Toward a pan-SARS-CoV-2 vaccine targeting conserved epitopes on spike and non-spike proteins for potent, broad and durable immune responses.

BACKGROUND: The SARS-CoV-2 non-Spike (S) structural protein targets on nucleocapsid (N), membrane (M) and envelope (E), critical in the host cell interferon response and memory T-cell immunity, are grossly overlooked in COVID vaccine development. The current Spike-only vaccines bear an intrinsic shortfall for promotion of a fuller T cell immunity. Vaccines designed to target conserved epitopes could elicit strong cellular immune responses that would synergize with B cell responses and lead to long-term vaccine success. We pursue a universal (pan-SARS-CoV-2) vaccine against Delta, Omicrons and ever-emergent new mutants. METHODS AND FINDINGS: We explored booster immunogenicity of UB-612, a multitope-vaccine that contains S1-RBD-sFc protein and sequence-conserved promiscuous Th and CTL epitope peptides on the Sarbecovirus N, M and S2 proteins. To a subpopulation (N = 1,478) of infection-free participants (aged 18-85 years) involved in a two-dose Phase-2 trial, a UB-612 booster (third dose) was administered 6-8 months after the second dose. The immunogenicity was evaluated at 14 days post-booster with overall safety monitored until the end of study. The booster induced high viral-neutralizing antibodies against live Wuhan WT (VNT50, 1,711) and Delta (VNT50, 1,282); and against pseudovirus WT (pVNT50, 11,167) vs. Omicron BA.1/BA.2/BA.5 variants (pVNT50, 2,314/1,890/854), respectively. The lower primary neutralizing antibodies in the elderly were uplifted upon boosting to approximately the same high level in young adults. UB-612 also induced potent, durable Th1-oriented (IFN-γ+-) responses (peak/pre-boost/post-boost SFU/106 PBMCs, 374/261/444) along with robust presence of cytotoxic CD8+ T cells (peak/pre-boost/post-boost CD107a+-Granzyme B+, 3.6%/1.8%/1.8%). This UB-612 booster vaccination is safe and well tolerated without SAEs. CONCLUSIONS: By targeting conserved epitopes on viral S2, M and N proteins, UB-612 could provide potent, broad and long-lasting B-cell and T-cell memory immunity and offers the potential as a universal vaccine to fend off Omicrons and new VoCs without resorting to Omicron-specific immunogens. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT04773067; ClinicalTrials.gov ID: NCT05293665; ClinicalTrials.gov ID: NCT05541861.

Evaluation of the clinical application of personalized 3D printing and CAD/CAM resin crowns to replace stainless steel crowns in paediatric dentistry.

BACKGROUND: Children with dental caries are treated with stainless steel metal crowns (SSC), but the aesthetics and precision still need to be improved. Currently, both 3D-printed resin crowns (PRC) and computer-aided design/computer-aided manufacture (CAD/CAM) resin crowns (CRC) meet the clinical requirements for crown applications in terms of strength, production time, cost, and aesthetics. AIM: This study replaced SSC with customized resin crowns by 3D printing and CAD/CAM. DESIGN: In this study, PRC, CRC, and SSC were used for incisor and molar restorations, and 60 crowns were made with 10 for each group. The fabrication efficiency, surface characteristics, marginal fit, and stability of the two different crowns were evaluated. RESULTS: PRC and CRC show superior color and surface characteristics, though production times are longer (5.3-12.4 times and 3.3-9.1 times, respectively) than for SSC (p < .05). They, however, can be completed within 80 min. Edge gaps for PRC and CRC are significantly lower (13.0-19.2 times and 13.0-13.7 times) than for SSC (p < .05). All materials exhibit good stability. CONCLUSION: The 3D-PRCs and CAD/CAM resin crowns may replace SSCs as a potential choice for clinical child caries.

The characteristics and treatment strategy for transolecranon fracture-dislocation of the elbow in children: a retrospective study.

