Evaluating drug interaction potential from cytokine release syndrome using a physiologically based pharmacokinetic model: A case study of teclistamab.

Cytokine release syndrome (CRS) was associated with teclistamab treatment in the phase I/II MajesTEC-1 study. Cytokines, especially interleukin (IL)-6, are known suppressors of cytochrome P450 (CYP) enzymes' activity. A physiologically based pharmacokinetic model evaluated the impact of IL-6 serum levels on exposure of substrates of various CYP enzymes (1A2, 2C9, 2C19, 3A4, 3A5). Two IL-6 kinetics profiles were assessed, the mean IL-6 profile with a maximum concentration (Cmax) of IL-6 (21 pg/mL) and the IL-6 profile of the patient presenting the highest IL-6 Cmax (288 pg/mL) among patients receiving the recommended phase II dose of teclistamab in MajesTEC-1. For the mean IL-6 kinetics profile, teclistamab was predicted to result in a limited change in exposure of CYP substrates (area under the curve [AUC] mean ratio 0.87-1.20). For the maximum IL-6 kinetics profile, the impact on omeprazole, simvastatin, midazolam, and cyclosporine exposure was weak to moderate (mean AUC ratios 1.90-2.23), and minimal for caffeine and s-warfarin (mean AUC ratios 0.82-1.25). Maximum change in exposure for these substrates occurred 3-4 days after step-up dosing in cycle 1. These results suggest that after cycle 1, drug interaction from IL-6 effect has no meaningful impact on CYP activities, with minimal or moderate impact on CYP substrates. The highest risk of drug interaction is expected to occur during step-up dosing up to 7 days after the first treatment dose (1.5 mg/kg subcutaneously) and during and after CRS.

Correlation of immune fitness with response to teclistamab in relapsed/refractory multiple myeloma in MajesTEC-1.

Teclistamab, an off-the-shelf B-cell maturation antigen (BCMA) × CD3 bispecific antibody that mediates T-cell activation and subsequent lysis of BCMA-expressing myeloma cells, is approved for the treatment of patients with relapsed/refractory multiple myeloma (RRMM). As a T-cell redirection therapy, clinical outcomes with teclistamab may be influenced by patient immune fitness and tumor antigen expression. We correlated tumor characteristics and baseline immune profiles with clinical response and disease burden in patients with RRMM from the pivotal phase 1/2 MajesTEC-1 study, focusing on patients treated with 1.5 mg/kg of teclistamab (N = 165). Peripheral blood samples were collected at screening and bone marrow samples were collected at screening and cycle 3. Better clinical outcomes to teclistamab correlated with higher baseline total T-cell counts in the periphery. In addition, responders (partial response or better) had a lower proportion of immunosuppressive regulatory T cells, T cells expressing co-inhibitory receptors (CD38, PD-1, PD-1/TIM-3), and soluble BCMA, and a T-cell profile suggestive of a more cytolytic potential, compared with nonresponders. Neither frequency of baseline bone marrow BCMA expression nor BCMA receptor density were associated with clinical response to teclistamab. Improved progression-free survival was observed in patients with a lower frequency of T cells expressing exhaustion markers and immunosuppressive regulatory T cells. Overall, response to teclistamab was associated with baseline immune fitness; nonresponders had immune profiles suggestive of immune suppression and T-cell dysfunction. These findings illustrate the importance of the contribution of the immune landscape to T-cell redirection therapy response. This trial was registered at www.ClinicalTrials.gov, NCT03145181/NCT04557098.

Assessing the severity of AstraZeneca COVID-19 vaccine-related side effects through pulse spectrum analysis.

