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BACKGROUND: Pegunigalsidase alfa is a PEGylated α-galactosidase A enzyme replacement therapy. BALANCE (NCT02795676) assessed non-inferiority of pegunigalsidase alfa versus agalsidase beta in adults with Fabry disease with an annualised estimated glomerular filtration rate (eGFR) slope more negative than -2 mL/min/1.73 m2/year who had received agalsidase beta for ≥1 year. METHODS: Patients were randomly assigned 2:1 to receive 1 mg/kg pegunigalsidase alfa or agalsidase beta every 2 weeks for 2 years. The primary efficacy analysis assessed non-inferiority based on median annualised eGFR slope differences between treatment arms. RESULTS: Seventy-seven patients received either pegunigalsidase alfa (n=52) or agalsidase beta (n=25). At baseline, mean (range) age was 44 (18-60) years, 47 (61%) patients were male, median eGFR was 74.5 mL/min/1.73 m2 and median (range) eGFR slope was -7.3 (-30.5, 6.3) mL/min/1.73 m2/year. At 2 years, the difference between median eGFR slopes was -0.36 mL/min/1.73 m2/year, meeting the prespecified non-inferiority margin. Minimal changes were observed in lyso-Gb3 concentrations in both treatment arms at 2 years. Proportions of patients experiencing treatment-related adverse events and mild or moderate infusion-related reactions were similar in both groups, yet exposure-adjusted rates were 3.6-fold and 7.8-fold higher, respectively, with agalsidase beta than pegunigalsidase alfa. At the end of the study, neutralising antibodies were detected in 7 out of 47 (15%) pegunigalsidase alfa-treated patients and 6 out of 23 (26%) agalsidase beta-treated patients. There were no deaths. CONCLUSIONS: Based on rate of eGFR decline over 2 years, pegunigalsidase alfa was non-inferior to agalsidase beta. Pegunigalsidase alfa had lower rates of treatment-emergent adverse events and mild or moderate infusion-related reactions. TRIAL REGISTRATION NUMBER: NCT02795676.

Cipaglucosidase alfa plus miglustat (cipa + mig) is a novel, two-component therapy for Pompe disease. We report data from the Phase I/II ATB200-02 study for up to 48 months of treatment. Four adult cohorts, including one non-ambulatory ERT-experienced (n = 6) and three ambulatory cohorts, (two enzyme replacement therapy [ERT]-experienced cohorts [2-6 years (n = 11) and ≥ 7 years (n = 6)]), one ERT-naïve cohort (n = 6), received 20 mg/kg intravenous-infused cipa plus 260 mg oral mig biweekly. Change from baseline (CFBL) for multiple efficacy endpoints at 12, 24, 36, and 48 months, pharmacodynamics, pharmacokinetics, safety, and immunogenicity data were assessed. Six-minute walking distance (% predicted) improved at 12, 24, 36, and 48 months: pooled ambulatory ERT-experienced cohorts, mean(± standard deviation [SD]) CFBL: 6.1(± 7.84), n = 16; 5.4(± 10.56), n = 13; 3.4(± 14.66), n = 12; 5.9(± 17.36), n = 9, respectively; ERT-naïve cohort: 10.7(± 3.93), n = 6; 11.0(± 5.06), n = 6; 9.0(± 7.98), n = 5; 11.7(± 7.69), n = 4, respectively. Percent predicted forced vital capacity was generally stable in ERT-experienced cohorts, mean(± SD) CFBL - 1.2(± 5.95), n = 16; 1.0(± 7.96), n = 13; - 0.3(± 6.68), n = 10; 1.0(± 6.42), n = 6, respectively, and improved in the ERT-naïve cohort: 3.2(± 8.42), n = 6; 4.7(± 5.09), n = 6; 6.2(± 3.35), n = 5; 8.3(± 4.50), n = 4, respectively. Over 48 months, CK and Hex4 biomarkers improved in ambulatory cohorts. Overall, cipa + mig was well tolerated with a safety profile like alglucosidase alfa. ATB200-02 results show the potential benefits of cipa + mig as a long-term treatment option for Pompe disease. Trial registration number: NCT02675465 January 26, 2016.

