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Abstract During recent decades, changes in lifestyle have led to widespread nutritional obesity and its related complications. Remodelling adipose tissue as a therapeutic goal for obesity and its complications has attracted much attention and continues to be actively explored. The endothelium lines all blood vessels and is close to all cells, including adipocytes. The endothelium has been suggested to act as a paracrine organ. We explore the role of endothelial insulin-like growth factor-1 receptor (IGF-1R), as a paracrine modulator of white adipose phenotype. We show that a reduction in endothelial IGF-1R expression in the presence of high-fat feeding in male mice leads to depot-specific beneficial white adipose tissue remodelling, increases whole-body energy expenditure and enhances insulin sensitivity via a non-cell-autonomous paracrine mechanism. We demonstrate that increased endothelial malonate may be contributory and that malonate prodrugs have potentially therapeutically relevant properties in the treatment of obesity-related metabolic disease.

Abstract Osteoarthritis (OA) represents a significant global health burden without a known disease modifying agent thereby necessitating pursuit of innovative therapeutic approaches. The infrapatellar fat pad (IFP) serves as a reservoir of mesenchymal stem/stromal cells (MSC), and with adjacent synovium plays key roles in joint disease affecting local inflammatory responses. Therapeutically, IFP-MSC have garnered attention for their potential in OA treatment due to their immunomodulatory and regenerative properties. However, optimizing their therapeutic efficacy necessitates a comprehensive understanding of how growth medium and inflammatory/hormonal priming influence their behavior. In this study, we isolated and expanded IFP-MSC in three different growth media: DMEM + 10% fetal bovine serum (FBS), DMEM + 10% human platelet lysate (HPL), and xeno-/serum-free synthetic (XFSF) medium. Subsequently, cells were induced with an inflammatory/fibrotic cocktail (TIC) with or without oxytocin (OXT). We evaluated various parameters including growth kinetics, phenotype, immunomodulatory capacity, gene expression, and macrophage polarization capacity. Our results revealed significant differences in the behavior of MSC cultured in different media. IFP-MSC cultured in HPL and XFSF exhibited superior growth kinetics and colony-forming abilities compared to those cultured in FBS. Furthermore, both HPL and XFSF media enhanced the expression of MSC markers (> 90%) and potentiated their immunomodulatory properties. Notably, XFSF-conditioned IFP-MSC demonstrated the highest attenuation of peripheral blood mononuclear cell (PBMC) proliferation, indicating their robust immunosuppressive capacity. Additionally, TIC priming further augmented the immunomodulatory functionality of MSC, with IFP-MSC exhibiting enhanced suppression of PBMC proliferation upon TIC priming. Of particular interest, gene expression analysis revealed distinct patterns in TIC + OXT induced MSC compared to TIC only induced, with upregulation of genes associated with immunomodulatory and regenerative functions. Furthermore, TIC + OXT priming promoted M2 polarization in macrophages, suggesting a potential therapeutic strategy for immune-mediated inflammatory joint conditions including OA. Our findings highlight the critical influence of growth medium and inflammatory/hormonal priming on MSC behavior and therapeutic potential. XFSF and HPL media offer promising alternatives to FBS, enhancing MSC growth and immunomodulatory properties. Moreover, TIC + OXT priming represents a novel approach to augment MSC immunomodulation and promote M2 polarization, providing insights into potential therapeutic strategies for OA and other immune-mediated inflammatory conditions.

Abstract Adaptation is essential to mitigate the effects of climate change, such as increasing flood risk. In response to widespread maladaptation, citizen-led approaches are increasingly championed, whereby people on the frontline of climate change determine their own objectives and strategies of adaptation. Enabling equitable and effective citizen-led adaptation requires an understanding of the barriers for different groups of people but this is currently lacking, especially in low- and middle-income countries. Using responses to a co-produced household survey (n = 286) in Tamale, Ghana, we show that barriers to citizen-led adaptation interventions (n = 11) differ between households which we relate to important components of adaptive capacity. Overall, awareness, education, and networks are the most important barriers, but resources and time are important for poor households of fewer members. Barriers also differ between interventions and overall structural interventions are preferred over behavioural. This work can inform policies and actions to support effective and equitable citizen-led adaptation.

Abstract Background This study examines the impact of SARS-CoV-2 (i.e., coronavirus, COVID, COVID-19) using data from a measurement-based care (MBC) system utilized in an outpatient psychiatric clinic providing telemedicine care. A novel Patient Rated Outcome Measure (PROM), the COVID-19 Events Checklist (CEC) was administered in a hospital system based ambulatory clinic beginning April 2020 to track COVID-19-19’s impact on patients’ mental, emotional, and health-related behaviors during the pandemic. The study (1) provides descriptive CEC data, and (2) compares CEC results with PROMs evaluating anxiety (Generalized Anxiety Disorder-7; GAD-7), depression (Patient Health Questionnaire; PHQ-9), and psychological distress (Brief Adjustment Scale-6; BASE-6). Methods This retrospective observational study included patient intake data collected from April 2020 to March 2021. Patient (N = 842) reports on the CEC’s five domain questions were aggregated to calculate average reports of COVID-19 related impacts at intake over the initial 12 months of the pandemic. Trends in COVID-19 related impacts were examined, and non-aggregated scores on the PHQ-9, GAD-7, and BASE-6 were compared to primary dichotomous (yes/no) CEC survey questions via Wilcoxon rand sum testing. Results Results capture the relationship between COVID-19 exposure, COVID-19- related sequelae and behaviors, and psychological symptom severity. Specifically, Wilcoxon rank-sum tests indicate that social determinants of health (SDOH), negative mental health impacts, and positive coping skill use were significantly associated with psychological symptomatology including overall psychological functioning via the BASE-6, anxiety via the GAD-7, and depressive symptoms via the PHQ-9. Results regarding SDOH were as follows: BASE-6 (w = 44,005, p

Abstract Background Despite high rates of adolescent mental-health problems, there are few effective whole-school interventions to address this. Whole-school interventions offer a feasible and sustainable means of promoting mental health. We previously evaluated the Learning Together (LT) intervention which was effective in preventing bullying (primary outcome), promoting mental well-being, psychological functioning, and reducing substance use (secondary outcomes). We adapted LT to develop Learning Together for Mental Health (LTMH) with a new menu of evidence-based actions to address mental health and an enhanced SEL curriculum. Methods We undertook a feasibility study of LTMH, a whole-school intervention featuring needs assessment, student and staff participation in decision-making via action groups selecting actions from an evidence-based menu, restorative practice, and a SEL and resilience skills curriculum between 2022 and 2023. This article examines the feasibility, acceptability, and potential mechanisms of LTMH, qualitatively, drawing on interviews and focus groups with 49 students in years 8 and 10, and 20 staff across four state secondary schools in southern England. Results The intervention was feasible and acceptable to implement. In terms of feasibility, the SEL curriculum was the most challenging to implement and was not prioritised by schools that had existing social and emotional learning lessons. Training and external facilitation were well-rated. Some schools struggled with the resourcing and workload implications of implementing actions from the evidence-based menu. Some aspects were not clear. Some staff were not aware that the various components worked together. Needs reports were not easy to understand for all. Students were generally supportive of restorative practice and SEL lessons. Data supported a potential mechanism involving increased school belonging and developing practical knowledge and skills to manage emotions and relationships. The intervention has little potential for harm. Conclusions The intervention is ready for phase III trial with minor adaptations. A phase III trial of effectiveness is justified. Trial registration ISRCTN15301591 https://doi.org/10.1186/ISRCTN15301591

Abstract The pathways involved in the pathophysiology of fetal growth restriction (FGR) and small for gestational age (SGA) are incompletely understood. We conduct a systematic review to identify metabolomic signatures in maternal and newborn tissues and body fluids samples associated with FGR/SGA. Here, we report that 825 non-duplicated metabolites were significantly altered across the 48 included studies using 10 different human biological samples, of which only 56 (17 amino acids, 12 acylcarnitines, 11 glycerophosphocholines, six fatty acids, two hydroxy acids, and eight other metabolites) were significantly and consistently up- or down-regulated in more than one study. Three amino acid metabolism-related pathways and one related with lipid metabolism are significantly associated with FGR and/or SGA: biosynthesis of unsaturated fatty acids in umbilical cord blood, and phenylalanine, tyrosine and tryptophan biosynthesis, valine, leucine and isoleucine biosynthesis, and phenylalanine metabolism in newborn dried blood spot. Significantly enriched metabolic pathways were not identified in the remaining biological samples. Whether these metabolites are in the causal pathways or are biomarkers of fetal nutritional deficiency needs to be explored in large, well-phenotyped cohorts.

