ARAF mutations confer resistance to the RAF inhibitor belvarafenib in melanoma.

Although RAF monomer inhibitors (type I.5, BRAF(V600)) are clinically approved for the treatment of BRAFV600-mutant melanoma, they are ineffective in non-BRAFV600 mutant cells1-3. Belvarafenib is a potent and selective RAF dimer (type II) inhibitor that exhibits clinical activity in patients with BRAFV600E- and NRAS-mutant melanomas. Here we report the first-in-human phase I study investigating the maximum tolerated dose, and assessing the safety and preliminary efficacy of belvarafenib in BRAFV600E- and RAS-mutated advanced solid tumours (NCT02405065, NCT03118817). By generating belvarafenib-resistant NRAS-mutant melanoma cells and analysing circulating tumour DNA from patients treated with belvarafenib, we identified new recurrent mutations in ARAF within the kinase domain. ARAF mutants conferred resistance to belvarafenib in both a dimer- and a kinase activity-dependent manner. Belvarafenib induced ARAF mutant dimers, and dimers containing mutant ARAF were active in the presence of inhibitor. ARAF mutations may serve as a general resistance mechanism for RAF dimer inhibitors as the mutants exhibit reduced sensitivity to a panel of type II RAF inhibitors. The combination of RAF plus MEK inhibition may be used to delay ARAF-driven resistance and suggests a rational combination for clinical use. Together, our findings reveal specific and compensatory functions for the ARAF isoform and implicate ARAF mutations as a driver of resistance to RAF dimer inhibitors.

15-epi-lipoxin A5 promotes neutrophil exit from exudates for clearance by splenic macrophages.

Specialized proresolving mediators (SPMs) promote local macrophage efferocytosis but excess leukocytes early in inflammation require additional leukocyte clearance mechanism for resolution. Here, neutrophil clearance mechanisms from localized acute inflammation were investigated in mouse dorsal air pouches. 15-HEPE (15-hydroxy-5Z,8Z,11Z,13E,17Z-eicosapentaenoic acid) levels were increased in the exudates. Activated human neutrophils converted 15-HEPE to lipoxin A5 (5S,6R,15S-trihydroxy-7E,9E,11Z,13E,17Z-eicosapentaenoic acid), 15-epi-lipoxin A5 (5S,6R,15R-trihydroxy-7E,9E,11Z,13E,17Z-eicosapentaenoic acid), and resolvin E4 (RvE4; 5S,15S-dihydroxy-6E,8Z,11Z,13E,17Z-eicosapentaenoic acid). Exogenous 15-epi-lipoxin A5, 15-epi-lipoxin A4 and a structural lipoxin mimetic significantly decreased exudate neutrophils and increased local tissue macrophage efferocytosis, with comparison to naproxen. 15-epi-lipoxin A5 also cleared exudate neutrophils faster than the apparent local capacity for stimulated macrophage efferocytosis, so the fate of exudate neutrophils was tracked with CD45.1 variant neutrophils. 15-epi-lipoxin A5 augmented the exit of adoptively transferred neutrophils from the pouch exudate to the spleen, and significantly increased splenic SIRPa+ and MARCO+ macrophage efferocytosis. Together, these findings demonstrate new systemic resolution mechanisms for 15-epi-lipoxin A5 and RvE4 in localized tissue inflammation, which distally engage the spleen to activate macrophage efferocytosis for the clearance of tissue exudate neutrophils.

ISM1 protects lung homeostasis via cell-surface GRP78-mediated alveolar macrophage apoptosis.

