Barley based gluten free beer - A blessing or an uncontrollable risk?

Recent reports have highlighted that beer labelled "gluten-free", crafted with enzymatic treatments to remove gluten, may contain polypeptides that could be immunotoxic to individuals with coeliac disease. As strict adherence to a gluten-free diet is the only way to manage this condition, accurate labelling is crucial to those with coeliac disease. This paper aims to discuss the presence, levels and immunogenicity of gluten peptides found in gluten-reduced barley beers. While advances have been made in the detection and quantification of gluten peptides in beer, there are still challenges to the interpretation of gluten measurements as well as to assess whether peptides are immunotoxic in vivo. To make progress, future efforts should involve a combination of in vivo toxicity assessment of the degraded proteins, development of standardised gluten-free production strategies to minimise variability in gluten fragment presence, guidance on how to control the outcome as well as to develop appropriate reference materials and calibrators.

Neonatal Outcomes after Maternal Biomarker-Guided Preterm Birth Intervention: The AVERT PRETERM Trial.

The AVERT PRETERM trial (NCT03151330) evaluated whether screening clinically low-risk pregnancies with a validated maternal blood biomarker test for spontaneous preterm birth (sPTB) risk, followed by preventive treatments for those screening positive, would improve neonatal outcomes compared to a clinically low-risk historical population that had received the usual care. Prospective arm participants with singleton non-anomalous pregnancies and no PTB history were tested for sPTB risk at 191/7-206/7 weeks' gestation and followed up with after neonatal discharge. Screen-positive individuals (≥16% sPTB risk) were offered vaginal progesterone (200 mg) and aspirin (81 mg) daily, with twice-weekly nurse phone calls. Co-primary outcomes were neonatal morbidity and mortality, measured using a validated composite index (NMI), and neonatal hospital length of stay (NNLOS). Endpoints were assessed using survival analysis and logistic regression in a modified intent-to-treat population comprising screen-negative individuals and screen-positive individuals accepting treatment. Of 1460 eligible participants, 34.7% screened positive; of these, 56.4% accepted interventions and 43.6% declined. Compared to historical controls, prospective arm neonates comprising mothers accepting treatment had lower NMI scores (odds ratio 0.81, 95% CI, 0.67-0.98, p = 0.03) and an 18% reduction in severe morbidity. NNLOS was shorter (hazard ratio 0.73, 95% CI, 0.58-0.92, p = 0.01), with a 21% mean stay decrease among neonates having the longest stays. Sensitivity analyses in the entire intent-to-treat population supported these findings. These results suggest that biomarker sPTB risk stratification and preventive interventions can ameliorate PTB complications in singleton, often nulliparous, pregnancies historically deemed low risk.

Peri-Alkylated Terrylenes and Ternaphthalenes Building-Blocks Towards Multi-Edge Nanographenes.

Since its first synthesis by Clar in 1948, terrylene - a fully connected ternaphthalene oligomer via naphthalene's peri-positions - has gained special focus within the rylene family, drawing interest for its unique chemical, structural, optoelectronic and single photon emission properties. In this study, we introduce a novel synthetic pathway that enhances the solubility of terrylene derivatives through complete peri-alkylation, while also facilitating extensions at the bay-positions. This approach not only broadens the scope of terrylene's chemical versatility but also opens new avenues for developing solution processable novel multi-edge nanographenes and tailoring electronic energy levels through topological edge structures. Our findings include a comprehensive structural and spectroscopic characterization along with transient absorption spectroscopy and photophysics of both the synthesized peri-alkylated terrylene and its phenylene-fused derivative.

'Snakes and ladders' in paleoanthropology: From cognitive surprise to skillfulness a million years ago.

