Synthesis and Performance of Bio-Based Amphoteric Surfactants.

As the global surfactant market continues to expand, there is an increasing need to develop bio-based alternatives in the shift towards a circular economy. This study focuses on the synthesis of polar, amphoteric, amine-oxide surfactants starting from biomass-derived monosaccharides and demonstrating their potential in various applications. The synthesis involved a reductive amination of the sugars with an alkylamine and formaldehyde followed by oxidation to produce N-oxide surfactants. These bio-based surfactants exhibited promising properties, including high solubility, foamability, surface tension reduction, and critical micelle concentration. In particular, N-GalA1.10 and N-GalA1.12 showed comparable performance to commercial surfactants. Furthermore, these bio-based surfactants demonstrated significantly lower skin irritation potential when compared to petrochemical-derived counterparts like sodium laureth sulfate (SLES), making them potentially suitable for personal care products. The biodegradability assessment revealed that N-GalA1.12 exhibited good biodegradation, indicating its potential environmental compatibility. In conclusion, this study highlights the potential of bio-based N-oxide surfactants derived from monosaccharides as sustainable and skin-friendly alternatives to traditional amphoteric surfactants, like cocamidopropyl betaine (CAPB).

Synthesis and Performance of Biobased Surfactants Prepared by the One-Pot Reductive Amination of l-Arabinose and d-Galacturonic Acid.

Herein, we report a method for the synthesis of biobased surfactants derived from sugar beet pulp (SBP) monosaccharides, l-Ara and d-GalA. The surfactants were prepared via one-pot reductive amination, allowing the introduction of different alkyl chain lengths and methyl modifications. Optimal reaction conditions were established to achieve high yields and easy purification. The synthesized surfactants including the tertiary amines exhibited desirable properties, including solubility, foamability, and reduction of surface tension. Notably, the anionic surfactants derived from d-GalA demonstrated better solubility and foam performance compared to those derived from l-Ara. In addition, these surfactants exhibited surface tension and critical micelle concentration (CMC) comparable to those of the commercial surfactant sodium lauryl ether sulfate (SLES). Furthermore, the biodegradable surfactant GalA1.8 displayed excellent emulsifying properties and low skin irritation potential. On the l-Ara surfactant with a short chain, Ara1.6 has potential as a hydrotrope. These findings suggest that biobased surfactants derived from SBP monosaccharides have promising applications in various industries, including pharmaceuticals, cosmetics, detergents, and chemicals.

Exploring the role of decision support systems in promoting healthier and more sustainable online food shopping: A card sorting study.

This study aims to identify opportunities and barriers in developing and implementing Food Shopping Support Systems (FSSS) for healthier and more sustainable choices, given the growing consumer demand and persistent societal problems related to food. The study examined the social and technical value of FSSS in an early development stage through one-on-one expert interviews (n = 20) and consumer focus groups (4 groups, n = 19). Experts were employed in the fields of behavioral sciences, digital marketing, decision aids, software development, persuasive technologies, and public health and sustainability. Consumer participants were used to shopping online. Through a card sorting task followed by semi-structured interview questions, responses were elicited. Participants were presented with 17 cards in 5 rounds, each addressing a different topic related to decision support. Results show that support is perceived useful, particularly when suggestions are personalized, transparent, and justified (using labelling or informative text). Opportunities for uptake were presenting suggestions early in the shopping trip in a visible but non-disruptive manner, allowing autonomy to choose the type of guidance (e.g., show sustainable but not healthier suggestions) and to (not) provide personal data, and educating consumers. Negative attitudes were associated with support being disruptive or steering, being of low credibility, and unclarity about what is healthy or sustainable. Consumer participants expressed concerns about too generic suggestions in relation to health and lack of knowledge about labelling. They emphasized that excessive support and required effort, such as repeatedly providing data, can be burdensome. Experts also worried about limited consumer interest and not having the required data to provide support. Results from this study reveal the potential for successful digital interventions to encourage healthier and more sustainable choices and what this means for further development.

The Effect of Propofol versus Inhalation Anesthetics on Survival after Oncological Surgery.

