Search

Background: Transfusion‐transmissible infection (TTI) prevalence among US blood donors has been widely documented. Here we estimate the prevalence of donors presenting with ≥2 TTIs (multiple infections past or present referred to as coinfections) and describe their demographics and associations. Methods: Data from the Transfusion‐Transmissible Infections Monitoring System were compiled for October 2020–September 2023 (3 years). Prevalence per million donations (pmd) was calculated for each TTI coinfection combination with demographic characteristics summarized. The odds of each TTI coinfection combination were estimated using logistic regression. Reactivity by NAT and/or serology (HIV, HBV, and HCV) defined donors as consensus positive (CP) for each infection while serology‐based algorithms defined syphilis CP and the subset with active syphilis infections (ASIs). Results: About 22 million donations were included, with 212 coinfections (9.7 pmd). Around 2% of donations positive for any TTI (n = 10,516) were coinfections. Coinfection prevalence per TTI combination ranged from 0.3 pmd for HIV CP and HCV CP, to 4.3 pmd for HIV CP and syphilis CP. There were high proportions of coinfections from donors who were male, aged 25–54 years, white or black, first time, and residing in the southern US Census Region. The odds of a second TTI occurring in an individual donor with a TTI ranged from 23 (95% CI: 13, 41) times more likely for HBV CP and ASI to 395 (95% CI: 298, 524) times more likely for HIV CP and ASI. Conclusions: Coinfections are relatively uncommon among blood donors in the United States; however, associations exist among HIV, HBV, HCV, and syphilis infections. [ABSTRACT FROM AUTHOR]

Objective: Obesity is a driver of non‐alcoholic fatty liver disease (NAFLD), and interventions that decrease body weight, such as bariatric surgery and/or calorie restriction (CR), may serve as effective therapies. This study compared the effects of Roux‐en‐Y gastric bypass surgery (RYGB) and CR on hepatic function in mice with obesity and NAFLD. Methods: C57BL/6J mice were fed a high‐fat diet to promote obesity. At 16 weeks of age, mice were randomized to sham surgery (sham), RYGB, or CR weight matched to RYGB (WM). Body weight/composition, food intake, and energy expenditure (EE) were measured throughout treatment. Liver histopathology was evaluated from H&E‐stained sections. Hepatic enzymes and glycogen content were determined by ELISA. Transcriptional signatures were revealed via RNA sequencing. Results: RYGB reduced hepatic lipid content and adiposity while increasing EE and lean body mass relative to WM. Hepatic glycogen and bile acid content were increased after RYGB relative to sham and WM. RYGB activated enterohepatic signaling and genes regulating hepatic lipid homeostasis. Conclusions: RYGB improved whole‐body composition and hepatic lipid homeostasis to a greater extent than CR in mice. RYGB was associated with discrete remodeling of the hepatic transcriptome, suggesting that surgery may be mechanistically additive to CR. [ABSTRACT FROM AUTHOR]

Objective: Stillbirth is a potentially preventable complication of pregnancy. Identifying women at high risk of stillbirth can guide decisions on the need for closer surveillance and timing of delivery in order to prevent fetal death. Prognostic models have been developed to predict the risk of stillbirth, but none has yet been validated externally. In this study, we externally validated published prediction models for stillbirth using individual participant data (IPD) meta-analysis to assess their predictive performance.Methods: MEDLINE, EMBASE, DH-DATA and AMED databases were searched from inception to December 2020 to identify studies reporting stillbirth prediction models. Studies that developed or updated prediction models for stillbirth for use at any time during pregnancy were included. IPD from cohorts within the International Prediction of Pregnancy Complications (IPPIC) Network were used to validate externally the identified prediction models whose individual variables were available in the IPD. The risk of bias of the models and cohorts was assessed using the Prediction study Risk Of Bias ASsessment Tool (PROBAST). The discriminative performance of the models was evaluated using the C-statistic, and calibration was assessed using calibration plots, calibration slope and calibration-in-the-large. Performance measures were estimated separately in each cohort, as well as summarized across cohorts using random-effects meta-analysis. Clinical utility was assessed using net benefit.Results: Seventeen studies reporting the development of 40 prognostic models for stillbirth were identified. None of the models had been previously validated externally, and the full model equation was reported for only one-fifth (20%, 8/40) of the models. External validation was possible for three of these models, using IPD from 19 cohorts (491 201 pregnant women) within the IPPIC Network database. Based on evaluation of the model development studies, all three models had an overall high risk of bias, according to PROBAST. In the IPD meta-analysis, the models had summary C-statistics ranging from 0.53 to 0.65 and summary calibration slopes ranging from 0.40 to 0.88, with risk predictions that were generally too extreme compared with the observed risks. The models had little to no clinical utility, as assessed by net benefit. However, there remained uncertainty in the performance of some models due to small available sample sizes.Conclusions: The three validated stillbirth prediction models showed generally poor and uncertain predictive performance in new data, with limited evidence to support their clinical application. The findings suggest methodological shortcomings in their development, including overfitting. Further research is needed to further validate these and other models, identify stronger prognostic factors and develop more robust prediction models. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