A paradigmatic account may suffice to explain behavioral evolution in early Homo. We propose a parsimonious account that (1) could explain a particular, frequently-encountered, archeological outcome of behavior in early Homo - namely, the fashioning of a Paleolithic stone 'handaxe' - from a biological theoretic perspective informed by the free energy principle (FEP); and that (2) regards instances of the outcome as postdictive or retrodictive, circumstantial corroboration. Our proposal considers humankind evolving as a self-organizing biological ecosystem at a geological time-scale. We offer a narrative treatment of this self-organization in terms of the FEP. Specifically, we indicate how 'cognitive surprises' could underwrite an evolving propensity in early Homo to express sporadic unorthodox or anomalous behavior. This co-evolutionary propensity has left us a legacy of Paleolithic artifacts that is reminiscent of a 'snakes and ladders' board game of appearances, disappearances, and reappearances of particular archeological traces of Paleolithic behavior. When detected in the Early and Middle Pleistocene record, anthropologists and archeologists often imagine evidence of unusual or novel behavior in terms of early humankind ascending the rungs of a figurative phylogenetic 'ladder' - as if these corresponded to progressive evolution of cognitive abilities that enabled incremental achievements of increasingly innovative technical prowess, culminating in the cognitive ascendancy of Homo sapiens. The conjecture overlooks a plausible likelihood that behavior by an individual who was atypical among her conspecifics could have been disregarded in a community of Hominina (for definition see Appendix 1) that failed to recognize, imagine, or articulate potential advantages of adopting hitherto unorthodox behavior. Such failure, as well as diverse fortuitous demographic accidents, would cause exceptional personal behavior to be ignored and hence unremembered. It could disappear by a pitfall, down a 'snake', as it were, in the figurative evolutionary board game; thereby causing a discontinuity in the evolution of human behavior that presents like an evolutionary puzzle. The puzzle discomforts some paleoanthropologists trained in the natural and life sciences. They often dismiss it, explaining it away with such self-justifying conjectures as that, maybe, separate paleospecies of Homo differentially possessed different cognitive abilities, which, supposedly, could account for the presence or absence in the Pleistocene archeological record of traces of this or that behavioral outcome or skill. We argue that an alternative perspective - that inherits from the FEP and an individual's 'active inference' about its surroundings and of its own responses - affords a prosaic, deflationary, and parsimonious way to account for appearances, disappearances, and reappearances of particular behavioral outcomes and skills of early humankind.

Grape cultivars adapted to hotter, drier growing regions exhibit greater photosynthesis in hot conditions despite less drought-resistant leaves.

BACKGROUND AND AIMS: Many agricultural areas are expected to face hotter, drier conditions from climate change. Understanding the mechanisms that crops use to mitigate these stresses can guide breeding for more tolerant plant material. We tested relationships between traits, physiological function in hot conditions and historical climate associations to evaluate these mechanisms for winegrapes. We expected a more negative leaf osmotic potential at full hydration (πo), which reduces leaf turgor loss during drought, and either a metabolically cheaper or more osmoprotectant leaf chemical composition, to allow cultivars associated with hot, dry regions to maintain greater gas exchange in hot growing conditions. METHODS: We measured πo, gas exchange and leaf chemistry for seven commercially important winegrape cultivars that vary widely in historical climate associations. Vines were grown in common-garden field conditions in a hot wine-growing region (Davis, CA, USA) and measured over the hottest period of the growing season (July-September). KEY RESULTS: The value of πo varied significantly between cultivars, and all cultivars significantly reduced πo (osmotically adjusted) over the study period, although osmotic adjustment did not vary across cultivars. The value of πo was correlated with gas exchange and climate associations, but in the direction opposite to expected. Photosynthesis and πo were higher in the cultivars associated with hotter, less humid regions. Leaf chemical composition varied between cultivars but was not related to climate associations. CONCLUSIONS: These findings suggest that maintenance of leaf turgor is not a primary limitation on grapevine adaptation to hot or atmospherically dry growing conditions. Thus, selecting for a more negative πo or greater osmotic adjustment is not a promising strategy to develop more climate-resilient grape varieties, contrary to findings for other crops. Future work is needed to identify the mechanisms increasing photosynthesis in the cultivars associated with hot, dry regions.

A candidate antibody drug for prevention of malaria.