BACKGROUND: Transolecranon fracture-dislocation of the elbow is rarely seen in children. The purpose of this retrospective study was to discuss the pathological characteristics and treatment strategy for this injury in children. METHODS: From October 2016 to March 2019, 15 patients seen and treated at our institutions for transolecranon fracture-dislocation of the elbow were identified, and their medical records and radiographs were reviewed retrospectively. There were 11 boys and 4 girls, with an average age of 8.3 years (from 5 to 14 years). The left arm was involved in 10 cases, and the right arm was involved in 5 cases. Type I (simple fracture) was found in 11 cases, and type II (comminuted fracture) was found in 4 cases, 3 of which with coronoid process involved. Closed reduction was successful under local anaesthesia in 14 cases but failed in 1 case. In 11 patients with type I fractures, 10 received fixation of Kirschner wire and tension band, and one patient underwent bone plate fixation. In 4 patients with comminuted fractures (type II), internal fixation was performed with Kirschner wires combined with reconstruction plates. RESULTS: The 15 patients were followed up for 24 to 48 months (average, 30.2 months). The final evaluation showed fine anatomical relationship of the elbow in all with no complications observed. Failure of internal fixation did not occur in any patient. The fractures acquired bony union in all patients after 8 to 12 weeks (average, 9.6 weeks). The therapeutic efficacy was evaluated at the final follow-up by the Mayo elbow performance score (MEPS) as excellent in 11 cases, good in 3 cases and fair in one case. CONCLUSIONS: As a type of complicated fracture-dislocation of the elbow, the transolecranon fracture-dislocation is rare in children. The fracture is mainly simple type. Treatment options depend on the type of fracture-dislocation. Only anatomical reduction of the olecranon fracture and restoration of a normal trochlear notch can lead to a stable humeroradial joint and good clinical efficacy.

Medical undergraduates' self-evaluation: before and after curriculum reform.

BACKGROUND: In 2013, Taiwan launched a curriculum reform-the 7-year undergraduate medical education program was shortened to 6 years. This study explored the evaluation results from students regarding the curriculum reform and investigated graduates' perceptions regarding the curriculum organization of the two academic training programs affected by this curricular reform. METHODS: A cross-sectional survey was conducted from May 14 to June 12, 2019. The 315 graduates from both the 7-year and 6-year curriculum programs in the same medical school in Taipei were invited to participate in this study. In total, 197 completed questionnaires were received, representing a response rate of 62.5%. The results of the principal component analysis confirmed the validity of the constructs employed in this self-administered questionnaire. RESULTS: The t-test results yielded two main findings. First, the graduates from the 6-year program had significantly lower scores for preparedness for the upcoming postgraduate-year residency training than did their 7-year program counterparts. Additionally, the male graduates had significantly higher scores in terms of perceptions regarding curriculum organization and preparedness for postgraduate-year residency training than the female graduates. The results of stepwise regression also indicated that the sex difference was significantly correlated with graduates' readiness for their postgraduate-year residency training. CONCLUSION: To avoid sex disparities in career development, a further investigation of female medical students' learning environment and conditions is necessary. In addition to the cross-sectional study of students' perceptions, further repeated measurements of the objective academic or clinical performance of graduates in clinical settings are desirable.

Sorafenib and Doxorubicin Show Synergistic Effects in Human and Canine Osteosarcoma Cell Lines.

Osteosarcoma (OSA) is the most common bone tumor in both humans and dogs and has a nearly ten-fold higher incidence in dogs than humans. Despite advances in the treatment of other cancers, the overall survival rates for OSA have stagnated for the past four decades. Therefore, there is a great need to identify novel and effective treatments. We screened a series of tyrosine kinase inhibitors and selected sorafenib, a multi-kinase inhibitor, for further evaluation alone and in combination with cisplatin, carboplatin, and doxorubicin on canine and human OSA cell lines. Our data point to synergistic effects when sorafenib is combined with doxorubicin, but not when combined with cisplatin or carboplatin, in both human and canine OSA. Based on current findings, clinical trials using a combination of doxorubicin and sorafenib in proof-of-concept studies in dogs are warranted. These studies can be carried out relatively quickly in dogs where case load is high and, in turn, provide useful data for the initiation of clinical trials in humans.

Effects of Exogenous α-Naphthaleneacetic Acid and 24-Epibrassinolide on Fruit Size and Assimilate Metabolism-Related Sugars and Enzyme Activities in Giant Pumpkin.