There is much to celebrate in the increasingly successful management of complicated monochorionic (MC) multiple pregnancy over the last three decades. We know that children born after a multiple pregnancy exhibit differences in neurodevelopment compared to their singleton counterparts and that these differences can be related to chorionicity, complications during pregnancy and fetal number5. It is important to emphasize that evidence derived from uncomplicated MC twin pregnancies cannot be extrapolated to complicated MC twin pregnancies, particularly after fetal interventions, because the nature of the prenatal insults and natural history of each MC twin pregnancy complication is different from the natural history of uncomplicated MC twin pregnancy36,37. Neurodevelopmental impairment in uncomplicated monochorionic pregnancy The prevailing assumption is that the majority of cases of NDI observed in multiple pregnancies are due to increased iatrogenic and spontaneous preterm birth, with the additional contribution of monochorionicity-specific complications in MC pregnancies. [Extracted from the article]

Background: Stillbirth accounts for over 2 million deaths a year worldwide and rates remains stubbornly high. Multivariable prediction models may be key to individualised monitoring, intervention or early birth in pregnancy to prevent stillbirth. Objectives: To collate and evaluate systematic reviews of factors associated with stillbirth in order to identify variables relevant to prediction model development. Search strategy: MEDLINE, Embase, DARE and Cochrane Library databases and reference lists were searched up to November 2019. Selection criteria: We included systematic reviews of association of individual variables with stillbirth without language restriction. Data collection and analysis: Abstract screening and data extraction were conducted in duplicate. Methodological quality was assessed using AMSTAR and QUIPS criteria. The evidence supporting association with each variable was graded. Results: The search identified 1198 citations. Sixty‐nine systematic reviews reporting 64 variables were included. The most frequently reported were maternal age (n = 5), body mass index (n = 6) and maternal diabetes (n = 5). Uterine artery Doppler appeared to have the best performance of any single test for stillbirth. The strongest evidence of association was for nulliparity and pre‐existing hypertension. Conclusion: We have identified variables relevant to the development of prediction models for stillbirth. Age, parity and prior adverse pregnancy outcomes had a more convincing association than the best performing tests, which were PAPP‐A, PlGF and UtAD. The evidence was limited by high heterogeneity and lack of data on intervention bias. Review shows key predictors for use in developing models predicting stillbirth include age, prior pregnancy outcome and PAPP‐A, PLGF and Uterine artery Doppler. Review shows key predictors for use in developing models predicting stillbirth include age, prior pregnancy outcome and PAPP‐A, PLGF and Uterine artery Doppler. [ABSTRACT FROM AUTHOR]

Background: Stillbirth prevention is an international priority – risk prediction models could individualise care and reduce unnecessary intervention, but their use requires evaluation. Objectives: To identify risk prediction models for stillbirth, and assess their potential accuracy and clinical benefit in practice. Search strategy: MEDLINE, Embase, DH‐DATA and AMED databases were searched from inception to June 2019 using terms relevant to stillbirth, perinatal mortality and prediction models. The search was compliant with Preferred Reporting Items for Systematic Reviews and Meta‐analyses (PRISMA) guidelines. Selection criteria: Studies developing and/or validating prediction models for risk of stillbirth developed for application during pregnancy. Data collection and analysis: Study screening and data extraction were conducted in duplicate, using the CHARMS checklist. Risk of bias was appraised using the PROBAST tool. Results: The search identified 2751 citations. Fourteen studies reporting development of 69 models were included. Variables consistently included were: ethnicity, body mass index, uterine artery Doppler, pregnancy‐associated plasma protein and placental growth factor. For almost all models there were significant concerns about risk of bias. Apparent model performance (i.e. in the development dataset) was highest in models developed for use later in pregnancy and including maternal characteristics, and ultrasound and biochemical variables, but few were internally validated and none were externally validated. Conclusions: Almost all models identified were at high risk of bias. There are first‐trimester models of possible clinical benefit in early risk stratification; these require validation and clinical evaluation. There were few later pregnancy models but, if validated, these could be most relevant to individualised discussions around timing of birth. Prediction models using maternal factors, blood tests and ultrasound could individualise stillbirth prevention, but existing models are at high risk of bias. Prediction models using maternal factors, blood tests and ultrasound could individualise stillbirth prevention, but existing models are at high risk of bias. [ABSTRACT FROM AUTHOR]

Objective: Selective fetal growth restriction (sFGR) occurs in monochorionic twin pregnancies when unequal placental sharing leads to restriction in the growth of just one twin. Management options include laser separation of the fetal circulations, selective reduction or expectant management, but what constitutes the best treatment is not yet known. New trials in this area are urgently needed but, in this rare and complex group, maximizing the relevance and utility of clinical research design and outputs is paramount. A core outcome set ensures standardized outcome collection and reporting in future research. The objective of this study was to develop a core outcome set for studies evaluating treatments for sFGR in monochorionic twins.Methods: An international steering group of clinicians, researchers and patients with experience of sFGR was established to oversee the process of development of a core outcome set for studies investigating the management of sFGR. Outcomes reported in the literature were identified through a systematic review and informed the design of a three-round Delphi survey. Clinicians, researchers, and patients and family representatives participated in the survey. Outcomes were scored on a Likert scale from 1 (limited importance for making a decision) to 9 (critical for making a decision). Consensus was defined a priori as a Likert score of ≥ 8 in the third round of the Delphi survey. Participants were then invited to take part in an international meeting of stakeholders in which the modified nominal group technique was used to consider the consensus outcomes and agree on a final core outcome set.Results: Ninety-six outcomes were identified from 39 studies in the systematic review. One hundred and three participants from 23 countries completed the first round of the Delphi survey, of whom 88 completed all three rounds. Twenty-nine outcomes met the a priori criteria for consensus and, along with six additional outcomes, were prioritized in a consensus development meeting, using the modified nominal group technique. Twenty-five stakeholders participated in this meeting, including researchers (n = 3), fetal medicine specialists (n = 3), obstetricians (n = 2), neonatologists (n = 3), midwives (n = 4), parents and family members (n = 6), patient group representatives (n = 3), and a sonographer. Eleven core outcomes were agreed upon. These were live birth, gestational age at birth, birth weight, intertwin birth-weight discordance, death of surviving twin after death of cotwin, loss during pregnancy or before final hospital discharge, parental stress, procedure-related adverse maternal outcome, length of neonatal stay in hospital, neurological abnormality on postnatal imaging and childhood disability.Conclusions: This core outcome set for studies investigating the management of sFGR represents the consensus of a large and diverse group of international collaborators. Use of these outcomes in future trials should help to increase the clinical relevance of research on this condition. Consensus agreement on core outcome definitions and measures is now required. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Increasing value and reducing research waste in obstetrics: towards woman-centered research Keywords: evidence-based practice; individual patient-data meta-analysis; meta-analysis; obstetrics; randomized controlled trial; research waste; systematic review Stopping early the trial in The Netherlands, when evidence emerged that sildenafil was actually associated with increased fetal risks, has changed clinical practice and demonstrates clearly how the responsible conduct of randomized controlled trials can protect women and children around the world[[12]]. A key limitation of meta-analyses is that only published trials are available for inclusion and the results of the trials are known prior to the initiation of evidence synthesis. [Extracted from the article]

