ROS-mediated lysosomal membrane permeabilization and autophagy inhibition regulate bleomycin-induced cellular senescence.

Bleomycin exhibits effective chemotherapeutic activity against multiple types of tumors, and also induces various side effects, such as pulmonary fibrosis and neuronal defects, which limit the clinical application of this drug. Macroautophagy/autophagy has been recently reported to be involved in the functions of bleomycin, and yet the mechanisms of their crosstalk remain insufficiently understood. Here, we demonstrated that reactive oxygen species (ROS) produced during bleomycin activation hampered autophagy flux by inducing lysosomal membrane permeabilization (LMP) and obstructing lysosomal degradation. Exhaustion of ROS with N-acetylcysteine relieved LMP and autophagy defects. Notably, we observed that LMP and autophagy blockage preceded the emergence of cellular senescence during bleomycin treatment. In addition, promoting or inhibiting autophagy-lysosome degradation alleviated or exacerbated the phenotypes of senescence, respectively. This suggests the alternation of autophagy activity is more a regulatory mechanism than a consequence of bleomycin-induced cellular senescence. Taken together, we reveal a specific role of bleomycin-induced ROS in mediating defects of autophagic degradation and further regulating cellular senescence in vitro and in vivo. Our findings, conversely, indicate the autophagy-lysosome degradation pathway as a target for modulating the functions of bleomycin. These provide a new perspective for optimizing bleomycin as a clinically applicable chemotherapeutics devoid of severe side-effects.Abbreviations: AT2 cells: type II alveolar epithelial cells; ATG7: autophagy related 7; bEnd.3: mouse brain microvascular endothelial cells; BNIP3L: BCL2/adenovirus E1B interacting protein 3-like; CCL2: C-C motif chemokine ligand 2; CDKN1A: cyclin dependent kinase inhibitor 1A; CDKN2A: cyclin dependent kinase inhibitor 2A; FTH1: ferritin heavy polypeptide 1; γ-H2AX: phosphorylated H2A.X variant histone; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HUVEC: human umbilical vein endothelial cells; HT22: hippocampal neuronal cell lines; Il: interleukin; LAMP: lysosomal-associated membrane protein; LMP: lysosome membrane permeabilization; MTORC1: mechanistic target of rapamycin kinase complex 1; NAC: N-acetylcysteine; NCOA4: nuclear receptor coactivator 4; PI3K: phosphoinositide 3-kinase; ROS: reactive oxygen species; RPS6KB/S6K: ribosomal protein S6 kinase; SA-GLB1/ß-gal: senescence-associated galactosidase, beta 1; SAHF: senescence-associated heterochromatic foci; SASP: senescence-associated secretory phenotype; SEC62: SEC62 homolog, preprotein translocation; SEP: superecliptic pHluorin; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB.

The ALDH2 gene rs671 polymorphism is associated with cardiometabolic risk factors in East Asian population: an updated meta-analysis.

Introduction: Acetaldehyde dehydrogenase 2 (ALDH2) had reported as a prominent role in the development of cardiometabolic diseases among Asians. Our study aims to investigate the relationship between ALDH2 polymorphism and cardiometabolic risk factors in East Asian population. Method: We searched databases of PubMed, Web of Science, and Embase updated to Oct 30th, 2023. We extracted data of BMI, Hypertension, SBP, DBP, T2DM, FBG, PPG, HbA1c, TG, TC, LDL-C and HDL-C. Result: In total, 46 studies were finally included in our meta-analysis, containing, 54068 GG and, 36820 GA/AA participants. All outcomes related to blood pressure revealed significant results (hypertension OR=0.83 [0.80, 0.86]; SBP MD=-1.48 [-1.82, -1.14]; DBP MD=-1.09 [-1.58, -0.61]). FBG showed a significant difference (MD=-0.10 [-0.13, -0.07]), and the lipid resulted significantly in some outcomes (TG MD=-0.07 [-0.09, -0.04]; LDL-C MD=-0.04 [-0.05, -0.02]). As for subgroups analysis, we found that in populations without severe cardiac-cerebral vascular diseases (CCVDs), GG demonstrated a significantly higher incidence of T2DM (T2DM OR=0.88 [0.79, 0.97]), while the trend was totally opposite in population with severe CCVDs (T2DM OR=1.29 [1.00, 1.66]) with significant subgroup differences. Conclusion: Our updated meta-analysis demonstrated that ALDH2 rs671 GG populations had significantly higher levels of BMI, blood pressure, FBG, TG, LDL-C and higher risk of hypertension than GA/AA populations. Besides, to the best of our knowledge, we first report GG had a higher risk of T2DM in population without severe CCVDs, and GA/AA had a higher risk of T2DM in population with severe CCVDs.Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO, identifier CRD42023389242.

