Targeting the Neuropilin-1 receptor with Ovatodiolide and progress in using periodontal ligament organoids for COVID-19 research and therapy.

The discovery of SARS-CoV-2 RNA in the periodontal tissues of patients who tested positive for COVID-19, 24 days post the initial symptom onset, indicates the oral cavity could serve as a viral reservoir. This research aims to investigate the antiviral capabilities of Ovatodiolide, introducing a novel periodontal ligament organoid model for the study of SARS-CoV-2. We have successfully established a reliable and expandable organoid culture from the human periodontal ligament, showcasing characteristics typical of epithelial stem cells. This organoid model enables us to delve into the lesser-known aspects of dental epithelial stem cell biology and their interactions with viruses and oral tissues. We conducted a series of in vitro and ex vivo studies to examine the inhibitory impacts of Ova on SARS-CoV-2. Our findings indicate that Ovatodiolide molecules can bind effectively to the NRP1 active domain. Our study identifies potential interaction sites for Ovatodiolide (OVA) within the b1 domain of the NRP1 receptor. We generated point mutations at this site, resulting in three variants: Y25A, T44A, and a double mutation Y25A/T44A. While these mutations did not alter the binding activity of the spike protein, they did impact the concentration of OVA required for inhibition. The inhibitory concentrations for these variants are 15 µM for Y25A, 15.2 µM for T44A, and 25 µM for the double mutant Y25A/T44A. In addition, in vitro inhibition experiments demonstrate that the EC50 of Ova against the main protease (Mpro) of the SARS-CoV-2 virus is 7.316 µM. Our in vitro studies and the use of the periodontal ligament organoid model highlight Ovatodiolide's potential as a small molecule therapeutic agent that impedes the virus's ability to bind to the Neuropilin-1 receptor on host cells. The research uncovers various pathways and biochemical strategies through which Ovatodiolide may function as an effective antiviral small molecule drug.

Biomechanical evaluation of 3D-printed joint-type orthosis for hallux valgus.

BACKGROUND: Orthoses play an important role in the conservative treatment of hallux valgus (HV) with different therapeutic effects. In this study, a new HV orthosis was developed using three-dimensional (3D) printing technology. In addition, its kinematic effect was evaluated using motion analysis. METHODS: Seventeen participants with an HV angle of >20° were included in the study. The first metatarsophalangeal abduction angle before and after the orthosis was measured statically. Subsequently, dynamic first metatarsophalangeal abduction, dorsiflexion angle and ground reaction force with and without the orthosis were recorded and calculated during walking using a Vicon motion analysis system and force plates. The patients' comfort scales were determined after the motion analysis. RESULTS: The angular corrections of the orthosis in the first metatarsophalangeal abduction were 14.6° and 6.3° under static and dynamic conditions, respectively. Reduced hallux dorsiflexion was observed with the orthosis in the early stance phase. However, no significant changes in ground reaction forces were observed. CONCLUSION: The results of our study confirm the potential of the 3D-printed HV orthosis in the static and dynamic correction of deformities while ensuring patient comfort with minimal impact on hallux kinematics, suggesting the potential of our design for long-term use.

Nanomaterials in the treatment and diagnosis of rheumatoid arthritis: Advanced approaches.

Rheumatoid arthritis (RA), a chronic inflammatory condition that affects persons between the ages of 20 and 40, causes synovium inflammation, cartilage loss, and joint discomfort as some of its symptoms. Diagnostic techniques for RA have traditionally been split into two main categories: imaging and serological tests. However, significant issues are associated with both of these methods. Imaging methods are costly and only helpful in people with obvious symptoms, while serological assays are time-consuming and require specialist knowledge. The drawbacks of these traditional techniques have led to the development of novel diagnostic approaches. The unique properties of nanomaterials make them well-suited as biosensors. Their compact dimensions are frequently cited for their outstanding performance, and their positive impact on the signal-to-noise ratio accounts for their capacity to detect biomarkers at low detection limits, with excellent repeatability and a robust dynamic range. In this review, we discuss the use of nanomaterials in RA theranostics. Scientists have recently synthesized, characterized, and modified nanomaterials and biomarkers commonly used to enhance RA diagnosis and therapy capabilities. We hope to provide scientists with the promising potential that nanomaterials hold for future theranostics and offer suggestions on further improving nanomaterials as biosensors, particularly for detecting autoimmune disorders.

