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Background Os odontoideum(OO) is a rare bone malformation at the craniovertebral junction, the presence of which can lead to potential instability of atlantoaxial joints. The cause, prevalence and treatment of OO are still controversial. There are two main theories regarding the pathogenesis of OO: congenital factors and traumatic factors. The congenital hypothesis suggests that the lesion results from segmental defects caused by incomplete fusion of the dens and the axis vertebral body during embryonic development. Our research team previously reported a case series involving three generations of a family affected by OO without a clear history of trauma, suggesting the existence of congenital pathogenic factors for this disease. Based on this, we conducted this study to further explore the pathogenesis of OO. Methods We consecutively recruited 25 OO patients including 15 males(60%) and 10 females(40%) from 2021 to 2023. The clinical manifestation and concomitant deformities were analyzed and whole-exome sequencing(WES) was performed. The variants in OO patients were compared with those from 79 normal population controls using a case-control association analysis of individual rare variants. The analysis results were used to prioritize disease-associated candidate genes by combining Odds Ratio(OR) values and P values. OR values measure the strength of association between genetic variations and the disease, while P values determine the statistical significance of the results. Nominally high OR values and low P values can indicate a potential association between genetic variations and the disease. By integrating these two metrics, genes with notable correlations to OO were identified. Results The analysis identified four genes nominally associated with OO based on their P values and OR values. Cell Division Cycle 27(CDC27) exhibited a P value of 0.002 and an OR of 5.08, indicating a notable association with the disease. Facioscapulohumeral Muscular Dystrophy Region Gene 1 Binding Protein(FRG1BP) showed a P value of 0.004 and an OR of 5.59, further supporting its potential relevance. Tripartite Motif Containing 8(TRIM8) had a P value of 0.02 and an OR of 4.58, suggesting a potential association. Centrosomal Protein 250(CEP250) demonstrated the most notable correlation among the four genes, with a P value of 0.005 and an OR of 7.78. Conclusion Our study identifies rare variants potentially linked to OO and provides preliminary data that could inform hypotheses regarding a complex genetic basis, though larger cohorts and functional studies are needed for validation. Our findings of rare variants associated with OO, though preliminary, highlight a potential complex genetic basis for this condition. This underscores the need for further research which may ultimately aid in risk stratification and early detection in high-risk families.

Background QL1706 (PSB205) is a single bifunctional MabPair (a novel technical platform) product consisting of two engineered monoclonal antibodies (anti-PD-1 IgG4 and anti-CTLA-4 IgG1), with a shorter elimination half-life (t 1/2 ) for CTLA-4. We report results from a phase I/Ib study of QL1706 in patients with advanced solid tumors who failed standard therapies. Methods In the phase I study, QL1706 was administered intravenously once every 3 weeks at one of five doses ranging from 0.3 to 10 mg/kg, and the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of QL1706 were investigated. In the phase Ib study, QL1706 was administered at the RP2D intravenously every 3 weeks, and the preliminary efficacies in non-small cell lung cancer (NSCLC), nasopharyngeal carcinoma (NPC), cervical cancer (CC), and other solid tumors were evaluated. Results Between March 2020 and July 2021, 518 patients with advanced solid tumors were enrolled (phase I, n  = 99; phase Ib, n  = 419). For all patients, the three most common treatment-related adverse events (TRAEs) were rash (19.7%), hypothyroidism (13.5%), and pruritus (13.3%). The TRAEs and immune-related adverse events (irAEs) of grade ≥ 3 occurred in 16.0% and 8.1% of patients, respectively. In phase I, 2 of 6 patients in the 10mg/kg group experienced dose-limiting toxicities (DLTs) (grade 3 thrombocytopenia and grade 4 immune-mediated nephritis), so the maximum tolerated dose (MTD) was reached at 10 mg/kg. The RP2D was determined to be 5 mg/kg based on comprehensive analysis of tolerability, PK/PD, and efficacy. For all patients who received QL1706 at the RP2D, the objective response rate (ORR) and median duration of response were 16.9% (79/468) and 11.7 months (8.3—not reached [NR]), respectively; and the ORRs were 14.0% (17/121) in NSCLC, 24.5% (27/110) in NPC, 27.3% (15/55) in CC, 7.4% (2/27) in colorectal cancer, 23.1% (6/26) in small cell lung cancer. For immunotherapy-naive patients, QL1706 exhibited promising antitumor activities, especially in NSCLC, NPC, and CC, with ORRs of 24.2%, 38.7%, and 28.3%, respectively. Conclusions QL1706 was well tolerated and demonstrated promising antitumor activity in solid tumors, especially in NSCLC, NPC, and CC patients. It is currently being evaluated in randomized phase II (NCT05576272, NCT05179317) and phase III (NCT05446883, NCT05487391) trials. Trial Registration ClinicalTrials.gov Identifier: NCT04296994 and NCT05171790.

