Functional and structural investigation of a broadly neutralizing SARS-CoV-2 antibody.

Since its emergence, SARS-CoV-2 has been continuously evolving, hampering the effectiveness of current vaccines against COVID-19. mAbs can be used to treat patients at risk of severe COVID-19. Thus, the development of broadly protective mAbs and an understanding of the underlying protective mechanisms are of great importance. Here, we isolated mAbs from donors with breakthrough infection with Omicron subvariants using a single-B cell screening platform. We identified a mAb, O5C2, which possesses broad-spectrum neutralization and antibody-dependent cell-mediated cytotoxic activities against SARS-CoV-2 variants, including EG.5.1. Single-particle analysis by cryo-electron microscopy revealed that O5C2 targeted an unusually large epitope within the receptor-binding domain of spike protein that overlapped with the angiotensin-converting enzyme 2 binding interface. Furthermore, O5C2 effectively protected against BA.5 Omicron infection in vivo by mediating changes in transcriptomes enriched in genes involved in apoptosis and interferon responses. Our findings provide insights into the development of pan-protective mAbs against SARS-CoV-2.

The Lived Experiences of Palliative Care Professionals in Cultivating Mindfulness: A Phenomenological Study.

Purpose: The aim of this study was to explore the essence of the lived experiences of palliative care professionals in cultivating mindfulness, with a focus on the meaning of mindfulness in their lives and how mindfulness is experienced throughout their process of caring for others. Design: This was a qualitative study using a phenomenological approach. Methods: Eleven palliative care professionals (three physicians, four nurses, three psychologists, and one spiritual care provider) partook in in-depth interviews. Data were collected from the in-depth interviews and analyzed according to the method of Giorgi. Findings: Two major themes emerged from this study. First, the palliative care professionals realized the need for self-care amid emotional burden, including recognizing their feelings of guilt and self-doubt, emotional contagion of grief, reflections of others' fragility on themself, and their self-imposed limitations. Second, they noticed the transformative impact of mindfulness on them, including detecting reconnection with their body, changes in their personal values, self-acceptance, and liberation. Conclusion: Palliative care professionals can cultivate self-acceptance and facilitate entirely new life experiences through the practice of mindfulness. For them, mindfulness is not merely a self-regulation technique but an existential epiphany, offering hope for self-care and empowerment.

Association between sodium-glucose cotransporter-2 (SGLT2) inhibitors and macular degeneration in patients with diabetes: a nationwide population-based study in Taiwan.

AIMS: Evidence showed that SGLT2 inhibitors have greater protective effects against retinal diseases compared to other hypoglycemic agents. Thus, we explore the association between SGLT2 inhibitor usage and macular degeneration (MD) in Taiwanese patients with diabetes. METHODS: The National Health Insurance (NHI) program's claim data are released as the National Health Insurance Research Database (NHIRD). This database covers more than 99% of the residents in Taiwan. We included data on patients who were newly diagnosed with type 2 diabetes mellitus (ICD-9-CM: 250, exclude 250.1x; ICD-10-CM: E11), with an age at diagnosis of over 20 years as our study population. Patients who received (sodium-glucose cotransporter 2 inhibitor) SGLT2i (ATC code: A10BK) over 90 days in 2016-2019 were defined as the SGLT2i cohort. Conversely, patients who did never received SGLT2i were defined as the non-SGLT2i cohort. The exclusion criteria were having MD before the index date, receiving SGLT2i within 1-89 days, and missing data on sex, age, or days of SGLT2i usage. Two cohorts were matched by 1:1 propensity score matching, which was based on age, sex, payroll bracket grade, urbanization, comorbidities, and medications. RESULTS: Compared to non-SGLT2i cohort, patients who received SGLT2i had a significantly lower risk of MD (adjusted hazard ratio = 0.70, 95%CI = 0.66-0.75). CONCLUSIONS: We found that SGLT2is has a strong protective effect against MD in patients with diabetes. SGLT2is may have benefits beyond glycemic control in patients with DR. However, additional clinical and experimental studies are required.

Taipei Medical University Clinical Research Database: a collaborative hospital EHR database aligned with international common data standards.

