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There are two main complementary feeding (CF) approaches: traditional spoon-feeding (TSF) and baby-led weaning (BLW). Many parents and healthcare professionals have concerns about the risk of choking associated with BLW. Since asphyxia is one of infants' main causes of death, this study aims to understand the influence of the CF approach adopted by caregivers on infants' risk of choking. A systematic review was performed. The search was conducted through PubMed, Scopus, and Web of Science databases. We included randomized controlled trials or observational studies published between January 2010 and November 2023, with a clear definition of the intervention and directly assessing the risk of choking. After the selection procedure, 7 of the 165 studies initially identified were included. No study reported statistically significant differences in the risk of choking between babies following BLW, baby-led introduction to solids (BLISS), and TSF. In five studies, although not statistically significant, infants in the TSF group had more choking episodes than those in the BLW or BLISS groups. The risk of choking does not seem to be associated with the CF approach. Instead, it may be related to the familiarity of the baby with each texture and the parent's understanding of the information about how to minimize the risk of choking. Recall bias may be present in all included studies. Advice on how to modify foods to make them safer needs to be clearer and reinforced to all parents., (© 2024 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Immunotherapies employing PD-1/PD-L1 immune checkpoint inhibitors (ICIs) are vital for primary liver cancer (PLC), but response rates remain unsatisfying. Accurate differentiation of responders from non-responders to immunotherapy is imperative. Here, single-cell-scaled mass cytometry analysis on sequential peripheral blood mononuclear cells (PBMCs) from ICI-treated PLC patients is conducted, and tissue residence of immune subpopulations is assessed via multiplex immunohistochemistry. In the discovery cohort (n = 24), responders have lower baseline B cell and HLA-DR + CD8 + T cell, and higher CD14 + CD16 - classical monocyte (CM) proportions. CMs decrease more in responders PBMCs, while HLA-DR + CD8 + T cells conformably amplify after ICI-exposure. Responsive individuals display upregulated exhaustion and activation markers in peripheral immune lineages. In the expanded cohort of 77 patients, the augment of the B cells in non-responders is re-confirmed. Responders demonstrate much higher enrichment of B cells or tertiary lymphoid structures in tumor compared to non-responders. A prospective model that excelled in early discrimination of responders is developed using generalized linear model and achieves a satisfactory AUC over 0.9 in all three independent cohorts. Integratedly, the study unveils dynamic immune landscapes in PLC patients undergoing ICI-based therapy, aiding in PLC patient stratification for ICI-based treatment and fostering new response monitoring strategies., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Our research on the chromium complex of macrocyclic ligands as a precursor for nitric oxide release makes a significant contribution to the field of chemistry. We conduct a detailed analysis of nitrito chromium complexes, specifically trans-[M(III)L 1-5 (ONO) 2 ] + , where M=Cr(III) and L 1 -L 5 represent different ligands such as L 1 =1,4,8,11-tetraazacyclotetradecane, L 2 = (5,7-dimethyl-6-benzylcyclam), L 3 = (5,7-dimethyl-6-anthracylcyclam), L 4 = (5,7-dimethyl-6-(p-hydroxymethylbenzyl)-1,4, 8,11-cyclam) and L 5 = (5,7-dimethyl-6-(1¢-methyl-4'-(1"-carboxymethylpyrene) benzyl)-1,4,8,11-tetraazacyclotetradecane). Our objective is to comprehensively understand the mechanism of NO release and identify the key factors influencing NO delivery. The optimized structure of the complexes at spin states S=1/2 or 3/2 indicates a decrease in the Cr(III)-O bond length (1.669-1.671 Å) along with an increase in the Cr(III)O-NO bond length (2.735-2.741 Å), which facilitates the release of NO. Furthermore, there is a significant change in the bond angle (Cr-O-NO), from 120.4° to 116.9°, to S=3/2, thus enlarging the O-NO bond and supporting the β-cleavage of NO from the complex. The calculated activation energy for the complexes reflects the energy difference between the low-spin doublet and high-spin quartet state due to spin crossover (SCO). Moreover, the Natural Transition Orbitals (NTOs) confirm the involvement of a hole-particle in the excitation. Additionally, TD-DFT reveals the pendant chromophore's role in generating NO, as the chromophore antenna effectively enhances light absorption., (© 2024 Wiley-VCH GmbH.)

Purpose: To assess the association between professional reintegration and mental health, quality of life (QoL) and community reintegration of stroke survivors., Methods: Using a cross-sectional study design, a structured questionnaire was administered to previously working stroke survivors, 18-24 months post-stroke. Data on sociodemographic characteristics, professional reintegration (prevalence of return to work (RTW), period of RTW, job placement, function at work, reintegration support, association of stroke with work and number of working hours), mental health (Hospital Anxiety and Depression Questionnaire), QoL (Stroke Specific Quality of Life Scale) and community integration (Community Integration Questionnaire) were reported by 553 stroke survivors., Results: Twenty months after stroke, 313 (56.6%; 95%CI 52.4-60.8) stroke survivors had return to work. RTW was positively associated with both global and sub-domains scores of Community Integration Questionnaire (CIQ) (global CIQ β = 3.50; 95%CI 3.30-3.79) and with depressive symptomatology (β = 0.63; 95%CI 0.20-1.46) measured by the Hospital Anxiety and Depression Scale. No significant differences were found regarding QoL, according to RTW status. For those who RTW, no significant associations were found between any of the professional reintegration determinants assessed and mental health, QoL and community integration scores., Conclusions: RTW seems to be associated to better community integration after stroke, but appears to be negatively associated to stroke survivor's mental health, namely considering depression symptoms. Future studies should explore the barriers to stroke survivors' RTW and the challenges and strategies used to overcome them, to allow the development of professional reintegration policies., (© 2024. The Author(s).)

