Unsatisfactory Outcomes Research Articles

Current perspectives of south african orthopaedic surgeons to the direct anterior approach in total hip arthroplasty

Background: Despite the global increase in popularity for the use of the Direct Anterior Approach (DAA) for Total Hip Arthroplasty (THA), the current beliefs and reasons for its use and disuse amongst South African orthopaedic surgeons is not well understood. Objective: To determine the perspectives regarding DAA compared to other surgical approaches to THA. Methods: We conducted an anonymous online survey sent to all current members of the South African Orthopedic Association (SAOA). Results: The response rate was 24.25% (n=194). There were 76 (39.18%) respondents that have performed DAA (DAA Performers) and 118 (60.82%) that have never performed DAA (DAA nonperformers). A proportion of 50% and 11.84% of DAA performers were between 30 to 45 years and older than 60 years of age, respectively (p<0.000). The DAA is the preferred approach to THA for 36.84% (n=28) of DAA performers, whilst 63.16% (n=48) prefer an alternative approach. Both DAA performers who prefer DAA and those who prefer alternative approaches consider DAA more satisfactory for length of hospital stay (p<0.000) and short-term functional outcomes (p=0.002) compared to other surgical approaches. For DAA non-performers, the primary reasons for not performing DAA THA were inexperience in surgical technique (72.09%), increased operative time (12.79%), unsatisfactory outcomes (27.91%) and learning curve (67.44%). There were 5 (18.52%) and 30 (70.33%) surgeons who have been in clinical practice for more than 10 years that do and do not intend to use DAA in the future, respectively (p<0.000). Conclusion: The trends of the adoption of the DAA by South African orthopaedic surgeons show increasing popularity, similar to patterns seen in the United Kingdom and the United States of America. Younger surgeons are more likely to perform the DAA THA whilst more experienced surgeons are less likely to deviate from their current standard of practice.

Exploring Convolutional Neural Networks for the Thermal Image Classification of Volcanic Activity

This paper addresses the classification of images depicting the eruptive activity of Mount Etna, captured by a network of ground-based thermal cameras. The proposed approach utilizes Convolutional Neural Networks (CNNs), focusing on pretrained models. Eight popular pretrained neural networks underwent systematic evaluation, revealing their effectiveness in addressing the classification problem. The experimental results demonstrated that, following a retraining phase with a limited dataset, specific networks such as VGG-16 and AlexNet, achieved an impressive total accuracy of approximately 90%. Notably, VGG-16 and AlexNet emerged as practical choices, exhibiting individual class accuracies exceeding 90%. The case study emphasized the pivotal role of transfer learning, as attempts to solve the classification problem without pretrained networks resulted in unsatisfactory outcomes.

Naphthylisoquinoline alkaloids: novel agents against the causative pathogens of eumycetoma and actinomycetoma-en route to broad-spectrum antimycetomal drugs.

Mycetoma is a devastating neglected tropical infection of the subcutaneous tissues. It is caused by fungal and bacterial pathogens recognized as eumycetoma and actinomycetoma, respectively. Mycetoma treatment involves diagnosing the causative microorganism as a prerequisite to prescribing a proper medication. Current therapy of fungal eumycetoma causative agents, such as Madurella mycetomatis, consists of long-term antifungal medication with itraconazole followed by surgery, yet with usually unsatisfactory clinical outcomes. Actinomycetoma, on the contrary, usually responds to treatment with co-trimoxazole and amikacin. Therefore, there is a pressing need to discover novel broad-spectrum antimicrobial agents to circumvent the time-consuming and costly diagnosis. Using the resazurin assay, a series of 23 naphthylisoquinoline (NIQ) alkaloids and related naphthoquinones were subjected to in vitro screening against two fungal strains of M. mycetomatis and three bacterial strains of Actinomadura madurae and A. syzygii. Seven NIQs, mostly dimers, showed promising in vitro activities against at least one strain of the mycetoma-causative pathogens, while the naphthoquinones did not show any activity. A synthetic NIQ dimer, 8,8'''-O,O-dimethylmichellamine A (18), inhibited all tested fungal and bacterial strains (IC50 = 2.81-12.07 µg/mL). One of the dimeric NIQs, michellamine B (14), inhibited a strain of M. mycetomatis and significantly enhanced the survival rate of Galleria mellonella larvae infected with M. mycetomatis at concentrations of 1 and 4 µg/mL, without being toxic to the uninfected larvae. As a result, broad-spectrum dimeric NIQs like 14 and 18 with antimicrobial activity are considered hit compounds that could be worth further optimization to develop novel lead antimycetomal agents.

