Allicin in pregnancy diets modulates steroid metabolism in pregnant sows and placental sulphate metabolism promoting placental angiogenesis and foetal development.

The low-birth-weight of piglets is an important factor affecting pig enterprises. The placenta, as a key organ for material exchange between mother and foetus, directly influences the growth and development of the foetus. Allicin exhibits various biological activities, including anti-inflammatory and antioxidant properties. It may also play a crucial role in enhancing sow reproductive performance and placental angiogenesis. In this study, we used 70 lactating Landrace × Yorkshire binary heterozygous sows to explore the effect of allicin on the reproductive performance of sows and placental development. The sows were randomly assigned into the Allicin group (Allicin), which was fed with a diet containing 0.25% allicin, and the negative control group, which was fed with basal feed. The experimental period lasted for 114 d from the date of mating to the end of farrowing. The results showed that the addition of allicin to the gestation diets increased the number of total born piglets, born alive piglets, and high-birth-weight piglets, reduced peripartum oxidative stress, alleviated dysregulation of glucose-lipid metabolism in sows, and increased the levels of antioxidant markers in the placenta. Differential analysis of metabolites in maternal plasma and placenta samples by non-targeted metabolomics revealed that allicin improved cholesterol metabolism, steroid biosynthesis, and increased plasma progesterone levels in sows. Allicin promoted sulphur metabolism, cysteine and methionine metabolism in placental samples and increased the hydrogen sulphide (H2S) content in the placenta. In addition, Quantitative Real-time PCR, Western blot and immunofluorescence results showed that allicin upregulated the expression of angiogenesis-related genes, VEGF-A, FLK 1 and Ang 1, in the placenta, implying that it promoted placental angiogenesis. These results indicate that supplementing the diet of pregnant sows with allicin reduces oxidative stress, alleviates dysregulation of glucose-lipid metabolism during the periparturient period, and promotes placental angiogenesis and foetal development by increasing plasma progesterone level and placental H2S content.

[Study on the clinical characteristics of auditory neuropathy patients with normal pure tone average or mild hearing loss].

Objective: The purpose of this study was to analyze the clinical characteristics of auditory neuropathy (AN) patients with normal hearing or mild hearing loss. Methods: Data from Multicenter Study on Clinical Diagnosis and Intervention of Acoustic Neuropathy (registration number: ChiCTR2100050125). According to the Chinese clinical practice guideline of auditory neuropathy (version 2022), these patients divided into two groups: the normal hearing group (PTA Normal, PTAN group, the average hearing threshold<20 dB HL) and the mild hearing loss group (PTA Mild hearing loss, PTAM group, the average hearing threshold between 20-35 dBHL). The audiology characteristics, clinical features, and follow-up were analyzed. Data analysis was conducted using GraphPad Prism 8 and SPSS 20.0 software. Results: A total of 75 AN with normal hearing or mild hearing loss were included in this study. The PTAN group consisted of 19 patients (38 ears), including 12 males and 7 females. The average onset age was (16.9±4.5) years old, while the test age was (22.1±5.8) years old for PTAN group. The PTAM group consisted of 56 patients (112 ears), including 29 males and 27 females. The average onset age was (16.2±7.9) years old, while the test age was (23.9±9.0) yeas old for PTAM group. The average hearing threshold of low frequency (0.125-0.5 kHz) was significantly decreased. ABR disappeared in 86.00% (126/150) of the patients. The speech recognition rate was 71.80±22.44% in the PTAN group and 58.08±29.28% in the PTAM group.-SP/AP was 0.98±0.47 in the PTAN and 1.07±0.63 in PTAM group; 40 (53.33%) patients had tinnitus. 29 patients (58 ears) were followed up, including 10 patients (20 ears) in the PTAN group and 19 patients (38 ears) in the PTAM group. There was no significant change in hearing threshold in short-term follow-up (<3 years). With the extension of the disease duration (>3 years), the PTAN group tended to decrease at low frequency, and the PTAM group decreased at high frequency first. The hearing threshold at 0.25 kHz in the PTAN group and 4 kHz in the PTAM group decreased significantly. Conclusions: AN patients with normal hearing or mild hearing loss exhibit abnormal results in audiological examination results, including ABR, electrocochleography and speech discrimination score. A combination of audiological tests should be used to make the diagnosis of AN. With the progression of the disease, AN with normal hearing or mild hearing loss tends to decrease.