Alveolar macrophages (AMs) are critical for lung immune defense and homeostasis. They are orchestrators of chronic obstructive pulmonary disease (COPD), with their number significantly increased and functions altered in COPD. However, it is unclear how AM number and function are controlled in a healthy lung and if changes in AMs without environmental assault are sufficient to trigger lung inflammation and COPD. We report here that absence of isthmin 1 (ISM1) in mice (Ism1-/- ) leads to increase in both AM number and functional heterogeneity, with enduring lung inflammation, progressive emphysema, and significant lung function decline, phenotypes similar to human COPD. We reveal that ISM1 is a lung resident anti-inflammatory protein that selectively triggers the apoptosis of AMs that harbor high levels of its receptor cell-surface GRP78 (csGRP78). csGRP78 is present at a heterogeneous level in the AMs of a healthy lung, but csGRP78high AMs are expanded in Ism1-/- mice, cigarette smoke (CS)-induced COPD mice, and human COPD lung, making these cells the prime targets of ISM1-mediated apoptosis. We show that csGRP78high AMs mostly express MMP-12, hence proinflammatory. Intratracheal delivery of recombinant ISM1 (rISM1) depleted csGRP78high AMs in both Ism1-/- and CS-induced COPD mice, blocked emphysema development, and preserved lung function. Consistently, ISM1 expression in human lungs positively correlates with AM apoptosis, suggesting similar function of ISM1-csGRP78 in human lungs. Our findings reveal that AM apoptosis regulation is an important physiological mechanism for maintaining lung homeostasis and demonstrate the potential of pulmonary-delivered rISM1 to target csGRP78 as a therapeutic strategy for COPD.

Agricultural waste-based modified biochars differentially affected the soil properties, growth, and nutrient accumulation by maize (Zea mays L.) plants.

Biochar (BC) is an organic compound formed by the pyrolysis of organic wastes. Application of BCs as soil amendments has many benefits including carbon sequestration, enhanced soil fertility and sustainable agriculture production. In the present study, we acidified the different BCs prepared from rice straw, rice husk, wheat straw, cotton stalk, poultry manure, sugarcane press mud and vegetable waste; following which, we applied them in a series of pot experiments. Comparisons were made between acidified and non- acidified BCs for their effects on seed germination, soil properties (EC, pH) nutrient contents (P, K, Na) and organic matter. The treatments comprised of a control, and all above-described BCs (acidified as well as non-acidified) applied to soil at the rate of 1% (w/w). The maize crop was selected as a test crop. The results showed that acidified poultry manure BC significantly improved germination percentage, shoot length, and biomass of maize seedlings as compared to other BCs and their respective control plants. However, acidified BCs caused a significant decrease in nutrient contents (P, K, Na) of soil,maize seedlings, and the soil organic matter contents as compared to non- acidified BCs. But when compared with control treatments, all BCs treatments (acidified and non-acidified) delivered higher levels of nutrients and organic matter contents. It was concluded that none of the BCs (acidified and non-acidified) had caused negative effect on soil conditions and growth of maize. In addition, the acidification of BC prior to its application to alkaline soils might had altered soil chemistry and delivered better maize growth. Moving forward, more research is needed to understand the long-term effects of modified BCs on nutrient dynamics in different soils. In addition, the possible effects of BC application timings, application rates, particle size, and crop species have to be evaluated systemtically.

Effects of biochar types on seed germination, growth, chlorophyll contents, grain yield, sodium, and potassium uptake by wheat (Triticum aestivum L.) under salt stress.

Soil salinity is a significant challenge in agriculture, particularly in arid and semi-arid regions such as Pakistan, leading to soil degradation and reduced crop yields. The present study assessed the impact of different salinity levels (0, 25, and 50 mmol NaCl) and biochar treatments (control, wheat-straw biochar, rice-husk biochar, and sawdust biochar applied @ 1% w/w) on the germination and growth performance of wheat. Two experiments: a germination study and a pot experiment (grown up to maturity), were performed. The results showed that NaCl-stress negatively impacted the germination parameters, grain, and straw yield, and agronomic and soil parameters. Biochar treatments restored these parameters compared to control (no biochar), but the effects were inconsistent across NaCl levels. Among the different biochars, wheat-straw biochar performed better than rice-husk and sawdust-derived biochar regarding germination and agronomic parameters. Biochar application notably increased soil pHs and electrical conductivity (ECe). Imposing NaCl stress reduced K concentrations in the wheat shoot and grains with concomitant higher Na concentrations in both parts. Parameters like foliar chlorophyll content (a, b, and total), stomatal and sub-stomatal conductance, and transpiration rate were also positively influenced by biochar addition. The study confirmed that biochar, particularly wheat-straw biochar, effectively mitigated the adverse effects of soil salinity, enhancing both soil quality and wheat growth. The study highlighted that biochar application can minimize the negative effects of salinity stress on wheat. Specifically, the types and dosages of biochar have to be optimized for different salinity levels under field conditions.