Abstract Purpose Targeted therapy development in soft tissue sarcoma (STS) has been burdened by the heterogeneity of this group of rare tumors. B7 homolog 3 protein (B7-H3) is a molecule in the same family as programmed death-ligand 1 (PD-L1). It has limited expression in noncancerous tissues and is overexpressed in many cancers, making it an attractive target for cancer therapy, and clinical trials targeting B7-H3 are actively underway. While available data demonstrate high expression levels of B7-H3 in individual sarcoma subtypes, its expression patterns across STS subtypes are not well described. The purpose of this study was to characterize the expression patterns of B7-H3 in STS. Patients and methods This retrospective analysis evaluated STS tumor specimens from patients with a variety of different subtypes. Specimens were evaluated by immunohistochemistry (IHC) for expression and staining pattern of B7-H3 both in tumors and in associated vasculature. Results Specimens from 153 sarcoma patients included 15 different STS subtypes. B7-H3 was broadly expressed in 97% of samples (95% CI 0.93–0.99) and 69.2% demonstrated high levels of B7-H3 expression (95% CI 0.61–0.76). No significant association between B7-H3 positivity or expression level and prior treatment(s), tumor size, tumor grade, or patient age. B7-H3 positivity in vessels was found in 94.7% (145/153) of samples. In tumors that had been previously assessed for PD-L1 and PD-1, there was no correlation between B7-H3 positivity or expression and the positivity or expression level of PD-L1 or PD-1. Conclusion These data show high levels of B7-H3 positivity across soft tissue sarcoma subtypes, suggesting its feasibility as a therapeutic target for future sarcoma treatments. Future clinical trials are needed to evaluate whether targeting B7-H3 can provide clinical benefit to help patients with sarcoma.

Polymer-based molecular tweezers have emerged as a prominent research area due to their enhanced ability to form host–guest complexes, driven by advancements in their design and synthesis. The impact of the spacer structure on the tweezers is predominant. They can be rigid, flexible, and stimuli-responsive. Herein, a new generation of molecular tweezers is introduced as polymer-based molecular tweezers. The integration of molecular tweezers onto biopolymers has significantly expanded their potential applications, making them promising candidates, especially in drug delivery, owing to their biocompatibility, adaptive structural features, and versatile interaction capabilities. The unique structure of polymer-based molecular tweezers, particularly when integrated with biopolymers, creates a unique nano-environment that enhances their interaction with guest molecules. This minireview focuses on the synthesis and applications of polymer-based molecular tweezers and examines how the incorporation of various spacers affects their binding affinity and specificity. These features highlight the advancement of these polymer-based systems, emphasizing their potential applications, particularly in drug delivery, water treatment technology, and future research opportunities.

Ye Rim Kim,1,2,&ast; Sung Won Chung,1,2,&ast; Min-Ju Kim,3 Won-Mook Choi,1,2 Jonggi Choi,1,2 Danbi Lee,1,2 Han Chu Lee,1,2 Ju Hyun Shim1,2,4 1Division of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 2Liver Cancer Center, Asan Cancer Institute, Asan Medical Center, Seoul, Republic of Korea; 3Clinical Epidemiology and Biostatistics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 4Digestive Diseases Research Center, University of Ulsan College of Medicine, Seoul, Republic of Korea&ast;These authors contributed equally to this workCorrespondence: Ju Hyun Shim, Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea, Tel +82-02-3010-3190, Fax +82-02-485-5782, Email s5854@amc.seoul.krIntroduction: We aimed to evaluate the generalizability of retrospective single-center cohort studies on prognosis of hepatocellular carcinoma (HCC) by comparing overall survival (OS) after various treatments between a nationwide multicenter cohort and a single-center cohort of HCC patients.Methods: Patients newly diagnosed with HCC between January 2008 and December 2018 were analyzed using data from the Korean Primary Liver Cancer Registry (multicenter cohort, n=16,443), and the Asan Medical Center HCC registry (single-center cohort, n=15,655). The primary outcome, OS after initial treatment, was compared between the two cohorts for both the entire population and for subcohorts with Child-Pugh A liver function (n=2797 and n=5151, respectively) treated according to the Barcelona-Clinic-Liver-Cancer (BCLC) strategy, using Log rank test and Cox proportional hazard models.Results: Patients of BCLC stages 0 and A (59.3% vs 35.2%) and patients who received curative treatment (42.1% vs 32.1%) were more frequently observed in the single-center cohort (Ps< 0.001). Multivariable analysis revealed significant differences between the two cohorts in OS according to type of treatment: the multicenter cohort was associated with higher risk of mortality among patients who received curative (adjusted hazard ratio [95% confidence interval], 1.48 [1.39– 1.59]) and non-curative (1.22 [1.17– 1.27]) treatments, whereas the risk was lower in patients treated with systemic therapy (0.83 [0.74– 0.92]) and best supportive care (0.85 [0.79– 0.91]). Subcohort analysis also demonstrated significantly different OS between the two cohorts, with a higher risk of mortality in multicenter cohort patients who received chemoembolization (1.72 [1.48– 2.00]) and ablation (1.44 [1.08– 1.92]).Conclusion: Comparisons of single-center and multicenter cohorts of HCC patients revealed significant differences in OS according to treatment modality after adjustment for prognostic variables. Therefore, the results of retrospective single-center cohort studies of HCC treatments may not be generalizable to real-world practice.Keywords: BCLC, UICC, liver cancer, retrospective cohort, external validation

Statistics reveal that egg production has increased in recent decades. This growth suggests there is a global rise in available eggshell biomass due to the current underutilization of this bio-waste material. A number of different applications for waste eggshells (WEGs) are known, that include their use as an additive in human/animal food, soil amendment, cosmetics, catalyst, sorbent, and filler in polymer composites. In this article, worldwide egg production and leading countries are examined, in addition to a discussion of the various applications of eggshell biomass. Eggshells are a rich supplement of calcium carbonate; therefore, they can be added as a particulate filler to polymer composites. In turn, the addition of a lower-cost filler, such as eggshell or calcium carbonate, can reduce overall material fabrication costs. Polylactic acid (PLA) is currently a high-demand biopolymer, where the fabrication of PLA composites has gained increasing attention due to its eco-friendly properties. In this review, PLA composites that contain calcium carbonate or eggshells are emphasized, and the mechanical properties of the composites (e.g., tensile strength, flexural strength, tensile elastic modulus, flexural modulus, and elongation (%) at break) are investigated. The results from this review reveal that the addition of eggshell/calcium carbonate to PLA reduces the tensile and flexural strength of PLA composites, whereas an increase in the tensile and flexural modulus, and elongation (%) at break of composites are described herein.

The General Transit Feed Specification (GTFS) is an open standard format for recording transit information, utilized by thousands of transit agencies worldwide. In this study, a new tool named GTFS2STN for converting GTFS data into the spatiotemporal networks is introduced. To analyze the travel time variability, it is important to transform a transit network to a spatiotemporal network to enable a comprehensive analysis of transit system accessibility. GTFS2STN is a new tool that converts General Transit Feed Specification (GTFS) data into spatiotemporal networks, addressing the lack of open-source solutions for transit analysis. The tool includes a web application that generates isochrone maps and calculates travel time variability between locations. Validation against Google Maps APIs shows that journey time (i.e., the summation of the transit time, walking time, and waiting time) differences in the Mean Absolute Percentage Error are typically within 12%. A before–after analysis shows that for the transit journey time in 2024 in Nashville, Tennessee, 8 out of 10 pivotal bus stops showed a significantly decreased journey time compared with the case of 2019. A further set of before–after analyses shows that although journey time between transit sites significantly dropped on May 2020 during COVID-19 emergencies, the journey time almost totally recovered to the before-COVID-19 level by November 2020. By supporting any valid GTFS schedule, GTFS2STN enables the analysis of historical and planned transit systems, making it valuable for long-term accessibility assessment and travel time variability studies.

Background Avoidant restrictive food intake disorder (ARFID) is a feeding and eating disorder with known acute and longstanding physical health complications in children and young people (CYP) and commonly presents to paediatricians.Objective To systematically review the published literature on physical health complications in CYP with ARFID using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.Methods A systematic search of PubMed, Embase, Web of Science, PsycINFO and Cochrane Library was performed on 14 February 2024. Studies reporting physical health complications in CYP ≤25 years with ARFID were included. We pooled studies for meta-analysis comparing ARFID with healthy controls or anorexia nervosa (AN).Results Of 9058 studies found in searches, we included 132 studies. We found evidence for low weight, nutritional deficiencies and low bone mineral density. CYP with ARFID can present across the weight spectrum; however, the majority of CYP with ARFID were within the healthy weight to underweight range. Most studies reported normal range heart rates and blood pressures in ARFID, but some CYP with ARFID do experience bradycardia and hypotension. CYP with ARFID had higher heart rates than AN (weighted mean difference: 12.93 bpm; 95% CI: 8.65 to 17.21; n=685); heterogeneity was high (I2: 81.33%).Conclusion There is a broad range of physical health complications associated with ARFID requiring clinical consideration. Many CYP with ARFID are not underweight yet still have complications. Less cardiovascular complications found in ARFID compared with AN may be related to chronicity.PROSPERO registration number CRD42022376866.

Maternally-loaded factors in the egg accumulate during oogenesis and are essential for the acquisition of oocyte and egg developmental competence to ensure the production of viable embryos. However, their molecular nature and functional importance remain poorly understood. Here, we present a collection of 9 recessive maternal-effect mutants identified in a zebrafish forward genetic screen that reveal unique molecular insights into the mechanisms controlling the vertebrate oocyte-to-embryo transition. Four genes, over easy, p33bjta, poached and black caviar, were found to control initial steps in yolk globule sizing and protein cleavage during oocyte maturation that act independently of nuclear maturation. The krang, kazukuram, p28tabj, and spotty genes play distinct roles in egg activation, including cortical granule biology, cytoplasmic segregation, the regulation of microtubule organizing center assembly and microtubule nucleation, and establishing the basic body plan. Furthermore, we cloned two of the mutant genes, identifying the over easy gene as a subunit of the Adaptor Protein complex 5, Ap5m1, which implicates it in regulating intracellular trafficking and yolk vesicle formation. The novel maternal protein Krang/Kiaa0513, highly conserved in metazoans, was discovered and linked to the function of cortical granules during egg activation. These mutant genes represent novel genetic entry points to decipher the molecular mechanisms functioning in the oocyte-to-embryo transition, fertility, and human disease. Additionally, our genetic adult screen not only contributes to the existing knowledge in the field but also sets the basis for future investigations. Thus, the identified maternal genes represent key players in the coordination and execution of events prior to fertilization.