OBJECTIVE: The objective of this paper is to provide a comprehensive overview of the development and features of the Taipei Medical University Clinical Research Database (TMUCRD), a repository of real-world data (RWD) derived from electronic health records (EHRs) and other sources. METHODS: TMUCRD was developed by integrating EHRs from three affiliated hospitals, including Taipei Medical University Hospital, Wan-Fang Hospital and Shuang-Ho Hospital. The data cover over 15 years and include diverse patient care information. The database was converted to the Observational Medical Outcomes Partnership Common Data Model (OMOP CDM) for standardisation. RESULTS: TMUCRD comprises 89 tables (eg, 29 tables for each hospital and 2 linked tables), including demographics, diagnoses, medications, procedures and measurements, among others. It encompasses data from more than 4.15 million patients with various medical records, spanning from the year 2004 to 2021. The dataset offers insights into disease prevalence, medication usage, laboratory tests and patient characteristics. DISCUSSION: TMUCRD stands out due to its unique advantages, including diverse data types, comprehensive patient information, linked mortality and cancer registry data, regular updates and a swift application process. Its compatibility with the OMOP CDM enhances its usability and interoperability. CONCLUSION: TMUCRD serves as a valuable resource for researchers and scholars interested in leveraging RWD for clinical research. Its availability and integration of diverse healthcare data contribute to a collaborative and data-driven approach to advancing medical knowledge and practice.

Trying a board game intervention on children with autism spectrum disorder in Macau: how do they react?

Limited special education and related services are available for children with autism spectrum disorder (ASD) in Macau, especially those who are educated in general education classrooms. No intervention study has been conducted on these children. This study was conducted to explore the relationship between a board game play intervention and board game play behaviors and social communication of children with ASD educated in general education classrooms in Macau. A repeated measures design was used and the results of this study showed the mean occurrence of unprompted board game play behaviors per session during intervention was not significantly different from that during pre- or post-intervention. The mean occurrence of social communication per session during intervention was significantly higher than that during pre- and post-intervention. These findings suggest a positive relationship existed between the board game intervention used in this study and social communication of children with ASD.

Colorectal Cancer and Subsequent Diabetes Risk: A Population-based Cohort Study in Taiwan.

CONTEXT: The association between colorectal cancer (CRC) and new-onset diabetes mellitus remains unclear. OBJECTIVE: To examine the association between CRC and the risk of subsequent diabetes mellitus and to further investigate the impact of chemotherapy on diabetes mellitus risk in CRC. DESIGN: A nationwide cohort study. METHODS: Using the Taiwan Cancer Registry Database (2007-2018) linked with health databases, 86,268 patients with CRC and an equal propensity score-matched cohort from the general population were enrolled. Among them, 37,277 CRC patients from the Taiwan Cancer Registry (2007-2016) were analyzed for diabetes mellitus risk associated with chemotherapy. Chemotherapy exposure within 3 years of diagnosis was categorized as no chemotherapy, <90 days, 90-180 days, and >180 days. Differences in diabetes mellitus risk were assessed across these categories. RESULTS: Each group involved 86,268 participants after propensity score matching. The patients with CRC had a 14% higher risk of developing diabetes mellitus than the matched general population (hazard ratio [HR]: 1.14, 95% confidence interval [CI]: 1.09-1.20). The highest risk was observed within the first year after diagnosis followed by a sustained elevated risk. Long-term chemotherapy (>180 days within 3 years) was associated with a 60-70% increased risk of subsequent diabetes mellitus (HR: 1.64, 95% CI: 1.07-2.49). CONCLUSION: Patients with CRC are associated with an elevated risk of diabetes mellitus, and long-term chemotherapy, particularly involving capecitabine, increases diabetes mellitus risk. Thus, monitoring blood glucose levels is crucial for patients with CRC, especially during extended chemotherapy.

Salpingectomy for ectopic pregnancy reduces ovarian cancer risk-a nationwide study.