Counting Phylogenetic Networks with Few Reticulation Vertices: Galled and Reticulation-Visible Networks.

We give exact and asymptotic counting results for the number of galled networks and reticulation-visible networks with few reticulation vertices. Our results are obtained with the component graph method, which was introduced by L. Zhang and his coauthors, and generating function techniques. For galled networks, we in addition use analytic combinatorics. Moreover, in an appendix, we consider maximally reticulated reticulation-visible networks and derive their number, too.

Oxidative stress and potential effects of metal nanoparticles: A review of biocompatibility and toxicity concerns.

Metal nanoparticles (M-NPs) have garnered significant attention due to their unique properties, driving diverse applications across packaging, biomedicine, electronics, and environmental remediation. However, the potential health risks associated with M-NPs must not be disregarded. M-NPs' ability to accumulate in organs and traverse the blood-brain barrier poses potential health threats to animals, humans, and the environment. The interaction between M-NPs and various cellular components, including DNA, multiple proteins, and mitochondria, triggers the production of reactive oxygen species (ROS), influencing several cellular activities. These interactions have been linked to various effects, such as protein alterations, the buildup of M-NPs in the Golgi apparatus, heightened lysosomal hydrolases, mitochondrial dysfunction, apoptosis, cell membrane impairment, cytoplasmic disruption, and fluctuations in ATP levels. Despite the evident advantages M-NPs offer in diverse applications, gaps in understanding their biocompatibility and toxicity necessitate further research. This review provides an updated assessment of M-NPs' pros and cons across different applications, emphasizing associated hazards and potential toxicity. To ensure the responsible and safe use of M-NPs, comprehensive research is conducted to fully grasp the potential impact of these nanoparticles on both human health and the environment. By delving into their intricate interactions with biological systems, we can navigate the delicate balance between harnessing the benefits of M-NPs and minimizing potential risks. Further exploration will pave the way for informed decision-making, leading to the conscientious development of these nanomaterials and safeguarding the well-being of society and the environment.

Peptide-Coated Bacteriorhodopsin-Based Photoelectric Biosensor for Detecting Rheumatoid Arthritis.

An effective early diagnosis is important for rheumatoid arthritis (RA) management. This study reveals a novel RA detection method using bacteriorhodopsin as a photoelectric transducer, a light-driven proton pump in purple membranes (PMs). It was devised by covalently conjugating a PM monolayer-coated electrode with a citrullinated-inter-alpha-trypsin inhibitor heavy chain 3 (ITIH3)542-556 peptide that recognizes the serum RA-associated autoantibodies. The direct serum coating decreased the photocurrents in the biosensor, with the reduction in the photocurrent caused by coating with an RA-patient serum that is significantly larger than that with a healthy-control serum (38.1% vs. 20.2%). The difference in the reduction in the photocurrent between those two serum groups widened after the serum-coated biosensor was further labeled with gold nanoparticle (AuNP)-conjugated anti-IgA (anti-IgA-AuNP) (53.6% vs. 30.6%). Both atomic force microscopic (AFM) and Raman analyses confirmed the sequential peptide, serum, and anti-IgA-AuNP coatings on the PM-coated substrates. The reductions in the photocurrent measured in both the serum and anti-IgA-AuNPs coating steps correlated well with the results using commercial enzyme-linked immunosorbent assay kits (Spearman rho = 0.805 and 0.787, respectively), with both a sensitivity and specificity close to 100% in both steps. It was shown that an RA diagnosis can be performed in either a single- or two-step mode using the developed biosensor.

Risks of posterior segment ocular ischaemic events in patients with systemic lupus erythematosus: a population-based cohort study in Taiwan.