Over 75% of malaria-attributable deaths occur in children under the age of 5 years. However, the first malaria vaccine recommended by the World Health Organization (WHO) for pediatric use, RTS,S/AS01 (Mosquirix), has modest efficacy. Complementary strategies, including monoclonal antibodies, will be important in efforts to eradicate malaria. Here we characterize the circulating B cell repertoires of 45 RTS,S/AS01 vaccinees and discover monoclonal antibodies for development as potential therapeutics. We generated >28,000 antibody sequences and tested 481 antibodies for binding activity and 125 antibodies for antimalaria activity in vivo. Through these analyses we identified correlations suggesting that sequences in Plasmodium falciparum circumsporozoite protein, the target antigen in RTS,S/AS01, may induce immunodominant antibody responses that limit more protective, but subdominant, responses. Using binding studies, mouse malaria models, biomanufacturing assessments and protein stability assays, we selected AB-000224 and AB-007088 for advancement as a clinical lead and backup. We engineered the variable domains (Fv) of both antibodies to enable low-cost manufacturing at scale for distribution to pediatric populations, in alignment with WHO's preferred product guidelines. The engineered clone with the optimal manufacturing and drug property profile, MAM01, was advanced into clinical development.

VALOR-CKD: A Multicenter, Randomized, Double-Blind Placebo-Controlled Trial Evaluating Veverimer in Slowing Progression of CKD in Patients with Metabolic Acidosis.

SIGNIFICANCE STATEMENT: Metabolic acidosis is a common complication of CKD and is associated with more rapid decline of kidney function, but well-powered controlled randomized trials testing the effect of treating metabolic acidosis on slowing CKD progression have not been conducted. The VALOR-CKD study randomized 1480 individuals with CKD and metabolic acidosis, across 320 sites to placebo or veverimer (a novel hydrochloric acid binder). The findings did not demonstrate the efficacy of veverimer in slowing CKD progression, but the difference in serum bicarbonate between placebo and drug arms was only approximately 1 mEq/L. Veverimer was safe and well tolerated. BACKGROUND: Metabolic acidosis is common in CKD, but whether its treatment slows CKD progression is unknown. Veverimer, a novel hydrochloric acid binder that removes acid from the gastrointestinal tract, leads to an increase in serum bicarbonate. METHODS: In a phase 3, double-blind, placebo-controlled trial, patients with CKD (eGFR of 20-40 ml/min per 1.73 m 2 ) and metabolic acidosis (serum bicarbonate of 12-20 mEq/L) from 35 countries were randomized to veverimer or placebo. The primary outcome was the composite end point of CKD progression, defined as the development of ESKD (kidney transplantation or maintenance dialysis), a sustained decline in eGFR of ≥40% from baseline, or death due to kidney failure. RESULTS: The mean (±SD) baseline eGFR was 29.2±6.3 ml/min per 1.73 m 2 , and serum bicarbonate was 17.5±1.4 mEq/L; this increased to 23.4±2.0 mEq/L after the active treatment run-in. After randomized withdrawal, the mean serum bicarbonate was 22.0±3.0 mEq/L and 20.9±3.3 mEq/L in the veverimer and placebo groups at month 3, and this approximately 1 mEq/L difference remained stable for the first 24 months. A primary end point event occurred in 149/741 and 148/739 patients in the veverimer and placebo groups, respectively (hazard ratio, 0.99; 95% confidence interval, 0.8 to 1.2; P = 0.90). Serious and overall adverse event incidence did not differ between the groups. CONCLUSIONS: Among patients with CKD and metabolic acidosis, treatment with veverimer did not slow CKD progression. The lower than expected bicarbonate separation may have hindered the ability to test the hypothesis. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: VALOR-CKD, NCT03710291 .

On some statistical and cerebral aspects of the limits of working memory capacity in anthropoid primates, with particular reference to Pan and Homo, and their significance for human evolution.

Some comparative ontogenetic data imply that effective working-memory capacity develops in ways that are independent of brain size in humans. These are interpreted better from neuroscientific considerations about the continuing development of neuronal architecture in adolescents and young adults, than from one about gross brain mass which already is reached in childhood. By contrast, working-memory capacity in Pan never develops beyond that of three- or four-year-old children. The phylogenetic divergence begs the question of whether it is any longer plausible to infer from the fossil record, that over the past two million years, an ostensibly gradual increase in endocranial volumes, assigned to the genus Homo, can be correlated in a scientifically-meaningful manner with the gradual evolution of our effective executive working memory. It is argued that whereas Pan's effective working-memory capacity is relatively similar to that of its storage working-memory, our working memory is relatively larger with deeper executive control.