AstraZeneca (AZ) vaccine is one of the most common vaccines against COVID-19 used globally. However, adverse reactions post-vaccination have been reported, including severe symptoms and cases of sudden death within several hours. Therefore, this study aimed to establish a database of spectral characteristics of blood pressure waveforms (BPWs) for the AZ vaccine and analyze reactions after vaccine administration using objective physiological signal and symptom analyses for identifying potential differences between heavy and slight groups defined in the study. In total, 24 participants were enrolled in the case-control study. BPW measurements were acquired pre- and post-vaccination. A questionnaire survey on side effects was conducted 5 days after vaccination. The related spectral characteristics of heavy and slight groups were acquired after Fourier transform analysis. Four types of harmonic indexes from BPW signals, including amplitude proportion (Cn), coefficient of variation of Cn (CVn), phase angle (Pn), and standard deviation of Pn (Pn_SD), were derived. The characteristics of harmonic indexes of arterial BPW for the AZ vaccine were in C6 (P = .011), CV2 (P = .027), P5 (P = .009), and P2_SD (P = .027) on the radial pulse. C5 (P = .037), C8 (P = .007), C9 (P = .037), CV5 (P = .015), CV8 (P = .005), and CV9 (P = .028) were significantly different at posttest between heavy and slight groups. In both pretest or posttest, C8 was almost significantly different between slight and heavy groups. More parameters changed significantly post-vaccination, with more severe side effects. Most average values of posttest/pretest of CVn and Pn_SD in the slight group exceeded 100%. All average values of posttest/pretest of CVn and Pn_SD in the heavy group were smaller than 100%. This approach may enable prediction of the risk of reactions post-vaccination to determine suitability of the AZ vaccine and evaluation of side effect severity in vaccinated individuals using pulse analysis to ensure relevant precautions are taken.

Incidence of nerve injury following acupuncture treatments in Taiwan.

OBJECTIVE: Acupuncture, a widely employed traditional therapeutic modality known for its efficacy in pain alleviation and diverse condition management, may inadvertently result in mechanical nerve injury due to its invasive nature. This research aimed to ascertain the incidence of nerve injuries post-acupuncture, identify associated risk factors, and map the distribution of nerve injury sites. METHODS: A case-control study nested in the National Health Insurance Research Database (NHIRD) 2000-2018 two million cohort was conducted. Patients previously diagnosed with nerve injury, surgery, or degeneration before acupuncture were excluded. Cases were defined as patients receiving acupuncture and seeking medical attention for nerve injury (ICD9-CM code 950-957) within 14 days post-procedure, while control groups comprised patients undergoing acupuncture without subsequent adverse events. Invasive treatments prior to adverse events and adverse events occurring more than 14 days post-acupuncture were excluded. To ensure case-control comparability, factors such as age, gender, socioeconomic status, and medical facility environment were controlled using propensity score matching. RESULTS: The study encompassed 14,507,847 acupuncture treatments administered to 886,753 patients, with 8361 instances of post-acupuncture nerve injury identified, representing an incidence rate of approximately 5.76 per 10,000 procedures. Age emerged as a significant risk factor, with the adjusted odds ratios escalating with age. Several comorbidities including diabetes, hypothyroidism, liver cirrhosis, chronic kidney disease, herpes zoster, hepatitis virus, rheumatoid arthritis, systemic lupus erythematosus, dementia, and cerebrovascular accidents were associated with an elevated risk of nerve injury post-acupuncture. CONCLUSION: This study underscores the importance of meticulous patient profiling and cautious therapeutic approach in acupuncture, considering the evident influence of various demographic, systemic, and treatment-related factors on the incidence of nerve injuries.

Identification of co-expressed genes and immune infiltration features related to the progression of atherosclerosis.

Atherosclerosis is a chronic inflammatory disease that affects arterial walls and is a leading cause of cardiovascular disease. Gene co-expression modules can provide insight into the molecular mechanisms underlying atherosclerosis progression. In this study, gene co-expression network analysis (WGCNA) was done to identify gene co-expression modules associated with atherosclerosis progression. Before conducting WGCNA, preprocessing and soft power selection were performed on the GSE28829, GSE100927, GSE43292, GSE10334, and GSE16134 datasets ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi ). Co-expression modules were identified using dynamic tree cuts, and their correlations and trait associations were visualized. Enrichment analysis was performed on the blue and magenta modules to identify biological processes (BP) and pathways related to atherosclerosis. The CIBERSORT algorithm was used to predict immune cell infiltration in early and advanced atherosclerotic plaques. We identified 12 co-expression modules, in which blue and magenta were most highly correlated with atherosclerosis progression. The blue module was enriched for inflammation- and immune-related BP and pathways, including phagosome, lysosome, osteoclast differentiation, chemokine signaling pathway, platelet activation, NF-kappa B signaling pathway, Fc gamma R-mediated phagocytosis, lipid and atherosclerosis, autophagy, and apoptosis. The magenta module was significantly enriched for vascular permeability regulation, positive and negative regulation of epithelial to mesenchymal transition, and lamellipodium. Additionally, the CIBERSORT algorithm predicted less abundance of T regulatory cells and monocytes in advanced compared to early atherosclerotic plaques. The enrichment analysis of BP, cellular components, molecular functions, and atherosclerosis-related pathways in the blue and magenta modules showed that inflammation and immune response played a key role in the progression of atherosclerosis. Our study provides insights into the molecular mechanisms underlying atherosclerosis progression and identifies potential therapeutic targets for the treatment of atherosclerosis. The identification of immune cell subtypes associated with atherosclerosis could lead to the development of immunomodulatory therapies to prevent or treat atherosclerosis.