[Research on the variation in distortion product otoacoustic emissions in patients with auditory neuropathy during the natural course of the disease].

Objective: The purpose of this study was to investigate the characteristics of distortion product otoacoustic emissions (DPOAE) in patients with auditory neuropathy (AN). The factors affecting DPOAE elicitation rate of each frequency, elicitation rate of each ear and change rate of first and last diagnosis in the natural course were analyzed. Methods: The sample was obtained from the Multicenter Study on Clinical Diagnosis and Intervention of AN (registration number: ChiCTR2100050125), and the diagnostic criteria for AN were based on the Chinese Clinical Practice Guidelines of Auditory Neuropathy (version 2022). Patients with bilateral AN who underwent 2 or more DPOAE tests were screened and divided into infant groups (≤3 years old) and non-infant groups (>3 years old) according to the age of detection, and the trend of DPOAE elicitation rate of each frequency, elicitation rate of each ear and change rate in the natural course of disease were analyzed, in order to explore the relevant influencing factors. Results: A total of 165 patients (330 ears) with AN were included in the study. The overall DPOAE elicitation rate per ear was 77.0%±29.4% at the initial diagnosis and 65.1%±35.2% at the final diagnosis, with a reduction observed in the elicitation rate of 171 ears (51.82%). In the infant group, there were 49 cases (98 ears), including 28 males and 21 females, whose found age ranged from 0 to 3 years old, with a median age of 0.7 years. DPOAE elicitation rate per ear was 57.9%±35.5% in the initial diagnosis, and 32.4%±32.1% in the final diagnosis, with a reduction observed in the elicitation rate of 69 ears (70.41%). In the non-infant group, there were 116 cases (232 ears), including 59 males and 57 females, ranging in found age from 3.9 to 40 years old, with a median age of 14 years old. DPOAE elicitation rate per ear was 84.6%±23.4% in the initial diagnosis, and 78.3%±27.1% in the final diagnosis, with a reduction observed in the elicitation rate of 102 ears (43.97%). Age was found to be correlated with DPOAE changes by multicategorical unordered logistic regression analysis (B=-0.224, OR=0.799, P<0.001). Conclusions: The elicitation rate of DPOAE in AN patients decreases or even disappears with increasing disease duration; The rate of DPOAE extraction is found to be lower in infant patients with auditory neuropathy (AN) compared to non-infant AN patients. Additionally, it is observed that the decrease in DPOAE extraction rate is more pronounced in infant AN patients as the disease progressed, as compared to non-infant AN patients. DPOAE and cochlear microphonic potentials should be fully combined for accurate diagnosis, and regular follow-up should be conducted to understand the natural course of the disease and give personalized guidance and assistance.

Association between enthesitis/dactylitis resolution and patient-reported outcomes in guselkumab-treated patients with psoriatic arthritis.

OBJECTIVES: To evaluate the association between enthesitis resolution (ER) and dactylitis resolution (DR) and meaningful improvements in patient-reported outcomes (PROs) among biologic-naïve patients with PsA receiving guselkumab in the DISCOVER-2 study. METHODS: Enthesitis and dactylitis, characteristic lesions of PsA, were evaluated by independent assessors using the Leeds Enthesitis Index (range, 0-6) and Dactylitis Severity Score (range, 0-60). Proportions of patients with ER or DR (score = 0) among those with score > 0 at baseline were determined at weeks 24, 52, and 100. PROs included: fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-Fatigue]), pain (0-100 visual analog scale), physical function (Health Assessment Questionnaire-Disability Index [HAQ-DI]), and health-related quality of life (36-item Short-Form Health Survey physical/mental component summary [SF-36 PCS/MCS]). Meaningful responses were defined as: improvements of ≥ 4 for FACIT-Fatigue, ≥ 0.35 for HAQ-DI, and ≥ 5 for SF-36 PCS/MCS and absolute scores of ≤ 15 for minimal pain and ≤ 0.5 for normalized HAQ-DI. Associations between ER/DR status and PRO response status were tested using a Chi-square test. RESULTS: Guselkumab-treated patients with ER were more likely than those without ER to achieve minimal pain (p < 0.001), normalized HAQ-DI (p < 0.001), and PCS response (p < 0.05) at weeks 24, 52, and 100. Patients with DR were more likely than those without DR to achieve FACIT-Fatigue response at week 24 and week 52 (both p ≤ 0.01) and minimal pain at week 24 and normalized HAQ-DI at week 52 (both p ≤ 0.03). CONCLUSION: In biologic-naïve patients with active PsA treated with guselkumab, achieving ER or DR was associated with durable improvements in selected PROs, including those of high importance to patients. TRIAL REGISTRATION: ClinicalTrials.gov ( https://clinicaltrials.gov ) NCT03158285; Registered: May 16, 2017. Key Points • At week 100, 65% and 76% of guselkumab-treated patients achieved enthesitis and dactylitis resolution (ER/DR). • Achieving ER was associated with achieving DR and vice versa through the end of study. • Achieving ER or DR was associated with durable and meaningful improvements in selected patient-reported outcomes.

