A Phase Ib Trial of Personalized Neoantigen Therapy Plus Anti-PD-1 in Patients with Advanced Melanoma, Non-small Cell Lung Cancer, or Bladder Cancer.

Neoantigens arise from mutations in cancer cells and are important targets of T cell-mediated anti-tumor immunity. Here, we report the first open-label, phase Ib clinical trial of a personalized neoantigen-based vaccine, NEO-PV-01, in combination with PD-1 blockade in patients with advanced melanoma, non-small cell lung cancer, or bladder cancer. This analysis of 82 patients demonstrated that the regimen was safe, with no treatment-related serious adverse events observed. De novo neoantigen-specific CD4+ and CD8+ T cell responses were observed post-vaccination in all of the patients. The vaccine-induced T cells had a cytotoxic phenotype and were capable of trafficking to the tumor and mediating cell killing. In addition, epitope spread to neoantigens not included in the vaccine was detected post-vaccination. These data support the safety and immunogenicity of this regimen in patients with advanced solid tumors (Clinicaltrials.gov: NCT02897765).

Regularized parametric survival modeling to improve risk prediction models.

We propose to combine the benefits of flexible parametric survival modeling and regularization to improve risk prediction modeling in the context of time-to-event data. Thereto, we introduce ridge, lasso, elastic net, and group lasso penalties for both log hazard and log cumulative hazard models. The log (cumulative) hazard in these models is represented by a flexible function of time that may depend on the covariates (i.e., covariate effects may be time-varying). We show that the optimization problem for the proposed models can be formulated as a convex optimization problem and provide a user-friendly R implementation for model fitting and penalty parameter selection based on cross-validation. Simulation study results show the advantage of regularization in terms of increased out-of-sample prediction accuracy and improved calibration and discrimination of predicted survival probabilities, especially when sample size was relatively small with respect to model complexity. An applied example illustrates the proposed methods. In summary, our work provides both a foundation for and an easily accessible implementation of regularized parametric survival modeling and suggests that it improves out-of-sample prediction performance.

Transport of the Proinflammatory Chemokines C-C Motif Chemokine Ligand 2 (MCP-1) and C-C Motif Chemokine Ligand 5 (RANTES) across the Intact Mouse Blood-Brain Barrier Is Inhibited by Heparin and Eprodisate and Increased with Systemic Inflammation.

One important function of the vascular blood-brain barrier (BBB) is to facilitate neuroimmune communication. The BBB fulfills this function, in part, through its ability to transport cytokines and chemokines. C-C motif chemokine receptor 2 (CCL2) (MCP-1) and C-C motif chemokine receptor 5 (CCL5) (RANTES) are proinflammatory chemokines that mediate neuroimmune responses to acute insults and aspects of brain injury and neurodegenerative diseases; however, a blood-to-brain transport system has not been evaluated for either chemokine in vivo. Therefore, we determined whether CCL2 and CCL5 in blood can cross the intact BBB and enter the brain. Using CD-1 mice, we found that 125I-labeled CCL2 and CCL5 crossed the BBB and entered the brain parenchyma. We next aimed to identify the mechanisms of 125I-CCL2 and 125I-CCL5 transport in an in situ brain perfusion model. We found that both heparin and eprodisate inhibited brain uptake of 125I-CCL2 and 125I-CCL5 in situ, whereas antagonists of their receptors, CCR2 or CCR5, respectively, did not, suggesting that heparan sulfates at the endothelial surface mediate BBB transport. Finally, we showed that CCL2 and CCL5 transport across the BBB increased following a single injection of 0.3 mg/kg lipopolysaccharide. These data demonstrate that CCL2 and CCL5 in the brain can derive, in part, from the circulation, especially during systemic inflammation. Further, binding to the BBB-associated heparan sulfate is a mechanism by which both chemokines can cross the intact BBB, highlighting a novel therapeutic target for treating neuroinflammation. SIGNIFICANCE STATEMENT: Our work demonstrates that C-C motif chemokine ligand 2 (CCL2) and C-C motif chemokine ligand 5 (CCL5) can cross the intact blood-brain barrier and that transport is robustly increased during inflammation. These data suggest that circulating CCL2 and CCL5 can contribute to brain levels of each chemokine. We further show that the transport of both chemokines is inhibited by heparin and eprodisate, suggesting that CCL2/CCL5-heparan sulfate interactions could be therapeutically targeted to limit accumulation of these chemokines in the brain.