Following intensive care unit hospitalization, survivors of acute neurological injury often experience debilitating short-term and long-term impairments. Although the physical/motor impairments experienced by survivors of acute neurological injury have been described extensively, fewer studies have examined cognitive, mental health, health-related quality of life (HRQoL), and employment outcomes. This scoping review describes the publication landscape beyond physical and/or motor sequelae in neurocritical care survivors. Databases were searched for terms related to critical illness, intensive care, and outcomes from January 1970 to March 2022. English-language studies of critically ill adults with a primary neurological diagnosis were included if they reported on at least one outcome of interest: cognition, mental health, HRQoL or employment. Data extraction was performed in duplicate for prespecified variables related to study outcomes. Of 16,036 abstracts screened, 74 citations were identified for inclusion. The studies encompassed seven worldwide regions and eight neurocritical diagnosis categories. Publications reporting outcomes of interest increased from 3 before the year 2000 to 71 after. Follow-up time points included ≤ 1 (n = 15 [20%] citations), 3 (n = 28 [38%]), 6 (n = 28 [38%]), and 12 (n = 21 [28%]) months and 1 to 5 (n = 19 [26%]) and > 5 years (n = 8 [11%]), with 28 (38%) citations evaluating outcomes at multiple time points. Sixty-six assessment tools were used to evaluate the four outcomes of interest: 22 evaluating HRQoL (56 [76%] citations), 21 evaluating cognition (20 [27%] citations), 21 evaluating mental health (18 [24%] citations), and 2 evaluating employment (9 [12%] citations). This scoping review aimed to better understand the literature landscape regarding nonphysical outcomes in survivors of neurocritical care. Although a rising number of publications highlight growing awareness, future efforts are needed to improve study consistency and comparability and characterize outcomes in a disease-specific manner, including outlining of a minimum core outcomes set and associated assessment tools., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Cordyceps sinensis , known as the caterpillar fungus, constitutes an invaluable and irreplaceable part of traditional Chinese medicine (TCM) and is now gaining widespread global recognition and dedicated attention owing to both highly promising characteristics as well as grave dangers that are suggestive of an impending doom. C. sinensis possibly holds the key to the treatment of many human ailments with minimal side effects due to a wide array of biologically active chemical constituents. The powerful potential harbored by this fungus has led to a meteoric rise in its prices in the domestic and international markets which has caused the involvement of an increasing number of harvesters, traders, and buyers and unchecked overexploitation of this bioresource thus threatening its long-term survival in its natural habitat of the Himalayan region. This review focuses on the ethnopharmacology of C. sinensis, and various aspects related to its conservation, such as natural distribution, sale and revenue, decline in population density, and conservational practices prevalent in the current scenario of fungal depletion. The paper concludes with a comprehensive evaluation of the discrete therapeutic capabilities possessed by C. sinensis , the mechanistic insights into the remarkable treatment of chronic ailments using the fungus or its derivatives, and a suggested strategic roadmap that may be adopted for fruitful conservation of this natural miracle., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Nitrogen oxides (NO x ) are major environmental pollutants and to neutralize this long-term environmental threat, new catalytic methods are needed. Although there are biological denitrification processes involving four different enzymatic reactions to convert nitrate (NO 3 - ) into dinitrogen (N 2 ), it is unfortunately difficult to apply in industry due to the complexity of the processes. In particular, nitrate is difficult to functionalize because of its chemical stability. Thus, there is no organometallic catalysis to convert nitrate into useful chemicals. Herein, we present a nickel pincer complex that is effective as a bifunctional catalyst to stepwise deoxygenate NO 3 - by carbonylation and further through C-N coupling. By using this nickel catalysis, nitrate salts can be selectively transformed into various oximes (>20 substrates) with excellent conversion (>90 %). Here, we demonstrate for the first time that the highly inert nitrate ion can be functionalized to produce useful chemicals by a new organonickel catalysis. Our results show that the NO x conversion and utilization (NCU) technology is a successful pathway for environmental restoration coupled with value-added chemical generation., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Nitrite (NO 2 - ) serves as a pool of nitric oxide (NO) in biological systems under hypoxic conditions, and it is transformed to NO by nitrite reductase (NiR) enzyme in the presence of acid (H + ions). However, NO synthases (NOSs) generate NO via L-arginine oxidation in normoxic conditions. Previously, acid-induced NO 2 - reduction chemistry was modeled on mono-metallic 3d-metals, generating metal-nitrosyls or NO (g) with H 2 O or H 2 O 2 products. Herein, to understand the relative potency of a bimetallic system, we report the acid-induced reductive conversion of η 2 -bound NO 2 - to NO on Cu II -Co II centers of a hetero-bimetallic Cu II -nitrito-Co II complex, [(LN 8 H)Cu II -NO 2 - -Co II ] 3+ (Cu II -NO 2 - -Co II , 2) bearing an octadentate N 8 -cryptand ligand (LN 8 H). The Cu II -NO 2 - -Co II generates [Cu II (LN 8 H)Co II ] 4+ (1) upon reaction with one equiv. acid (HClO 4 , H + ions source) with NO (g) via a presumed transient nitrousacid (ONOH) intermediate species. Likewise, this NO 2 - reduction was found to form H 2 O, which is believed to be from the decomposition of H 2 O 2 , an intermediate species. In addition, complex 2, in the presence of more than one equiv. H + ions also showed the formation of NO (g) with H 2 O. Mechanistic investigations, using 15 N-labeled- 15 NO 2 - , 18 O-labeled- 18 O 14 N 16 O - and 2 H-labeled-DClO 4 (D + source), revealed that the N-atom and O-atom in the 14/15 NO and 14 N 18 O gases are derived from NO 2 - ligand and H-atom in H 2 O derived from H + -source, respectively., (© 2024 Wiley-VCH GmbH.)

Flavodiiron NO reductases (FNORs) are important enzymes in microbial pathogenesis, as they equip microbes with resistance to the human immune defense agent nitric oxide (NO). Despite many efforts, intermediates that would provide insight into how the non-heme diiron active sites of FNORs reduce NO to N 2 O could not be identified. Computations predict that iron-hyponitrite complexes are the key species, leading from NO to N 2 O. However, the coordination chemistry of non-heme iron centers with hyponitrite is largely unknown. In this study, we report the reactivity of two non-heme iron complexes with preformed hyponitrite. In the case of [Fe(TPA)(CH 3 CN) 2 ](OTf) 2 , cleavage of hyponitrite and formation of an Fe 2 (NO) 2 diamond core is observed. With less Lewis-acidic [Fe 2 (BMPA-PhO) 2 (OTf) 2 ] (2), reaction with Na 2 N 2 O 2 in polar aprotic solvent leads to the formation of a red complex, 3. X-ray crystallography shows that 3 is a tetranuclear iron-hyponitrite complex, [{Fe 2 (BMPA-PhO) 2 } 2 (μ-N 2 O 2 )](OTf) 2 , with a unique hyponitrite binding mode. This species provided the unique opportunity to us to study the interaction of hyponitrite with non-heme iron centers and the reactivity of the bound hyponitrite ligand. Here, either protonation or oxidation of 3 is found to induce N 2 O formation, supporting the hypothesis that hyponitrite is a viable intermediate in NO reduction., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Human-caused mortality can be pervasive and even highly selective for individuals in groups of cooperative breeders. Many studies of cooperative breeders, however, do not address human-caused mortality. Similarly, studies focused on the effects of human-caused mortality on wildlife populations often do not consider the ecology of cooperative breeders. We searched the literature and identified 58 studies where human-caused mortality affected a group characteristic, vital rate, or population state of a cooperative breeder. Of studies reporting population growth or decline, 80% reported a link between human-caused mortality and population declines in cooperative breeders. Such studies often did not identify the mechanism behind population declines, but 28% identified concurrent declines in adult survival and another 21% reported concurrent declines in recruitment or reproduction. There was little overlap between the cooperative breeding and human-caused mortality literatures, limiting our ability to accrue knowledge. Future work would be beneficial if it (i) identified the vital rate(s) causing population declines, (ii) leveraged management actions such as lethal removal to ask questions about the ecology of group-living in cooperative breeders, and (iii) used insights from cooperative breeding theory to inform management actions and conservation of group-living species., (© 2024 Cambridge Philosophical Society.)

People can use their internal state to determine if they are hungry or thirsty. Although the meaning of some interoceptive cues may be innate (e.g., pain), it is possible that others-including those for hunger and thirst-are acquired. There has been little exploration of this idea in humans. Consequently, we conducted a survey among child caregivers to determine if the basic conditions necessary for interoceptive learning were present. Two-hundred and thirty-five caregivers of children aged 1-12 years were asked if they had recently noticed stomach rumbling, hunger-related irritability, and a dry mouth in their child. They were also asked how they would respond. The impact of several moderating variables, especially caregiver beliefs about the causes of hunger, fullness, and thirst, was also explored. Fifteen percent of caregivers had recently noticed stomach rumbling in their child, 28% hunger-related irritability, and 14% a dry mouth. Forty-four percent of caregivers had noticed at least one of these three cues. Noticing hunger cues was significantly moderated by caregiver beliefs about their cause, by child age, and in one case by temporal context (around vs. outside mealtimes). Key caregiver responses were providing the need (e.g., offer food) and/or asking the child if they had a need (e.g., hungry?). Each type of response could potentially support a different form of interoceptive learning. In conclusion, we suggest the necessary conditions for children to learn interoceptive hunger and thirst cues, are present in many caregiver-offspring dyads., (© 2024 The Author(s). Developmental Psychobiology published by Wiley Periodicals LLC.)

The cytochrome P450 homolog, TxtE, efficiently catalyzes the direct and regioselective aromatic nitration of the indolyl moiety of L-tryptophan to 4-nitro-L-tryptophan, using nitric oxide (NO) and dioxygen (O 2 ) as co-substrates. Pathways for such direct and selective nitration of heteroaromatic motifs present platforms for engineering new nitration biocatalysts for pharmacologically beneficial targets, among a medley of other pivotal industrial applications. Precise mechanistic details concerning this pathway are only weakly understood, albeit a heme iron(III)-peroxynitrite active species has been postulated. To shed light on this unique reaction landscape, we investigated the indole nitration pathway of a series of biomimetic ferric heme superoxide mimics, [(Por)Fe III (O 2 - ⋅)], in the presence of NO. Therein, our model systems gave rise to three distinct nitroindole products, including 4-nitroindole, the product analogous to that obtained with TxtE. Moreover, 15 N and 18 O isotope labeling studies, along with meticulously designed control experiments lend credence to a heme peroxynitrite active nitrating agent, drawing close similarities to the tryptophan nitration mechanism of TxtE. All organic and inorganic reaction components have been fully characterized using spectroscopic methods. Theoretical investigation into several mechanistic possibilities deem a unique indolyl radical based reaction pathway as the most energetically favorable, products of which, are in excellent agreement with experimental findings., (© 2024 Wiley-VCH GmbH.)

