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[Display omitted] • A plant-based phytochemical derivative, N-ethylacetamide, was extracted and purified. • N-ethylacetamide showed antibacterial activity against S. aureus and Methicillin-resistant S. aureus. • It inhibits biofilms at concentrations of 5–15 µg/mL against microbial clusters. • Tests on RAW 264.7 and 3 T3 fibroblast cell lines indicated low cytotoxicity and therapeutic potential for the chemical. • The antibacterial effectiveness of N-ethylacetamide was shown in in-vitro infection tests and in-vivo in Balb/c mice. Bacterial resistance to conventional antibiotics is a pressing concern in the realm of infectious disease treatment, given its rapid evolution. This underscores the urgency of identifying novel therapeutic compounds. Recent efforts have been concentrated on exploring natural sources of antibacterial compounds, with a particular focus on plant-based derivatives due to their enhanced biocompatibility. In this context, our research has led to the isolation and purification of a groundbreaking plant-based phytochemical derivative known as N-ethylacetamide. We meticulously tested its antibacterial activity against bacterial strains, Staphylococcus aureus and Methicillin-resistant Staphylococcus aureus. Remarkably, N-ethylacetamide exhibited substantial antibacterial and anti-biofilm effects within the concentration range of 5–15 µg/mL, offering promise for combating these pathogens. Our investigations revealed N-ethylacetamide's compatibility with mammalian cells, as evidenced by tests conducted on RAW 264.7 and 3 T3 fibroblast cell lines. The potential antibacterial efficacy of this purified compound was validated through in-vitro infection studies, and a positive immune response was observed in an in-vivo mice model (Balb/c). The accumulated experimental evidence underscores the potential of N-ethylacetamide as a therapeutic agent against bacterial infections. It presents the exciting possibility of addressing these challenges with minimal side effects, offering hope for a more effective and safer approach to combat bacterial diseases. [ABSTRACT FROM AUTHOR]

It is commonly assumed that ionizable molecules, such as drugs, permeate through the skin barrier in their neutral form. By using molecular dynamics simulations of the charged and neutral states separately, we can study the dynamic protonation behavior during the permeation process. We have studied three weak acids and three weak bases and conclude that the acids are ionized to a larger extent than the bases, when passing through the headgroup region of the lipid barrier structure, at pH values close to their pKa. It can also be observed that even if these dynamic protonation simulations are informative, in the cases studied herein they are not necessary for the calculation of permeability coefficients. It is sufficient to base the calculations only on the neutral form, as is commonly done.

Antibiotic resistance poses human health risks, and there are concerns about the effect of environmental antibiotic residues in the selection and spread of antibiotic resistance. The aim of this study was to identify antibiotic residue levels that are likely to select for resistance and relative contributions from different aquatic sources, of various aquatic environmental compartments of the WHO Western Pacific region (WPR) and the WHO South-East Asia region (SEAR), including in China and India.

A molecular-level understanding of skin permeation may rationalize and streamline product development, and improve quality and control, of transdermal and topical drug delivery systems. It may also facilitate toxicity and safety assessment of cosmetics and skin care products. Here, we present new molecular dynamics simulation approaches that make it possible to efficiently sample the free energy and local diffusion coefficient across the skin’s barrier structure to predict skin permeability and the effects of chemical penetration enhancers. In particular, we introduce a new approach to use two-dimensional reaction coordinates in the accelerated weight histogram method, where we combine sampling along spatial coordinates with an alchemical perturbation virtual coordinate. We present predicted properties for 20 permeants, and demonstrate how our approach improves correlation with ex vivo/in vitro skin permeation data. For the compounds included in this study, the obtained log KPexp-calcmean square difference was 0.9 cm2h−2.

A major role of the skin is to serve as a barrier toward the environment. The skin's permeability barrier consists of a lipid structure positioned in the stratum corneum. Recent progress in high-resolution cryo-electron microscopy (cryo-EM) has allowed for elucidation of the architecture of the skin's barrier and its stepwise formation process representing the final stage of epidermal differentiation. In this review, we present an overview of the skin's barrier structure and its formation process, as evidenced by cryo-EM.

