Efficacy and Safety of Orally and Intravenously Administration of Tranexamic Acid in Patients with Elderly Femoral Neck Fracture.

OBJECTIVE: For elderly femoral neck fracture patients, anemia is one of the most common complications, increasing the risk of postoperative adverse events. Tranexamic acid (TXA) has been widely applied to the perioperative blood management. However, the optimal route of TXA administration in elderly femoral neck fracture remains unclear. The aim of this study is to evaluate the efficacy and safety of oral and intravenous (IV) application of TXA in elderly patients with femoral neck fracture undergoing total hip arthroplasty (THA) and hemiarthroplasty (HA). METHODS: All elderly patients aged over 65 years old diagnosed with femoral neck fracture admitted to the trauma orthopedics from August 1, 2020 to February 28, 2022 were enrolled in this prospective cohort study. Participants were divided into three groups: oral group: TXA 2g orally 2 h before incision; IV group: intravenous infusion of TXA 1g 15 min before incision; and control group: usual hemostatic method. The primary outcomes were total blood loss, allogeneic transfusion rate, and postoperative thromboembolic events. SPSS 23.0 (IBM, Armonk, NY, USA) was used for statistical analysis, and p ≤ 0.05 was considered statistically significant. RESULTS: A total of 100 patients were enrolled, including 32 cases in the oral group, 34 cases in the IV group and 34 cases in the control group. Compared with the control group, the total perioperative blood loss in the oral and IV groups was significantly decreased (763.92 ± 358.64 mL vs 744.62 ± 306.88 mL vs 1250.60 ± 563.37 mL, p = 0.048). No significant difference was identified between the oral and IV groups (p = 0.970). The rate of allogeneic transfusion was lower in the oral and IV groups than in the control group, but the difference had no statistical significant (6 vs 5 vs 12, p = 0.108), However, subgroup analysis showed that the IV and oral groups in patients who underwent THA have significant lower transfusion rate compared with the control group (1 vs 3 vs 7, p = 0.02). During 6 months follow-up, no thromboembolic events were identified. Two patients (one from the oral group and one from the control group) died of respiratory failure. The cost of blood management from the oral group was significantly lower than IV (p < 0.001) and control groups (p = 0.009). CONCLUSION: Elderly patients with femoral neck fracture undergoing THA can benefit from both IV and oral administration of tranexamic acid. The results of these two administration routes are similar in safety and effectiveness. A similar tendency was observed in patients undergoing HA. Oral TXA is more cost-benefit compared with intravenous applications.

A Conserved Intramolecular Ion-Pair Plays a Critical but Divergent Role in Regulation of Dimerization and Transport Function among the Monoamine Transporters.

The monoamine transporters, including the serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET), are the therapeutic targets for the treatment of many neuropsychiatric disorders. Despite significant progress in characterizing the structures and transport mechanisms of these transporters, the regulation of their transport functions through dimerization or oligomerization remains to be understood. In the present study, we identified a conserved intramolecular ion-pair at the third extracellular loop (EL3) connecting TM5 and TM6 that plays a critical but divergent role in the modulation of dimerization and transport functions among the monoamine transporters. The disruption of the ion-pair interactions by mutations induced a significant spontaneous cross-linking of a cysteine mutant of SERT and an increase in cell surface expression but with an impaired specific transport activity. On the other hand, similar mutations of the corresponding ion-pair residues in both DAT and NET resulted in an opposite effect on their oxidation-induced dimerization, cell surface expression, and transport function. Reversible biotinylation experiments indicated that the ion-pair mutations slowed down the internalization of SERT but stimulated the internalization of DAT. In addition, cysteine accessibility measurements for monitoring SERT conformational changes indicated that substitution of the ion-pair residues resulted in profound effects on the rate constants for cysteine modification in both the extracellular and cytoplasmatic substrate permeation pathways. Furthermore, molecular dynamics simulations showed that the ion-pair mutations increased the interfacial interactions in a SERT dimer but decreased it in a DAT dimer. Taken together, we propose that the transport function is modulated by the equilibrium between monomers and dimers on the cell surface, which is regulated by a potential compensatory mechanism but with different molecular solutions among the monoamine transporters. The present study provided new insights into the structural elements regulating the transport function of the monoamine transporters through their dimerization.

