Comparing outcomes of plate augmentation, nail exchange, and nail exchange with plate augmentation in the treatment of atrophic femoral shaft nonunion after intramedullary nailing: a multicenter retrospective study.

INTRODUCTION: Intramedullary (IM) nailing is the treatment of choice for femoral shaft fractures, but nonunion rates have been reported to be as high as 12%. Surgical interventions for nonunion involve exchange nailing or plate augmentation. Recently, a combined treatment of exchange nailing and plate augmentation has demonstrated good results, but its comparative effectiveness remains unclear. This study aimed to compare the clinical and radiographic outcomes of three different surgical interventions for atrophic femoral shaft nonunion, and investigate the factors that affect bone healing after reoperation. MATERIALS AND METHODS: A retrospective study was conducted at five university hospitals involving 149 patients with aseptic atrophic nonunion after IM nailing. These patients underwent reoperation with plate augmentation, exchange nailing, or combined treatment. Clinical and radiographic outcomes were assessed and compared according to reoperation procedure. Logistic regression analysis was performed to identify factors affecting persistent nonunion after reoperation. RESULTS: Of the cohort, 57 patients underwent plate augmentation, 64 underwent exchange nailing, and 28 received combined treatment. There were no significant differences in patient demographics among the groups. Exchange nailing produced a significantly lower union rate than did the combined treatment (82.8% vs. 100%, p = 0.016), whereas no significant difference was observed in the union rate and time to the union between plate augmentation and the combined treatment. Combined treatment showed the longest operative time and the greatest transfusion requirements. The risk factors for persistent nonunion included age, absence of autogenous bone grafts, and use of an exchange nailing technique. CONCLUSIONS: Exchange nailing as a treatment for atrophic femoral shaft nonunion after IM nailing resulted in a lower union rate. The efficacy of the combined treatment requires further study, and persistent nonunion may be influenced by age, bone grafting, and surgical techniques. A comprehensive approach targeting both biological environment and mechanical stability is crucial in the treatment of atrophic femoral shaft nonunion.

Surgical Outcomes of Percutaneous Pinning and Open Locking Plating in Patients With Intra-articular Fractures of the Base of the Fifth Metacarpal.

PURPOSE: The purpose of the study was to demonstrate the results of surgical treatment, including percutaneous K-wire fixation after closed reduction (CRKF) or locking plate fixation after open reduction (ORPF), in patients with intra-articular fractures of the base of the fifth metacarpal. METHODS: We retrospectively reviewed data of 29 patients who received surgical treatment for closed, intra-articular fractures of the base of the fifth metacarpal and were followed up for at least 1 year after surgery. Sixteen of the 29 patients underwent CRKF, whereas 13 patients underwent ORPF. Attempts were made to address intra-articular step-off with closed reduction in all the patients; however, if inadequate, ORPF was performed. Clinical outcomes were evaluated using Disabilities of the Arm, Shoulder, and Hand scores, visual analog scale pain scores, the total active motion (TAM) of the little finger, and grip strength. Osseous union and posttraumatic arthritis of the fifth carpometacarpal joint were also evaluated. RESULTS: K-wire fixation after closed reduction was performed for 13 simple fractures and 3 comminuted fractures; ORPF was performed for 6 simple fractures and 7 comminuted fractures. All the patients had satisfactory subjective outcomes with over 90% grip strength compared with that on the contralateral side and nearly full TAM. All the patients in both the groups achieved osseous union. There were five cases of grade 1 posttraumatic arthritis after CRKF and seven cases of grade 1 posttraumatic arthritis after ORPF. CONCLUSIONS: Surgical treatment provided satisfactory results in patients with intra-articular fractures of the base of the fifth metacarpal treated with either CRKF or ORPF. Our data showed that the patients who underwent CPKF had good results, and those who underwent ORPF after attempt failure of close reduction also had good results. Our experience suggests that ORPF can be a backup plan when CRKF cannot be accomplished in a satisfactory way. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Discovery of 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one and 3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one derivatives as novel ENPP1 inhibitors.

Ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) negatively regulates the anti-cancer Stimulator of Interferon Genes (STING) pathway. We discovered that 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one and 3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one derivatives possessed inhibitory activities on ENPP1. A structure-activity relationship (SAR) study led to the identification of 46 and 23 as potent ENPP1 inhibitors. Also, compounds 46 and 23 possessed high microsomal stabilities in human, rat, and mouse liver microsome. Additionally, CYPs (1A2, 2C9, 2C19, 2D6, and 3A4) were not inhibited by 46 and 23. Molecular dynamics simulations provided an insight of binding modes between ENPP1 and compounds (46 and 23).

Comparison of tibial plateau fracture surgical outcomes between young and elderly patients: are outcomes really poorer in the elderly?

INTRODUCTION: Several studies have reported that total knee arthroplasty (TKA) is a suitable solution to treat elderly patients with complex tibial plateau fractures. The purpose of the present study was to compare surgical treatment outcomes after open reduction internal fixation (ORIF) between elderly and younger patients. MATERIALS AND METHODS: We reviewed patients with plateau fracture (OTA/AO classification types 41B and 41C) who underwent ORIF at two academic trauma centers between November 2006 and October 2019. Of the 341 patients, 76 were ultimately included in the younger group (< 60 years old) and 77 in the elderly group (≥ 60 years). The average follow-up was 24 months (range 12-96 months). The primary outcome was any common complication of plateau fracture, namely post-traumatic arthritis and alignment change. Conversion to TKA, Reduction loss, coronal malalignment, non-union, union time, infection, and limb length discrepancy (LLD) were also assessed. RESULTS: The elderly group had a significantly higher prevalence of diabetes, but there were no other significant differences between the groups in terms of patient demographics, fracture characteristics, and operation characteristics. We detected no differences between the groups in terms of post-traumatic arthritis (p = 0.216), alignment change (p = 0.093), conversion to TKA (p = 0.681), reduction loss (p = 0.079), coronal malalignment (p = 0.484), non-union rate (p = 0.719), infection (p = 0.063), LLD (p = 0.154), or time to union (p = 0.513). Logistic regression analysis revealed that age > 60 years was not associated with treatment failure, defined as either post-traumatic arthritis greater than grade II or non-union (p = 0.468). OTA/AO classification type 41C2 (p = 0.019), type 41C3 (p = 0.008), and malreduction (p = 0.050) were significant risk factors for failure. CONCLUSION: Age ≥ 60 years is not an independent risk factor of poor radiographic outcome and high complication rate in tibial plateau fractures. This indicates that ORIF is still a good solution to treat elderly patients, similar to their younger counterparts.

Target-Specific Drug Design Method Combining Deep Learning and Water Pharmacophore.

Following identification of a target protein, hit identification, which finds small organic molecules that bind to the target, is an important first step of a structure-based drug design project. In this study, we demonstrate a target-specific drug design method that can autonomously generate a series of target-favorable compounds. This method utilizes the seq2seq model based on a deep learning algorithm and a water pharmacophore. Water pharmacophore models are used to screen compounds that are favorable to a given target in a large compound database, and seq2seq compound generators are used to train the screened compounds and generate entirely new compounds based on the training model. Our method was tested through binding energy calculation studies of six pharmaceutically relevant targets in the directory of useful decoys (DUD) set with docking. The compounds generated by our method had lower average binding energies than decoy compounds in five out of six cases and included a number of compounds that had lower binding energies than the average binding energies of the active compounds in four cases. The generated compound lists for these four cases featured compounds with lower binding energies than even the most active compounds.

Excellent outcomes after double-locked plating in very low periprosthetic distal femoral fractures.