Prospective assessment of dynamic changes in frailty and its impact on early clinical outcomes following physician-modified fenestrated-branched endovascular repair of complex abdominal and thoracoabdominal aortic aneurysms.

INTRODUCTION: Frailty, a predictor of poor outcomes, has been widely studied as a screening tool in surgical decision-making. However, the impact of frailty on the outcomes after fenestrated-branched endovascular aortic repairs (FBEVARs) is less well established. In addition, the changes in frailty during recovery after FBEVAR are unknown. We aim to assess the impact of frailty on outcomes of high-risk patients undergoing physician-modified FBEVARs for complex abdominal and thoracoabdominal aortic aneurysms, as well as the changes in frailty during follow-up. METHODS: Consecutive patients enrolled in a single-center prospective Physician-Sponsored Investigational Device Exemption protocol (FDA# G200159) were evaluated. In addition to the baseline characteristics, frailty was assessed using the Hopkins Frailty Score (HFS) and frailty index (FI) measured by the Frailty Meter. Sarcopenia was measured by L3 total psoas muscle area (PMA). These measurements were repeated during follow-up. The follow-up HFS and FI were compared with baseline scores using the Wilcoxon signed-rank test, whereas follow-up PMA measurements were compared with the baseline using the paired t test. The association between baseline frailty and morbidity was evaluated by the Wilcoxon rank-sum test. RESULTS: Seventy patients were analyzed in a prospective Physician-Sponsored Investigational Device Exemption study from February 9, 2021, to June 2, 2023. At baseline, HFS identified 54% of patients as not frail, 43% as intermediately frail, and 3% as frail. Technical success of FBEVAR was 94% with one in-hospital mortality. Early major adverse events were seen in 10 (14.3%) patients. No difference in baseline FI was seen between patients with early morbidity and those without. Patients who were not frail per HFS were less likely to experience early morbidity (P = .033), and there was a significantly lower baseline PMA in patients who experienced early morbidity (P = .016). At 1 month, patients experienced a significant increase in HFS and HFS category (P = .001 and P = .01) and a significant decrease in sarcopenia (mean PMA: -96 mm2, P = .005). At 6 months, HFS and HFS category as well as PMA returned toward baseline (P = .42, P = .38, and mean PMA: +4 mm2, P = .6). CONCLUSIONS: Preoperative frailty and sarcopenia were associated with early morbidity after physician-modified FBEVAR. During follow-up, patients became more frail and sarcopenic by 1 month. Recovery from this initial decline was seen by 6 months, suggesting that frailty and sarcopenia are reversible processes rather than a unidirectional phenomenon of continued decline.

Atopic Dermatitis Severity and Risk for Psoriasis: A Nationwide Population-Based Study.

INTRODUCTION: As research on the role of the Th17/IL-23 pathway gains importance, the relationship between atopic dermatitis (AD) and psoriasis is becoming elucidated. OBJECTIVE: The objective of this study wasto evaluate whether AD and its severity affect the risk for psoriasis. METHODS: This retrospective population-based study used the database from the 2009 National Health Insurance Services-Health Screening Cohort in Korea. A total of 3,957,922 adult subjects were included and observed until 2018. The primary outcome was newly diagnosed psoriasis. RESULTS: After adjusting for possible confounding factors, the moderate-to-severe AD group had the highest hazard ratio (HR) for psoriasis (HR = 2.50; 95% confidence interval (CI), 2.40-2.61), followed by the mild AD group (HR = 2.31; 95% CI: 2.19-2.44) compared with the non-AD group during a median 8.11 ± 1.19 years of follow-up. LIMITATIONS: It is difficult to define AD, which is not standardized, using a claims database and exclude patients who were misdiagnosed with AD. CONCLUSION: Patients with severe AD showed an increased risk for psoriasis compared to controls, and the risk for psoriasis was increased according to AD severity. This suggests that psoriasis and AD could share inflammatory, immune, and genetic features.

Natural Products for the Management of Asthma and COPD.