The importance of mechanical loading and its relationship to orthobiologic therapies in the treatment of post-traumatic osteoarthritis (PTOA) is beginning to receive attention. This review explores the current efficacy of orthobiologic interventions, notably platelet-rich plasma (PRP), bone marrow aspirate (BMA), and mesenchymal stem/stromal cells (MSCs), in combating PTOA drawing from a comprehensive review of both preclinical animal models and human clinical studies. This review suggests why mechanical joint loading, such as running, might improve outcomes in PTOA management in conjunction with orthiobiologic administration. Accumulating evidence underscores the influence of mechanical loading on chondrocyte behavior and its pivotal role in PTOA pathogenesis. Dynamic loading has been identified as a key factor for optimal articular cartilage (AC) health and function, offering the potential to slow down or even reverse PTOA progression. We hypothesize that integrating the activation of mechanotransduction pathways with orthobiologic treatment strategies may hold a key to mitigating or even preventing PTOA development. Specific loading patterns incorporating exercise and physical activity for optimal joint health remain to be defined, particularly in the clinical setting following joint trauma.

Herein, we report a study that provides new insight on the knowledge gaps that relate to the role of biopolymer structure and adsorption properties for chitosan adsorbents that are cross-linked with glutaraldehyde. The systematic modification of chitosan cross-linked with glutaraldehyde (CG) and its quaternized forms (QCG) was studied in relation to the reaction conditions: mole ratios of reactants and pH conditions. Complementary adsorbent characterization employed 13C NMR/FTIR spectroscopy, TGA and DSC, point-zero-charge (PZC), solvent swelling, and sorption studies using selected dye probes. The spectral and thermal techniques provide complementary evidence that affirm the key role of cross-linker content and quaternization on variation of the physicochemical properties of chitosan. The PZC results reveal a neutral surface charge for the modified materials between pH 6.0 to 6.3 ± 0.3, as compared with pH 8.7 ± 0.4 for pristine chitosan. Solvent swelling in water decreased with greater cross-linking, while the QCG materials had greater swelling over CG materials due to enhanced hydration. The adsorption results reveal variable dye uptake properties according to the cross-linker content. Similarly, surface versus micropore adsorption was demonstrated, according to the nature and ionization state of the dye for the modified adsorbents, where the CG and QCG materials had tunable sorption properties that exceeded that of unmodified chitosan. A key step in tuning the structure and surface chemical properties of cross-linked chitosan involves pH control during synthesis. The facile tunability of the physicochemical properties of the modified biopolymers reported herein means that they possess features of biomimetics that are relevant to advanced drug delivery, antimicrobial materials for wound healing, biosensors, and biosorbents for biomedical applications.

An amphiphilic cellulose (CLH) hydrogel was synthesized via grafting of quaternary ammonium groups onto cellulose. The structural properties of CLH were characterized via Fourier transform infrared (FTIR)/13C solid-state NMR spectroscopy, elemental (CHN) analysis, particle size distribution (PSD), thermogravimetric analysis (TGA), and wettability was assessed through contact angle measurements. Pickering emulsions of apolar oils in water were prepared using variable weights of the CLH hydrogel as the stabilizing agent, along with different methods of agitation (mechanical shaking and sonication). The characterization results for CLH provide support for the successful grafting of quaternary ammonium groups onto cellulose to produce hydrogels. Different methods of agitation of an oil/water mixture revealed the formation of an oil-in-water (O/W) Pickering emulsion that was stable to coalescence for over 14 days. The resulting emulsions showed variable droplet sizes and stability according to the dosage of CLH in the emulsion and the agitation method, where the emulsion droplet size is related to the particle size of CLH. The addition of methyl orange (MO), a probe to evaluate the phase partitioning of the dye, had minor effects on the emulsion droplet size, and the emulsion prepared with 0.8 wt.% of CLH and agitated via sonication exhibited the smallest droplet size and greatest stability. This study is anticipated to catalyze further research and the development of low-cost and sustainable biopolymer hydrogels as stabilizers for tunable Pickering emulsion. Grafted cellulose materials of this type represent versatile stabilizing agents for foods, agrochemicals, and pharmaceutical products and technologies.

This paper presents a novel centrifugal microfluidic approach (so-called lab-on-a-CD) for magnetic circulating tumor cell (CTC) separation from the other healthy cells according to their physical and acquired chemical properties. This study enhances the efficiency of CTC isolation, crucial for cancer diagnosis, prognosis, and therapy. CTCs are cells that break away from primary tumors and travel through the bloodstream; however, isolating CTCs from blood cells is difficult due to their low numbers and diverse characteristics. The proposed microfluidic device consists of two sections: a passive section that uses inertial force and bifurcation law to sort CTCs into different streamlines based on size and shape and an active section that uses magnetic forces along with Dean drag, inertial, and centrifugal forces to capture magnetized CTCs at the downstream of the microchannel. The authors designed, simulated, fabricated, and tested the device with cultured cancer cells and human cells. We also proposed a cost-effective method to mitigate the surface roughness and smooth surfaces created by micromachines and a unique pulsatile technique for flow control to improve separation efficiency. The possibility of a device with fewer layers to improve the leaks and alignment concerns was also demonstrated. The fabricated device could quickly handle a large volume of samples and achieve a high separation efficiency (93%) of CTCs at an optimal angular velocity. The paper shows the feasibility and potential of the proposed centrifugal microfluidic approach to satisfy the pumping, cell sorting, and separating functions for CTC separation.

Kendra L Walsh,1,2 Abhishek Yadav,3 Michael Cradeur,1 Henry Huang,3 Daniel Lee,3 Harry Owusu-Dapaah,3 Chao Ji,3 Mark C Kendall,1,3 Shyamal Asher1,3 1The Warren Alpert Medical School of Brown University, Providence, RI, 02903, USA; 2Pharmacy Services, Rhode Island Hospital, Providence, RI, 02903, USA; 3Department of Anesthesiology, Rhode Island Hospital, Providence, RI, 02903, USACorrespondence: Shyamal Asher, The Warren Alpert Medical School of Brown University, 222 Richmond Street, Providence, RI, 02903, USA, Tel +1 401-527-4775, Email ashershy@gmail.comPurpose: First- and second-year medical students typically have limited exposure to the field of anesthesiology, yet recent match data shows growing interest in the specialty. Early, structured exposure to anesthesiology in the form of a preclinical elective may allow medical students to make more informed decisions on their specialty of choice.Methods: The anesthesiology preclinical elective, BIOL 6704: “Anesthesia: Much More than Putting you to Sleep”, is a one-credit course taught at The Warren Alpert Medical School of Brown University. A survey consisting of fifteen questions assessing changes in attitudes, perceptions, and interest in anesthesiology was distributed to first- and second-year medical students before and after course participation. The results were analyzed using the Wilcoxon’s signed-rank test for paired samples.Results: The biggest impact of the preclinical elective was observed in the students’ subjective understanding of key aspects of the practice of anesthesiology. Statistically significant improvement was seen in the understanding of airway management, anesthetic pharmacology, basics of ultrasound, vascular access, anesthesiology subspecialties, and an understanding of anesthesiology residency. Overall, results were limited by our small sample size.Conclusion: Our elective allows medical students to explore anesthesiology early in their medical school career. After taking this course, students noted more familiarity with various topics in anesthesiology. Peer institutions lacking a similar course may consider using our experience to increase interest about the specialty of anesthesiology for future students.Keywords: anesthesiology, medical education, preclinical curriculum, medical school electives, medical students

The Educational Doctorate (EdD) is designed to meet the needs of current practitioners who aim to expand their professional expertise by leveraging deep knowledge and research methods to address specific and contextualized problems of practice. This approach centers on developing scholarly practitioners that are equipped with the skills necessary to bridge the knowledge-to-doing gap and contribute meaningfully to school improvement (CPED, 2020; Donovan, 2013; Hochbein & Perry, 2013; Jackson & Sun, 2022; Lewis et al., 2020; Perry, Zambo, & Crow, 2020). To achieve this goal, program faculty and their respective thinking must be concerned with and oriented to the scholarly practitioner and their unique positionality. This paper explores two considerations related to centering scholarly practitioners and their impact to illustrate the possibilities inherent within EdD programs.