Objective: Primary studies and systematic reviews provide estimates of varying accuracy for different factors in the prediction of pre-eclampsia. The aim of this study was to review published systematic reviews to collate evidence on the ability of available tests to predict pre-eclampsia, to identify high-value avenues for future research and to minimize future research waste in this field.Methods: MEDLINE, EMBASE and The Cochrane Library including DARE (Database of Abstracts of Reviews of Effects) databases, from database inception to March 2017, and bibliographies of relevant articles were searched, without language restrictions, for systematic reviews and meta-analyses on the prediction of pre-eclampsia. The quality of the included reviews was assessed using the AMSTAR tool and a modified version of the QUIPS tool. We evaluated the comprehensiveness of search, sample size, tests and outcomes evaluated, data synthesis methods, predictive ability estimates, risk of bias related to the population studied, measurement of predictors and outcomes, study attrition and adjustment for confounding.Results: From 2444 citations identified, 126 reviews were included, reporting on over 90 predictors and 52 prediction models for pre-eclampsia. Around a third (n = 37 (29.4%)) of all reviews investigated solely biochemical markers for predicting pre-eclampsia, 31 (24.6%) investigated genetic associations with pre-eclampsia, 46 (36.5%) reported on clinical characteristics, four (3.2%) evaluated only ultrasound markers and six (4.8%) studied a combination of tests; two (1.6%) additional reviews evaluated primary studies investigating any screening test for pre-eclampsia. Reviews included between two and 265 primary studies, including up to 25 356 688 women in the largest review. Only approximately half (n = 67 (53.2%)) of the reviews assessed the quality of the included studies. There was a high risk of bias in many of the included reviews, particularly in relation to population representativeness and study attrition. Over 80% (n = 106 (84.1%)) summarized the findings using meta-analysis. Thirty-two (25.4%) studies lacked a formal statement on funding. The predictors with the best test performance were body mass index (BMI) > 35 kg/m2 , with a specificity of 92% (95% CI, 89-95%) and a sensitivity of 21% (95% CI, 12-31%); BMI > 25 kg/m2 , with a specificity of 73% (95% CI, 64-83%) and a sensitivity of 47% (95% CI, 33-61%); first-trimester uterine artery pulsatility index or resistance index > 90th centile (specificity 93% (95% CI, 90-96%) and sensitivity 26% (95% CI, 23-31%)); placental growth factor (specificity 89% (95% CI, 89-89%) and sensitivity 65% (95% CI, 63-67%)); and placental protein 13 (specificity 88% (95% CI, 87-89%) and sensitivity 37% (95% CI, 33-41%)). No single marker had a test performance suitable for routine clinical use. Models combining markers showed promise, but none had undergone external validation.Conclusions: This review of reviews calls into question the need for further aggregate meta-analysis in this area given the large number of published reviews subject to the common limitations of primary predictive studies. Prospective, well-designed studies of predictive markers, preferably randomized intervention studies, and combined through individual-patient data meta-analysis are needed to develop and validate new prediction models to facilitate the prediction of pre-eclampsia and minimize further research waste in this field. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Objective: Although fetal growth restriction (FGR) is well known to be associated with adverse outcomes for the mother and offspring, effective interventions for the management of FGR are yet to be established. Trials reporting interventions for the prevention and treatment of FGR may be limited by heterogeneity in the underlying pathophysiology. The aim of this study was to conduct a systematic review of outcomes reported in randomized controlled trials (RCTs) assessing interventions for the prevention or treatment of FGR, in order to identify and categorize the variation in outcome reporting.Methods: MEDLINE, EMBASE and The Cochrane Library were searched from inception until August 2018 for RCTs investigating therapies for the prevention and treatment of FGR. Studies were assessed systematically and data on outcomes that were reported in the included studies were extracted and categorized. The methodological quality of the included studies was assessed using the Jadad score.Results: The search identified 2609 citations, of which 153 were selected for full-text review and 72 studies (68 trials) were