Chronic airway inflammatory diseases like asthma, chronic obstructive pulmonary disease (COPD), and their associated exacerbations cause significant socioeconomic burden. There are still major obstacles to effective therapy for controlling severe asthma and COPD progression. Advances in understanding the pathogenesis of the two diseases at the cellular and molecular levels are essential for the development of novel therapies. In recent years, significant efforts have been made to identify natural products as potential drug leads for treatment of human diseases and to investigate their efficacy, safety, and underlying mechanisms of action. Many major active components from various natural products have been extracted, isolated, and evaluated for their pharmacological efficacy and safety. For the treatment of asthma and COPD, many promising natural products have been discovered and extensively investigated. In this chapter, we will review a range of natural compounds from different chemical classes, including terpenes, polyphenols, alkaloids, fatty acids, polyketides, and vitamin E, that have been demonstrated effective against asthma and/or COPD and their exacerbations in preclinical models and clinical trials. We will also elaborate in detail their underlying mechanisms of action unraveled by these studies and discuss new opportunities and potential challenges for these natural products in managing asthma and COPD.

Rapid response of nail psoriasis to secukinumab in patients with moderate to severe psoriasis after 12 weeks of treatment with a total of 24 weeks of follow-up.

BACKGROUND/OBJECTIVES: Nail psoriasis, a subtype of psoriasis, can cause significant pain, disability, and reduced quality of life. Despite the established efficacy of anti-IL17 secukinumab in improving skin psoriasis, there is a lack of clinical trials focusing on nail psoriasis as primary endpoint. This study aims to investigate the efficacy of secukinumab in treating nail psoriasis in patients with moderate to severe psoriasis. METHODS: We prospectively recruited patients newly diagnosed with moderate to severe psoriasis in single centre from January 2021 to January 2022 who were treated with secukinumab. RESULTS: A total of 16 patients consisting of 9 males and 7 females were included. Their mean age was 38.88 ± 10.29 years. They had an average initial Nail Psoriasis Severity Index (NAPSI) score of 45.06 ± 20.39 and an average NAPSI score at 12 weeks of 8.94 ± 13.50, showing a significant (p < 0.05) decrease of NAPSI score after 12 weeks of secukinumab treatment. After 24 weeks of treatment, NAPSI score was decreased to 5.12 ± 8.52. CONCLUSION: Secukinumab rapidly improved nail psoriasis after 12 weeks of treatment, with further enhancement at 24 weeks, suggesting its potential as a potent therapeutic option for nail psoriasis.

[Evidence mapping of traditional Chinese medicine intervention in diabetic retinopathy].

This study aims to assess the quality of evidence for the treatment of diabetic retinopathy with traditional Chinese medicine based on the systematic reviews/Meta-analyses of relevant studies. CNKI, Wanfang, VIP, SinoMed, PubMed, Web of Science, EMbase, and Cochrane Library were searched for the systematic reviews/Meta-analyses of traditional Chinese medicine interventions in diabetic retinopathy published from the inception to November 2023. A Measurement Tool to Assess Systematic Reviews 2(AMSTAR2) scale was used to assess the methodological quality of the included studies. An evidence map was built to present the information on intervention measures, the number of studies included in the systematic reviews/Meta-analyses, research conclusions, and methodological quality assessment results. A total of 51 studies were included. Traditional Chinese medicine interventions accounted for a large proportion of the intervention measures, followed by Chinese patent medicines. The treatment methods mainly included tonifying deficiency, activating blood, and resolving stasis. According to the AMSTAR2 scale assessment results, the descriptions of funding information for included studies, lists of excluded articles, and preliminary research protocols were particularly lacking. The evidence map showed that 48, 2, and 1 studies concluded with beneficial effects, possible beneficial effects, and unclear effects, respectively. On the whole, traditional Chinese medicine demonstrated definite efficacy in the treatment of diabetic retinopathy, while the evidence pre-sents moderate to low quality. It is suggested that higher-quality studies remain to be carried out to provide more evidence.

Eosinophil Phenotypes Are Functionally Regulated by Resolvin D2 during Allergic Lung Inflammation.