LIGHTSITE III: 13-Month Efficacy and Safety Evaluation of Multiwavelength Photobiomodulation in Nonexudative (Dry) Age-Related Macular Degeneration Using the Lumithera Valeda Light Delivery System.

PURPOSE: The LIGHTSITE III study evaluated multiwavelength photobiomodulation (PBM) therapy in nonexudative (dry) age-related macular degeneration (AMD) using the LumiThera Valeda Light Delivery System. METHODS: LIGHTSITE III is a randomized, controlled trial to assess the safety and effectiveness of PBM in dry AMD. Subjects were given multiwavelength PBM (590, 660, and 850 nm) or Sham treatment delivered in a series of nine sessions over 3 to 5 weeks every four months over 24 months. Subjects were assessed for efficacy and safety outcomes. Data from the 13-month analysis are presented in this report. RESULTS: A total of 100 subjects (148 eyes) with dry AMD were randomized. LIGHTSITE III met the primary efficacy best-corrected visual acuity endpoint with a significant difference between PBM (n = 91 eyes) and Sham (n = 54 eyes) groups (Between group difference: 2.4 letters (SE 1.15), CI: -4.7 to -0.1, P = 0.02) (PBM alone: 5.4 letters (SE 0.96), CI: 3.5 to 7.3, P < 0.0001; Sham alone: 3.0 letters (SE 1.13), CI: 0.7-5.2, P < 0.0001). The PBM group showed a significant decrease in new onset geographic atrophy ( P = 0.024, Fisher exact test, odds ratio 9.4). A favorable safety profile was observed. CONCLUSION: LIGHTSITE III provides a prospective, randomized, controlled trial showing improved clinical and anatomical outcomes in intermediate dry AMD following PBM therapy.

Clinically and industrially relevant incurred reference materials to improve analysis of food allergens, milk, egg, almond, hazelnut and walnut.

Measurement of food allergen protein concentrations against thresholds can improve allergen risk management and precautionary allergen labelling. Such measurement suffers well known problems which could be ameliorated by well characterised reference materials (RMs) providing meaningful information for risk assessors. We investigated the preparation and characterisation of the first consensus informed industrially and clinically relevant multi-allergen matrix RM kit for five priority allergens. It is a medium analytical difficulty processed food chocolate paste matrix (a) devoid of allergens, and (b) incurred with five allergens at the clinically relevant concentration of 10 mg kg-1 expressed as protein. The allergen raw materials: hens' egg white powder, skimmed cows' milk powder, almond powder (full fat), hazelnut powder (partially defatted), and walnut powder (partially defatted), are also available as RMs. The preparation, gravimetric traceability to the SI, homogeneity, and stability were found to be fit-for-purpose and the RMs are now available to the analytical community.

Imitation fidelity increases with age in boys, but not in girls: An intriguing finding in a cohort of children aged 3 to 6 years.

Imitation that entails faithful reproduction of demonstrated behavior by reenacting a sequence of actions accurately is a fast and efficient way to acquire new skills as well as to conform to social norms. Previous studies reported that both culture and gender might impinge on young children's fidelity of imitation. We analyzed the imitative behavior of 87 children whose ages ranged from 3 to 6 years. An instrumental task was administered that offered partial (opaque apparatus) or total (transparent apparatus) information about causal connection between the demonstrated actions and their effect in achieving a desired reward. Imitative fidelity (imitating the actions that were demonstrated by an adult model yet were unnecessary for achieving the instrumental goal) increased as a function of age in boys, whereas no differences were found in girls. This lack of increase in girls can be ascribed to their displaying higher degrees of imitation fidelity at an earlier age.

Go with the flow: deep learning methods for autonomous viscosity estimations.