Abstract Background Malignant hemangioendothelioma is an endothelial cancer with heterogeneous clinical behavior that can range from indolent to aggressive, of which the majority are epithelioid (EHE). Its incidence and demographics have not been previously well defined in a large cohort. Methods This retrospective analysis used the US Cancer Statistics National Program of Cancer Registries – Surveillance Epidemiology End Results (SEER) combined database to identify patients in the US newly diagnosed with hemangioendothelioma between the years of 2001 and 2017 (n = 1986). Survival analyses were performed on a subset of patients within the SEER‐18 database with survival information available (n = 417). Outcomes included incidence, demographics of patients newly diagnosed with hemangioendothelioma, extent of disease at presentation, and overall survival. Results The incidence of hemangioendothelioma in the US is 0.4 cases per million person‐years. Although cases rose to 122 newly diagnosed in the year 2017 (90 EHE, 32 other hemangioendothelioma), incidence rates were stable. Skin and connective tissues were the most common presenting sites (33.4%), followed by liver (24.5%), lung (17.6%), and bone (12.5%). Median age at diagnosis was 55 years; 27.2% of patients were pediatric, adolescent, or young adult (

Renewable bioenergy has the potential to contribute sustainably to the energy sector. Forestry is the main source of biomass for energy in Europe, and poplar (genus Populus) is widely used for short rotation coppice (SRC). Many studies have assessed poplar clones’ productivity but there is a lack of regional studies and links with the climate. We investigated the biomass productivity of twenty hybrid poplar clones for SRC. Clones were planted in sixteen locations across nine countries in Europe, although not all clones were replicated in all locations. In each location, clones were planted in three replicated plots. All plots were harvested after four years, and the aboveground dry biomass estimated. We fitted clone-specific linear mixed models of total aboveground dry biomass production at plot level as function of climatic variables. For many clones (eight) only annual heat moisture deficit negatively affected productivity, in few cases (3) together with a quadratic term for a smoother relationship. In some other clones (five) only the mean summer precipitation positively and linearly affected productivity. On average, the variance explained by the fixed effects in those models was 56%. For the remaining clones (seven), no climate variables resulted significant. Our study explicitly investigated the quantitative link between water availability and poplar SRC productivity, one of the most important known factors but not often studied with a modelling approach. Further, we show the most productive clones in dried conditions. We also highlight the need to larger scale regional experiments to produce models that can be used in climate change scenarios.

This paper builds a quantitative thermodynamic model for the microbial hydrolysis process (MHP, which uses Caldicellulosiruptor bescii at 75°C for pre-digestion) for producing biogas from a 5-10% aqueous suspension of dairy manure (naturally buffered near pH 7.8 by ammonium bicarbonate) by anaerobic digestion with a mix of acetoclastic and syntrophic methanogenesis. Standard Gibbs energy changes were calculated for the major reactions in pre-digestion, for reactions producing H2, acetate, and CO2 in the digester, and for methanogenesis reactions in the digester. The available data limit the study to analyzing reactions in the digester to reactions of short-chain volatile fatty acids anions. Results are presented as curves of ΔrxnG (Gibbs energy change) vs. acetate concentration. The H2(aq) concentration must be above 1.2×10-9 M to get significant syntrophic methanogenesis, i.e., for ΔrxnG to be negative. The results show syntrophic methanogenesis of propionate, butyrate, and valerate slows as acetate concentration increases because hydrogen production also decreases, and consequently, biogas production from syntrophic methanogenesis slows as acetate increases. Bicarbonate also inhibits both acetoclastic and syntrophic methanogenesis but is necessary to prevent acidification (souring) of the digester. At identical steady-state conditions, acetoclastic methanogenesis runs about 1.4 times faster than syntrophic methanogenesis. Because syntrophic methanogenesis produces acetate catabolized by acetoclastic methanogens, both types of methanogens are necessary to maximize biogas production. The culture in the digester is predicted to evolve to optimize the ratio of acetoclastic methanogens to syntrophic methanogens, a condition signaled by a constant, low acetate concentration in the digester effluent. Obtaining volatile solids reduction as high as 75% with MHP requires a feedstock with less than 25% lignin and a culture of acetoclastic methanogens and syntrophic methanogens and their symbiotic bacteria.

With the increased need for improved adsorbents for efficient water treatment, sodium alginate (NaAlg) and chitosan (Chi) represent promising platform biopolymers for the preparation of biocomposite adsorbents for the effective removal of waterborne oxyanion (arsenate (Asi) and orthophosphate (Pi)) contaminants. The TMCs were characterized by spectroscopy (infrared (IR), SEM with an energy dispersive X-ray (SEM-EDX)), point-of-zero-charge (PZC) measurements, and dye adsorption by employing p-nitrophenol at variable pH. Based on dye adsorption results, the adsorbent surface area (SA) was 271 m2/g for Al-TMC, 286 m2/g for Fe-TMC, and 311 m2/g for Cu-TMC. This indicates the role of adsorbent pore structure and swelling in water. Further, the role of either aluminum (Al), copper (Cu), or iron (Fe) for the preparation of TMCs for the selective Asi removal in the presence of Pi as a competitor anion was evaluated. While Al, Fe, and Cu coordinate to the biopolymer framework at C=O sites, only Fe coordinates to –NH2 sites. While Al coordinated via Al-O and interfacial hydroxy groups, Cu showed the formation of Cu2(OH)3NO3 in contrast to Fe, which observed FeOOH formation. Adsorption of Asi was highest for Al-TMC (80 mg/g), followed by Fe-TMC (77 mg/g) and Cu-TMC (31 mg/g). Adsorption of Pi was highest for Al-TMC (93 mg/g), followed by Fe-TMC (66 mg/g) and Cu-TMC (17 mg/g). While Al-TMC showed the highest adsorption capacity overall, only Fe-TMC (followed by Cu-TMC) showed strong arsenate selectivity over orthophosphate. The selectivity toward Asi in presence of Pi was determined and the binary separation factor (αt/c) and the selectivity coefficient (βt) were calculated, where Cu-TMC (αt/c = 6.1; βt = 4.4) and Fe-TMC (αt/c = 8.3; βt = 5.0) exceeded Al-TMC (αt/c = 1.5; βt = 1.2). This work contributes to the field of oxyanion-selective adsorbents via judicious selection of the metal salt precursor during the synthetic design of the ternary biocomposite systems, as demonstrated herein.

The availability of a sustainable technique for degumming lignocellulose fibers is a challenge for the fiber processing industry. Removal of non-cellulosic content from lignocellulose fibers is essential for improving their mechanical and chemical properties, which makes the fibers more suitable for various applications. Herein, a catalytic Fenton-based oxidation process was employed to isolate microcellulose fibers from raw flax fibers. Various complementary methods such as FT-IR/NMR spectroscopy and TGA were used to obtain insight into the thermal behavior of the treated fibers. The morphology of the fibers was studied using Scanning Electron Microscopy (SEM), whereas the surface chemical properties of the fibers was evaluated by a dye-based adsorption method, along with a potentiometric point-of-zero-charge method. To obtain fibers with suitable properties, such as uniform fiber diameter, several Fenton reaction parameters were optimized: pH (7), reaction time (15 h), iron sulfate (2 wt.%), and hydrogen peroxide (10 wt.%). The results indicate that, under the specified conditions, the average diameter of the raw fibers (12.3 ± 0.5 µm) was reduced by 58%, resulting in an average diameter of 5.2 ± 0.3 µm for the treated fibers. We demonstrate that the treated fibers had a lower dye adsorption capacity for methylene blue, consistent with the smoother surface features of the treated fibers over the raw flax fibers. Overall, this study contributes to utilization of the Fenton reaction an efficient oxidation technique for the production of lignocellulose fibers with improved physicochemical properties, such as reduced fiber diameter distribution, in contrast with traditional alkali-based chemical treatment.

Monitoring pavement conditions is critical to pavement management and maintenance. Traditionally, pavement distress is mainly identified via accelerometers, videos, and laser scanning. However, the geographical coverage and temporal frequency are constrained by the limited amount of equipment and labor, which sometimes may delay road maintenance. By contrast, crowdsourced data, in a manner of crowdsensing, can provide real-time and valuable roadway information for extensive coverage. This study exploited crowdsourced Waze pothole and weather reports for pavement condition evaluation. Two surrogate measures are proposed, namely, the Pothole Report Density (PRD) and the Weather Report Density (WRD). They are compared with the Pavement Quality Index (PQI), which is calculated using laser truck data from the Tennessee Department of Transportation (TDOT). A geographically weighted random forest (GWRF) model was developed to capture the complicated relationships between the proposed measures and PQI. The results show that the PRD is highly correlated with the PQI, and the correlation also varies across the routes. It is also found to be the second most important factor (i.e., followed by pavement age) affecting the PQI values. Although Waze weather reports contribute to PQI values, their impact is significantly smaller compared to that of pothole reports. This paper demonstrates that surrogate pavement condition measures aggregated by crowdsourced data could be integrated into the state decision-making process by establishing nuanced relationships between the surrogated performance measures and the state pavement condition indices. The endeavor of this study also has the potential to enhance the granularity of pavement condition evaluation.