Nitrogen oxides represent one of the main threats for the environment. Despite decades of intensive research efforts, a sustainable solution for NO x removal under environmental conditions is still undefined. Using theoretical modelling, material design, state-of-the-art investigation methods and mimicking enzymes, it is found that selected porous hybrid iron(II/III) based MOF material are able to decompose NO x , at room temperature, in the presence of water and oxygen, into N 2 and O 2 and without reducing agents. This paves the way to the development of new highly sustainable heterogeneous catalysts to improve air quality., (© 2024 Wiley‐VCH GmbH.)

The Kynurenine pathway (KP) which is involved in the synthesis of nicotinamide adenine dinucleotide (NAD) from tryptophan (Trp) is intricate in the development of insulin resistance (IR) and type 2 diabetes (T2D). Inflammatory reactions in response to cardiometabolic disorders can induce the development of IR through the augmentation of KP. However, kynurenine (KYN), a precursor of kynurenic acid (KA) is increased following physical exercise and involved in the reduction of IR. Consequently, KP metabolites KA and KYN have anti-diabetogenic effects while other metabolites have diabetogenic effects. KP modulators, either inhibitors or activators, affect glucose homeostasis and insulin sensitivity in T2D in a bidirectional way, either protective or detrimental, that is not related to the KP effect. However, metformin through inhibition of inflammatory signaling pathways can reduce the activation of KP in T2D. These findings indicated a strong controversy regarding the role of KP in T2D. Therefore, the objectives of this mini review were to clarify how KP induces the development of IR and T2D. In addition, this review aimed to find the mechanistic role of antidiabetic drug metformin on the KP, and how KP modulators affect the pathogenesis of T2D., (© 2024 Wiley Periodicals LLC.)

Abstract: Vascular cognitive impairment (VCI) encompasses a wide spectrum of cognitive disorders, ranging from mild cognitive impairment to vascular dementia. Its diagnosis relies on thorough clinical evaluations and neuroimaging. VCI predominately arises from vascular risk factors (VRFs) and cerebrovascular disease, either independently or in conjunction with neurodegeneration. Growing evidence underscores the prevalence of VRFs, highlighting their potential for early prediction of cognitive impairment and dementia in later life. The precise mechanisms linking vascular pathologies to cognitive deficits remain elusive. Chronic cerebrovascular pathology is the most common neuropathological feature of VCI, often interacting synergistically with neurodegenerative processes. Current research efforts are focused on developing and validating reliable biomarkers to unravel the etiology of vascular brain changes in VCI. The collaborative integration of these biomarkers into clinical practice, alongside routine incorporation into neuropathological assessments, presents a promising strategy for predicting and stratifying VCI. The cornerstone of VCI prevention remains the control of VRFs, which includes multi-domain lifestyle modifications. Identifying appropriate pharmacological approaches is also of paramount importance. In this review, we synthesize recent advancements in the field of VCI, including its definition, determinants of vascular risk, pathophysiology, neuroimaging and fluid-correlated biomarkers, predictive methodologies, and current intervention strategies. Increasingly evident is the notion that more rigorous research for VCI, which arises from a complex interplay of physiological events, is still needed to pave the way for better clinical outcomes and enhanced quality of life for affected individuals., (Copyright © 2024 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

The objective was to investigate, through a systematic review, which independent variables predict health-related quality of life (HRQoL) one year after stroke. Searches were conducted in LILACS, MEDLINE, Scielo, Web of Science, and PEDro. The inclusion criteria were observational longitudinal studies, which included at least one independent variable measured at baseline, as a potential predictor of HRQoL measured 12 months after stroke. The predictors of interest were variables across all domains of the International Classification of Function, Disability and Health. The quality of evidence was rated according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). A total of 17 papers were included, involving 8338 participants, and 10 possible predictors of the HRQoL one year after stroke. The meta-analysis was performed for six of them (cognition, depression, neurological deficit, stroke severity, motor impairment, and limitation in activities of daily living), and significant results were found only for limitation in activities of daily living (odds ratio, 1.30 [95% confidence interval, 1.09-1.57]; I2  = 72%; P  < 0.01). The descriptive analysis of the remaining four predictors suggested a significant predictive value of balance and functional independence, whereas the results for trunk control were not significant and for social participation were unclear. In conclusion, individuals within the first 11.5 weeks after stroke with lower limitation in activities of daily living, higher functional independence, and better balance, are more likely to have a higher HRQoL one year after stroke. Thus, these predictors, all modifiable factors, need to be targeted during acute rehabilitation., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The HIV epidemic has devastated millions of people globally, with approximately 40 million deaths since its start. The availability of antiretroviral therapy (ART) has transformed the prognosis of millions of individuals infected with HIV such that a diagnosis of HIV infection no longer automatically confers death. However, morbidity and mortality remain substantial among people living with HIV. HIV can directly infect the kidney to cause HIV-associated nephropathy (HIVAN) - a disease characterized by podocyte and tubular damage and associated with an increased risk of kidney failure. The reports of HIVAN occurring primarily in those of African ancestry led to the discovery of its association with APOL1 risk alleles. The advent of ART has led to a substantial decrease in the prevalence of HIVAN; however, reports have emerged of an increase in the prevalence of other kidney pathology, such as focal segmental glomerulosclerosis and pathological conditions associated with co-morbidities of ageing, such as hypertension and diabetes mellitus. Early initiation of ART also results in a longer cumulative exposure to medications, increasing the likelihood of nephrotoxicity. A substantial body of literature supports the use of kidney transplantation in people living with HIV, demonstrating significant survival benefits compared with that of people undergoing chronic dialysis, and similar long-term allograft and patient survival compared with that of HIV-negative kidney transplant recipients., (© 2024. Springer Nature Limited.)

Purpose of Review: Published clinical practice guidelines frequently have difficulties for implementation of the recommendations and adherence in daily clinical practice. The present review summarizes the current knowledge on the barriers encountered when implementing clinical practice guideline and the strategies proposed to address these barriers., Recent Findings: Studies on strategies for implementation of clinical guidelines are scarce. Evidence indicates that a multidisciplinary policy is necessary in order to address the barriers at various levels. Continuous education and motivation of the stakeholders, together with structural adaptations are key elements in the process., Summary: The barriers for implementation of guidelines involve different levels, including the healthcare system, organizational, societal and cultural specificities, and individual attitudes. All of these should be addressed with policy-driven strategies. Such strategies could include optimization of resources allocations, and establishing well coordinated multidisciplinary networks, finally, future studies should also evaluate the effectiveness of the potential strategies., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Liver fibrosis is the integral process of chronic liver diseases caused by multiple etiologies and characterized by excessive deposition of extracellular matrix (ECM). During liver fibrosis, hepatic stellate cells (HSCs) transform into a highly proliferative, activated state, producing various cytokines, chemokines, and ECM. However, the precise mechanisms that license HSCs into the highly proliferative state remain unclear. Cyclin-dependent kinase 1 (CDK1) is a requisite event for the transition of the G1/S and G2/M phases in eukaryotic cells. In this study, it is demonstrated that CDK1 and its activating partners, Cyclin A2 and Cyclin B1, are upregulated in both liver fibrosis/cirrhosis patient specimens and the murine hepatic fibrosis models, especially in activated HSCs. In vitro, CDK1 is upregulated in spontaneously activated HSCs, and inhibiting CDK1 with specific small-molecule inhibitors (CGP74514A, RO-3306, or Purvalanol A) orshort hairpin RNAs (shRNAs) resulted in HSC apoptosis and cell cycle arrest by regulating Survivin expression. Above all, it is illustrated that increased CDK1 expression licenses the HSCs into a highly proliferative state and can serve as a potential therapeutic target in liver fibrosis., (© 2023 Wiley-VCH GmbH.)