Blood-brain barrier penetration of non-replicating SARS-CoV-2 and S1 variants of concern induce neuroinflammation which is accentuated in a mouse model of Alzheimer's disease.

COVID-19 and especially Long COVID are associated with severe CNS symptoms and may place persons at risk to develop long-term cognitive impairments. Here, we show that two non-infective models of SARS-CoV-2 can cross the blood-brain barrier (BBB) and induce neuroinflammation, a major mechanism underpinning CNS and cognitive impairments, even in the absence of productive infection. The viral models cross the BBB by the mechanism of adsorptive transcytosis with the sugar N-acetylglucosamine being key. The delta and omicron variants cross the BB B faster than the other variants of concern, with peripheral tissue uptake rates also differing for the variants. Neuroinflammation induced by icv injection of S1 protein was greatly enhanced in young and especially in aged SAMP8 mice, a model of Alzheimer's disease, whereas sex and obesity had little effect.

Design, Synthesis, and Physicochemical Studies of Configurationally Stable ß-Carboline Atropisomers.

Axially chiral atropisomers have energetic barriers to rotation, ΔGrot, that prevent racemization of the respective enantiomers. We used computational modeling to develop a suite of 10 bio-inspired 1-aryl-ß-carbolines with varying ΔGrot, from which a strong structure-activity relationship was observed for 2-substituted-1-naphthyl substituents. We then synthesized two of these atropisomers, 1d and 1f, by a four-step racemic synthesis and resolved the enantiomers via chiral chromatography. Racemization studies revealed experimental ΔGrot values of 39.5 and 33.0 kcal/mol for 1d and 1f, respectively, which were consistent with our computational results. These atropisomers exhibited long half-lives, which allowed for their physicochemical characterization and stereochemical assignment via UV-vis spectroscopy, fluorescence spectroscopy, electronic circular dichroism, and vibrational circular dichroism.

External validation of prognostic models to predict stillbirth using International Prediction of Pregnancy Complications (IPPIC) Network database: individual participant data meta-analysis.

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.

Can risk prediction models help us individualise stillbirth prevention? A systematic review and critical appraisal of published risk models.

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. TWEETABLE ABSTRACT: Prediction models using maternal factors, blood tests and ultrasound could individualise stillbirth prevention, but existing models are at high risk of bias.

Small-scale intraspecific patterns of adaptive immunogenetic polymorphisms and neutral variation in Lake Superior lake trout.

Many fishes express high levels of intraspecific variability, often linked to resource partitioning. Several studies show that a species' evolutionary trajectory of adaptive divergence can undergo reversals caused by changes in its environment. Such a reversal in neutral genetic and morphological variation among lake trout Salvelinus namaycush ecomorphs appears to be underway in Lake Superior. However, a water depth gradient in neutral genetic divergence was found to be associated with intraspecific diversity in the lake. To investigate patterns of adaptive immunogenetic variation among lake trout ecomorphs, we used Illumina high-throughput sequencing. The population's genetic structure of the major histocompatibility complex (MHC Class IIß exon 2) and 18 microsatellite loci were compared to disentangle neutral and selective processes at a small geographic scale. Both MHC and microsatellite variation were partitioned more by water depth stratum than by ecomorph. Several metrics showed strong clustering by water depth in MHC alleles, but not microsatellites. We report a 75% increase in the number of MHC alleles shared between the predominant shallow and deep water ecomorphs since a previous lake trout MHC study at the same locale (c. 1990s data). This result is consistent with the reverse speciation hypothesis, although adaptive MHC polymorphisms persist along an ecological gradient. Finally, results suggested that the lake trout have multiple copies of the MHC II locus consistent with a historic genomic duplication event. Our findings indicated that conservation approaches for this species could focus on managing various ecological habitats by depth, in addition to regulating the fisheries specific to ecomorphs.

Random-effects meta-analysis of the clinical utility of tests and prediction models.

The use of data from multiple studies or centers for the validation of a clinical test or a multivariable prediction model allows researchers to investigate the test's/model's performance in multiple settings and populations. Recently, meta-analytic techniques have been proposed to summarize discrimination and calibration across study populations. Here, we rather consider performance in terms of net benefit, which is a measure of clinical utility that weighs the benefits of true positive classifications against the harms of false positives. We posit that it is important to examine clinical utility across multiple settings of interest. This requires a suitable meta-analysis method, and we propose a Bayesian trivariate random-effects meta-analysis of sensitivity, specificity, and prevalence. Across a range of chosen harm-to-benefit ratios, this provides a summary measure of net benefit, a prediction interval, and an estimate of the probability that the test/model is clinically useful in a new setting. In addition, the prediction interval and probability of usefulness can be calculated conditional on the known prevalence in a new setting. The proposed methods are illustrated by 2 case studies: one on the meta-analysis of published studies on ear thermometry to diagnose fever in children and one on the validation of a multivariable clinical risk prediction model for the diagnosis of ovarian cancer in a multicenter dataset. Crucially, in both case studies the clinical utility of the test/model was heterogeneous across settings, limiting its usefulness in practice. This emphasizes that heterogeneity in clinical utility should be assessed before a test/model is routinely implemented.

