Design and Assessment of First-Generation Heterobifunctional PPARα/STING Modulators.

Inflammatory retinal diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD) are prominent causes of blindness in industrialized countries. The complexity of these diseases, involving diverse cell types and pathways that give rise to a multifactorial pathogenesis, complicates drug discovery. As such, therapies exhibiting polypharmacology are expected to improve outcomes through broader disease stage coverage and beneficial spatiotemporal effects. We report herein the first dual modulator of PPARα and STING, two targets tied to disparate pathologies in retinal diseases. Recognizing structural similarities between a reported STING inhibitor SN-013 and our previously described PPARα agonist A229, we designed BH400, which agonizes PPARα (EC50 = 1.2 µM) and inhibits STING (IC50 = 8.1 µM). BH400 demonstrates superior protection over single-target PPARα or STING modulation in microglial and photoreceptor cells. These findings provide compelling evidence for the potential benefit of polypharmacology in common retinal diseases through dual PPARα/STING modulation, motivating further studies.

Correction to "The interpersonal costs of dishonesty: How dishonest behavior reduces individuals' ability to read others' emotions" by Lee et al. (2019).

Reports an error in "The interpersonal costs of dishonesty: How dishonest behavior reduces individuals' ability to read others' emotions" by Julia J. Lee, Ashley E. Hardin, Bidhan Parmar, and Francesca Gino (Journal of Experimental Psychology: General, 2019[Sep], Vol 148[9], 1557-1574). Concerns were raised regarding the findings reported in Study 3 related to data exclusions that may have affected the results. As a result, the findings reported in Study 3 cannot be relied upon. The remaining base of empirical evidence presented in this publication, excluding Study 3, supports the assertion that dishonesty reduces empathic accuracy. The authors (Lee, Hardin, Parmar, & Gino) have requested this correction. (The following abstract of the original article appeared in record 2019-38884-001.) In this research, we examine the unintended consequences of dishonest behavior for one's interpersonal abilities and subsequent ethical behavior. Specifically, we unpack how dishonest conduct can reduce one's generalized empathic accuracy-the ability to accurately read other people's emotional states. In the process, we distinguish these 2 constructs from one another and demonstrate a causal relationship. The effects of dishonesty on empathic accuracy that we found were significant, but modest in size. Across 8 studies (n = 2,588), we find support for (a) a correlational and causal account of dishonest behavior reducing empathic accuracy; (b) an underlying mechanism of reduced relational self-construal (i.e., the tendency to define the self in terms of close relationships); (c) negative downstream consequences of impaired empathic accuracy, in terms of dehumanization and subsequent dishonesty; and (d) a physiological trait (i.e., vagal reactivity) that serves as a boundary condition for the relationship between dishonest behavior and empathic accuracy. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Physiological state matching in a pair bonded poison frog.

More than a century ago, Charles Darwin hypothesized that the empathy-like phenotype is a phylogenetically widespread phenomenon. This idea remains contentious, due to the challenges of empirically examining emotions, and few investigations among non-mammalian vertebrates. We provide support for Darwin's hypothesis by discovering partial evidence for the most ancestral form of empathy, emotional contagion (i.e. matching another individual's emotional state), in the pair bonding mimetic poison frog, Ranitomeya imitator. We found that male corticosterone, a physiological biomarker of stress, positively correlates with female partners in experimental and semi-natural conditions. This does not appear to coincide with behavioural state-matching. However, it is specific to female partners relative to familiar female non-partners, and is independent of effects that commonly confound studies on emotional contagion. Furthermore, this physiological state-matching is irrespective of partnership longevity or lifetime reproductive output. These results physiologically indicate socially selective emotional contagion in a monogamous amphibian, and paradigms that elicit coinciding neural and behavioural indicators and morphogenic co-variation are needed for further corroboration. Further studies on ancestral forms of empathy in non-mammalian vertebrates are warranted.

Health professional attitudes and perceptions of prehabilitation and nutrition before haematopoietic cell transplantation.