Reciprocal inhibition between TP63 and STAT1 regulates anti-tumor immune response through interferon-γ signaling in squamous cancer.

Squamous cell carcinomas (SCCs) are common and aggressive malignancies. Immune check point blockade (ICB) therapy using PD-1/PD-L1 antibodies has been approved in several types of advanced SCCs. However, low response rate and treatment resistance are common. Improving the efficacy of ICB therapy requires better understanding of the mechanism of immune evasion. Here, we identify that the SCC-master transcription factor TP63 suppresses interferon-γ (IFNγ) signaling. TP63 inhibition leads to increased CD8+ T cell infiltration and heighten tumor killing in in vivo syngeneic mouse model and ex vivo co-culture system, respectively. Moreover, expression of TP63 is negatively correlated with CD8+ T cell infiltration and activation in patients with SCC. Silencing of TP63 enhances the anti-tumor efficacy of PD-1 blockade by promoting CD8+ T cell infiltration and functionality. Mechanistically, TP63 and STAT1 mutually suppress each other to regulate the IFNγ signaling by co-occupying and co-regulating their own promoters and enhancers. Together, our findings elucidate a tumor-extrinsic function of TP63 in promoting immune evasion of SCC cells. Over-expression of TP63 may serve as a biomarker predicting the outcome of SCC patients treated with ICB therapy, and targeting TP63/STAT/IFNγ axis may enhance the efficacy of ICB therapy for this deadly cancer.

The supplementation of Rothia as a potential preventive approach for bone loss in mice with ovariectomy-induced osteoporosis.

There is an inseparable link between bone metabolism and gut microbiota, and the supplementation of probiotics exhibits a significant role in maintaining the homeostasis of gut microbiota and inhibiting bone loss. This study aims to explore the preventive and therapeutic potentials and the specific mechanisms of Rothia on osteoporosis. The mice models of osteoporosis induced by ovariectomy (OVX) were built, and the regular (once a day) and quantitative (200 µL/d) gavage of Rothia was performed for 8 weeks starting from 1 week after OVX. Microcomputed tomography was used to analyze the bone mass and bone microstructure of mice in each group after sacrifice. Histological staining and immunohistochemistry were then applied to identify the expression of pro-inflammatory cytokines, intestinal permeability, and osteogenic and osteoclastic activities of mice. The collected feces of mice in each group were used for 16S rRNA high-throughput sequencing to detect the alterations in composition, abundance, and diversity of gut microbiota. This study demonstrated that the gavage of Rothia alleviated bone loss in mice with OVX-induced osteoporosis, improved OVX-induced intestinal mucosal barrier injury, optimized intestinal permeability (zonula occludens protein 1 and occludin), reduced intestinal inflammation (tumor necrosis factor-α and interleukin-1ß), and regulated imbalance of gut microbiota. Based on "gut-bone" axis, this study revealed that regular and quantitative gavage of Rothia can relieve bone loss in mice with OVX-induced osteoporosis by repairing the intestinal mucosal barrier injury, optimizing the intestinal permeability, inhibiting the release of pro-inflammatory cytokines, and improving the disorder of gut microbiota.

Establishing mouse and human oral esophageal organoids to investigate the tumor immune response.

Organoid culture systems are very powerful models that recapitulate in vivo organ development and disease pathogenesis, offering great promise in basic research, drug screening and precision medicine. However, the application of organoids derived from patients with cancer to immunotherapeutic research is a relatively untapped area. Esophageal cancer is one of the most lethal malignancies worldwide, including two major pathological subtypes: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma. ESCC shares many biological and genomic features with oral squamous cell cancers. Herein, we provide a versatile protocol for the establishment and maintenance of oral and esophageal organoid cultures derived from both murine and human samples. We describe culture conditions for organoids derived from normal tongue, esophagus and gastroesophageal junction, esophageal cancer and Barrett's esophagus. In addition, we establish an ex vivo model by co-culturing patient tumor-derived organoids and autologous CD8+ T lymphocytes to assess CD8+ T cell-mediated tumor killing. Our protocol can also be modified for organoid establishment from other squamous epithelia and carcinomas. The co-culture model can serve as a template for studies of other tumor-immune cell interactions and the efficacy of immune checkpoint blockade therapy.