First-line chemoimmunotherapy (with or without bevacizumab) has improved outcomes in advanced non-small cell lung cancer (NSCLC). Here, this open-label, multi-cohort phase II study (NCT05329025) was done to investigate the safety and efficacy of QL1706 (a single bifunctional MabPair product against PD-1 and CTLA-4) and chemotherapy with or without bevacizumab in this population. Patients were enrolled into five different cohorts based on genotype (cohorts 1-4, epidermal growth factor receptor [EGFR] wild-type; cohort 5, EGFR-mutant and progressed on EGFR-tyrosine kinase inhibitors [TKIs]). Between June 11, 2021 and December 29, 2021, 91 patients were enrolled. Most frequent treatment-related adverse events (TRAEs) included decreased appetite (60 [65.9%]), anemia (60 [65.9%]), infusion-related reactions (48 [52.7%]), and pruritus (44 [48.4%]). Grade ≥ 3 TRAEs occurred in 30 (33.0%) patients. Twenty-seven (45%) patients with wild-type EGFR achieved partial response (PR) (objective response rate [ORR] = 45%) and had a median progression-free survival (mPFS) of 6.8 months (95% CI: 5.2-9.7). For 31 patients harboring mutated EGFR, 17 (54.8%) achieved PR (ORR = 54.8%), with an mPFS of 8.5 months (95% CI: 5.72-not evaluable). Overall, QL1706 plus chemotherapy, regardless of having bevacizumab, was generally tolerable and had promising antitumor activity for EGFR wild-type advanced NSCLC in first-line setting. Moreover, QL1706 plus chemotherapy and bevacizumab showed favorable antitumor activity for patients who had EGFR mutated NSCLC but failed in TKI therapy, demonstrating a potential for treating this population.

Irreducible atlantoaxial dislocation is a challenging condition for spine surgeons and carries a particularly high risk of postoperative infection due to its trans-oral approach for peri-odontoid soft tissue release. Conventional antibacterial implant coatings are limited by rapid burst release, leading to short-term efficacy and potential cytotoxicity. To address this, we developed a composite coating of silver nanoparticle-decorated ZIF-8 (AgZ) within a tunable methacrylate gelatin (GelMA) and silk fibroin (SF) matrix (AgZ/GelSF) for 3D-printed Ti-6Al-4V fusion cages. The AgZ nanocomposite enhanced silver dispersibility and potency, reducing the minimum bactericidal concentration against MRSA and E. coli by over 4-fold and 13-fold, respectively. By adjusting the GelMA-to-SF mass ratio, we finely tuned the degradation rate and silver release profile, ensuring a sustained release over 28 days, which aligns with the typical wound healing timeline. RNA sequencing indicated the coating's mechanism involves bacterial membrane disruption and metabolic interference, preventing biofilm formation. Optimization of the coating components demonstrated excellent biocompatibility and osteogenic performance both in vitro and in a rabbit femoral defect model. In a bacteria-contaminated porcine model for atlantoaxial fixation and intra-articular fusion, the AgZ/GelSF-coated implant effectively eliminated bacterial infection and supported successful bone fusion, all while showing no systemic toxicity. Compared with previous studies, this work demonstrates significant advantages in antibacterial efficiency, drug release duration and evaluation models. These findings suggest that the AgZ/GelSF composite coating is a promising strategy for preventing implant-associated infections through a degradation-controlled drug release platform. [Display omitted] •Enhanced silver nanoparticle bioavailability via improved dispersibility, boosting bactericidal action and reducing cytotoxicity.•Engineered composite coating with tunable degradation and controlled silver release by matrix composition adjustment.•Porcine model verified antibacterial and osteogenic properties of silver-loaded interbody fusion cage.•Degradation-Tunable Coating with Sustained Silver Release for Spinal Implants to Prevent Postoperative Infections.

Purpose To verify the relationship between muscle volume, lateral centre-edge angle (LCEA), alpha angle (AA), body mass index (BMI) and Beighton score with stiffness coefficient (SC). To analyse the difference of traction force at different physical states of hip joint capsule. Methods Thirty-six patients who underwent hip arthroscopy operation were included. The volumes of some related muscles were measured in MRI images by 3D Slicer. We recorded and tested differences in traction force of five joint capsule physical states, including before (State 1) and after joint capsule puncture (State 2), after the establishment of anterolateral and mid-anterior approaches (State 3) and after incision of the joint capsule through these two approaches (States 4, 5). The correlation between muscle volume, BMI, LCEA, AA and SC was verified by Spearman test. Poisson regression was used to explain confounding variables. Results The average force at State 1 was 531.8 N. There were significant differences in traction force between these five states ( p  < 0.001). There was a significant positive correlation between muscle volumes and SC ( p  < 0.001). BMI had no correlation with SC ( n.s. ). The preoperative LCEA of the affected side was correlated with SC ( p  = 0.043). AA and SC were not correlated ( n.s. ). Conclusion The physical states of the hip joint capsule affected traction force. Muscle volume rather than BMI is an ideal index to estimate preoperative traction force. LCEA affected traction force, whilst AA and Beighton score did not. Measuring the muscle volume can help estimate the most suitable traction force for the patient. Levels of evidence IV.