The Initial Experience of Laparoscopic Management for Type VI Choledochal Cyst in Children.

Purposes: Dilatation of cystic duct is very rare and had been classified as Todani type VI choledochal cyst. Choledochal cyst combined with dilatation of cystic duct is difficult to diagnose preoperatively. The purpose of this study is to report the rare variants and discuss the significance and laparoscopic management strategy in children. Methods: The subjects for this study were 10 consecutive patients with type VI choledochal cyst who had laparoscopic procedures at our institute between January 2009 and January 2023. Laparoscopic cholecystectomy, excision of the dilated cystic duct, and choledochal cyst were carried out, and the continuity of the biliary duct was re-established through a Roux-en-Y hepaticojejunostomy. Results: Cystic duct combined with the common bile duct dilatation was revealed in all the patients intraoperatively. Laparoscopic procedures were completed with no conversions. The postoperative recovery was uneventful. The mean follow-up duration was 27 ± 12.7 months (range 5-36 months) with no postoperative complications encountered. Conclusions: The rare entity of type VI choledochal cyst should be recognized as a distinct type of choledochal cyst and need to be given enough attention clinically. The laparoscopic procedure is a feasible option for experienced surgeons.

Iodine-doped TiO2 nanotube coatings: a technique for enhancing the antimicrobial properties of titanium surfaces against Staphylococcus aureus.

BACKGROUND: Implant-related infections are a challenging complication of orthopedic surgery, primarily due to the formation of bacterial biofilms on the implant surface. An antibacterial coating for titanium implants was developed to provide novel insights into the prevention and treatment of implant-related infections. METHODS: Titanium plates were coated with TiO2 nanotubes by anodization, and iodine was doped onto the coating via electrophoretic deposition. The obtained plates were characterized using a range of analytical techniques. Subsequently, Staphylococcus aureus was inoculated onto the surfaces of untreated titanium plates (control group), TiO2-nanocoated titanium plates (TiO2 group), and iodine-doped TiO2-nanocoated titanium plates (I-TiO2 group) to compare their antibacterial properties. RESULTS: Twenty-four hour in vitro antimicrobial activity test of the I-TiO2 group against Staphylococcus aureus was superior to those of the other groups, and this difference was statistically significant (P < 0.05). CONCLUSIONS: This coating technology provides a new theoretical basis for the development of anti-infective implants against Staphylococcus aureus in orthopedics.

Population Pharmacokinetics and Exposure-Response with Teclistamab in Patients With Relapsed/Refractory Multiple Myeloma: Results From MajesTEC-1.