Eosinophils (Eos) reside in multiple organs during homeostasis and respond rapidly to an inflammatory challenge. Although Eos share chemical staining properties, they also demonstrate phenotypic and functional plasticity that is not fully understood. Here, we used a murine model of allergic lung inflammation to characterize Eos subsets and determine their spatiotemporal and functional regulation during inflammation and its resolution in response to resolvin D2 (RvD2), a potent specialized proresolving mediator. Two Eos subsets were identified by CD101 expression with distinct anatomic localization and transcriptional signatures at baseline and during inflammation. CD101low Eos were predominantly located in a lung vascular niche and responded to allergen challenge by moving into the lung interstitium. CD101high Eos were predominantly located in bronchoalveolar lavage (BAL) and extravascular lung, only present during inflammation, and had transcriptional evidence for cell activation. RvD2 reduced total Eos numbers and changed their phenotype and activation by at least two distinct mechanisms: decreasing interleukin 5-dependent recruitment of CD101low Eos and decreasing conversion of CD101low Eos to CD101high Eos. Collectively, these findings indicate that Eos are a heterogeneous pool of cells with distinct activation states and spatiotemporal regulation during resolution of inflammation and that RvD2 is a potent proresolving mediator for Eos recruitment and activation.

Primary cilia: Structure, dynamics, and roles in cancer cells and tumor microenvironment.

Despite the initiation of tumor arises from tumorigenic transformation signaling in cancer cells, cancer cell survival, invasion, and metastasis also require a dynamic and reciprocal association with extracellular signaling from tumor microenvironment (TME). Primary cilia are the antenna-like structure that mediate signaling sensation and transduction in different tissues and cells. Recent studies have started to uncover that the heterogeneous ciliation in cancer cells and cells from the TME in tumor growth impels asymmetric paracellular signaling in the TME, indicating the essential functions of primary cilia in homeostasis maintenance of both cancer cells and the TME. In this review, we discussed recent advances in the structure and assembly of primary cilia, and the role of primary cilia in tumor and TME formation, as well as the therapeutic potentials that target ciliary dynamics and signaling from the cells in different tumors and the TME.

Single-cell RNA sequencing reveals species-specific time spans of cell cycle transitions in early oogenesis.

Oogenesis is a highly regulated process and its basic cellular events are evolutionarily conserved. However, the time spans of oogenesis differ substantially among species. To explore these interspecies differences in oogenesis, we performed single-cell RNA-sequencing on mouse and monkey female germ cells and downloaded the single-cell RNA-sequencing data of human female germ cells. The cell cycle analyses indicate that the period and extent of cell cycle transitions are significantly different between the species. Moreover, hierarchical clustering of critical cell cycle genes and the interacting network of cell cycle regulators also exhibit distinguished patterns across species. We propose that differences in the regulation of cell cycle transitions may underlie female germ cell developmental allochrony between species. A better understanding of the cell cycle transition machinery will provide new insights into the interspecies differences in female germ cell developmental time spans.

Bioconversion of retinol and its cell barrier function in human immortalized keratinocytes cells and artificial epidermis-dermis skin.

The current study aimed to characterize cellular uptake and bioconversion of retinol in fully differentiated human immortalized keratinocytes cells (HaCaT) and artificial skin by measuring the cell integrity of skin barriers, time-dependent transport of retinol, and bioconversion to its metabolites. The expression of epidermal differentiation related genes including Keratin 1 (KRT1), Keratin 10 (KRT10), and Involucrin (IVL) significantly increased in differentiated HaCaT. TEER of HaCaT did not decrease after incubating retinol compared to control (p > 0.05), indicating that retinol tends to maintain strength and integrity of epidermal barrier. TEER of artificial skin decreased treatment of retinol for 2 h, but it was recovered after 4 h. During retinol transport, metabolite was eluted at 13.37 and 13.82 min of basal medium of both keratinocytes and artificial skin, which was identified as retinoic acid by product ion of m/z 283.47. Retinol appeared to be accumulated in keratinocytes, but its uptake tends to be reduced in a time-dependent manner. Retinoic acid converted from retinol in keratinocytes was time dependently transported. In case of artificial skin, retinol was mostly found in apical at initial incubation time, but it was reduced during incubation for 24 h. Retinoic acid was time-dependently found in a basal, which was converted via epidermis-dermis. Results from the current study suggest that topical application of retinol to human skin optimal concentration and time exposure could maintain epidermal barrier function and promote skin function due to its remarkable bioconversion to retinoic acid in the epidermis-dermis.

