grasslands has shown potential to improve efficacy of management. However, such species need to be tested for their ability to suppress weed growth under grazing conditions. The parthenium weed suppressive and fodder production capacity of six selected pasture species [purple pigeon grass (Setaria incrassata), buffel grass (Cenchrus ciliaris), butterfly pea (Clitoria ternatea), Kangaroo grass (Themeda triandra), bull Mitchell grass (Astrebla squarrosa) and Indian bluegrass (Bothriochloa pertusa)] was tested under no (0%), low (25%), moderate (50%) and heavy (75%) simulated grazing pressures in a grassland area of south-central Queensland, Australia. Purple pigeon grass, buffel grass and butterfly pea legume suppressed the growth of parthenium weed by >50% under low and moderate simulated grazing pressures, as well as generating moderate to high amounts of fodder biomass (up to 5.07 t ha-1 per year). Native species, Kangaroo grass and bull Mitchell grass both suppressed the parthenium weed's growth by >50% under low simulated grazing pressure, however, they generated low to moderate amounts of biomass, 1.83 t ha-1 and 2.7 t ha-1 per year, respectively. The sowing of selected suppressive pasture species in parthenium weed infested grasslands with low-to-moderate grazing pressure, assuming this corresponds closely with the simulated treatment, would provide an additional tool to the best practice weed management strategy as well as sustaining fodder production.

Development of novel MnO2 coated carbon felt cathode for microbial electroreduction of CO2 to biofuels.

Fabrication of superior and cost-effective cathodic materials is vital in manufacturing sustainable microbial electrolysis cells (MECs) for biofuels production. In the present study, a novel manganese dioxide (MnO2) coated felt cathode (Mn/CF) has been developed for MECs using electrodeposition method via potentiostat. MnO2 is considered to encourage exogenous electron exchange and, in this way, improves the reduction of carbon dioxide (CO2). MnO2, as a cathodic catalyst, enhances the rate of biofuel production, electron transfer, and significantly reduces the cost of MECs. A maximum stabilized current density of 3.70 ±â€¯0.5 mA/m2 was obtained in case of MnO2-coated Mn/CF based MEC, which was more than double the non-coated carbon felt (CF) cathode (1.70 ±â€¯0.5 mA/m2). The dual chamber Mn/CF-MEC achieved the highest production rate of acetic acid (37.9 mmol/L) that was significantly higher (43.0%) in comparison to the non-coated CF-MEC. The cyclic voltammograms further verified the substantial enhancement in the electron transfer between the MnO2 coated cathode and microbes. The obtained results demonstrate that MnO2 interacted electrochemically with microbial cells and enhanced the extracellular electron transfer, therefore validating its potential role in biofuel production. The MnO2 coated CF further offered higher electrode surface area and better electron transfer efficiency, suggesting its applicability in the large-scale MECs.