BACKGROUND: Teclistamab, a B-cell maturation antigen × CD3 bispecific antibody, is approved in patients with relapsed/refractory multiple myeloma (RRMM) who have previously received an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody. OBJECTIVE: We report the population pharmacokinetics of teclistamab administered intravenously and subcutaneously (SC) and exposure-response relationships from the phase I/II, first-in-human, open-label, multicenter MajesTEC-1 study. METHODS: Phase I of MajesTEC-1 consisted of dose escalation and expansion at the recommended phase II dose (RP2D; 1.5 mg/kg SC weekly, preceded by step-up doses of 0.06 and 0.3 mg/kg); phase II investigated the efficacy of teclistamab RP2D in patients with RRMM. Population pharmacokinetics and the impact of covariates on teclistamab systemic exposure were assessed using a 2-compartment model with first-order absorption for SC and parallel time-independent and time-dependent elimination pathways. Exposure-response analyses were conducted, including overall response rate (ORR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and the incidence of grade ≥ 3 anemia, neutropenia, lymphopenia, leukopenia, thrombocytopenia, and infection. RESULTS: In total, 4840 measurable serum concentration samples from 338 pharmacokinetics-evaluable patients who received teclistamab were analyzed. The typical population value of time-independent and time-dependent clearance were 0.449 L/day and 0.547 L/day, respectively. The time-dependent clearance decreased rapidly to < 10% after 8 weeks of teclistamab treatment. Patients who discontinue teclistamab after the 13th dose are expected to have a 50% reduction from Cmax in teclistamab concentration at a median (5th to 95th percentile) time of 15 days (7-33 days) after Tmax and a 97% reduction from Cmax in teclistamab concentration at a median time of 69 days (32-163 days) after Tmax. Body weight, multiple myeloma type (immunoglobulin G vs non-immunoglobulin G), and International Staging System (ISS) stage (II vs I and III vs I) were statistically significant covariates on teclistamab pharmacokinetics; however, these covariates had no clinically relevant effect on the efficacy of teclistamab at the RP2D. Across all doses, ORR approached a plateau at the concentration range associated with RP2D, and in patients who received the RP2D, a flat exposure-response curve was observed. No apparent relationship was observed between DoR, PFS, OS, and the incidence of grade ≥3 adverse events across the predicted exposure quartiles. CONCLUSION: Body weight, myeloma type, and ISS stage impacted systemic teclistamab exposure without any clinically relevant effect on efficacy. The exposure-response analyses for ORR showed a positive trend with increasing teclistamab systemic exposure, with a plateau at the RP2D, and there was no apparent exposure-response trend for safety or other efficacy endpoints. These analyses support the RP2D of teclistamab in patients with RRMM. CLINICAL TRIAL REGISTRATION: NCT03145181 (phase I, 09 May 2017); NCT04557098 (phase II, 21 September 2020).

Elevated plasma neurofilament light chain in immune-mediated neurological disorders (IMND) detected by immunomagnetic reduction (IMR).

BACKGROUND: In cases of immune-mediated neurological disorders (IMND), different syndromes are associated with antibodies against neuronal surface antigens, intra-neuronal antigens, astrocytic aquaporin, and gangliosides. These autoantibodies can be pathogenic or connected to neuroinflammation and resulting neuronal injuries. This study aims to identify a blood biomarker that can detect neuronal damage in individuals with IMND. To this end, we use immunomagnetic reduction (IMR) nanobead technology to measure plasma neurofilament light chain (NfL). METHODS: The patients with IMND were enrolled in the Chang Gung Memorial Hospital at Keelung from 2018 to 2023. Seronegative patients were excluded based on the results of antibody tests. The healthy controls (HC) were community-dwelling adults from the Northeastern Taiwan Community Medicine Research Cohort (NTCMRC) conducted by the Community Medicine Research Center of the Keelung CGMH from 2020 to 2022. IMR technique detects magnetic susceptibility via measuring magnetic signal reduction caused by antigen-antibody immunocomplex formation on magnetic nanobeads. The plasma level of NfL was determined by the magnetic susceptibility changes in IMR. RESULTS: The study enrolled 57 IMND patients from the hospital and 73 HC participants from the communities. The plasma NfL was significantly higher in the IMND than in the HC (11.022 ± 2.637 vs. 9.664 ± 2.610 pg/mL, p = 0.004), regardless of age effects on plasma NfL in an analysis of covariance (ANCOVA) (F = 0.720, p = 0.950). In the receiver of operation curve analysis, the area under curve for plasma NfL to discriminate IMND and HC was 0.664 (95% CI = 0.549 to 0.739, p = 0.005). The subgroup analysis of plasma NfL in the IMND patients showed no difference between peripheral immune-mediated neuropathy (IMN) and central immune-mediated encephalomyelitis (IMEM) (11.331 ± 2.895 vs. 10.627 ± 2.260 pg/mL, p = 0.322), nor between tumor and non-tumor IMND (10.784 ± 3.446 vs. 11.093 ± 2.391 pg/mL, p = 0.714). Additionally, the antibody class of ganglioside antibodies in IMN did not have an impact on plasma NfL level (p = 0.857). CONCLUSION: Plasma NfL measurement is a reliable indicator of axonal injuries in patients with IMND. It is equally effective in detecting nerve injuries in inflammatory peripheral neuropathies and central neuroinflammation. The IMR nanobead technology offers a feasible method of detecting plasma NfL, which helps identify axonal injuries in IMND.

