OBJECTIVE To analyze the characteristics of pediatric medicines with priority review and approval for marketing in China， providing a reference for promoting enterprise R&D and production， as well as improving the supply guarantee mechanism for pediatric medicines. METHODS Based on publicly available data sources such as List of Approved Information for Pediatric Medications Subject to Priority Review and Approval， Pharnexcloud biomedical database， and National Medical Insurance Drug Directory， this study conducted a comprehensive analysis of the main characteristics of pediatric medicines with priority review and approval for marketing. RESULTS As of June 30， 2024， a total of 68 pediatric medicines had been approved through the priority review and approval process， covering 12 therapeutic areas， with oral dosage forms accounting for 64.71%. The median time from application to inclusion in priority review was 35.50 days， with an average of 41.69 days. The median time from inclusion in priority review to market approval was 1.24 years， with an average of 1.42 years. This included 12 domestic new medicines， 21 domestic generic medicines， 35 imported medicines， as well as 29 pediatric-specific medicines and 21 orphan medicines. Additionally， 31 of these medicines had been included in the medical insurance catalog， representing a proportion of 45.59%. CONCLUSIONS Currently， a trend of differentiated competition is emerging between domestic and imported pediatric medicines. The therapeutic areas for pediatric medicines are continuously expanding， and the dosage forms are becoming more tailored to children’s needs. However， there are still issues such as slow progress in new medicine development， insufficient stability in the medicine review and approval process， and a need to increase the proportion of medicines included in medical insurance.

Revision of anterior cruciate ligament (ACL) reconstruction is more challenging than primary ACL reconstruction and often yields less favorable outcomes. The European Society of Sports Traumatology, Knee Surgery and Arthroscopy (ESSKA) has established a consensus regarding preoperative diagnosis, assessment, and selection criteria for ACL revision surgery. This consensus addresses 18 key issues that are most pertinent to clinical practice, providing guiding recommendations aimed at improving the prognosis of ACL revisions.
Humans ; Anterior Cruciate Ligament Reconstruction/methods* ; Arthroscopy/methods* ; Anterior Cruciate Ligament Injuries ; Societies, Medical ; Reoperation ; Consensus ; Anterior Cruciate Ligament/surgery* ; Europe ; Sports Medicine ; Knee Injuries/surgery* ; Knee Joint/surgery*

Primary cilia function as critical sensory organelles that mediate multiple signaling pathways, including the Hedgehog (Hh) pathway, which is essential for organ patterning and morphogenesis. Disruptions in Hh signaling have been implicated in supernumerary tooth formation and molar fusion in mutant mice. Cilk1, a highly conserved serine/threonine-protein kinase localized within primary cilia, plays a critical role in ciliary transport. Loss of Cilk1 results in severe ciliopathy phenotypes, including polydactyly, edema, and cleft palate. However, the role of Cilk1 in tooth development remains unexplored. In this study, we investigated the role of Cilk1 in tooth development. Cilk1 was found to be expressed in both the epithelial and mesenchymal compartments of developing molars. Cilk1 deficiency resulted in altered ciliary dynamics, characterized by reduced frequency and increased length, accompanied by downregulation of Hh target genes, such as Ptch1 and Sostdc1, leading to the formation of diastemal supernumerary teeth. Furthermore, in Cilk1^-/-;PCS1-MRCS1^△/△ mice, which exhibit a compounded suppression of Hh signaling, we uncovered a novel phenomenon: diastemal supernumerary teeth can be larger than first molars. Based on these findings, we propose a progressive model linking Hh signaling levels to sequential changes in tooth patterning: initially inducing diastemal supernumerary teeth, then enlarging them, and ultimately leading to molar fusion. This study reveals a previously unrecognized role of Cilk1 in controlling tooth morphology via Hh signaling and highlights how Hh signaling levels shape tooth patterning in a gradient-dependent manner.
Animals ; Hedgehog Proteins/physiology* ; Mice ; Signal Transduction/physiology* ; Tooth, Supernumerary ; Molar ; Cilia/physiology* ; Odontogenesis/physiology* ; Patched-1 Receptor ; Protein Serine-Threonine Kinases/physiology* ; Mice, Knockout ; Adaptor Proteins, Signal Transducing

