ATG-101 Is a Tetravalent PD-L1×4-1BB Bispecific Antibody That Stimulates Antitumor Immunity through PD-L1 Blockade and PD-L1-Directed 4-1BB Activation.

Immune checkpoint inhibitors (ICI) have transformed cancer treatment. However, only a minority of patients achieve a profound response. Many patients are innately resistant while others acquire resistance to ICIs. Furthermore, hepatotoxicity and suboptimal efficacy have hampered the clinical development of agonists of 4-1BB, a promising immune-stimulating target. To effectively target 4-1BB and treat diseases resistant to ICIs, we engineered ATG-101, a tetravalent "2+2″ PD-L1×4-1BB bispecific antibody. ATG-101 bound PD-L1 and 4-1BB concurrently, with a greater affinity for PD-L1, and potently activated 4-1BB+ T cells when cross-linked with PD-L1-positive cells. ATG-101 activated exhausted T cells upon PD-L1 binding, indicating a possible role in reversing T-cell dysfunction. ATG-101 displayed potent antitumor activity in numerous in vivo tumor models, including those resistant or refractory to ICIs. ATG-101 greatly increased the proliferation of CD8+ T cells, the infiltration of effector memory T cells, and the ratio of CD8+ T/regulatory T cells in the tumor microenvironment (TME), rendering an immunologically "cold" tumor "hot." Comprehensive characterization of the TME after ATG-101 treatment using single-cell RNA sequencing further revealed an altered immune landscape that reflected increased antitumor immunity. ATG-101 was well tolerated and did not induce hepatotoxicity in non-human primates. According to computational semimechanistic pharmacology modeling, 4-1BB/ATG-101/PD-L1 trimer formation and PD-L1 receptor occupancy were both maximized at around 2 mg/kg of ATG-101, providing guidance regarding the optimal biological dose for clinical trials. In summary, by localizing to PD-L1-rich microenvironments and activating 4-1BB+ immune cells in a PD-L1 cross-linking-dependent manner, ATG-101 safely inhibits growth of ICI resistant and refractory tumors. SIGNIFICANCE: The tetravalent PD-L1×4-1BB bispecific antibody ATG-101 activates 4-1BB+ T cells in a PD-L1 cross-linking-dependent manner, minimizing the hepatotoxicity of existing 4-1BB agonists and suppressing growth of ICI-resistant tumors. See related commentary by Ha et al., p. 1546.

[Effectiveness of preemptive analgesia with imrecoxib on analgesia after anterior cruciate ligament reconstruction: a randomized controlled study].

Objective: To investigate the effectiveness of preemptive analgesia with imrecoxib on analgesia after anterior cruciate ligament (ACL) reconstruction. Methods: A total of 160 patients with ACL injuries who met the selection criteria and were admitted between November 2020 and August 2021 were selected and divided into 4 groups according to the random number table method (n=40). Group A began to take imrecoxib 3 days before operation (100 mg/time, 2 times/day); group B began to take imrecoxib 1 day before operation (100 mg/time, 2 times/day); group C took 200 mg of imrecoxib 2 hours before operation (5 mL of water); and group D did not take any analgesic drugs before operation. There was no significant difference in gender, age, body mass index, constituent ratio of meniscal injuries with preoperative MRI grade 3, constituent ratio of cartilage injury Outerbridge grade 3, and visual analogue scale (VAS) score at the time of injury and at rest among 4 groups (P>0.05). The operation time, hospitalization stay, constituent ratio of perioperative American Society of Anesthesiologists (ASA) grade 1, postoperative opioid dosage, and complications were recorded. The VAS scores were used to evaluate the degree of knee joint pain, including resting VAS scores before operation and at 6, 24, 48 hours, and 1, 3, 6, and 12 months after operation, and walking, knee flexion, and night VAS scores at 1, 3, 6, and 12 months after operation. The knee injury and osteoarthritis score (KOOS) was used to evaluate postoperative quality of life and knee-related symptoms of patients, mainly including pain, symptoms, daily activities, sports and entertainment functions, knee-related quality of life (QOL); and the Lysholm score was used to evaluate knee joint function. Results: All patients were followed up 1 year. There was no significant difference in operation time, hospitalization time, or constituent ratio of perioperative ASA grade 1 among 4 groups (P>0.05); the dosage of opioids in groups A-C was significantly less than that in group D (P<0.05). Except for 1 case of postoperative fever in group B, no complications such as joint infection, deep vein thrombosis of the lower extremities, or knee joint instability occurred in each group. The resting VAS scores of groups A-C at 6 and 24 hours after operation were lower than those of group D, and the score of group A at 6 hours after operation was lower than those of group C, and the differences were significant (P<0.05). At 1 month after operation, the knee flexion VAS scores of groups A-C were lower than those of group D, the walking VAS scores of groups A and B were lower than those of groups C and D, the differences were significant (P<0.05). At 1 month after operation, the KOOS pain scores in groups A-C were higher than those in group D, there was significant difference between groups A, B and group D (P<0.05); the KOOS QOL scores in groups A-C were higher than that in group D, all showing significant differences (P<0.05), but there was no significant difference between groups A-C (P>0.05). There was no significant difference in VAS scores and KOOS scores between the groups at other time points (P>0.05). And there was no significant difference in Lysholm scores between the groups at 1, 3, 6, and 12 months after operation (P>0.05). Conclusion: Compared with the traditional analgesic scheme, applying the concept of preemptive analgesia with imrecoxib to manage the perioperative pain of ACL reconstruction can effectively reduce the early postoperative pain, reduce the dosage of opioids, and promote the early recovery of limb function.