Childhood epilepsy affects up to 1 % of children. It has been shown that 30 % of patients are resistant to drug treatments, making further investigation of other potential treatment strategies necessary. One such approach is the ketogenic diet (KD) showing promising results and potential benefits beyond the use of current antiepileptic drugs. This study aims to investigate the effects of KD on inflammation and oxidative stress, as one of the main suggested mechanisms of neuroprotection, in children with epilepsy. This narrative review was conducted using the Medline and Google Scholar databases, and by searching epilepsy, drug-resistant epilepsy, child, children, ketogenic, ketogenic diet, diet, ketogenic, keto, ketone bodies (BHB), PUFA, gut microbiota, inflammation, inflammation mediators, neurogenic inflammation, neuroinflammation, inflammatory marker, adenosine modulation, mitochondrial function, MTOR pathway, Nrf2 pathway, mitochondrial dysfunction, PPARɣ, oxidative stress, ROS/RNS, and stress oxidative as keywords. Compelling evidence underscores inflammation and oxidative stress as pivotal factors in epilepsy, even in cases with genetic origins. The ketogenic diet effectively addresses these factors by reducing ROS and RNS, enhancing antioxidant defenses, improving mitochondrial function, and regulating inflammatory genes. Additionally, KD curbs pro-inflammatory cytokine and chemokine production by dampening NF-κB activation, inhibiting the NLRP3 inflammasome, increasing brain adenosine levels, mTOR pathway inhibition, upregulating PPARɣ expression, and promoting a healthy gut microbiota while emphasizing the consumption of healthy fats. KD could be considered a promising therapeutic intervention in patients with epilepsy particularly in drug-resistant epilepsy cases, due to its targeted approach addressing oxidative stress and inflammatory mechanisms., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

N-heterocyclic carbenes (NHCs) have garnered much attention due to their unique properties, such as strong σ-donating and π-accepting abilities, as well as their transition-metal-like reactivity toward small molecules. In 2015, we discovered that NHCs can react with nitric oxide (NO) gas to form radical adducts that resemble transition metal nitrosyl complexes. To elucidate the analogy between NHC and transition metal NO adducts, here we have undertaken a systematic investigation of the electron- and proton-transfer chemistry of [NHC-NO]⋅ (N-heterocyclic carbene nitric oxide radical) compounds. We have accessed a suite of compounds, comprised of [NHC-NO] + , [NHC-NO] - , [NHC-NOH] 0 , and [NHC-NHOH] + species. In particular, [NHC-NO] - was isolated as potassium and lithium ion adducts. Most interestingly, a monomeric potassium [NHC-NO] - compound was isolated with the assistance of 18-crown-6, which is the first instance of a monomeric alkali N-oxyl compound to the best of our knowledge. Our results demonstrate that [NHC-NO]⋅ exhibits redox behavior broadly similar to metal nitrosyl complexes, which opens up more possibilities for utilizing NHCs to build on the known reactivity of metal complexes., (© 2023 Wiley-VCH GmbH.)

Osteocytes have recently been identified as a new regulator of bone remodeling, but the detailed mechanism of their differentiation from osteoblasts remains unclear. The purpose of this study is to identify cell cycle regulators involved in the differentiation of osteoblasts into osteocytes and determine their physiological significance. The study uses IDG-SW3 cells as a model for the differentiation from osteoblasts to osteocytes. Among the major cyclin-dependent kinases (Cdks), Cdk1 is most abundantly expressed in IDG-SW3 cells, and its expression is down-regulated during differentiation into osteocytes. Inhibition of CDK1 activity reduces IDG-SW3 cell proliferation and differentiation into osteocytes. Osteocyte and Osteoblast-specific Cdk1 knockout in mice (Dmp1-Cdk1 KO ) results in trabecular bone loss. Pthlh expression increases during differentiation, but inhibiting CDK1 activity reduces Pthlh expression. Parathyroid hormone-related protein concentration is reduced in the bone marrow of Dmp1-Cdk1 KO mice. Four weeks of Parathyroid hormone administration partially recovers the trabecular bone loss in Dmp1-Cdk1 KO mice. These results demonstrate that Cdk1 plays an essential role in the differentiation from osteoblast to osteocyte and the acquisition and maintenance of bone mass. The findings contribute to a better understanding of the mechanisms of bone mass regulation and can help develop efficient therapeutic strategies for osteoporosis treatment., (© 2023 Wiley-VCH GmbH.)

Intraguild interactions among carnivores have long held the fascination of ecologists. Ranging from competition to facilitation and coexistence, these interactions and their complex interplay influence everything from species persistence to ecosystem functioning. Yet, the patterns and pathways of such interactions are far from understood in tropical forest systems, particularly across countries in the Global South. Here, we examined the determinants and consequences of competitive interactions between dholes Cuon alpinus and the two large felids (leopards Panthera pardus and tigers Panthera tigris) with which they most commonly co-occur across Asia. Using a combination of traditional and novel data sources (N = 118), we integrate information from spatial, temporal, and dietary niche dimensions. These three species have faced catastrophic declines in their extent of co-occurrence over the past century; most of their source populations are now confined to Protected Areas. Analysis of dyadic interactions between species pairs showed a clear social hierarchy. Tigers were dominant over dholes, although pack strength in dholes helped ameliorate some of these effects; leopards were subordinate to dholes. Population-level spatio-temporal interactions assessed at 25 locations across Asia did not show a clear pattern of overlap or avoidance between species pairs. Diet-profile assessments indicated that wild ungulate biomass consumption by tigers was highest, while leopards consumed more primate and livestock prey as compared to their co-predators. In terms of prey offtake (ratio of wild prey biomass consumed to biomass available), the three species together harvested 0.4-30.2% of available prey, with the highest offtake recorded from the location where the carnivores reach very high densities. When re-examined in the context of prey availability and offtake, locations with low wild prey availability showed spatial avoidance and temporal overlap among the carnivore pairs, and locations with high wild prey availability showed spatial overlap and temporal segregation. Based on these observations, we make predictions for 40 Protected Areas in India where temporally synchronous estimates of predator and prey densities are available. We expect that low prey availability will lead to higher competition, and in extreme cases, to the complete exclusion of one or more species. In Protected Areas with high prey availability, we expect intraguild coexistence and conspecific competition among carnivores, with spill-over to forest-edge habitats and subsequent prey-switching to livestock. We stress that dhole-leopard-tiger co-occurrence across their range is facilitated through an intricate yet fragile balance between prey availability, and intraguild and conspecific competition. Data gaps and limitations notwithstanding, our study shows how insights from fundamental ecology can be of immense utility for applied aspects like large predator conservation and management of human-carnivore interactions. Our findings also highlight potential avenues for future research on tropical carnivores that can broaden current understanding of intraguild competition in forest systems of Asia and beyond., (© 2023 Cambridge Philosophical Society.)

Nucleic acid therapy has emerged as a potential alternative for promoting wound healing by gene expression modification. On the other hand, protecting the nucleic acid payload from degradation, efficient bioresponsive delivery and effective transfection into cells remain challenging. A glucose-responsive gene delivery system for treating diabetic wounds would be advantageous as it would be responsive to the underlying pathology giving a regulated payload delivery with fewer side effects. Herein a GOx-based glucose-responsive delivery system is designed based on fibrin-coated polymeric microcapsules (FCPMC) using the layer-by-layer (LbL) approach that simultaneously delivers two nucleic acids in diabetic wounds. The designed FCPMC displays an ability to effectively load many nucleic acids in polyplexes and release it over a prolonged period with no cytotoxic effects seen in in vitro studies. Furthermore, the developed system does not show any undesired effects in vivo. When applied to wounds in genetically diabetic db/db mice, the fabricated system on its own improves reepithelialization and angiogenesis while decreasing inflammation. Also, key proteins involved in the wound healing process, i.e., Actn2, MYBPC1, and desmin, are upregulated in the glucose-responsive fibrin hydrogel (GRFHG) treated group of animals. In conclusion, the fabricated hydrogel promotes wound healing. Furthermore, the system may be encapsulated with various therapeutic nucleic acids that aid wound healing., (© 2023 The Authors. Advanced Biology published by Wiley-VCH GmbH.)