Kinetochore scaffold 1 regulates SAC function during mouse oocyte meiotic maturation.

Precise regulation of chromosome separation through spindle assembly checkpoint (SAC) during oocyte meiosis is critical for mammalian reproduction. The kinetochore plays an important role in the regulation of SAC through sensing microtubule tension imbalance or missing microtubule connections. Here, we report that kinetochore scaffold 1 (KNL1, also known as CASC5), an outer kinetochore protein, plays a critical role in the SAC function of mouse oocytes. KNL1 localized at kinetochores from GVBD to the MII stage, and microinjection of KNL1-siRNA caused accelerated metaphase-anaphase transition and premature first meiosis completion, producing aneuploid eggs. The SAC was prematurely silenced in the presence of unstable kinetochore-microtubule attachments and misaligned chromosomes in KNL1-depleted oocytes. Additionally, KNL1 and MPS1 had a synergistic effect on the activation and maintenance of SAC. Taken together, our results suggest that KNL1, as a kinetochore platform protein, stabilizes SAC to ensure timely anaphase entry and accurate chromosome segregation during oocyte meiotic maturation.

FDG metabolic parameter-based models for predicting recurrence after upfront surgery in synchronous colorectal cancer liver metastasis.

OBJECTIVE: This study aimed to develop and validate post- and preoperative models for predicting recurrence after curative-intent surgery using an FDG PET-CT metabolic parameter to improve the prognosis of patients with synchronous colorectal cancer liver metastasis (SCLM). METHODS: In this retrospective multicenter study, consecutive patients with resectable SCLM underwent upfront surgery between 2006 and 2015 (development cohort) and between 2006 and 2017 (validation cohort). In the development cohort, we developed and internally validated the post- and preoperative models using multivariable Cox regression with an FDG metabolic parameter (metastasis-to-primary-tumor uptake ratio [M/P ratio]) and clinicopathological variables as predictors. In the validation cohort, the models were externally validated for discrimination, calibration, and clinical usefulness. Model performance was compared with that of Fong's clinical risk score (FCRS). RESULTS: A total of 374 patients (59.1 ± 10.5 years, 254 men) belonged in the development cohort and 151 (60.3 ± 12.0 years, 94 men) in the validation cohort. The M/P ratio and nine clinicopathological predictors were included in the models. Both postoperative and preoperative models showed significantly higher discrimination than FCRS (p < .05) in the external validation (time-dependent AUC = 0.76 [95% CI 0.68-0.84] and 0.76 [0.68-0.84] vs. 0.65 [0.57-0.74], respectively). Calibration plots and decision curve analysis demonstrated that both models were well calibrated and clinically useful. The developed models are presented as a web-based calculator ( https://cpmodel.shinyapps.io/SCLM/ ) and nomograms. CONCLUSIONS: FDG metabolic parameter-based prognostic models are well-calibrated recurrence prediction models with good discriminative power. They can be used for accurate risk stratification in patients with SCLM. KEY POINTS: • In this multicenter study, we developed and validated prediction models for recurrence in patients with resectable synchronous colorectal cancer liver metastasis using a metabolic parameter from FDG PET-CT. • The developed models showed good predictive performance on external validation, significantly exceeding that of a pre-existing model. • The models may be utilized for accurate patient risk stratification, thereby aiding in therapeutic decision-making.

Transparent Rule Enablement Based on Commonization Approach in Heterogeneous IoT Edge Networks.

The paradigm of the Internet of Things (IoT) and edge computing brings a number of heterogeneous devices to the network edge for monitoring and controlling the environment. For reacting to events dynamically and automatically in the environment, rule-enabled IoT edge platforms operate the deployed service scenarios at the network edge, based on filtering events to perform control actions. However, due to the heterogeneity of the IoT edge networks, deploying a consistent rule context for operating a consistent rule scenario on multiple heterogeneous IoT edge platforms is difficult because of the difference in protocols and data formats. In this paper, we propose a transparent rule enablement, based on the commonization approach, for enabling a consistent rule scenario in heterogeneous IoT edge networks. The proposed IoT Edge Rule Agent Platform (IERAP) deploys device proxies to share consistent rules with IoT edge platforms without considering the difference in protocols and data formats. Therefore, each device proxy only considers the translation of the corresponding platform-specific and common formats. Also, the rules are deployed by the corresponding device proxy, which enables rules to be deployed to heterogeneous IoT edge platforms to perform the consistent rule scenario without considering the format and underlying protocols of the destination platform.