The pharmacokinetics and metabolism of diclofenac in chimeric humanized and murinized FRG mice.

The pharmacokinetics of diclofenac were investigated following single oral doses of 10 mg/kg to chimeric liver humanized and murinized FRG and C57BL/6 mice. In addition, the metabolism and excretion were investigated in chimeric liver humanized and murinized FRG mice. Diclofenac reached maximum blood concentrations of 2.43 ± 0.9 µg/mL (n = 3) at 0.25 h post-dose with an AUCinf of 3.67 µg h/mL and an effective half-life of 0.86 h (n = 2). In the murinized animals, maximum blood concentrations were determined as 3.86 ± 2.31 µg/mL at 0.25 h post-dose with an AUCinf of 4.94 ± 2.93 µg h/mL and a half-life of 0.52 ± 0.03 h (n = 3). In C57BL/6J mice, mean peak blood concentrations of 2.31 ± 0.53 µg/mL were seen 0.25 h post-dose with a mean AUCinf of 2.10 ± 0.49 µg h/mL and a half-life of 0.51 ± 0.49 h (n = 3). Analysis of blood indicated only trace quantities of drug-related material in chimeric humanized and murinized FRG mice. Metabolic profiling of urine, bile and faecal extracts revealed a complex pattern of metabolites for both humanized and murinized animals with, in addition to unchanged parent drug, a variety of hydroxylated and conjugated metabolites detected. The profiles in humanized mice were different to those of both murinized and wild-type animals, e.g., a higher proportion of the dose was detected in the form of acyl glucuronide metabolites and much reduced amounts as taurine conjugates. Comparison of the metabolic profiles obtained from the present study with previously published data from C57BL/6J mice and humans revealed a greater, though not complete, match between chimeric humanized mice and humans, such that the liver humanized FRG model may represent a model for assessing the biotransformation of such compounds in humans.

Duplications and losses of genes encoding known elements of the stress defence system of the Aspergilli contribute to the evolution of these filamentous fungi but do not directly influence their environmental stress tolerance.

The contribution of stress protein duplication and deletion events to the evolution of the Aspergilli was studied. We performed a large-scale homology analysis of stress proteins and generated and analysed three stress defence system models based on Saccharomyces cerevisiae, Schizosaccharomyces pombe and Aspergillus nidulans. Although both yeast-based and A. nidulans-based models were suitable to trace evolutionary changes, the A. nidulans-based model performed better in mapping stress protein radiations. The strong Mantel correlation found between the positions of species in the phylogenetic tree on the one hand and either in the A. nidulans-based or S. cerevisiae-based models on the other hand demonstrated that stress protein expansions and reductions contributed significantly to the evolution of the Aspergilli. Interestingly, stress tolerance attributes correlated well with the number of orthologs only for a few stress proteins. Notable examples are Ftr1 iron permease and Fet3 ferro-O2-oxidoreductase, elements of the reductive iron assimilation pathway, in the S. cerevisiae-based model, as well as MpkC, a HogA-like mitogen activated protein kinase in the A. nidulans-based model. In the case of the iron assimilation proteins, the number of orthologs showed a positive correlation with H2O2-induced stress tolerance while the number of MpkC orthologs correlated positively with Congo Red induced cell wall stress, sorbitol induced osmotic stress and H2O2 induced oxidative stress tolerances. For most stress proteins, changes in the number of orthologs did not correlate well with any stress tolerance attributes. As a consequence, stress tolerance patterns of the studied Aspergilli did not correlate with either the sets of stress response proteins in general or with the phylogeny of the species studied. These observations suggest that stress protein duplication and deletion events significantly contributed to the evolution of stress tolerance attributes of Aspergilli. In contrast, there are other processes, which may counterbalance the effects of stress gene duplications or deletions including (i) alterations in the structures of stress proteins leading to changes in their biological activities, (ii) varying biosynthesis of stress proteins, (iii) rewiring stress response regulatory networks or even (iv) acquiring new stress response genes by horizontal gene transfer. All these multilevel changes are indispensable for the successful adaptation of filamentous fungi to altering environmental conditions, especially when these organisms are entering new ecological niches.