Size is the most important quality attribute of giant pumpkin fruit. Different concentrations and application frequencies of α-naphthaleneacetic acid (NAA) and 24-epibrassinolide (EBR) were sprayed on the leaves and fruits of giant pumpkin at different growth stages to determine their effects and the mechanism responsible for fruit size increase. NAA+EBR application improved source strength, and further analysis indicated that NAA+EBR markedly boosted net photosynthetic rate (Pn), stomatal conductance (Gs), transpiration rate (Tr) and the expression level and activity of galactitol synthetase (GolS), raffinose synthetase (RS), and stachyose synthetase (STS), resulting in an increase in the synthesis of photoassimilate, especially stachyose. Concomitantly, NAA+EBR spray increased stachyose and sucrose contents throughout pumpkin fruit growth and the concentrations of glucose and fructose at 0 and 20 days post-anthesis (DPA) in peduncle phloem sap, implying that such treatment improved the efficiency of assimilate transport from the peduncle to the fruit. Furthermore, it improved the expression and activity of alkaline α-galactosidase (AGA), facilitating assimilate unloading, providing carbon skeletons and energy for fruit growth, and increasing fruit weight by more than 44.1%. Therefore, exogenous NAA and EBR increased source capacity, transportation efficiency, and sink strength, overall promoting the synthesis and distribution of photoassimilate, ultimately increasing fruit size.

Serum Total Bile Acid is Closely Related to the Significant Liver Injury in Patients with Non-Cholestatic Chronic Hepatitis B Virus Infection: a Cross-Sectional Study.

BACKGROUND: The relationship between non-cholestatic liver disease and total bile acid (TBA) remains obscure. The present study aimed to verify this relationship in patients with non-cholestatic chronic hepatitis B virus (HBV) infection. METHODS: A total of 922 consecutive chronic HBV infected patients with alkaline phosphatase (ALP) ≤ 1.5 upper limit of normal (ULN) and gamma-glutamyl transferase (GGT) ≤ 3 ULN were rigorously included in this cross-sectional study. Liver biopsy was performed in 53 patients and Scheuer scoring system was used to evaluate inflammation grade. G3/G4 or Child-Pugh B/C were considered to be significant liver injury. RESULTS: Compared to Child-Pugh A, TBA, total bilirubin (TBIL), ALP, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and AST to ALT ratio (AST/ALT) were significantly higher in Child-Pugh B/C, while TBIL to TBA ratio (TBIL/TBA) was significantly lower (all p < 0.001). In multivariate analysis, TBA and AST/ALT were independently correlated with Child-Pugh B/C [odds ratio (OR) = 1.04, p < 0.001; OR = 1.79, p < 0.001, respectively]. The area under the curve (AUC) of TBA (0.82) was significantly higher than that of AST (0.73, p < 0.001) and ALT (0.63, p < 0.001). Furthermore, in patients with liver biopsy, TBA was also significantly higher in G3/G4 while TBIL/TBA was significantly lower (p < 0.05). After adjusting the factors related to bile excretion, TBIL/TBA was independently associated with G3/G4 (OR = 0.89, p = 0.037). CONCLUSIONS: Serum TBA shows a close relationship with significant liver injury in chronic HBV infected patients without cholestasis. Assessment of TBA, especially in combination with TBIL/TBA, may serve as a non-invasive marker for the diagnosis of non-cholestatic hepatic damage.

Case study: international healthcare service quality, building a model for cultivating cultural sensitivity.