Recent studies propose fallopian tubes as the tissue origin for many ovarian epithelial cancers. To further support this paradigm, we assessed whether salpingectomy for treating ectopic pregnancy had a protective effect using the Taiwan Longitudinal National Health Research Database. We identified 316 882 women with surgical treatment for ectopic pregnancy and 3 168 820 age- and index-date-matched controls from 2000 to 2016. In a nested cohort, 91.5% of cases underwent unilateral salpingectomy, suggesting that most surgically managed patients have salpingectomy. Over a follow-up period of 17 years, the ovarian carcinoma incidence was 0.0069 (95% confidence interval [CI] = 0.0060 to 0.0079) and 0.0089 (95% CI = 0.0086 to 0.0092) in the ectopic pregnancy and the control groups, respectively (P < .001). After adjusting the events to per 100 person-years, the hazard ratio (HR) in the ectopic pregnancy group was 0.70 (95% CI = 0.61 to 0.80). The risk reduction occurred only in epithelial ovarian cancer (HR = 0.73, 95% CI = 0.63 to 0.86) and not in non-epithelial subtypes. These findings show a decrease in ovarian carcinoma incidence after salpingectomy for treating ectopic pregnancy.

Rapid simulation of glycoprotein structures by grafting and steric exclusion of glycan conformer libraries.

Most membrane proteins are modified by covalent addition of complex sugars through N- and O-glycosylation. Unlike proteins, glycans do not typically adopt specific secondary structures and remain very mobile, shielding potentially large fractions of protein surface. High glycan conformational freedom hinders complete structural elucidation of glycoproteins. Computer simulations may be used to model glycosylated proteins but require hundreds of thousands of computing hours on supercomputers, thus limiting routine use. Here, we describe GlycoSHIELD, a reductionist method that can be implemented on personal computers to graft realistic ensembles of glycan conformers onto static protein structures in minutes. Using molecular dynamics simulation, small-angle X-ray scattering, cryoelectron microscopy, and mass spectrometry, we show that this open-access toolkit provides enhanced models of glycoprotein structures. Focusing on N-cadherin, human coronavirus spike proteins, and gamma-aminobutyric acid receptors, we show that GlycoSHIELD can shed light on the impact of glycans on the conformation and activity of complex glycoproteins.

A strategy of novel molecular hydrogen-producing antioxidative auxiliary system improves virus production in cell bioreactor.

In the increasing demand for virus vaccines, large-scale production of safe, efficient, and economical viral antigens has become a significant challenge. High-cell-density manufacturing processes are the most commonly used to produce vaccine antigens and protein drugs. However, the cellular stress response in large-scale cell culture may directly affect host cell growth and metabolism, reducing antigen production and increasing production costs. This study provided a novel strategy of the antioxidant auxiliary system (AAS) to supply molecular hydrogen (H2) into the cell culture media via proton exchange membrane (PEM) electrolysis. Integrated with a high-density cell bioreactor, the AAS aims to alleviate cellular stress response and increase viral vaccine production. In the results, the AAS stably maintained H2 concentration in media even in the high-air exposure tiding cell bioreactor. H2 treatment was shown safe to cell culture and effectively alleviated oxidative stress. In two established virus cultures models, bovine epidemic fever virus (BEFV) and porcine circovirus virus type 2 (PCV-2), were employed to verify the efficacy of AAS. The virus yield was increased by 3.7 and 2.5 folds in BEFV and PCV-2 respectively. In conclusion, the AAS-connected bioreactor effectively alleviated cellular oxidative stress and enhanced virus production in high-density cell culture.

Differential histone acetylation and super-enhancer regulation underlie melanoma cell dedifferentiation.

Dedifferentiation or phenotype switching refers to the transition from a proliferative to an invasive cellular state. We previously identified a 122-gene epigenetic gene signature that classifies primary melanomas as low versus high risk (denoted as Epgn1 or Epgn3). We found that the transcriptomes of the Epgn1 low-risk and Epgn3 high-risk cells are similar to the proliferative and invasive cellular states, respectively. These signatures were further validated in melanoma tumor samples. Examination of the chromatin landscape revealed differential H3K27 acetylation in the Epgn1 low-risk versus Epgn3 high-risk cell lines that corroborated with a differential super-enhancer and enhancer landscape. Melanocytic lineage genes (MITF, its targets and regulators) were associated with super-enhancers in the Epgn1 low-risk state, whereas invasiveness genes were linked with Epgn3 high-risk status. We identified the ITGA3 gene as marked by a super-enhancer element in the Epgn3 invasive cells. Silencing of ITGA3 enhanced invasiveness in both in vitro and in vivo systems, suggesting it as a negative regulator of invasion. In conclusion, we define chromatin landscape changes associated with Epgn1/Epgn3 and phenotype switching during early steps of melanoma progression that regulate transcriptional reprogramming. This super-enhancer and enhancer-driven epigenetic regulatory mechanism resulting in major changes in the transcriptome could be important in future therapeutic targeting efforts.