Guselkumab provides durable improvement across psoriatic arthritis disease domains: post hoc analysis of a phase 3, randomised, double-blind, placebo-controlled study.

OBJECTIVE: Evaluate long-term guselkumab effectiveness across Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA)-recognised domains/related conditions of psoriatic arthritis (PsA). METHODS: Post hoc analyses used data from DISCOVER-2 (NCT03158285) biologic/Janus-kinase inhibitor-naïve participants with active PsA (≥5 swollen/≥5 tender joints, C-reactive protein ≥0.6 mg/dL), randomised (1:1:1) to guselkumab every 4 or 8 weeks (Q4W/Q8W) or placebo with crossover to guselkumab. Outcomes aligned with key GRAPPA-recognised domains of overall disease activity, peripheral arthritis, axial disease, enthesitis/dactylitis and skin psoriasis (nail psoriasis was not evaluated). PsA-related conditions (inflammatory bowel disease (IBD)/uveitis) were assessed via adverse events through W112. Least squares mean changes from baseline through W100 in continuous outcomes employed repeated measures mixed-effects models adjusting for baseline scores. Binary measure response rates were determined with non-responder imputation for missing data. RESULTS: 442/493 (90%) of guselkumab-randomised patients completed treatment through W100. Following early reductions in disease activity with guselkumab, durable improvements were observed across key PsA domains (swollen/tender joints, psoriasis, spinal pain, enthesitis/dactylitis) through W100. Response rates of therapeutically relevant targets generally increased through W100 with guselkumab Q4W/Q8W: Disease Activity Index for PsA low disease activity (LDA) 62%/59%, enthesitis resolution 61%/70%, dactylitis resolution 72%/83%, 100% improvement in Psoriasis Area and Severity Index 59%/53%, Psoriatic Arthritis Disease Activity Score LDA 51%/49% and minimal disease activity 38%/40%. Through W112, no cases of IBD developed among guselkumab-randomised patients and one case of uveitis was reported. CONCLUSION: In biologic-naïve patients with active PsA, guselkumab provided early and durable improvements in key GRAPPA-recognised domains through 2 years, with substantial proportions achieving important treatment targets.

[Advancements in research on immune responses associated with adeno-associated virus vector-mediated ocular gene therapy].

Adeno-associated virus (AAV) vectors have been widely employed in gene therapy for ocular and systemic diseases. However, clinical trial outcomes have indicated that gene therapy may trigger severe adverse events associated with immune-inflammatory reactions, thereby impacting the safety and efficacy of gene therapy. The immune-inflammatory reaction induced after gene therapy in the eye is referred to as gene therapy-associated uveitis, which has become a major obstacle limiting the long-term and effective use of ocular gene therapy. This review comprehensively explores four aspects: the immune response mechanisms of gene therapy, ocular manifestations of associated uveitis, factors influencing immune inflammation, and preventive and therapeutic strategies. The aim is to provide insights for the development of safer and more effective ocular gene therapy.

Continuous improvement through differential trajectories of individual minimal disease activity criteria with guselkumab in active psoriatic arthritis: post hoc analysis of a phase 3, randomized, double-blind, placebo-controlled study.