Retrospective case series. The aim of this study was to evaluate the clinical outcomes and effectiveness of using 3D printed implants in upper cervical spine and occipitocervical junction surgery. C2 primary tumor patients who required axial en bloc resection and other patients who required partial bone decompression using customized 3D printed implants or fixation devices for surgery were included. Evaluate the stability and surgical outcomes of 3D printed implants through perioperative and follow-up period. Five tumor patients underwent reconstruction using customized 3D printed artificial vertebral bodies, while another five patients with atlantoaxial joint dislocation underwent reduction and decompression using customized 3D printed internal fixation devices. The postoperative imaging results showed that the 3D printed structures had good immediate stability and had no signs of displacement or subsidence. Follow up showed that all five cases of vertebral body reconstruction had achieved fusion. Only one patient died one month after surgery due to infection and respiratory difficulties. Other patients showed excellent improvement in neurological function in follow up. The use of 3D printed implants in surgery involving the occipitocervical area is a feasible and reliable alternative choice. It is a valuable attempt for complex atlantoaxial dislocation that cannot be treated with conventional instruments. 3D printed implants can improve the safety and accuracy of surgery, provide good immediate stability, have a low incidence of subsidence, fewer related complications during the follow-up period.

The associations of air pollution and meteorological factors with the outpatient visits of urticaria remain poorly studied. This study aimed to assess the association between air pollution, meteorological factors, and daily outpatient visits for urticaria in Shijiazhuang, China, during 2014–2019. Daily recordings of air pollutant concentrations, meteorological data, and outpatient visits data for urticaria were collected during the 6 years. Descriptive research methods were used to describe the distribution characteristics and demographic features of urticaria. A combination of the generalized linear regression model (GLM) and distribution lag nonlinear model (DLNM) was used to evaluate the lag association between environmental factors and daily outpatient visits for urticaria. Stratified analyses by gender (male; female) and age (< 18 years; 18–39 years; > 39 years) were further conducted. The dose–response relationship between daily urticaria visits and CO, NO 2 , O 3 , temperature, and relative humidity was nonlinear. High concentrations of CO, NO 2 , O 3 , and high temperatures increased the risk of urticaria outpatient visits. The maximum cumulative association of high concentrations of CO, NO 2 , and O 3 was lag 0–14 days (CO: RR = 1.10, 95%CI: 1.06, 1.31; NO 2 : RR = 1.09, 95%CI: 1.01, 1.08; O 3 : RR = 1.16, 95%CI: 1.08, 1.25), and high temperatures was lag 0–7 days (RR = 1.27, 95%CI: 1.14, 1.41). Low concentrations of NO 2 , O 3 , and high humidity, on the other hand, act as protective factors for urticaria outpatient. The maximum cumulative association of low concentrations of NO 2 was the 0-day lag (RR = 0.97, 95%CI: 0.95, 0.99), O 3 was lag 0–5 days (RR = 0.94, 95%CI: 0.88, 0.99), and high humidity was lag 0–10 days (RR = 0.93, 95%CI: 0.89, 0.98). Stratified analyses showed that the risk of urticaria outpatient visits was higher for the males and in the < 18 years age group. In conclusion, we found that the development of urticaria in Shijiazhuang has a distinct seasonal and cyclical nature. Air pollutants and meteorological factors had varying degrees of influence on the risk of urticaria outpatient visits. This study provides indirect evidence for a link between air pollution, meteorological factors, and urticaria outpatient visits.

The combination of congenital C1 occipitalization and C2-3 non-segmentation (i.e. “sandwich fusion”) results in early development of atlantoaxial dislocation (AAD). A thorough understanding of the morphometry of the C1-2 zygapophysial joints is important to ensure a safe surgery. This study was aimed to evaluate the C1-2 zygapophysial joint in AAD patients with sandwich fusion by morphological research based on CT scans. This was a retrospective case-control study including 155 AAD patients with sandwich fusion in sandwich group and 55 with os odontoideum (OO) in control group. The C1 listhetic distance, sagittal inclination angle (SIA), coronal inclination angles (CIA) were measured from the CT and compared between two groups. The listhetic grade was defined according to the ratio of the listhetic distance and length of the superior facet of C2: less than 25% as mild, 25–75% as moderate, and greater than 75% as severe. Patients in the sandwich group had higher listhetic grade than the OO group (17.4% vs. 70.6%, 50.3% vs. 29.4% and 32.3% vs. 0 were of mild, moderate, and severe, respectively). The SIA and CIA in the sandwich group were greater than those in the OO group (30.1° vs. 5.0°, 36.6° vs. 31.0°, respectively). Asymmetric listhesis was found in 0.0%, 63.3%, and 85.7% of sandwich patients with mild, moderate and severe listhetic grade, respectively. AAD with sandwich fusion was a three-dimensional deformity characterized by the high prevalence of asymmetric and moderate-to-severe listhesis.