Xiang-Sheng-PoDi-Wan May Reduce the Risk of Pneumonia retain-->in Unilateral Vocal Fold Paralysis: A Nationwide Population-Based Cohort Study.

BACKGROUND: Pneumonia is a serious complication in patients with unilateral vocal fold paralysis (UVFP). Traditional Chinese medicine Xiang-Sheng-PoDi-Wan plays a role in promoting health and may reduce pneumonia rates in those with UVFP. The study aimed to evaluate Xiang-Sheng-PoDi-Wan treatment's effectiveness in preventing pneumonia hospitalization in patients with UVFP. METHODS: We analyzed a cohort of two million participants from 2000 to 2018 from the National Health Insurance Research Database of Taiwan. We identified patients with UVFP (International Classification of Diseases, Ninth Revision, Clinical Modification code 478.32) and documented outpatient, inpatient, and treatment records from the first diagnosis until hospitalization due to pneumonia, death, or the end of the study. We calculated the incidence of pneumonia and compared the risk of pneumonia in patients receiving Xiang-Sheng-PoDi-Wan treatment or conventional treatment and tracked the use of speech therapy. We used the Cox proportional regression model to estimate the hazard ratio with a 95% confidence interval. Our corrected covariants include age, gender, degree of urbanization, insured amount, and disease comorbidity. RESULT: The use of Xiang-Sheng-PoDi-Wan was associated with a lower risk of hospitalization for pneumonia in UVFP patients, with an adjusted hazard ratio (aHR) of 0.40 (0.21-0.77). The combination of Xiang-Sheng-PoDi-Wan and speech therapy could further reduce the risk of pneumonia hospitalization (aHR = 0.25 [0.02-0.82]). UVFP patients with comorbidities such as respiratory cancer 0.34 (0.12-0.98) or diabetes (aHR = 0.30 [0.09-0.96]) had higher rates of pneumonia hospitalization. CONCLUSION: The results suggest that Xiang-Sheng-PoDi-Wan may play a role in UVFP patients to reduce the long-term risk of pneumonia.

Laparoscopic Kasai Procedure of Treating Biliary Atresia with an Aberrant Right Hepatic Artery.

Background: An aberrant vascular anatomy might present a technical pitfall for biliary atresia (BA) surgery. The purpose of this study was to report the rare cases and discuss the significance and management strategy for BA with an aberrant right hepatic artery (ARHA) by laparoscopic Kasai procedure in children. Methods: The subjects for this study were 10 consecutive type III BA patients with an ARHA who had laparoscopic Kasai procedure at our institute between January 2012 and August 2021. The common bile duct was mobilized between the right hepatic artery and the right branch of portal vein, and then lifted to the liver hilum. The fibrous cord was transected and then the laparoscopic Kasai was carried out. Results: All patients survived the laparoscopic Kasai without any intraoperative complications. The mean operative time was 235 minutes for each laparoscopic Kasai. The mean follow-up time was 32.6 months. The total and direct bilirubin dropped to normal within 4 months of surgery in 7 patients. One patient died of repeated cholangitis and liver failure 1 year after surgery. In the additional 2 patients the bilirubin levels dropped significantly after the surgery but elevated again because of repeated cholangitis and requiring ongoing observation and intermittent treatment. Conclusions: With the perfect laparoscopic skills, the common bile duct could be safely mobilized between the right hepatic artery and right branch of portal vein for the infants with type III BA associated with an ARHA, and laparoscopic Kasai could be carried out safely and successfully.

Acupuncture is associated with reduced dementia risk in patients with insomnia: A propensity-score-matched cohort study of real-world data.