Efficacy and safety of tranexamic acid in elderly patients with femoral neck fracture treated with hip arthroplasty: A systematic review and meta-analysis.

BACKGROUND: Elderly patients with femoral neck fracture have high perioperative blood loss according to the trauma and hip arthroplasty surgery. Tranexamic acid is a fibrinolytic inhibitor and has been widely used in hip fracture patients to against perioperative anemia. The aim of the present meta-analysis was to evaluate the efficacy and safety of Tranexamic acid (TXA) in elderly patients with femoral neck fracture undergoing hip arthroplasty. METHODS: We performed search using Pubmed, EMBASE, Cochrane Reviews, and Web of Science databases to identify all relevant research studies published from inception to June 2022. Randomized controlled studies and high-quality cohort studies that reported the perioperative use of TXA in patients with femoral neck fractures treated with arthroplasty, and made a comparison with the control group were included. Meta-analysis was performed using Review Manager 5.3 to assess the efficacy and safety of TXA. Subgroup analysis was conducted to further investigate the impact caused by surgery types and administration routes on the efficacy and safety outcomes. RESULTS: Five randomized controlled trials (RCTs) and eight cohort studies published from January 2015 to June 2022 were included in this meta-analysis. The results showed significant reductions in the rate of allogeneic blood transfusion, total blood loss (TBL) and postoperative hemoglobin (Hb) drop in the TXA group compared with the control group, while no significant difference was found in the intraoperative blood loss, postoperative drainage, hospital length of stay (LOS), re-admission rate, and wound complications between the two groups. The incidence of thromboembolic events and mortality showed no significant difference. Subgroup analysis indicated that surgery types and administration routes did not change the overall tendency. CONCLUSION: The current evidence shows that both intravascular administration (IV) and topical administration of TXA can significantly decrease the perioperative transfusion rate and TBL without increasing the risk of thromboembolic complications in elderly patients with femoral neck fracture.

The Preventive Effects of Probiotic Prevotella histicola on the Bone Loss of Mice with Ovariectomy-Mediated Osteoporosis.

It has been demonstrated that the disturbance of gut microbiota (GM) is closely related to the reduction of bone mass and incidence of osteoporosis (OP). The aim of this study is to investigate whether the supplementation of Prevotella histicola (Ph) can prevent the bone loss in mice with ovariectomy (OVX)-mediated OP, and further explore relevant mechanisms. Regular (once a day for 8 consecutive weeks) and quantitative (200 µL/d) perfusion of Ph (the bacteria that orally gavaged) was conducted starting from 1 week after the construction of mice models. Bone mass and bone microstructure were detected by Micro-computed tomography (Micro-CT). Expressions of intestinal permeability, pro-inflammatory cytokines, and osteogenic and osteoclastic activities of mice were analyzed by histological staining and immunohistochemistry (IHC). 16S rRNA high throughput sequencing technique was applied to analyze the alterations of composition, abundance, and diversity of collected feces. Regular and quantitative perfusion of Ph mitigated the bone loss in mice with OVX-mediated OP. Compared with OVX + PBS group, perfusion of Ph repressed osteoclastogenesis and promoted osteogenesis, reduced release of pro-inflammatory cytokine cytokines (interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α)), and reversed expressions of tight junction proteins (zonula occludens protein 1 (ZO-1) and Occludin). Besides, the perfusion of Ph improved the composition, abundance, and diversity of GM. Collectively, this study revealed that regular and quantitative perfusion of Ph can improve the bone loss in mice with OVX-mediated OP by repairing intestinal mucosal barrier damage, optimizing intestinal permeability, inhibiting release of pro-osteoclastogenic cytokines, and improving disturbance of GM.

Postoperative awake prone position in geriatric patients with hip fractures: a protocol for a randomized controlled trial on the efficacy of postoperative prone position in reducing pulmonary complications and improving oxygenation.