Every year, 19.3 million patients worldwide are diagnosed with cancer. Surgical resection represents a major therapeutical option and the vast majority of these patients receive anesthesia. However, despite surgical resection, almost one third of these patients develop local recurrence or distant metastases. Perioperative factors, such as surgical stress and anesthesia technique, have been suggested to play a role to a greater or lesser extent in the development of recurrences, but oncology encompasses a complicated tumor biology of which much is still unknown. The effect of total intravenous anesthesia (TIVA) or volatile anesthesia (VA) on survival after oncological surgery has become a popular topic in recent years. Multiple studies conclude in favor of propofol. Despite the a priori probability that relevant differences in postoperative outcomes are due to the anesthesia technique employed, TIVA or VA, is extremely small. The existing literature includes mainly hypothesis-forming retrospective studies and small randomized trials with many methodological limitations. To date, it is unlikely that use of TIVA or VA affect cancer-free survival days to a clinically relevant extent. This review addresses all relevant studies in the field and provides a substantiated different view on this deeply controversial research topic.

Gamma-Aminobutyric Acid A Receptor Subunit Expression and Cellular Localization in the Human Parkinsonian Globus Pallidus.

BACKGROUND: The gamma-aminobutyric acid A (GABAA) receptor is an important mediator of cellular signaling in the globus pallidus and might be implicated in the pathophysiology of Parkinson disease (PD). The goal of the present study was to characterize GABAA receptor subunit expression in the normal and parkinsonian human globus pallidus. METHODS: Postmortem brain specimens were obtained from 8 patients with pathological evidence of PD at autopsy and from 4 control patients without such evidence. These tissues were exposed to primary antibodies directed against the α1 and α3 subunits of the GABAA receptor and were visualized and quantified using fluorescence microscopy. RESULTS: No differences were found in the pallidal neuronal density in the control versus PD tissues. Projection neurons strongly expressed the α1, α3, and ß2 GABAA receptor subunits. After normalizing the immunofluorescence intensities in the globus pallidus to those in the adjacent structures, no significant differences were found in GABAA receptor subunit expression in the globus pallidus between the PD specimens and the control specimens. CONCLUSIONS: Compensatory changes in GABAA receptor α1 and α3 subunit expression in response to PD-related signaling abnormalities in the globus pallidus did not occur in our PD cohort.

Inpatient Capacity Management during COVID-19 Pandemic: The Yale New Haven Hospital Capacity Expansion Experience.

The 2019 SARS-CoV2 virus presented a capacity demand scenario for Yale New Haven Hospital. The response was created with a focus on clinical needs, but was also driven by the unique characteristics of the buildings within our institution. These physical characteristics were considered in the response as a safety measure as little was known about the transmissibility risk in the acute hospital setting of SARS-CoV2 at the time of response. The lessons learned in capacity expansion to meet the potentially catastrophic demand for acute care services due to a novel, poorly understood pathogen are discussed here.

The use of food swaps to encourage healthier online food choices: a randomized controlled trial.

BACKGROUND: Online grocery stores offer opportunities to encourage healthier food choices at the moment that consumers place a product of their choice in their basket. This study assessed the effect of a swap offer, Nutri-Score labeling, and a descriptive norm message on the nutrient profiling (NP) score of food choices in an online food basket. Additionally explored was whether these interventions made it more motivating and easier for consumers to select healthier foods and whether potential effects were moderated by consumer health interest. METHODS: Hypotheses were tested with a randomized controlled trial (RCT) in a simulated online supermarket. Dutch participants (n = 550) chose their preferred product out of six product options for four different categories (breakfast cereals, crackers, pizza, and muesli bars). Participants were randomly allocated to one of eight groups based on the interventions in a 2 (Nutri-Score: present, not present) X 2 (swap offer: present, not present) X 2 (norm message: present, not present) between subject design. The primary outcome was the difference in combined NP score of product choices, for which a lower score represented a healthier product. RESULTS: Swap offer (B = - 9.58, 95% CI: [- 12.026; - 7.132], È 2 = 0.098) and Nutri-Score labeling (B = - 3.28, 95% CI: [- 5.724; -.829], È 2 = 0.013) significantly improved the combined NP score compared to the control condition (NP score M = 18.03, SD = 14.02), whereas a norm message did not have a significant effect (B = - 1.378, 95% CI [- 3.825; 1.070], È 2 = 0.002). No evidence was found that interventions made it more motivating or easier for consumers to select healthier food, but situational motivation significantly influenced the healthiness score of food choices for both swap offer (b = - 3.40, p < .001) and Nutri-Score (b = - 3.25, p < .001). Consumer health interest only significantly moderated the influence of Nutri-Score on ease of identifying the healthy food option (b = .23, p = .04). CONCLUSIONS: Swap offer and Nutri-Score labeling were effective in enhancing healthy purchase behavior in the online store environment. TRIAL REGISTRATION: This study was retrospectively registered in the ISRCTN database on 02-09-2021 ( ISRCTN80519674 ).