INTRODUCTION: Very low periprosthetic distal femur fractures (PPDFFs) are rare injuries and often have a relatively high failure rate after single lateral locked plating. The double plating technique yields good outcomes in osteoporotic fractures of the distal femur. To date, there is limited information on double-locked plate fixation of very low PPDFFs. This study aimed to evaluate the outcomes and complications of surgically treated very low PPDFFs using double-locked plate fixation. MATERIALS AND METHODS: Between January 2013 and December 2018, sixty-one consecutive patients with PPDFFs have been conducted. Only Su type III PPDFFs with double-locked plate fixation through a lateral minimally invasive approach and a medial subvastus approach to the distal femur were analyzed. Patients were encouraged to perform straight leg raising exercises and active knee motion on the second postoperative day. Assisted weight bearing from the early postoperative days was supported, and full weight-bearing was allowed after healing the fracture site. All patients were evaluated according to the time to union, limb alignment, range of knee motion, Knee Society Score, and presence of complications. RESULTS: Twenty one patients (17 females and 4 males, mean age 76 years, range 56-90) were included in the study. There were 10 of 33-A1, 6 of 33-A2 and 5 of 33 A3 fractures, according to the AO classification. Of 21 patients, 20 achieved union at an average of 14 weeks postoperatively. Postoperative limb alignment was satisfactory in all cases, with an average mechanical distal lateral femur angle of 89° and average mechanical posterior distal femur angle of 86°. All patients recovered the knee joint motion similar to that of the contralateral side, and daily life pre-injury. The average knee and function scores were 94 and 89, respectively. There were one case of non-union and three cases of superficial wound infection, which resolved after intravenous antibiotic therapy. CONCLUSIONS: Double locked plating showed excellent radiographic and functional outcomes with few complications in patients with very low PPDFFs. Based on these promising results, we propose the consideration of double-locked plate fixation in the treatment of very low PPDFFs.

Surgical outcomes of simple distal femur fractures in elderly patients treated with the minimally invasive plate osteosynthesis technique: can percutaneous cerclage wiring reduce the fracture healing time?

INTRODUCTION: Achieving adequate reduction is difficult when performing minimally invasive plate osteosynthesis (MIPO) in elderly patients with simple distal femur fracture. This study aimed to evaluate the elderly patients who had undergone percutaneous wiring-assisted reduction with MIPO for simple distal femur fractures to determine the effect of this technique on reduction quality and fracture union. MATERIALS AND METHODS: Between January 2009 and September 2017, 56 patients (56 femurs) with displaced simple distal femur fractures treated with MIPO at three trauma centers were finally enrolled. The MIPO technique with percutaneous cerclage wire reduction was performed in 25 patients (Group A). Among them, 12 patients had a simple spiral metaphyseal fracture (Group A*). In comparison, MIPO without percutaneous cerclage wire reduction was performed in 31 patients (Group B). Among them, seven patients had a simple spiral metaphyseal fracture (Group B*). Medical records containing surgical records were retrospectively reviewed to investigate demographic data, comorbidities, complications, operative time, and fluoroscopic time. Radiographs were evaluated for assessing the quality of the reduction and fracture union. RESULTS: The mean fracture union time of Group A* was 21.7 weeks, which was significantly shorter than that of Group B* (28.6 weeks). The mean coronal and sagittal angulation in Group A* was 0.6° and 0.7°, respectively, which were significantly lesser than those in Group B* (2.4° and 3.2°, respectively). Mean translation in Group A* was 1.43 mm, which was significantly shorter than that in Group B* (3.81 mm). Nonunion occurred in two patients in Group B. CONCLUSION: Surgical treatment of simple spiral distal femur fractures with percutaneous cerclage wiring-assisted reduction and the MIPO technique in elderly patients resulted in better reduction and faster union time. Therefore, this technique could be a good solution if used in accordance with the indication.

Ginsenoside Rd Inhibits the Metastasis of Colorectal Cancer via Epidermal Growth Factor Receptor Signaling Axis.

Ginsenoside Rd is a saponin from ginseng and has been reported to have various biological activities. However, the effect of ginsenoside Rd on the metastasis of colorectal cancer (CRC) remains unknown. Here, we found that ginsenoside Rd decreased the colony-forming ability, migration, invasion, and wound-healing abilities of CRC cells, although it did not affect cell proliferation. In addition, using an inverse-docking assay, we found that ginsenoside Rd bound to epidermal growth factor receptor (EGFR) with a high binding affinity, inducing the downregulation of stemness- and epithelial-mesenchymal transition-related genes; these were partially rescued by either exogenous EGF treatment or ectopic expression of SOX2. Furthermore, ginsenoside Rd significantly decreased the number and size of tumor metastasis nodules in the livers, lungs, and kidneys of mouse model of metastasis. © 2018 IUBMB Life, 71(5):601-610, 2019.

Passivation of black phosphorus saturable absorbers for reliable pulse formation of fiber lasers.

