Search Results (125)

Influence of surface pretreatment Hydrofluoric acid (HFA), Erbium yttrium scandium gallium garnet (Er, Cr: YSGG) laser (ECL), and Phthalocyanine (Pc) photosensitizer (Ps) activated by Low-level laser therapy (LLLT) via a light-emitting diode (LED) device on surface roughness (Ra) and shear bond strength (SBS) of ceramic bracket bonded to enamel via unmodified and Sepiolite-modified adhesive. Sixty non-cavitated human maxillary premolars were obtained. Ninety ceramic brackets were classified into three groups based on different pretreatment methods: Group 1: HFA; Group 2: ECL; and Group 3: Pc-LLLT. Twenty samples from each cohort were allocated into two subgroups by adhesive type: unmodified Transbond XT(A) and adhesive-modified Sep-NPs(B) (n = 10). Ra was measured using profilometry followed by surface topography via SEM, SBS via universal testing machine, and degree of conversion (DC) through FTIR spectroscopy. ANOVA and Tukey’s post hoc tests compared Ra, SBS, and DC across groups (p ˂ 0.05). Maximum Ra was observed in the ECL group (1087.43 ± 0.043 µm), while Group 3 (Pc-LLLT) showed the lowest Ra (706.53 ± 0.054 µm). Maximum SBS was recorded in Group 2B (ECL + SepNPs modified adhesive) (8.79 ± 0.48 MPa), while Group 3A (Pc-LLLT + unmodified adhesive) (5.23 ± 0.32 MPa) showed minimum bond integrity. ECL serves as an appropriate substitute for HFA in improving Ra and SBS of ceramic brackets to enamel. SepNPs improved the SBS of orthodontic adhesive to enamel with no significant difference in DC. Full article

Background/Objectives: Epilepsy is a major neurological disorder associated with significant comorbidity and treatment challenges. In low- and middle-income countries, access to newer antiseizure medications (ASMs) remains limited, and prescription patterns often rely on older agents. This study aimed to characterize national prescribing patterns of ASMs among patients with epilepsy in Kazakhstan from 2021 to 2023. Methods: We conducted a retrospective observational study using de-identified electronic health record data from the Unified National Electronic Health System of Kazakhstan. All patients with an ICD-10 diagnosis of epilepsy (G40) and at least one ASM prescription during 2021–2023 were included. Prescription frequencies, therapy type, and chronic polytherapy levels were analyzed. Associations between therapy type, age, and comorbidity status were determined. Results: A total of 54,274 patients were identified (median age 42 years; interquartile range (IQR) 31–57). Monotherapy predominated: 61.7% remained on monotherapy, 18.5% remained on polytherapy, and 19.8% had mixed exposure. Carbamazepine and valproic acid were most frequently prescribed (64.3% and 45.6% of patients, respectively). Among those with chronic medication data (n = 15,752), nervous-system drugs were common (70.1%), led by psycholeptics (49.7%); frequently dispensed agents included chlorpromazine (n = 5991), clozapine (n = 1875), and risperidone (n = 1642). Cardiovascular agents were recorded in 37.2% (acetylsalicylic acid n = 4056; atorvastatin n = 2235), and diabetes drugs in 12.1% (metformin n = 1430). Conclusions: Epilepsy treatment in Kazakhstan remains dominated by older broad-spectrum ASMs, while the use of lamotrigine and levetiracetam is steadily increasing. The frequent co-prescription of psychotropic and cardiometabolic drugs underscores the need for coordinated, multidisciplinary care and continued monitoring of prescribing patterns to enhance treatment safety and effectiveness. Full article

HER2-low breast cancer has been recognized as a heterogenous group of tumors influenced by hormone receptor (HR) expression, giving rise to tumors with either a luminal-like phenotype or features resembling triple-negative breast cancer (TNBC). Despite the development of HER2-targeted therapies, several studies have demonstrated their limited efficacy in patients diagnosed with HER2-low breast cancer. However, recent research has led to the development of antibody-drug conjugates (ADCs), such as trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd), with the latter showing promising results in treating these patients. Despite this breakthrough, the availability of a single effective therapy fails to account for tumor heterogeneity and may contribute to the emergence of therapy resistance, leaving HER2-low patients without treatment options. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at a post-transcriptional level and are capable of modulating key cellular processes. Recent studies have highlighted their potential as therapeutic targets, contributing to the advancement of personalized, patient-center therapies. In this context, the interplay between miRNAs and HER2-targeted therapies, particularly their modulation of common essential genes and signaling pathways, could reshape HER2-low therapy strategies to transform current practices aimed at improving the overall patient outcomes. Therefore, this review aims to elucidate the mechanisms underlying current HER2-targeted therapy and explore a potential crosstalk with miRNAs, ultimately serving as a guide for the development of personalized therapeutic strategies. Full article