Untargeted metabolomics and infrared ion spectroscopy identify biomarkers for pyridoxine-dependent epilepsy.

BackgroundPyridoxine-dependent epilepsy (PDE-ALDH7A1) is an inborn error of lysine catabolism that presents with refractory epilepsy in newborns. Biallelic ALDH7A1 variants lead to deficiency of α-aminoadipic semialdehyde dehydrogenase/antiquitin, resulting in accumulation of piperideine-6-carboxylate (P6C), and secondary deficiency of the important cofactor pyridoxal-5'-phosphate (PLP, active vitamin B6) through its complexation with P6C. Vitamin B6 supplementation resolves epilepsy in patients, but intellectual disability may still develop. Early diagnosis and treatment, preferably based on newborn screening, could optimize long-term clinical outcome. However, no suitable PDE-ALDH7A1 newborn screening biomarkers are currently available.MethodsWe combined the innovative analytical methods untargeted metabolomics and infrared ion spectroscopy to discover and identify biomarkers in plasma that would allow for PDE-ALDH7A1 diagnosis in newborn screening.ResultsWe identified 2S,6S-/2S,6R-oxopropylpiperidine-2-carboxylic acid (2-OPP) as a PDE-ALDH7A1 biomarker, and confirmed 6-oxopiperidine-2-carboxylic acid (6-oxoPIP) as a biomarker. The suitability of 2-OPP as a potential PDE-ALDH7A1 newborn screening biomarker in dried bloodspots was shown. Additionally, we found that 2-OPP accumulates in brain tissue of patients and Aldh7a1-knockout mice, and induced epilepsy-like behavior in a zebrafish model system.ConclusionThis study has opened the way to newborn screening for PDE-ALDH7A1. We speculate that 2-OPP may contribute to ongoing neurotoxicity, also in treated PDE-ALDH7A1 patients. As 2-OPP formation appears to increase upon ketosis, we emphasize the importance of avoiding catabolism in PDE-ALDH7A1 patients.FundingSociety for Inborn Errors of Metabolism for Netherlands and Belgium (ESN), United for Metabolic Diseases (UMD), Stofwisselkracht, Radboud University, Canadian Institutes of Health Research, Dutch Research Council (NWO), and the European Research Council (ERC).

Genetic variation in the farnesoid X-receptor predicts Crohn's disease severity in female patients.

The farnesoid X receptor (FXR) is implicated in Crohn's disease (CD) pathogenesis. It is unclear how genetic variation in FXR impacts CD severity versus genetic variation in nuclear receptors such as pregnane X receptor (PXR) and the multi-drug resistance protein 1 (MDR1, ABCB1). To evaluate FXR-1G > T as a genomic biomarker of severity in CD and propose a plausible molecular mechanism. A retrospective study (n = 542) was conducted in a Canadian cohort of CD patients. Genotypic analysis (FXR-1G > T, MDR1 3435C > T and PXR -25385C > T) as well as determination of the FXR downstream product, fibroblast growth factor (FGF) 19 was performed. Primary outcomes included risk and time to first CD-related surgery. The effect of estrogen on wild type and variant FXR activity was assessed in HepG2 cells. The FXR-1GT genotype was associated with the risk of (odds ratio, OR = 3.34, 95% CI = 1.58-7.05, p = 0.002) and earlier progression to surgery (hazard ratio, HR = 3.00, 95% CI = 1.86-4.83, p < 0.0001) in CD. Female carriers of the FXR-1GT genotype had the greatest risk of surgery (OR = 14.87 95% CI = 4.22-52.38, p < 0.0001) and early progression to surgery (HR = 6.28, 95% CI = 3.62-10.90, p < 0.0001). Women carriers of FXR-1GT polymorphism had a three-fold lower FGF19 plasma concentration versus women with FXR-1GG genotype (p < 0.0001). In HepG2 cells cotransfected with estrogen receptor (ER) and FXR, presence of estradiol further attenuated variant FXR activity. MDR1 and PXR genotypes were not associated with surgical risk. Unlike MDR1 and PXR, FXR-1GT genetic variation is associated with earlier and more frequent surgery in women with CD. This may be through ER-mediated attenuation of FXR activation.