Introduction/BackgroundIparomlimab and tuvonralimab (QL1706), a bifunctional PD-1/CTLA-4 dual blocker, showed preliminary efficacy in patients with cervical cancer in phase 1 trial.MethodologyThis multi-center, open-label, single-arm, phase 2 trial (NCT05557565) recruited immune checkpoint inhibitors naïve patients with recurrent or metastatic cervical cancer (r/m CC) who failed first-line platinum-based chemotherapy with or without bevacizumab, regardless of PD-L1 status. Intravenous injection of iparomlimab and tuvonralimab 5.0 mg/kg every three weeks was administered. The primary endpoint was objective response rate (ORR) evaluated by the independent review committee (IRC).ResultsAs of April 28, 2023, 148 participants were included in the full analysis set. Eastern Cooperative Oncology Group Performance Status scored 1 in 109 (73.6%) patients. Fifty-nine (39.9%) patients received prior bevacizumab. Fifty-five patients (37.2%) had received ≥2 lines of prior treatment. Median follow-up was 11.0 (0.7, 15.5) months. Per IRC, ORR was 33.8% (95% confidence interval [CI]: 26.2%-42.0%), and disease control rate was 64.9% (95% CI: 56.6%-72.5%). Median progression-free survival achieved 5.4 month (95% CI: 3.9–6.9). Median overall survival was not reached. ORR was 25.6% (95% CI: 13.5–41.2) and 37.1% (95% CI: 27.9%-47.1%) in patients with combined positive score (CPS) <1 (n=43) and with CPS≥1 (n=105), respectively. Treatment-related adverse events (TRAE) occurred in 104 (70.3%) patients. TRAE of grade ≥3 occurred in 36 (24.3%) patients, and the most common were anemia (4.1%), gamma-glutamyl transferase increased (2.7%), and lipase increased (2.7%). Three (2.0%) participants had TRAE leading to treatment discontinuation. Nine (6.1%) participants died due to treatment-emergent adverse events, which were all unrelated to the treatment.ConclusionIparomlimab and tuvonralimab showed promising efficacy and manageable safety in patients with r/m CC who failed first-line chemotherapy. A phase 3 trial (NCT05446883) evaluating iparomlimab and tuvonralimab plus chemotherapy as first-line treatment for r/m CC is ongoing.DisclosuresThe presenting author, Jihong Liu, and the co-authors Hanmei Lou, Yun Zhou, Dapeng Li, Hongping Zhang, Mingjun Zhang, Lihua Wang, Huijun Cheng, Zi Liu, Wei Duan, and Mei Feng, declare that they have no conflict of interest. The co-authors Chao Wang, Shilin Xue, Hui Li, and Xiaoyan Kang are full-time employees of the company Qilu Pharmaceutical Co., Ltd.

The development of polymers with switchable glass transition temperatures ( T g ) can address scientific challenges such as the healing of cracks in high- T g polymers and the processing of hard polymers at room temperature without using plasticizing solvents. Here, we demonstrate that light can switch the T g of azobenzene-containing polymers (azopolymers) and induce reversible solid-to-liquid transitions of the polymers. The azobenzene groups in the polymers exhibit reversible cis – trans photoisomerization abilities. Trans azopolymers are solids with T g above room temperature, whereas cis azopolymers are liquids with T g below room temperature. Because of the photoinduced solid-to-liquid transitions of these polymers, light can reduce the surface roughness of azopolymer films by almost 600%, repeatedly heal cracks in azopolymers, and control the adhesion of azopolymers for transfer printing. The photoswitching of T g provides a new strategy for designing healable polymers with high T g and allows for control over the mechanical properties of polymers with high spatiotemporal resolution. Reversibly inducing solid-to-liquid transitions of polymers at room temperature represents a challenge for enhanced processability and applications of polymers. Now, three azopolymers have been shown to exhibit photoswitchable glass transition temperatures, resulting in reversible solid-to-liquid transitions. Light exposure can heal cracks in hard azopolymers, reduce surface roughness of azopolymer films and control azopolymer adhesion.