BACKGROUND: To explore the trajectory of, and factors contributing to, achievement of individual criteria of minimal disease activity (MDA) in patients with active psoriatic arthritis (PsA) treated with guselkumab. METHODS: The Phase 3, randomized, placebo-controlled DISCOVER-2 study enrolled adults (N = 739) with active PsA despite standard therapies who were biologic/Janus kinase inhibitor-naive. Patients were randomized 1:1:1 to guselkumab 100 mg every 4 weeks; guselkumab 100 mg at week 0, week 4, then every 8 weeks; or placebo. In this post hoc analysis, patients randomized to guselkumab were included and pooled (N = 493). Longitudinal trajectories of achieving each MDA criterion through week 100 were derived using non-responder imputation. Time to achieve each criterion was estimated with Kaplan-Meier analysis. Multivariate regression for time to achieve each criterion (Cox regression) and achievement at week 100 (logistic regression) was used to identify contributing factors. RESULTS: Continuous improvement across all MDA domains was shown over time. ~70% of patients achieved near remission in swollen joint count (SJC), Psoriasis Area and Severity Index (PASI), and enthesitis through week 100. Median times to achieve individual criteria differed significantly (p < 0.0001), with SJC ≤ 1 (20 weeks), PASI ≤ 1 (16 weeks), and ≤ 1 tender entheses (16 weeks) being faster than patient-reported criteria (pain ≤ 15 mm, patient global assessment of arthritis and psoriasis ≤ 20 mm, Health Assessment Questionnaire-Disability Index ≤ 0.5) and tender joint count ≤ 1. Higher baseline domain scores, older age, worse fatigue, and increased body mass index were significant predictors of longer time to achieve minimal levels of disease activity assessed via patient-reported criteria. CONCLUSIONS: Substantial proportions of guselkumab-treated patients achieved individual MDA criteria, each showing continuous improvement through week 100, although with distinct trajectories. Median times to achieve physician-assessed MDA criteria were significantly faster compared with patient-driven criteria. Identification of modifiable factors affecting the time to achieve patient-reported criteria has the potential to optimize the achievement and sustainability of MDA in the clinic via a multidisciplinary approach to managing PsA, involving both medical and lifestyle interventions. TRIAL REGISTRATION NUMBER: NCT03158285. TRIAL REGISTRATION DATE: May 16, 2017.

Modulation of Interleukin-23 Signaling With Guselkumab in Biologic-Naive Patients Versus Tumor Necrosis Factor Inhibitor-Inadequate Responders With Active Psoriatic Arthritis.

OBJECTIVE: We assessed and compared immunologic differences and associations with clinical response to guselkumab, a fully human interleukin (IL)-23p19 subunit inhibitor, in participants with active psoriatic arthritis (PsA) who were biologic-naive or had inadequate response to tumor necrosis factor inhibitors (TNFi-IR). METHODS: Serum biomarker levels at baseline and after treatment with guselkumab 100 mg every 8 weeks were compared between biologic-naive (n = 251) and TNFi-IR (n = 93) subgroups identified in the pooled DISCOVER-1/DISCOVER-2/COSMOS data set. Baseline biomarker levels determined by achievement of week 24 clinical responses (≥75%/90% improvement in Psoriasis Area and Severity Index [PASI 75/90], Investigator's Global Assessment [IGA] of psoriasis score 0/1 and ≥2-point improvement], ≥20% improvement in American College of Rheumatology criteria [ACR20]) were compared between prior treatment subgroups. RESULTS: Baseline IL-22, TNFα, and beta defensin-2 (BD-2) levels were significantly lower in biologic-naive than in TNFi-IR participants. With guselkumab, week 24 IL-17A, IL-17F, IL-22, serum amyloid A, C-reactive protein, IL-6, and BD-2 levels were significantly reduced from baseline in biologic-naive and TNFi-IR participants (≥1.4-fold difference, nominal P < 0.05). Clinical responders to guselkumab exhibited significantly higher baseline levels of several biomarkers than nonresponders (IL-17A, IL-17F, BD-2 in biologic-naive PASI 90 responders; IL-17A, BD-2 in TNFi-IR IGA 0/1 responders; IL-22, BD-2 in TNFi-IR PASI 90 responders [nominal P < 0.05]) and trended higher in TNFi-IR ACR20 responders. CONCLUSION: Guselkumab modulates IL-23 signaling and provides consistent pharmacodynamic effects in both biologic-naive and TNFi-IR PsA patients. Significantly elevated baseline IL-22, TNFα, and BD-2 levels and associations between baseline IL-22, IL-17A, and BD-2 levels and skin responses to guselkumab suggest greater dysregulation of IL-23/Th17 signaling in patients with TNFi-IR.

Prognostic role of the systemic immune-inflammation index and pan-immune inflammation value for outcomes of breast cancer: a systematic review and meta-analysis.