Effects of a Health Literacy Education Program on Mental Health and Renal Function in Patients With Chronic Kidney Disease: A Randomized Controlled Trial.

BACKGROUND: Chronic kidney disease (CKD) refers to permanent damage to the kidneys that occurs gradually over time. Further progression may be preventable depending on its stage. PURPOSE: This study was developed to evaluate the effect of a health literacy education program (HLEP) on mental health and renal functioning in patients with CKD. METHODS: A single-blind, randomized controlled trial study was conducted. Data were collected from March 25 to December 18, 2021. Participants were randomly assigned to either the experimental group (n = 42), which received multidisciplinary care and HLEP, or the control group (n = 42), which received multidisciplinary care only. Data were collected at baseline (T1), Month 3 (T2), and Month 6 (T3), and the data included patient characteristics, estimated glomerular filtration rate, and responses to the Mandarin Multidimensional Health Literacy Questionnaire and Beck Depression Inventory. RESULTS: After 6 months of the HLEP intervention, the results of generalized estimating equations analysis showed that, compared with the control group, the experimental group had significantly higher health literacy at Month 3 (ß = -3.37, 95% CI [-5.68, -1.06]), significantly improved depression at Month 3 (ß = -2.24, 95% CI [-4.11, -0.37]) and Month 6 (ß = -4.36, 95% CI [-6.60, -2.12]), and a significantly higher estimated glomerular filtration rate at Month 6 (ß = 5.87, 95% CI [1.35, 10.38]). CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The findings of this study may provide a reference for healthcare providers to educate patients with Stage 3-4 CKD using the HLEP. Positive effects on health literacy, depression, and renal function in patients with Stage 3-4 CKD were observed in the short term. Findings from this study may facilitate the implementation of multidisciplinary and nurse-led strategies in primary care to reinforce patients' health literacy, self-care ability, and adjustment to CKD as well as delay disease progression.

Machine-Learning Based Risk Assessment for Cancer Therapy-Related Cardiac Adverse Events Among Breast Cancer Patients.

The study aims to develop machine-learning models to predict cardiac adverse events in female breast cancer patients who receive adjuvant therapy. We selected breast cancer patients from a retrospective dataset of the Taipei Medical University Clinical Research Database and Taiwan Cancer Registry between January 2004 and December 2020. Patients were monitored at the date of prescribed chemo- and/or -target therapies until cardiac adverse events occurred during a year. Variables were used, including demographics, comorbidities, medications, and lab values. Logistics regression (LR) and artificial neural network (ANN) were used. The performance of the algorithms was measured by the area under the receiver operating characteristic curve (AUC). In total, 1321 patients (an equal 15039 visits) were included. The best performance of the artificial neural network (ANN) model was achieved with the AUC, precision, recall, and F1-score of 0.89, 0.14, 0.82, and 0.2, respectively. The most important features were a pre-existing cardiac disease, tumor size, estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2), cancer stage, and age at index date. Further research is necessary to determine the feasibility of applying the algorithm in the clinical setting and explore whether this tool could improve care and outcomes.

Structure, dynamics, and stability of the smallest and most complex 71 protein knot.

Proteins can spontaneously tie a variety of intricate topological knots through twisting and threading of the polypeptide chains. Recently developed artificial intelligence algorithms have predicted several new classes of topological knotted proteins, but the predictions remain to be authenticated experimentally. Here, we showed by X-ray crystallography and solution-state NMR spectroscopy that Q9PR55, an 89-residue protein from Ureaplasma urealyticum, possesses a novel 71 knotted topology that is accurately predicted by AlphaFold 2, except for the flexible N terminus. Q9PR55 is monomeric in solution, making it the smallest and most complex knotted protein known to date. In addition to its exceptional chemical stability against urea-induced unfolding, Q9PR55 is remarkably robust to resist the mechanical unfolding-coupled proteolysis by a bacterial proteasome, ClpXP. Our results suggest that the mechanical resistance against pulling-induced unfolding is determined by the complexity of the knotted topology rather than the size of the molecule.