Background: Post-stroke depression (PSD) as one of the most common neuropsychiatric disorders after a stroke and is caused by many factors. However, the relationships among different factors and their potential contributions to PSD remain unclear., Methods: Two hundred and seventy-six patients were recruited into this study. The general information questionnaire, the Patient Health Questionnaire-9, the Perceived Social Support Scale, the Family Assessment Device, the General Well-Being Scale, the Barthel Index, and the modified Rankin Scale were used to assess the condition of patients. Subsequently, we identify the main causes associated with the PSD and then performed a path analysis to clarify the direct, indirect and total effects among the variables., Results: We found that age, stroke with coronary heart disease, neurological function, family function, social support, and general well-being had a significant impact on PSD (P < 0.05). Of these, neurological function had the largest total effect on PSD (β = 0.451), social support contributed the most as a direct effect (β = -0.306), and family function showed the largest indirect effect (β = -0.264)., Conclusion: Individual, disease, and social-psychological factors all contributed to the development of PSD. We should pay more attention to comprehensive assessment, especially for those with poor neurological function, and lacking family or social support. In addition, it would be preferable to provide them with necessary support and care strategies to reduce the incidence of PSD., (© 2023 Japanese Psychogeriatric Society.)

Diet analysis is a vital tool for understanding trophic interactions and is frequently used to inform conservation and management. Molecular approaches can identify diet items that are impossible to distinguish using more traditional visual-based methods. Yet, our understanding of how different variables, such as predator species or prey ration size, influence molecular diet analysis is still incomplete. Here, we conducted a large feeding trial to assess the impact that ration size, predator species, and temperature had on digestion rates estimated with visual identification, qPCR, and metabarcoding. Our trial was conducted by feeding two rations of Chinook salmon (Oncorhynchus tshawytscha) to two piscivorous fish species (largemouth bass [Micropterus salmoides] and channel catfish [Ictalurus punctatus]) held at two different temperatures (15.5 and 18.5°C) and sacrificed at regular intervals up to 120 h from the time of ingestion to quantify the prey contents remaining in the digestive tract. We found that ration size, temperature, and predator species all influenced digestion rate, with some indication that ration size had the largest influence. DNA-based analyses were able to identify salmon smolt prey in predator gut samples for much longer than visual analysis (~12 h for visual analysis vs. ~72 h for molecular analyses). Our study provides evidence that modelling the persistence of prey DNA in predator guts for molecular diet analyses may be feasible using a small set of controlling variables for many fish systems., (© 2023 John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Sustainable forest management highlights the multipurpose use of all forest resources, including the use of wild mushrooms, by a variety of forest users and especially for rural livelihoods. To achieve sustainable forest management, among others, decision-makers and forest managers need to identify the important elements for the livelihoods of local communities dependent on forests. Therefore, our aim is to analyse the importance of contemporary use of wild mushrooms for daily livelihoods in rural areas of the Carpathian Mountains by comparing two ethnic groups, Hutsuls and Romanians, living in a similar ecological environment and formerly belonging to the historical region of Bukovina, but currently split by the border between Ukraine and Romania which have different governments and economic situations. One hundred and twenty-one face-to-face semi-structured interviews were conducted in the summers of 2018 and 2019. We compared the Traditional Ecological Knowledge (TEK) of Romanians and Hutsuls living, respectively, in lowlands and mountain areas on both sides of the border. Our results demonstrated the homogenous use of mushroom species for cultural purposes (e.g. ritual foods). Yet, we detected a remarkable difference in the role mushrooms play in providing income: Hutsuls in Ukraine use forest products as a main (rarely additional) source of income, while Romanian Hutsuls use them solely as additional income. Romanians on both sides considered mushrooms mainly as food and did not sell them (probably due in part to less abundance in the area). We also documented the fear of local residents that forest management and protected areas could suppress the right to collect wild mushrooms. The use of mushrooms is an important aspect of local TEK and needs to be considered as a part of sustainable forest management and as a means of poverty reduction in the region., (© 2022. The Author(s).)

Molecular methods including metabarcoding and quantitative polymerase chain reaction have shown promise for estimating species abundance by quantifying the concentration of genetic material in field samples. However, the relationship between specimen abundance and detectable concentrations of genetic material is often variable in practice. DNA mixture analysis represents an alternative approach to quantify specimen abundance based on the presence of unique alleles in a sample. The DNA mixture approach provides novel opportunities to inform ecology and conservation by estimating the absolute abundance of target taxa through molecular methods; yet, the challenges associated with genotyping many highly variable markers in mixed-DNA samples have prevented its widespread use. To advance molecular approaches for abundance estimation, we explored the utility of microhaplotypes for DNA mixture analysis by applying a 125-marker panel to 1179 Chinook salmon (Oncorhynchus tshawytscha) smolts from the Sacramento-San Joaquin Delta, California, USA. We assessed the accuracy of DNA mixture analysis through a combination of mock mixtures containing DNA from up to 20 smolts and a trophic ecological application enumerating smolts in predator diets. Mock DNA mixtures of up to 10 smolts could reliably be resolved using microhaplotypes, and increasing the panel size would likely facilitate the identification of more individuals. However, while analysis of predator gastrointestinal tract contents indicated DNA mixture analysis could discern the presence of multiple prey items, poor and variable DNA quality prevented accurate genotyping and abundance estimation. Our results indicate that DNA mixture analysis can perform well with high-quality DNA, but methodological improvements in genotyping degraded DNA are necessary before this approach can be used on marginal-quality samples., (© 2023 John Wiley & Sons Ltd.)