OBJECTIVE: This review examined the literature for evidence on the prognostic ability of systemic immune-inflammation index (SII) and pan-immune inflammation value (PIV) for predicting overall survival (OS) and disease-free survival (DFS) in breast cancer patients. MATERIALS AND METHODS: PubMed, Embase, Scopus, and Web of Science were searched with Google Scholar for gray literature. All types of studies reporting the association between SII or PIV and OS or DFS of breast cancer were eligible. RESULTS: 13 studies on SII and 4 studies on PIV were included. Meta-analysis showed that a high SII was a significant predictor of OS (HR: 1.97 95% CI: 1.54, 2.52 I2=76%) and DFS (HR: 2.07 95% CI: 1.50, 2.86 I2=79%) in breast cancer patients. These results did not change on sensitivity analysis and were more or less stable on multiple subgroup analyses. Pooled analysis showed that high PIV was also a significant predictor of poor OS (HR: 2.63 95% CI: 1.46, 4.74 I2=71%) and DFS (HR: 1.64 95% CI: 1.23, 2.17 I2=0%) in breast cancer patients. CONCLUSIONS: High SII and PIV can predict poor OS and DFS in breast cancer patients. High heterogeneity and the observational nature of data are important limitations of the review. Further studies are needed specifically on PIV to increase the strength of the evidence.

[Clinicopathological study of epithelioid and spindle cell rhabdomysarcoma with EWSR1/FUS-TFCP2 fusion].

Objective: To investigate the clinicopathological and genetic features of epithelioid and spindle cell rhabdomysarcoma with EWSR1-TFCP2 or FUS-TFCP2 fusion. Methods: The clinical, morphological and immunohistochemical features of 14 cases of epithelioid and spindle cell rhabdomysarcoma with EWSR1-TFCP2 or FUS-TFCP2 fusion diagnosed from January 2019 to December 2022 in the Department of Pathology, Foshan Traditional Chinese Medicine Hospital, Foshan, China were retrospectively analyzed. The cases were all subject to FISH or next generation sequencing for analysis of molecular genetic features. The literature was reviewed. Results: There were 5 males and 9 females, with the age at presentation ranging from 6 to 36 years (mean, 22 years). Tumors occurred in the head and neck (9 cases), pelvic region (2 cases), bladder (one case), right humerus (one case), and the abdominal wall, humerus and pubic at the same time (one case). Presenting symptoms varied by location but often included pain or discomfort. Most of the patients showed aggressive radiographic features with soft tissue extension. The tumors had a median size of 6.6 cm (range, 2-23 cm). The tumors were poorly defined and irregularly shaped. Microscopic examination showed diffuse proliferation of spindle or epithelioid cells. While morphologically high-grade tumors displayed obvious cytological atypia, a high mitotic count and tumor necrosis, low-grade tumors grew in sheets and fascicles composed of spindle, epithelioid cells with moderate or abundant amounts of eosinophilic cytoplasm, without pronounced cytological atypia. The tumor cells expressed Desmin, MyoD1, and Myogenin, as well as ALK, EMA, and CKpan. EWSR1/FUS-TFCP2 gene fusion was detected in 14 cases with next generation sequencing and confirmed by FISH. Six cases had EWSR1-TFCP2 fusions and 8 cases showed FUS-TFCP2 fusions. Follow-up information was available in 13 patients, ranged from 5 to 37 months. At the end of follow-up period, 7 patients died of the disease. Six patients were alive:two cases had local recurrences and metastases, two cases of recurrences, one case of metastasis and one case without recurrences and metastasis. Conclusions: Epithelioid and spindle cell rhabdomysarcomas with EWSR1-TFCP2 or FUS-TFCP2 fusion show a very aggressive clinical course, and more commonly occur in the head and neck. Their genetic hallmark is the presence of EWSR1/FUS-TFCP2 fusions. Familiarity with its clinicopathological characteristics is helpful in avoiding misdiagnoses.

[Clinical update in critical care of pulmonary medicine 2023].