Black phosphorus (BP) has attracted increasing attention due to its unique electrical properties. In addition, the outstanding optical nonlinearity of BP has been demonstrated in various ways. Its functionality as a saturable absorber, in particular, has been validated in demonstrations of passive mode-locked lasers. However, normally, the performance of BP is degraded eventually by both thermal and chemical damage in ambient conditions. The passivation of BP is the critical issue to guarantee a stable performance of the optical devices. We quantitatively characterized the mode-locked lasers operated by BP saturable absorbers with diversified passivation materials such as polydimethylsiloxane (PDMS) or Al2O3, considering the atomic structure of the materials, and therefore the hydro-permeability of the passivation layers. Unlike the BP layers without passivation, we demonstrated that the Al2O3-passivated BP layer was protected from the surface oxidation reaction in the long-term, and the PDMS-passivated one had a short-term blocking effect. The quantitative analysis showed that the time-dependent characteristics of the pulsed laser without passivation were changed with respect to the pulse duration, spectral width, and time-bandwidth product displaying 550 fs, 2.8 nm, and 0.406, respectively. With passivation, the changes were limited to <43 fs, <0.3 nm, and <0.012, respectively.

Air-stable few-layer black phosphorus phototransistor for near-infrared detection.

We have demonstrated a few-layer black phosphorus (BP) phototransistor of stable operation in ambient air environment and at near-infrared light (λ = 1550 nm). The air-stable electronic and optoelectronic properties of the few-layer BP phototransistor have been achieved by a proper Al2O3 passivation. The optical identification method and qualitative and quantitative electrical characterizations of the few-layer BP phototransistor in dark state confirmed that the device performance was robust in ambient air, to further chemical treatments, and storage of more than six months. In addition, the low-frequency noise characterizations had revealed that the noise spectral density related to the sensitivity of phototransistor was reduced. Owing to the suppression of interaction between few-layer BP and adsorbates arising from the Al2O3 passivation, a fast rise time of the few-layer BP phototransistor, less than 100 µs, had been observed, demonstrating the intrinsic photoresponse properties of few-layer BP. The low dark current of ∼4 nA at the operation bias and the reasonable responsivity of ∼6 mA W-1 were obtained under the condition lacking adsorbates interactions. Internally, the dark current and responsivity level was tunable by changing the operation bias. Our results are close to the intrinsic properties of the few-layer BP phototransistor, implying that it can be a building block of functioned few-layer BP photodetectors.

Comparison of outcomes according to fixation technique following the modified Ludloff osteotomy for hallux valgus in patients with rheumatoid arthritis.

BACKGROUND: Clinical and radiological outcomes including fixation stability of osteotomy site were compared in rheumatoid arthritis (RA) patients who underwent modified Ludloff osteotomy to correct hallux valgus with osteotomy site fixation using two screws versus those who underwent additional fixation using a plate. METHODS: The fixation technique performed with two screws was used to fix the osteotomy sites following modified Ludloff osteotomy in 15 patients (15 feet, Group S), while the augmented plate fixation technique was used in 14 patients (16 feet, Group P). Surgical outcomes were analysed using the American Orthopedic Foot and Ankle Society (AOFAS) scores, and radiologic parameters measured before surgery and during follow-up examinations. To evaluate the stability of each osteotomy site fixation technique, the 1-2 inter-metatarsal angle (IMA) and angle of the altered margin of the lateral cortex (AMLC) were measured immediately and 6 weeks after surgery, and variations in the angles were compared. In addition, bone mineral density (BMD) values were compared between patients with correction loss at the osteotomy site and those with no loss of correction. RESULTS: No significant differences between groups were found for total AOFAS scores before surgery and at the final follow-up. However, significant differences were observed in the 1-2 IMA, beginning at 6 weeks postoperatively and continuing through the final follow-up. The 1-2 IMA and angle of AMLC measured immediately after and 6 weeks after surgery showed significantly greater variation in Group S than in Group P. In Group S, patients with correction loss (5 feet) at osteotomy site showed significantly lower BMD values than those with no loss of correction (10 feet). Despite the lower BMD values of patients in Group P than in Group S, a loss of correction did not occur in these patients. CONCLUSIONS: Correction loss occurred at the osteotomy site within 6 weeks postoperatively in patients who underwent fixation using only the two-screw fixation technique following modified Ludloff osteotomy; such loss could be reduced using the augmented plate fixation technique even in patients with osteoporosis.