Stroke is a common cerebrovascular disease with high morbidity, mortality, and disability worldwide. Post-stroke dysfunction is related to the death of neurons and impairment of synaptic structure, which results from cerebral ischemic damage. Currently, transcranial magnetic stimulation (TMS) techniques are available to provide clinically effective interventions and quantitative diagnostic and prognostic biomarkers. The development of TMS has been 40 years and a range of repetitive TMS (rTMS) protocols are now available to regulate neuronal plasticity in many neurological disorders, such as stroke, Parkinson disease, psychiatric disorders, Alzheimer disease, and so on. Basic studies in an animal model with ischemic stroke are significant for demonstrating potential mechanisms of neural restoration induced by rTMS. In this review, the mechanisms were summarized, involving synaptic plasticity, neural cell death, neurogenesis, immune response, and blood-brain barrier (BBB) disruption in vitro and vivo experiments with ischemic stroke models. Those findings can contribute to the understanding of how rTMS modulated function recovery and the exploration of novel therapeutic targets. The mechanisms of rTMS in treating ischemic stroke from animal models. rTMS can prompt synaptic plasticity by increasing NMDAR, AMPAR and BDNF expression; rTMS can inhibit pro-inflammatory cytokines TNF and facilitate the expression of anti-inflammatory cytokines IL-10 by shifting astrocytic phenotypes from A1 to A2, and shifting microglial phenotypes from M1 to M2; rTMS facilitated the release of angiogenesis-related factors TGFβ and VEGF in A2 astrocytes, which can contribute to vasculogenesis and angiogenesis; rTMS can suppress apoptosis by increasing Bcl-2 expression and inhibiting Bax, caspase-3 expression; rTMS can also suppress pyroptosis by decreasing caspase-1, IL-1β, ASC, GSDMD and NLRP1 expression. rTMS, repetitive transcranial magnetic stimulation; NMDAR, N-methyl-D-aspartic acid receptors; AMPAR: α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors; BDNF, brain-derived neurotrophic factor; VEGF, vascular endothelial growth factor; GSDMD: cleaved Caspase-1 cleaves Gasdermin D; CBF: cerebral blood flow., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To investigate the consistency between the international guidelines recommendations and worldwide standard practices regarding diagnostic work-up and follow-up strategies for managing patients with Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) in the era of monoclonal antibodies., Methods: A questionnaire developed by the Rhinology section of the Young Otolaryngologists of the International Federation of Oto-rhino-laryngological Societies (Yo-IFOS) included items regarding the management of CRSwNP patients, monoclonal prescription, surgical and follow-up procedures, awareness of biologicals availability, and other relevant clinical practices. The online survey was directed to otolaryngologists and distributed in Europe, North America, South America, and the Middle East through otolaryngological and/or rhinological societies., Results: A total of 202 responses were analyzed; the mean participants' age was 45 ± 11 (73% men and 27% women), and 31% were from the United States, Canada 19%, Europe 45%, Middle East and South America 5%. Only 60% of the respondents declared using validated symptoms and endoscopic score systems in their clinical practice. Several practice discrepancies emerged in our cohort, including preferred surgical approach, prescription of preoperative oral steroids, and perioperative antibiotics (59% and 58%, respectively), as well as divergent awareness levels of available biologics for CRSwNP worldwide., Conclusions: CRSwNP needs a complex and time-consuming assessment, according to the latest guidelines. There seems to be a gap between these recommendations and the real-world data, which should draw more attention to bringing them into uniform clinical practice in the near future., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Immunotherapy has achieved revolutionary success in clinics, but it remains challenging for treating hepatocellular carcinoma (HCC) characterized by high vascularization. Here, it is reported that metal-organic framework-801 (MOF-801) can be employed as a stimulator of interferon genes (STING) through Toll-like receptor 4 (TLR4) not just as a drug delivery carrier. Notably, cytosine-phosphate-guanine oligodeoxynucleotides (CpG ODNs) and 5, 6-dimethylxanthenone-4-acetic acid (DMXAA) STING agonist with vascular disrupting function coordinates with MOF-801 to self-assemble into a nanoparticle (MOF-CpG-DMXAA) that effectively delivers CpG ODNs and DMXAA to cells for synergistically improving the tumor microenvironment by reprogramming tumor-associated macrophages (TAMs), promoting dendritic cells (DCs) maturation, as well as destroying tumor blood vessels. In HCC-bearing mouse models, it is demonstrated that MOF-CpG-DMXAA triggers systemic immune activation and stimulates robust tumoricidal immunity, resulting in a superior immunotherapeutic efficiency in orthotopic and recurrent HCC., (© 2023 Wiley-VCH GmbH.)

Neurofilament light chain (NfL), a neuron-specific protein, has been related to several neurodegenerative diseases. In addition, elevated levels of NfL have also been observed in patients admitted to the hospital for stroke, suggesting that NfL as a biomarker may extend well beyond neurodegenerative diseases. Therefore, using data from the Chicago Health and Aging Project (CHAP), a population-based cohort study, we prospectively investigated the association of serum NfL levels with incident stroke and brain infarcts. During a follow-up of 3603 person-years, 133 (16.3%) individuals developed incident stroke, including ischemic and hemorrhagic. The HR (95%CI) of incident stroke was 1.28 (95%CI 1.10-1.50) per 1 standard deviation (SD) increase of log10 NfL serum levels. Compared to participants in the first tertile of NfL (i.e., lower levels), the risk of stroke was 1.68 times higher (95%CI 1.07-2.65) in those in the second tertile and 2.35 times higher (95%CI 1.45-3.81) in those in the third tertile of NfL. NfL levels were also positively associated with brain infarcts; 1-SD in log10 NfL levels was associated with 1.32 (95%CI 1.06-1.66) higher odds of one or more brain infarcts. These results suggest that NfL may serve as a biomarker of stroke in older adults., (© 2023. Springer Nature B.V.)

Purpose: To provide understanding about feeding experiences of women who provide breast milk through direct breastfeeding and exclusive expression and to compare these experiences., Study Design and Methods: A qualitative study was conducted to gather experiences from the perspectives of women who had given birth to a healthy, term infant within the past 12 months and exclusively fed breast milk for at least 2 weeks. The sample was recruited from motherhood and breastfeeding support groups on Facebook. Groups had state- or national-based memberships. Interviews were examined for themes that were compared between feeding groups using thematic analysis., Results: Fifteen new mothers participated. Under the primary themes of Similarities and Differences, seven subthemes were identified: Fatigue, Importance of Support, Finding Joy in a Common Goal, Mixed Feelings, Trusting versus Tracking, Latching versus Body Failure, and Pumping in Isolation., Clinical Implications: Mothers who provide breast milk share common experiences and feelings of satisfaction. Expressed breast milk feeding offers some mothers a way to provide the benefits of breast milk while preserving a balance between maternal and infant physical and mental health needs. Understanding the different ways in which women manage breast milk feeding while balancing maternal and infant needs can prepare nurses to discuss various methods of breast milk feeding and provide individualized support., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

First stage larvae of an unknown lungworm (Protostrongylidae) were isolated in the feces of a wild reindeer (Rangifer tarandus) from Taimyr, Russia. Larvae were 365-366 μm long and had a tail spike lacking a dorsal spine. DNA analyses using BLAST showed that nuclear sequences obtained (LSU rDNA, 825 bp and ITS2 rDNA, 395 bp) were highly similar (99.50% and 98.88% identity, respectively) to an isolate of Orthostrongylus macrotis (GenBank: EU595592.1) from North America. It cannot be confirmed whether these larvae represent an uncharacterized species of Orthostrongylus or can be referred to O. macrotis, a species that has historically only been reported from the Nearctic. This is the first report of lungworms attributable to Protostrongylinae in R. tarandus across its vast geographic in the Holarctic., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

We previously proposed the term 'opportunistic non-communicable diseases (NCDs)' to raise awareness of how NCDs thrive in societies with inadequate healthcare services. However, we did not anticipate that within the next year the new coronavirus disease (COVID-19) would sweep the globe. Lockdowns became the primary strategy for mitigation in most countries. However, the extensive restrictions and allocation of resources towards the containment of the pandemic have likely served as a catalyst of NCDs, especially in populations, societies and individuals already at high risk. We are presenting evidence to qualify two primary factors responsible for the potential impact on the development of NCDs during the COVID-19 pandemic. The first is disrupted healthcare services including avoidance and postponement of healthcare visits. The second is effects of changing lifestyle and living conditions including isolation, loss of job and income. The accumulated effect of these factors will likely further accelerate the development of NCDs and impair their management, especially in low- and middle-income countries. Insufficient vaccination coverage due to inequality in vaccine distribution and vaccine hesitancy left room for the incubation of immune-evasive variants that threatened to sustain or reinitiate the pandemic. We believe the concept of opportunistic NCDs and the potential catalytic effect that pandemics may have on the development of NCDs and their management, should be used as further arguments to secure equal vaccine distribution, promote global vaccine acceptance and to speed up and increase investments in primary health care in low- and middle-income countries to cope with the already existing NCD crisis and to prepare for future epidemics., (© 2022 Scandinavian Societies for Pathology, Medical Microbiology and Immunology.)

Competing Interests: R. Claure-Del Granado reports consultancy for Medtronic; honoraria for Nova Biomedical; and an advisory or leadership role for Acute Kidney Injury Committee of the Latin American Society of Nephrology and Hypertension (member); International Society of Nephrology (member at large of the executive committee). E. Macedo reports an advisory or leadership role for the International Society of Nephrology. The remaining author has nothing to disclose.