The gold-standard genome of Aspergillus niger NRRL 3 enables a detailed view of the diversity of sugar catabolism in fungi.

The fungal kingdom is too large to be discovered exclusively by classical genetics. The access to omics data opens a new opportunity to study the diversity within the fungal kingdom and how adaptation to new environments shapes fungal metabolism. Genomes are the foundation of modern science but their quality is crucial when analysing omics data. In this study, we demonstrate how one gold-standard genome can improve functional prediction across closely related species to be able to identify key enzymes, reactions and pathways with the focus on primary carbon metabolism. Based on this approach we identified alternative genes encoding various steps of the different sugar catabolic pathways, and as such provided leads for functional studies into this topic. We also revealed significant diversity with respect to genome content, although this did not always correlate to the ability of the species to use the corresponding sugar as a carbon source.

Experiences of patients and healthcare professionals of NHS cardiovascular health checks: a qualitative study.

BACKGROUND: NHS Health Checks are a national cardiovascular risk assessment and management programme in England and Wales. We examined the experiences of patients attending and healthcare professionals (HCPs) conducting NHS Health Checks. METHODS: Interviews were conducted with a purposive sample of 28 patients and 16 HCPs recruited from eight general practices across a range of socio-economic localities. Interviews were audio recorded, transcribed, anonymized and analysed thematically. RESULTS: Patients were motivated to attend an NHS Health Check because of health beliefs, the perceived value of the programme, a family history of cardiovascular and other diseases and expectations of receiving a general health assessment. Some patients reported benefits including reassurance and reinforcement of healthy lifestyles. Others experienced confusion and frustration about how results and advice were communicated, some having a poor understanding of the implications of their results. HCPs raised concerns about the skill set of some staff to competently communicate risk and lifestyle information. CONCLUSIONS: To improve the satisfaction of patients attending and improve facilitation of lifestyle change, HCPs conducting the NHS Health Checks require sufficient training to equip them with appropriate skills and knowledge to deliver the service effectively.

Patterns of chromosomal variation in natural populations of the neoallotetraploid Tragopogon mirus (Asteraceae).

Cytological studies have shown many newly formed allopolyploids (neoallopolyploids) exhibit chromosomal variation as a result of meiotic irregularities, but few naturally occurring neoallopolyploids have been examined. Little is known about how long chromosomal variation may persist and how it might influence the establishment and evolution of allopolyploids in nature. In this study we assess chromosomal composition in a natural neoallotetraploid, Tragopogon mirus, and compare it with T. miscellus, which is an allotetraploid of similar age (~40 generations old). We also assess whether parental gene losses in T. mirus correlate with entire or partial chromosome losses. Of 37 T. mirus individuals that were karyotyped, 23 (62%) were chromosomally additive of the parents, whereas the remaining 14 individuals (38%) had aneuploid compositions. The proportion of additive versus aneuploid individuals differed from that found previously in T. miscellus, in which aneuploidy was more common (69%; Fisher's exact test, P=0.0033). Deviations from parental chromosome additivity within T. mirus individuals also did not reach the levels observed in T. miscellus, but similar compensated changes were observed. The loss of T. dubius-derived genes in two T. mirus individuals did not correlate with any chromosomal changes, indicating a role for smaller-scale genetic alterations. Overall, these data for T. mirus provide a second example of prolonged chromosomal instability in natural neoallopolyploid populations.

When is birthweight at term (≥37 weeks' gestation) abnormally low? A systematic review and meta-analysis of the prognostic and predictive ability of current birthweight standards for childhood and adult outcomes.