Minimally invasive plate augmentation in the treatment of long-bone non-unions.

INTRODUCTION: Exchange nailing is most acceptable for treating hypertrophic non-union of the long bones, requiring the removal of previously fixed implant. However, its main effect of mechanical stabilization is controversial in non-isthmal area. We hypothesized that minimally invasive plate augmentation over the non-union site may have a better option, without the need of bone grafting or removing pre-existing implants. MATERIALS AND METHODS: Seventeen patients with hypertrophic non-union of the long bones between 2010 and 2014 on radiography who previously underwent intramedullary (IM) nailing or plate osteosynthesis for long-bone fractures were included. A locking compression plate was inserted with at least three mono- or bicortical screws at each proximal and distal segment. Broken or loosened interlocking screws of IM nail were simultaneously re-fixed. Fracture site exposure, pre-fixed implant removal, and bone grafting were not performed. We investigated whether union occurred and analyzed functional outcomes and complications. RESULTS: Eleven femoral and six tibial non-unions were prospectively included. In the pre-existing implants, 13 nails and 4 plates were found. All cases achieved union at a mean 22.7 weeks. One case of superficial infection was managed with oral antibiotics. Deep infection or implant failure did not occur. CONCLUSIONS: Minimally invasive plate augmentation can achieve additional stability and promote healing of hypertrophic non-union of the long bones. When indicated, this technique is the least invasive alternative to exchange nailing and reduces surgical risks in the treatment of diaphyseal non-union.

Thermal damage suppression of a black phosphorus saturable absorber for high-power operation of pulsed fiber lasers.

Recent studies of black phosphorus (BP) have shown its future potential in the field of photonics. We determined the optical damage threshold of BP at 21.8 dBm in a fiber ring laser cavity, and demonstrated the high-power operation capacity of an evanescent field interaction-based BP saturable absorber. The long-term stability of a passively mode-locked fiber laser with a saturable absorber operating at the optical power of 23.3 dBm was verified for 168 h without any significant performance degradation. The center wavelength, spectral width, and pulse width of the laser output are 1558.8 nm, 14.2 nm, and 805 fs, respectively.

Hand-manageable graphene sticker for ultrafast mode-locked fiber lasers.

We have developed a graphene sticker prepared by simply detaching graphene directly grown on a self-catalytic γ-Al2O3 substrate with a spin-coated polymer film. Our scheme is highlighted by the metal-free and bare-hand manageable process. The sticker is attached onto the flat surface of a D-shaped fiber to demonstrate an efficient fiber mode-locked laser. The 1-ps output pluses have the center wavelength, spectral width, and repetition rate of 1558.2 nm, 5.42 nm, and 4.77 MHz, respectively.

Percutaneous cerclage wiring followed by intramedullary nailing for subtrochanteric femoral fractures: a technical note with clinical results.

BACKGROUND: Although intramedullary nailing is an ideal treatment for subtrochanteric femoral fractures, it is technically challenging in fractures extending into the nail entry area and/or involving the lesser trochanter. Although the application of circumferential wire may facilitate reduction in these situations, its use remains controversial due to possible blood supply disturbances to underlying bone. In the present study, we evaluated complex subtrochanteric fractures treated by percutaneous cerclage wiring followed by intramedullary (IM) nailing for anatomical fracture reduction and union. METHODS: Twelve patients (mean age 48.3 years) with an unstable subtrochanteric fracture were prospectively treated. Indications of percutaneous cerclage wiring followed by IM nailing were a fracture extending proximally into the nail entry area deemed difficult to treat by anatomical reconstruction by IM nailing or a fracture with long oblique or spiral component. One or two cerclage wires were percutaneously applied for the temporary reduction of main fragments, and then, a cephalo-medullary or a reconstruction nail was fixed. We assessed radiologic results (union time, alignment), functional results, and complications. RESULTS: All 12 cases healed, without a bone graft, at an average of 19.1 weeks after surgery (range 16-24). In 11 cases, acceptable alignment was achieved (mean, valgus 0.3° extension 0.6°) with minimal leg-length discrepancy; the other exhibited 1 cm of shortening. All patients were able to return to pre-injury activity levels, and median Merle d'Aubigne score was 16.9 (15-18). No infection or implant-related complication was encountered to latest follow-up (minimum 12 months postoperatively). CONCLUSION: Temporary reduction by percutaneous wiring offers a means of satisfactory nailing in difficult subtrochanteric femoral fractures, and affords anatomical reconstruction and favorable bony union.