Design Issue Analysis and Operation Effect Evaluation of Large-Scale Storage Tank

In order to address the issue of combined sewer overflows (CSOs), W city has constructed a large-scale storage tank with a volume of 220,000 m3. The storage tank is planned for CSO control in the near term and stormwater runoff pollution control in the long term. However, the actual operation of the storage tank is unsatisfactory. This paper elucidates the design scheme and operation mode of the tank and analyzes the challenges encountered during its design and operation. A storm water management model (SWMM) model was constructed to simulate the effect of the storage tank working in a combined sewer system (CSS), a separate sewer system (SSS) and a decentralized storage situation. This study determined that during the 2022 rainy season, the actual reduction in pollutants by the storage tank was only about 60% of the designed value. As a result, the inadequate treatment capacity of the downstream wastewater treatment plant (WWTP) resulted in the water being retained in the tank for a long time, leading to unsatisfactory operation outcomes. If the storage tank works in SSS and the problem of water retention can be solved, it could reduce the total runoff volume by 30% and the total amount of pollutants by 40% during the same rainy season. At the same time, under the premise of constant total storage volume, if decentralized storage tanks were used to control runoff pollution, the reduction effect can be increased by up to 11.6% compared with that of the centralized storage.

Clinical experience of using loop threads for tendon suturing of injured tendons of finger flexors in children's hands

BACKGROUND: Despite a significant progress in hand surgery, to date, the number of unsatisfactory functional outcomes in patients with injured flexor tendons of fingers still remains high, which underlines the importance and significance of the problem of flexor tendon repair in children. CLINICAL CASE DESCRIPTION: The authors present a series of clinical cases with the application of loop threads for suturing tendons in children with tendon injuries in deep finger flexors at different anatomical sites. They share their experience in using loop threads for tendon suturing in zones II, III, IV, V including tendon end reinsertion in zone I again with a loop thread. The primary task of surgical treatment of children with injured tendons of finger flexors is their restoration. In order to prevent secondary tendon ruptures, finger contractures, infectious complications and scarring of the tendon with surrounding tissues, it is recommended to use optimal suture material and surgical sutures that meets the basic requirements for tendon suturing . Specific pediatric anatomy must be taken into consideration as well. As the authors' clinical experience shows, a new approach to the restoration of injured finger flexor tendons with loop threads allows to avoid complications in 98% of cases. CONCLUSION: The implementation of loop tendon suturing into pediatric practice in combination with appropriate rehabilitation and motivation for the rehabilitation of a child and his/her parents opens up new prospects for the successful treatment of children with injured tendons of deep flexors of hand fingers.

Design, Synthesis, and Anti-Leukemic Evaluation of a Series of Dianilinopyrimidines by Regulating the Ras/Raf/MEK/ERK and STAT3/c-Myc Pathways.

Although the long-term survival rate for leukemia has made significant progress over the years with the development of chemotherapeutics, patients still suffer from relapse, leading to an unsatisfactory outcome. To discover the new effective anti-leukemia compounds, we synthesized a series of dianilinopyrimidines and evaluated the anti-leukemia activities of those compounds by using leukemia cell lines (HEL, Jurkat, and K562). The results showed that the dianilinopyrimidine analog H-120 predominantly displayed the highest cytotoxic potential in HEL cells. It remarkably induced apoptosis of HEL cells by activating the apoptosis-related proteins (cleaved caspase-3, cleaved caspase-9 and cleaved poly ADP-ribose polymerase (PARP)), increasing apoptosis protein Bad expression, and decreasing the expression of anti-apoptotic proteins (Bcl-2 and Bcl-xL). Furthermore, it induced cell cycle arrest in G2/M; concomitantly, we observed the activation of p53 and a reduction in phosphorylated cell division cycle 25C (p-CDC25C) / Cyclin B1 levels in treated cells. Additionally, the mechanism study revealed that H-120 decreased these phosphorylated signal transducers and activators of transcription 3, rat sarcoma, phosphorylated cellular RAF proto-oncogene serine / threonine kinase, phosphorylated mitogen-activated protein kinase kinase, phosphorylated extracellular signal-regulated kinase, and cellular myelocytomatosis oncogene (p-STAT3, Ras, p-C-Raf, p-MEK, p-MRK, and c-Myc) protein levels in HEL cells. Using the cytoplasmic and nuclear proteins isolation assay, we found for the first time that H-120 can inhibit the activation of STAT3 and c-Myc and block STAT3 phosphorylation and dimerization. Moreover, H-120 treatment effectively inhibited the disease progression of erythroleukemia mice by promoting erythroid differentiation into the maturation of erythrocytes and activating the immune cells. Significantly, H-120 also improved liver function in erythroleukemia mice. Therefore, H-120 may be a potential chemotherapeutic drug for leukemia patients.