Lithium Salt Dissociation Promoted by 18-Crown-6 Ether Additive toward Dilute Electrolytes for High Performance Lithium Oxygen Batteries.

Lithium-oxygen batteries (LOBs) are well known for their high energy density. However, their reversibility and rate performance are challenged due to the sluggish oxygen reduction/evolution reactions (ORR/OER) kinetics, serious side reactions and uncontrollable Li dendrite growth. The electrolyte plays a key role in transport of Li+ and reactive oxygen species in LOBs. Here, we tailored a dilute electrolyte by screening suitable crown ether additives to promote lithium salt dissociation and Li+ solvation through electrostatic interaction. The electrolyte containing 100 mM 18-crown-6 ether (100-18C6) exhibits enhanced electrochemical stability and triggers a solution-mediated Li2 O2 growth pathway in LOBs, showing high discharge capacity of 10 828.8 mAh gcarbon -1 . Moreover, optimized electrode/electrolyte interfaces promote ORR/OER kinetics on cathode and achieve dendrite-free Li anode, which enhances the cycle life. This work casts new lights on the design of low-cost dilute electrolytes for high performance LOBs.

Is Ankle Arthrodesis With an Ilizarov External Fixator an Effective Treatment for Septic Ankle Arthritis? A Study With a Minimum of 6 Years of Follow-up.

BACKGROUND: Septic ankle arthritis is a devastating clinical problem with a high potential for permanent disability and amputation. Successful treatment of septic ankle arthritis remains a challenge for the surgeon and patient. Ankle arthrodesis combined with radical debridement may be an effective option to eradicate infection and salvage the limb. Although numerous fusion methods have been proposed, there is controversy about the most effective technique. QUESTIONS/PURPOSES: At a minimum follow-up of 6 years after ankle arthrodesis performed using an Ilizarov external fixator, we asked, (1) In what proportion of patients was bony fusion achieved? (2) What complications were observed, and what reoperations were performed in these patients? (3) How much did patient-reported outcomes improve from before surgery to the most recent follow-up in this group? METHODS: Between April 2010 to March 2015, we treated 59 patients for septic ankle arthritis. Of those, we considered patients who were at least 18 years of age with irreversible destruction of the joint as potentially eligible. During that time period, all patients met the prespecified criteria and were treated with ankle arthrodesis using an Ilizarov external fixator. Two percent (one of 59) of patients were excluded because they died in the second year after surgery for reasons unrelated to the procedure, and another 7% (four of 59) of patients were excluded because they were lost before the minimum study follow-up interval of 6 years. Finally, 92% (54 of 59) of patients were analyzed at a mean follow-up time of 9 ± 1 years. A total of 61% (33 of 54) were men, and they had a mean age of 48 ± 12 years. Forty-six percent (25 of 54) of patients were smokers, and 13% (seven of 54) of patients had Type 2 diabetes mellitus. All patients received radical debridement and primary arthrodesis with an Ilizarov external fixator, followed by antibiotic therapy. Postoperatively, patients were instructed to perform lower extremity functional exercises and external fixator care; weightbearing ambulation as tolerated was encouraged as early as possible. Fusion was assessed with a radiographic review that was performed by an individual who was not involved in the surgical care of these patients. We defined bony fusion as continuous trabeculae and complete cortical bridging in the fusion interface achieved before 9 months; delayed union was defined as fusion achieved by 9 to 12 months; and nonunion was defined as patients in whom fusion was not achieved by 12 months. Complications and reoperations were tallied through a record review that was performed by an individual who was not involved in the surgical care of these patients. We defined complications as any deviation from the expected postoperative course. We used the American Orthopedic Foot and Ankle Society (AOFAS) ankle-hindfoot score, the VAS active pain score, and the SF-12 questionnaire (including the physical component summary [PCS] score and mental component summary [MCS] score) to assess patient-reported outcomes. The minimum clinically important difference (MCID) for the AOFAS score was 30 points of 100, the MCID for the VAS active pain score was 2 points of 10, and the MCID of PCS and MCS scores was 7 points and 9 points, respectively. RESULTS: Primary bony fusion was achieved in 94% (51 of 54) of patients. Delayed union was found in 2% (one of 54) of patients. Nonunion was found in 6% (three of 54); one of these patients underwent autologous bone grafting during revision, and bony fusion was ultimately achieved. Final bony fusion was achieved in 96% (52 of 54) of patients. Recurrent infection was found in 2% (one of 54). The median (range) AOFAS score improved from 28 points (8 to 59) before surgery to 80 points (52 to 86) at the most recent follow-up (median difference 52; p < 0.001). The median (range) VAS active pain score decreased from 8 points (6 to 9) before surgery to 2 points (0 to 5) at the most recent follow-up (median difference -6; p < 0.001). For the Short Form 12-item score, the median (range) PCS score improved from 0 points (0 to 30) before surgery to 70 points (40 to 95) at the most recent follow-up (median difference 70; p < 0.001), and the median (range) MCS score improved from 46 points (21 to 75) before surgery to 75 points (50 to 92) at the most recent follow-up (median difference 29; p < 0.001). CONCLUSION: Ankle arthrodesis with Ilizarov external fixation might eradicate an infection and restore foot function in patients with septic ankle arthritis. However, patients should be fully informed of the complications related to the external fixator, such as pin-tract infections, recurrent infection, and nonunion. Standardized and professional pin care is important. Additionally, because Ilizarov external fixators can be inconvenient to the patients' daily lives, future studies should explore how psychologic support affects patients who undergo ankle arthrodesis with these devices. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Development of a bispecific antibody targeting PD-L1 and TIGIT with optimal cytotoxicity.