Closed-loop experiments can accelerate material discovery by automating both experimental manipulations and decisions that have traditionally been made by researchers. Fast and non-invasive measurements are particularly attractive for closed-loop strategies. Viscosity is a physical property for fluids that is important in many applications. It is fundamental in application areas such as coatings; also, even if viscosity is not the key property of interest, it can impact our ability to do closed-loop experimentation. For example, unexpected increases in viscosity can cause liquid-handling robots to fail. Traditional viscosity measurements are manual, invasive, and slow. Here we use convolutional neural networks (CNNs) as an alternative to traditional viscometry by non-invasively extracting the spatiotemporal features of fluid motion under flow. To do this, we built a workflow using a dual-armed collaborative robot that collects video data of fluid motion autonomously. This dataset was then used to train a 3-dimensional convolutional neural network (3D-CNN) for viscosity estimation, either by classification or by regression. We also used these models to identify unknown laboratory solvents, again based on differences in fluid motion. The 3D-CNN model performance was compared with the performance of a panel of human participants for the same classification tasks. Our models strongly outperformed human classification in both cases. For example, even with training on fewer than 50 videos for each liquid, the 3D-CNN model gave an average accuracy of 88% for predicting the identity of five different laboratory solvents, compared to an average accuracy of 32% for human observation. For comparison, random category selection would give an average accuracy of 20%. Our method offers an alternative to traditional viscosity measurements for autonomous chemistry workflows that might be used both for process control (e.g., choosing not to pipette liquids that are too viscous) or for materials discovery (e.g., identifying new polymerization catalysts on the basis of viscosification).

Prediction and Prevention of Preterm Birth: Secondary Analysis of a Randomized Intervention Trial.

Our objective was to evaluate whether pregnancy is prolonged by the use of a proteomics-based maternal serum screening test followed by treatment interventions. This is a secondary analysis of the PREVENT-PTB randomized trial comparing screening with the PreTRM test versus no screening. The primary trial analysis found no significant between-group difference in the preterm birth rate. Rather than considering a dichotomous outcome (preterm versus term), we treated gestational age at birth as a continuous variable using survival analysis. We also evaluated between-group difference in NICU length of stay and duration of respiratory support. Results indicated that pregnancy was significantly prolonged in subjects screened with the PreTRM test compared to controls (adjusted hazard ratio 0.53, 95% confidence interval 0.36-0.78, p < 0.01). Newborns of screened subjects had significantly shorter NICU stays but no significant decrease in duration of respiratory support. In the PreTRM screen-positive group, interventions that were associated with pregnancy prolongation included care management and low-dose aspirin but not 17-hydroxyprogesterone caproate. We conclude that screening with the PreTRM test followed by interventions for screen-positive pregnancies may prolong pregnancy and reduce NICU LOS, but these observations need to be confirmed by additional research.

Trustworthy Data and AI Environments for Clinical Prediction: Application to Crisis-Risk in People With Depression.

Depression is a common mental health condition that often occurs in association with other chronic illnesses, and varies considerably in severity. Electronic Health Records (EHRs) contain rich information about a patient's medical history and can be used to train, test and maintain predictive models to support and improve patient care. This work evaluated the feasibility of implementing an environment for predicting mental health crisis among people living with depression based on both structured and unstructured EHRs. A large EHR from a mental health provider, Mersey Care, was pseudonymised and ingested into the Natural Language Processing (NLP) platform CogStack, allowing text content in binary clinical notes to be extracted. All unstructured clinical notes and summaries were semantically annotated by MedCAT and BioYODIE NLP services. Cases of crisis in patients with depression were then identified. Random forest models, gradient boosting trees, and Long Short-Term Memory (LSTM) networks, with varying feature arrangement, were trained to predict the occurrence of crisis. The results showed that all the prediction models can use a combination of structured and unstructured EHR information to predict crisis in patients with depression with good and useful accuracy. The LSTM network that was trained on a modified dataset with only 1000 most-important features from the random forest model with temporality showed the best performance with a mean AUC of 0.901 and a standard deviation of 0.006 using a training dataset and a mean AUC of 0.810 and 0.01 using a hold-out test dataset. Comparing the results from the technical evaluation with the views of psychiatrists shows that there are now opportunities to refine and integrate such prediction models into pragmatic point-of-care clinical decision support tools for supporting mental healthcare delivery.

Food allergen analysis: A review of current gaps and the potential to fill them by matrix-assisted laser desorption/ionization.