Objective: Lipoprotein (a) (Lp[a]), which is a highly heritable trait, is associated with coronary artery disease (CAD). However, the insight into whether the association between Lp(a) and CAD differs according to the family history of CAD remains unclear. Methods: We investigated clinical data of 4,512 participants who underwent serum Lp(a) level measurement at Kanazawa University Hospital between 2008 and 2016. The association between Lp(a) and CAD according to CAD family history was investigated through logistic regression analyses. Results: CAD family history and Lp(a) levels were significantly associated with CAD development (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.12–1.52; p<0.001 and OR, 1.13; 95% CI, 1.03–1.23; p<0.001 per 10 mg/dL, respectively). In patients without CAD family history, those with Lp(a) levels ≥30 mg/dL had higher CAD risk than those with Lp(a) levels <30 mg/dL (reference) (OR, 1.33; 95% CI, 1.05–1.61; p<0.001). In patients with CAD family history, those who had Lp(a) levels <30 and ≥30 mg/dL were both highly at risk for CAD (OR, 1.24; 95% CI, 1.04–1.44; p<0.001 and OR, 1.68; 95% CI, 1.34–2.02; p<0.001, respectively). Adding CAD family history and Lp(a) information to other conventional risk factors enhanced CAD risk discrimination (C-statistics: 0.744 [0.704–0.784] to 0.768 [0.730–0.806], and 0.791 [0.751–0.831], respectively; p<0.05 for both). Conclusion Lp(a) level was associated with CAD development regardless of CAD family history status.

Objective: Lipoprotein (a) (Lp[a]), which is a highly heritable trait, is associated with coronary artery disease (CAD). However, the insight into whether the association between Lp(a) and CAD differs according to the family history of CAD remains unclear. Methods: We investigated clinical data of 4,512 participants who underwent serum Lp(a) level measurement at Kanazawa University Hospital between 2008 and 2016. The association between Lp(a) and CAD according to CAD family history was investigated through logistic regression analyses. Results: CAD family history and Lp(a) levels were significantly associated with CAD development (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.12–1.52; p<0.001 and OR, 1.13; 95% CI, 1.03–1.23; p<0.001 per 10 mg/dL, respectively). In patients without CAD family history, those with Lp(a) levels ≥30 mg/dL had higher CAD risk than those with Lp(a) levels <30 mg/dL (reference) (OR, 1.33; 95% CI, 1.05–1.61; p<0.001). In patients with CAD family history, those who had Lp(a) levels <30 and ≥30 mg/dL were both highly at risk for CAD (OR, 1.24; 95% CI, 1.04–1.44; p<0.001 and OR, 1.68; 95% CI, 1.34–2.02; p<0.001, respectively). Adding CAD family history and Lp(a) information to other conventional risk factors enhanced CAD risk discrimination (C-statistics: 0.744 [0.704–0.784] to 0.768 [0.730–0.806], and 0.791 [0.751–0.831], respectively; p<0.05 for both). Conclusion Lp(a) level was associated with CAD development regardless of CAD family history status.

Objective: Uterine carcinosarcoma (UCS) is uncommon high-grade endometrial cancer with limited treatment options. We evaluated the prognostic significance of human epidermal growth factor receptor 2 (HER2) expression and HER2 gene amplification within large cohorts of UCS, and clarify clinicopathologic characteristics of HER2-low UCS. Methods: We examined HER2 protein expression in 148 patients of UCS using in vivo diagnostic HER2 immunohistochemistry (IHC) kits and HER2 gene amplification using fluorescence in situ hybridization (FISH) in 72 patients. Results: HER2 IHC score was evaluated according to the latest American Society of Clinical Oncology/College of American Pathologists criteria for gastric cancer, which was negative in 41 patients, low expression of 1+ was observed in 57 patients, and HER2 high expression was observed in 50 patients (2+ in 38 and 3+ in 12 patients). There was no significant statistical difference in clinicopathological characteristics based on HER2 protein expression status.HER2 negative and low expression compared to high expression revealed poor overall survival in stage I/ II. The concordance between IHC and FISH results were relatively low compared to other cancer types (HER2 IHC score 1+, 2+, and 3+ were 5%, 15%, and 50%), and combining these results was not efficient as a prognostic factor in UCS. In contrast, the HER2 IHC score alone was a prognostic factor in stage I/II UCS. HER2 low group did not show specific clinicopathologic features. Conclusion Since the HER2 IHC score low in advanced UCS is a predictive factor, stratification of UCS using HER2 IHC score for HER2 IHC score low group and developing adjuvant therapy may be proposed in the near future.