Purpose: Health-related quality of life (QoL) is poor after stroke, but may be improved with comprehensive care plans. We aimed to determine the effects of an individualized management program on QoL in people with stroke or transient ischemic attack (TIA), describe changes in QoL over time, and identify variables associated with QoL., Methods: This was a multicenter, cluster randomized controlled trial with blinded assessment of outcomes and intention-to-treat analysis. Patients with stroke or TIA aged ≥ 18 years were randomized by general practice to receive usual care or an intervention comprising a tailored chronic disease management plan and education. QoL was assessed at baseline and 3, 12, and 24 months after baseline using the Assessment of Quality of Life instrument. Patient responses were converted to utility scores ranging from - 0.04 (worse than death) to 1.00 (good health). Mixed-effects models were used for analyses., Results: Among 563 participants recruited (mean age 68.4 years, 64.5% male), median utility scores ranged from 0.700 to 0.772 at different time points, with no difference observed between intervention and usual care groups. QoL improved significantly from baseline to 3 months (ß = 0.019; P = 0.015) and 12 months (ß = 0.033; P < 0.001), but not from baseline to 24 months (ß = 0.013; P = 0.140) in both groups combined. Older age, females, lower educational attainment, greater handicap, anxiety and depression were longitudinally associated with poor QoL., Conclusion: An individualized management program did not improve QoL over 24 months. Those who are older, female, with lower educational attainment, greater anxiety, depression and handicap may require greater support., Clinical Trial Registration: https://www.anzctr.org.au . Unique identifier: ACTRN12608000166370., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Social relationships have physiological impacts. Here, we investigate whether loss of the mother/offspring relationship has lasting effects on fecal glucocorticoid metabolite (fGCM) concentrations in wild African elephant orphans several years following their mothers' deaths. We find no difference in fGCM concentrations between orphans and nonorphans, but find lower fGCM concentrations in elephants with more age mates in their family. We also unexpectedly identify lower concentrations in orphans without their natal family versus nonorphans and natal orphans, which we speculate may be due to the development of hypocortisolism following a prolonged period without familial support. An index of plant productivity (i.e. food) shows the largest correlation with fGCM concentrations. Our findings indicate no lasting differences in glucocorticoid concentrations of surviving orphan elephants who are with their family, suggest the presence of age mates may reduce glucocorticoid concentrations in elephants, and emphasize that basic survival needs are the primary regulators of the stress response., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Multidrug-resistant (MDR) pathogenic bacterial infections have become a major danger to public health. Synergetic therapy through multiple approaches is more powerful than the respective one alone, but has been rarely achieved in defeating MDR bacterial infections so far. Herein, indocyanine green-functionalized Mn 3 O 4 nanosheets are engineered as an efficient and safe antibacterial agent with photothermal, photodynamic, and oxidase-like activities, which display powerful ability in treating MDR bacterial infections. Therein, photothermal and photodynamic activities can be triggered by a single low-powered near-infrared laser (808 nm, 0.33 W cm -2 ), resulting in the generation of localized hyperthermia (photothermal conversion efficiency, 67.5%) and singlet oxygen. Meanwhile, oxidase-like activity of this material further leads to the generation of hydroxyl radical as well as superoxide radical. Sheet-like structure with rough surfaces make them tends to adhere on bacterial surface and thus damage membrane system as well as influence bacterial metabolism. As a result, Gram-positive and Gram-negative bacteria can both be eradicated. Animal experiments further indicate that the functionalized Mn 3 O 4 nanosheets can effectively treat methicillin-resistant Staphylococcus aureus-infected wounds through the triple synergetic therapy. Moreover, toxicity evaluation in vitro and in vivo has proved the superior biosafety of this material, which is promising to apply in clinical anti-infective therapy., (© 2022 Wiley-VCH GmbH.)

Objectives: To test if the early kinetics of neurofilament light (NFL) in blood adds to the absolute values of NFL in the prediction of outcome, and to evaluate if NFL can discriminate individuals with severe hypoxic-ischemic brain injury (sHIBI) from those with other causes of poor outcome after out-of-hospital cardiac arrest (OHCA)., Design and Setting: Monocentric retrospective study involving individuals following non-traumatic OHCA between April 2014 and April 2016. NFL concentrations were determined on a SiMoA HD-1 device using NF-Light Advantage Kits., Participants: Of 73 patients screened, 53 had serum samples available for NFL measurement at three timepoints (after 3, 24, and 48 h of admission). Of these 53 individuals, 43.4% had poor neurologic outcome at discharge as assessed by Glasgow-Pittsburgh cerebral performance categories, and, according to a current prognostication algorithm, poor outcome due to sHIBI in 20.7%., Main Outcome Measure: Blood NFL and its early kinetics for prognostication of outcome and prediction of sHIBI after OHCA., Results: An absolute NFL > 508.6 pg/ml 48 h after admission, or a change in NFL > 494 pg/ml compared with an early baseline value predicted outcome, and discriminated severe sHIBI from other causes of unfavorable outcome after OHCA with high sensitivity (100%, 95%CI 70.0-100%) and specificity (91.7%, 95%CI 62.5-100%)., Conclusions: Not only absolute values of NFL, but also early changes in NFL predict the outcome following OHCA, and may differentiate sHIBI from other causes of poor outcome after OHCA with high sensitivity and specificity. Our study adds to published data, overall corroborating that NFL measured in blood should be implemented in prognostication algorithms used in clinical routine., (© 2021. The Author(s).)

Cortisol is involved in a broad range of physiological processes and enables animals to adapt to new situations and challenges. Diurnal fluctuations in circulating cortisol concentrations in elephants have been demonstrated based on samples from urine and saliva. The aims of this study were to demonstrate diurnal cortisol fluctuations based on blood samples and compare concentrations between seasons, species, and changes in reproductive hormone concentrations. Nine African (Loxodonta africana) and three Asian (Elephas maximus) elephants at two facilities in the United States were included in this study. Blood samples were collected every 2-3 h at one location and every 1-6 h at another. Peak serum concentrations of cortisol averaged 28 ng/ml for both African and Asian elephants, and diurnal cycles included a fivefold decrease from morning peak to evening nadir concentrations. Diurnal cortisol profiles varied uniquely among individual elephants. During the winter, nadir concentrations of cortisol were slightly higher, and the timing of peak concentrations was less predictable. There was no correlation between diurnal serum concentrations of progesterone and cortisol; however, a significant correlation (p = .02) was identified between serum concentrations of testosterone and cortisol when a time lag of ~2-3 h was considered. The physiological significance of the positive correlations between diurnal serum concentrations of cortisol and testosterone in male elephants remains to be determined. If cortisol concentrations are being used to evaluate elephant health or welfare, samples should be obtained at the same time each day to minimize variation due to diurnal fluctuations, and ideally seasonal variations and individuality in diurnal profiles should also be considered., (© 2021 Wiley Periodicals LLC.)

Purpose of Review: Ketogenic diets (KD) are validated treatments of pharmacoresistant epilepsy. Their interest in neurodegenerative diseases such as Alzheimer's disease (AD) has been suggested, because ketone bodies may reduce neuroinflammation, improve neurotransmitters transport pathway, synaptic maintenance, and reduce brain β-amyloid deposition. In this updated review, we aimed at critically examining the evidence of the past 2 years regarding KD or ketogenic supplements (KS) on cognitive and biological/neuropathological outcomes. We conducted our search in preclinical studies (animal models of AD) or in humans with or without cognitive impairment., Recent Findings: Overall, 12 studies were included: four in animal models of AD and eight in humans. In preclinical studies, we found additional evidence for a decrease in cerebral inflammation as well as in specific features of AD: β-amyloid, aggregates of tau protein under KD/KS. Several AD mouse models experienced clinical improvements. Human studies reported significant cognitive benefits, improved brain metabolism and biomarkers change under KD/KS, despite rather short-term interventions. Adherence to KD or KS was acceptable with frequent, but minor gastrointestinal adverse effects., Summary: The present review gathered additional evidence for both pathophysiological and clinical benefits of KS/KD in AD. Further studies are warranted with a biomarker-based selection of AD participants and long-term follow-up., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: COVID-19 has placed unprecedented pressure on health systems globally, whereas simultaneously stimulating unprecedented levels of transformation. Here, we review digital adoption that has taken place during the pandemic to drive improvements in ophthalmic clinical care, with a specific focus on out-of-hospital triage and services, clinical assessment, patient management, and use of electronic health records. We show that although there have been some successes, shortcomings in technology infrastructure prepandemic became only more apparent and consequential as COVID-19 progressed. Through our review, we emphasize the need for clinicians to better grasp and harness key technology trends such as telecommunications and artificial intelligence, so that they can effectively and safely shape clinical practice using these tools going forward., Competing Interests: The authors have no funding or conflicts of interest to declare., (Copyright © 2021 Asia-Pacific Academy of Ophthalmology. Published by Wolters Kluwer Health, Inc. on behalf of the Asia-Pacific Academy of Ophthalmology.)