Background and aim: Insomnia is a subjective illness that has been identified as a risk factor for dementia. In this study, we investigated the association of acupuncture treatment for insomnia with the risk of dementia. We collected data from the National Health Insurance Research Database (NHIRD) of Taiwan to analyze the incidence of dementia in patients with insomnia who received acupuncture treatment. Experimental procedure: This retrospective matched-cohort study included 152,585 patients, selected from the NHIRD, who were newly diagnosed with insomnia between 2000 and 2010. The follow-up period ranged from the index date to the date of dementia diagnosis, date of withdrawal from the insurance program, or December 31, 2013. A 1:1 propensity score method was used to match an equal number of patients (N = 18,782) in the acupuncture and non-acupuncture cohorts. We employed Cox proportional hazards models to evaluate the risk of dementia. The cumulative incidence of dementia in both cohorts was estimated using the Kaplan-Meier method, and the difference between them was assessed through a log-rank test. Results and conclusion: Patients with insomnia who received acupuncture treatment were observed to have a lower risk of dementia (adjusted hazard ratio = 0.54, 95% confidence interval = 0.50-0.60) than those who did not undergo acupuncture treatment. The cumulative incidence of dementia was significantly lower in the acupuncture cohort than in the non-acupuncture cohort (log-rank test, p < 0.001). The results suggest that acupuncture treatment significantly reduced or slowed the development of dementia in patients with insomnia.

Bleeding risk after acupuncture in patients taking anticoagulant drugs: A case control study based on real-world data.

OBJECTIVES: Patients on anticoagulant medications may be at a higher risk of bleeding after acupuncture. This study aimed to assess the association between anticoagulant drug use and bleeding after acupuncture. DESIGN: Case control study SETTING: We analysed the diagnosis and treatment records (2000-2018) of a random sample of two million patients from the National Health Insurance Research Database in Taiwan. INTERVENTIONS: anticoagulant and antiplatelet drugs MAIN OUTCOME MEASURES: The incidence rates of major (visceral bleeding or ruptured blood vessels requiring transfusion) and minor (skin bleeding or contusion) bleeding after acupuncture RESULTS: We included the records of 13,447,563 acupuncture sessions in 821,946 participants and followed up the patients for 14 days after each session. The incidence of minor bleeding was 8.31 per 10,000 needles, whereas that of major bleeding was 4.26 per 100,000 needles. Anticoagulants significantly increased the risk of minor bleeding (adjusted OR = 1.15 (1.03-1.28)), but the risk of major bleeding did not reach statistical significance (adjusted OR = 1.18 (0.8 0-1.75)). Anticoagulants, such as warfarin (adjusted OR = 4.95 (2.55-7.64)), direct oral anticoagulants (adjusted OR = 3.07 (1.23-5.47)), and heparin (adjusted OR = 3.72 (2.18-6.34)) significantly increased the risk of bleeding. However, antiplatelet drug was not significantly associated with post-acupuncture bleeding. Comorbidities including liver cirrhosis, diabetes, and coagulation defects, were the risk factors for bleeding after acupuncture. CONCLUSIONS: Anticoagulant drugs may increase the risk of bleeding after acupuncture. We encourage physicians to ask patients in detail about their medical history and drug use prior to acupuncture treatment.

Risk factors of significant relapse and appropriate maintenance therapy strategy in SLE-associated immune thrombocytopenia.