10.1038/s41575-021-00526-1T and B cells employ integrin α4β7 to migrate to intestine under homeostatic conditions. Whether those cells differentially rely on α4β7 for homing during inflammatory conditions has not been fully examined. This may have implications for our understanding of the mode of action of anti-integrin therapies in inflammatory bowel disease (IBD). Here, we examined the role of α4β7 integrin during chronic colitis using IL-10−/−mice, β7-deficient IL-10−/−, IgA-deficient IL-10−/−mice, and antibody blockade of MAdCAM-1. We found that α4β7 was predominantly expressed by B cells. β7 deficiency and MAdCAM-1 blockade specifically depleted antibody secreting cells (ASC) (not T cells) from the colonic LP, leading to a fecal pan-immunoglobulin deficit, severe colitis, and alterations of microbiota composition. Colitis was not due to defective regulation, as dendritic cells (DC), regulatory T cells, retinaldehyde dehydrogenase (RALDH) expression, activity, and regulatory T/B-cell cytokines were all comparable between the strains/treatment. Finally, an IgA deficit closely recapitulated the clinical phenotype and altered microbiota composition of β7-deficient IL-10−/−mice. Thus, a luminal IgA deficit contributes to accelerated colitis in the β7-deficient state. Given the critical/nonredundant dependence of IgA ASC on α4β7:MAdCAM-1 for intestinal homing, B cells may represent unappreciated targets of anti-integrin therapies.

Efficient IgA transcytosis is critical for the maintenance of a homeostatic microbiota. In the canonical model, locally-secreted dimeric (d)IgA reaches the polymeric immunoglobulin receptor (pIgR) on intestinal epithelium via simple diffusion. A role for integrin αE(CD103)β7 during transcytosis has not been described, nor its expression by intestinal B cell lineage cells. We found that αE-deficient (αE−/−) mice have a luminal IgA deficit, despite normal antibody-secreting cells (ASC) recruitment, local IgA production and increased pIgR expression. This deficit was not due to dendritic cell (DC)-derived retinoic acid (RA) nor class-switching defects, as stool from RAG−/−mice reconstituted with αE−/−B cells was also IgA deficient. Flow cytometric, ultrastructural and transcriptional profiling showed that αEβ7-expressing ASC represent an undescribed subset of terminally-differentiated intestinal plasma cells (PC) that establishes direct cell to cell contact with intestinal epithelium. We propose that IgA not only reaches pIgR through diffusion, but that αEβ7+ PC dock with E-cadherin-expressing intestinal epithelium to directly relay IgA for transcytosis into the intestinal lumen.

Efficient IgA transcytosis is critical for the maintenance of a homeostatic microbiota. In the canonical model, locally-secreted dimeric (d)IgA reaches the polymeric immunoglobulin receptor (pIgR) on intestinal epithelium via simple diffusion. A role for integrin αE(CD103)β7 during transcytosis has not been described, nor its expression by intestinal B cell lineage cells. We found that αE-deficient (αE−/−) mice have a luminal IgA deficit, despite normal antibody-secreting cells (ASC) recruitment, local IgA production and increased pIgR expression. This deficit was not due to dendritic cell (DC)-derived retinoic acid (RA) nor class-switching defects, as stool from RAG−/−mice reconstituted with αE−/−B cells was also IgA deficient. Flow cytometric, ultrastructural and transcriptional profiling showed that αEβ7-expressing ASC represent an undescribed subset of terminally-differentiated intestinal plasma cells (PC) that establishes direct cell to cell contact with intestinal epithelium. We propose that IgA not only reaches pIgR through diffusion, but that αEβ7+ PC dock with E-cadherin-expressing intestinal epithelium to directly relay IgA for transcytosis into the intestinal lumen.

ABSTRACTINTRODUCTIONAs the immigrant communities in high-income countries become larger and increasingly multicultural and ethnically diverse, health professionals are more likely to see girls and women with, or at risk of, female genital mutilation or ‘cutting’ (FGM/C) in clinical practice. To provide good care and support, other health-care professionals may learn from the experiences of midwifes caring for infibulated women during labour in Sweden.AIMTo describe Swedish midwives’ experiences in caring for infibulated women during labour.METHODSThis is a qualitative study. Semi-structured interviews with six midwives working at obstetric clinics in Sweden used open-ended questions. The interviews were recorded, transcribed verbatim and analysed by using thematic analysis.RESULTSTwo main themes were identified: experienced challenges during the process of labour; and midwives’ emotional experiences. Midwives experienced challenges during their professional encounters with infibulated women and a variety of emotions were evoked when caring for these women during labour. Lack of general guidelines and standardised routines complicated their work.DISCUSSIONThe midwives’ experiences were negatively affected by organisational factors and being emotionally affected by the fact that these women were not perceived to be given appropriate care because of their FGM/C. Policymakers in Sweden should consider implementing national guidelines for how to care for women exposed to FGM/C, ideally at an early stage in their reproductive life.