BACKGROUND: Health outcomes throughout the life course have been linked to fetal growth restriction and low birthweight. A variety of measures exist to define low birthweight, with a lack of consensus regarding which predict adverse outcome. OBJECTIVES: To evaluate the relationship between birthweight standards and childhood and adult outcomes in term-born infants (≥37 weeks' gestation). SEARCH STRATEGY: MEDLINE (1966-January 2011), EMBASE (1980-January 2011), and the Cochrane Library (2011:1) and MEDION were included. SELECTION CRITERIA: Studies comprising live term-born infants (gestation ≥37 completed weeks), with weight or other anthropometric measurements recorded at birth along with childhood and adult outcomes. DATA COLLECTION AND ANALYSIS: Data were extracted to populate 2 × 2 tables relating birthweight standard with outcome, and meta-analysis was performed where possible. MAIN RESULTS: Fifty-nine articles (2 600 383 individuals) were selected. There was no significant relationship between birthweight <2.5 kg (odds ratio [OR] 0.98, 95% confidence intervals [CI] 0.87-1.10) and composite measure of childhood morbidity. Weight <10th centile on the population nomogram showed a small association (OR 1.49, 95% CI 1.02-2.19) for the same outcome. There was no significant association between either of the above measures and adult morbidity. The relationship between other measures and individual outcomes varied. AUTHOR'S CONCLUSIONS: The association between low birthweight, by any definition, and childhood and adult morbidity was inconsistent. None of the current standards of low birthweight was a good predictor of adverse outcome.

When is birthweight at term abnormally low? A systematic review and meta-analysis of the association and predictive ability of current birthweight standards for neonatal outcomes.

BACKGROUND: Intrauterine growth restriction is a cause of neonatal morbidity and mortality. A variety of definitions of low birthweight are used in clinical practice, with a lack of consensus regarding which definitions best predict adverse outcomes. OBJECTIVES: To evaluate the relationship between birthweight standards and neonatal outcome in term-born infants (at ≥ 37 weeks of gestation). SEARCH STRATEGY: MEDLINE (1966-January 2011), EMBASE (1980-January 2011), and the Cochrane Library (2011:1) and MEDION were included in our search. SELECTION CRITERIA: Studies comprising live term-born infants (gestation ≥ 37 completed weeks), with weight or other anthropometric measurements recorded at birth along with neonatal outcomes. DATA COLLECTION AND ANALYSIS: Data were extracted to populate 2 × 2 tables relating birthweight standard with outcome, and meta-analysis was performed where possible. MAIN RESULTS: Twenty-nine studies including 21 034 114 neonates were selected. Absolute birthweight was strongly associated with mortality, with birthweight < 1.5 kg giving the largest association (OR 48.6, 95% CI 28.62-82.53). When using centile charts, regardless of threshold, the summary odds ratios were significant but closer to 1 than when using absolute birthweight. For all tests, summary predictive ability comprised high specificity and positive likelihood ratio for neonatal death, but low sensitivity and a negative likelihood ratio close to 1. AUTHOR'S CONCLUSIONS: Absolute birthweight is a prognostic factor for neonatal mortality. The indirect evidence suggests that centile charts or other definitions of low birthweight are not as strongly associated with mortality as the absolute birthweight. Further research is required to improve predictive accuracy.

Association and prediction of amniotic fluid measurements for adverse pregnancy outcome: systematic review and meta-analysis.

BACKGROUND: Measurements of amniotic fluid volume are used for pregnancy surveillance despite a lack of evidence for their predictive ability. OBJECTIVE: To evaluate the association and predictive value of ultrasound measurements of amniotic fluid volume for adverse pregnancy outcome. SEARCH STRATEGY: Electronic databases (inception to October 2011), reference lists, hand searching of journals, contact with experts. SELECTION CRITERIA: Studies comparing measurements of amniotic fluid volume with adverse outcome, excluding pre-labour ruptured membranes or congenital/structural anomalies. DATA COLLECTION: Data on study characteristics, design, quality. Random effects meta-analysis to estimate summary odds ratios (prognostic association) and summary sensitivity, specificity and likelihood ratios (predictive ability). MAIN RESULTS: Forty-three studies (244,493 fetuses) were included demonstrating a strong association between oligohydramnios (varying definitions) and birthweight <10th centile (summary odds ratio [OR] 6.31, 95% confidence interval [95% CI] 4.15-9.58; high-risk population [author definition] n = 6 studies, 28,510 fetuses), and mortality (neonatal death any population summary OR 8.72, 95% CI 2.43-31.26; n = 6 studies, 55,735 fetuses; and perinatal mortality high-risk population summary OR 11.54, 95% CI 4.05-32.9; n = 2 studies, 27;891 fetuses). There was a strong association between polyhydramnios (maximum pool depth >8 cm or amniotic fluid index ≥25 cm) and birthweight >90th centile (OR 11.41, 95% CI 7.09-18.36; n = 1 study, 3960 fetuses). Despite strong associations, predictive accuracy for perinatal outcome was poor. AUTHOR'S CONCLUSION: Current evidence suggests that oligohydramnios is strongly associated with being small for gestational age and mortality, and polyhydramnios with birthweight >90th centile. Despite strong associations with poor outcome, they do not accurately predict outcome risk for individuals.