Effects of a Hybrid Teaching Program on Lower Limb Muscle Strength, Knee Function, and Depression in Older Adults After Total Knee Replacement: A Randomized Controlled Trial.

The aim of the current study was to evaluate the effects of a nurse-led hybrid teaching program on lower limb strength, knee function, and depression in older adults after total knee replacement (TKR). This was a single-blind, randomized controlled trial. Fifty-two patients who underwent TKR were randomly assigned to either the experimental group (EG; n = 26), which received routine care plus 16 weeks of home rehabilitation through a hybrid teaching program, or the control group (CG; n = 26), which received routine care only. The intervention included pre-discharge face-to-face education, video instructions to follow at home after discharge, and four monthly telephone-based follow ups during the 16 weeks post-surgery. After the 16-week intervention, participants in the EG exhibited improved quadriceps strength, hamstring strength, and Knee Injury and Osteoarthritis Outcome Score (KOOS) compared to those in the CG. Generalized estimating equation analyses revealed a significant group-by-time interaction effect on quadriceps strength, overall KOOS score, and Geriatric Depression Scale-Short Form score. Findings suggest that a nurse-led hybrid teaching program enhances physical and psychological function after TKR when compared to routine care. This hybrid teaching program, involving exercise and postoperative education, proves to be a feasible and cost-effective intervention for improving outcomes in older adults following TKR. Health care teams should consider it as a viable home rehabilitation option for older adults who undergo TKR. [Research in Gerontological Nursing, 17(1), 31-40.].

Machine learning-based prediction of medication refill adherence among first-time insulin users with type 2 diabetes.

AIMS: The prevalence of Type 2 Diabetes Mellitus (T2DM) is projected to be 7 % in 2030. Despite its need for long-term diabetes care, the adherence rate of injectable medications such as insulin is around 60 %, lower than the acceptable threshold of 80 %. This study aims to create classification models to predict insulin adherence among adult T2DM naïve insulin users. METHODS: Clinical data were extracted from Taipei Medical University Clinical Research Database (TMUCRD) from January 1st, 2004 to December 30th, 2020. A patient was regarded as adherent if his/her medication possession ratio (MPR) was at least 80 %. Seven domains of predictors were created, including demographics, baseline medications, baseline comorbidities, baseline laboratory data, healthcare resource utilization, index insulins, and the concomitant non-insulin T2DM medications. We built two Xgboost models for internal and external testing respectively. RESULTS: Using a cohort of 4134 patients from Taiwan, our model achieved the Area Under the curve of the Receiver Operating Characteristic (AUROC) of the internal test was 0.782 and the AUROC of the external test was 0.771. the SHAP (SHapley Additive exPlanations) value showed that the number of prescribed medications, the number of outpatient visits, and laboratory data were predictive of future insulin adherence. CONCLUSIONS: This is the first study to predict adherence among adult naïve insulin users. The developed model is a potential clinical decision support tool to identify possible non-adherent patients for healthcare providers to design individualized education plans.

Isolation of three different sizes of exosomes in an Asian population with different retinal diseases before and after treatment: preliminary results.

Exosomes are membranous structures measuring between 40-120 nm that are secreted by various cells of the human body into the body fluid system. Exosomes contain proteins, mRNA, miRNA, and signaling molecules, and physiologically they assist in the intercellular transport of proteins and RNA molecules. In this study, we used an immunoaffinity filter paper platform combined with scanning electron microscopy and microfluidic systems to detect the size of exosomes within the aqueous humor. Eight aqueous humor samples showed three distinct sizes of exosomes that were significantly different on scanning electron microscopy(P < 0.01). We further used nanoparticle tracking analysis to assess the size distribution of exosomes within the aqueous humor. We found significantly different distributions of exosomes between patients with three different ocular diseases and patients with normal cataracts as controls. An obvious peak of exomeres(size around 35 nm)was found in the patients with central retinal vein occlusion and vitreous hemorrhage. Flare-ups of large exosomes(size 90-120 nm)were found in the patients with the inflammatory ocular disease pars planitis. No obvious peaks in exomeres or large exosomes were found in the control group. There was a high association between the distribution of exosomes and the pathogenesis of ocular diseases. After intravitreal anti-vascular endothelial growth factor treatment, the aqueous humor from the patients with neovascular diseases showed a significant reduction in exosomes in nanoparticle tracking analysis. These findings suggest that at least three distinct sizes of exosomes exist in the aqueous humor:(1)exomeres:<35 nm;(2)small exosomes:60-80 nm; and (3)large exosomes:90-120 nm. Different sizes of exosomes may have different implications in normal or diseased eyes.