BACKGROUND: Nutritional prehabilitation may improve haematopoietic cell transplantation (HCT) outcomes, although little evidence exists. The present study aimed to understand healthcare professional (HCP) perceptions of prehabilitation and nutritional care pre-HCT in UK centres. METHODS: An anonymous online survey (developed and refined via content experts and piloting) was administered via email to multidisciplinary HCPs in 39 UK adult centres, between July 2021 and June 2022. Data are presented as proportions of responses. Routine provision denotes that care was provided >70% of time. RESULTS: Seventy-seven percent (n = 66) of HCPs, representing 61.5% (n = 24) of UK adult HCT centres, responded. All HCPs supported prehabilitation, proposing feasible implementation between induction chemotherapy (60.4%; n = 40) and first HCT clinic (83.3%; n = 55). Only 12.5% (n = 3) of centres had a dedicated prehabilitation service. Nutrition (87.9%; n = 58), emotional wellbeing (92.4%; n = 61) and exercise (81.8%; n = 54) were considered very important constituents. HCPs within half of the HCT centres (n = 12 centres) reported routine use of nutrition screening pre-HCT with a validated tool; 66.7% of HCPs (n = 36) reported using the malnutrition universal screening tool (MUST). Sixty-two percent (n = 41) of HCPs reported those at risk, received nutritional assessments, predominantly by dietitians (91.6%; n = 22) using the dietetic care process (58.3%; n = 14). Body mass index (BMI) was the most frequently reported body composition measure used by HCPs (70.2%, n = 33). Of 59 respondents, non-dietitians most routinely provided dietary advice pre-HCT (82.4%; n = 28 vs. 68%; n = 17, p = 0.2); including high-energy/protein/fat and neutropenic diet advice. Prophylactic enteral feeding pre-HCT was rare, indicated by low BMI and significant unintentional weight loss. Just under half (n = 25 of 59, 42.4%) HCPs reported exercise advice was given routinely pre-HCT. CONCLUSIONS: Nutrition and prehabilitation pre-HCT are considered important and deliverable by HCPs, but current provision in UK centres is limited and inconsistent.

Comparison of home-based spirometry and oscillometry measurements in school-age children with bronchopulmonary dysplasia.

INTRODUCTION: This study compares home-based oscillometry and spirometry for characterizing respiratory system disease in school-aged children with bronchopulmonary dysplasia (BPD) in clinical research. We hypothesized higher rates of successful completion and abnormal cases identified through oscillometry, with correlations between device measurements. METHODS: Participants 6-12 years old with BPD in the ongoing Air Quality, Environment and Respiratory Outcomes in BPD (AERO-BPD) study performed oscillometry followed by spirometry at two separate home visits. Parameters measured included airway resistance at 5 Hz(R5), resistance from 5 to 19 Hz(R5-19), resonance frequency(Fres), reactance at 5 Hz(X5), area under the curve between Fres and X5(AX), forced expiratory volume in 1 second(FEV1), forced vital capacity(FVC), and FEV1/FVC. Descriptive statistics identified the proportion of successful tests, correlation in measurements, and rate of lung disease for each device. RESULTS: Among 76 subjects with 120 paired observations, 95% and 71% of participants successfully performed oscillometry and spirometry, respectively, at home visit one. 98% and 77% successfully performed oscillometry and spirometry, respectively, at home visit two. Odds ratios favored oscillometry (range 5.31-10.13, p < 0.01). FEV1 correlated with AX (correlation coefficient r = -0.27, p = 0.03); FEV1/FVC with AX (r = -0.32, p = 0.02); and FEV1/FVC with R5 (r = -0.37, p = 0.01). AX exhibited the highest prevalence of abnormality at 25%; other oscillometry parameters ranged from 5%-22%. Forty-five to sixty-four percent of participants had abnormal spirometry. Oscillometry assessments had significantly lower odds of capturing lung disease (odds ratios 0.07-0.24, p < 0.0001). CONCLUSIONS: School-aged children with BPD demonstrated higher success rates in field-based oscillometry than spirometry. Spirometry exhibited higher rates of abnormality than oscillometry. Moderate correlation exists between device measurements.