Abstract In a previous study, it has been shown that the population of Th17 lymphocytes was increased in patients with FMF. IL-21 and IL-23 play significant roles in the production and differentiation of Th17 cells. In this study, we aimed to evaluate serum levels of IL-21 and IL-23 in FMF patients both at diagnosis and after treatment, and to compare these levels with those of healthy controls. Twenty-seven newly diagnosed patients with FMF in attack-free periods and twenty-seven healthy volunteers enrolled in the study. The groups were comparable with respect to age and gender. IL-21 and IL-23 levels in serum samples from patients at the time of diagnosis, in remission after treatment, and from the control groups were analysed using the ELISA method. There was no significant difference between the cytokine levels of the patient group at the time of diagnosis and the cytokine levels of the control group (for IL-21, p: 0.28 and for IL-23, p: 0.56). Similarly, there was no significant difference between the patients’ cytokine levels at the time of diagnosis and after treatment (for IL-21, p: 0.99 and for IL-23, p: 0.08). Interleukin levels at the time of diagnosis did not differ among patient groups based on the presence of clinical findings or the M694V genotype. Our results suggest that IL-21 and IL-23 do not play a role in the pathogenesis of the disease. However, while interpreting these findings, it should be considered that patients with active episodes were excluded and cytokine levels were not measured in tissue samples.

The tumor microenvironment (TME) plays a crucial role in cancer development and metastasis. This review summarizes the current research on how the TME promotes metastasis through molecular pathways, focusing on key components, such as cancer-associated fibroblasts, immune cells, endothelial cells, cytokines, and the extracellular matrix. Significant findings have highlighted that alterations in cellular communication within the TME enable tumor cells to evade immune surveillance, survive, and invade other tissues. This review highlights the roles of TGF-β and VEGF signaling in promoting angiogenesis and extracellular matrix remodeling, which facilitate metastasis. Additionally, we explored how metabolic reprogramming of tumor and stromal cells, influenced by nutrient availability in the TME, drives cancer progression. This study also evaluated the therapeutic strategies targeting these interactions to disrupt metastasis. By providing a multidisciplinary perspective, this study suggests that understanding the molecular basis of the TME can lead to more effective cancer therapies and identify potential avenues for future research. Future research on the TME should prioritize unraveling the molecular and cellular interactions within this complex environment, which could lead to novel therapeutic strategies and personalized cancer treatments. Moreover, advancements in technologies such as single-cell analysis, spatial transcriptomics, and epigenetic profiling offer promising avenues for identifying new therapeutic targets and improving the efficacy of immunotherapies, particularly in the context of metastasis.

Signal timings at signalized intersections are frequently optimized by considering commonly used vehicle delay models. It is generally believed that reducing the average number of stops can also decrease the average vehicle delay. Therefore, the aim of this research is to address the question: “Can similar performance outcomes be achieved through the Minimization of Average Vehicle Delay (MAVD) and the Minimization of Average Number of Stops (MANS)?” The first phase of the study entails the creation of two distinct signal timing optimization models based on the Akcelik average vehicle delay and average number of stops models. Subsequently, scripts were developed in MATLAB to identify the optimal signal timings for both approaches utilizing the Differential Evolution Algorithm. In the third phase, 30 traffic scenarios were generated, each varying in overall traffic volumes at the intersection. Subsequently, the signal timings derived from the MAVD and MANS approaches were applied independently to these scenarios, and performance indicators (average vehicle delay and average number of stops) were compared. The results reveal that the utilization of MANS-based signal timings instead of MAVD may lead to an increase in average vehicle delays of up to 113.55%. Additionally, it is demonstrated that when MAVD-based signal timings are applied instead of MANS, the average number of stops can increase by up to 16.28%. Finally, it is concluded that as the overall traffic volume at the intersection increases, these growth rates tend to decrease.

Long non-coding RNAs (lncRNAs) play a dynamic role in gene expression regulation and serve as potential therapeutic targets in breast cancer. The anticancer effect of propofol, an anesthetic agent, has been proven, but its interaction with lncRNAs has not been adequately investigated. This study aims to reveal the interactions between propofol and lncRNAs and contribute to the understanding of its therapeutic potential in the treatment of breast cancer. We evaluated the effects of propofol on cell viability, apoptosis, and mitochondrial membrane potential in MCF7 cells. The study used qRT-PCR to analyze cancer-related lncRNA expressions following propofol treatment; this was supported by RNA-RNA interaction predictions and in silico functional analysis using selected datasets and the R cluster Profiler GSEABase package. Propofol showed a cytotoxic effect at higher doses in MCF7 breast cancer cells, inducing necrosis. Propofol regulated (IGF2-AS, MRPL23-AS1, PANDAR, HULC) and down-regulated (IWT1-AS, HOXA-AS2, H19, GACAT1, MIAT) the expression levels of various lncRNAs in MCF7 cells. Our research revealed complex interactions of MALAT1 lncRNA with both upregulated and downregulated genes. Additionally, three rRNA genes (LSU-rRNA, RNA45SN3, and SSU-rRNA) were identified to interact with both groups of lncRNAs. Propofol potentially targets chemotherapy resistance by regulating UCA1, LINC-RoR1, and MEG3. Wikipathways' pathway enrichment analysis identified two downregulated lncRNAs, UCA1 and LINC-RoR1, and an upregulated MEG3, implicated in lncRNA-mediated chemotherapeutic resistance mechanisms. Our study illuminates the intricate interplay of lncRNAs and their potential contribution to propofol's anti-cancer effects in breast cancer, offering new avenues for therapeutic exploration and advancement.