INTRODUCTION: Postoperative pulmonary complications (PPCs) are prevalent in geriatric patients with hip fractures. Low oxygen level is one of the most important risk factors for PPCs. Prone position has been proven efficacy in improving oxygenation and delaying the progress of pulmonary diseases, especially in patients with acute respiratory distress syndrome induced by multiple etiologies. The application of awake prone position (APP) has also attracted widespread attention in recent years. A randomized controlled trial (RCT) will be carried out to measure the effect of postoperative APP in a population of geriatric patients undergoing hip fracture surgery. METHODS: This is an RCT. Patients older than 65 years old admitted through the emergency department and diagnosed with an intertrochanteric or femoral neck fracture will be eligible for enrollment and assigned randomly to the control group with routine postoperative management of orthopedics or APP group with an additional prone position for the first three consecutive postoperative days (PODs). Patients receiving conservative treatment will not be eligible for enrollment. We will record the difference in the patient's room-air-breathing arterial partial pressure of oxygen (PaO2) values between the 4th POD (POD 4) and emergency visits, the morbidity of PPCs and other postoperative complications, and length of stay. The incidence of PPCs, readmission rates, and mortality rates will be followed up for 90 PODs. DISCUSSION: We describe the protocol for a single-center RCT that will evaluate the efficacy of postoperative APP treatment in reducing pulmonary complications and improving oxygenation in geriatric patients with hip fractures. ETHICS AND DISSEMINATION: This protocol was approved by the independent ethics committee (IEC) for Clinical Research of Zhongda Hospital, Affiliated to Southeast University, and is registered on the Chinese Clinical Trial Registry. The findings of the trial will be disseminated through peer-reviewed journals. ETHICS APPROVAL NUMBER: 2021ZDSYLL203-P01 TRIAL REGISTRATION: ChiCTR ChiCTR2100049311 . Registered on 29 July 2021. TRIAL STATUS: Recruiting. Recruitment is expected to be completed in December 2024.

General Anesthesia Versus Regional Anesthesia in the Elderly Patients Undergoing Hip Fracture Surgeries: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

BACKGROUND: Surgery is the preferred treatment option for the elderly patients with hip fractures. However, the choice of general anesthesia (GA) or regional anesthesia (RA) remains controversial. The quality of evidence has further improved with the advent of several high-quality randomized clinical trials (RCTs) in the last two years. The purpose of this study was to compare the clinical outcomes of two anesthetic techniques in elderly patients undergoing hip fracture surgeries. METHODS: Eligible studies were identified from PubMed/MEDLINE, Web of Science, Scopus, EMBASE and reference lists from January 2000 to June 2022 in this current systematic review and meta-analysis. The outcomes included the surgery-related outcomes (duration of surgery, duration of anesthesia, intraoperative blood loss and number of transfusions) and postoperative outcomes (30-day mortality, postoperative delirium,cardiovascular events and other complications). RESULTS: A total of 10 RCTs were included, and a total of 3594 patients were analyzed. RA was associated with shorter duration of surgery, shorter length of hospital stays and less intraoperative blood loss compared to GA. There were no significant differences between the two groups in the number of blood transfusions, duration of anesthesia, 30-day mortality or postoperative delirium. CONCLUSIONS: Our pooled analysis identified no significant differences in terms of the safety between RA and GA, while RA reduces intraoperative blood loss, length of hospital stays and duration of surgery. These results suggest that RA appears to be preferable for the elderly patients with hip fractures.

What are Risk Factors of Postoperative Pneumonia in Geriatric Individuals after Hip Fracture Surgery: A Systematic Review and Meta-Analysis.