Ceftaroline Fosamil for the Treatment of Methicillin-Resistant Staphylococcus Aureus Bacteremia: A Real-World Comparative Clinical Outcomes Study.

Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia results in substantial morbidity and mortality. As current treatments often lead to unsatisfactory outcomes, evidence guiding alternative treatment options is needed. This study evaluated real-world clinical outcomes of ceftaroline fosamil for the treatment of MRSA bacteremia. This retrospective study included adults hospitalized with MRSA bacteremia between 2011 and 2019. Patients were classified according to treatment with ceftaroline fosamil (ceftaroline), vancomycin, or daptomycin: Group 1, ceftaroline; Group 2, vancomycin or daptomycin (without ceftaroline); Group 3, combination therapy with ≥ 2 of these three agents. Clinical outcomes were compared using propensity-score-adjusted odds ratios (ORs) from logistic regression models. Overall, 24,479 patients were included (Group 1, n=532; Group 2, n=21,555; Group 3, n=2392). Mean age was 59.6, 60.8, and 57.4 years in Groups 1, 2, and 3, respectively. Mean post-index treatment length of stay was 8.8, 8.8, and 8.0 days, respectively. The most frequent line of therapy was ceftaroline first-line (42.1%), vancomycin or daptomycin first-line (95.4%), and combination therapy third-line or later (67.8%) in Groups 1, 2, and 3, respectively. Compared with Group 2, Groups 1 and 3 had similar favorable clinical responses {odds ratio [OR]=1.18 [95% confidence interval (CI) 0.98-1.44], p=0.08; OR=1.20 [95% CI 0.97-1.47], p=0.09, respectively} and were less likely to switch treatment (both p<0.001). Compared with Group 2, Group 1 was more likely to undergo 30-day all-cause readmission [OR=1.38 (95% CI 1.06-1.80), p=0.02], whereas this was less likely for Group 3 [OR=0.77 (95% CI 0.58-1.00), p=0.05]. Patients receiving ceftaroline more often had favorable clinical responses than those receiving vancomycin or daptomycin monotherapy. In the absence of large-scale randomized controlled trials, these real-world data provide insights into the potential role of ceftaroline for treating MRSA bacteremia.

Correlation between psychological status, revised Müller AO classification and patient-reported outcomes: a prospective cohort analysis.

The impact of psychological status on clinical outcomes is valued in several medical conditions, but rare attention is given to it in orthopedic trauma. We aimed to assess the correlation between psychological status, fracture severity and patient-reported outcomes in fractured patients needing urgency surgical treatment. We prospectively followed 139 consecutive patients undergoing urgency surgical treatment of a lower/upper limb fracture. Before surgery, all patients were divided into grades of fracture severity according to the Revised AO Müller Classification (AO grades). On the 15th and the 120th days after surgery, all patients underwent a psychological status assessment through the Hospital Anxiety and Depression Score (HADS), in addition to a pain evaluation through VAS. One year after surgery, patient-reported outcomes were obtained by using specific scales depending on the site of fracture. AO grades and VAS scores were significantly correlated to scores at HADS-A (anxiety component) and HADS-D (depression component), both on the 15th and the 120th. Patients presenting persistent HADS-A and HADS-D scores equal or greater than 8 points had a risk of more than 2.5 or 2.0 times of experiencing unsatisfactory surgical outcomes, respectively [HADS-A: RR = 2.8 (95% CI: 2.2-3.5)] [HADS-D: RR = 2.2 (95% CI: 1.7-3.1)]. AO grade C and the persistency of significant symptoms of anxiety or depression were independent predictors of unsatisfactory patient-reported outcomes (OR: 1.7, p = 0.03 // OR: 2.9, p < 0.01). Female gender, age, and BMI did not present any statistically significant utility in predicting unsatisfactory patient-reported outcomes. In fractured patients needing urgency surgical treatment, the risk of presenting unsatisfactory outcomes is more than twice as high in patients that present significant persistent changes in psychological status. Changes in psychological status are more frequent in patients presenting more severe pain and more severe fractures. AO grades and HADS scores are independent predictors of unsatisfactory outcomes in these patients.