This article reviewed the clinical progress in the field of pulmonary and critial care medicine, both domestically and internationally during the year 2023 (from October 1, 2022 to September 30, 2023). In 2023, there have been significant modifications to the global definition of Acute Respiratory Distress Syndrome (ARDS). These include the inclusion of SpO2/FiO2 as a diagnostic criterion for ARDS, the addition of parameters for high-flow nasal cannula humidified oxygen therapy as a basis for diagnosing ARDS in non-intubated patients, clarification of the need to diagnose ARDS in non-intubated patients with PEEP≥5 cmH2O under non-invasive positive pressure ventilation, and the increased diagnostic value of ultrasound. Bedside electrical impedance, transpulmonary pressure and severe ultrasound provide effective means for for individualized assessment of critically ill patients. End-tidal alveolar dead space fraction, intestinal microecological imbalance, and ICU-acquired weakness are important warning indicators for the prognosis of critically ill patients. Machine learning models based on big data can effectively predict the prognosis of critically ill patients, and ECMO combined with prone positioning can improve patient outcomes. Cognition and fatigue were the most common persistent symptoms in critically ill patients after discharge. Intervention on specific cellular subtypes of lung injury receptors may be a future target for personalized treatment of lung injury tissue repair.

Earlier clinical response predicts low rates of radiographic progression in biologic-naïve patients with active psoriatic arthritis receiving guselkumab treatment.

OBJECTIVE: Assess relationship between earlier clinical improvement and radiographic progression (RP) over 2 years in guselkumab-treated patients with active psoriatic arthritis (PsA). METHOD: Post hoc analyses combined data from DISCOVER-2 biologic-naïve adults with active PsA randomized to either guselkumab 100 mg every 4 weeks (Q4W) or guselkumab at W0, W4, then Q8W. Correlations (Spearman's coefficient) between baseline disease parameters and total PsA-modified van der Heijde-Sharp (vdH-S) score were examined. Repeated-measures mixed models, adjusted for known RP risk factors, assessed the relationship between Disease Activity Index in PsA (DAPSA) improvement, DAPSA improvement exceeding the median or the minimal clinically important difference (MCID), or DAPSA low disease activity (LDA) at W8 and RP rate, assessed by change from baseline in vdH-S score through W100. RESULTS: Baseline age, PsA duration, CRP level, and swollen joint count, but not psoriasis duration/severity, weakly correlated with baseline vdH-S score. Elevated baseline CRP (parameter estimate [ß] = 0.17-0.18, p < 0.03) and vdH-S score (ß = 0.02, p < 0.0001) significantly associated with greater RP through W100. Greater improvement in DAPSA (ß = -0.03, p = 0.0096), achievement of DAPSA improvement > median (least squares mean [LSM] difference: -0.66, p = 0.0405) or > MCID (-0.67, p = 0.0610), or DAPSA LDA (-1.44, p = 0.0151) by W8 with guselkumab significantly associated with less RP through W100. The effect of W8 DAPSA LDA on future RP was strengthened over time among achievers vs. non-achievers (LSM difference enhanced from -1.05 [p = 0.0267] at W52 to -1.84 [p = 0.0154] at W100). CONCLUSIONS: In guselkumab-treated patients with active PsA, earlier improvement in joint symptoms significantly associated with lower RP rates through 2 years, indicating blockade of the IL-23 pathway may modify long-term disease course and prevent further joint damage. Key Points • Greater improvement in DAPSA at Week 8 of guselkumab treatment was significantly associated with less progression of structural joint damage at 2 years in patients with active psoriatic arthritis (PsA). • Early control of peripheral joint disease activity with blockade of the IL-23 pathway may modify long-term PsA trajectory and prevent further joint damage.

[Clinical characteristics of epileptic seizure in neurofibromatosis type 1 in 15 cases].