Programmed death-ligand 1 (PD-L1) and T cell immunoreceptor with Ig and ITIM domains (TIGIT) are two potential targets for cancer immunotherapy, early clinical studies showed the combination therapy of anti-PD-L1 and anti-TIGIT had synergistic efficacy both in the terms of overall response rate (ORR) and overall survival (OS). It is rational to construct bispecific antibodies targeting PD-L1 and TIGIT, besides retaining the efficacy of the combination therapy, bispecific antibodies (BsAbs) can provide a new mechanism of action, such as bridging between tumor cells and T/NK cells. Here, we developed an IgG1-type bispecific antibody with optimal cytotoxicity. In this study, we thoroughly investigated 16 IgG-VHH formats with variable orientations and linker lengths, the results demonstrated that (G4S)2 linker not only properly separated two binding domains but also had the highest protein yield. Moreover, VHH-HC orientation perfectly maintained the binding and cytotoxicity activity of the variable domain of the heavy chain of heavy-chain-only antibody (VHH) and immunoglobulin G (IgG). Following treatment with BiPT-23, tumor growth was significantly suppressed in vivo, with more cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells infiltration, and selective depletion of Regulatory T cells (Tregs). BiPT-23 represents novel immunotherapy engineered to prevent hyperprogression of cancer with PD-1 blockade, and preferentially killed PD-L1+ tumor cells, and TIGIT+ Tregs but maintained CD11b+F4/80+ immune cells within the tumor microenvironment (TME).

Management of Elderly Traumatic Ankle Arthritis with Ilizarov External Fixation.

OBJECTIVE: To evaluate the clinical curative effect of Ilizarov external fixation and ankle arthrodesis in the treatment of elderly traumatic ankle arthritis. METHODS: From June 2013 to August 2019, 72 patients with elderly traumatic ankle arthritis were treated with arthrodesis through Ilizarov external fixation technique in our institution. Conventional double-feet standing X-ray films were taken before and after operation. The tibiotalar angle on X-ray image was measured to evaluate the degree of talipes varus and valgus. The Foot and Ankle pain score of American Orthopaedics Foot and Ankle Society (AOFAS) and Visual Analog Scale (VAS) were compared by using paired t-test to evaluate the functional recovery. RESULTS: All of the patients acquired effective postoperative 18-49 months follow-up, with an average of 31.5 months. All patients were included in the analysis, among which 38 cases were males and 34 cases were females, with an average of 65.4 years (ranging from 60 to 74). All ankles achieved bony fusion; the clinical healing time was 12.7 weeks on average (11-18 weeks). The AOFAS score was 45.36 ± 6.43 preoperatively and 80.25 ± 9.16 at 12 months post-operation, with a statistically significant difference (p < 0.0001). The VAS score was 8.56 ± 1.85 on average preoperatively and 2.72 ± 0.83 at 12 months post-operation, with a statistically significant difference (p < 0.0001). The tibiotalar angle was 101.93° ± 4.12° preoperatively and 94.45° ± 2.37° at 12 months post-operation, with a statistically significant difference (p < 0.0001). The results of the functional evaluation indicated that 44 patients (61.1%) had excellent results, 18 (25%) had good results, and 10 (13.9%) had fair results. CONCLUSION: Our study demonstrated that it is possible to obtain satisfactory outcome with Ilizarov external fixation and ankle arthrodesis in the treatment of elderly traumatic ankle arthritis.