The growing use of experimental radiopharmaceuticals for targeted radionuclide therapy (TRT) highlights the need for robust “in house” radiolabeling protocols. Among these, PSMA-ALB-56 is a PSMA ligand incorporating an albumin-binding moiety to enhance pharmacokinetics, which showed promise for prostate cancer treatment. This study investigated manual radiolabeling conditions of this vector molecule with lutetium-177 and developed a corresponding automated synthesis protocol. Manual experiments on low activities explored buffer systems and antioxidants, identifying sodium acetate buffer and L-methionine as optimal, achieving radiochemical purities above 97% with excellent stability over 48 h. However, when these conditions were transposed directly to an automated process on a GAIA^® module with activities > 2 GBq, radiochemical purity dropped below 70% due to significant radiolysis. This result emphasized that conditions optimized at low activities are not directly transferable to high-activity automated production, and highlighted the crucial role of antioxidant concentration. An optimized automated method was subsequently developed, integrating a solid-phase extraction purification step, higher antioxidant levels during radiolabeling and formulation, and a larger final product volume. These changes led to radiochemical purities above 98.9% and excellent product stability over 120 h for 3 test batches. The presence of high concentrations of methionine and ascorbic acid was essential to protect against radiolysis. This work underscores the importance of adjusting radiolabeling strategies during process scale-up and confirmed that antioxidant concentration is essential for successful ¹⁷⁷Lu radiolabeling. The optimized automated method developed here for [¹⁷⁷Lu]Lu-PSMA-ALB-56 may also be adapted to other radiopharmaceuticals in development for TRT. Full article

Chronic wound healing is a complex and tightly regulated process requiring coordinated epithelial and stromal regeneration. Photobiomodulation (PBM) using low-level red light-emitting diode (LED) therapy has emerged as a non-invasive approach to enhancing skin repair. In this study, we evaluated the therapeutic efficacy of a pulsed, multi-wavelength LED system on full-thickness excisional wound healing in a normal murine model. Daily LED treatment significantly accelerated wound closure, promoted re-epithelialization, and improved dermal architecture. Histological and immunohistochemical analyses revealed enhanced epidermal stratification, reduced inflammation, and improved collagen organization. Molecular profiling demonstrated increased expression of proliferation marker Ki67, keratins CK14 and CK17, and extracellular matrix-related genes including MMPs, Col1a1, and Col3a1. In vitro assays using HaCaT keratinocytes showed accelerated scratch wound closure and cytoskeletal remodeling following PBM exposure. These findings suggest that pulsed PBM promotes coordinated epithelial regeneration and matrix remodeling, highlighting its potential as a tunable and effective therapeutic modality for accelerating cutaneous wound healing under physiological conditions. Full article

Background: The outgrowth of castration-resistant prostate cancer (CRPC) dictates patient morbidity and mortality. Recurrence of prostate cancer (PC) following androgen-deprivation therapy (ADT) often occurs due to constitutively active androgen receptor (AR) splice variants (AR-Vs), primarily AR-V7. Therefore, safe and effective therapies enabling the suppression of both full-length AR (AR-FL) and AR-Vs are urgently needed. The natural compound dimethyl sulfoxide (DMSO) has negligible cytotoxicity at concentrations below 5% and has anticancer potential. DMSO has been broadly used in biomedical research as a solvent for pharmaceuticals, as a cryoprotectant for cells, and as a topical treatment to suppress pain and inflammation. We investigated the effect of low-dose DMSO on AR expression, cell viability, and metastatic ability in PC cell lines expressing both AR-FL and AR-V7 (e.g., 22Rv1) and those expressing only AR-FL (e.g., C4-2B). Methods: MTT cell viability assays were performed to measure DMSO-induced cytotoxicity. Wound-healing assays were conducted to monitor the effect of DMSO on the migratory phenotype of cancer cells. Western blot analyses were performed to study the efficacy of DMSO in suppressing the protein levels of AR-FL and AR-V7, and expression of heterogeneous nuclear ribonucleoprotein H1 (hnRNPH1) was measured as a possible mechanism. Results: At concentrations of 0.1–1% (v/v), DMSO treatment showed minimal cytotoxicity, whereas the highest concentration used (2.5%) showed approximately 20% cytotoxicity at 96 h. Interestingly, however, DMSO treatment at concentrations of 1.0 and 2.5% significantly inhibited the migration of PC cells. Treatment with DMSO led to a dose-dependent inhibition of both AR-FL and AR-V7. Notably, in 22Rv1 cells, DMSO potently downregulated the expression of hnRNPH1, a splicing factor often associated with AR expression and signaling. Conclusions: Our findings suggest that low concentrations of DMSO may have potential as an effective anticancer agent, both at the initial and later stages when PC cells become castration resistant. Full article