Outpatient-based diagnostic criteria for partial ACL injury: clinical outcomes of non-operative treatment and radiographic predictor.

INTRODUCTION: This study aimed to (1) evaluate the short-term clinical outcomes of patients who underwent non-operative treatment for partial anterior cruciate ligament (ACL) tears diagnosed using the outpatient-based diagnostic criteria and (2) investigate the radiographic predictors distinguishing patients at risk of non-operative treatment failure. METHODS: From 2010 to 2019, patients diagnosed with partial ACL tears and treated with non-operative treatment were reviewed retrospectively. Patients were then classified into two groups: those who successfully responded to non-operative treatment (group S) and those who failed to respond to non-operative treatment and required surgical reconstruction within 6 months after injury (group F). ACL laxity, patient-reported outcomes (PROs), and several radiographic parameters were analyzed. To identify radiographic predictors related to clinical outcomes, radiographic parameters were compared between the groups, which were statistically matched for potential confounders (age and activity level) using inverse probability of treatment weighting. RESULTS: A total of 44 patients were analyzed (mean age, 28.7 ± 8.7 years; 31 men), and classified into two groups (group S, 23 patients; group F, 21 patients). There were no significant differences in ACL laxity and PROs between the groups at 1 year after either non-operative treatment or surgical reconstruction. A comparison of radiographic parameters between the groups revealed significant differences in several parameters related to secondary signs of ACL injury. Subsequent regression analyses revealed that anterior tibial translation and extent of bone bruises were radiographic predictors related to clinical outcomes. CONCLUSION: Non-operative treatment for partial ACL tears diagnosed using the outpatient-based diagnostic criteria can provide successful short-term clinical outcomes in selective patients. Secondary signs of ACL injuries, particularly the amount of anterior tibial translation and the extent of bone bruises, are radiographic predictors that could differentiate patients at risk of non-operative treatment failure. LEVEL OF EVIDENCE: Retrospective cohort study, III.

Complicated Bosworth fracture-dislocation: A case report and review of the literature.

Bosworth fracture and dislocation is relatively rare, accounting for about 1% of ankle fractures. It is characterized by the proximal fibula fracture embedded in the posterolateral distal tibia. Due to an insufficient understanding of this fracture, it is easy to cause missed diagnosis and misdiagnosis in clinical practice. Due to the insertion of the fracture, it is challenging to perform closed reduction, and improper treatment is easy to cause complications. Surgical treatment is recommended for this type of fracture. In order to improve the understanding of orthopedic surgeons about Bosworth fracture and dislocation, this paper reports the diagnosis and treatment of 2 cases of Bosworth fracture and dislocation, and reviews the literature on Bosworth fracture's mechanism, diagnosis, classification, complications, and treatment options in recent years.

The action of topical application of Vitamin B12 ointment on radiodermatitis in a porcine model.

Radiodermatitis is an inevitable side effect of radiotherapy in cancer treatment and there is currently no consensus on effective drugs for treating the condition. Vitamin B12 is known to be effective for repairing and regenerating damaged skin. However, there are few studies on the use of Vitamin B12 for treating radiodermatitis. This study explored the therapeutic efficacy and mechanism of action of Vitamin B12 ointment on radiodermatitis. A porcine model of grade IV radiodermatitis was established. The ointment was applied for 12 weeks after which histological staining, transmission electron microscopy, RT-qPCR, western blotting, and gene sequencing were performed for the evaluation of specific indicators in skin samples. After 12 weeks of observation, the Vitamin B12 treatment was found to have significantly alleviated radiodermatitis. The treatment also significantly reduced the expression levels of NF-κB, COX-2, IL-6, and TGF-ß in the skin samples. The pathways involved in the effects of the treatment were identified by analysing gene expression. In conclusion, Vitamin B12 ointment was found to be highly effective for treating radiodermatitis, with strong anti-radiation, anti-inflammatory, and anti-fibrosis effects. It is thus a promising drug candidate for the treatment of severe radiodermatitis.