Legg-Calvé-Perthes Disease: Diagnosis, Decision Making, and Outcome.

ABSTRACT: Legg-Calvé-Perthes disease (LCPD), or idiopathic avascular necrosis of the proximal capital femoral epiphysis in children, has a variable presentation and can result in significant femoral head deformity that can lead to long-term functional deficits. Plain radiographic imaging is crucial in diagnosing LCPD and guiding treatment. Although the etiology of LCPD remains unknown, the evolution of the disease has been well characterized to include the phases of ischemia, revascularization, and reossification. The mechanical weakening during these phases of healing place the femoral head at high risk of deformity. Treatment of LCPD, therefore, focuses on minimizing deformity through operative and nonoperative strategies to reduce the risk of premature osteoarthritis. Advanced imaging using perfusion MRI may refine surgical decision making in the future, and biological treatments to improve femoral head healing are on the horizon.

Enhanced recovery after surgery in patients after hip and knee arthroplasty: a systematic review and meta-analysis.

PURPOSE: Enhanced recovery after surgery (ERAS) was characterized as patient-centered, evidence-based, multidisciplinary team-developed routes for a surgical speciality and institution to improve postoperative recovery and attenuate the surgical stress response. However, evidence of their effectiveness in osteoarthroplasty remains sparse. This study aimed to develop an ERAS standard and evaluate the significance of ERAS interventions for postoperative outcomes after primary total hip arthroplasty (THA) or total knee arthroplasty (TKA). METHODS: We searched Medline, Embase, Cochrane databases, and Clinicaltrials.gov for randomized controlled trials, cohort studies, and case-control studies until 24 February 2023. All relevant data were collected from studies meeting the inclusion criteria. Two reviewers independently assessed the risk of bias and extracted data. The primary outcome was the length of stay (LOS), postoperative complications, and readmission rate. The secondary outcomes included transfusion rate, mortality rate, visual analog score (VAS), the Western Ontario and McMaster University Osteoarthritis Index (WOMAC), Short Form 36 (SF-36) bodily pain (SF-36 BP), SF-36 physical function (SF-36 PF), oxford knee score, and range of motion (ROM). RESULTS: A total of 47 studies involving 76 971 patients (ERAS group: 29 702, control group: 47 269) met the inclusion criteria and were included in the meta-analysis. The result showed that ERAS could significantly shorten the LOS (WMD = -2.65, P < .001), reduce transfusion rate (OR = 0.40, P < .001), and lower 30-day postoperative mortality (OR = 0.46, P = .01) without increasing postoperative complications or readmission rate. Apart from that, ERAS may decrease patients' VAS (WMD = -0.88, P = .01) while improving their ROM (WMD = 6.65, P = .004), SF-36 BP (WMD = 4.49, P < .001), and SF-36 PF (WMD = 3.64, P < .001) scores. However, there was no significant difference in WOMAC, oxford knee score between the ERAS and control groups.Furthermore, we determined that the following seven components of the ERAS program are highly advised: avoid bowel preparation, PONV prophylaxis, standardized anesthesia, use of local anesthetics for infiltration analgesia and nerve blocks, tranexamic acid, prevent hypothermia, and early mobilization. CONCLUSION: Our meta-analysis suggested that the ERAS could significantly shorten the LOS, reduce transfusion rate, and lower 30-day postoperative mortality without increasing postoperative complications or readmission rate after THA and TKA. Meanwhile, ERAS could decrease the VAS of patients while improving their ROM, SF-36 BP, and SF-36 PF scores. Finally, we expect future studies to utilize the seven ERAS elements proposed in our meta-analysis to prevent increased readmission rate for patients with THA or TKA.

SalterHarris fractures in paediatric skiers and snowboarders.

The incidence of paediatric fractures among winter sport athletes is not adequately studied. Our objective was to categorize fractures that occurred in paediatric skiers and snowboarders at a single ski resort. X-rays of 756 skiers/snowboarders aged 3-17 diagnosed with a fracture were categorized using the Salter-Harris (SH) classification. SH fractures were seen in 158 (21%) patients, with 123 (77%) being Type II. There were no significant differences between patients with a SH fracture and patients with a non-SH fracture for age, sex, snowboarding or skiing, mechanism of injury, terrain or the resort conditions on the day of injury. The most common mechanism of injury was falling onto snow while collisions resulted in more severe injuries. Compared to fractures without growth plate involvement, a higher proportion of SH fractures were seen in the humerus, radius, fibula and thumb; a lower proportion of SH fractures were observed at the tibia and clavicle.

