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 .

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.

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.

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.

'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.

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.

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.

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.