T and B cells employ integrin α4β7 to migrate to intestine under homeostatic conditions. Whether those cells differentially rely on α4β7 for homing during inflammatory conditions has not been fully examined. This may have implications for our understanding of the mode of action of anti-integrin therapies in inflammatory bowel disease (IBD). Here, we examined the role of α4β7 integrin during chronic colitis using IL-10−/−mice, β7-deficient IL-10−/−, IgA-deficient IL-10−/−mice, and antibody blockade of MAdCAM-1. We found that α4β7 was predominantly expressed by B cells. β7 deficiency and MAdCAM-1 blockade specifically depleted antibody secreting cells (ASC) (not T cells) from the colonic LP, leading to a fecal pan-immunoglobulin deficit, severe colitis, and alterations of microbiota composition. Colitis was not due to defective regulation, as dendritic cells (DC), regulatory T cells, retinaldehyde dehydrogenase (RALDH) expression, activity, and regulatory T/B-cell cytokines were all comparable between the strains/treatment. Finally, an IgA deficit closely recapitulated the clinical phenotype and altered microbiota composition of β7-deficient IL-10−/−mice. Thus, a luminal IgA deficit contributes to accelerated colitis in the β7-deficient state. Given the critical/nonredundant dependence of IgA ASC on α4β7:MAdCAM-1 for intestinal homing, B cells may represent unappreciated targets of anti-integrin therapies.

Water resources contaminated with antibiotic-resistant (ABR) gastrointestinal pathogens pose severe health risks to society. Unfortunately, the limitations of traditional water treatment methodologies are leading to the evolution and dissemination of ABR microbes. In this aspect, a sonophotocatalytic (SPC) process is demonstrated for the successful disinfection of ABR SalmonellaTyphimurium (STm) using Fe-doped ZnO nanoparticles (Fe–ZnO NPs) under visible-LED light. Reactive oxygen species (ROS) produced during SPC contributed to the detrimental effects on the microbes. In general, little is known regarding how bacteria modulate their phenotypic attributes during the course of disinfection. Our investigations to understand the effects of sublethal SPC on the expression of numerous phenotypic features of STm revealed changes in the virulence and ABR profiles. Sublethal SPC caused STm to adhere more on HCT116 cells, whereas their invasion properties were substantially reduced. The loss of ABR was recorded after sublethal SPC, although the resistance was partially regained after a nutrient source was provided to the bacteria. The manifestation of a morphological transition in STm from rod to cocci observed after sublethal SPC may have resulted in the significant loss of invasiveness and ABR. Further, SPC did not result in any process resistance; thus, it is a good candidate for water disinfection.

Antimicrobial resistance (AMR) poses a multifaceted threat to the human, animal, and environment sectors. In response, China has formulated a series of policies since the 2000s. Thus far, there has been no comprehensive assessment of these policy documents. This study aims to review the content of AMR policy documents at the national level using a governance framework covering three areas: Policy Design; Implementation Tools; and Monitoring and Evaluation. We identified 44 AMR documents from 2003 to 2022 sourced from government agency websites. Our findings have revealed noticeable discrepancies across the three governance areas. The Policy Designand Monitoring and Evaluationareas should be strengthened, particularly in the domains of ‘Coordination’, ‘Accountability’, ‘Sustainability’, and ‘Effectiveness’. From a ‘One Health’ perspective, the environment sector has received less attention compared to the human and animal sectors. Effectively addressing these challenges requires a stronger commitment and widespread support from diverse stakeholders.

Background: Patients with critical illness have a high risk of mortality. Key decision-making in the health system affecting the outcomes of critically ill patients requires epidemiological evidence, but the burden of critical illness is largely unknown. This study aimed to estimate the prevalence of critical illness in a Swedish region. Secondary objectives were to estimate the proportion of hospital inpatients who are critically ill and to describe the in-hospital location of critically ill patients. Methods: A prospective, multi-center, population-based, point-prevalence study on specific days in 2017–2018. All adult (> 18 years) in-patients, regardless of admitting specially, in all acute hospitals in Sörmland, and the patients from Sörmland who had been referred to university hospitals, were included. Patients in the operating theatres, with a psychiatric cause of admission, women in active labor and moribund patients, were excluded. All participants were examined by trained data collectors. Critical illness was defined as “a state of ill health with vital organ dysfunction, a high risk of imminent death if care is not provided and a potential for reversibility”. The presence of one or more severely deranged vital signs was used to classify critical illness. The prevalence of critical illness was calculated as the number of critically ill patients divided by the number of adults in the region. Results: A total of 1269 patients were included in the study. Median age was 74 years and 50% of patients were female. Critical illness was present in 133 patients, resulting in an adult population prevalence of critical illness per 100,000 people of 19.4 (95% CI 16.4–23.0). The proportion of patients in hospital who were critically ill was 10.5% (95% CI 8.8–12.3%). Among the critically ill, 125 [95% CI 94.0% (88.4–97.0%)] were cared for in general wards. Conclusions: The prevalence of critical illness was higher than previous, indirect estimates. One in ten hospitalized patients were critically ill, the large majority of which were cared for in general wards. This suggests a hidden burden of critical illness of potential public health, health system and hospital management significance.