Purpose: To investigate the therapeutic potential of eliminating insulin-like growth factor-binding protein 5 (IGFBP5) expression in improving erectile function in mice with cavernous nerve injury (CNI)-induced erectile dysfunction (ED). Materials and Methods: Eight-week-old male C57BL/6 mice were divided into four groups: a sham-operated group and three CNI-induced ED groups. The CNI-induced ED groups were treated with intracavernous injections 3 days before the CNI procedure.These injections included phosphate-buffered saline, scrambled control short hairpin RNA (shRNA), or shRNA targeting mouse IGFBP5 lentiviral particles. One week after CNI, erectile function was evaluated and the penile tissue was then harvested for histological examination and western blot analysis. Additionally, the major pelvic ganglia (MPG) and dorsal root ganglia (DRG) were cultured for ex vivo neurite outgrowth assays. Results: Following CNI, IGFBP5 expression in the cavernous tissues significantly increased, reaching its peak at day 7. First, ablation of IGFBP5 expression promotes neurite sprouting in MPG and DRG when exposed to lipopolysaccharide. Second, ablating IGFBP5 expression in CNI-induced ED mice improved erectile function, likely owing to increased neurovascular contents, including endothelial cells, pericytes, and neuronal processes. Third, ablating IGFBP5 expression in CNI-induced ED mice promoted neurovascular regeneration by increasing cell proliferation, reducing apoptosis, and decreasing Reactive oxygen species production. Finally, western blot analysis demonstrated that IGFBP5 ablation attenuated the JNK/c-Jun signaling pathway, activated the PI3K/AKT signaling pathway, and increased vascular endothelial growth factor and neurotrophic factor expression. Conclusions Ablating IGFBP5 expression enhanced neurovascular regeneration and ultimately improved erectile function in CNI-induced ED mice.

Objective: Uterine carcinosarcoma (UCS) is uncommon high-grade endometrial cancer with limited treatment options. We evaluated the prognostic significance of human epidermal growth factor receptor 2 (HER2) expression and HER2 gene amplification within large cohorts of UCS, and clarify clinicopathologic characteristics of HER2-low UCS. Methods: We examined HER2 protein expression in 148 patients of UCS using in vivo diagnostic HER2 immunohistochemistry (IHC) kits and HER2 gene amplification using fluorescence in situ hybridization (FISH) in 72 patients. Results: HER2 IHC score was evaluated according to the latest American Society of Clinical Oncology/College of American Pathologists criteria for gastric cancer, which was negative in 41 patients, low expression of 1+ was observed in 57 patients, and HER2 high expression was observed in 50 patients (2+ in 38 and 3+ in 12 patients). There was no significant statistical difference in clinicopathological characteristics based on HER2 protein expression status.HER2 negative and low expression compared to high expression revealed poor overall survival in stage I/ II. The concordance between IHC and FISH results were relatively low compared to other cancer types (HER2 IHC score 1+, 2+, and 3+ were 5%, 15%, and 50%), and combining these results was not efficient as a prognostic factor in UCS. In contrast, the HER2 IHC score alone was a prognostic factor in stage I/II UCS. HER2 low group did not show specific clinicopathologic features. Conclusion Since the HER2 IHC score low in advanced UCS is a predictive factor, stratification of UCS using HER2 IHC score for HER2 IHC score low group and developing adjuvant therapy may be proposed in the near future.