Background: Systemic lupus erythematosus-associated immune thrombocytopenia (SLE-ITP) is characterized by relapse. The risk factors of relapse and appropriate maintenance therapy strategy deserve further exploration. Objectives: To determine the risk factors for relapse and appropriate maintenance therapy in significant SLE-ITP patients (a platelet count ⩽30 × 109/l) after the first complete response. Design: Retrospective cohort study using the medical records of 105 patients diagnosed as significant SLE-ITP in Fujian Medical University Union Hospital during December 2012 to March 2021. Patients were followed through a call for observations in January 2022. Methods: Data including demographics, initial clinical feature, induction and maintenance therapy, and outcome at the end of follow-up were analyzed. Risk factors for significant relapse were analyzed using multivariate logistic regression models. The cumulative hazard of significant relapse and the duration of response were estimated, and the differences in outcome between groups were compared using the Cox regression analysis. Results: A total of 65 significant SLE-ITP patients were eligible for the final analysis. Median [interquartile range (IQR)] follow-up duration and median [IQR] duration of response were 62.2 [41.0-79.6] months and 43.4 [20.3-68.7] months, respectively. After the first complete response, 19/65 (29.2%) had a significant relapse. Compared with sustained clinical remission (SCR) + sustained response (SR) group, significant relapse group had a higher proportion of discontinued patients (47.4% versus 8.7%, p = 0.001). Among the 13 discontinued patients, the duration of maintenance therapy of the patients in significant relapse group was significantly shorter than that of the patients in SCR + SR group (months, median [IQR], 43.1 [32.0-62.4] versus 12.0 [5.1-22.0], p = 0.009). Multivariate logistic regression analysis showed that drug withdrawal was an independent risk factor for significant relapse [odds ratio (OR) = 10.4, confidence interval (CI) 95% 2.2-47.8, p = 0.003]. There was no significant difference between glucocorticoids (GCs) + hydroxychloroquine (HCQ) group and GCs + HCQ + immunosuppressive agents (ISAs) group in significant relapse rate (26.7% versus 22.2%, p > 0.05). The two SR curves of GCs + HCQ and GCs + HCQ+ ISA group basically coincided by the Cox regression analysis, demonstrating comparable long-term outcomes (p > 0.05). Conclusion: Drug withdrawal, especially abrupt withdrawal with insufficient duration of maintenance therapy, is an independent risk factor for significant relapse of SLE-ITP. HCQ combined with GCs is expected to be the first choice of the maintenance therapy for SLE-ITP patients.

Non-surgical treatment of giant tumor-like lumbar disc herniation based on enhanced MRI: A case series.

RATIONALE: In recent clinical follow-up, it has been vertified that resorption in lumbar disc herniation (LDH) could be of great curative effect in non-surgical treatment for LDH. However, reports of resorption in giant tumor-like LDH are rarely mentioned due to its risk of irreversible neurological damage which could be caused by long-term non-surgical treatment. In our clinical observations, we have found that enhanced MRI helps to distinguish LDH from intradural tumours and to predict the probability of resorption in LDH. We analyzed 8 patients with giant tumor-like LDH who underwent non-surgical treatment, and these patients had resorption during follow-up. All patients were examined with enhanced MRI before treatment, and the type of "bull's eye" sign classification was determined by images. The MRI protrusion volume(VP), resorption rate(HR%) and JOA score of patients at the first visit and the last follow-up were recorded. PATIENT CONCERNS: 8 patients of Han ethnicity were admitted to the department of orthopedic complaining of low back pain for 1week to 12months. They were diagnosed with giant tumor-like LDH by enhanced MRI. DIAGNOSES: These patients were diagnosed with giant tumor-like LDH. INTERVENTIONS: We adopted a non-surgical treatment plan for the patients, including taking oral non-steroidal anti-inflammatory agents and performing rehabilitation exercise. In consideration of the risk of irreversible neurological damage, patients were closely observed during treatment and follow-up. Once the following conditions occur, surgical treatment is required immediately: The symptoms are not signifcantly relieved after 3 to 6 months of non-surgical treatment; The symptoms are aggravated by non-surgica treatment; The clinical manifestations of cauda equina syndrome. OUTCOMES: After treated with oral non-steroidal anti-inflammatory agents and rehabilitation exercise, the resorption was accompanied by clinical symptom relief. No neurological damage occurred in all patients, and the clinical symptoms did not recur in the subsequent follow-up. LESSONS: Clinicians should fully consider the possibility of resorption prior to surgical treatment in patients with giant LDH. We can predict the probability of resorption in patients with giant LDH based on enhanced MRI. For patients with a high probability of resorption, we can choose non-surgical treatment in the absence of progressive neurological impairment and cauda equina syndrome.

Several ML Algorithms and Their Feature Vector Design for Gas Discrimination and Concentration Measurement with an Ultrasonically Catalyzed MOX Sensor.