included in the final analysis. There were 44 trials relating to the prevention of FGR and 24 trials investigating interventions for the treatment of FGR. The mean Jadad score of all studies was 3.07, and only nine of them received a score of 5. We identified 238 outcomes across the included studies. The most commonly reported were birth weight (88.2%), gestational age at birth (72.1%) and small-for-gestational age (67.6%). Few studies reported on any measure of neonatal morbidity (27.9%), while adverse effects of the interventions were reported in only 17.6% of trials.Conclusions: There is significant variation in outcome reporting across RCTs of therapies for the prevention and treatment of FGR. The clinical applicability of future research would be enhanced by the development of a core outcome set for use in future trials. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Objective: To explore the impact of severity and management (expectant, laser treatment or selective reduction) on perinatal outcome of monochorionic twin pregnancies complicated by selective fetal growth restriction (sFGR).Methods: MEDLINE, EMBASE, CINAHL, ClinicalTrials.gov and The Cochrane Library databases were searched for studies on outcome following expectant management, laser treatment or selective reduction in monochorionic twin pregnancies complicated by sFGR. Only pregnancies affected by sFGR and categorized according to the Gratacós classification (Type I, II or III) were included. The primary outcome was mortality, including single and double intrauterine (IUD), neonatal (NND) and perinatal deaths. Secondary outcomes were neonatal morbidity, abnormal postnatal brain imaging, intraventricular hemorrhage, periventricular leukomalacia, respiratory distress syndrome, admission to neonatal intensive care unit and survival free from neurological complications (intact survival). Meta-analyses of proportions were used to analyze the extracted data according to management, severity of sFGR and fetal size (smaller vs larger twin).Results: Sixteen observational studies (786 monochorionic twin pregnancies) were included. In pregnancies complicated by Type-I sFGR managed expectantly, IUD occurred in 3.1% (95% CI, 1.1-5.9%) of fetuses and 97.9% (95% CI, 93.6-99.9%) of twins had intact survival. In pregnancies complicated by Type-I sFGR treated using laser therapy, IUD occurred in 16.7% (95% CI, 0.4-64.1%) of fetuses and, in those treated using selective reduction, IUD occurred in 0% (95% CI, 0-34.9%) of cotwins, with no evidence of neurological complications in the survivors. In pregnancies complicated by Type-II sFGR managed expectantly, IUD occurred in 16.6% (95% CI, 6.9-29.5%) and NND in 6.4% (95% CI, 0.2-28.2%) of fetuses, and 89.3% (95% CI, 71.8-97.7%) of twins survived without neurological compromise. In Type-II sFGR pregnancies treated using laser therapy, IUD occurred in 44.3% (95% CI, 22.2-67.7%) of fetuses, while none of the affected cases experienced morbidity and survivors were free of neurological complications. Of pregnancies undergoing selective reduction, IUD of the cotwin occurred in 5.0% (95% CI, 0.03-20.5%) and NND in 3.7% (95% CI, 0.2-11.1%), and 90.6% (95% CI, 42.3-94.3%) of surviving cotwins were free from neurological complications. In pregnancies complicated by Type-III sFGR managed expectantly, IUD occurred in 13.2% (95% CI, 7.2-20.5%) and NND in 6.8% (95% CI, 0.7-18.6%) of fetuses, and 61.9% (95% CI, 38.4-81.9%) of twins had intact survival. In pregnancies complicated by Type-III sFGR treated with laser therapy, IUD occurred in 32.9% (95% CI, 20.9-46.2%) of fetuses and all surviving twins were without neurological complications. Finally, in pregnancies with Type-III sFGR treated with selective reduction, NND occurred in 5.2% (95% CI, 0.8-12.8%) of cotwins and 98.8% (95% CI, 93.9-99.9%) had intact survival.Conclusion: Type-I sFGR is characterized by good perinatal outcome when managed expectantly, which represents the most reasonable management strategy for the large majority of affected cases. Pregnancies complicated by Type-II or -III sFGR treated with fetoscopic laser ablation have a higher rate of mortality but lower rate of morbidity compared with those managed expectantly, supporting the use of fetal therapy at gestations remote from neonatal viability. Data on outcome following selective reduction are scarce. In view of the lack of evidence from randomized controlled trials, prenatal management of sFGR should be individualized according to gestational age at diagnosis, severity of growth discordance and magnitude of Doppler anomalies. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