Effectiveness of Ilizarov Ankle Arthrodesis in the Treatment of End-Stage Varus Ankle Osteoarthritis: A Retrospective Study.

OBJECTIVE: To evaluate the outcomes of Ilizarov ankle arthrodesis in the treatment of end-stage varus ankle osteoarthritis (OA). METHODS: This was a retrospective study of 63 patients with varus ankle OA who underwent Ilizarov ankle arthrodesis between June 2013 and December 2018. There were 24 males and 39 females with an average age of 56.57 ± 4.45 years (range, 47-64 years). Thirty-six cases were affected on the left side, and 27 were affected on the right side. The patients' mean body mass index (BMI) was 25.18 ± 2.93 kg/m2 . According to the modified Takakura staging criteria, there were 18 cases of stage 3b (28.57%) and 45 cases of stage 4 (71.43%). Nine patients were primary (14.29%), 48 were traumatic (76.19%), and six were caused by rheumatoid OA (9.52%). Functional assessments were performed according to the American Orthopedic Foot and Ankle Society (AOFAS) ankle-hindfoot score, Ankle Osteoarthritis Scale (AOS), and visual analogue scale (VAS). The tibial anterior surface angle (TAS), coronal plane tibial-talar angle (CPT), talar tilt angle (TT), deformity angle (DA), and tibial lateral surface angle (TLS) were assessed on X-ray films. RESULTS: The average operation time was 147.84 ± 13.67 min (range, 135-168 min). The average follow-up time was 34.24 ± 8.72 months (range, 24-61 months). Bony fusion was achieved in all ankles, and the fusion time was 12.43 ± 1.99 weeks on average. The average AOFAS score at the final follow-up increased from 42.14 ± 8.66 to 80.90 ± 6.80. The average VAS score and AOS pain and disability scores at the final follow-up decreased from 7.29 ± 1.27 to 2.24 ± 0.94, from 67.94 ± 7.68 to 27.92 ± 5.82, and from 71.64 ± 9.37 to 41.32 ± 8.99, respectively. The average TAS, CPT, and TLS at the final follow-up increased from 77.76° ± 4.44° to 89.81° ± 1.25°, from 69.04° ± 3.73° to 90.43° ± 1.80°, and from 82.14° ± 3.77° to 88.67° ± 2.50°, respectively. The average TT and DA at the final follow-up decreased from 8.76° ± 4.30° to 2.05° ± 1.28° and from 20.95° ± 3.73° to 1.57° ± 0.93°, respectively. Three patients developed superficial pin tract infections, all settled with local dressing and antibiotic treatment. Two patients were found to have subtalar arthritis and underwent conservative treatment. CONCLUSION: Ankle arthrodesis using the Ilizarov technique is efficient in treating end-stage varus ankle OA.

Evolution and Development of Ilizarov Technique in the Treatment of Infected Long Bone Nonunion with or without Bone Defects.

The treatment of infected bone nonunion and bone defects is a considerable challenge in the orthopedics field. The standard clinical therapy methods include local free bone transplantation, vascularized bone graft, and the Ilizarov technique; the first two are controversial due to the iatrogenic self-injury. The Ilizarov bone transport technique has been widely used to treat infected bone nonunion and bone defects, and good clinical effect has been demonstrated. Yet, it brings many related complications, which exerts additional suffering to the patient. The best treatment is to combine bone defect rehabilitation with infection control, intramedullary nail fixation, appropriate time for bone grafts, beaded type scaffold slippage and new Taylor fixation, reducing the external fixation time and the incidence of complications, thereby reducing the occurrence of patients' physical and psychological problems. This review focuses on the induction, summary and analysis of the Ilizarov bone transport technique in the treatment of infected long bone nonunion with or without bone defects, providing new ideas and methods for orthopedic disease prevention and treatment by the Ilizarov technique, which is following the development direction of digital orthopedics.

Porous copper- and lithium-doped nano-hydroxyapatite composite scaffold promotes angiogenesis and bone regeneration in the repair of glucocorticoids-induced osteonecrosis of the femoral head.