BACKGROUD/AIM: Ocular involvement in systemic lupus erythematosus (SLE) is often primarily recognised by ophthalmologists rather than internists. This study aims to investigate the incidence and risk factors for the occurrence of posterior ocular ischaemic events (OIE), including retinal vein occlusion (RVO), retinal artery occlusion (RAO) and ischaemic optic neuropathy (ION), in patients with SLE. METHODS: A national database in Taiwan was used to identify 24 472 patients newly diagnosed with SLE and 244 720 age-matched and sex-matched controls between 1997 and 2012. New occurrences of OIE and confounding factors were recorded. The Kaplan-Meier method was used to compare the risk of OIE between the two groups. Fixed effect models were applied to evaluate the risk factors for OIE. RESULTS: The mean age was 36.24±15.82 years and women accounted for 88.4%. Patients with SLE had significantly increased risk of overall OIE (HR 3.89, 95% CI 3.36 to 4.50, p<0.001) as well as each OIE subtype. End-stage renal disease (ESRD; HR 2.91, 95% CI 2.05 to 4.14, p<0.001), hypertension (HR 1.77, 95% CI 1.21 to 2.58, p=0.003) and congestive heart failure (HR 1.67, 95% CI 1.12 to 2.48, p=0.01) were associated with RVO development. Hypertension (HR 2.89, 95% CI 1.10 to 3.96, p=0.02) and ischaemic stroke (HR 3.58, 95% CI 1.97 to 6.48, p<0.001) had increased risk of RAO. ESRD was associated with ION (HR 3.03, 95% CI 1.41 to 6.51, p=0.004). Intravenous steroid was associated with RVO development (HR 2.54, 95% CI 1.67 to 3.84, p<0.001). CONCLUSIONS: SLE increases the risk of developing OIE. Systemic comorbidities and higher dosage of steroid in patients with SLE are associated with severe ocular ischaemic complications.

Autoantibodies to Oxidatively Modified Peptide: Potential Clinical Application in Coronary Artery Disease.

Coronary artery disease (CAD) is a global health issue. Lipid peroxidation produces various by-products that associate with CAD, such as 4-hydroxynonenal (HNE) and malondialdehyde (MDA). The autoantibodies against HNE and MDA-modified peptides may be useful in the diagnosis of CAD. This study included 41 healthy controls (HCs) and 159 CAD patients with stenosis rates of <30%, 30−70%, and >70%. The plasma level of autoantibodies against four different unmodified and HNE-modified peptides were measured in this study, including CFAH1211−1230, HPT78−108, IGKC2−19, and THRB328−345. Furthermore, feature ranking, feature selection, and machine learning models have been utilized to exploit the diagnostic performance. Also, we combined autoantibodies against MDA and HNE-modified peptides to improve the models' performance. The eXtreme Gradient Boosting (XGBoost) model received a sensitivity of 78.6% and a specificity of 90.4%. Our study demonstrated the combination of autoantibodies against oxidative modification may improve the model performance.

Association of interferon-based therapy with risk of autoimmune diseases in patients with chronic hepatitis C virus infection: A population-based Taiwanese cohort study.

Background: Interferon in combination with ribavirin has been the standard of care for chronic hepatitis C virus infection (HCV) for the past few decades. However, its effect on the risk of autoimmune diseases (ADs) among patients with HCV infection remains unclear. We assessed the potential association between interferon-based therapy (IBT) and AD risk in patients with HCV infection. Methods: This retrospective cohort study identified patients diagnosed with HCV infection between January 1, 2006, and December 31, 2015, from Taiwan's National Health Insurance Research Database. In total, 16,029 patients with HCV infection who received IBT and 141,214 patients with HCV infection who did not receive IBT were included. Both cohorts were followed up to assess the development of ADs. Hazard ratios (HRs) were calculated using the Cox proportional hazards regression model, which was adjusted for potential confounders. Results: The median follow-up period for IBT and non-IBT users was 4.53 and 3.34 years, respectively. No significant difference in the risk of overall ADs (adjusted HR [aHR]: 0.96, 95% confidence interval [CI]: 0.81-1.14) or systemic ADs (aHR: 0.88, 95% CI: 0.71-1.10) was noted during the study period. However, a slight increase in the risk of organ-specific ADs was noted among IBT users (incidence rate ratio: 1.33, 95% CI: 1.02-1.72). Furthermore, analysis of AD subgroups revealed a significant increase in the risks of Graves' disease (aHR: 6.06, 95% CI: 1.27-28.8) and Hashimoto's thyroiditis (aHR 1.49, 95% CI 1.01-2.21) among IBT users. Conclusions: IBT use increases the risk of autoimmune thyroid diseases (Hashimoto's thyroiditis and Graves' disease) in patients with HCV infection to a greater extent than non-IBT use.