Towards facilitated interpretation of shotgun metagenomics long-read sequencing data analyzed with KMA for the detection of bacterial pathogens and their antimicrobial resistance genes.

Metagenomic sequencing is a promising method that has the potential to revolutionize the world of pathogen detection and antimicrobial resistance (AMR) surveillance in food-producing environments. However, the analysis of the huge amount of data obtained requires performant bioinformatics tools and databases, with intuitive and straightforward interpretation. In this study, based on long-read metagenomics data of chicken fecal samples with a spike-in mock community, we proposed confidence levels for taxonomic identification and AMR gene detection, with interpretation guidelines, to help with the analysis of the output data generated by KMA, a popular k-mer read alignment tool. Additionally, we demonstrated that the completeness and diversity of the genomes present in the reference databases are key parameters for accurate and easy interpretation of the sequencing data. Finally, we explored whether KMA, in a two-step procedure, can be used to link the detected AMR genes to their bacterial host chromosome, both detected within the same long-reads. The confidence levels were successfully tested on 28 metagenomics datasets which were obtained with sequencing of real and spiked samples from fecal (chicken, pig, and buffalo) or food (minced beef and food enzyme products) origin. The methodology proposed in this study will facilitate the analysis of metagenomics sequencing datasets for KMA users. Ultimately, this will contribute to improvements in the rapid diagnosis and surveillance of pathogens and AMR genes in food-producing environments, as prioritized by the EU.

Artificial intelligence in shoulder and elbow surgery: overview of current and future applications.

Artificial intelligence (AI) is amongst the most rapidly growing technologies in orthopedic surgery. With the exponential growth in healthcare data, computing power, and complex predictive algorithms, this technology is poised to aid providers in data processing and clinical decision support throughout the continuum of orthopedic care. Understanding the utility and limitations of this technology is vital to practicing orthopedic surgeons, as these applications will become more common place in everyday practice. AI has already demonstrated its utility in shoulder and elbow surgery for imaging-based diagnosis, predictive modeling of clinical outcomes, implant identification, and automated image segmentation. The future integration of AI and robotic surgery represents the largest potential application of AI in shoulder and elbow surgery with the potential for significant clinical and financial impact. This editorial's purpose is to summarize common AI terms, provide a framework to understand and interpret AI model results, and discuss current applications and future directions within shoulder and elbow surgery.

Scutellarin, a flavonoid compound from Scutellaria barbata, suppresses growth of breast cancer stem cells in vitro and in tumor-bearing mice.

BACKGROUND: Scutellaria barbata D. Don (SB), commonly known as Ban Zhi Lian and firstly documented by Shigong Chen, is a dried whole plant that has been studied for its therapeutic effects on breast cancer, colon cancer, and prostate cancer. Among its various compounds, scutellarin (SCU) has been demonstrated with anti-tumor effects. PURPOSE: This study aimed to evaluate the effects of SB water extract (SBW) and scutellarin on breast cancer stem cells (BCSCs), and to investigate their potential therapeutic effects on breast tumors in mice. METHODS: BCSCs were enriched from human breast cancer cells (MDA-MB-231 and MDA-MB-361) and their characteristics were analyzed. The effects of varying concentrations of SBW and scutellarin on cell viability, proliferation, self-renewal, and migration abilities were studied, along with the underlying mechanisms. The in vivo anti-tumor effects of scutellarin were further evaluated in SCID/NOD mice. Firstly, mice were inoculated with naïve BCSCs and subjected to treatment with scutellarin or vehicle. Secondly, BCSCs were pre-treated with scutellarin or vehicle prior to inoculation into mice. RESULTS: The derived BCSCs expressed CD44, CD133 and ALDH1, but not CD24, indicating that BCSCs have been successfully induced from both MDA-MB-231 and MDA-MB-361 cells. Both SBW and scutellarin reduced the viability, proliferation, sphere and colony formation, and migration of BCSCs. In mice with tumors derived from naïve BCSCs, scutellarin significantly reduced tumor growth, expression of proliferative (Ki67) and stem cell markers (CD44), and lung metastasis. In addition, pre-treatment with scutellarin also slowed tumor growth. Western blot results suggested the involvement of Wnt/ß-catenin, NF-κB, and PTEN/Akt/mTOR signaling pathways underlying the inhibitory effects of scutellarin. CONCLUSION: Our study demonstrated for the first time that both SB water extract and scutellarin could reduce the proliferation and migration of BCSCs in vitro. Scutellarin was shown to possess novel inhibitory activities in BCSCs progression. These findings suggest that Scutellaria barbata water extract, in particular, scutellarin, may have potential to be further developed as an adjuvant therapy for reducing breast cancer recurrence.