A differentiated approach to comprehensive surgical treatment of combined combat thermomechanical injuries

In recent years, there has been a notable increase in the incidence of thermomechanical injuries, which frequently manifest as a combination of various types of damage. The majority of these injuries require long‑term treatment and result in the development of decompensated (critical) conditions during the early stages, with a substantial death rate ranging from 75% to 80%.&#x0D; Objective — to improve the results of surgery for combined combat thermomechanical injuries by developing and implementing a differentiated surgical approach that incorporates the assessment of injury severity within the context of medical support.&#x0D; Materials and methods. A retrospective‑prospective study was carried out to determine the effectiveness of medical care provided for wounded individuals with combined combat thermomechanical injuries sustained during combat operations between 2017 and 2023. The study included a cohort of 97 wounded individuals, who were subsequently divided into two separate clinical groups. The main group (n=56) underwent treatment according to a differentiated surgical approach that included the assessment of the severity of the patient’s condition using the admission trauma scale (AdTS) and the perfusion index (PI). The control group (n=41) received treatment based on established protocols using conventional treatment approaches for combined combat thermomechanical injuries without considering prioritisation.&#x0D; Results. A differentiated surgical strategy for managing combined combat thermomechanical injuries, which included an objective assessment of injury severity using the AdTS and the perfusion index (PI), allowed for a notable decrease in the occurrence of late purulent‑septic complications as well as a significant reduction in the mortality rate in the main group to 21.4%, compared to 38.8% in the control group (p=0.038). This was related to a decrease in the frequency of fatal outcomes among individuals with serious injuries: 21.2% in the main group, 37.0% in the control group (p=0.013). Furthermore, surgical treatment improved anatomical and functional outcomes in the main group compared to the control group. Group 1 had a higher specific weight of favourable outcomes 52.0±14.2% and a lower specific weight of unsatisfactory outcomes (17.6), [8.7;28.7] %, compared to group 2 20.6±13.4% and 47.3±14.7%. The difference was statistically significant at p=0.001.&#x0D; Conclusions. The implementation of a differentiated surgical approach with an objective assessment of injury severity resulted in a reduction in mortality from 7.3% to 1.8%, specific weight of amputations from 34.2% to 8.9%, and contractures from 26.8% to 10.5% (p&lt;0.05). Early vacuum therapy in the surgical treatment of combined combat thermomechanical injuries reduced treatment time and allowed for early reconstructive and restorative operations, leading to better functional outcomes. The specific weight of favourable outcomes increased from 20.6% to 52.0%, while the relative number of unsatisfactory outcomes decreased from 47.3% to 17.6% (p&lt;0.05).&#x0D; &#x0D;

The biological characteristic and therapeutic prospect of bladder cancer stem cells