Objectives: Although early recognition of sepsis is vital to improving outcomes, the diagnosis may be missed or delayed in many patients. Acute kidney injury is one of the most common organ failures in patients with sepsis but may not be apparent on presentation. Novel biomarkers for acute kidney injury might improve organ failure recognition and facilitate earlier sepsis care., Design: Retrospective, international, Sapphire study., Setting: Academic Medical Center., Patients: Adults admitted to the ICU without evidence of acute kidney injury at time of enrollment., Interventions: None., Measurements and Main Results: We stratified patients enrolled in the Sapphire study into three groups-those with a clinical diagnosis of sepsis (n = 216), those with infection without sepsis (n = 120), and those without infection (n = 387) at enrollment. We then examined 30-day mortality stratified by acute kidney injury within each group. Finally, we determined the operating characteristics for kidney stress markers (tissue inhibitor of metalloproteinases-2) × (insulin-like growth factor binding protein 7) for prediction of acute kidney injury as a sepsis-defining organ failure in patients with infection without a clinical diagnosis of sepsis at enrollment. Combining all groups, 30-day mortality was 23% for patients who developed stage 2-3 acute kidney injury within the first 3 days compared with 14% without stage 2-3 acute kidney injury. However, this difference was greatest in the infection without sepsis group (34% vs 11%; odds ratio, 4.09; 95% CI, 1.53-11.12; p = 0.005). Using a (tissue inhibitor of metalloproteinases-2) × (insulin-like growth factor binding protein 7) cutoff of 2.0 units, 14 patients (11.7%), in the infection/no sepsis group, tested positive of which 10 (71.4%) developed stage 2-3 acute kidney injury. The positive test result occurred a median of 19 hours (interquartile range, 0.8-34.0 hr) before acute kidney injury manifested by serum creatinine or urine output. Similar results were obtained using a cutoff of 1.0 for any stage of acute kidney injury., Conclusions: Use of the urinary (tissue inhibitor of metalloproteinases-2) × (insulin-like growth factor binding protein 7) test could identify acute kidney injury in patients with infection, possibly helping to detect sepsis, nearly a day before acute kidney injury is apparent by clinical criteria., Competing Interests: Dr. Kellum’s institution received funding from Astute Medical and bioMerieux. Drs. Kellum, Rimmelé, Shi, and Chawla received funding from Astute Medical. Drs. Kampf, Kwan, and McPherson are employees of Astute Medical/bioMerieux; Drs. Kellum, Rimmelé, Shi, and Chawla are paid consultants of Astute Medical/bioMerieux; and Dr. Kellum has received grant support from Astute Medical/bioMerieux apart from the current work. Dr. Artigas’s institution received funding from Lilly Foundation, and he received funding from Grifols, Fisher & Paykel. Drs. Kampf, Kwan, and McPherson received funding from Astute Medical (employee). Drs. Nguyen’s and Shapiro’s institutions received funding from Astute Medical. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

Premating barriers such as variation in reproductive behaviour can evolve quickly, but because gametic and postzygotic incompatibilities often evolve more slowly, circumstances that bring gametes into contact can breach the boundaries of premating isolation. In aquatic environments, the gametes of organisms with external fertilization are released into a constantly moving environment and may come into contact with heterospecific gametes. In fishes, nest association (spawning in another species' nest) is a behaviour that brings gametes from different species into close spatiotemporal proximity. These interactions might increase chances of hybridization, especially when multiple species associate with a single nest builder. This study addresses these interactions in the largest clade of North American freshwater fishes, the minnows (Cyprinidae). We compiled a list of over 17,000 hybrid specimens in conjunction with species distribution data, breeding behaviours, and an inferred phylogeny to test if breeding behaviour, in addition to evolutionary history, is an important predictor of hybridization. We find that breeding behaviour is a significant predictor of hybridization, even when phylogenetic relatedness and divergence time are accounted for. Specifically, nest associates are more likely to hybridize with other nest associates whereas non-nesting species had relatively low rates of hybridization., (© 2020 European Society for Evolutionary Biology. Journal of Evolutionary Biology © 2020 European Society for Evolutionary Biology.)

The wild water buffalo (Bubalus arnee) is one of the most endangered and least studied large bovid in the Indian subcontinent. India retains 90% of the estimated global population of >4000 individuals as two fragmented populations in Assam and Chhattisgarh, both threatened by habitat loss and degradation, hunting, disease from livestock, and hybridization with the domestic buffalos. Small, fragmented population size and potential hybridisation pressures from co-occurring domestic buffalos are the major conservation challenges. For the first time, we sequenced the 16,357 bp long mitogenome of three opportunistically collected wild water buffalo samples from Assam (n = 1) and Chhattishgarh (n = 2). The annotated sequence has a base composition of 26.4% T, 26.6% C, 33.1% A and 13.9% G depicting an AT-rich mitogenome composition, including 13 protein-coding genes (11,361 bp), 22 transfer RNA (tRNA) (1514 bp), two ribosomal genes (2525 bp), and a non-coding control region (928 bp). The gene order is conserved with other bovid species. Comparative mitogenome analyses showed both populations are genetically similar but significantly different from domestic buffalo. We also identified structural differences in seven tRNA secondary structures between both species. The genetic distance between wild buffalo and other bovids varied between 0.103 and 0.122. Multiple Bayesian phylogenetic trees showed that both wild and domestic water buffalo formed sister clades which were paraphyletic to other potentially sympatric species of genus Bos. This study provides baseline information on wild buffalo mitogenome for further research on phylogeny, phylogeography and hybrid assessment and help conserving this endangered species.

Purpose: Part A of the open-label, phase I KEYNOTE-434 study evaluated the safety and tolerability of epacadostat, an indoleamine 2,3-dioxygenase-1 inhibitor, alone and in combination with pembrolizumab in Japanese patients with advanced solid tumors., Methods: Japanese patients with refractory/recurrent metastatic or locally advanced tumors were enrolled. Cohort 1 received oral epacadostat 25 mg or 100 mg twice daily (BID) and subsequently received epacadostat in combination with intravenous pembrolizumab 200 mg every 3 weeks. Cohort 2 received epacadostat 25 mg or 100 mg BID with pembrolizumab 200 mg every 3 weeks. The primary objective was evaluation of safety and tolerability using a modified toxicity probability interval method. Secondary objectives were pharmacokinetic (PK) and pharmacodynamic profiles of epacadostat alone and in combination with pembrolizumab., Results: Six patients were enrolled in cohort 1 (epacadostat 25 mg, n = 3; epacadostat 100 mg, n = 3); none experienced dose-limiting toxicities (DLTs). Nine patients were enrolled in cohort 2 (epacadostat 25 mg and pembrolizumab, n = 3; epacadostat 100 mg and pembrolizumab, n = 6); one patient receiving epacadostat 100 mg and pembrolizumab experienced grade 4 rhabdomyolysis-a DLT. Grade 3 or 4 treatment-related adverse events occurred in two patients (13.3%). There were no treatment-related deaths. Pembrolizumab had no impact on epacadostat PK and vice versa. The PK profile of pembrolizumab in the current study was comparable with historical pembrolizumab PK data., Conclusion: Epacadostat in combination with pembrolizumab was generally safe and well tolerated among Japanese patients with advanced solid tumors. Clinical trial registration NCT02862457.

Tumor-homing peptides are widely used for improving tumor selectivity of anticancer drugs and imaging agents. The goal is to increase tumor uptake and reduce accumulation at nontarget sites. Here, we describe current approaches for tumor-homing peptide identification and validation, and provide comprehensive overview of classes of tumor-homing peptides undergoing preclinical and clinical development. We focus on unique mechanistic features and applications of a recently discovered class of tumor-homing peptides, tumor-penetrating C-end Rule (CendR) peptides, that can be used for tissue penetrative targeting of extravascular tumor tissue. Finally, we discuss unanswered questions and future directions in the field of development of peptide-guided smart drugs and imaging agents.