Glucocorticoids-induced osteonecrosis of the femoral head (GIONFH) is a common refractory disease. In the present study, we aimed to synthesize the nano-hydroxyapatite-copper-lithium (Cu-Li-nHA) composite porous scaffold to promote osteogenesis and angiogenesis functions to repair GIONFH by regulating the Wnt/ß-catenin and HIF-1α/VEGF pathways. The physicochemical property of the scaffold was characterized and their osteogenic and angiogenic effects were tested through a serial of experimentsin vitroandin vivo. Results showed that 0.25% Cu-Li-nHA scaffolds possessed the highest mechanical and biocompatibilityin vitro. Then the 0.25% Cu-Li-nHA scaffolds significantly enhanced the new bone formation on defects in GIONFH rabbitsin vivo. Moreover, the scaffold could increase the expression of osteogenic and angiogenic factors along with the activation of factors in Wnt/ß-catenin and HIF-1α/VEGF pathwaysin vitroandin vivo. In conclusion, the 0.25% Cu-Li-nHA scaffold could improve the osteogenesis and angiogenesis by upregulating the Wnt/ß-catenin and HIF-1α/VEGF pathways which benefited to repair the GIONFH in rabbit models.

Synergistic antitumor effect of the anti-ErbB2 antibodies trastuzumab and H2-18 on trastuzumab-resistant gastric cancer cells.

Trastuzumab resistance is a severe problem in the treatment of ErbB2-amplified cancer. Although trastuzumab plus pertuzumab is able to partly overcome trastuzumab resistance in ErbB2-overexpressing cancer, its antitumor efficacy remains limited. The present study investigated the antitumor activity of the combination of trastuzumab with H2-18, which is an antibody targetinsg ErbB2 domain I. Cell proliferation and inhibition experiments indicated that H2-18 and trastuzumab synergistically inhibited the proliferation of both the trastuzumab-sensitive gastric cancer cell line, NCI-N87 and the trastuzumab-resistant gastric cancer cell line, NCI-N87-TraRT. Furthermore, H2-18 plus trastuzumab inhibited the growth of NCI-N87-TraRT cells more effectively than trastuzumab plus pertuzumab, both in vitro and in vivo. Compared with trastuzumab plus pertuzumab, H2-18 plus trastuzumab had a potent ability to inhibit NCI-N87-TraRT cells to form colonies. Notably, H2-18 plus trastuzumab was more effective in inducing cell death than trastuzumab plus pertuzumab. The in vivo studies demonstrated that H2-18 plus trastuzumab effectively inhibited the growth of both NCI-N87 and NCI-N87-TraRT xenograft tumors. Further experiments revealed that in NCI-N87-TraRT cells, H2-18 plus trastuzumab was comparable to trastuzumab plus pertuzumab in the inhibition of phosphorylated (p-)HER3, p-AKT and p-ERK. However, compared with trastuzumab plus pertuzumab, H2-18 plus trastuzumab effectively activated ROS production and the phosphorylation of JNK and c-jun in NCI-N87-TraRT cells. Therefore, the superior antitumor efficacy of H2-18 plus trastuzumab over trastuzumab plus pertuzumab may be mainly attributable to the potent cell death-inducing activity. In addition, the in vitro and in vivo antitumor effect of the combination of H2-18, trastuzumab and pertuzumab were further investigated. The results revealed that H2-18 plus trastuzumab plus pertuzumab exhibited a maximal antitumor effect among all the anti-ErbB2 monoclonal antibody combinations tested. In summary, H2-18 plus trastuzumab may have potential as an effective strategy to overcome the resistance to trastuzumab in ErbB2-amplified gastric cancer cell lines.

Transarticular external fixation versus deltoid ligament repair in treating SER IV ankle fractures: a comparative study.

BACKGROUND: The topic that whether the injured deltoid ligament should be repaired when associated with ankle joint fractures is still discussed. The objective of this study was to compare the clinical effect of open reduction and internal fixation (ORIF) with deltoid ligament repair (DLR) or transarticular external fixation (TEF) in treating supination-external rotation type IV (SER IV) ankle fractures. METHODS: Between January 2012 and December 2015, 43 patients were diagnosed as SER IV ankle fractures, 20 underwent ORIF and transarticular external fixation (TEF) without DLR (group 1), 23 were treated with ORIF and DLR (group 2). The pre- and post-operative radiographic examination were performed, the American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot score, the visual analog scale (VAS), the Medical Outcomes Short Form 36-item questionnaire score (SF-36), and the ankle range of motion (ROM) were used for functional evaluation. RESULTS: In both groups, the three scores improved significantly after surgery, but there was no significant difference between the two groups. At 6 weeks after surgery, patients in group 2 had better ankle ROM than group 1 (29.35 ± 2.033 vs. 40.35 ± 3.550, P <  0.001), but there was no difference at 12 months postoperatively. No cases of bone nonunion or post-traumatic arthritic changes were seen during the follow-up. Patients in group 1 required a shorter time to achieve fracture union than patients in group 2. CONCLUSIONS: ORIF with TIF is an optional strategy to manage SER IV ankle fractures as it achieves comparable functional results to ORIF with DLR. It also allows patients to start relatively earlier weight-bearing and may promote fracture union.