Summary: Background: The Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) describes three primary avoidant/restrictive food intake disorder (ARFID) subtypes including sensory sensitivity, lack of interest in food or eating, and fear of aversive consequences. Studies exploring these subtypes have yielded varying results. We used latent class analysis (LCA) based on the psychopathology of ARFID in a sample of children and adolescents to empirically identify classes. Methods: We carried out a surveillance study of ARFID in collaboration with the British Paediatric Surveillance Unit (BPSU) and the Child and Adolescent Psychiatry Surveillance System (CAPSS) in the United Kingdom and the Republic of Ireland from 1st of March 2021 to 31st of March 2022. Paediatricians and child and adolescent psychiatrists were contacted monthly to report newly diagnosed cases of ARFID electronically and complete a detailed clinical questionnaire. Cases aged 5–18 years were included. LCA was performed specifying 1–6 classes and likelihood-based tests for model selection. The Bayesian Information Criterion (BIC), the Akaike Information Criterion (AIC) and the Sample-Size Adjusted BIC were used to determine the most parsimonious model. Analysis of variance (ANOVA) and χ2 tests were used to compare the characteristics of the identified classes. A multinomial logistic regression (MLR) was performed to investigate predicting factors for the latent classes. Findings: We identified 319 children and adolescents with ARFID. LCA revealed four distinct classes which were labelled as Fear subtype, Lack of Interest subtype, Sensory subtype, and Combined subtype. The probability of being classified as these were 7.2% (n = 23), 25.1% (n = 80), 29.5% (n = 94) and 38.2% (n = 122), respectively. Age at diagnosis, sex, weight loss, distress associated with eating, and autism spectrum disorder diagnosis were identified as predictors of class membership. Interpretation: LCA identified four different classes in a sample of children and adolescents with ARFID. The Combined Subtype, a mixed presentation was the most common. The other three classes resembled the subtypes described in the literature. Clinicians should be aware of these different presentations of ARFID as they may benefit from different clinical interventions. Funding: This study was funded by the Former EMS Ltd (charity number 1098725, registered October 9th 2017).

The purpose of this work was to provide a simple method to determine reactive strength during the 6-meter timed hop test (6mTH) and evaluate its association with isokinetic peak torque in patients following anterior cruciate ligament reconstruction (ACLR). Twenty-nine ACLR patients who were at least four months from surgery were included in this analysis. Participants were brought into the laboratory on one occasion to complete functional testing. Quadriceps and hamstring isokinetic testing was completed bilaterally at 60, 180, and 300 deg∙s-1, using extension peak torque from each speed as the outcome measure. The 6mTH was completed bilaterally using a marker-based motion capture system, and reactive strength ratio (RSR) was calculated from the vertical velocity of the pelvis during the test. An adjustment in RSR was made using the velocity of the 6mTH test to account for different strategies employed across participants. Repeated measures correlations were used to determine associations among isokinetic and hop testing variables. A two-way mixed analysis of variance was used to determine differences in isokinetic and hop testing variables between operated and non-operated legs and across male and female participants. Moderate positive associations were found between RSR (and adjusted RSR) and isokinetic peak torque at all speeds (r = .527 to .577). Mean comparisons showed significant main effects for leg and sex. Patients showed significant deficits in their operated versus non-operated legs in all isokinetic and hop testing variables, yet only isokinetic peak torque and timed hop time showed significant differences across male and female groups. Preliminary results are promising but further development is needed to validate other accessible technologies available to calculate reactive strength during functional testing after ACLR. Pending these developments, the effects of movement strategies, demographics, and levels of participation on RSR can then be explored to translate this simple method to clinical environments.

Discordance between the genetic sex and phenotype seen on ultrasound can identify disorders of sexual development (DSD) that previously escaped detection until puberty. We describe a 46, XY disorder of sexual differentiation caused by a rare mutation in the SF1 gene (OMIM]184757, (NR5A1). The mutation (NR5A1)-c.205C > G (p. Arg69Gly) was discovered after a phenotype-genotype discrepancy was encountered during prenatal care. The baby with 46, XY DSD has female external genitalia but evidence of Y chromosome-related regression of Müllerian structures and the absence of palpable gonads. We discussed the literature on phenotype-genotype discrepancy and the importance of care coordination between the antenatal and postnatal teams to ensure a timely diagnosis of DSD.

Chicken eggshells (ESs) consist of 96%–97% calcium carbonate, while about 3%–4% consists of organic substances, mainly in the form of protein-based membranes and occluded organic matter. Recently, ESs have been studied as a filler in polymer composite materials, which represents an innovative solution to address ES valorization. In this study, thermal and chemical treatments were investigated for membrane removal since the membrane may alter various properties when the ES fillers are added to the composite material. A nanoindentation method was used to measure changes in the ES mechanical properties. Scanning electron microscopy (SEM), thermogravimetric analysis (TGA), and Fourier-transform infrared (FT-IR) spectroscopy were used to characterize the ES membrane removal through chemical treatment. The results showed that even at a heating temperature of 100°C, the ES mechanical properties were negatively affected, while a low concentration of bleach solution (25% bleach solution and 10 min of holding time) was able to remove the membrane without reducing the ES mechanical properties. The chemical treatment method offers a means for ES membrane removal while conserving the quality of the mineral fraction (calcite; CaCO3).

Composite materials (CCFe and CGCFe) were prepared from carboxymethyl cellulose, chitosan, glutaraldehyde, and iron III species. The composite materials were characterized by FTIR, TGA, ICP-OES and SEM studies that provided evidence of cross-linking between chitosan and glutaraldehyde, along with variable iron doping and morphology of the composites. The equilibrium uptake study indicates that CGCFe surpassed the adsorption capacity of CCFe, where greater uptake was noted at lower versus higher temperatures (283 – 303 K). The monolayer adsorption capacity (Qm; mg g−1) of CGCFe for 2-naphthoxy acetic acid (S6) was 263 mg/g and 484 mg/g at alkaline and acidic pH conditions, according to the Sips and Langmuir isotherm models. The composite materials show limited discrimination of OSPW naphthenate components. Regeneration studies revealed that CGCFe retained 95% of its adsorption capacity after 5 cycles via a “zippering effect” in the presence of saline water. The enhanced regeneration and zipper-like structural transition of CGCFe represents a unique application of saline responsive supramolecular function driven by changes in ionic strength. This study advances the design of modular polysaccharide adsorbents according to the insight on the role of Fe (III) species, cross-linking effects, and biopolymer structure that relate to anion binding properties in aqueous solution.

A facile and sustainable synthesis of unique flax fiber composites (FFCs) is reported, where raw flax fiber (FFR) was immobilized with variable chitosan content. FFCs were structurally characterized via TGA, XRD, SEM analysis, and spectroscopy (IR, NMR, and Raman mapping). Physicochemical characterization of FFCs enabled estimation of the point-of-zero-charge (PZC), solvent swelling at variable pH. Dye adsorption with Rose Bengal (RB) and Methylene Blue (MB) afforded characterization of the surface chemistry of the materials. This contribution study is a first reported example that highlights the unique structure-property relationships of FFC materials and the role of electrostatic interactions between the pristine fiber substrate and chitosan. FFCs with incremental chitosan content display the following trends: (i) greater solvent swelling at variable pH (350 % for FFCs and ca. 100 % for FFR and commercial absorbents), (ii) two-fold enhanced adsorption of RB (FFC 0.5 to FFC 2.0) and (iii) 1.5-fold decreased adsorption of MB (FFC 2.0 to FFC 0.5). The unique “switchable” sorption properties of the FFCs toward solvent and dyes was revealed upon facile and noncovalent immobilization of chitosan onto FFR. The sustainable composites reported herein offer a potential adsorption-based technology suitable for filter-based applications in “smart textiles” to biomedical sorbents for wound healing.

Abstract Background Measurement-Based Care (MBC) is an evidence-based practice shown to enhance patient care. Despite being efficacious, MBC is not commonly used in practice. While barriers and facilitators of MBC implementation have been described in the literature, the type of clinicians and populations studied vary widely, even within the same practice setting. The current study aims to improve MBC implementation in adult ambulatory psychiatry by conducting focus group interviews while utilizing a novel virtual brainwriting premortem method. Methods Semi-structured focus group interviews were conducted with clinicians (n = 18) and staff (n = 7) to identify their current attitudes, facilitators, and barriers of MBC implementation in their healthcare setting. Virtual video-conferencing software was used to conduct focus groups, and based on transcribed verbatin, emergent barriers/facilitators and four themes were identified. Mixed methods approach was utilized for this study. Specifically, qualitative data was aggregated and re-coded separately by three doctoral-level coders. Quantitative analyses were conducted from a follow-up questionnaire surveying clinician attitudes and satisfaction with MBC. Results The clinician and staff focus groups resulted in 291 and 91 unique codes, respectively. While clinicians identified a similar number of barriers (40.9%) and facilitators (44.3%), staff identified more barriers (67%) than facilitators (24.7%) for MBC. Four themes emerged from the analysis; (1) a description of current status/neutral opinion on MBC; (2) positive themes that include benefits of MBC, facilitators, enablers, or reasons on why they conduct MBC in their practice, (3) negative themes that include barriers or issues that hinder them from incorporating MBC into their practice, and (4) requests and suggestions for future MBC implementation. Both participant groups raised more negative themes highlighting critical challenges to MBC implementation than positive themes. The follow-up questionnaire regarding MBC attitudes showed the areas that clinicians emphasized the most and the least in their clinical practice. Conclusion The virtual brainwriting premortem focus groups provided critical information on the shortcomings and strengths of MBC in adult ambulatory psychiatry. Our findings underscore implementation challenges in healthcare settings and provide insight for both research and clinical practice in mental health fields. The barriers and facilitators identified in this study can inform future training to increase sustainability and better integrate MBC with positive downstream outcomes in patient care.