Postoperative pneumonia (POP) is a common postoperative complication. Negative consequences associated with POP included prolonged hospital length of stay, more frequent intensive care unit (ICU) stays, and a higher rate of sepsis, readmission, and mortality. This meta-analysis aimed to assess the incidence and risk factors associated with POP after hip fracture surgery in elderly patients. PubMed, Web of Science, and Cochrane Library were searched (up to March 31, 2022). All studies on the risk factors for POP after hip fracture surgery in elderly patients, published in English, were reviewed. The qualities of the included studies were assessed using the Newcastle-Ottawa Scale. Data were pooled, and a meta-analysis was performed. Ten studies, including 12,084 geriatric patients undergoing hip fracture surgery, were included. Of these 12,084 patients, POP occurred in 809 patients. The results indicated that age (mean difference [MD] = 4.95, 95% confidence interval [CI]: 3.22-6.69), male (odds ratio [OR] = 1.41, 95% CI: 1.02-1.93), the American Society of Anaesthesiologists classification ≥3 (OR = 3.48, 95% CI: 1.87-6.47), dependent functional status (OR = 5.23, 95% CI: 2.18-12.54, P = 0.0002), smoking (OR = 1.33, 95% CI: 1.07-1.65), chronic obstructive pulmonary disease (OR = 3.76, 95% CI: 2.07-6.81), diabetes mellitus (OR = 1.19, 95% CI: 1.01-1.40), coronary heart disease (OR = 1.74, 95% CI: 1.23-2.46), arrhythmia (OR = 1.47, 95% CI: 1.01-2.14), cerebrovascular disease (OR = 1.88, 95% CI: 1.56-2.27), dementia (OR = 2.36, 95% CI: 1.04-5.36), chronic renal failure (OR = 1.85, 95% CI: 1.29-2.67), hip arthroplasty (OR = 1.30, 95% CI: 1.08-1.56), delayed surgery (OR = 6.40, 95% CI: 3.00-13.68), preoperative creatinine (MD = 5.32, 95% CI: 0.55-10.08), and preoperative serum albumin (MD = -3.01, 95% CI: -4.21 - -1.80) were risk factors for POP. Related prophylactic measures should be provided in geriatric patients with the above-mentioned risk factors to prevent POP after hip fracture surgery.

Cross-Linking and Functional Analyses for Dimerization of a Cysteine Mutant of Glycine Transporter 1.

Glycine transporter 1 (GlyT1) is responsible for the reuptake of glycine, which regulates glutamate signaling as a co-agonist with N-methyl-D-aspartic acid (NMDA) receptors in the excitatory synapse and has been proposed to be a potential target in the development of therapies for a broad range of disorders of the central nervous system. Despite significant progress in characterizing structure and transport mechanism of the transporter, the regulation of transport function through oligomerization remains to be understood. In the present work, association of two forms of GlyT1 into dimers and higher order oligomers was detected by coimmunoprecipitation. To investigate functional properties of dimers of a GlyT1 cysteine mutant L288C, we performed oxidative cross-linking of the positioned cysteine residues in extracellular loop 3 (EL3) near the extracellular end of TM6. By analyzing the effect of copper phenanthroline (CuP)-induced dimerization on transport function, cross-linking of L288C was found to inhibit transport activity. In addition, an intramolecular ion pair Lys286-Glu289 was revealed to be critical for stabilizing EL3 in a conformation that modulates CuP-induced dimerization and transport function of the GlyT1 L288C mutant. Furthermore, the influence of transporter conformation on GlyT1 L288C dimerization was investigated. The substrate glycine, in the presence of both Na+ and Cl-, significantly reduced oxidative cross-linking, suggesting a large-scale rotation of the bundle domain during substrate transport impairs interfacial interactions between L288C protomers. The present study provides new insights into structural and functional elements regulating GlyT1 transport activity through its dimerization or oligomerization.

Fecal microbiota transplantation ameliorates bone loss in mice with ovariectomy-induced osteoporosis via modulating gut microbiota and metabolic function.

Background: Osteoporosis (OP) is a systemic metabolic bone disease characterized by decreased bone mass and destruction of bone microstructure, which tends to result in enhanced bone fragility and related fractures. The postmenopausal osteoporosis (PMOP) has a relatively high proportion, and numerous studies reveal that estrogen-deficiency is related to the imbalance of gut microbiota (GM), impaired intestinal mucosal barrier function and enhanced inflammatory reactivity. However, the underlying mechanisms remain unclear and the existing interventions are also scarce. Methods: In this study, we established a mouse model induced by ovariectomy (OVX) and conducted fecal microbiota transplantation (FMT) by gavage every day for 8 weeks. Subsequently, the bone mass and microarchitecture of mice were evaluated by the micro computed tomography (Micro-CT). The intestinal permeability, pro-osteoclastogenic cytokines expression, osteogenic and osteoclastic activities were detected by the immunohistological analysis, histological examination, enzyme-linked immunosorbent assay (ELISA) and western blot analysis accordingly. Additionally, the composition and abundance of GM were assessed by 16S rRNA sequencing and the fecal short chain fatty acids (SCFAs) level was measured by metabolomics. Results: Our results demonstrated that FMT inhibited the excessive osteoclastogenesis and prevented the OVX-induced bone loss. Specifically, compared with the OVX group, FMT enhanced the expressions of tight junction proteins (zonula occludens protein 1 (ZO-1) and Occludin) and suppressed the release of pro-osteoclastogenic cytokines (tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß)). Furthermore, FMT also optimized the composition and abundance of GM, and increased the fecal SCFAs level (mainly acetic acid and propionic acid). Conclusions: Collectively, based on GM-bone axis, FMT prevented the OVX-induced bone loss by correcting the imbalance of GM, improving the SCFAs level, optimizing the intestinal permeability and suppressing the release of pro-osteoclastogenic cytokines, which may be an alternative option to serve as a promising candidate for the prevention and treatment of PMOP in the future. The translational potential of this article: This study indicates the ingenious involvement of GM-bone axis in PMOP and the role of FMT in reshaping the status of GM and ameliorating the bone loss in OVX-induced mice. FMT might serve as a promising candidate for the prevention and treatment of PMOP in the future.