QUALITY PROBLEM OR ISSUE: In the context of medical tourism, cultural differences and language barriers are unneglectable factors, which compromise the shared decision-making between doctor and patients. INITIAL ASSESSMENT: This study constructs a cultural sensitivity cultivation (CSC) model that could be used to train medical professionals in the sector of medical tourism. CHOICE OF SOLUTION: Since 2016, there have been explorations in new strategies to offer better services. A critical step added is to include clients' perspectives in the re-examining process as a way to cultivate cultural sensitivity among the service providers. This practice expands to the sector of medical tourism. In our case study, we are able to conclude a new model that could yield quality international healthcare services. IMPLEMENTATION: The steps of our CSC model include (i) 'Promote Awareness' for shifting mindset, (ii) 'Share Scenarios' for developing empathy and compassion, (iii) 'Review Process' for collecting detail feedback, (iv) 'Identify Gaps' for targeting areas for improvement and (v) 'Improve Systems,' for changing standard operation procedures (SOPs) based on the strategies through Assmann's theory with a cultural-anthropological approach. EVALUATION: After Kuang Tien General Hospital (KTGH) implemented the new model for 1 year, the number of international patients has increased by 64%. More research could be done in the future to cover all the important aspects of providing international medical services and could apply the CSC model to different healthcare settings. LESSONS LEARNED: To optimize the shared decision-making between the doctor and medical traveler patients, healthcare providers should not only overcome language and cultural barriers but also should avoid unnecessary gestures in terms of status respect. Inviting patients to be co-investigator for quality improvement is a viable solution.

Assessment of Polyethylene Glycol-Coated Gold Nanoparticle Toxicity and Inflammation In Vivo Using NF-κB Reporter Mice.

Polyethylene glycol (PEG) coating of gold nanoparticles (AuNPs) improves AuNP distribution via blood circulation. The use of PEG-coated AuNPs was shown to result in acute injuries to the liver, kidney, and spleen, but long-term toxicity has not been well studied. In this study, we investigated reporter induction for up to 90 days in NF-κB transgenic reporter mice following intravenous injection of PEG-coated AuNPs. The results of different doses (1 and 4 µg AuNPs per gram of body weight), particle sizes (13 nm and 30 nm), and PEG surfaces (methoxyl- or carboxymethyl-PEG 5 kDa) were compared. The data showed up to 7-fold NF-κB reporter induction in mouse liver from 3 h to 7 d post PEG-AuNP injection compared to saline-injected control mice, and gradual reduction to a level similar to control by 90 days. Agglomerates of PEG-AuNPs were detected in liver Kupffer cells, but neither gross pathological abnormality in liver sections nor increased activity of liver enzymes were found at 90 days. Injection of PEG-AuNPs led to an increase in collagen in liver sections and elevated total serum cholesterol, although still within the normal range, suggesting that inflammation resulted in mild fibrosis and affected hepatic function. Administrating PEG-AuNPs inevitably results in nanoparticles entrapped in the liver; thus, further investigation is required to fully assess the long-term impacts by PEG-AuNPs on liver health.

A positive legacy of trauma? A study on the impact of natural disasters on medical utilization.

OBJECTIVE: The impact of natural disasters on medical utilization is largely unknown and often overlooked how it affects bereaving and non-bereaving survivors. The aim of this study is to determine the medical utilization between both survivor groups and long-term effects. STUDY DESIGN: A 10-year 1999-2009 population-based retrospective study by using the National Health Insurance claim database and the Household Registration database from the Department of Health, Executive Yuan, Taiwan. SETTINGS: Taiwan 1999 Chi-Chi earthquake-affected areas. PARTICIPANTS: A total of 49 834 individuals which included 1183 bereaving survivors and 48 651 non-bereaving earthquake survivors. INTERVENTION(S): None. MAIN OUTCOME MEASURES: Medical utilization of bereaving and non-bereaving survivors. RESULTS: The results showed that bereaving survivors had significantly more outpatient visits before the earthquake, within 3-month period and 1 year after earthquake (odds ratio (OR) = 1.11, 1.16 and 1.08). However, after 1 year after earthquake their outpatient visits were not significantly different from non-bereaving, and even significantly less in some years. Inpatient visits of bereaving survivors had similar trend to outpatient visits, i.e. visits were more both before earthquake and within 3-month period after earthquake (OR = 1.59 and 1.89), however, they were not significantly higher than non-bereaving survivors for the following years of the study. CONCLUSION: Our study reveals that compared to non-bereaving survivors, bereaving survivors slightly had higher medical utilization in the beginning stage of earthquake, i.e. for the first 3-month period or 1 year after earthquake. However, there were no differences between these two groups in medical utilization including outpatient and inpatient visits in long run.