Epidemiological Investigation of Pediatric Fractures-A Retrospective Cohort Study of 1129 Patients.

Background and Objectives: Fractures are common in pediatric trauma, and they are caused by a broad spectrum of factors. Only a few studies have discussed the mechanisms of injury and their relationships to different types of fractures. The most frequent type of fractures in different age groups remains unclear. Therefore, we aim to summarize the epidemiological characteristics of pediatric fractures in a medical center in Zhuhai, China from 2006 to 2021 and analyze the causes of fractures with the highest frequency in different age groups. Materials and Methods: We extracted the information from the Zhuhai Center for Maternal and Child Health Care of those under 14 years old who had fractures from 2006 to 2021. Results: We reviewed the information of 1145 children. The number of patients increased during the 15 years (p < 0.0001). The number of patients was significantly different between genders after Y2 (p = 0.014). In addition, more than two-thirds of patients (71.3%) had upper limb fractures, and all types of falls were the most common cause of fractures (83.6%). The incidence demonstrated an insignificant difference in age groups except for the fractures of humerus and radius. Moreover, we discovered that the prevalence of fall-related injuries decreased with age, while that of sports-related injuries increased with age. Conclusions: Our study demonstrates that the prevalence of fall-related injuries decreases with age, and that of sports-related injuries increases with age. Most patients have upper limb fractures, and all types of falls are the most common cause of fractures. Fracture types with the highest frequency differ in each age group. These findings might supplement current epidemiological knowledge of childhood fracture and provide references for decision-making in children's health policies.

Intelligent geometry compensation for additive manufactured oral maxillary stent by genetic algorithm and backpropagation network.

Recently, laser powder bed fusion (LPBF) has shown great potential in advanced manufacturing. However, the rapid melting and re-solidification of the molten pool in LPBF leads to the distortion of parts, especially thin-walled parts. The traditional geometric compensation method, which is used to overcome this problem, is simply based on mapping compensation, with the general effect of distortion reduction. In this study, we used a genetic algorithm (GA) and backpropagation (BP) network to optimize the geometric compensation of Ti6Al4V thin-walled parts fabricated by LPBF. The GA-BP network method can generate free-form thin-walled structures with enhanced geometric freedom for compensation. For the GA-BP network training, an arc thin-walled structure was designed and printed by LBPF and measured via optical scanning measurements. The final distortion of the compensated arc thin-walled part based on GA-BP was reduced by 87.9% compared with PSO-BP and mapping method. The effectiveness of this GA-BP compensation method is further evaluated in an application case using new data points, and the result shows that the final distortion of the oral maxillary stent was reduced by 71%. In summary, the GA-BP-based geometric compensation proposed in this study can better reduce the distortion of thin-walled parts with higher time and cost efficiencies.

A Combination of Ilizarov Frame, Externalized Locking Plate and Tibia Bridging for an Adult with Large Tibial Defect and Severe Varus Deformity Due to Chronic Osteomyelitis in Childhood: A Case Report.

Background: Various techniques have been reported to treat large, segmental tibial defects, such as autogenous bone graft, vascularized free fibula transfer and bone transport. We present a case of a 24-year-old male with a 17-year history of chronic osteomyelitis with obvious lower limb length discrepancy and severe varus deformity of the tibia secondary to osteomyelitis in childhood. Aim: The aim of this work is to provide an alternative choice for treating patients in developing countries with severe lower limb deformity caused by chronic osteomyelitis. Case Presentations: Without surgical intervention for a prolonged period of time, the patient was admitted in our institute for corrective surgery. Corrective surgery consisted of three stages: lengthening with Ilizarov frame, removal of Ilizarov frame and fixation with externalized locking plate, and removal of externalized locking plate. Tibia bridging was achieved at the distal and proximal junction. The range of motion (ROM) of the knee joint was nearly normal, but the stiffness of the ankle joint was noticeable. The remaining leg discrepancy of 0.1 cm required no application of a shoe lift. Moreover, the patient could engage in daily activities without noted limping. Conclusions: Distraction-compression osteogenesis using the Ilizarov apparatus is a powerful tool to lengthen the shortened long bone and adjust the deformity of the lower limbs. Externalized locking plates provide an alternative to the traditional bulky external fixator, as its low profile makes it more acceptable to patients without compromising axial and torsional stiffness. In all, a combination of Ilizarov frame, externalized locking plate and tibia bridging is an alternative for patients in similar conditions.

Adverse events of bevacizumab for triple negative breast cancer and HER-2 negative metastatic breast cancer: A meta-analysis.