Eun Kyung Jun,1,&ast; Sunghwan Lim,2,&ast; Joonho Seo,3 Kae Hong Lee,1 Jae Hee Lee,1 Deukhee Lee,2 Jae Chul Koh1 1Department of Anesthesiology and Pain Medicine, Korea University Anam Hospital, Seoul, Korea; 2Center for Healthcare Robotics, Artificial Intelligence and Robotics Institute, Korea Institute of Science and Technology, Seoul, Korea; 3Department of Medical Assistant Robot, Korea Institute of Machinery and Materials, Daegu, Korea&ast;These authors contributed equally to this workCorrespondence: Deukhee Lee, Center for Bionics, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul, 136-791, Republic of Korea, Tel +82-2-958-5633, Fax +82-2-920-2275, Email dkylee@kist.re.kr Jae Chul Koh, Department of Anesthesiology and Pain Medicine, Korea University Anam Hospital, 73, Goryeodae-ro, Seongbukgu, Seoul, 02841, Korea, Tel +82-2-920-5632, Fax +82-2-920-2275, Email jaykoh@korea.ac.krPurpose: Multiple studies have attempted to demonstrate the benefits of augmented reality (AR)-assisted navigation systems in surgery. Lumbosacral transforaminal epidural injection is an effective treatment commonly used in patients with radiculopathy due to spinal degenerative pathologies. However, few studies have applied AR-assisted navigation systems to this procedure. The study aimed to investigate the safety and effectiveness of an AR-assisted navigation system for transforaminal epidural injection.Patients and Methods: Through a real-time tracking system and a wireless network to the head-mounted display, computed tomography images of the spine and the path of a spinal needle to the target were visualized on a torso phantom with respiration movements installed. From L1/L2 to L5/S1, needle insertions were performed using an AR-assisted system on the left side of the phantom, and the conventional method was performed on the right side.Results: The procedure duration was approximately three times shorter, and the number of radiographs required was reduced in the experimental group compared to the control group. The distance from the needle tips to the target areas in the plan showed no significant difference between the two groups. (AR group 1.7 ± 2.3mm, control group 3.2 ± 2.8mm, P value 0.067).Conclusion: An AR-assisted navigation system may be used to reduce the time required for spinal interventions and ensure the safety of patients and physicians in view of radiation exposure. Further studies are essential to apply AR-assisted navigation systems to spine interventions.Keywords: interventional procedure, epidural injection, augmented reality, navigation system, radiation exposure

Chaemin Lim,1,&ast; Yuseon Shin,2,&ast; Kioh Kang,2 Patihul Husni,2 Dayoon Lee,2 Sehwa Lee,2 Han-Gon Choi,3 Eun Seong Lee,4 Yu Seok Youn,5 Kyung Taek Oh1,2 1College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea; 2Department of Global Innovative Drugs, The Graduate School of Chung-Ang University, Seoul, 06974, Republic of Korea; 3College of Pharmacy, Hanyang University, Ansan, 15588, South Korea; 4Department of Biotechnology, The Catholic University of Korea, Bucheon-si, Gyeonggi-do, 14662, Republic of Korea; 5School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, 16419, Republic of Korea&ast;These authors contributed equally to this workCorrespondence: Kyung Taek Oh, College of Pharmacy, Chung-Ang University, 221 Heukseok-dong, Dongjak-gu, Seoul, 06974, Republic of Korea, Tel +82-2-824-5617, Email kyungoh@cau.ac.krIntroduction: Ligand-conjugated liposomes are promising for the treatment of specific receptor-overexpressing cancers. However, previous studies have shown inconsistent results because of the varying properties of the ligand, presence of a polyethylene glycol (PEG) coating on the liposome, length of the linker, and density of the ligand.Methods: Here, we prepared PEGylated liposomes using PEG-linkers of various lengths conjugated with folate and evaluated the effect of the PEG-linker length on the nanoparticle distribution and pharmacological efficacy of the encapsulated drug both in vitro and in vivo.Results: When folate was conjugated to the liposome surface, the cellular uptake efficiency in folate receptor overexpressed KB cells dramatically increased compared to that of the normal liposome. However, when comparing the effect of the PEG-linker length in vitro, no significant difference between the formulations was observed. In contrast, the level of tumor accumulation of particles in vivo significantly increased when the length of the PEG-linker was increased. The tumor size was reduced by > 40% in the Dox/FL-10K-treated group compared to that in the Dox/FL-2K- or 5K-treated groups.Discussion: Our study suggests that as the length of PEG-linker increases, the tumor-targeting ability can be enhanced under in vivo conditions, which can lead to an increase in the antitumor activity of the encapsulated drug.Graphical Abstract: Keywords: PEGylated liposome, ligand-conjugated liposome, folate receptor, PEG-linker length

Jae-Ho Jeon,1,&ast; Somyoung Im,1,&ast; Hyo Shin Kim,1 Dongyun Lee,1 Kwiwan Jeong,2 Jin-Mo Ku,2 Tae-Gyu Nam1 1Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA campus, Ansan, Gyeonggi-do, 15588, Republic of Korea; 2Gyeonggi Bio-Center, Gyeonggido Business and Science Accelerator, Suwon, Gyeonggi-do, 16229, Republic of Korea&ast;These authors contributed equally to this workCorrespondence: Tae-Gyu Nam, Tel +82-31-400-5807, Fax +82-31-400-5958, Email tnam@hanyang.ac.krAbstract: The endoplasmic reticulum (ER) is responsible for structural transformation or folding of de novo proteins for transport to the Golgi. When the folding capacity of the ER is exceeded or excessive accumulation of misfolded proteins occurs, the ER enters a stressed condition (ER stress) and unfolded protein responses (UPR) are triggered in order to rescue cells from the stress. Recovery of ER proceeds toward either survival or cell apoptosis. ER stress is implicated in many pathologies, such as diabetes, cardiovascular diseases, inflammatory diseases, neurodegeneration, and lysosomal storage diseases. As a survival or adaptation mechanism, chaperone molecules are upregulated to manage ER stress. Chemical versions of chaperone have been developed in search of drug candidates for ER stress-related diseases. In this review, synthetic or semi-synthetic chemical chaperones are categorized according to potential therapeutic area and listed along with their chemical structure and activity. Although only a few chemical chaperones have been approved as pharmaceutical drugs, a dramatic increase in literatures over the recent decades indicates enormous amount of efforts paid by many researchers. The efforts warrant clearer understanding of ER stress and the related diseases and consequently will offer a promising drug discovery platform with chaperone activity.Keywords: endoplasmic reticulum stress, unfolded protein response, chemical chaperone, drug discovery, diabetes, cardiovascular disease, neurodegeneration, lysosomal storage disease

The dual pathway hypothesis of risk for substance use was tested by examining risk from symptoms of conduct problems and depressive symptoms in adolescence (from ages 10-11 to 17-18 years) to substance use—including tobacco, alcohol, cannabis, and other illicit drugs—in both early adulthood (approximately from ages 20 to 29 years) and middle adulthood (approximately from ages 29 to 38 years). Hypotheses were tested on a sample of boys who were at risk for conduct problems by virtue of the neighborhoods where they lived in childhood (the Oregon Youth Study; N = 206 at Wave 1). Dual-trajectory modeling (Latent Class Analysis) resulted in a 3-group solution of high, moderate, and low co-occurring symptoms. The latent class of boys with co-occurring symptoms in adolescence showed higher levels of substance use in adulthood; namely, higher levels of cannabis and illicit substance use during early adulthood compared to either of the moderate or low symptom classes, and higher use of cannabis in midadulthood than the low symptom class. Those with co-occurring symptoms also showed, overall, higher vulnerability to use of tobacco in these 2 periods, but not to higher use of alcohol. Regression analyses indicated that the higher substance use of the co-occur group of men was related to their adolescent conduct problems, but was not related to their adolescent depressive symptoms; however, these associations were nonsignificant when adolescent use of the respective substances were included in the models. Thus, the dual-trajectory hypothesis was not supported. However, the findings indicated that, as assessed in the present study, the psychopathology symptoms of boys with conduct problems in adolescence who show risk for later substance use may be complex, involving depressive symptoms.

Cell spreading and migration play central roles in many physiological and pathophysiological processes. We have previously shown that MFN2 regulates the migration of human neutrophil-like cells via suppressing Rac activation. Here, we show that in mouse embryonic fibroblasts, MFN2 suppresses RhoA activation and supports cell polarization. After initial spreading, the wild-type cells polarize and migrate, whereas the Mfn2-/- cells maintain a circular shape. Increased cytosolic Ca2+ resulting from the loss of Mfn2 is directly responsible for this phenotype, which can be rescued by expressing an artificial tether to bring mitochondria and endoplasmic reticulum to close vicinity. Elevated cytosolic Ca2+ activates Ca2+/calmodulin-dependent protein kinase II, RhoA, and myosin light-chain kinase, causing an overactivation of nonmuscle myosin II, leading to a formation of a prominent F-actin ring at the cell periphery and increased cell contractility. The peripheral actin band alters cell physics and is dependent on substrate rigidity. Our results provide a novel molecular basis to understand how MFN2 regulates distinct signaling pathways in different cells and tissue environments, which is instrumental in understanding and treating MFN2-related diseases.