Reduced neurosteroid potentiation of GABAA receptors in epilepsy and depolarized hippocampal neurons.

OBJECTIVE: Neurosteroids regulate neuronal excitability by potentiating γ-aminobutyric acid type-A receptors (GABARs). In animal models of temporal lobe epilepsy, the neurosteroid sensitivity of GABARs is diminished and GABAR subunit composition is altered. We tested whether similar changes occur in patients with epilepsy and if depolarization-induced increases in neuronal activity can replicate this effect. METHODS: We determined GABAR α4 subunit expression in cortical tissue resected from pediatric epilepsy patients. Modulation of human GABARs by allopregnanolone and Ro15-4513 was measured in Xenopus oocytes using whole-cell patch clamp. To extend the findings obtained using tissue from epilepsy patients, we evaluated GABAR expression and modulation by allopregnanolone and Ro15-4513 in cultured rat hippocampal neurons exposed to high extracellular potassium (HK) to increase neuronal activity. RESULTS: Expression of α4 subunits was increased in pediatric cortical epilepsy specimens encompassing multiple pathologies. The potentiation of GABA-evoked currents by the neurosteroid allopregnanolone was decreased in Xenopus oocytes expressing GABARs isolated from epilepsy patients. Furthermore, receptors isolated from epilepsy but not control tissue were sensitive to potentiation by Ro15-4513, indicating higher expression of α4 ßx γ2 subunit-containing receptors. Correspondingly, increasing the activity of cultured rat hippocampal neurons reduced allopregnanolone potentiation of miniature inhibitory postsynaptic currents (mIPSCs), increased modulation of tonic GABAR current by Ro15-4513, upregulated the surface expression of α4 and γ2 subunits, and increased the colocalization of α4 and γ2 subunit immunoreactivity. INTERPRETATION: These findings suggest that seizure activity-induced upregulation of α4 ßx γ2 subunit-containing GABARs could affect the anticonvulsant actions of neurosteroids.

mTORC2 Steals the Spotlight.

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Pathogenic Variants in CEP85L Cause Sporadic and Familial Posterior Predominant Lissencephaly.

Lissencephaly (LIS), denoting a "smooth brain," is characterized by the absence of normal cerebral convolutions with abnormalities of cortical thickness. Pathogenic variants in over 20 genes are associated with LIS. The majority of posterior predominant LIS is caused by pathogenic variants in LIS1 (also known as PAFAH1B1), although a significant fraction remains without a known genetic etiology. We now implicate CEP85L as an important cause of posterior predominant LIS, identifying 13 individuals with rare, heterozygous CEP85L variants, including 2 families with autosomal dominant inheritance. We show that CEP85L is a centrosome protein localizing to the pericentriolar material, and knockdown of Cep85l causes a neuronal migration defect in mice. LIS1 also localizes to the centrosome, suggesting that this organelle is key to the mechanism of posterior predominant LIS.

Conversion of a Conference Room into a Low-Acuity Inpatient Medical Unit: A Creative Response to Influenza-Related Surge.

The 2017-2018 influenza season was associated with high demand for both emergency department (ED) care and inpatient acute care for influenza-like illness (ILI). This high demand resulted in increased numbers of inpatients and ED patients, including prolonged ED length of stay. A large, urban, academic medical center in a cold-weather region was limited in its ability to expand its footprint to create de novo locations of care, such as temporary outbuildings or tents. As such, a large conference room was rapidly converted and placed in service as a temporary inpatient unit for adults requiring inpatient admission. LOGISTICS AND IMPLEMENTATION: The logistical, infection prevention, safety, information technology, staffing, and other concerns of creating a clinical environment during a high demand scenario is challenging. However, the lessons learned in this study are reproducible despite the complexity of this issue. CONCLUSION: This is believed to be the first published account of successful conversion of a nonclinical area to an operational clinical unit in response to a surge in demand for hospital care and admission. This may be a valid option for hospitals of all sizes as part of a surge or disaster plan.

The Space-Time Continuum of Cortical Dysplasia.