Although gas-borne ultrasound catalysis has been developed as a new method to discriminate gas species and measure the concentration, applications of machine learning methods in gas analyses with a single metal oxide (MOX) gas sensor catalyzed by gas-borne ultrasound are still scarce. In this work, with an ultrasonically catalyzed MOX gas sensor, we explored the effectiveness of K-nearest neighbors (KNN), support vector machine (SVM), and single-hidden-layer BP-ANN (SHBP) in gas discrimination and the application of the SHBP in concentration measurement. The target gases in this work are ethanol, acetone, methanol, hydrogen, and n-butane in clean air, respectively, and the discrimination and concentration regression are implemented by two different ML models. With the properly designed feature vectors, the SHBP method has an acceptable capability of both of species discrimination and concentration regression (success rate of gas discrimination = 99.5%, relative error of concentration regression = 6.406%). The KNN and SVM methods have similar capabilities of gas discrimination as the SHBP. This work also demonstrates a method to design the feature vectors for the ultrasonically catalyzed MOX gas sensor and to choose the feature parameters.

Development of Therapeutic Proteins for a New Subcutaneous Route of Administration After the Establishment of Intravenous Dosages: A Systematic Review.

Therapeutic proteins may first be developed as intravenous (i.v.) therapies with new subcutaneous (s.c.) dosage forms being subsequently developed to provide an alternative route of administration. As of August 2022, there have been 9 therapeutic proteins which were developed as a new s.c. dosage form after the approval of the corresponding i.v. product. This article provides a systematic review of prior experiences in the i.v. to s.c. switch development programs. We describe what types of clinical studies were conducted to support the i.v. to s.c. switch for these nine therapeutic proteins. Publicly available scientific advice from health authorities is summarized, particularly regarding recommendations on overall development strategy, dose selection, immunogenicity assessment, and indication extrapolation. The clinical data from these i.v. to s.c. development programs demonstrate that: (1) when switching from i.v. dosing to s.c. dosing, trough drug concentration (Ctrough ) from s.c. dosing should not be inferior to i.v. dosing with average drug concentration (Cavg ; equivalent to AUC, area under the curve after correcting for dosing intervals between i.v. and s.c. administration) being matched or non-inferior to i.v. dosing; and (2) with appropriate s.c. dose regimens, treatment with s.c. therapeutic proteins can generally achieve similar efficacy and safety as the corresponding i.v. products, suggesting that the much higher maximum concentration (Cmax ) after i.v. infusion as compared with that from s.c. injection is often not relevant to the treatment effect.

Immunogenicity of inactivated COVID-19 vaccine in patients with autoimmune inflammatory rheumatic diseases.

Progress has been made in COVID-19 vaccine development, with encouraging safety and efficacy data. The purpose of this study was to investigate the immunogenicity of inactivated COVID-19 vaccine in patients with autoimmune inflammatory rheumatic diseases (AIIRD). Patients with AIIRD (n = 101) were included in this study. All patients received 2 doses of inactivated COVID-19 vaccine. Serum anti-S1/RBD protein IgG was detected 2-16 weeks after the second vaccination. Seropositivity was defined as IgG ≥ 1.00 bound antibody unit S/CO. Immunogenicity of inactivated COVID-19 vaccine was assessed by seropositivity rate and the levels of serum IgG antibody against anti-S1/RBD protein, compared with the general population (n = 46). There was no difference by statistical significance in the seropositivity rate between patients with AIIRD (82.2%) and SLE (86.1%) and the control group (93.5%), p > 0.05. The level of anti-S1/RBD protein IgG antibodies in patients with AIIRD (median [IQR], 8.8 [2.2-17.3]) and SLE (median [IQR], 9.6 [2.4-20.4]) was comparable to that in the control group (median [IQR], 7.2 [3.1-14.2]), p > 0.05. Patients treated with glucocorticoids(GCs) (median dose, [IQR]: 2.5 mg/day [IQR 2.5-5.0]) or hydroxychloroquine(HCQ) or GCs + HCQ without other immunomodulatory medications, had an appropriate immunogenic response(88.1%) with high levels of anti-S1/RBD protein IgG(median [IQR], 12.1 [6.5-20.4]). Neither of patients treated with rituximab had positive serum antibodies, which was statistically significant, compared with the control group (p < 0.01). Compared with the control group, methotrexate(MTX) and iguratimod(IGU) was significantly reduced the level of anti-S1/RBD protein IgG antibodies. Inactivated COVID-19 vaccine had appropriate immunogenicity in patients with AIIRD. Immunogenicity of inactivated COVID-19 vaccine was severely impaired by rituximab, and also suppressed by MTX and IGU, while low doses of GC and HCQ had negligible effect.