In 2017, 400 million people in sub-Saharan Africa (SSA) were still using unimproved drinking water sources, 80 million of whom relied on untreated surface water. Urban areas are vastly expanding all over the continent and many larger cities in SSA struggle to provide safely managed drinking water. Phytoremediation implemented in constructed wetlands (CWs) is a low-cost and sustainable alternative to highly costly and energy-consuming wastewater treatment plants. In addition, CWs offer the potential to be integrated into farming and aqua-culture systems and can therefore improve food quality and production. The most prominent pollutants in urban SSA surface waters and the pollutant removal efficiencies for microbial and chemical contaminations of different plant species were identified from the literature and the accumulation rates for Pb, Cr, and Cd were compared with each other. A strong focus was given to studies conducted in SSA or other (sub)tropical regions. This review identified a range of potential phytoremediators to treat contaminated surface water and highlights the need for further in situ studies in SSA. Plant species such as Lemna minor, Ipomoea aquatica, Spirodela polyrhiza and Brachiaria mutica show a high potential to phytoremediate the heavy metals Pb, Cr and Cd from surface water. HIGHLIGHTS Review and analysis of water quality and wetland studies undertaken mainly in sub-Saharan Africa.; Review and analysis of phytoremediators able to improve urban surface water quality impacted by microbial and heavy metal contamination in tropical settings.;

Abstract Background Opioid-related overdose death is a public health epidemic in much of the USA, yet little is known about how people who use opioids (PWUO) experience overdose deaths in their social networks. We explore these experiences through a qualitative study of opioid-related overdose death bereavement among PWUO. Methods We recruited 30 adults who inject opioids from a syringe service program in the Midwestern USA and interviewed them using a semi-structured guide that addressed experiences of opioid use, opioid-related overdose, and overdose reversal via the medication naloxone. Interviews were transcribed verbatim and analyzed thematically. Findings Participants described overdose death as ever-present in their social worlds. Most (approximately 75%) reported at least one overdose death in their social network, and many came to consider death an inevitable end of opioid use. Participants described grief shaped by complex social relations and mourning that was interrupted due to involvement with social services and criminal legal systems. They also reported several ways that overdose deaths influenced their drug use, with some increasing their use and others adopting safer drug use practices. Despite the high prevalence of overdose deaths in their social networks, only one participant reported receiving grief support services. Discussion Findings underscore the need for interventions that not only maintain life, such as naloxone distribution, but also improve quality of life by attending to grief related to overdose death bereavement. We discuss policies and practices with the potential to address the unique psychological, social, and structural challenges of grief for this population.

Jennifer M Lee,1 David Lee,2 Sandy Christiansen,3 Jonathan M Hagedorn,4 Zheyan Chen,3 Timothy Deer5 1Department of Sports & Spine, EvergreenHealth Medical Group, Kirkland, WA, USA; 2Fullerton Orthopedic Surgery Medical Group, Fullerton, CA, USA; 3Department of Anesthesiology & Perioperative Medicine, Oregon Health Sciences University, Portland, OR, USA; 4iSpine Pain Physicians, Maple Grove, MN, USA; 5The Spine and Nerve Center of the Virginias, Charleston, WV, USACorrespondence: Jennifer M Lee, Email jelee@evergreenhealthcare.orgAbstract: Chronic bleeding disorders, allergy to implants, and chronic infections are all complicating factors when considering neuromodulation therapies. The American Society of Pain and Neuroscience (ASPN) determined a need for clinical guidance in these special patient populations that have increased risk of complications, in order to ensure patient safety and optimal outcomes with device implantation. The purpose of this publication was to review the published literature and explore the unique clinical challenges encountered among several special patient populations with relation to spinal cord stimulation. The executive board of the ASPN appointed a diverse group of well-established physicians to develop best practice guidelines regarding spinal cord stimulation implantation in these special populations. The physicians used the United States Preventive Services Task Force (USPSTF) structured guidelines for grading and level of certainty to make evidence-based recommendations about clinical practice. Where sufficient evidence was lacking to justify a USPSTF ranking, the physicians queried experts in neuromodulation and achieved consensus. These best practices and interventional guideline found the evidence for the use of neuromodulation in specialized patient populations to be relatively modest.Keywords: guidelines, metallurgic allergy, epidural hematoma, epidural abscess

Abstract The pig is an ideal model system for studying human development and disease due to its similarities to human anatomy, physiology, size, and genome. Further, advances in CRISPR gene editing have made genetically engineered pigs viable models for the study of human pathologies and congenital anomalies. However, a detailed atlas illustrating pig development is necessary for identifying and modeling developmental defects. Here we describe normal development of the pig abdominal system and show examples of congenital defects that can arise in CRISPR gene edited SAP130 mutant pigs. Normal pigs at different gestational ages from day 20 (D20) to term were examined and the configuration of the abdominal organs was studied using 3D histological reconstructions with episcopic confocal microscopy, magnetic resonance imaging (MRI) and necropsy. This revealed prominent mesonephros, a transient embryonic organ present only during embryogenesis, at D20, while the developing metanephros that will form the permanent kidney are noted at D26. By D64 the mesonephroi are absent and only the metanephroi remain. The formation of the liver and pancreas was observed by D20 and complete by D30 and D35 respectively. The spleen and adrenal glands are first identified at D26 and completed by D42. The developing bowel and the gonads are identified at D20. The bowel appears completely rotated by D42, and testes in the male were descended at D64. This atlas and the methods used are excellent tools for identifying developmental pathologies of the abdominal organs in the pig at different stages of development.

Three ternary metal composites (TMCs) with iron nitrate, aluminum nitrate, and copper nitrate (Fe-TMC-N, Al-TMC-N, Cu-TMC-N) were synthesized and their physicochemical properties were investigated. Characterization of the TMCs was achieved by elemental analysis (XPS), infrared (IR) spectroscopy and thermogravimetric analysis (TGA). The surface charge of the TMCs was estimated from the point-of-zero-charge (PZC), which depended on the type of metal nitrate precursor. The adsorption properties of the TMCs showed the vital role of the metal center, where methylene blue (MB) is a cationic dye probe that confirmed the effects of surface charge for effective methyl orange (MO) anion dye uptake. MB uptake was negligible for Al-TMC-N and Cu-TMC-N, whereas moderate MB uptake occurs for Fe-TMC-N (26 mg/g) at equilibrium. The adsorption capacity of MO adopted the Langmuir isotherm model, as follows: Al-TMC-N (422 mg/g), Cu-TMC-N (467 mg/g) and Fe-TMC-N (42 mg/g). The kinetic adsorption profiles followed the pseudo-second order model. Generally, iron incorporation within the TMC structure is less suitable for MO anion removal, whereas Cu- or Al-based materials show greater (10-fold) MO uptake over Fe-based TMCs. The dye uptake results herein provide new insight on adsorbent design for controlled adsorption of oxyanion species from water.

The removal of model hydrocarbon oil systems (4-nitrophenol (PNP) and naphthalene) from laboratory water was evaluated using a ferric sulfate and a lime-softening coagulant system. This study addresses the availability of a methodology that documents the removal of BTEX related compounds and optimizes the ferric-based coagulant system in alkaline media. The Box–Behnken design with Response Surface Methodology enabled the optimization of the conditions for the removal (%) of the model compounds for the coagulation process. Three independent variables were considered: coagulant dosage (10–100 mg/L PNP and 30–100 mg/L naphthalene), lime dosage (50–200%), and initial pollutant concentration (1–35 mg/L PNP and 1–25 mg/L naphthalene). The response optimization showed a 28% removal of PNP at optimal conditions: 74.5 mg/L ferric sulfate, 136% lime dosage, and initial PNP concentration of 2 mg/L. The optimal conditions for naphthalene removal were 42 mg/L ferric sulfate, 50% lime dosage, and an initial concentration of naphthalene (16.3 mg/L) to obtain a 90% removal efficiency. The coagulation process was modeled by adsorption isotherms (Langmuir for PNP; Freundlich for Naphthalene). The surface properties of flocs were investigated with pHpzc, solid-state UV absorbance spectra, and optical microscopy to gain insight into the role of adsorption in the ferric coagulation process.

With climate change predicted to alter water column stability and mixing across the world’s oceans, a mesocosm experiment was designed to ascertain how a natural phytoplankton community would respond to these changes. As a departure from other mesocosm experiments, we used heating and cooling to produce four different climate-inspired mixing scenarios ranging from well-mixed water columns representative of typical open turbulence (ϵ = 3 x 10-8 m2/s3) through to a quiescent water column with stable stratification (ϵ = 5 x 10-10 m2/s3). This method of turbulence generation is an improvement on previous techniques (e.g., grid, shaker, and aeration) which tend to produce excessive dissipation rates inconsistent with oceanic turbulence observations. Profiles of classical physical parameters used to describe turbulence and mixing (turbulent dissipation rate, buoyancy frequency, turbulent eddy diffusivity, Ozmidov scale) were representative of the profiles found in natural waters under similar mixing conditions. Chlorophyll-a profiles and cell enumeration showed a clear biological response to the different turbulence scenarios. However, the responses of specific phytoplankton groups (diatoms and dinoflagellates) did not conform to the usual expectations: diatoms are generally expected to thrive under convective, turbulent regimes, while dinoflagellates are expected to thrive in converse conditions, i.e., in stable, stratified conditions. Our results suggest that responses to mixing regimes are taxon-specific, with no overwhelming physical effect of the turbulence regime. Rather, each taxon seemed to very quickly reach a given vertical distribution that it managed to hold, whether actively or passively, with a high degree of success. Future studies on the effects of climate change on phytoplankton vertical distribution should thus focus on the factors and mechanisms that combine to determine the specific distribution of species within taxa. Our convection-based mesocosm approach, because it uses a primary physical force that generates turbulence in open waters, should prove a valuable tool in this endeavor.