Background: Triple-negative breast cancer (TNBC) and HER-2 negative metastatic breast cancer (HER-2 negative MBC) are intractable to various treatment schemes. Bevacizumab as a novel anti-VEGF drug, its safety for these two high-risk breast cancers remains controversial. Therefore, we conducted this meta-analysis to assess the safety of Bevacizumab for TNBC and HER-2 negative MBC. Methods: We searched Medline, Embase, Web of science and Cochrane databases updated to 1 Oct 2022 for relevant randomized controlled trials (RCTs). In all, 18 RCTs articles with 12,664 female patients were included. We used any grade Adverse Events (AEs) and grade ≥3 AEs to assess the AEs of Bevacizumab. Results: Our study demonstrated that the application of Bevacizumab was associated with increased incidence of grade ≥3 AEs (RR = 1.37, 95% CI 1.30-1.45, Rate: 52.59% vs. 41.32%). Any grade AEs (RR = 1.06, 95% CI 1.04-1.08, Rate: 64.55% vs. 70.59%) did not show a significant statistical difference in both overall results and among the subgroups. In subgroup analysis, HER-2 negative MBC (RR = 1.57, 95% CI 1.41-1.75, Rate: 39.49% vs. 25.6%), dosage over 15 mg/3w (RR = 1.44, 95% CI 1.07-1.92, Rate: 28.67% vs. 19.93%) and endocrine therapy (ET) (RR = 2.32, 95% CI 1.73-3.12, Rate: 31.17% vs. 13.42%) were associated with higher risk of grade ≥3 AEs. Of all graded ≥3 AEs, proteinuria (RR = 9.22, 95%CI 4.49-18.93, Rate: 4.22% vs. 0.38%), mucosal inflammation (RR = 8.12, 95%CI 2.46-26.77, Rate: 3.49% vs. 0.43%), palmar-plantar erythrodysesthesia syndrome (RR = 6.95, 95%CI 2.47-19.57, Rate: 6.01% vs. 0.87%), increased Alanine aminotransferase (ALT) (RR = 6.95, 95%CI 1.59-30.38, Rate: 3.13% vs. 0.24%) and hypertension (RR = 4.94, 95%CI 3.84-6.35, Rate: 9.44% vs. 2.02%) had the top five risk ratios. Conclusion: The addition of Bevacizumab for TNBC and HER-2 negative MBC patients showed an increased incidence of AEs especially for grade ≥3 AEs. The risk of developing different AEs varies mostly dependent on the type of breast cancer and combined therapy. Systematic Review Registration: [https://www.crd.york.ac.uk/PROSPERO/#recordDetails], identifier [CRD42022354743].

Is abaloparatide more efficacious on increasing bone mineral density than teriparatide for women with postmenopausal osteoporosis? An updated meta-analysis.

PURPOSE: Osteoporosis poses a challenge to public health, causing fragility fractures, especially in postmenopausal women. Abaloparatide (ABL) is an effective anabolic agent to improve bone formation and resorption among postmenopausal women with osteoporosis. Our meta-analysis aims to assess the effectiveness and safety of ABL versus teriparatide (TPTD) in improving bone mineral density (BMD). METHODS: We searched Medline, Embase, Web of Science, Cochrane databases and Clinicaltrial.gov until September 2, 2022. We included data from randomized controlled trials (RCTs) and post hoc analyses of RCTs. Outcomes included BMD change from baseline and risks of adverse events. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) tool was used to evaluate the quality of outcomes. RESULTS: Four studies including 16 subgroups were included in this study. In particular, RCTs with head-to-head comparisons of ABL and TPTD were used in the meta-analysis, and all were from manufacturer-sponsored trials. All parameters in 24 weeks except lumbar spine (versus TPTD) showed significant advantages in the ABL group. Only the results of two subgroups in ABL versus TPTD demonstrated High GRADE quality (femoral neck: weighted mean difference (WMD) = 1.58 [0.52, 2.63]; Total hip: WMD = 1.46 [0.59, 2.32]). However, our fracture data were insufficient. Besides, we found no evident difference in serious adverse events or deaths in either group and the incidence of hypercalcemia in the ABL group lessened by 51% compared with the TPTD group. Nevertheless, compared with placebo, ABL demonstrated higher risks of nausea and palpitations. CONCLUSION: ABL demonstrated a beneficial effect on BMD compared to both placebo and TPTD for postmenopausal women with osteoporosis. ABL also had insignificantly lowered adverse event risk than TPTD. ABL is an alternative for patients with postmenopausal osteoporosis.