The stratum corneum is the outermost layer of human skin and the primary barrier toward the environment. The barrier function is maintained by stacked layers of saturated long-chain ceramides, free fatty acids, and cholesterol. This structure is formed through a reorganization of glycosylceramide-based bilayers with cubic-like symmetry into ceramide-based bilayers with stacked lamellar symmetry. The process is accompanied by deglycosylation of glycosylceramides and dehydration of the skin barrier lipid structure. Using coarse-grained molecular dynamics simulation, we show the effects of deglycosylation and dehydration on bilayers of human skin glycosylceramides and ceramides, folded in three dimensions with cubic (gyroid) symmetry. Deglycosylation of glycosylceramides destabilizes the cubic lipid bilayer phase and triggers a cubic-to-lamellar phase transition. Furthermore, subsequent dehydration of the deglycosylated lamellar ceramide system closes the remaining pores between adjacent lipid layers and locally induces a ceramide chain transformation from a hairpin-like to a splayed conformation.

To present and analyze treatments and clinical outcomes of Chinese patients with influenza-like illness.

ABSTRACT:We study the effect of birth weight on long-run outcomes using data on Swedish twins born between 1926 and 1958 linked to administrative records spanning entire life-time labor market histories. We find that birth weight positively affects permanent income and income across large parts of the lifecycle. The timing of the birth weight–income relationship is in line with the role of birth weight in determining takeup of sickness benefits and morbidity. The effect of birth weight on labor market outcomes even for cohorts born 30 years apart are similar; for short run health outcomes, birth weight plays a decreasing role over time.

Cellular blebbing, caused by local alterations in cell-surface tension, has been shown to increase the invasiveness of cancer cells. However, the regulatory mechanisms balancing cell-surface dynamics and bleb formation remain elusive. Here, we show that an acute reduction in cell volume activates clathrin-independent endocytosis. Hence, a decrease in surface tension is buffered by the internalization of the plasma membrane (PM) lipid bilayer. Membrane invagination and endocytosis are driven by the tension-mediated recruitment of the membrane sculpting and GTPase-activating protein GRAF1 (GTPase regulator associated with focal adhesion kinase-1) to the PM. Disruption of this regulation by depleting cells of GRAF1 or mutating key phosphatidylinositol-interacting amino acids in the protein results in increased cellular blebbing and promotes the 3D motility of cancer cells. Our data support a role for clathrin-independent endocytic machinery in balancing membrane tension, which clarifies the previously reported role of GRAF1 as a tumor suppressor.

Our skin constitutes an effective permeability barrier that protects the body from exogenous substances but concomitantly severely limits the number of pharmaceutical drugs that can be delivered transdermally. In topical formulation design, chemical permeation enhancers (PEs) are used to increase drug skin permeability. In vitroskin permeability experiments can measure net effects of PEs on transdermal drug transport, but they cannot explain the molecular mechanisms of interactions between drugs, permeation enhancers, and skin structure, which limits the possibility to rationally design better new drug formulations. Here we investigate the effect of the PEs water, lauric acid, geraniol, stearic acid, thymol, ethanol, oleic acid, and eucalyptol on the transdermal transport of metronidazole, caffeine, and naproxen. We use atomistic molecular dynamics (MD) simulations in combination with developed molecular models to calculate the free energy difference between 11 PE-containing formulations and the skin’s barrier structure. We then utilize the results to calculate the final concentration of PEs in skin. We obtain an RMSE of 0.58 log units for calculated partition coefficients from water into the barrier structure. We then use the modified PE-containing barrier structure to calculate the PEs’ permeability enhancement ratios (ERs) on transdermal metronidazole, caffeine, and naproxen transport and compare with the results obtained from in vitroexperiments. We show that MD simulations are able to reproduce rankings based on ERs. However, strict quantitative correlation with experimental data needs further refinement, which is complicated by significant deviations between different measurements. Finally, we propose a model for how to use calculations of the potential of mean force of drugs across the skin’s barrier structure in a topical formulation design.