The effects of isavuconazole (active moiety of isavuconazonium sulfate) on cardiac ion channels in vitro and cardiac repolarization clinically were assessed in a phase I, randomized, double-blind study in healthy individuals who received isavuconazole (after 2-day loading dose), at therapeutic or supratherapeutic doses daily for 11 days, moxifloxacin (400 mg q.d.), or placebo. A post-hoc analysis of the phase III SECURE trial assessed effects on cardiac safety. L-type Ca2+ channels were most sensitive to inhibition by isavuconazole. The 50% inhibitory concentrations for ion channels were higher than maximum serum concentrations of nonprotein-bound isavuconazole in vivo. In the phase I study ( n = 161), isavuconazole shortened the QT interval in a dose- and plasma concentration-related manner. There were no serious treatment-emergent adverse events; palpitations and tachycardia were observed in placebo and supratherapeutic isavuconazole groups; no cardiac safety signals were detected in the SECURE study ( n = 257). Isavuconazole was associated with a shortened cardiac QT interval. [ABSTRACT FROM AUTHOR]

Objective: Roux-en-Y gastric bypass surgery (RYGB) results in sustained lowering of body weight in most patients, but the mechanisms involved are poorly understood. The aim of this study was to obtain support for the notion that reprogramming of defended body weight, rather than passive restriction of energy intake, is a fundamental mechanism of RYGB.Methods: Male C57BL6J mice reaching different degrees of obesity on a high-fat diet either with ad libitum access or with caloric restriction (weight-reduced) were subjected to RYGB.Results: RYGB-induced weight loss and fat mass loss were proportional to pre-surgical levels, with moderately obese mice losing less body weight and fat compared with very obese mice. Remarkably, mice that were weight-reduced to the level of chow controls before surgery immediately gained weight after surgery, exclusively accounted for by lean mass gain.Conclusions: The results provide additional evidence for reprogramming of a new defended body weight as an important principle by which RYGB lastingly suppresses body weight. RYGB appears to selectively abolish defense of a higher fat mass level, while remaining sensitive to the defense of lean mass. The molecular and physiological mechanisms underlying this reprogramming remain to be elucidated. [ABSTRACT FROM AUTHOR]

Objective: Placental insufficiency contributes to the risk of stillbirth. Cerebroplacental ratio (CPR) is an emerging marker of placental insufficiency. The aim of this study was to evaluate the association of third-trimester fetal CPR, uterine artery (UtA) Doppler and estimated fetal weight (EFW) with stillbirth and perinatal death.Methods: This was a retrospective cohort study including 2812 women with a singleton pregnancy who underwent an ultrasound scan in the third trimester. EFWs were converted into centiles, and Doppler indices (UtA and CPR) were converted into multiples of the median (MoM), adjusting for gestational age. Regression analysis was performed to identify, and adjust for, potential confounders, and receiver-operating characteristics (ROC) curve analysis was used to assess the predictive value.Results: When adjusting for EFW centile and UtA mean pulsatility index (UtA-PI) MoM, CPR-MoM remained an independent predictor of stillbirth (odds ratio (OR) = 0.003 (95% CI, 0.00-0.11), P = 0.003) and perinatal mortality (OR = 0.001 (95% CI, 0.00-0.03), P < 0.001). UtA-PI ≥ 1.5 MoM was significantly associated with low CPR-MoM, even after adjusting for EFW centile (OR = 5.22 (95% CI, 3.88-7.04), P < 0.001) or small-for-gestational age (SGA; OR = 4.73 (95% CI, 3.49-6.41), P < 0.001). These associations remained significant, even when excluding pregnancies with SGA or including only cases in which Doppler indices were recorded at term (P < 0.01). For prediction of stillbirth, the area under the ROC curve, using a combination of these three parameters, was 0.88 (95% CI, 0.77-0.99) with a sensitivity of 66.7%, specificity of 92.1%, positive likelihood ratio (LR) of 8.46 and negative LR of 0.36.Conclusions: Third-trimester CPR is an independent predictor of stillbirth and perinatal mortality. The role of UtA Doppler, CPR and EFW in assessing risk of adverse pregnancy outcome should be evaluated prospectively. [ABSTRACT FROM AUTHOR]

An abstract of the article "Fetal brain abnormalities in twin pregnancies complicated by Twin-twin transfusion syndrome: systematic review and meta-analysis" by A. Khalil is presented.

An abstract of the article "Are fetal cerebroplacental ratio and impaired placental perfusion recorded in the third trimester predictors of stillbirth and perinatal loss?" by A. Khalil and colleagues is presented.

Aims To assess the cost-effectiveness of dapagliflozin, a sodium-glucose co-transporter-2 ( SGLT-2) inhibitor, compared with a sulfonylurea, when added to metformin for treatment of UK people with Type 2 diabetes mellitus inadequately controlled on metformin alone. Methods Clinical inputs sourced from a head-to-head randomized controlled trial ( RCT) informed the Cardiff diabetes decision model. Risk equations developed from the United Kingdom Prospective Diabetes Study ( UKPDS) were used in conjunction with the clinical inputs to predict disease progression and the incidence of micro- and macrovascular complications over a lifetime horizon. Cost and utility data were generated to present the incremental cost-effectiveness ratio ( ICER) for both treatment arms, and sensitivity and scenario analyses were conducted to assess the impact of uncertainty on the final model results. Results The dapagliflozin treatment arm was associated with a mean incremental benefit of 0.467 quality-adjusted life years ( QALYs) [95% confidence interval ( CI): 0.420; 0.665], with an incremental cost of £1246 (95% CI: £613; £1637). This resulted in an ICER point estimate of £2671 per QALY gained. Incremental costs were shown to be insensitive to parameter variation, with only treatment-related weight change having a significant impact on the incremental QALYs. Probabilistic sensitivity analysis determined that dapagliflozin had a 100% probability of being cost-effective at a willingness-to-pay threshold of £20 000 per QALY. Conclusions Dapagliflozin in combination with metformin was shown to be a cost-effective treatment option compared with sulfonylurea from a UK healthcare perspective for people with Type 2 diabetes mellitus who are inadequately controlled on metformin monotherapy. [ABSTRACT FROM AUTHOR]

Objective To test the commonly held assumption that gastric bypass surgery lowers body weight because it limits the ability to eat large amounts of food. Methods Central melanocortin signaling was blocked by ICV infusion of the melanocortin-3/4 receptor antagonist SHU9119 for 14 days in rats whose high-fat diet-induced obesity had been reversed by Roux-en-Y gastric bypass surgery. Results SHU9119 increased daily food intake (+ 100%), body weight (+30%), and fat mass (+50%) in rats with RYGB, surpassing the presurgical body weight and that of saline-treated sham-operated rats. Doubling of food intake was entirely due to increased meal frequency, but not meal size. After termination of SHU9119, body weight promptly returned to near preinfusion levels. In sham-operated rats, SHU9119 produced even larger increases in food intake and body weight. Conclusions RYGB rats do not settle at a lower level of body weight because they cannot eat more food as they can easily double food intake by increasing meal frequency. The reversible obesity suggests that RYGB rats actively defend the lower body weight. However, because both RYGB and sham-operated rats responded to SHU9119, central melanocortin signaling is not the critical mechanism in RYGB rats responsible for this defense. [ABSTRACT FROM AUTHOR]