Kajian Rintis Penilaian Literasi Digital: Kesediaan Guru Prasekolah Menggunakan Platform Pembelajaran dalam Talian untuk Pendidikan Pemakanan (A Pilot Study Assessing Digital Literacy: Preschool Teachers’ Readiness to Use Online Learning Platforms in Nutrition Education) / Jurnal Sains Kesihatan Malaysia

@#eToyBox is a learning management system for preschool teachers to improve their health literacy, which ultimately aims to improve children’s obesity-related behaviour. As part of the development process of eToyBox, assessment on digital literacy, acceptance of digitization of education materials, and perceived barriers in adopting online learning is needed. Fifty-four preschool teachers under the Community Development Department (KEMAS) in Kuala Lumpur, Selangor, and Sarawak, who participated in ToyBox Study Malaysia intervention in 2018, took part in this cross-sectional study. An online self-administered questionnaire was used to assess sociodemographic background, use of communication tools and media, and teacher’s views on adapting the ToyBox modules to digital education materials. Respondents were contacted, and questionnaire link was shared through WhatsApp messages. Most participants (74.0%) were Malay females aged 31 to 40 years old. Most participants had internet access (94.4%) and owned at least a smart phone, laptop or tablet (94.4%). Participants perceived their computer skills to be average (75.0%). Majority of respondents (65.0%) reported advanced and higher abilities in word processing and email, but only 22.0% in spreadsheet skills. The main barrier to accessing online material was unstable internet connection (74.1%). Most respondents (90.0%) agree that adapting effective modules to online learning will be beneficial for professional development and teaching practices. In conclusion, most participants supported digitizing Toybox Study Malaysia educational content and were comfortable 72 with its implementation via an online learning platform. The findings from this study can advise future development of online learning materials for preschool teachers in Malaysia.

Genetic characterization of a multidrug-resistant Salmonella enterica serovar Agona isolated from a dietary supplement in Germany.

Salmonella enterica subsp. enterica serovar Agona has a history of causing food-borne outbreaks and any emergence of multidrug-resistant (MDR) isolates in novel food products is of concern. Particularly, in food products frequently consumed without sufficient heating prior to consumption. Here, we report about the MDR isolate, 18-SA00377, which had been isolated from a dietary supplement in Germany in 2018 and submitted to the German National Reference Laboratory for Salmonella. WGS-based comparative genetic analyses were conducted to find a potential reservoir of the isolate itself or mobile genetic elements associated with MDR. As a phylogenetic analysis did not yield any closely related S. Agona isolates, either globally or from Germany, a detailed analysis of the largest plasmid (295,499 bp) was performed as it is the main carrier of resistances. A combined approach of long-read and short-read sequencing enabled the assembly of the isolate's chromosome and its four plasmids. Their characterization revealed the presence of 23 different antibiotic resistance genes (ARGs), conferring resistance to 12 different antibiotic drug classes, as well as genes conferring resistance to six different heavy metals. The largest plasmid, pSE18-SA00377-1, belongs to the IncHI2 plasmid family and carries 16 ARGs, that are organized as two distinct clusters, with each ARG associated with putative composite transposons. Through a two-pronged approach, highly similar plasmids to pSE18-SA00377-1 were identified in the NCBI database and a search for Salmonella isolates with a highly similar ARG resistance profile was conducted. Mapping and structural comparisons between pSE18-SA00377-1 and these plasmids and Salmonella isolates showed that both the plasmid backbone and identical or similar ARG clusters can be found not only in Salmonella isolates, originating mostly from a wide variety of livestock, but also in a diverse range of bacterial genera of varying geographical origins and isolation sources. Thus, it can be speculated that the host range of pSE18-SA00377-1 is not restricted to Salmonella and its spread already occurred in different bacterial populations. Overall, this hints at a complex history for pSE18-SA00377-1 and highlights the importance of surveilling multidrug-resistant S. enterica isolates, especially in novel food items that are not yet heavily regulated.