Bladder cancer (BC), arising from bladder epithelial cells, is the most prevalent malignant tumor of the urinary system. Its main pathological variants include transitional cell carcinoma (TCC), squamous cell carcinoma, and adenocarcinoma, with TCC further divided into non-muscle-invasive BC (NMIBC) and muscle-invasive BC (MIBC). NMIBC accounts for 70% of all BC cases and is characterized by a favorable prognosis yet a high recurrence rate (31 &amp;ndash; 78%). Conversely, MIBC accounts for the remainder of BC cases, characterized by high heterogeneity and poor prognosis. Current treatment methods for BC predominantly encompass surgical resection, radiotherapy, chemotherapy, and immunotherapy. However, these methods lack specificity, exhibit limited clinical efficacy, and often yield unsatisfactory treatment outcomes, predisposing BC to recurrence. On the other hand, BC stem cells (BCSCs) are a subset of cells within heterogeneous BC, possessing robust abilities in self-renewal, differentiation, tumorigenicity, metastasis, and drug resistance. They play a pivotal role in the initiation, progression, metastasis, and relapse of BC, rendering them ideal targets for targeted therapy. Research efforts in this field are currently focused on investigating the evolutionary origins, biomarkers, mechanism governing stemness maintenance, drug resistance, metastasis, metabolic reprogramming, immune evasion, and targeted therapies related to BCSCs. This article provides a comprehensive review of the latest advancements in the biological characteristics and therapeutic prospects of BCSCs.

Investigation of cellular communication and signaling pathways in tumor microenvironment for high TP53-expressing osteosarcoma cells through single-cell RNA sequencing.

Osteosarcoma (OS) stands as the most prevalent primary bone cancer in children and adolescents, and its limited treatment options often result in unsatisfactory outcomes, particularly for metastatic cases. The tumor microenvironment (TME) has been recognized as a crucial determinant in OS progression. However, the intercellular dynamics between high TP53-expressing OS cells and neighboring cell types within the TME are yet to be thoroughly understood. In our study, we harnessed the single-cell RNA sequencing (scRNA-seq) technology in combination with the computational tool-Cellchat, aiming to elucidate the intercellular communication networks present within OS. Through meticulous quantitative inference and subsequent analysis of these networks, we succeeded in identifying significant signaling pathways connecting high TP53-expressing OS cells with proximate cell types, namely Macrophages, Monocytes, Endothelial Cells, and PVLs. This research brings forth a nuanced understanding of the intricate patterns and coordination involved in the TME's intercellular communication signals. These findings not only provide profound insights into the molecular mechanisms underpinning OS but also indicate potential therapeutic targets that could revolutionize treatment strategies.

The Dual Role of the NFATc2/galectin-9 Axis in Modulating Tumor-Initiating Cell Phenotypes and Immune Suppression in Lung Adenocarcinoma.

Tumor-initiating cells (TICs) resilience and an immunosuppressive microenvironment are aggressive oncogenic phenotypes that contribute to unsatisfactory long-term outcomes in lung adenocarcinoma (LUAD) patients. The molecular mechanisms mediating the interaction between TICs and immune tolerance have not been elucidated. The role of Galectin-9 in oncogenesis and immunosuppressive microenvironment is still unknown. This study explored the potential role of galectin-9 in TIC regulation and immune modulation in LUAD. The results show that galectin-9 supports TIC properties in LUAD. Co-culture of patient-derived organoids and matched peripheral blood mononuclear cells showed that tumor-secreted galectin-9 suppressed T cell cytotoxicity and induced regulatory T cells (Tregs). Clinically, galectin-9 is upregulated in human LUAD. High expression of galectin-9 predicted poor recurrence-free survival and correlated with high levels of Treg infiltration. LGALS9, the gene encoding galectin-9, is found to be transcriptionally regulated by the nuclear factor of activated T cells 2 (NFATc2), a previously reported TIC regulator, via in silico prediction and luciferase reporter assays. Overall, the results suggest that the NFATc2/galectin-9 axis plays a dual role in TIC regulation and immune suppression.

Single cell deciphering of progression trajectories of the tumor ecosystem in head and neck cancer