Food allergy remains a public health, business, and regulatory challenge. Risk analysis (RA) and risk management (RM) of food allergens are of great importance and analysis for food allergens is necessary for both. The current workhorse techniques for allergen analysis (enzyme linked immunosorbent assay [ELISA] and real-time polymerase chain reaction) exhibit recognized challenges including variable and antibody specific responses and detection of species DNA rather than allergen protein, respectively. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) enables protein identification, with potential for multiplex analysis and traceability to the System of International units (SI), aiding global measurement standardization. In this review, recent literature has been systematically reviewed to assess progress in LC-MS/MS and define the potential and benefits of matrix-assisted laser desorption/ionization-time-of-flight MS (MALDI-ToF-MS) technology for allergen analysis. MALDI-ToF-MS of initially intact protein is already applied to verify in silico-derived peptide sequences for LC-MS/MS analysis. We describe the origins of MALDI and its future perspectives, including affinity bead-assisted assays coupled to MALDI. Based on the proliferation of reliable and reproducible MALDI-based clinical applications, the technique should emulate the detection capability (sensitivity) of established allergen detection techniques, whilst reducing technical support and having equivalent multiplexing potential to competing techniques, for example, LC-MS/MS and ELISA. Although unlikely to offer inherent SI traceability, MALDI-based allergen analysis will complement existing MS approaches for allergens. Affinity bead-MALDI appears capable of higher throughput at lower cost per sample than almost any existing technique, enabling repeated sub-sampling as a way to reduce representative sampling issues.

Effect of Microstructure and Dislocation Density on Material Removal and Surface Finish of Laser Powder Bed Fusion 316L Stainless Steel Subject to a Self-Terminating Etching Process.

Postprocessing of additively manufactured (AM) metal parts to remove support structures or improve the surface condition can be a manually intensive process. One novel solution is a two-step, self-terminating etching process (STEP), which achieves both support removal and surface smoothing. While the STEP has been demonstrated for laser powder bed fusion (L-PBF) 316L stainless steel, this work evaluates the impact of pre-STEP heat treatments and resulting changes in dislocation density and microstructure on the resulting surface roughness and amount of material removed. Two pre-STEP heat treatments were evaluated: stress relief at 470°C for 5 h and recrystallization-solution annealing at 1060°C for 1 h. Additionally, one set of specimens was processed without the pre-STEP heat treatment (as-printed condition). Dislocation density and phase composition were quantified using X-ray diffraction along with standard, metallurgical stain-etching techniques. This work, for the first time, highlights the mechanisms of sensitization of AM L-PBF 316L stainless steel and provides fundamental insights into selective etching of these materials. Results showed that the sensitization depth decreased with increasing dislocation density. For samples etched at a STEP bias of 540 mVSHE, material removal terminated at grain boundaries; therefore, the fine-grained stress-relieved specimen had the lowest post-STEP surface roughness. For surface roughness optimization, parts should be stress relived pre-STEP. However, to achieve more material removal, pre-STEP solution annealing should be performed.

Variation in histone configurations correlates with gene expression across nine inbred strains of mice.

The Diversity Outbred (DO) mice and their inbred founders are widely used models of human disease. However, although the genetic diversity of these mice has been well documented, their epigenetic diversity has not. Epigenetic modifications, such as histone modifications and DNA methylation, are important regulators of gene expression and, as such, are a critical mechanistic link between genotype and phenotype. Therefore, creating a map of epigenetic modifications in the DO mice and their founders is an important step toward understanding mechanisms of gene regulation and the link to disease in this widely used resource. To this end, we performed a strain survey of epigenetic modifications in hepatocytes of the DO founders. We surveyed four histone modifications (H3K4me1, H3K4me3, H3K27me3, and H3K27ac), as well as DNA methylation. We used ChromHMM to identify 14 chromatin states, each of which represents a distinct combination of the four histone modifications. We found that the epigenetic landscape is highly variable across the DO founders and is associated with variation in gene expression across strains. We found that epigenetic state imputed into a population of DO mice recapitulated the association with gene expression seen in the founders, suggesting that both histone modifications and DNA methylation are highly heritable mechanisms of gene expression regulation. We illustrate how DO gene expression can be aligned with inbred epigenetic states to identify putative cis-regulatory regions. Finally, we provide a data resource that documents strain-specific variation in the chromatin state and DNA methylation in hepatocytes across nine widely used strains of laboratory mice.