Distal biceps reconstruction: a long-term follow-up of the complications and durability of the single-incision power optimizing cost-effective (SPOC) repair.

Background: The Single-Incision Power Optimizing Cost-Effective Repair (SPOC) method reattaches the distal biceps tendon to its original posterior anatomic footprint and utilizes the anterior cortex of the supinated radius for fixation. The purpose of the study was to define the long-term complications and durability of the SPOC method. Methods: Two hundred and eighteen patients underwent the SPOC repair of distal biceps ruptures from 2008 to 2020, with 185 having at least 1-year follow-up data. The average follow-up was 50.1 months. Information regarding smoking, body mass index, interval between injury and surgery, peripheral nerve injury, heterotopic ossification, vascular injury, re-rupture, chronic regional pain syndrome, fracture of the radius, loss of motion, pain with use, and deformity were acquired. Results: No complication occurred beyond the third postoperative month. No patient complained of severe lateral antebrachial cutaneous nerve-related symptoms. Major complications exclusive of re-rupture occurred include 1 case of heterotopic ossification and 1 deep infection. Major complications with re-ruptures occurred in 9 patients (4.8%). Seven of the re-ruptures (78%) were associated with an unexpected forceful contraction within the first 4 weeks postop. All complications aside from 1 minor complication occurred in the chronic group. Long term follow-up revealed no re-ruptures and high satisfaction rate with return of strength, motion, and biceps profile. Conclusion: The safety profile of the SPOC repair is consistent with those of other published repairs. Major complications were associated with prolonged intervals between injury and reconstruction. Re-ruptures were associated with worker's compensation status and patient noncompliance with postoperative protocols.

From ToyBox Study to eToyBox: Advancing Childhood Obesity Reduction in Malaysian Kindergartens.

Prevention and treatment of childhood obesity is a global concern, and in Malaysia, it is considered a national public health priority. Determinants of childhood obesity are multifactorial and include factors that directly and indirectly influence energy balance-related behaviours, including energy intake and energy expenditure. Interventions to address childhood obesity that have multiple components at different levels have been shown to be the most influential. The ToyBox-study is a childhood obesity intervention aimed at preschool-aged children and their families that had been shown to be effective in several European countries and so was chosen for adaption for the Malaysian setting. Materials were translated and adjusted for the Malaysian context and audience and implemented in kindergartens in Peninsular Malaysia and Sarawak. However, during the COVID-19 pandemic and lockdown, teaching transitioned to being online. This brought an opportunity to reach a wider audience and consider the long-term sustainability of the intervention, and thus eToybox was born. eToybox aims to bring support for healthy energy balance behaviours directly to the teachers, into kindergartens and homes, to encourage families to be active and eat healthily, and prevent or reduce obesity. Through online innovation, the Toybox Study Malaysia programme has been expanded to enhance its potential to impact the promotion of healthy lifestyles among preschoolers and their families, highlighting the importance of a holistic approach to preventing and treating childhood obesity in Malaysia.

Design, Synthesis, and Structure-Activity Relationships of Biaryl Anilines as Subtype-Selective PPAR-alpha Agonists.