Efficacy and safety of platelet-rich plasma in the treatment of carpal tunnel syndrome: A network meta-analysis of different injection treatments.

Purpose: Carpal tunnel syndrome (CTS) is a common form of median nerve compression in the wrist caused by focal peripheral neuropathy. Platelet-rich plasma (PRP) therapy could improve the healing ability by exposing the injured tissues to high concentrations of autologous growth factors. Our study aims to compare all injective treatments for CTS and assess the efficacy and priority of PRP therapy. Methods: We searched Medline, Embase, Web of Science, Cochrane databases, and Clinicaltrial.gov until 17 October 2022. We only included data from randomized controlled trials (RCTs) that evaluated PRP injection therapy or drug injection therapy. The included RCTs measured at least one of the following three outcomes with validated instruments: in the visual analog scale (VAS), symptom severity scale (SSS), and functional status scale (FSS). Results: Overall, 19 studies with 1,066 patients were included in this study. We used the SUCRA rankings to determine the merits of various therapies. In all, 5% dextrose injections were the best treatment strategy for the VAS (MD -1.22, 95% CI -2.66 to 0.23; SUCRA = 79.2%), followed by triamcinolone (high-dose) injections (MD -0.69, 95% CI -2.11 to 0.73; SUCRA = 62.7%) and PRP injections (MD -0.39, 95% CI -1.67 to 0.89; SUCRA = 60.0%). In the SSS, the most effective intervention was hydroxyprogesterone injections (MD -0.62, 95% CI -1.09 to -0.16; SUCRA = 91.0%). The SUCRA ranking of PRP was second only to steroids and estrogen (MD -0.39, 95% CI -0.60 to -0.18; SUCRA = 60.8%). In the FSS, the best regimen strategy was hydroxyprogesterone injections (MD 0.12, 95% CI -0.30 to 0.54; SUCRA = 99.5%), followed by triamcinolone (low-dose) injections (MD -0.02, 95% CI -0.54 to 0.49; SUCRA = 87.4%) and PRP injections (MD -0.26, 95% CI -0.43 to -0.09; SUCRA = 77.1%). Conclusion: PRP is an alternative choice for CTS treatment. PRP injection is second only to steroids and estrogen in the treatment efficacy of CTS, with a wide indication and safe outcome.

Operative choice for subtrochanteric femoral fracture in school-aged children: Triple elastic stable intramedullary nail versus locking plate.

Background: The management strategy of subtrochanteric fractures remains controversial, and triple elastic stable intramedullary nail (ESIN) has not been reported for pediatric subtrochanteric fractures. This study aimed to compare the clinical effects of treating school-aged children with subtrochanteric fractures with triple ESINs versus locking plates. Methods: We conducted a retrospective review of pediatric patients with subtrochanteric femoral fracture receiving either triple ESINs (TE) or locking plates (LPs) between January 2010 and January 2018. Sixteen patients in each group with matched age, sex, and fracture characteristics were included in the study. The preoperative data, including baseline information of the patients, fracture pattern, and types of surgical procedure, were collected from the hospital database. Patients were followed-up at the outpatient clinic in the 3rd month, 6th month, 12th month, and annually afterward. Hardware removal was performed at 9 - 18 months after the primary surgery. Results: In all, 16 patients (8.4 ± 1.5-year-old, 7 boys, 9 girls) in the TE group and 16 patients (8.4 ± 1.4-year-old, 7 boys, 9 girls) in the LP group were included. There was significantly less operative time, reduced estimated blood loss, and shortened hospital stay for the TE as compared with the LP (P < 0.001). However, higher fluoroscopy frequency was observed in the TE group than in the LP group (P < 0.001). The time to union was faster in the TE group than in the LP group (P = 0.031). However, the angulation was higher in the TE group (3.2 ± 0.6) than the LP group (1.8 ± 0.5), and the incidence of implant prominence was higher in the TE group (7/16, 43.8%) than the LP group (1/16, 6.3%). Conclusion: Compared with the locking plates, triple ESINs demonstrated significantly less operative time, reduced estimated blood loss, and shortened hospital stay. Besides, both TE and LP groups produced satisfactory outcomes in school-aged children with subtrochanteric fractures. Therefore, TE remains a feasible choice for subtrochanteric fractures in school-aged children.

Plating versus elastic stable intramedullary nailing for displaced pediatric midshaft clavicular fractures.