Mobilization of Transplanted Bone Marrow Mesenchymal Stem Cells by Erythropoietin Facilitates the Reconstruction of Segmental Bone Defect.

Reconstruction of segmental bone defects poses a tremendous challenge for both orthopedic clinicians and scientists, since bone rehabilitation is requisite substantially and may be beyond the capacity of self-healing. Bone marrow mesenchymal stem cells (BMSCs) have been identified as an optimal progenitor cell source to facilitate bone repair since they have a higher ability for proliferation and are more easily accessible than mature osteoblastic cells. In spite of the potential of BMSCs in regeneration medicine, particularly for bone reconstruction, noteworthy limitations still remain in previous application of BMSCs, including the amount of cells that could be recruited, the compromised bone migration of grafted cells, reduced proliferation and osteoblastic differentiation ability, and likely tumorigenesis. Our current work demonstrates that BMSCs transplanted through the caudal vein can be mobilized by erythropoietin (EPO) to the bone defect area and participate in regeneration of new bone. Based on the histological analysis and micro-CT findings of this study, EPO can dramatically promote the effects on the osteogenesis and angiogenesis efficiency of BMSCs in vivo. Animals that underwent EPO+BMSC administration demonstrated a remarkable increase in new bone formation, tissue structure organization, new vessel density, callus formation, and bone mineral density (BMD) compared with the BMSCs alone and control groups. At the biomechanical level, we demonstrated that combing transplantation of EPO and BMSCs enhances bone defect reconstruction by increasing the strength of the diaphysis, making it less fragile. Therefore, combination therapy using EPO infusion and BMSC transplantation may be a new therapeutic strategy for the reconstruction of segmental bone defect.

Comparison of the modified Heuter approach and the Kocher-Langenbeck approach in the treatment of Pipkin type I and type II femoral head fractures.

PURPOSE: To evaluate and compare the effectiveness of the modified Heuter approach and the Kocher-Langenbeck approach in the treatment of Pipkin type I and II femoral head fractures. METHODS: The study cohort consisted of 39 patients with Pipkin type I or type II femoral head fractures who were treated by open reduction and internal fixation through the modified Heuter approach (the Heuter group) or the Kocher-Langenbeck approach (the K-L group) between June 2013 and January 2016. Standard radiographs and computed tomography (CT) scans were obtained before surgery and during the follow-up. The two approaches were compared in reference to operative time, amount of blood loss, the occurrence of complications, and final functional outcome. The Brooker classification was used to document heterotopic ossification and the Thompson-Epstein scores were used for final evaluation. RESULTS: The mean operative time and estimated blood loss in the Heuter group were lower than those in the K-L group (P < 0.001 for both measures). The incisions healed primarily in all patients after surgery, no infection or deep venous thromboses were detected in either group, post-operative imaging data showed that dislocation and fractures were reduced, and the fractures finally achieved bony union. There were no significant differences in the incidence of complications or final functional outcomes between the two groups. CONCLUSIONS: Compared with the Kocher-Langenbeck approach, the modified Heuter approach can effectively reduce the blood loss and operative time without increasing the risk of complications; this approach is simple, straightforward, and atraumatic and may be a viable option for open reduction and internal fixation of Pipkin type I and type II femoral head fractures.

Effect of Traditional Chinese Medicine plus narrow-band medium-wave ultraviolet B radiation on moderate-to-severe psoriasis vulgaris in a case series.

OBJECTIVE: To investigate the efficacy and safety of Traditional Chinese Medicine (TCM) therapy combined with ultraviolet B light therapy in the treatment of moderate-to-severe psoriasis. METHODS: Patients with moderate-to-severe psoriasis (skin lesion area > 10% of the body surface area) for 2 consecutive years were treated with TCM (oral and external use of herbal medicines, acupuncture, and herbal bathing) and narrow-band medium-wave ultraviolet B light treatment for 12 weeks. The treatment effect was evaluated based on the Psoriasis Area Severity Index (PASI), the achievement of a 50% reduction in the PASI (PASI50), the achievement of a 75% reduction in the PASI (PASI75), pruritus score, Dermatology Life Quality Index, and safety. RESULTS: A total of 95 outpatients were enrolled, and 92 subjects (96.8%) completed the 12-week treatment course. At baseline, the average proportion of the body surface area covered by skin lesions was 12.4%, and the average PASI was 17.7. All patients had previously been treated with conventional medicine (89.1% of patients received ultraviolet light treatment, 50.0% received glucocorticoids, and 21.7% received acitretin). After the 12-week treatment course, 22 patients (23.9%) achieved PASI75, and 43 (46.7%) achieved PASI50. The post-treatment pruritus score and Dermatology Life Quality Index of all treated patients were significantly lower than the respective baseline values (P < 0.0001). No adverse effects were detected by the monitoring of blood, urine, stools, liver and kidney function, and echocardiography. CONCLUSION: Comprehensive therapy comprising TCM therapy combined with ultraviolet B light therapy achieved good outcomes for patients with moderate-to-severe psoriasis.