ABSTRACTBackground Fibromyalgia (FM) is a complex, still poorly understood, and difficult-to-treat chronic pain condition for which many people struggle to find adequate care.Aims This study investigated the research question, “What do people accessing health care services for fibromyalgia perceive as helpful, hindering, and absent but desired?” with the aim of identifying clear, implementable changes for clinical practice.Materials and methods This study used the enhanced critical incident technique (ECIT), a qualitative research method that focuses on helping, hindering, and desired factors, to explore the health care experiences of 14 individuals (12 women and 2 men) diagnosed with FM.Results Using qualitative data analysis, results identified three categories of health care experiences: (1) systemic navigation, including financial and economic security; accessibility, flexibility, and continuity of care; and diversity of treatment options; (2) clinician–patient alliance, including invalidation and prejudice; therapeutic bond; and clinician–patient alignment on treatment plan; and (3) patient self-management strategies, including information-seeking and education, self-advocacy, social supports, symptom management strategies, and other coping strategies. Participants tended to conceptualize their health care concerns as a multilayered systemic problem.Conclusions Participants described a medical system they perceived as poorly equipped to support their needs and tended to invalidate their health concerns. Helping experiences tended to be the result of unique efforts on the part of individual clinicians. Findings emphasize the importance of recognizing the complexities and psychological impact of pain, trusting clinician–patient relationships, multidisciplinary/interdisciplinary care within a biopsychosocial framework, and improved education and awareness around psychosocial aspects of FM and effective management of chronic pain.

The harmful algal bloom (HABs) refers to the rapid growth of toxic or high-biomass-producing microalgae. The impact of this phenomenon can cause significant economic loss affecting many industries and causing harm to wildlife and human health. As technology develops, greater research has been conducted to monitor and reduce HABs occurrence’s impact, including mitigating agents. This review presents the advantages and disadvantages of currently used and recently developed biological, chemical, and physical approaches to tackle issues related to HABs. The present review also emphasizes the interaction between the mitigating agents and the algal cells, thus identifying the gap of knowledge that needs to be addressed. Understanding the advantages and disadvantages of the approaches and the interaction between the mitigating agents and algal cells will enable researchers to develop a better sustainable system for managing HAB.

Krishnan Chakravarthy,1,2 David Lee,3 Jennifer Tram,1 Samir Sheth,4 Robert Heros,5 Smith Manion,6 Vikas Patel,7 Kyle Kiesel,8 Yousef Ghandour,9 Christopher Gilligan10 1Department of Anesthesiology and Pain Medicine, University of California San Diego Health Sciences, San Diego, CA, USA; 2VA San Diego Healthcare System, San Diego, CA, USA; 3Fullerton Orthopedic Surgery Medical Group, Fullerton, CA, USA; 4Sutter Health System, Roseville, CA, USA; 5Spinal Diagnostics PC, Tualatin, OR, USA; 6Advent Health Pain Specialists, Merriam, KS, USA; 7Department of Orthopedic Surgery, University of Colorado, Denver, CO, USA; 8Department of Physical Therapy, University of Evansville, Evansville, IN, USA; 9Physical Rehabilitation Network (PRN), University of St. Augustine, San Diego, CA, USA; 10Division of Pain Medicine, Brigham & Women’s Hospital/Harvard Medical School, Boston, MA, USACorrespondence: Krishnan Chakravarthy, Department of Anesthesiology and Pain Medicine, University of California San Diego Health Sciences, San Diego, CA, USA, Email kvchakravarthy@health.ucsd.eduAbstract: In this review, we present a comprehensive clinical approach to restorative neurostimulation, a novel form of stimulation for refractory chronic mechanical low back pain, targeting impaired neuromuscular control and degeneration of the multifidus muscle. We focus on patient identification, technique guidance, and review of the scientific background and clinical evidence. As our understanding of back pain grows, there is clear evidence that impaired neuromuscular control and consequent degeneration of the multifidus muscle contribute to mechanical low back pain development and maintenance. We provide clinical guidance regarding an implantable restorative neurostimulation system that targets impaired neuromuscular control. Supported by results from a randomized, active-sham-controlled clinical trial with long-term follow-up, we provide clinicians with a comprehensive overview and practical clinical guidance for the adoption of this therapy modality.Keywords: restorative neurostimulation, multifidus, arthrogenic inhibition, neuromodulation, chronic mechanical low back pain, neuromuscular control

Joonki Hong,1,2 Hai Hong Tran,1 Jinhwan Jung,1 Hyeryung Jang,3 Dongheon Lee,1 In-Young Yoon,4,5 Jung Kyung Hong,4,5,&ast; Jeong-Whun Kim5,6,&ast; 1Asleep Inc., Seoul, Korea; 2Korea Advanced Institute of Science and Technology, Daejeon, Korea; 3Dongguk University, Seoul, Korea; 4Department of Psychiatry, Seoul National University Bundang Hospital, Seongnam, Korea; 5Seoul National University College of Medicine, Seoul, Korea; 6Department of Otorhinolaryngology, Seoul National University Bundang Hospital, Seongnam, Korea&ast;These authors contributed equally to this workCorrespondence: Jeong-Whun Kim, Department of Otorhinolaryngology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, 82, Gumi-ro 173beon-gil, Bundang-gu, Seongnam, Gyeonggi-do, 463-707, Korea, Email kimemails7@gmail.com Jung Kyung Hong, Department of Psychiatry, Seoul National University College of Medicine, Seoul National University Bundang Hospital, 82, Gumi-ro 173beon-gil, Bundang-gu, Seongnam, Gyeonggi-do, 463-707, Korea, Email hongjk15@gmail.comPurpose: Nocturnal sounds contain numerous information and are easily obtainable by a non-contact manner. Sleep staging using nocturnal sounds recorded from common mobile devices may allow daily at-home sleep tracking. The objective of this study is to introduce an end-to-end (sound-to-sleep stages) deep learning model for sound-based sleep staging designed to work with audio from microphone chips, which are essential in mobile devices such as modern smartphones.Patients and Methods: Two different audio datasets were used: audio data routinely recorded by a solitary microphone chip during polysomnography (PSG dataset, N=1154) and audio data recorded by a smartphone (smartphone dataset, N=327). The audio was converted into Mel spectrogram to detect latent temporal frequency patterns of breathing and body movement from ambient noise. The proposed neural network model learns to first extract features from each 30-second epoch and then analyze inter-epoch relationships of extracted features to finally classify the epochs into sleep stages.Results: Our model achieved 70% epoch-by-epoch agreement for 4-class (wake, light, deep, REM) sleep stage classification and robust performance across various signal-to-noise conditions. The model performance was not considerably affected by sleep apnea or periodic limb movement. External validation with smartphone dataset also showed 68% epoch-by-epoch agreement.Conclusion: The proposed end-to-end deep learning model shows potential of low-quality sounds recorded from microphone chips to be utilized for sleep staging. Future study using nocturnal sounds recorded from mobile devices at home environment may further confirm the use of mobile device recording as an at-home sleep tracker.Keywords: respiratory sounds, sleep stages, deep learning, smartphone, polysomnography

The fabrication of chitosan (CH) biocomposite beads with variable copper (Cu2+) ion doping was achieved with a glutaraldehyde cross-linker (CL) through three distinct methods: (1) formation of CH beads was followed by imbibition of Cu(II) ions (CH-b-Cu) without CL; (2) cross-linking of the CH beads, followed by imbibition of Cu(II) ions (CH-b-CL-Cu); and (3) cross-linking of pristine CH, followed by bead formation with Cu(II) imbibing onto the beads (CH-CL-b-Cu). The biocomposites (CH-b-Cu, CH-b-CL-Cu, and CH-CL-b-Cu) were characterized via spectroscopy (FTIR, 13C solid NMR, XPS), SEM, TGA, equilibrium solvent swelling methods, and phosphate adsorption isotherms. The results reveal variable cross-linking and Cu(II) doping of the CH beads, in accordance with the step-wise design strategy. CH-CL-b-Cu exhibited the greatest pillaring of chitosan fibrils with greater cross-linking, along with low Cu(II) loading, reduced solvent swelling, and attenuated uptake of phosphate dianions. Equilibrium and kinetic uptake results at pH 8.5 and 295 K reveal that the non-CL Cu-imbibed beads (CH-b-Cu) display the highest affinity for phosphate (Qm = 133 ± 45 mg/g), in agreement with the highest loading of Cu(II) and enhanced water swelling. Regeneration studies demonstrated the sustainability and cost-effectiveness of Cu-imbibed chitosan beads for controlled phosphate removal, whilst maintaining over 80% regenerability across several adsorption–desorption cycles. This study offers a facile synthetic approach for controlled Cu2+ ion doping onto chitosan-based beads, enabling tailored phosphate oxyanion uptake from aqueous media by employing a sustainable polysaccharide biocomposite adsorbent for water remediation by mitigation of eutrophication.