Cerebral Hemodynamics and Regional Oxygen Metabolism during Ductus Arteriosus Ligation in Preterm Infants.

INTRODUCTION: Neurodevelopmental impairment is a growing concern for preterm infants who received surgical ligation of patent ductus arteriosus (PDA). We aimed to explore the cerebral hemodynamics during the critical period of PDA ligation. METHODS: Very-low-birth-weight (VLBW) preterm infants who underwent PDA ligation were prospectively enrolled. Patients were monitored preoperatively and until 72 h post-ligation. Middle cerebral artery (MCA) flow, regional cerebral oxygen saturation (rcSO2), and cardiac output were measured through Doppler ultrasound, near-infrared spectroscopy, and electrical cardiometry, respectively. Using rcSO2 <55% indicating cerebral hypoxia, the duration (% of time) and burden (cumulative negative quantity of rsSO2 <55% × the period [minutes]) were estimated. An abnormal MCA was defined as an MCA flow of <10th percentile of flow velocity or >90th percentile of pulsatility or resistance index. Poor outcomes were defined as in-hospital death or neurologic disorders, either neuroimaging or functional abnormalities, upon discharge. RESULTS: Thirty-two VLBW infants were examined, and 15 (46.9%) had poor outcomes. Infants with poor outcomes had significantly longer duration of cerebral hypoxia (5.4 [2.2-32.3] vs. 1.8 [0.4-5.6] %, p = 0.033) and worse hypoxic burden (2,118 [684-13,549] vs. 622 [88-1,669] %minutes, p = 0.027). In a linear mixed model, rcSO2 was positively correlated with arterial saturation (ß 0.860, 95% CI: 0.649-1.070) and negatively correlated with abnormal MCA flow (ß -5.287, 95% CI: -8.238 to -2.335). CONCLUSION: Longer duration of cerebral hypoxia and worse hypoxic burden post-ligation was associated with an increased risk of in-hospital mortality or neurologic disorders upon discharge in VLBW preterm infants.

Using anti-malondialdehyde-modified peptide adduct autoantibodies in serum of taiwanese women to diagnose primary Sjogren's syndrome.

BACKGROUND: Sjogren's syndrome (SS) is a systemic autoimmune disease featured with a dry mouth and dry eyes. Several autoantibodies, including anti-SSA, anti-SSB, antinuclear antibodies can be detected in patients with SS. Oxidation-specific epitopes (OSEs) can be formed from malondialdehyde (MDA)-modified protein adducts and trigger chronic inflammation. In this study, our purposes were used serum levels of anti-MDA-modified peptide adducts autoantibodies to evaluate predictive performance by machine learning algorithms in primary Sjögren's syndrome (pSS) and assess the association between pSS and healthy controls. METHODS: Three novel MDA-modified peptide adducts, including immunoglobulin (Ig) gamma heavy chain 1 (IGHG1)102-131, complement factor H (CFAH)1045-1062, and Ig heavy constant alpha 1 (IGHA1)307-327 were identified and validated. Serum levels of protein, MDA-modified protein adducts, MDA, and autoantibodies recognizing unmodified peptides and MDA-modified peptide adducts were measured. Statistically significance in correlations and odds ratios (ORs) were estimated. RESULTS: The random forest classifier utilized autoantibodies combination composed of IgM anti-IGHG1102-131, IgM anti-IGHG1102-131 MDA and IgM anti-IGHA1307-327 achieved predictive performance as an accuracy of 88.0%, a sensitivity of 93.7%, and a specificity of 84.4% which may be as potential diagnostic biomarkers to differentiate patients with pSS from rheumatoid arthritis (RA), and secondary SS in RA and HCs. CONCLUSIONS: Our findings imply that low levels of IgA anti-IGHG1102-131 MDA (OR = 2.646), IgA anti-IGHG1102-131 (OR = 2.408), IgA anti-CFAH1045-1062 (OR = 2.571), and IgA anti-IGHA1307-327 (OR = 2.905) may denote developing risks of pSS, respectively.