The past decade has seen the development of immunotherapy for the treatment of multiple myeloma (MM), beginning with monoclonal antibodies (mAbs) in the relapsed and refractory setting and culminating in the market approval of chimeric antigen receptor T cells (CAR-T) and bispecific antibodies (BsAbs). The medical community is evaluating the efficacy and safety of these targeted immunotherapies, most of which currently target B-cell maturation antigen (BCMA) on the surface of plasma cells. Two anti-BCMA CAR-T products are available for treating relapsed or refractory MM: idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel). Ide-cel and cilta-cel demonstrate the ability to induce deep responses in heavily pretreated diseases, including patients with triple-class-refractory and penta-refractory diseases. However, there are key similarities and differences regarding these agents, unknowns regarding their comparative efficacy and toxicity, and mechanisms underlying resistance to these new immunotherapies. This review discusses CAR-T cell therapy in relapsed refractory MM, with a focus on efficacy, toxicities, and the evolving trajectories of these therapies in the USA, as well as access in Turkey.

Introduction: Compound Muscle Action Potential Scan (CMAP) Scan is an electrophysiological method for diagnosing neuromuscular diseases with axonal loss. Significant differences between CMAPs are termed as Steps. The percentage ratio of all detected steps to the maximum CMAP, a parameter being evidence of motor unit loss and enlargement due to reinnervation is defined as Step Percentage. Materials and Methods: Motor neuron groups were created and stimulated gradually through a simulator software for CMAP Scan. CMAPs were utilized to compute the step sizes. Their cumulative sum greater than two standard deviations were taken for computing Step Percentage. The simulator data were exported for processing in a MATLABⓇ Code for these calculations and for computing regression coefficients of the model for step percentage and the number of axons by the Least Square Method. Results: The greatest step percentage value corresponded to the lowest motor unit number. A steep reduction was observed from 5 axons to 120 axons with increasing axon numbers. The step percentages converged to a steady-state value for the axon numbers between 120 and 300. Discussion and Conclusion: Step percentage values were found greater for lower axon numbers as in the case of Motor Unit loss in neurogenic diseases. They tended to decrease with increasing axon numbers approaching a steady-state value as the presence of intact Motor Units. A new algorithm was proposed to determine the lowest step size quantitatively rather than detecting by inspection as in routine clinical applications for estimating the step percentage. A mathematical model was built to demonstrate the relationship between the step percentage and the number of axons.

(1) Background: The use of alumina particles for surface treatment of dental implants is a common practice aimed at enhancing osseointegration. However, the biological effects of residual alumina particles on implant surfaces remain a subject of debate. This systematic review evaluates the impact of residual alumina particles on the osseointegration, biocompatibility, and bacterial adhesion of dental implants based on available in vivo experimental animal studies. (2) Methods: A comprehensive literature search was conducted across PubMed, Web of Science, and Scopus to identify relevant studies. The inclusion criteria focused on experimental animal studies that assessed the biological effects of alumina-blasted dental implants. Data extraction was carried out, and quality assessments were performed using the SYRCLE risk-of-bias tool. (3) Results: Ten studies met the inclusion criteria, involving various animal models, such as rabbits, pigs, dogs, and sheep. The findings demonstrated that residual alumina particles did not negatively impact osseointegration. Some studies reported accelerated bone growth and improved osseointegration with residual alumina. Additionally, residual alumina showed potential bactericidal properties, reducing bacterial adhesion. (4) Conclusions: The available evidence from animal studies suggests that residual alumina particles do not adversely affect the osseointegration and biocompatibility of dental implants. These particles may even enhance bone growth and reduce bacterial adhesion. However, due to the scarcity of human studies and the impracticality of histological assessments in humans, further research, including long-term clinical trials, is necessary to confirm these findings.