INTRODUCTION: Traditionally, operative treatment for displaced midshaft clavicle fractures in adolescents has been achieved by using a plate and screws. However, a minimally invasive trend has led surgeons to use the elastic stable intramedullary nail (ESIN) for displaced midshaft clavicle fractures. This study aims to compare the clinical outcomes of adolescent patients who were operated on with an ESIN vs. a plate. METHODS: All patients aged between 10 and 14 years with displaced midshaft clavicle fractures who were operated on at our institute between January 2014 and January 2018 were reviewed retrospectively. The preoperative data, including baseline information on the patients, and types of surgical procedure were collected from the hospital database. The postoperative data, including clinical outcome and complications, were collected during the follow-up visits. Clinical outcome was evaluated during outpatient visits using the American Shoulder and Elbow Surgeons (ASES) score. The scar problem was evaluated according to the Scar Cosmesis Assessment and Rating (SCAR) scale. RESULTS: A total of 73 patients were included. Patients were categorized into two groups: ESIN (n = 45; 27 males, 18 females) and plate (n = 28; 17 males, 11 females), according to surgical technique. The average age of the patients in the ESIN group was 12.2 ± 1.5 years, and that in the plate group was 12.2 ± 1.4 years. The ESIN group presented significantly less operative time (31.1 vs. 59.8 min), a shorter hospital stay (1.5 vs. 2.5 days), and a smaller incision (2.4 vs. 5.4 cm) as compared to the plate group (P < .001). The rate of scar concern was much higher in the plate group (71.4%) than the ESIN group (22.2%) (P < .001). There was no statistically significant difference in shoulder function between the ESIN group and the plate group at different time points. CONCLUSION: A conservative approach remains the first choice for a pediatric clavicle fracture. Both the ESIN and the plate are safe and effective treatment methods for displaced midshaft clavicle fractures in adolescents. The ESIN is superior to the plate given its shorter operative time, shorter hospital stay, lower rate of scar concern, and easier implant removal. LEVEL OF EVIDENCE: III, retrospective observational study.

Perthes Disease in a Child With Osteogenesis Imperfecta From a Rare Genetic Variant: A Case Report.

Background: Although certain genetic components have been reported as contributing factors for Perthes disease, its etiology remains unclear. We present a rare case of Perthes disease in a child with osteogenesis imperfecta (OI) caused by a mutation in the COL1A1 gene (NM_000088):exon25:c.1726C>T, (p.Gln576X). Case presentations: A 7-year-old boy was initially treated at our medical facility in March 2016 with a history of chronic pain in right hip joint and limping for a year. He was diagnosed as Perthes disease in the right hip joint. He underwent acetabular osteotomy and ipsilateral proximal femoral varus osteotomy for better containment. During the follow-ups, the right hip demonstrated a normal range of motion without pain, and the pelvic X-ray demonstrated Stulberg Type II hip joint with a round femoral head. In the latest admission in 2022, he suffered from a right femoral shaft fracture after petty violence. After reviewing his medical history, he was suspected of having OI. The whole exome sequencing demonstrated a gene mutation in COL1A1 (OMIM 166200) and confirmed the diagnosis of OI. Telescopic nailing was used to treat the femoral shaft fracture. After the nailing of the right femur, the appearance of the lower extremity seemed normal and symmetrical. Conclusion: This study revealed that there might be an association between OI and Perthes disease. Our case report enriches the phenotypes of osteogenesis imperfecta and provides insight into the pathogenesis of LCPD.

Efficacy and Safety of Capecitabine for Triple-Negative Breast Cancer: A Meta-Analysis.

Background: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with limited treatment options and poor prognosis. Capecitabine, as a novel adjuvant chemotherapy for TNBCs, remains controversial. Therefore, we conducted this meta-analysis to assess the efficacy and safety of capecitabine for early-stage TNBCs combined with neo-/adjuvant chemotherapy. Methods: We searched Medline, Embase, Web of Science, and Cochrane databases updated on Mar 18, 2022 for relevant RCTs. In all, 11 RCTs with 5,175 patients were included. We used hazard ratios (HRs) and odds ratios (ORs) to assess the differences between disease-free survival (DFS), overall survival (OS), and adverse events. Results: Our study demonstrated significance differences in both DFS and OS (DFS: HR=0.77; 95% CI 0.68-0.86; OS: HR=0.73, 95% CI 0.63-0.85). In subgroup analysis, the lower dosage group showed higher DFS (HR=0.79, 95% CI 0.69-0.91), higher frequency (HR=0.72, 95%CI 0.62-0.83), and adjuvant chemotherapy (HR=0.74, 95% CI 0.65-0.84). However, capecitabine was also associated with a higher risk of diarrhea (OR=3.10, 95% CI 2.32-4.15), hand-foot syndrome (OR=25.79, 95% CI 15.32-43.42), and leukopenia (OR=2.08, 95% CI 1.13-3.84). Conclusion: The addition of capecitabine to early-stage TNBC patients receiving standard adjuvant chemotherapy showed significant DFS and OS improvement with tolerable adverse events. The lower dosage and higher frequency of capecitabine combined with adjuvant chemotherapy demonstrated a better survival outcome.