Efficacy of Minimally Invasive Reduction With Cerclage Fixation in Spiral or Oblique Subtrochanteric Femoral Fractures: A Retrospective Cohort Study Comparing Cables and Wires.

OBJECTIVES: To compare the outcomes of a minimally invasive reduction (MIR) technique using a cable and wire in spiral or oblique subtrochanteric femoral fractures (SFFs). DESIGN: Retrospective cohort study. SETTING: Two University Hospitals. PATIENT SELECTION CRITERIA: Skeletally mature patients with spiral or oblique SFFs (OTA/AO 32A1 and 32A2) treated with intramedullary nailing and MIR with a cerclage wire passer using either a single-loop cable or cerclage wire or MIR without cable or wire between May 2016 and November 2021 were included. OUTCOME MEASURES AND COMPARISONS: Coronal and sagittal interfragmentary gap, neck-shaft angle, coronal and sagittal angulation, fracture union, time to union, and Radiographic Union Score for Hip (RUSH) at 6 months post operation were compared. RESULTS: A total of 46 patients were included, with 16 each in the cable and wire groups and 14 in the non-wiring group. There were no differences in demographics ( P > 0.05), fracture classification ( P = 0.710), or operative data ( P > 0.05) between the three groups. The cable group showed significantly better coronal ( P = 0.003) and sagittal ( P = 0.003) interfragmentary gap, shorter union time ( P < 0.001), and higher 6-month RUSH score ( P < 0.001) among the three groups. There were no significant differences in outcome measures between the wire and non-wiring groups (all P > 0.05). No mechanical complications or reoperations were observed in all three groups. CONCLUSIONS: Minimally invasive reduction using a cable is more effective than wire or non-wiring reduction to improve reduction quality and promote bone union in the SFFs. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

A retrospective cohort study of autogenous iliac strut bone grafting in large bone defects of the lower extremity.

Autogenous iliac bone graft (AIBG) is the treatment of choice for managing bone defects, and favorable results have been reported for bone defects < 5 cm in length. In large bone defects ≥ 5 cm, it is difficult to obtain good results with simple bone grafting, and other management options have drawbacks, such as long immobilization periods and high complication rates. We hypothesized that AIBG in the strut form might show favorable results in large bone defects with minimal complications. This study aimed to investigate the outcomes of strut-type AIBG and evaluate its effectiveness compared to cancellous AIBG. This retrospective study included 50 patients who underwent AIBG for bone defects at a single institution between March 2011 and April 2020. We performed corticocancellous AIBG in a strut form to manage bone defects ≥ 5 cm in the lower extremities. The strut bone was harvested along the iliac crest and grafted slightly longer than the bone defect to apply a sufficient compressive force. Demographic information and radiographic and clinical results of patients who underwent strut AIBG (Group S) were analyzed. The outcomes of union, time to union, complications, and reoperation were compared with those of patients who underwent cancellous AIBG (Group C). The study population comprised 37 men (74%) and 13 women (26%), with a mean age of 50.0 (range: 19-78). The average follow-up period was 25.6 months (12-104 months). Group S included 16 patients with a mean bone defect length of 6.8 ± 1.2 cm. In Group S, union was achieved in all patients, with an average time to union of 6.7 months. Complications occurred in four cases, all related to wound problems. Group C comprised d 34 patients with a mean defect length of 2.8 ± 1.1 cm. Complications occurred in five patients in Group C, including four soft tissue problems and one implant failure. When comparing the outcomes of Groups S and C, no significant differences were observed. AIBG is an effective and safe technique for managing bone defects. Strut AIBG can be used effectively for bone defects ≥ 5 cm in the lower extremities.