Head and neck squamous cell carcinoma is the sixth most common cancer worldwide and has high heterogeneity and unsatisfactory outcomes. To better characterize the tumor progression trajectory, we perform single-cell RNA sequencing of normal tissue, precancerous tissue, early-stage, advanced-stage cancer tissue, lymph node, and recurrent tumors tissue samples. We identify the transcriptional development trajectory of malignant epithelial cells and a tumorigenic epithelial subcluster regulated by TFDP1. Furthermore, we find that the infiltration of POSTN+ fibroblasts and SPP1+ macrophages gradually increases with tumor progression; their interaction or interaction with malignant cells also gradually increase to shape the desmoplastic microenvironment and reprogram malignant cells to promote tumor progression. Additionally, we demonstrate that during lymph node metastasis, exhausted CD8+ T cells with high CXCL13 expression strongly interact with tumor cells to acquire more aggressive phenotypes of extranodal expansion. Finally, we delineate the distinct features of malignant epithelial cells in primary and recurrent tumors, providing a theoretical foundation for the precise selection of targeted therapy for tumors at different stages. In summary, the current study offers a comprehensive landscape and deep insight into epithelial and microenvironmental reprogramming throughout initiation, progression, lymph node metastasis and recurrence of head and neck squamous cell carcinoma.

Abstract 394: Preclinical evaluation of ERX-208, a potent inducer of ER stress for the treatment of ovarian cancer

Abstract Background: Ovarian cancer (OCa) is the deadliest kind of gynecologic cancer in the United States. The long-term survival rate for OCa is less than 20% after five years. Intra-tumoral and inter-tumoral heterogeneity is implicated in tumor resistance to conventional therapies and the unsatisfactory clinical outcomes. Addressing these issues necessitates innovative therapies that target intrinsic common vulnerabilities within OCa. Recent studies have highlighted that high basal level of endoplasmic reticulum stress (ERS) in OCa as a critical vulnerability. We have identified a promising compound, ERX-208 that potently induces ERS in cancer cells. The objective of this study is to characterize the mechanisms and activity of ERX-208 using preclinical models. Methods: The biological activity of ERX-208 was examined across 17 distinct OCa cells, representing 5 diverse OCa subtypes. Mechanistic studies utilized Western blotting, immunohistochemistry (IHC), RNA-Seq analysis, and CRISPR/Cas9 knockouts (KO). Pharmacokinetics (PK) and toxicity studies were performed on C57BL/6 mice. Comprehensive preclinical assessments were carried out through cell line-derived xenografts (CDXs), patient-derived xenografts (PDXs), organoids (PDOs) and explants (PDEs). Results: ERX-208 demonstrated an IC50 of approximately 50-100 nM inducing ERS and reducing cell viability in OCa cells. Conversely, normal ovarian surface epithelial cells exhibited minimal effects from ERX-208. In vitro experiments revealed strong ERX-208-induced apoptosis in OCa cell lines. Mechanistic studies employing RNA sequencing, Western blotting, and RT-qPCR, confirmed activation of ERS pathways observed as early as 5 hours post-ERX-208 treatment. Our studies identified LIPA as a potential target, and KO of LIPA significantly diminished ERX-208 activity. Moreover, LIPA KO substantially impeded in vivo OCa tumor growth. ERX-208 up to a dose of 25 mg/kg showed no observable organ toxicity and had no effect on the mice's body weight. Dose range studies identified 10 mg/kg intraperitoneal as the minimal effective dose, achieving more than 50% tumor reduction. In preclinical models, ERX-208 inhibited the growth of OCa CDXs, PDXs, and ex vivo PDEs and PDO’s. IHC analyses indicated reduced proliferation (Ki-67) and increased activation of ERS markers, such as GRP78 and p-PERK. Conclusions: Collectively, our findings underscore the preclinical promise of ERX-208 as a potential therapeutic agent for treating OCa. Conflict: The patents surrounding ERX-208 are licensed to EtiraRx. Citation Format: Suryavathi Viswanadhapalli, Tae-Kyung Lee, Scott Elmore, Gaurav Sharma, Rahul Gopalam, Karla Parra, Tanner Reese, Michael Hsieh, Uday P. Pratap, Xue Yang, Behnam Ebrahimi, Henry Neal, Chia-Yuan Chen, Kara Kassees, Christian Cervantes, Zhenming Xu, Edward Kost, Gangadhara Reddy Sareddy, Rajeshwar R. Tekmal, Jung-Mo Ahn, Ganesh V. Raj, Ratna K. Vadlamudi. Preclinical evaluation of ERX-208, a potent inducer of ER stress for the treatment of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 394.