Early and mid-term results of transarticular external fixation in the treatment of supination-external rotation type IV equivalent ankle fractures.

PURPOSE: To investigate the early and mid-term results of open reduction and internal fixation (ORIF) with transarticular external fixation (TEF) but no deltoid ligament repair (DLR) in the treatment of supination-external rotation type IV equivalent (SER IV E) ankle fractures (AO/OTA classification 44-B 3.1) and provide evidence for clinical practice. METHODS: This study cohort consisted of 22 patients with SER IV E ankle fractures that underwent ORIF with TEF but no DLR between December 2011 and December 2014. There were 13 males and 9 females, mean age 38.9 years (range, 17-73 years). Eight cases involved the left side and 14 the right side. The causes of fractures included road traffic accidents (11 cases), falling from height (6 cases) and sports injuries (5 cases). The mean period of hospitalization was 9.8 days (range, 6-14 days). For all the patients, MRI and three-dimensional CT were done before surgery and X-rays done preoperatively and during follow-ups. The external frame was kept for 8-10 weeks. The preoperative American Orthopedic Foot and Ankle Society (AOFAS) ankle-hindfoot score was 56.86 ± 4.400, the Medical Outcomes Short Form 36-item (SF-36) questionnaire score was 57.41 ± 4.102 and the visual analog score (VAS) was 5.50 ± 1.058. Patients' main complaints about inconvenience of daily life were also recorded. RESULTS: All the 22 patients were followed up for 24-63 months (mean, 33.6 months). None of them developed nonunion during the follow-up; pin site infection was observed in one patient and posttraumatic osteoarthritis in another. At the final follow-up, the average AOFAS score, SF-36 score and VAS score were respectively 90.59 ± 5.096, 79.59 ± 5.394 and 1.82 ± 1.181, which were significantly improved compared with the preoperative data (t = 26.221, p < 0.001; t = 11.910, p < 0.001; t = 11.571, p < 0.001). The therapeutic effect was excellent in 13 cases, good in 7 cases and fair in 2 cases, with a good-excellent rate of 90.9%. Patients' main complaints were inconvenience of clothing (17 cases) and extremity cleaning (5 cases). CONCLUSION: In the treatment of SER IV E ankle fractures, ORIF with TEF but no DLR can achieve satisfactory outcome, but long-term effect should be confirmed by large sample randomized controlled trials.

Middle-term follow-up results of Pipkin type IV femoral head fracture patients treated by reconstruction plate and bioabsorbable screws.

PURPOSE: To investigate the mid-term curative effects of the treatment of Pipkin type IV femoral head fractures using a reconstruction plate and bioabsorbable screws and provide the evidence for clinical practice. METHODS: From February 2010 to September 2014, 21 patients with Pipkin type IV femoral head fractures were treated surgically. There were 13 males and 8 females with an average age of 41.1 years (range, 20-65 years). The causes of the fractures included traffic accidents (13 cases), falls from a height (four cases), heavy lifting injuries (three cases), and sport injury (one case). All patients were followed up with radiography and three-dimensional reconstruction computed tomography and other checks and any complications were actively managed. Closed reduction of fracture-dislocation of the hip was attempted under general anesthesia using the Kocher-Langenbeck approach. Femoral head fractures were treated with internal fixation or excision based on the size of the fracture fragments, whereas acetabular fractures were fixed with a reconstruction plate and screws following anatomic reduction. RESULTS: The incisions healed by primary intention in all patients after surgery, without any infection, deep venous thrombosis, or other complications. All 21 patients were followed up for 36-76 months, with an average follow-up duration of 49 months. Postoperative imaging data showed that all dislocations and fractures were anatomically reduced, and bony union of the fractures was achieved. Heterotopic ossification was found in four patients, post-traumatic osteoarthritis in three, and avascular necrosis of the femoral head in two. At the final follow-up, the assessment of hip joint function according to the Thompson-Epstein scoring scale was excellent in 10 cases, good in six cases, fair in three cases, and poor in two cases. The rate of excellent and good functional outcomes was 76.1%. CONCLUSION: The mid-term curative effects of a reconstruction plate and bioabsorbable screws in the treatment of Pipkin type IV femoral head fractures is significant, and such the treatment can significantly improve the patient's joint function and quality of life.