Structural Modification and Biological Evaluation of 2,8-Disubstituted Adenine and Its Nucleosides as A2A Adenosine Receptor Antagonists: Exploring the Roles of Ribose at Adenosine Receptors.

Building on the preceding structural analysis and a structure-activity relationship (SAR) of 8-aryl-2-hexynyl nucleoside hA2AAR antagonist 2a, we strategically inverted C2/C8 substituents and eliminated the ribose moiety. These modifications aimed to mitigate potential steric interactions between ribose and adenosine receptors. The SAR findings indicated that such inversions significantly modulated hA3AR binding affinities depending on the type of ribose, whereas removal of ribose altered the functional efficacy via hA2AAR. Among the synthesized derivatives, 2-aryl-8-hexynyl adenine 4a demonstrated the highest selectivity for hA2AAR (Ki,hA2A = 5.0 ± 0.5 nM, Ki,hA3/Ki,hA2A = 86) and effectively blocked cAMP production and restored IL-2 secretion in PBMCs. Favorable pharmacokinetic properties and a notable enhancement of anticancer effects in combination with an mAb immune checkpoint blockade were observed upon oral administration of 4a. These findings establish 4a as a viable immune-oncology therapeutic candidate.

Prophylactic nailing of incomplete atypical femoral fractures.

INTRODUCTION: Recent reports have described the occurrence of low-energy subtrochanteric and femoral shaft fractures associated with long-term bisphosphonate use. Although information regarding the surgical treatment of these atypical femoral fractures is increasing, it is unclear if the preventive operation is useful in incomplete fractures. This study examined the results of preventive intramedullary nailing for incomplete atypical femoral fractures. MATERIAL AND METHODS: A retrospective search was conducted for patients older than 50 years receiving bisphosphonate therapy, with incomplete, nondisplaced fractures in either the subtrochanteric or diaphyseal area of the femur. Seventeen patients with a total of 20 incomplete, non-displaced lesions were included. The mean duration of bisphosphonate use was 50.5 months. Eleven of the 17 (64.7%) patients had complete or incomplete fractures on the contralateral femur. All were treated with prophylactic fixation of an intramedullary (IM) nail. The minimum followup was 12 months. RESULTS: All cases healed with a mean period of 14.3 weeks. Nineteen of the 20 cases healed with the dissolution of incomplete fractures of the lateral aspect. A complete fracture developed at the time of nailing in one patient, but it healed with callus bridging. CONCLUSION: IM nailing appears to be a reliable way of preventing the progress of incomplete atypical femoral fractures.

A multicenter study of factors affecting nonunion by radiographic analysis after intramedullary nailing in segmental femoral shaft fractures.

The factors affecting the outcomes of segmental femoral shaft fractures are currently unknown. We evaluated the outcomes of intramedullary (IM) nail fixation and investigated factors affecting nonunion of femoral shaft segmental fractures. A total of 38 patients who underwent IM nail fixation for femoral shaft segmental fractures (AO/OTA 32C2) at three university hospitals with a minimum 1-year follow-up period were retrospectively reviewed. The patients were divided into union (n = 32) and nonunion (n = 6) groups. We analyzed smoking status, diabetes mellitus, location of the segmental fragment, segment comminution, filling of the IM nail in the medullary canal, residual gap at the fracture site, use of a cerclage wire or blocking screws as factors that may affect the surgical outcome. In the union group, the average union time was 5.4 months (4-9 months). In the nonunion group, five patients required additional surgery within an average of 7.2 months (5-10 months) postoperatively, whereas one patient remained asymptomatic and did not require further intervention. On comparing the two groups, insufficient canal filling of the IM nail (union, 25.0%; nonunion, 83.3%; p = 0.012) and the presence of a residual gap at the fracture site after reduction (union, 31.3%; nonunion, 83.3%; p = 0.027) were significantly different. In the multivariate analysis, only insufficient canal filling of the IM nail was found to be a factor affecting nonunion, with an odds ratio of 13.3 (p = 0.036). In this study, a relatively high nonunion rate (15.8%) was observed after IM nail fixation. Insufficient IM nail canal filling and a residual gap at the fracture site post reduction were factors affecting segmental femoral shaft fracture nonunion after IM nail fixation.