Objective: Lipoprotein (a) (Lp[a]), which is a highly heritable trait, is associated with coronary artery disease (CAD). However, the insight into whether the association between Lp(a) and CAD differs according to the family history of CAD remains unclear. Methods: We investigated clinical data of 4,512 participants who underwent serum Lp(a) level measurement at Kanazawa University Hospital between 2008 and 2016. The association between Lp(a) and CAD according to CAD family history was investigated through logistic regression analyses. Results: CAD family history and Lp(a) levels were significantly associated with CAD development (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.12–1.52; p<0.001 and OR, 1.13; 95% CI, 1.03–1.23; p<0.001 per 10 mg/dL, respectively). In patients without CAD family history, those with Lp(a) levels ≥30 mg/dL had higher CAD risk than those with Lp(a) levels <30 mg/dL (reference) (OR, 1.33; 95% CI, 1.05–1.61; p<0.001). In patients with CAD family history, those who had Lp(a) levels <30 and ≥30 mg/dL were both highly at risk for CAD (OR, 1.24; 95% CI, 1.04–1.44; p<0.001 and OR, 1.68; 95% CI, 1.34–2.02; p<0.001, respectively). Adding CAD family history and Lp(a) information to other conventional risk factors enhanced CAD risk discrimination (C-statistics: 0.744 [0.704–0.784] to 0.768 [0.730–0.806], and 0.791 [0.751–0.831], respectively; p<0.05 for both). Conclusion Lp(a) level was associated with CAD development regardless of CAD family history status.

BACKGROUND:The reasonable implantation range of femoral prosthesis in unicompartmental knee arthroplasty in patients with osteoporosis has not been investigated,and previous studies have often been based on unicompartmental knee arthroplasty models in normal bone,with fewer mechanical studies in models with non-normal bone.Complications after unicompartmental knee arthroplasty have been shown to be highly associated with osteoporosis. OBJECTIVE:To analyze the biomechanical effects of the coronal inclination of the Sled fixed platform femoral prosthesis on unicompartmental knee arthroplasty in patients with osteoporosis and to find the correlation between osteoporosis and mid-and long-term complications after unicompartmental knee arthroplasty. METHODS:Based on the digital imaging technology to obtain the data of the knee joint and prosthesis,a normal bone knee model is then created by using specialized software such as Mimics and Geomagic studio.Based on a validated normal bone knee model,an osteoporotic knee model was created by changing the material parameters.Totally 14 unicompartmental knee arthroplasty finite element models were created using Sled fixed platform femoral prosthesis:standard position(0°),varus and valgus angles:3°,6°,9° in the normal bone and osteoporosis groups.Stress changes on the surface of polyethylene liner,cancellous bone under tibial prosthesis,and cortical bone were calculated and analyzed in all unicompartmental knee arthroplasty models. RESULTS AND CONCLUSION:(1)In the osteoporotic models,the high stress values of the polyethylene liner surface and the cancellous bone under the tibial prosthesis increased with the increase of the tilt angle of the femoral prosthesis,and the high stress values of the cortical bone surface under the tibial prosthesis increased with the increase of the prosthesis valgus angles and decreased with the increase of the varus angles.(2)For the polyethylene liner surface as well as the subcortical bone surface of the tibial prosthesis,the high stress values of the models for each inclination angle in the osteoporosis group were greater than those of the corresponding models in the normal bone group.For the surface of the cancellous bone under the tibial prosthesis,the high stress values of the tilt angle models of the osteoporosis groups were smaller than those of the normal bone groups.(3)Osteoporosis may cause biomechanical abnormalities in the internal structures of the knee after unicondylar replacement,increasing the potential risk of postoperative aseptic loosening of the prosthesis and periprosthetic fractures.Varus and valgus of the femoral prosthesis in the coronal plane should be avoided as much as possible when performing medial unicompartmental knee arthroplasty with a Sled fixation platform in osteoporotic knees.