Optimizing implant lattice design for large distal femur defects: Stimulating interface bone growth to enhance osseointegration

Large bone defects in the distal femur present a significant challenge due to the lack of inherent self-healing capabilities. Traditional approaches, such as utilizing polymethyl methacrylate (PMMA) in conjunction with a plate for distal femur reconstruction, have shown unsatisfactory osseointegration outcome, which leads to complications. To address this challenge, this study focuses on developing a lattice-structured implant for reconstructing distal femoral bone defects. The lattice geometry is based on the cuboctahedron lattice, with its design optimized through the adjustment of pillar diameter and arrangement angle. The lattice structure is designed to stimulate the surrounding bone, ultimately enhancing osseointegration in distal femur reconstruction. Finite element analysis revealed that for promoting bone ingrowth toward the implant, setting the optimal lattice structure parameters, i.e., a 45&amp;deg; arrangement angle and a 0.8 mm pillar diameter, is required. Fabricated using state-of-the-art metal three-dimensional printing, the implant underwent rigorous validation through biomechanical testing, in vitro biological assays, and animal experiments. The comprehensive results affirmed the bioactivity of the lattice-structured implant, underscoring its capability to improve osseointegration in distal femoral defect reconstruction.

TMEM158 functions as an oncogene and promotes lung adenocarcinoma progression through the PI3K/AKT pathway via interaction with TWIST1

Lung adenocarcinoma (LUAD) is a common and deadly form of lung cancer, with high rates of metastasis and unsatisfactory clinical outcomes. Herein, we examined the influence of TMEM158 on the LUAD progression. A combination of bioinformatic analyses was used to assess the TMEM158 expression pattern, prognostic implications, and potential function in LUAD. The levels of TMEM158 and TWIST1 were evaluated in clinical samples from LUAD patients using Western blot analysis and qRT-PCR. To discover the function and underlying molecular pathways of TMEM158 in LUAD, we employed a combination of experimental approaches in vitro, such as flow cytometry analysis and colony formation, Co-IP, CCK-8, Transwell, and wound-healing assays. Elevated expression of TMEM158 in LUAD is associated with increased cancer aggressiveness and a poor prognosis. In vitro experiments demonstrated that high levels of TMEM158 promote cell proliferation, progression through the cell cycle, migration, and invasion while suppressing apoptosis. Knockdown of TMEM158 produced opposite effects. The underlying mechanism involves TMEM158 and TWIST1 directly interacting, stimulating the PI3K/AKT signaling pathway in LUAD cells. This investigation emphasizes the molecular functions of TMEM158 in LUAD progression and proposes targeting it as a promising treatment approach for managing LUAD.

How Democratic Police Reforms Fail: A Law and Development Perspective on Institutional Processes of Change and Resistance

Abstract Democratic police reform (DPR) is a type of institutional reform that aims to make polices compatible with democratic political regimes. Though distinct approaches have been attempted in distinct contextual circumstances, promoting DPR has proven remarkably difficult. Successful cases are hard to find; across the globe, DPR efforts have had unsatisfactory outcomes, amounting to little or no sustainable change in dysfunctional police forces. What explains this systematic failure of DPR? Existing research has focused on determining the sociopolitical circumstances and/or reform methods that correlate with positive or negative DPR outcomes. However, there is a gap in the literature regarding how DPR fails – that is, the processes through which the above-mentioned variables interact with the police’s organizational environments, rules, and resistance mechanisms to produce unsatisfactory outcomes/failed reform. This paper proposes that an analytical framework based on law and development scholarship can help police reform scholars address these gaps. To develop this argument, I review and discuss existing theorizations on DPR failure, demonstrating the potential contributions of a law and development perspective. I suggest that a framework based on this perspective nuances existing approaches by emphasizing the contentious processes surrounding reform enactment and implementation. Unpacking these processes can represent a new research agenda for police reform scholarship.