S- Cis Diene Conformation: A New Bathochromic Shift Strategy for Near-Infrared Fluorescence Switchable Dye and the Imaging Applications.

In this paper, we present a novel charge-free fluorescence-switchable near-infrared (IR) dye based on merocyanine for target specific imaging. In contrast to the typical bathochromic shift approach by extending π-conjugation, the bathochromic shift of our merocyanine dye to the near-IR region is due to an unusual S- cis diene conformer. This is the first example where a fluorescent dye adopts the stable S- cis conformation. In addition to the novel bathochromic shift mechanism, the dye exhibits fluorescence-switchable properties in response to polarity and viscosity. By incorporating a protein-specific ligand to the dye, the probes (for SNAP-tag and hCAII proteins) exhibited dramatic fluorescence increase (up to 300-fold) upon binding with its target protein. The large fluorescence enhancement, near-IR absorption/emission, and charge-free scaffold enabled no-wash and site-specific imaging of target proteins in living cells and in vivo with minimum background fluorescence. We believe that our unconventional approach for a near-IR dye with the S- cis diene conformation can lead to new strategies for the design of near-IR dyes.

Value-added strategy models to provide quality services in senior health business.

OBJECTIVE: The rapid population aging is now a global issue. The increase in the elderly population will impact the health care industry and health enterprises; various senior needs will promote the growth of the senior health industry. Most senior health studies are focused on the demand side and scarcely on supply. Our study selected quality enterprises focused on aging health and analyzed different strategies to provide excellent quality services to senior health enterprises. DESIGN: We selected 33 quality senior health enterprises in Taiwan and investigated their excellent quality services strategies by face-to-face semi-structured in-depth interviews with CEO and managers of each enterprise in 2013. SETTING: A total of 33 senior health enterprises in Taiwan. PARTICIPANTS: Overall, 65 CEOs and managers of 33 enterprises were interviewed individually. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Core values and vision, organization structure, quality services provided, strategies for quality services. RESULTS: This study's results indicated four type of value-added strategy models adopted by senior enterprises to offer quality services: (i) residential care and co-residence model, (ii) home care and living in place model, (iii) community e-business experience model and (iv) virtual and physical portable device model. The common part in these four strategy models is that the services provided are elderly centered. These models offer virtual and physical integrations, and also offer total solutions for the elderly and their caregivers. Through investigation of successful strategy models for providing quality services to seniors, we identified opportunities to develop innovative service models and successful characteristics, also policy implications were summarized. CONCLUSIONS: The observations from this study will serve as a primary evidenced base for enterprises developing their senior market and, also for promoting the value co-creation possibility through dialogue between customers and those that deliver service.

The Regulations of Deubiquitinase USP15 and Its Pathophysiological Mechanisms in Diseases.

Deubiquitinases (DUBs) play a critical role in ubiquitin-directed signaling by catalytically removing the ubiquitin from substrate proteins. Ubiquitin-specific protease 15 (USP15), a member of the largest subfamily of cysteine protease DUBs, contains two conservative cysteine (Cys) and histidine (His) boxes. USP15 harbors two zinc-binding motifs that are essential for recognition of poly-ubiquitin chains. USP15 is grouped into the same category with USP4 and USP11 due to high degree of homology in an N-terminal region consisting of domains present in ubiquitin-specific proteases (DUSP) domain and ubiquitin-like (UBL) domain. USP15 cooperates with COP9 signalosome complex (CSN) to maintain the stability of cullin-ring ligase (CRL) adaptor proteins by removing the conjugated ubiquitin chains from RBX1 subunit of CRL. USP15 is also implicated in the stabilization of the human papillomavirus type 16 E6 oncoprotein, adenomatous polyposis coli, and IκBα. Recently, reports have suggested that USP15 acts as a key regulator of TGF-ß receptor-signaling pathways by deubiquitinating the TGF-ß receptor itself and its downstream transducers receptor-regulated SMADs (R-SMADs), including SMAD1, SMAD2, and SMAD3, thus activating the TGF-ß target genes. Although the importance of USP15 in pathologic processes remains ambiguous so far, in this review, we endeavor to summarize the literature regarding the relationship of the deubiquitinating action of USP15 with the proteins involved in the regulation of Parkinson's disease, virus infection, and cancer-related signaling networks.