Intranasal inoculation of an MVA-based vaccine induces IgA and protects the respiratory tract of hACE2 mice from SARS-CoV-2 infection.

Current vaccines have greatly diminished the severity of the COVID-19 pandemic, even though they do not entirely prevent infection and transmission, likely due to insufficient immunity in the upper respiratory tract. Here, we compare intramuscular and intranasal administration of a live, replication-deficient modified vaccinia virus Ankara (MVA)-based Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) spike (S) vaccine to raise protective immune responses in the K18-hACE2 mouse model. Using a recombinant MVA expressing firefly luciferase for tracking, live imaging revealed luminescence of the respiratory tract of mice within 6 h and persisting for 3 d following intranasal inoculation, whereas luminescence remained at the site of intramuscular vaccination. Intramuscular vaccination induced S-binding-Immunoglobulin G (IgG) and neutralizing antibodies in the lungs, whereas intranasal vaccination also induced Immunoglobulin A (IgA) and higher levels of antigen-specific CD3+CD8+IFN-γ+ T cells. Similarly, IgG and neutralizing antibodies were present in the blood of mice immunized intranasally and intramuscularly, but IgA was detected only after intranasal inoculation. Intranasal boosting increased IgA after intranasal or intramuscular priming. While intramuscular vaccination prevented morbidity and cleared SARS-CoV-2 from the respiratory tract within several days after challenge, intranasal vaccination was more effective as neither infectious virus nor viral messenger (m)RNAs were detected in the nasal turbinates or lungs as early as 2 d after challenge, indicating prevention or rapid elimination of SARS-CoV-2 infection. Additionally, we determined that neutralizing antibody persisted for more than 6 mo and that serum induced to the Wuhan S protein neutralized pseudoviruses expressing the S proteins of variants, although with less potency, particularly for Beta and Omicron.

Does Tranexamic Acid Reduce the Blood Loss in Various Surgeries? An Umbrella Review of State-of-the-Art Meta-Analysis.

Background: Tranexamic acid (TXA) has been applied in various types of surgery for hemostasis purposes. The efficacy and safety of TXA are still controversial in different surgeries. Guidelines for clinical application of TXA are needed. Materials and method: We systematically searched multiple medical databases for meta-analyses examining the efficacy and safety of TXA. Types of surgery included joint replacement surgery, other orthopedic surgeries, cardiac surgery, cerebral surgery, etc. Outcomes were blood loss, blood transfusion, adverse events, re-operation rate, operative time and length of hospital stay, hemoglobin (Hb) level, and coagulation function. Assessing the methodological quality of systematic reviews 2 (AMSTAR 2) and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) were used for quality assessment of the included meta-analyses. Overlapping reviews were evaluated by calculating the corrected covered area (CCA). Result: In all, we identified 47 meta-analyses, of which 44 of them were of "high" quality. A total of 319 outcomes were evaluated, in which 58 outcomes were assessed as "high" quality. TXA demonstrates significant hemostatic effects in various surgeries, with lower rates of blood transfusion and re-operation, shorter operative time and length of stay, and higher Hb levels. Besides, TXA does not increase the risk of death and vascular adverse events, but it is a risk factor for seizure (a neurological event) in cardiac surgery. Conclusion: Our study demonstrates that TXA has a general hemostatic effect with very few adverse events, which indicates TXA is the recommended medication to prevent excessive bleeding and reduce the blood transfusion rate. We also recommend different dosages of TXA for different types of adult surgery. However, we could not recommend a unified dosage for different surgeries due to the heterogeneity of the experimental design. Systematic Review Registration: clinicaltrials.gov/, identifier CRD42021240303.

Is Early Surgical Intervention Necessary for Acute Neonatal Humeral Epiphyseal Osteomyelitis: A Retrospective Study of 31 Patients.