A neoteric antibacterial ceria-silver nanozyme for abiotic surfaces

Community-associated and hospital-acquired infections caused by bacteria continue to yield major global challenges to human health. Bacterial contamination on abiotic surfaces is largely spread via high-touch surfaces and contemporary standard disinfection practices show limited efficacy, resulting in unsatisfactory therapeutic outcomes. New strategies that offer non-specific and broad protection are urgently needed. Herein, we report our novel ceria-silver nanozyme engineered at a molar ratio of 5:1 and with a higher trivalent (Ce3+) surface fraction. Our results reveal potent levels of surface catalytic activity on both wet and dry surfaces, with rapid, and complete eradication of Pseudomonas aeruginosa, Staphylococcus aureus, and methicillin resistant S. aureus, in both planktonic and biofilm form. Preferential electrostatic adherence of anionic bacteria to the cationic nanozyme surface leads to a catastrophic loss in both aerobic and anaerobic respiration, DNA damage, osmodysregulation, and finally, programmed bacterial lysis. Our data reveal several unique mechanistic avenues of synergistic ceria-Ag efficacy. Ag potentially increases the presence of Ce3+ sites at the ceria-Ag interface, thereby facilitating the formation of harmful H2O2, followed by likely permeation across the cell wall. Further, a weakened Ag-induced Ce–O bond may drive electron transfer from the Ec band to O2, thereby further facilitating the selective reduction of O2 toward H2O2 formation. Ag destabilizes the surface adsorption of molecular H2O2, potentially leading to higher concentrations of free H2O2 adjacent to bacteria. To this end, our results show that H2O2 and/or NO/NO2−/NO3− are the key liberators of antibacterial activity, with a limited immediate role being offered by nanozyme-induced ROS including O2•- and OH•, and likely other light-activated radicals. A mini-pilot proof-of-concept study performed in a pediatric dental clinic setting confirms residual, and continual nanozyme antibacterial efficacy over a 28-day period. These findings open a new approach to alleviate infections caused by bacteria for use on high-touch hard surfaces.

Automated Life Stage Classification of Malaria Using Deep Learning

INTRODUCTION: Malaria, an infectious illness spread by mosquitoes, is a serious hazard to humans and animals, with an increasing number of cases recorded yearly. Prompt and precise diagnosis, as well as preventative actions, are critical for effectively combating this condition. Malaria is now diagnosed using standard techniques. Microscopy of blood smears, which consists of small pictures, is used by trained specialists to identify diseased cells and define their life phases. The World Health Organisation (WHO) has approved this microscopy-based malaria diagnostic method. Drawing a blood sample from the finger, pricking it, spreading it onto a clean glass slide, and allowing it to dry naturally are all steps in the method. Thin blood smears were previously used to identify parasites under the microscope, but thick blood smears are utilized when parasite levels are low. OBJECTIVES: Due to its reliance on medical knowledge, high prices, time-consuming nature, and unsatisfactory outcomes, this technique has significant disadvantages. However, as deep learning algorithms progress, these activities may be completed more effectively and with fewer human resources. METHODS: This study demonstrates the usefulness of transfer learning, a type of deep learning, in categorizing microscopic pictures of parasitized versus uninfected malaria cells. Six models were evaluated using the publicly accessible NIH dataset, proving the usefulness of the suggested technique. RESULTS: VGG19 model fared better than its competitors, obtaining 95.05% accuracy, 92.83% precision, 96.88% sensitivity, 93.46% specificity, and 94.81% F1-score. CONCLUSION: This categorization of malaria cell photos will benefit microscopists in particular, as it will improve their workflow and provide a viable alternative for detecting malaria using microscopic cell images.

The propensity to control: Non-sexual violence as probative of sexual offending in the intimate partner context

This article explores, with reference to four recent New Zealand appellate court decisions, the use of evidence of prior non-sexual offending by a defendant against the same complainant offered to prove sexual offence charges. Such ‘relationship propensity evidence’ can be particularly crucial for explaining the defendant–complainant dynamic in cases involving intimate partner violence. However, in some cases, courts have applied traditional common law ‘similar fact’ notions of linkage and coincidence to exclude evidence of non-sexual offending in relation to sexual charges. We argue that this is an unsatisfactory outcome that is largely resultant from the governing provision being designed to assess similar fact reasoning. Rather, we submit that in the context of intimate partner violence, seemingly discrete and unrelated forms of violence should be understood as potentially linked by the underpinning dynamic of coercive control. This shift in characterisation of varying forms of violence—from discrete and dissimilar to connected by a dynamic of coercive control—will result in a more flexible approach to the cross-admissibility of relationship propensity evidence in appropriate cases, including when it comes to offering evidence of physical violence as probative of sexual offending.