Aims Indirect evidence from randomized controlled trials ( RCTs) was used to estimate the effect of dapagliflozin, a new agent with a novel mechanism of action ( SGLT-2 inhibition), relative to other anti-diabetes therapies after 1 year of treatment. Methods A systematic literature review and Bayesian network meta-analysis ( NMA) of RCTs involving anti-diabetes treatments added to metformin were conducted. RCTs enrolling subjects with type 2 diabetes inadequately controlled on metformin monotherapy were included. Comparators included dipeptidyl peptidase-4 ( DPP-4) inhibitors, thiazolidinediones ( TZDs), sulphonylureas, glucagon-like peptide-1 ( GLP-1) analogues and dapagliflozin. Outcomes of interest were mean change from baseline HbA1c, weight and systolic blood pressure, and incidence of hypoglycaemia. Results From 4270 abstracts, six RCTs were included in the primary analysis; no RCTs involving GLP-1 analogues met primary inclusion criteria. All RCTs were actively controlled with sulphonylureas. The mean change in HbA1c from baseline was similar across comparators. The treatment effect (95% credible interval) of dapagliflozin on HbA1c was −0.08% (−0.25, 0.10) relative to DPP-4 inhibitors, −0.02% (−0.24, 0.21) relative to TZDs and 0.00% (−0.16, 0.16) relative to sulphonylureas. Non-sulphonylureas showed significantly lower risk of hypoglycaemia relative to sulphonylureas. Dapagliflozin had a significant effect on weight change: the relative difference was −2.74 kg (−5.35, −0.10) compared with DPP-4 inhibitors, and −4.67 kg (−7.03, −2.35) compared with sulphonylureas. Systolic blood pressure was not meta-analysed due to infrequent reporting. Conclusion Compared with DPP-4 inhibitors, TZDs and sulphonylureas, dapagliflozin offers similar HbA1c control after 1 year, with similar or reduced risk of hypoglycaemia and the additional benefit of weight loss, when added to metformin. [ABSTRACT FROM AUTHOR]

Conclusions COVID-19 mRNA vaccination in pregnancy appears to be effective in preventing proven SARS-CoV-2 infection in pregnancy. To synthesise evidence on vaccine effectiveness and perinatal outcomes after COVID-19 vaccination in pregnancy. Studies reporting perinatal outcomes or vaccine effectiveness after COVID-19 vaccination in pregnancy were included. [Extracted from the article]

Detailed mapping of bathymetry and three-dimensional water velocities using a boat-mounted single-beam sonar and acoustic Doppler current profiler (ADCP) was carried out in the vicinity of two submerged wing dikes located in the Lower Missouri River near Columbia, Missouri. During high spring flows the wing dikes become submerged, creating a unique combination of vertical flow separation and overtopping (plunging) flow conditions, causing large-scale three-dimensional turbulent flow structures to form. On three different days and for a range of discharges, sampling transects at 5 and 20 m spacing were completed, covering the area adjacent to and upstream and downstream from two different wing dikes. The objectives of this research are to evaluate whether an ADCP can identify and measure large-scale flow features such as recirculating flow and vortex shedding that develop in the vicinity of a submerged wing dike; and whether or not moving-boat (single-transect) data are sufficient for resolving complex three-dimensional flow fields. Results indicate that spatial averaging from multiple nearby single transects may be more representative of an inherently complex (temporally and spatially variable) three-dimensional flow field than repeated single transects. Results also indicate a correspondence between the location of calculated vortex cores (resolved from the interpolated three-dimensional flow field) and the nearby scour holes, providing new insight into the connections between vertically oriented coherent structures and local scour, with the unique perspective of flow and morphology in a large river. [ABSTRACT FROM AUTHOR]

Four formal rounds of Trans-Pacific Partnership Agreement (TPPA) negotiations took place in 2010. They involved over 200 officials from Australia, the United States, New Zealand, Chile, Singapore, Brunei, Peru, Vietnam and Malaysia. Future negotiations officially are set to include three issues with public health and medicines policy implications for Australia and our region: ways to approach regulatory coherence and transparency; how to benefit multinational and small-medium enterprises; and multilateral investor-state dispute settlement. US-based multinational pharmaceutical companies are lobbying for TPPA provisions like those in the Australia-US Free Trade Agreement, which reduce government cost-effectiveness regulatory control of pharmaceuticals, threatening equitable access to medicines. They also advocate increased TPPA intellectual monopoly privilege protection, which will further limit the development of Australian generic medicine enterprises and restrict patient access to cheap, bioequivalent prescription drugs. Of particular concern is that proposed TPPA multilateral investor-state dispute settlement procedures would allow US corporations (as well as those of other TPPA nations) to obtain damages against Australian governments through international arbitral proceedings if their investments are impeded by Australian public health and environment protection legislation. [ABSTRACT FROM AUTHOR]