Cancer therapy is on the brink of a significant transformation with the inclusion of patient-derived organoids (PDOs) in drug development. These three-dimensional cell cultures, directly derived from a patient’s tumor, accurately replicate the complex structure and genetic makeup of the original cancer. This makes them a promising tool for advancing oncology. In this review, we explore the practical applications of PDOs in clinical drug screening and pharmacognostic assessment, as well as their role in refining therapeutic strategies. We provide insights into the latest advancements in PDO technology and its implications for predicting treatment responses and facilitating novel drug discoveries. Additionally, we address the operational challenges associated with incorporating PDOs into the drug development process, such as scaling up organoid cultures, ensuring consistent results, and addressing the ethical use of patient-derived materials. Aimed at researchers, clinicians, and key stakeholders in oncology, this article aims to succinctly present both the extraordinary potential and the obstacles to integrating PDOs, thereby shedding light on their prospective impact on the future of cancer treatment.

Objective This study aimed to evaluate the prevalence of sarcopenia and its clinical significance in Turkish women with SLE, exploring the association between muscle mass, muscle strength and SLE disease activity.Methods A cross-sectional study was conducted at Gazi University Hospital’s Department of Rheumatology from January to December 2020. It involved 82 patients with SLE, diagnosed according to the 2019 American College of Rheumatology/European Alliance of Associations for Rheumatology criteria, and 69 healthy controls. Sarcopenia was assessed using hand grip dynamometry (hand grip strength (HGS)) and bioelectrical impedance analysis for muscle mass, with sarcopenia defined according to the 2018 European Working Group on Sarcopenia in Older People criteria and specific cut-offs for the Turkish population. The main outcomes measured were the presence of sarcopenia and probable sarcopenia, HGS values, skeletal muscle mass index and SLE Disease Activity Index 2000 (SLEDAI-2K).Results Among the patients with SLE, 51.2% met the criteria for probable sarcopenia and 12.9% were diagnosed with sarcopenia. The mean HGS was significantly lower in the SLE group (21.7±4.9 kg) compared with controls, indicating reduced muscle strength. The prevalence of anti-double-stranded DNA (anti-dsDNA) antibodies was 82.9%. Multivariate regression analysis identified height and levels of anti-dsDNA antibodies as independent predictors for developing probable sarcopenia. No significant association was found between clinical parameters, including SLEDAI-2K scores, and sarcopenia status.Conclusions Sarcopenia is prevalent among Turkish women with SLE, with a significant proportion showing reduced muscle strength. The study found no direct association between sarcopenia and SLE disease activity or clinical parameters. These findings underscore the importance of including muscle strength assessments in the routine clinical evaluation of patients with SLE to potentially improve management and quality of life.

Psychiatry is concerned with mental health. Cognition is one of the key mental functions and manifests itself primarily as behavior. A behavior exhibited in response to a stimulus is influenced by biological (inherited), psychological (individual), and social (environmental) factors. During consolidation of an exhibited behavior, the factors affecting the individual’s cognitive structure and personality play crucial roles. Underlying factors for a problematic behavior, and their weakness/strength levels are determined via the Biopsychosocial model. Empirically effective current practices to intervene the problematic behaviors do not always result in success. One of the reasons may be other elements that were omitted during the case formulation process. This article aims to stress the idea that whatever the underlying factor of a problematic behavior is, the most crucial determinant and/or pre-emptive factor in developing or maintaining that behavior might actually be the religion as a governing and directive philosophy on how to conduct oneself. In this instance, the key is in the hands of the parents or caregivers.