Correction: Chon-Kit Chou, et al. The Regulations of Deubiquitinase USP15 and Its Pathophysiological Mechanisms in Diseases. Int. J. Mol. Sci. 2017, 18, 483.

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[An Experience of Providing Palliative Care in a Long-Term Care Facility: Let Good Death in Place Become a Feasible Reality].

As the number of elderly in long-term care facilities (LTCFs) continues to increase, the number of resident deaths in these facilities is expected to increase. Thus, LTCFs may become a main focus for end-of-life (EoL) care in the future. Therefore, promoting quality EoL care in LTCFs should be a priority issue. Currently, the four types of hospice services include hospice wards and hospice-share-services in hospitals and home hospice care and community hospice care in patient homes. However, to date, there has been limited discussion regarding promoting palliative care in LTCFs. The present article describes the LTCF nursing process that was used in caring for an EoL resident. Several interventions were used to assist this EoL resident to experience a dignified and peaceful death. These interventions included promoting the advance directive on hospice palliative care, linking community hospice palliative teams, ceating a warm environment, integrating the multidisciplinary team to alleviate the resident's distress symptoms, supporting the resident's psycho-social-spiritual needs, and accompanying family members through the process of anticipatory grief. This experience illustrates the feasibility of maintaining EoL residents in familiar LTCF environs in order to help them experience a good death in place.

Co-creating value through demand and supply integration in senior industry-observations on 33 senior enterprises in Taiwan.

OBJECTIVE: With global population aging, great business opportunities are driven by the various needs that the elderly face in everyday living. Internet development makes information spread faster, also allows elderly and their caregivers to more easily access information and actively participate in value co-creation in the services. This study aims to investigate the designs of value co-creation by the supply and demand sides of the senior industry. DESIGN: This study investigated senior industry in Taiwan and analyzed bussiness models of 33 selected successful senior enterprises in 2013. We adopted series field observation, reviews of documentations, analysis of meeting records and in-depth interviews with 65 CEOs and managers. SETTING: Thirty-three quality enterprises in senior industry. PARTICIPANTS: Sixty-five CEOs and managers in 33 senior enterprises. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Value co-creation design, value co-creating process. RESULTS: We constructed a conceptual model that comprehensively describes essential aspects of value co-creation and categorized the value co-creation designs into four types applying for different business models: (i) interaction in experience spaces co-creation design, (ii) on-site interacting co-creation design, (iii) social networking platform co-creation design and (iv) empowering customers co-creation design. Through value co-creation platform design, the senior enterprises have converted the originally passive roles of the elderly and caregivers into active participants in the value co-creation process. CONCLUSIONS: The new paradigm of value co-creation designs not only promote innovative development during the interactive process, lead enterprises reveal and meet customers' needs but also increase markets and profits.

Observations on quality senior health business: success patterns and policy implications.

OBJECTIVE: Population ageing is a global issue that affects almost every country. Most ageing researches focused on demand side and studies related to supply side were relatively scarce. This study selected quality enterprises focus on ageing health and analysed their patterns on providing quality services successfully. DESIGN: Our study selected quality senior health enterprises and explored their success patterns through face-to-face semi-structured in-depth interviews with CEO of each enterprise in 2013. SETTING: Thirty-three quality senior health enterprises in Taiwan. PARTICIPANTS: Thirty-three CEO's of enterprises were interviewed individually. INTERVENTION: None. MAIN OUTCOME MEASURES: Core values and vision, historical development, organization structure, services/products provided, delivering channels, customer relationships and further development strategies. RESULTS: Our results indicated success patterns for senior enterprises that there were meeting diversified lifestyles and substitutive needs for the elderly and their caregivers, providing a total solution for actual/virtual integration and flexible one-stop shopping services. We classified these enterprises by used degree of clicks-and-mortar of services and residing situation of the elderly. Industry characteristics and policy implications were summarized. CONCLUSIONS: Our observations will serve as a primary evidenced base for enterprises developing their senior market, and also for opening dialogue between customers and enterprises to facilitate valuable opportunities for co-creation between the supply and demand sides.