The oral commensal bacterium Streptococcus gordonii has been gathering interest as a candidate live mucosal vaccine delivery vector. S. gordonii has been shown to be capable of activating antigen presenting immune cells in a manner which leads to their activation and maturation, yet the mechanism used by S. gordonii to do so is poorly understood. The aim of this work was to investigate the immunostimulatory components of S. gordonii in inducing murine dendritic cell (DC) activation and maturation. Lipoteichoic acid (LTA), lipoprotein (LP), peptidoglycan (PGN), and DNA were isolated from S. gordonii, and used to stimulate murine DC. Cytokine production and DC surface marker upregulation in response to the bacterial components was quantified by enzyme-linked immunosorbent assay and flow cytometry respectively. The results were contrasted against data obtained from DC derived from MyD88, TRIF [TIR(Toll/Interleukin-1 Receptor)-domain-containing adapter-inducing interferon-beta] or toll-like receptor-2 (TLR-2) knockout mice. The four S. gordonii bacterial components were found to differentially induce cytokine production and surface marker upregulation by murine DC. Activation of DC by both whole S. gordonii cells and the four bacterial components was abrogated in the absence of MyD88, but not in the absence of TRIF. LTA, LP and PGN, but not DNA and whole S. gordonii, required TLR-2 to induce a DC response. The results collectively indicate that S. gordonii activates DC predominantly through a MyD88-dependent and TRIF-independent pathway. This activation can be attributed to multiple immunostimulatory components present within S. gordonii bacterial cells. [ABSTRACT FROM AUTHOR]

Aims and objectives. To establish patients' experiences after discharge from critical care and to evaluate implementation of a follow-up service. Background. Government recommendations advise critical care follow-up to prevent readmission and address problems after discharge. Admission to critical care results in significant psychological and physiological sequelae. Design. A prospective, longitudinal and exploratory study of surgical cancer patients requiring >48 hours in critical care. Qualitative interviews were conducted and short questionnaires were used. Methods. Patient Expert Advisory Groups were invited to participate in research design. Patients were visited in the ward at days 1 and 5 after discharge, invited to nurse-led follow-up clinic and interviewed at three and six months. Short questionnaires were administered at six and 12 months. Findings. Twenty-seven patients participated in the study. All patients experienced benefit from the service. Emergent themes included: rehabilitation from critical care: physiological issues and needs, memories: real and unreal, uncertainty and fear and empathy. A core theme of reassurance was underlying through the research. Issues while in critical care included: the need for nursing presence, nightmares, delusions, confusion, fear of ward transfer, inability to remember, disorientation and being prepared for the experience. After discharge, issues shifted to longer term needs. Psychological support, in the form of the follow-up clinic, proved useful. The ability to move on with life after discharge varied and uncertainty about the future and their cancer had an impact upon this. Recovery was made easier through the follow-up clinic. Patients required reassurances that their experiences were valid and also wanted reassurances about their cancer. Conclusion. Critical care causes various difficulties for patients that may impinge on recovery. Incorporating patients into the design process helps identify needs more closely. Follow-up proved beneficial and highlighted the role nurses have in improving patient experiences after discharge from critical care. Nurses should be vigilant for both immediate and longer-term needs. Relevance to clinical practice. This research into nurse-led follow-up clinics after critical care highlights an important, and often neglected, part of the critical illness continuum. Attending such clinics may help reassure patients after discharge from critical care. [ABSTRACT FROM AUTHOR]

Entamoeba histolytica is a protozoan intestinal parasite that causes amoebic colitis and amoebic liver abscess. To identify virulence factors of E. histolytica, we first defined the phenotypes of two E. histolytica strains, HM-1:IMSS, the prototype virulent strain, and E. histolytica Rahman, a strain that was reportedly less virulent than HM-1:IMSS. We found that compared with HM-1:IMSS, Rahman has a defect in erythrophagocytosis and the ability to cause amoebic colitis in human colonic xenografts. We used differential in-gel 2D electrophoresis to compare the proteome of Rahman and HM-1:IMSS, and identified six proteins that were differentially expressed above a fivefold level between the two organisms. These included two proteins with antioxidative properties (peroxiredoxin and superoxide dismutase), and three proteins of unknown function, grainin 1, grainin 2 and a protein containing a LIM-domain. Overexpression of peroxiredoxin in Rahman rendered the transgenic trophozoites more resistant to killing by H2O2 in vitro, and infection with Rahman trophozoites expressing higher levels of peroxiredoxin was associated with higher levels of intestinal inflammation in human colonic xenografts, and more severe disease based on histology. In contrast, higher levels of grainin appear to be associated with a reduced virulence phenotype, and E. histolytica HM-1:IMSS trophozoites infecting human intestinal xenografts show marked decreases in grainin expression. Our data indicate that there are definable molecular differences between Rahman and HM-1:IMSS that may explain the phenotypic differences, and identify peroxiredoxin as an important component of virulence in amoebic colitis. [ABSTRACT FROM AUTHOR]

Investigates the duration of maize pollen viability and the effectiveness of isolation distance for controlling gene flow in Mexico. Changes in pollen visual appearance; Atmospheric conditions during pollination treatment; Cross pollination frequency at various distances.