Somatic Mutations Activating the mTOR Pathway in Dorsal Telencephalic Progenitors Cause a Continuum of Cortical Dysplasias D'Gama AM, Woodworth MB, Hossain AA, Bizzotto S, Hatem NE, LaCoursiere CM, Najm I, Ying Z, Yang E, Barkovich AJ, Kwiatkowski DJ, Vinters HV, Madsen JR, Mathern GW, Blümcke I, Poduri A, Walsh CA. Cell Rep. 2017;21:3754-3766. Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) are epileptogenic neurodevelopmental malformations caused by mutations in mTOR pathway genes. Deep sequencing of these genes in FCD/HME brain tissue identified an etiology in 27 (41%) of 66 cases. Radiographically indistinguishable lesions are caused by somatic activating mutations in AKT3, MTOR, and PIK3CA and germline loss-of-function mutations in DEPDC5, NPRL2, and TSC1/2, including TSC2 mutations in isolated HME demonstrating a "two-hit" model. Mutations in the same gene cause a disease continuum from FCD to HME to bilateral brain overgrowth, reflecting the progenitor cell and developmental time when the mutation occurred. Single-cell sequencing demonstrated mTOR activation in neurons in all lesions. Conditional Pik3ca activation in the mouse cortex showed that mTOR activation in excitatory neurons and glia, but not interneurons, is sufficient for abnormal cortical overgrowth. These data suggest that mTOR activation in dorsal telencephalic progenitors, in some cases specifically the excitatory neuron lineage, causes cortical dysplasia.

α-Selective Glycosylation with ß-Glycosyl Sulfonium Ions Prepared via Intramolecular Alkylation.

Stereoselective glycosylation remains the main challenge in the chemical synthesis of oligosaccharides. Herein we report a simple method to convert thioglycosides into ß-sulfonium ions via an intramolecular alkylation reaction, leading to highly α-selective glycosylations for a variety of glycosyl acceptors. The influence of the thioglycoside substituent and the protecting group pattern on the glycosyl donor was investigated and showed a clear correlation with the observed stereoselectivity.

CYP2D6 genotype and endoxifen plasma concentration do not predict hot flash severity during tamoxifen therapy.

PURPOSE: Tamoxifen is frequently prescribed to prevent breast cancer recurrence. Tamoxifen is a prodrug and requires bioactivation by CYP2D6. Tamoxifen use is often limited by adverse effects including severe hot flashes. There is paucity of prospectively collected data in terms of CYP2D6 genotype and measured tamoxifen, 4-hydroxytamoxifen and endoxifen concentrations in relation to hot flash severity during tamoxifen therapy. METHODS: We conducted a longitudinal prospective study of breast cancer patients on tamoxifen (n = 410). At each visit, blood samples were collected, and patients completed a standardized hot flash survey (n = 1144) that reflected hot flash severity during the 7 days prior to the visit. Plasma concentrations of tamoxifen, 4-hydroxytamoxifen, and endoxifen were measured using liquid chromatography-tandem mass spectrometry and genotyping was carried out for CYP2D6. A linear mixed-effects regression analysis assessed the association of covariates in relation to the hot flash severity score (HFSS). RESULTS: Median age at first assessment was 50 years with 61.9% of patients considered peri-menopausal. Most patients (92.2%) experienced hot flash symptoms with 51.0% having low HFSS (0-4) and 7.32% experiencing HFSS > 25. Age was significantly associated with hot flash severity, with patients aged 45-59 more likely to have higher HFSS. Neither duration of tamoxifen therapy nor observed tamoxifen, endoxifen and 4-hydroxy tamoxifen plasma concentration predicted hot flash severity. Genetic variation in CYP2D6 or CYP3A4 was not predictive of hot flash severity. CONCLUSIONS: Hot flash severity during tamoxifen therapy can not be accounted for by CYP2D6 genotype or observed plasma concentration of tamoxifen, 4-hydroxytamoxifen, or endoxifen.

Pharmacogenomics Guided-Personalization of Warfarin and Tamoxifen.

The use of pharmacogenomics to personalize drug therapy has been a long-sought goal for warfarin and tamoxifen. However, conflicting evidence has created reason for hesitation in recommending pharmacogenomics-guided care for both drugs. This review will provide a summary of the evidence to date on the association between cytochrome P450 enzymes and the clinical end points of warfarin and tamoxifen therapy. Further, highlighting the clinical experiences that we have gained over the past ten years of running a personalized medicine program, we will offer our perspectives on the utility and the limitations of pharmacogenomics-guided care for warfarin and tamoxifen therapy.