Determining Ligand and Ion-Induced Conformational Changes in Serotonin Transporter with Its Fluorescent Substrates.

Conformational changes are fundamental events in the transport mechanism. The serotonin transporter (SERT) catalyzes reuptake of the neurotransmitter serotonin after its release by serotonergic neurons and is the molecular target for antidepressant drugs and psychostimulants. Despite significant progress in characterizing the structure-function relationship of SERT, its conformational mechanism has not been fully understood. We present here a cell-based method for determining conformational changes in SERT with its fluorescent substrates by fluorescence imaging analysis. This method fluorometrically measures accessibility of strategically positioned cysteine residues in the substrate permeation pathway to calculate the rate constants of reactivity with MTS reagents in live or permeabilized cells. We validated this method by investigating ligand and ion-induced conformational changes in both the extracellular and cytoplasmic pathways of SERT. Furthermore, we applied this method for examining the influence of Cl- binding and vilazodone inhibition on SERT conformation. Our results showed that Cl- ion, in the presence of Na+, facilitates the conformational conversion from outward to inward open states, and that vilazodone binding stabilizes SERT in an outward open and inward-closed conformation. The present work provided insights into the conformational mechanism of SERT and also indicated that the cell-based fluorometric method is robust, straightforward to perform, and potentially applicable to any monoamine transporters in exploring the transport mechanism and mechanism of action of therapeutic agents for the treatment of several psychiatric disorders.

A systematic review of ankle fracture-dislocations: Recent update and future prospects.

Background: Ankle fracture-dislocations are one of the most severe types of ankle injuries. Compared to the simple ankle fractures, ankle fracture-dislocations are usually more severely traumatized and can cause worse functional outcomes. The purpose of this study was to review the previous literatures to understand the anatomy, mechanisms, treatment, and functional outcomes associated with ankle fracture-dislocations. Methods: The available literatures from January 1985 to December 2021 in three main medical databases were searched and analyzed. The detailed information was extracted for each article, such as researchers, age, gender, groups, type of study, type of center research, level of evidence, significant findings, study aim, cause of injury, time from injury to surgery, type of fracture, direction of dislocation, follow-up, postoperative complications and functional evaluation scores. Results: A total of 15 studies (1,089 patients) met the inclusion criteria. Only one study was a prospective randomized trial. The top-ranked cause of injury was high-energy injury (21.3%). Moreover, the most frequent type of fracture in ankle dislocations was supination-external rotation (SER) ankle fracture (43.8%), while the most common directions of dislocation were lateral (50%) and posterior (38.9%). Conclusions: Collectively, most ankle fracture-dislocations are caused by high-energy injuries and usually have poor functional outcomes. The mechanism of injury can be dissected by the ankle anatomy and Lauge-Hansen's classification. The treatment of ankle fracture-dislocations still requires more detailed and rational solutions due to the urgency of occurrence, the severity of injury, and the postoperative complications.

The Efficacy and Safety of Intravenous Iron in Geriatric Hip Fracture Surgeries: A Systematic Review and Meta-Analysis.