Electrochemical biosensor with electrokinetics-assisted molecular trapping for enhancing C-reactive protein detection.

C-Reactive protein (CRP) is an essential biomarker relevant to various disease prognoses. Current biosensors require a significant amount of time for detecting CRP. To address this issue, this work proposes electrokinetic flow-assisted molecule trapping integrated with an impedance biosensor, where a driving signal in terms of a gated sine wave is provided to circularly arranged electrodes which detect proteins. To verify the biosensor's efficacy, protein aggregation on the electrode surface was evaluated through a fluorescence analysis and measurement of the electrochemical impedance spectrum (EIS). The fluorescence analysis with avidin showed that target samples largely accumulated on the electrode surface upon provision of the driving signal. The EIS measurement of CRP accumulation on the electrode surface further confirmed a significant electrokinetic phenomenon at the electrode/electrolyte interface. Even at the low CRP concentration of 10 pg/ml, the proposed device's sensitivity and reliability were as high as 3.92 pg/ml with a signal-to noise ratio (SNR) of ≥3, respectively. In addition, the protein detection time (without considering the preparation time) was minimized to as low as 90 s with the proposed device. This device's advantage is its minimal time consumption, and simple drop-analysis process flow; hence, it was used for monitoring clinical serum samples.

H1-Antihistamines Reduce the Risk of Hepatocellular Carcinoma in Patients With Hepatitis B Virus, Hepatitis C Virus, or Dual Hepatitis B Virus-Hepatitis C Virus Infection.

PURPOSE: H1-antihistamines (AHs) may exert protective effects against cancer. This study investigated the association of AH use with the risk of hepatocellular carcinoma (HCC) in patients with hepatitis B virus (HBV), hepatitis C virus (HCV), or dual HBV-HCV virus infection. MATERIALS AND METHODS: Patients with HBV, HCV, or dual HBV-HCV infection were enrolled from Taiwan's National Health Insurance Research Database and examined for the period from January 1, 2006, to December 31, 2015. We used the Kaplan-Meier method and Cox proportional hazards regression to evaluate the association between AH use and HCC risk. RESULTS: We included patients with HBV infection (n = 521,071), HCV (n = 169,159), and dual HBV-HCV (n = 39,016). Patients with HBV, HCV, or dual virus infection who used AHs exhibited significantly lower risk of HCC relative to patients who did not use AH, with their adjusted hazard ratio being 0.489 (95% CI, 0.455 to 0.524), 0.484 (95% CI, 0.450 to 0.522), and 0.469 (95% CI, 0.416 to 0.529), respectively. Furthermore, there was a dose-response relationship between AH use and the risk of HCC in the HBV cohort. The adjusted hazard ratios were 0.597 (95% CI, 0.530 to 0.674), 0.528 (0.465 to 0.600), 0.470 (0.416 to 0.531), and 0.407 (0.362 to 0.457) for AH use of 28-42, 43-63, 64-119, and ≥ 120 cumulative defined daily doses, respectively, relative to no AH use. Additionally, there was also a dose-response relationship between AH use and the risk of HCC in the HCV and dual HBV-HCV cohorts. CONCLUSION: AH use may reduce the risk for HCC among patients with HBV, HCV, or dual infection in a dose-dependent manner. Further mechanistic research is needed.

Peptide-based electrochemical sensor with nanogold enhancement for detecting rheumatoid arthritis.