Objective: To review the treatment experience of neonatal humeral epiphyseal osteomyelitis retrospectively. Study design: Retrospective cohort study of infants with neonatal humeral epiphyseal osteomyelitis. Patients were divided into conservative group and surgical group, and the surgical group was subdivided into early and delayed surgical group. Results: In total, there were 7 patients in the conservative group and 24 in the surgical group. The length of hospital stay and intravenous course of antibiotic therapy were both significantly shorter in the surgical group (p < 0.001). The full recovery rate was also higher in the surgical group (83.3%) than the conservative group (14.3%) (p < 0.001). Early surgery group (n = 14) had an insignificantly higher positive rate of pus/aspirate culture and full recovery rate than delayed surgery group (n = 10). Conclusion: Surgical treatment for neonatal humeral epiphyseal osteomyelitis demonstrated significantly higher rates of positive culture for the pathogen, a shorter course of intravenous oral antibiotics, and lower incidence of growth abnormality than conservative treatment. In our institution, most of culture outcome Gram-positive bacteria, and early surgical treatment was recommended with better outcome than delayed surgical group. Empirical antibiotics should be tailored to the epidemiological characteristics of local virulent bacteria.

Interferon α/ß Decoy Receptor Encoded by a Variant in the Dryvax Smallpox Vaccine Contributes to Virulence and Correlates with Severe Vaccine Side Effects.

Although providing long-lasting immunity, smallpox vaccination was associated with local and systemic reactions and rarely with severe complications, including progressive vaccinia and postvaccinia encephalitis. As the Dryvax smallpox vaccine consists of a population of variants, we investigated a particularly pathogenic isolate called clone 3 (CL3). Virus replication was monitored by inserting the gene encoding firefly luciferase (Luc) into the genomes of CL3 and ACAM2000, the second-generation smallpox vaccine derived from a less virulent clone. Greater luminescence occurred following intranasal or intraperitoneal inoculation of mice with CL3-Luc than ACAM2000-Luc. Previous genome sequencing of CL3 and ACAM2000 revealed numerous differences that could affect pathogenicity. We focused on a 4.2-kbp segment, containing several open reading frames, in CL3 that is absent from ACAM2000 and determined that lower virulence of the latter was associated with a truncation of the interferon α/ß (IFN-α/ß) decoy receptor. Truncation of the decoy receptor in CL3-Luc and repair of the truncated version in ACAM2000-Luc decreased and increased virulence, respectively. Blockade of the mouse type 1 IFN receptor increased the virulence of ACAM2000-Luc to that of CL3-Luc, consistent with the role of IFN in attenuating the former. The severities of disease following intracranial inoculation of immunocompetent mice and intraperitoneal inoculation of T cell-depleted mice were also greater in viruses expressing the full-length decoy receptor. Previous evidence for the low affinity of a similarly truncated decoy receptor for IFN and the presence of a full-length decoy receptor in virus isolated from a patient with progressive vaccinia support our findings. IMPORTANCE Attenuated live viruses make effective vaccines, although concerns exist due to infrequent complications, particularly in individuals with immunological defects. Such complications occurred with smallpox vaccines, which were shown to be comprised of populations of variants. Clone 3, isolated from Dryvax, the vaccine most widely used in the United States during the smallpox eradication campaign, was particularly pathogenic in animal models. We demonstrated that the full-length IFN-α/ß decoy receptor in CL3 and a truncation of the receptor in the clone used for the second-generation smallpox vaccine ACAM2000 account for their difference in pathogenicity. Viruses expressing the full-length decoy receptor were more virulent following intranasal, intraperitoneal, or intracranial inoculation of mice than ACAM2000, and disease was exacerbated following T cell depletion. Correspondingly, the full-length decoy receptor is present in smallpox vaccines with high rates of side effects and in a Dryvax clone obtained from a lesion in a patient with progressive vaccinia.

Glenohumeral joint dislocation is rare in children with proximal humeral fractures: a descriptive study and literature review.

BACKGROUND: Glenohumeral dislocation combined with fracture of the proximal humerus is extremely rare in children, and this study aims to investigate its incidence in the pediatric population and review the treatment strategy for this condition. METHODS: Between Jan 2014 and Jan 2019, 280 patients with unilateral proximal humeral fractures were retrospectively reviewed. Imaging and follow-up notes were reviewed for patients with a predilection for glenohumeral joint dislocation. Six (2.14%) patients between the ages of 5 and 10 years were confirmed as glenohumeral joint dislocation and included in the study. All these patients underwent closed reduction and external fixation under general anesthesia. RESULTS: Out of 280 patients with proximal humeral fractures, only 6 patients, including 4 males and 2 females, were confirmed as glenohumeral joint dislocation. ROM was normal compared with the contralateral shoulder in every patient at the last follow-up. There was no case of radiological abnormality, including avascular necrosis or devascularization of the humeral head. CONCLUSIONS: Glenohumeral dislocation is a rare entity associated with the proximal humerus fracture in children, with an overall incidence in our case series was 2.14%. Reduction and stabilization of such injury using an external fixator is a suitable choice for pediatric patients that failed closed reduction.