To evaluate the pharmacokinetics and acid‐suppressive effects of esomeprazole in infants with gastroesophageal reflux disease (GERD). In this single‐blind, randomized, parallel‐group study, 50 infants 1 to 24 months old with symptoms of GERD, and ≥5% of time with intraesophageal pH <4 during 24‐hour dual pH monitoring, received oral esomeprazole 0.25 mg/kg (n = 26) or 1 mg/kg (n = 24) once daily for 1 week. Intraesophageal and intragastric pH were recorded at 1 week, and blood samples were taken for pharmacokinetic analysis. At baseline, mean percentages of time with intragastric pH >4 and intraesophageal pH <4 were 30.5% and 11.6%, respectively, in the esomeprazole 0.25 mg/kg group and 28.6% and 12.5% in the esomeprazole 1 mg/kg group. After 1 week of treatment, times with intragastric pH >4 were 47.9% and 69.3% in the esomeprazole 0.25 mg/kg and 1 mg/kg groups, respectively (P< 0.001 vs baseline), and times with intraesophageal pH <4 were 8.4% (P< 0.05 vs baseline) and 5.5% (P< 0.001 vs. baseline), respectively. The mean number of acid reflux episodes of >5 minutes duration decreased from 6 at baseline to 3 and 2 with esomeprazole 0.25 mg/kg and 1 mg/kg, respectively. The geometric mean AUC0–tof esomeprazole were 0.24 and 1.79 μmol·h/L for the 0.25 mg/kg and 1 mg/kg dosages of esomeprazole, respectively. Both esomeprazole dosages were well tolerated. Oral treatment with esomeprazole 0.25 mg/kg and 1 mg/kg was well tolerated and provided dose‐related acid suppression, dose‐related exposure to esomeprazole, and decreased esophageal acid exposure in infants 1–24 months old with GERD.

Computational chemistry and other simulation fields are critically dependent on computing resources, but few problems scale efficiently to the hundreds of thousands of processors available in current supercomputersparticularly for molecular dynamics. This has turned into a bottleneck as new hardware generations primarily provide more processing units rather than making individual units much faster, which simulation applications are addressing by increasingly focusing on sampling with algorithms such as free-energy perturbation, Markov state modeling, metadynamics, or milestoning. All these rely on combining results from multiple simulations into a single observation. They are potentially powerful approaches that aim to predict experimental observables directly, but this comes at the expense of added complexity in selecting sampling strategies and keeping track of dozens to thousands of simulations and their dependencies. Here, we describe how the distributed execution framework Copernicus allows the expression of such algorithms in generic workflows: dataflow programs. Because dataflow algorithms explicitly state dependencies of each constituent part, algorithms only need to be described on conceptual level, after which the execution is maximally parallel. The fully automated execution facilitates the optimization of these algorithms with adaptive sampling, where undersampled regions are automatically detected and targeted without user intervention. We show how several such algorithms can be formulated for computational chemistry problems, and how they are executed efficiently with many loosely coupled simulations using either distributed or parallel resources with Copernicus.

Abstract: Objectives: To develop and test the long-term feasibility of an interdisciplinary independent drug information service providing both written and oral drug information to physicians in an urban area of Sweden (>400 000 inhabitants). Methods: A drug information service was developed encouraging a cooperative approach between a department of clinical pharmacology, general practitioners (GPs), pharmacists, and Drug and Therapeutic Committees. Scientifically-based drug information was condensed and interpreted by a team and presented in both written and oral form. In one part of the area, both oral and written information was provided, while in another part of the area, only written information was distributed. Questionnaires and one prescription survey were performed to elucidate the knowledge and attitudes of the GPs regarding drug treatment of one condition (urinary tract infection, UTI, and norfloxacin were used as examples), as well as their opinion of our services. Results: Over a period of 10 years, 75 issues of a drug bulletin (2000 copies) were distributed. Oral, producer-independent drug information, provided jointly by a GP and a pharmacist, was given on 16 occasions in each of 30 health centres (150 GPs). Around 80% of the GPs participated in the meetings. Of these GPs, 75% found the service important for their daily work. A majority of the GPs had prescribed the test drug, norfloxacin, not a first-line drug according to local recommendations, 1 year after approval. A significantly lower proportion of prescribers were observed in the area where the GPs had been provided with both written and oral information regarding recommended treatment (including first-line drugs) for uncomplicated cystitis. The approximate cost for this service in 1995 was SEK 0.685 million (USD 0.1 million); the prescribing costs of the 150 GPs were estimated at SEK 255 million per year. This means that the cost of the service per GP is only around 0.3% of normal prescribing costs. Conclusion: Over a period of 10 years the information/education method described here has proven sustainable and feasible in terms of providing the information, regarding participation of the target group GPs in the oral sessions, and regarding integration of the service into the existing health care system.