The role of peroxisome proliferator-activated receptor alpha (PPARα) in retinal biology is clarifying, and evidence demonstrates that novel PPARα agonists hold promising therapeutic utility for diseases like diabetic retinopathy and age-related macular degeneration. Herein, we disclose the design and initial structure-activity relationships for a new biaryl aniline PPARα agonistic chemotype. Notably, this series exhibits subtype selectivity for PPARα over other isoforms, a phenomenon postulated to be due to the unique benzoic acid headgroup. This biphenyl aniline series is sensitive to B-ring functionalization but allows isosteric replacement, and provides an opportunity for C-ring extension. From this series, 3g, 6j, and 6d were identified as leads with <90 nM potency in a cell-based luciferase assay cell and exhibited efficacy in various disease-relevant cell contexts, thereby setting the stage for further characterization in more advanced in vitro and in vivo models.

Natural product Eriocalyxin B suppressed triple negative breast cancer metastasis both in vitro and in vivo.

Breast cancer is the most commonly diagnosed cancer among women, and its metastasis to distant organs accounts for the majority of death. Eriocalyxin B (Eri B), an ent-kaurane diterpenoid isolating from Isodon eriocalyx var. laxiflora, has previously been reported to have anti-tumor and anti-angiogenic effects in breast cancer. Here, we investigated the effect of Eri B on cell migration and adhesion in triple negative breast cancer (TNBC) cells, as well as aldehyde dehydrogenases 1 family member A1 (ALDH1A1) expression, colony- and sphere-formation in cancer stem cell (CSC) enriched MDA-MB-231 cells. The in vivo anti-metastatic activities of Eri B were determined in 3 different breast tumor-bearing mouse models. Our results indicated that Eri B inhibited TNBC cell migration and adhesion to extracellular matrix proteins, and also reduced ALDH1A1 expression and colony formation in CSC-enriched MDA-MB-231 cells. The metastasis-related pathways, such as epidermal growth factor receptor/ mitogen-activated protein kinase kinases 1/2/ extracellular regulated protein kinase signaling altered by Eri B was firstly shown in MDA-MB-231 cells. The potent anti-metastatic efficacies of Eri B were demonstrated in breast xenograft-bearing mice and syngeneic breast tumor-bearing mice. Gut microbiome analysis results revealed the change in the diversity and composition of microbiome after Eri B treatment, and the potential pathways that are involved in the anti-cancer efficacy of Eri B. In conclusion, Eri B was shown to inhibit breast cancer metastasis in both in vitro and in vivo models. Our findings further support the development of Eri B as an anti-metastatic agent for breast cancer.

Benchmarking of survival outcomes following Haematopoietic Stem Cell Transplantation (HSCT): an update of the ongoing project of the European Society for Blood and Marrow Transplantation (EBMT) and Joint Accreditation Committee of ISCT and EBMT (JACIE).

From 2016 EBMT and JACIE developed an international risk-adapted benchmarking program of haematopoietic stem cell transplant (HSCT) outcome to provide individual EBMT Centers with a means of quality-assuring the HSCT process and meeting FACT-JACIE accreditation requirements relating to 1-year survival outcomes. Informed by previous experience from Europe, North America and Australasia, the Clinical Outcomes Group (COG) established criteria for patient and Center selection, and a set of key clinical variables within a dedicated statistical model adapted to the capabilities of the EBMT Registry. The first phase of the project was launched in 2019 to test the acceptability of the benchmarking model through assessment of Centers' performance for 1-year data completeness and survival outcomes of autologous and allogeneic HSCT covering 2013-2016. A second phase was delivered in July 2021 covering 2015-2019 and including survival outcomes. Reports of individual Center performance were shared directly with local principal investigators and their responses were assimilated. The experience thus far has supported the feasibility, acceptability and reliability of the system as well as identifying its limitations. We provide a summary of experience and learning so far in this 'work in progress', as well as highlighting future challenges of delivering a modern, robust, data-complete, risk-adapted benchmarking program across new EBMT Registry systems.