Objective: To summarize the clinical characteristics of epileptic seizure associated with neurofibromatosis type 1 (NF1). Methods: From January 2017 to July 2023 at Children's Hospital Capital Institute of Pediatrics, medical records of patients with both NF1 and epileptic seizure were reviewed in this case series study. The clinical characteristics, treatment and prognosis were analyzed retrospectively. Results: A total of 15 patients(12 boys and 3 girls) were collected. Café-au-lait macules were observed in all 15 patients. There were 6 patients with neurodevelopmental disorders and the main manifestations were intellectual disability or developmental delay. The age at the first epileptic seizure was 2.5 (1.2, 5.5) years. There were various seizure types, including generalized tonic-clonic seizures in 8 patients, focal motor seizures in 6 patients, epileptic spasm in 4 patients, tonic seizures in 1 patient, absence in 1 patient, generalized myoclonic seizure in 1 patient and focal to bilateral tonic-clonic seizure in 1 patient. Among 14 patients whose brain magnetic resonance imaging results were available, there were abnormal signals in corpus callosum, basal ganglia, thalamus or cerebellum in 6 patients, dilated ventricles of different degrees in 3 patients, blurred gray and white matter boundary in 2 patients, agenesis of corpus callosum in 1 patient and no obvious abnormalities in the other patients. Among 13 epilepsy patients, 8 were seizure-free with 1 or 2 antiseizure medications(ASM), 1 with drug resistant epilepsy was seizure-free after left temporal lobectomy, and the other 4 patients who have received 2 to 9 ASM had persistent seizures. One patient with complex febrile convulsion achieved seizure freedom after oral administration of diazepam on demand. One patient had only 1 unprovoked epileptic seizure and did not have another seizure without taking any ASM. Conclusions: The first epileptic seizure in NF1 patients usually occurs in infancy and early childhood, with the main seizure type of generalized tonic-clonic seizure and focal motor seizure. Some patients have intellectual disability or developmental delay. Most epilepsy patients achieve seizure freedom with ASM.

Efficacy of Guselkumab on Axial-Related Symptoms Through up to 2 Years in Adults with Active Psoriatic Arthritis in the Phase 3, Randomized, Placebo-Controlled DISCOVER-2 Study.

INTRODUCTION: Guselkumab previously showed greater improvements versus placebo in axial symptoms in patients with psoriatic arthritis (PsA) (assessed by Bath Ankylosing Spondylitis Disease Activity Index [BASDAI] and Ankylosing Spondylitis Disease Activity Score [ASDAS]), in post hoc analyses of the phase 3, placebo-controlled, randomized DISCOVER-1 and DISCOVER-2 studies. We now evaluate durability of response in axial-related outcomes through 2 years of DISCOVER-2. METHODS: DISCOVER-2 biologic-naive adults with active PsA (≥ 5 tender/ ≥ 5 swollen joints, C-reactive protein ≥ 0.6 mg/dl) were randomized to guselkumab 100 mg every 4 weeks (Q4W) or at week 0, week 4, then Q8W, or placebo → guselkumab Q4W at week 24. Among patients with imaging-confirmed sacroiliitis (investigator-identified), axial symptoms were assessed through 2 years utilizing BASDAI, BASDAI Question #2 (spinal pain), modified BASDAI (mBASDAI; excludes Question #3 [peripheral joint pain]), and ASDAS. Mean changes in scores and proportions of patients achieving ≥ 50% improvement in BASDAI (BASDAI 50) and ASDAS responses, including major improvement (decrease ≥ 2.0), were determined through week 100. Treatment failure rules (through week 24) and nonresponder imputation of missing data (post-week 24) were utilized. Mean BASDAI component scores were assessed through week 100 (observed data). Exploratory analyses evaluated efficacy by sex and HLA-B*27 status. RESULTS: Among 246 patients with PsA and imaging-confirmed sacroiliitis, guselkumab-treated patients had greater mean improvements in BASDAI, mBASDAI, spinal pain, and ASDAS scores, lower mean BASDAI component scores, and greater response rates in achieving BASDAI 50 and ASDAS major improvement vs. placebo at week 24. Differences from placebo were observed for guselkumab-treated patients in selected endpoints regardless of sex or HLA-B*27 status. At week 100, mean improvements were ~ 3 points for all BASDAI scores and 1.6-1.7 for ASDAS; 49-54% achieved BASDAI 50 and 39% achieved ASDAS major improvement at week 100. CONCLUSIONS: Guselkumab treatment provided durable and meaningful improvements in axial symptoms and disease activity in substantial proportions of patients with active PsA and imaging-confirmed sacroiliitis. TRIAL REGISTRATION: Clinicaltrials.gov NCT03158285.

[Efficacy and safety of bendamustine-rituximab combination therapy for newly diagnosed indolent B-cell non-Hodgkin's lymphoma and elderly mantle cell lymphoma: a multi-center prospective phase II clinical trial in China].