Enzyme-linked immunosorbent assay (ELISA) was shown to be a sensitive method for the detection of Spiroplasma citri in plants and insect hosts. S. citri was detected in Vinca rosea less than 1 week after infection by grafting, and reached a peak titre of up to 109 spiroplasmas per gram of tissue in infected shoots and root tips. Multiplication of S. citri in the leafhopper Euscelidius variegatus was also monitored by ELISA. S. citri could be detected in a single insect, showing that this technique is suitable for screening insect populations to the field for potential vectors of spiroplasma diseases. A method is described for raising a pathogen-specific antiserum from r. rosea infected with S. citri which reacted with cultured S. citri and also with S. citri in plant tissue. [ABSTRACT FROM AUTHOR]

Ten subjects were exposed to 3.5K Hz tone pubes of 660 msec duration, presented 24-hr-per-day for 30 days. The interstimulus interval was 22 sec. There were 10 days each at 80, 85, and 90 dB in that order. The average evoked potential (AEP) at C[sub3] referenced to linked mastoids was obtained from contiguous slake 2 and REM sleep segments on the first, second, and last recorded nights of tone-pulse exposure. The AEP was consistently larger in stake 2 than in REM sleep. In both stage 2 and REM sleep, AEP amplitude on the second recorded night bore no consistent relationship to first or last recorded night AEPs. Only the N2-P3 amplitude yielded consistent decreases, with 9 of 10 subjects in both stage 2 and REM sleep having smaller N2-P3 amplitudes on the last than on the first recorded night. There were no changes in latency of any component. During sleep there is little, if any, habituation of the auditory AEP during long-duration exposures to non-meaningful stimuli, and certainly no extinction of the AEP under these conditions. [ABSTRACT FROM AUTHOR]

KEG and autonomic habituation were studied during sleep stages 2 and REM, and during awake. Repeated presentations of the same stimulus to the same subjects within sleep stages and when awake permitted evaluation of habituation between tone sets within stage 2, REM, and awake, and from sleep to awake. Forty-six subjects were exposed to 800 Hz, 75 dB, 1- or 2-sec tones, presented in sets of 20 tones. During sleep, there was no habituation of the EEG response. Habituation occurred for both FPR and HRR during stage 2, with no evidence of within-stage, between tone set habituation. No significant habituation occurred during REM for HRR or FPR. Evoked skin resistance responses were rare during both stage 2 and REM. In the awake state, HRR was unresponsive but all other variables showed habituation. Tones presented during the night had no effect on the awake response. [ABSTRACT FROM AUTHOR]

Cointegration techniques were used to identify valid long-run relationships between macroeconomic variables and agriculture. Then, identifying restrictions were imposed on a VAR system and three long-run equilibrium relationships were found, with exports, the real price of outputs and net farm income as the dependent variables. Some of the elasticities had perverse signs that could be explained by the activities of the Marketing Boards and other distortionary policies. Tests shows that the macroeconomic variables were causally prior to the agricultural variables and that the system was becoming more responsive later in the period, as some of the distortion was removed. © 1998 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The cystic fibrosis transmembrane conductance regulator (CFTR) gene encodes an apical membrane C1− channel regulated by protein phosphorylation. To identify cAMP-dependent protein kinase (PKA)-phosphorylated residues in full-length CFTR, immobilized metal-ion affinity chromatography (IMAC) was used to selectively purify phosphopeptides. The greater specificity of iron-loaded (Fe3+) nitrilotriacetic (NTA) Sepharose compared to iminodiacetic acid (IDA) metal-chelating matrices was demonstrated using a PKA-phosphorylated recombinant NBD1-R protein from CFTR. Fe3+-loaded NTA Sepharose preferentially bound phosphopeptides, whereas acidic and poly-His-containing peptides were co-purified using the conventional IDA matrices. IMAC using NTA Sepharose enabled the selective recovery of phosphopeptides and identification of phosphorylated residues from a complex proteolytic digest. Phosphopeptides from PKA-phosphorylated full-length CFTR, generated in Hi5 insect cells using a baculovirus expression system, were purified using NTA Sepharose. Phosphopeptides were identified using matrix-assisted laser desorption mass spectrometry (MALDI/MS) with post-source decay (PSD) analysis and collision-induced dissociation (CID) experiments. Phosphorylated peptides were identified by mass and by the metastable loss of HPO3 and H3PO4 from the parent ions. Peptide sequence and phosphorylation at CFTR residues 660Ser, 737Ser, and 795Ser were confirmed using MALDI/PSD analysis. Peptide sequences and phosphorylation at CFTR residues 700Ser, 712Ser, 768Ser, and 813Ser were deduced from peptide mass, metastable fragment ion formation, and PKA consensus sequences. Peptide sequence and phosphorylation at residue 753Ser was confirmed using MALDI/CID analysis. This is the first report of phosphorylation of 753Ser in full-length CFTR. [ABSTRACT FROM AUTHOR]

Body movements during sleep stages 2 and REM were measured using an artifact method to determine the effects of a tone pulse given every 22 sec, 24 hfs a day, over a period of 30 consecutive days in 10 Navy recruits, aged 19 to 23. The tone pulse produced no significant increase in the number of body movements during stage 2, but it increased body movements in REM sleep to a significant but small (3 movement increase per night) extent. The percentages of body movements observed in the first 7 see after the tone pulse in sleep stages 2 and REM were significantly higher than those observed during the epochs 8-14 and 15-21 see, and those observed to the pseudostimulus. The tone pulse used in this study redistributed or regulated the appearance of the body movements to the proximity of the noise, but did not increase the total number of body movements which appeared to be under endogenous control. [ABSTRACT FROM AUTHOR]

OC07.01: Perinatal mortality and morbidity in twin pregnancies with selective fetal growth restriction according to their management: a meta-analysis To quantify perinatal mortality and morbidity in monochorionic twin pregnancies complicated by selective fetal growth restriction (sFGR) according to their management (expectant, laser or selective reduction) and by Gratacos classification. Primary outcomes were intact survival, survival of at least one twin, intrauterine death (IUD), perinatal death. [Extracted from the article]