Three different sized exosomes were identified in aqueous humor.The distribution of exosome size was significantly different between the patients with inflammatory and neovascularization retinal diseases.After intravitreal anti-vascular endothelial growth factor treatment, the aqueous humor from patients with neovascular diseases showed a significant reduction in exosomes in nanoparticle tracking analysis.

Maternal gestational diabetes mellitus and risk of allergic diseases in offspring.

BACKGROUND: Gestational diabetes mellitus has been linked to inflammation, immune dysregulation in offspring, and changes in the microbiota. It may have long-term implications for the health of children. The aim of this study was to determine if gestational diabetes mellitus increases the risk of allergic diseases in offspring. METHODS: The data source was the National Health Insurance Research Database (NHIRD) of Taiwan. The pairing of mothers and children was established by connecting the NHIRD with the Taiwan Maternal and Child Health Database. First-time pregnant mothers between 2004 and 2019 were enrolled. The GDM group consisted of 22,741 cases. The control group was selected from individuals without GDM matched by maternal age, neonatal gender, and neonatal birthdate at a ratio of 1-4. The primary endpoint was the incidence of childhood allergic diseases, such as asthma, allergic rhinitis, atopic dermatitis, and urticaria. The secondary endpoint was the risk associated with the development of allergic diseases in offspring, considering the presence or absence of insulin therapy. RESULTS: The development of allergic rhinitis, atopic dermatitis, and urticaria were found to be significantly associated with GDM. However, no significant association was observed between GDM and asthma. GDM control without insulin was associated with an increased risk of developing allergic rhinitis, urticaria, and atopic dermatitis. However, in the group receiving insulin treatment, there was no significant elevation in the risk of any allergic diseases. CONCLUSION: GDM may elevate the risk of certain atopic diseases in offspring, such as allergic rhinitis, atopic dermatitis, and urticaria.

The protective effects of beta-mangostin against sodium iodate-induced retinal ROS-mediated apoptosis through MEK/ERK and p53 signaling pathways.

Previous studies have indicated that NaIO3 induces intracellular reactive oxygen species (ROS) production and has been used as a model for age-related macular degeneration (AMD) due to the selective retinal pigment epithelium (RPE) cell damage it induces. Beta-mangostin (BM) is a xanthone-type natural compound isolated from Cratoxylum arborescens. The influence of BM on NaIO3-induced oxidative stress damage in ARPE-19 cells has not yet been elucidated. In this study, we investigated how BM protects ARPE-19 cells from NaIO3-induced ROS-mediated apoptosis. Our results revealed that BM notably improved cell viability and prevented ARPE-19 cell mitochondrial dysfunction mediated-apoptosis induced by NaIO3; it was mediated by significantly reduced NaIO3-upregulated ROS, cellular H2O2 production and improved downregulated glutathione and catalase activities. Furthermore, we found that BM could suppress the expression of Bax, cleaved PARP, and cleaved caspase-3 by decreasing phosphorylation of MEK/ERK and p53 expression in NaIO3-induced ARPE-19 cells. At the same time, we also used MEK inhibitors (PD98059) to confirm the above phenomenon. Moreover, our animal experiments revealed that BM prevented NaIO3 from causing retinal deformation; it led to thicker outer and inner nuclear layers and downregulated cleaved caspase-3 expression compared to the group receiving NaIO3 only. Collectively, these results suggest that BM can protect the RPE and retina from NaIO3-induced apoptosis through ROS-mediated mitochondrial dysfunction involving the MEK/ERK and p53 signaling pathways.