BACKGROUND: With the increasing evidence provided by recent high-quality studies, the intravenous iron appears to be a reliable therapy for blood administration in geriatric patients with hip fractures. Here, this systematic review and meta-analysis were aimed to assess the effectiveness and safety of intravenous iron in geriatric patients sustaining hip fractures. METHODS: Potential pertinent literatures evaluating the effects of intravenous iron in the geriatric patients undergoing hip fractures were identified from Web of Science, PubMed, Embase, and Scopus. We performed a pairwise meta-analysis using fixed- and random-effects models, and the pooling of data was carried out by using RevMan 5.1. RESULTS: Four randomized controlled trials and four observational studies conform to inclusion criteria. The results of meta-analysis showed that intravenous iron reduced transfusion rates compared to the control group, yet the result did not reach statistical significance. The intravenous iron was related to lower transfusion volumes, shorter length of stay, and a reduced risk of nosocomial infections. And there was no significant difference in terms of the mortality and other complications between the treatment group and the control group. CONCLUSION: Current evidence suggests that intravenous iron reduces the transfusion volume, length of hospital stay, and risk of nosocomial infections. It takes about 7 days for intravenous iron to elevate hemoglobin by 1 g/dl and about 1 month for 2 g/dl. The safety profile of intravenous iron is also reassuring, and additional high-quality studies are needed.

A recurrent homozygous missense mutation in CCDC103 causes asthenoteratozoospermia due to disorganized dynein arms.

Asthenoteratozoospermia is one of the most severe types of qualitative sperm defects. Most cases are due to mutations in genes encoding the components of sperm flagella, which have an ultrastructure similar to that of motile cilia. Coiled-coil domain containing 103 (CCDC103) is an outer dynein arm assembly factor, and pathogenic variants of CCDC103 cause primary ciliary dyskinesia (PCD). However, whether CCDC103 pathogenic variants cause severe asthenoteratozoospermia has yet to be determined. Whole-exome sequencing (WES) was performed for two individuals with nonsyndromic asthenoteratozoospermia in a consanguineous family. A homozygous CCDC103 variant segregating recessively with an infertility phenotype was identified (ENST00000035776.2, c.461A>C, p.His154Pro). CCDC103 p.His154Pro was previously reported as a high prevalence mutation causing PCD, though the reproductive phenotype of these PCD individuals is unknown. Transmission electron microscopy (TEM) of affected individuals' spermatozoa showed that the mid-piece was severely damaged with disorganized dynein arms, similar to the abnormal ultrastructure of respiratory ciliary of PCD individuals with the same mutation. Thus, our findings expand the phenotype spectrum of CCDC103 p.His154Pro as a novel pathogenic gene for nonsyndromic asthenospermia.

Two Lignan Glycosides from Albizia julibrissin Durazz. Noncompetitively Inhibit Serotonin Transporter.

Albizia julibrissin Durazz. is one of the most common herbs used for depression and anxiety treatment, but its molecular basis and mechanism of action as an antidepressant or anxiolytic drug are not understood. In this study, we separated and identified two lignan glycosides that inhibit serotonin transporter (SERT) noncompetitively by decreasing Vmax with little change in Km for its fluorescence substrate. In addition, treatment with lignan glycosides did not alter total and cell surface expression levels of the transporter protein. The two compounds decreased the accessibility of a cysteine residue placed in the extracellular substrate permeation pathway by inducing a conformational shift toward an outward-closed state of SERT. These results are consistent with molecular docking for the association of the lignan glycosides to the allosteric site in SERT. The present work supports the proposal that these compounds act on SERT by a novel underlying mechanism of action different from that of conventional antidepressant drugs.

3D Mapping of the Lateral Malleolus Fractures for Predicting Syndesmotic Injuries in Supination External Rotation Type Ankle Fractures.