Clinical analysis of peri-operative hidden blood loss of elderly patients with intertrochanteric fractures treated by unreamed proximal femoral nail anti-rotation.

The purpose of this study was to quantify the peri-operative blood loss of elderly patients with intertrochanteric fractures treated by unreamed proximal femoral nail anti-rotation (PFNA) and analyze whether the substantial hidden blood loss was induced by initial trauma or the operation. The clinical data of 123 patients with intertrochanteric fracture treated with unreamed PFNA from Jan 2013 to Apr 2017 were analyzed retrospectively. Blood routine on admission day (ADM), pre-operative day one (PRE), post-operative days one and three (POD1 and POD3) and the visible blood loss (VBL) were obtained. The total blood loss (TBL) from ADM to POD1 and POD3 were 693.5 ± 359.6 ml and 863.8 ± 429.9 ml, of which the corresponding hidden blood loss (HBL) was 86.8% and 89.4% respectively. The mean TBL and HBL from ADM to PRE (375.5 ± 242.0 ml, 375.5 ± 242.0 ml) were higher than that from PRE to POD1 (318.0 ± 183.4 ml, 226.5 ± 163.2 ml), p < 0.001 respectively. There was no significant difference between HBL from ADM to PRE and HBL from PRE to POD3 (375.5 ± 242.0 ml, 396.7 ± 254.0 ml, p = 0.361). The majority of peri-operative HBL occurred before surgery, it was mainly associated with the initial trauma rather than the operation.

Ilizarov external fixation versus plate internal fixation in the treatment of end-stage ankle arthritis: decision analysis of clinical parameters.

The purpose of this study was to evaluate the effect of Ilizarov external fixation (IEF) and plate internal fixation (PIF) in the treatment of end-stage ankle arthritis on pain relieving and function improvement. The study cohort consisted of 59 patients with end-stage ankle arthritis underwent ankle arthrodesis with IEF or PIF between June 2011 and June 2015. Standard radiographs and computed tomography (CT) scans were obtained before surgery and during the follow-up. Functional assessments were performed using Foot and Ankle pain score of American Orthopedics Foot and Ankle Society (AOFAS) and Visual Analogue Scale (VAS). The average AOFAS scores in both IEF group and PIF groups increased significantly after operation, from 45.5 ± 6.3 to 84.8 ± 4.9 and from 45.9 ± 6.6 to 86.6 ± 5.4, respectively. The average VAS scores in both groups decreased significantly after operation, from 8.4 ± 1.9 to 2.5 ± 0.6 and from 8.2 ± 1.5 to 2.3 ± 0.7, respectively. Nevertheless, there was no significant difference for preoperative or postoperative AOFAS and VAS scores between the two groups. The IEF would result in comparable postoperative functional recovery and pain relieving to PIF and may be an effective substitute to PIF in the treatment of end-stage ankle arthritis.

Ascites-derived IL-6 and IL-10 synergistically expand CD14+HLA-DR-/low myeloid-derived suppressor cells in ovarian cancer patients.

Myeloid-derived suppressor cells (MDSC) play a key immunosuppressive role in various types of cancer, including ovarian cancer (OC). In this study, we characterized CD14+HLA-DR-/lo MDSC with a typical monocytic phenotype (M-MDSC) in the peripheral blood (PB) and ascites from OC patients. Compared to healthy donors, OC patients had a significantly increased abundance of M-MDSC in both PB and ascites; importantly, their abundance in both compartments was inversely associated with the prognosis where OC patients with higher level of M-MDSC having a shorter relapse-free survival. Intriguingly, we demonstrated that M-MDSC could be readily induced by ascitic fluids (AF) from OC patients, which was predominantly dependent on IL-6, IL-10 and STAT3 activation as neutralization of IL-6 and/or IL-10 or inhibition of STAT3 abrogated MDSC's expansion while recombinant IL-6 and IL-10 recapitulated the expansive effect of AF; furthermore, predominantly elevated levels of IL-6 and IL-10 has been noted in the AF which was positively correlated with the abundance of M-MDSC as well as poor prognosis of OC patients. As expected, we observed that AF-driven STAT3 activation upregulated the expression of arginase (ARG1) and inducible nitric oxide synthase (iNOS) in induced M-MDSC through which these MDSC executed the immunosuppressive activity. Taken together, these results demonstrate that abundant M-MDSC are present in both periphery and ascites of OC patients whose accumulation and suppressive activity is critically attributable to ascites-derived IL-6 and IL-10 and their downstream STAT3 signal, thus providing a potentially novel therapeutic option by locally targeting MDSC to improve antitumor efficacy.