Objectives: This study aimed to assess the efficacy and safety of bendamustine in combination with rituximab (BR regimen) for the treatment of newly diagnosed indolent B-cell non-Hodgkin's lymphoma (B-iNHL) and elderly mantle cell lymphoma (eMCL) . Methods: From December 1, 2020 to September 10, 2022, a multi-center prospective study was conducted across ten Grade A tertiary hospitals in Shandong Province, China. The BR regimen was administered to evaluate its efficacy and safety in newly diagnosed B-iNHL and eMCL patients, and all completed at least four cycles of induction therapy. Results: The 72 enrolled patients with B-iNHL or MCL were aged 24-74 years, with a median age of 55 years. Eastern Cooperative Oncology Group (ECOG) performance status scores of 0-1 were observed in 76.4% of patients, while 23.6% had scores of 2. Disease distribution included follicular lymphoma (FL) (51.4% ), marginal zone lymphoma (MZL) (33.3% ), eMCL (11.1% ), and the unknown subtype (4.2% ). According to the Ann Arbor staging system, 16.7% and 65.3% of patients were diagnosed with stage Ⅲ and stage Ⅳ lymphomas, respectively. Following four cycles of BR induction therapy, the overall response rate was 98.6%, with a complete response (CR) rate of 83.3% and a partial response (PR) rate of 15.3%. Only one eMCL patient experienced disease progression during treatment, and only one FL patient experienced a relapse. Even when evaluated using CT alone, the CR rate was 63.9%, considering the differences between PET/CT and CT assessments. The median follow-up duration was 11 months (range: 4-22), with a PFS rate of 96.8% and an OS rate of 100.0%. The main hematologic adverse reactions included grade 3-4 leukopenia (27.8%, with febrile neutropenia observed in 8.3% of patients), grade 3-4 lymphopenia (23.6% ), grade 3-4 anemia (5.6% ), and grade 3-4 thrombocytopenia (4.2% ). The main non-hematologic adverse reactions such as fatigue, nausea/vomiting, rash, and infections occurred in less than 20.0% of patients. Conclusion: Within the scope of this clinical trial conducted in China, the BR regimen demonstrated efficacy and safety in treating newly diagnosed B-iNHL and eMCL patients.

Guselkumab Modulates Differentially Expressed Genes in Blood of Patients With Psoriatic Arthritis: Results from Two Phase 3, Randomized, Placebo-Controlled Trials.

OBJECTIVE: To evaluate gene expression in blood of patients with psoriatic arthritis (PsA) versus healthy controls and identify changes associated with guselkumab treatment. METHODS: Whole blood transcriptome profiling via paired-end RNA sequencing was conducted using samples from DISCOVER-1 and DISCOVER-2 at baseline (n = 673) and at weeks 4 and 24 from a representative subgroup that received placebo or guselkumab (n = 227 [longitudinal PsA cohort]). Baseline samples were compared with demographically matched healthy controls (n = 21). Guselkumab-mediated changes in gene expression were assessed in participants from the longitudinal PsA cohort who did versus did not achieve at least 20% improvement in American College of Rheumatology response criteria (ACR20) or at least 75% improvement in Psoriasis Area and Severity Index (PASI75). Differential gene expression was analyzed using edgeR. RESULTS: At baseline, 355 upregulated and 314 downregulated genes (PsA-associated genes) were identified in patients with PsA versus healthy controls. Upregulated genes were related to neutrophil, mononuclear cell, and CD11b+ gene sets. No cell type-specific gene sets were identified among downregulated genes. Most PsA-associated genes were modulated by guselkumab treatment. At week 24, genes downregulated by guselkumab were enriched with neutrophil, monocyte, eosinophil, and macrophage gene sets; genes upregulated by guselkumab were enriched with B cell, T cell, and natural killer cell gene sets. Reductions in expression of upregulated PsA-associated gene sets were more pronounced in ACR20 and PASI75 responders than in nonresponders. CONCLUSION: These findings suggest a dysregulation of immune cell profiles in blood from patients in the baseline PsA cohort that approached levels in healthy controls after guselkumab treatment.

[Advances in gene therapy of ocular surface and corneal diseases].

With the continual advancement of gene editing technology, gene therapy has been increasingly explored as a potential treatment option for both hereditary and acquired diseases. Due to its unique physiological and anatomical characteristics, the eye has emerged as an optimal target for gene therapy. In fact, ophthalmology was among the first clinical fields to obtain approval for in vivo gene therapy. Despite the widespread development of gene therapy targeting ocular surface and corneal diseases in recent years, a systematic review of these projects is still lacking. Thus, this review aims to comprehensively summarize the research progress and clinical application of gene therapy for ocular surface and corneal diseases, providing valuable guidance for future research and clinical translation.