Objective: The objective of this study is to demonstrate any inner ear injury caused by drilling in mastoid surgery with prestin, outer hair cell motor protein specific to the cochlea. Methods: The patients with chronic otitis media requiring mastoidectomy (n = 21) and myringoplasty (n = 21) were included. Serum prestin level obtained from blood samples was measured before surgery and on postoperative days 0, 3, and 7 using Human Prestin (SLC26A5) ELISA Kit. All patients underwent the Pure Tone Audiometry (PTA) test before surgery and on the postoperative 7th day. The drilling time was also recorded for all patients who underwent mastoidectomy. Results: In both mastoidectomy and myringoplasty groups, the postoperative serum prestin levels increased on days 0 and 7 (pday-0 = 0.002, pday-7 = 0.001 and pday-0 = 0.005, pday-7 = 0.001, respectively). There was no significant difference in the serum prestin levels between the two groups, postoperatively. The PTA thresholds at day 7 did not change in either group. A significant decline at 2000 Hz of bone conduction hearing threshold in both groups and a decline at 4000 Hz in the myringoplasty group were found. There was no correlation between the drilling time and the increase of prestin levels in the postoperative day 0, 3, and 7. Conclusion: Our results showed that mastoid drilling is not related to a significant inner ear injury. Although the myringoplasty group was not exposed to drill trauma, there was a similar increase in serum prestin levels as the mastoidectomy group. Also, a significant decline at 2000 Hz of bone conduction hearing threshold in both groups and a decline at 4000 Hz in the myringoplasty group were found. These findings suggest that suction and ossicular manipulation trauma can lead to an increase in serum prestin levels and postoperative temporary or permanent SNHL at 2000 and 4000 Hz. Level of evidence: Level-4.

Abstract Aim The aim of this study is to evaluate the functional outcomes and complications after non-fusion knee arthrodesis with a modular segmental intramedullary implant used for infected total knee arthroplasty revisions. Methods A retrospective review of the patients who had been surgically treated with a modular intramedullary arthrodesis implant for recurrent infection after revision TKA between January 2016 and February 2020 were included. The indications for arthrodesis were failed infected TKA with massive bone loss, deficient extensor mechanism and poor soft tissue coverage that precluded joint reconstruction with revision TKA implants. Clinical outcomes were assesed with visual analogue scale for pain (pVAS), Oxford knee score (OKS) and 12-item short form survey (SF-12). Full-length radiographs were used to verify limb length discrepancies (LLD). Results Fourteen patients (4 male and 10 female) patients with a mean age of 69.3 (range, 59 to 81) years at time of surgery were available for final follow-up at a mean of 28.8 months (range, 24–35 months). All clinical outcome scores improved at the final follow-up (pVAS, 8.5 to 2.6, p = .01; OKS, 12.6 to 33.8, p = .02; SF-12 physical, 22.9 to 32.1, p = .01 and SF-12 mental, 27.7 to 40.2, p = .01). The mean LLD was 1.0 cm (range, + 15 – 2.3 cm). Re-infection was detected in three patients (21.4%). Two patients were managed with suppressive antibiotic treatment and a third patient required repeat 2-stage revision procedure. In one patient, a periprosthetic femur fracture was observed and treated with plate osteosynthesis. Conclusion Uncontrolled infection after total knee arthroplasty can be effectively treated with arthrodesis using a modular intramedullary nail and satisfactory functional results can be obtained. Level of evidence Level 4, Retrospective cohort study.

GBA1-associated Parkinson’s disease (GBA1-PD) is increasingly recognized as a distinct entity within the spectrum of parkinsonian disorders. This review explores the unique pathophysiological features, clinical progression, and genetic underpinnings that differentiate GBA1-PD from idiopathic Parkinson’s disease (iPD). GBA1-PD typically presents with earlier onset and more rapid progression, with a poor response to standard PD medications. It is marked by pronounced cognitive impairment and a higher burden of non-motor symptoms compared to iPD. Additionally, patients with GBA1-PD often exhibit a broader distribution of Lewy bodies within the brain, accentuating neurodegenerative processes. The pathogenesis of GBA1-PD is closely associated with mutations in the GBA1 gene, which encodes the lysosomal enzyme beta-glucocerebrosidase (GCase). In this review, we discuss two mechanisms by which GBA1 mutations contribute to disease development: ‘haploinsufficiency,’ where a single functional gene copy fails to produce a sufficient amount of GCase, and ‘gain of function,’ where the mutated GCase acquires harmful properties that directly impact cellular mechanisms for alpha-synuclein degradation, leading to alpha-synuclein aggregation and neuronal cell damage. Continued research is advancing our understanding of how these mechanisms contribute to the development and progression of GBA1-PD, with the ‘gain of function’ mechanism appearing to be the most plausible. This review also explores the implications of GBA1 mutations for therapeutic strategies, highlighting the need for early diagnosis and targeted interventions. Currently, small molecular chaperones have shown the most promising clinical results compared to other agents. This synthesis of clinical, pathological, and molecular aspects underscores the assertion that GBA1-PD is a distinct clinical and pathobiological PD phenotype, necessitating specific management and research approaches to better understand and treat this debilitating condition.