Simultaneous High-Frame-Rate Acoustic Plane-Wave and Optical Imaging of Intracranial Cavitation in Polyacrylamide Brain Phantoms during Blunt Force Impact.

Blunt and blast impacts occur in civilian and military personnel, resulting in traumatic brain injuries necessitating a complete understanding of damage mechanisms and protective equipment design. However, the inability to monitor in vivo brain deformation and potential harmful cavitation events during collisions limits the investigation of injury mechanisms. To study the cavitation potential, we developed a full-scale human head phantom with features that allow a direct optical and acoustic observation at high frame rates during blunt impacts. The phantom consists of a transparent polyacrylamide material sealed with fluid in a 3D-printed skull where windows are integrated for data acquisition. The model has similar mechanical properties to brain tissue and includes simplified yet key anatomical features. Optical imaging indicated reproducible cavitation events above a threshold impact energy and localized cavitation to the fluid of the central sulcus, which appeared as high-intensity regions in acoustic images. An acoustic spectral analysis detected cavitation as harmonic and broadband signals that were mapped onto a reconstructed acoustic frame. Small bubbles trapped during phantom fabrication resulted in cavitation artifacts, which remain the largest challenge of the study. Ultimately, acoustic imaging demonstrated the potential to be a stand-alone tool, allowing observations at depth, where optical techniques are limited.

Neurocognitive predictors of transition to psychosis: medium- to long-term findings from a sample at ultra-high risk for psychosis.

BACKGROUND: Individuals at ultra-high risk (UHR) for psychosis show reduced neurocognitive performance across domains but it is unclear which reductions are associated with transition to frank psychosis. The aim of this study was to investigate differences in baseline neurocognitive performance between UHR participants with (UHR-P) and without transition to psychosis (UHR-NP) and a healthy control (HC) group and examine neurocognitive predictors of transition over the medium to long term. METHOD: A sample of 325 UHR participants recruited consecutively from the Personal Assessment and Crisis Evaluation (PACE) Clinic in Melbourne and 66 HCs completed a neurocognitive assessment at baseline. The UHR group was followed up between 2.39 and 14.86 (median = 6.45) years later. Cox regression was used to investigate candidate neurocognitive predictors of psychosis onset. RESULTS: The UHR group performed more poorly than the HC group across a range of neurocognitive domains but only performance on digit symbol coding and picture completion differed between the groups. The risk of transition was only significantly associated with poorer performance on visual reproduction [hazard ratio (HR) 0.919, 95% confidence interval (CI) 0.876-0.965, p = 0.001] and matrix reasoning (HR 0.938, 95% CI 0.883-0.996, p = 0.037). These remained significant even after controlling for psychopathology at baseline. CONCLUSIONS: This study is the longest follow-up of an UHR sample to date. UHR status was associated with poorer neurocognitive performance compared to HCs on some tasks. Cognition at identification as UHR was not a strong predictor of risk for transition to psychosis. The results suggests the need to include more experimental paradigms that isolate discrete cognitive processes to better understand neurocognition at this early stage of illness.

Dissecting the relative contribution of OATP1B1-mediated uptake of xenobiotics into human hepatocytes using siRNA.

1. Organic anion transporting polypeptide 1B1 plays a pivotal role in the disposition of many anionic drugs. Significant overlap in substrate specificity between individual OATP isoforms has hampered the identification of the relative importance of individual isoforms for hepatic uptake of xenobiotics. 2. The present study focused on the use of siRNA technology to decrease OATP1B1 selectively in human hepatocytes. Following delivery of siRNA by the novel lipid, AtuFECT01, mRNA expression of OATP1B1 was reduced by 94%-98% with no significant toxicity. Off-target effects were also shown to be minimal as evidenced by the expression of common drug metabolizing enzymes, transporters, nuclear receptors and associated co-regulators. Uptake of estrone-3-sulfate (5 nM) by OATP1B1 was reduced by 82%-95%. This methodology was subsequently used to assess the relative contribution of OATP1B1 uptake in human hepatocytes for olmesartan (42%-62%), valsartan (28%-81%), rosuvastatin (64%-72%), pitavastatin (84%-98%) and lopinavir (64%-89%). These data are consistent with previous values obtained using a relative activity factor approach. 3. The siRNA approach provides a robust and reproducible method for assessing the relative contribution of OATP1B1 to hepatic uptake of new chemical entities. The technique also has potential utility in facilitating detailed characterization of drug-drug interactions involving hepatic drug transporters.