Rheumatoid arthritis (RA), an autoimmune and chronic inflammatory disorder, is an incurable disease. We developed a peptide-based electrochemical sensor using electrochemical impedance spectroscopy that can be used to detect autoantibodies for RA diagnostics. We first validated that the developed peptide showed high sensitivity and could compliment the current gold standard method of an anti-cyclic citrullinated peptide antibody (anti-CCP) ELISA. The developed peptide can be modified on the nanogold surface of the working electrode of sensing chips through the method of a self-assembling monolayer. The sensing process was first optimized using a positive control cohort and a healthy control cohort. Subsequently, 10 clinically confirmed samples from RA patients and five healthy control samples were used to find the threshold value of the impedance between RA and healthy subjects. Furthermore, 10 clinically confirmed samples but with low values of anti-CCP autoantibodies were used to evaluate the sensitivity of the present method compared to the conventional method. The proposed method showed better sensitivity than the current conventional anti-CCP ELISA method.

Pneumocystis Jirovecii Pneumonia in Systemic Lupus Erythematosus: A Nationwide Cohort Study in Taiwan.

OBJECTIVE: To evaluate Pneumocystis jirovecii pneumonia (PJP) infection risk in patients with systemic lupus erythematosus (SLE) in Taiwan. METHODS: We identified 24,367 patients with SLE from the National Health Insurance research database between 1997 and 2012 and compared the PJP incidence rates (IRs) with those in 243,670 age- and sex-matched non-SLE controls. PJP risk in the patients was evaluated using a Cox multivariate proportional hazards model. RESULTS: The SLE patients exhibited a significantly higher PJP risk than the controls, with an IR of 2.63 per 10,000 person-years and IR ratio of 27.65 (95% confidence interval 17.2-45.3; P < 0.001). Male sex (hazard ratio [HR] 2.42, P < 0.01), end-stage renal disease (ESRD; HR 1.74, P = 0.01), recent use of mycofenolate mofetil (MMF; HR 4.43, P < 0.001), intravenous steroid pulse therapy (HR 108.73, P < 0.001), and average oral dosage of >7.5 mg/day prednisolone or equivalent treatment (HR 4.83, P < 0.001) were associated with PJP in SLE, whereas hydroxychloroquine use reduced its risk (HR 0.51, P = 0.01). Of note, cyclophosphamide was not associated with PJP infection in the multivariate Cox proportional hazard model. CONCLUSION: Patients with SLE have a considerably high PJP risk. Cyclophosphamide does not increase PJP risk. Male sex, ESRD, MMF use, intravenous steroid pulse therapy, and oral prednisolone or equivalent treatment (>7.5 mg/day) are risk factors for PJP, whereas hydroxychloroquine use reduces PJP risk.

Effects of biologics on reducing the risks of total knee replacement and total hip replacement in rheumatoid arthritis.

OBJECTIVES: RA damages the joints and increases the risks of total knee replacement (TKR) and total hip replacement (THR). However, the benefits of biologics in preventing TKR or THR remain unclear. METHODS: This retrospective nationwide study used the 2000-2013 claims-based National Health Insurance dataset. Biologics are reimbursed for refractory cases. The risks of TKR and THR in the biologic cohort were compared with those of an age- and sex-matched csDMARD cohort. A multivariate Cox regression model was used to investigate the benefits of bDMARDs for TKR and THR. RESULTS: TKR was performed in 5979 biologic cases and 11 958 matched controls, of which 249 (4.16%) and 871 (7.28%) cases received TKR, respectively. THR was performed in 6245 biologic cases and 12 490 matched controls, of which 159 (2.55%) and 516 (4.13%) cases had THR, respectively. The biologic cohort had significantly lower incidence rates of TKR (11.73 vs 16.33/1000 person-years, P < 0.001) and THR (7.09 vs 9.16/1000 person-years, P < 0.001). After adjustment for confounding factors, the regular bDMARD subgroup (average dose >0.95 defined daily dose/day) had significantly lower risks of TKR (aHR: 0.55, 95% CI: 0.38, 0.81) and THR (aHR: 0.63, 95% CI: 0.40, 0.98). Those without MTX use, with steroid use, with biologic switch, and overlapping antiphospholipid syndrome had significantly higher risks of TKR and THR. CONCLUSIONS: Compared with the csDMARD cohort, the risks of TKR and THR in the bDMARD cohort were the same as those in the low-to-moderate dose subgroups and significantly lower in those with regular bDMARD use.