Supination external rotation (SER) type ankle fracture is the most common ankle fracture in the Lauge-Hansen classification and is often accompanied with syndesmotic injury. However, the mechanism of this injury is indistinct and a suggestive role can be given by preoperative imaging. This study was to preoperatively predict whether SER type ankle fractures are accompanied with syndesmotic injuries by the means of lateral malleolus fracture mapping. One hundred and forty-eight patients diagnosed with SER type ankle fractures were retrospectively enrolled in this study. The baseline data were collected and computed tomography data were reconstructed in 3-dimensional (3D) model. Patients were divided into stable and unstable groups according to intraoperative Cotton test and whether the inferior tibiofibular screw was placed. All fracture lines were superimposed on the ankle template to create a fracture map, and the data on the fracture map were further measured. Logistic regression was conducted to identify relevant factors and the cutoff values were given using receiver operating characteristic curves. Forty-one patients were enrolled in the unstable group and 107 patients were enrolled in the stable group. The lateral malleolus fracture lines of the unstable group were higher and steeper than that in the stable group on lateral and posterior views. The fracture height of the posterior cortex and peak height were the significant contributing factors, and the cut-off values of posterior cortex, peak height and inclination angle were 40.35 mm (sensitivity: 78%, specificity: 82%), 55.34 mm (sensitivity: 85%, specificity: 70%) and 55.6° (sensitivity: 66%, specificity: 86%), respectively. In general, when the fracture lines of the lateral malleolus were high and steep, it was usually indicative of a syndesmotic injury and can be predicted by the preoperative 3D reconstruction of fracture height of posterior cortex, peak height and inclination angle. If the cut-off values of these indicators are exceeded, the syndesmotic injuries may be presented and need to be verified in the intraoperative Cotton test to decide whether to insert an inferior tibiofibular screw.

The Novel Application of Three-Dimensional Printing Assisted Patient-Specific Instrument Osteotomy Guide in the Precise Osteotomy of Adult Talipes Equinovarus.

OBJECTIVE: This current research is aimed at assessing clinical efficacy and prognosis of three-dimensional (3D) printing assisted patient-specific instrument (PSI) osteotomy guide in precise osteotomy of adult talipes equinovarus (ATE). METHODS: We included a total of 27 patients of ATE malformation (including 12 males and 15 females) from June 2014 to June 2018 in the current research. The patients were divided into the routine group (n = 12) and 3D printing group (n = 15) based on different operative methods. The parameters, including the operative time, intraoperative blood loss, complications, time to obtain bony fusion, functional outcomes based on American Orthopedic Foot and Ankle Society (AOFAS), and International Congenital Clubfoot Study group (ICFSG) scoring systems between the two groups were observed and recorded regularly. RESULTS: The 3D printing group exhibits superiorities in shorter operative time, less intraoperative blood loss, higher rate of excellent, and good outcomes presented by ICFSG score at last follow-up (P < 0.001, P < 0.001, P = 0.019) than the routine group. However, there was no significant difference exhibited in the AOFAS score at the last follow-up and total rate of complications between the two groups (P = 0.136, P = 0.291). CONCLUSION: Operation assisted by 3D printing PSI osteotomy guide for correcting the ATE malformation is novel and feasible, which might be an effective method to polish up the precise osteotomy of ATE malformation and enhance the clinical efficacy.

Coiled-Coil Domain Containing 80 Suppresses Nonylphenol-Induced Colorectal Cancer Cell Proliferation by Inhibiting the Activation of ERK1/2.

Recently, the effect of endocrine-disrupting chemicals on the cancer procession has been a concern. Nonylphenol (NP) is a common environmental estrogen that has been shown to enhance the proliferation of colorectal cancer (CRC) cells in our previous studies; however, the underlying mechanism remains unclear. In this study, we confirmed the increased concentration of NP in the serum of patients with CRC. RNA sequencing was used to explore the differentially expressed genes after NP exposure. We found 16 upregulated genes and 12 downregulated genes in COLO205 cells after NP treatment. Among these differentially expressed genes, we found that coiled-coil domain containing 80 (CCDC80) was downregulated by NP treatment and was associated with CRC progression. Further experiments revealed that the overexpression of CCDC80 significantly suppressed NP-induced cell proliferation and recovered the reduced cell apoptosis. Meanwhile, the overexpression of CCDC80 significantly inhibited the activation of ERK1/2 induced by NP treatment. ERK1/2 inhibitor (PD98059) treatment also suppressed NP-induced CRC cell growth, but the overexpression of CCDC80 did not enhance the effect of ERK1/2 inhibitor. Taken together, NP treatment significantly inhibited the expression of CCDC80, and the overexpression of CCDC80 suppressed NP-induced CRC cell growth by inhibiting the activation of ERK1/2. These results suggest that NP could induce CRC cell growth by influencing the expression of multiple genes. CCDC80 and ERK1/2 inhibitors may be suitable therapeutic targets in NP-related CRC progression.