Retrotransposons exhibit increased activity in cancer cells. One possible approach to anticancer therapy is to use this activity to influence the energy balance in cells. Abnormal distribution of retrotransposons in the genome requires additional energy consumption, which can lead to a significant decrease in the total amount of free ATP molecules in the cell. A decrease in ATP levels below a certain threshold can in turn trigger a cell death program. To investigate the possibility of such a scenario, we developed a mathematical model of the cellular energy balance that describes the dynamics of energy consumption by the main cellular processes, including costs of retrotransposon activity. The model considers changes in the concentrations of ATP, active retrotransposons (LINE-1 and SINE) in the human genome, as well as mRNAs and proteins that are expression products of retrotransposon and constitutive genes. We estimated the parameter values in the model based on literature data and numerical optimization. We found a single stable stationary solution, characterized by low retrotransposon activity, and used it as the reference steady state for further analysis. Parametric sensitivity analysis revealed the parameters whose changes had the greatest impact on cellular ATP levels. The LINE-1 deactivation rate constant and the maximum LINE-1 transcription rate were the most sensitive among the transposon-related parameters. Perturbation of these parameters led to a decrease in the number of free ATP to 30% of the reference value and below. Transcription of retrotransposons under perturbed parameters became comparable to the translation of constitutive genes in terms of energy costs. The presented results indicate that cancer cell death can be initiated by increasing the load on the energy balance due to the activation of transposons. Full article

Specific venom immunotherapy (VIT) in patients with hymenoptera venom allergy (HVA) represents a well-studied approach to reduce the severity of a possible anaphylactic reaction. Currently, data on mechanisms of tolerance induction at the cellular level within the first hours of therapy are lacking. To address this, total and unoccupied high-affinity IgE receptor (FcεRI) numbers per basophil, soluble FcεRI (sFcεRI) and serum tryptase levels were measured before and after the first day of VIT induction in HVA patients. Additionally, basophil activation tests (BATs) were performed at those time points. In the early phase of VIT induction, no significant change in total FcεRI receptor density on basophils was observed, but a significant increase in unoccupied FcεRI was noticeable, predominantly in patients with high total IgE and low baseline unoccupied FcεRI density. No meaningful difference in serum tryptase levels or sFcεRI levels was observed after VIT induction. BATs showed heterogeneous results, often unchanged before and after VIT (in 47% of the cases), sometimes increased (in 40%) and only rarely decreased EC₅₀ sensitivity (in 13%). Changes in the BAT EC₅₀ correlated with FcεRI receptor density changes in basophils. In summary, VIT induction led to an increased ratio of unoccupied-to-total FcεRI without notable tryptase or sFcεRI serum elevation, pointing towards subthreshold cell activation with receptor internalization and recycling. However, the mostly unchanged or even increased basophil sensitivity in EC₅₀ calls for further research to clarify the clinical relevance of these rapid receptor modulations. Full article

Background: Antimicrobial resistance (AMR) poses a significant threat to public health, especially in low- and middle-income countries (LMICs), where surveillance infrastructure is underdeveloped. Bihar, India’s third most populous state and one of its least-resourced states, has remained largely absent from national AMR monitoring initiatives. Methods: This study aimed to characterize the AMR infection landscape across five public tertiary care hospitals in Bihar over three years (2022–2024) and to assess the feasibility of integrating digital workflows for real-time microbiological reporting. Standardized antimicrobial susceptibility testing (AST) was performed on >48,000 urine, pus, and blood samples using CLSI guidelines. Facility-level data were digitized into an open-source AMR reporting system, enabling automated antibiogram generation. Results: The findings revealed substantial resistance: high resistance to beta-lactams, carbapenems, and fluoroquinolones across pathogens. For instance, E. coli sensitivity to nitrofurantoin varied from 86.5% at NMCH (Patna) to 44.7% at JLNMCH (Bhagalpur), while cephalosporin sensitivity in Klebsiella spp. dropped below 2% in several hospitals. MRSA prevalence exceeded 65% in two facilities, far above the national average of 47.8%. Digital integration led to a four-fold increase in culture testing in all facilities and improved data completeness and turnaround times. Spatial analysis and microbiology laboratory assessment revealed significant geographic disparities in diagnostic access, with facilities in remote districts facing delays of over four hours for basic testing. Conclusions: Our study is the first study from India to create such a broad, facility-associated AMR picture over time at a state level. Policy implications include the need for a state-level AMR surveillance dashboard, alignment of procurement with facility-specific resistance patterns, and routine stewardship audits. Clinically, this study demonstrates the utility of localized antibiograms for guiding empirical therapy in resource-limited settings. This study provides a scalable framework for embedding AMR surveillance into routine health system workflows in LMICs. Full article

Chronic diabetic wounds affect 15–20% of patients and are characterized by impaired healing due to disrupted hemostasis, inflammation, proliferation, and extracellular matrix (ECM) remodeling. Low-level light therapy (LLLT) has emerged as a promising noninvasive strategy for enhancing tissue regeneration. Here, we developed a multispectral pulsed LED system combining red and near-infrared light to stimulate wound healing. In vitro photostimulation of human keratinocytes and fibroblasts on biomimetic hydrogels enhanced adhesion, spreading, migration, and proliferation via increased focal adhesion kinase (pFAK), paxillin, and F-actin expression. In vivo, daily LED treatment of streptozotocin-induced diabetic wounds accelerated closure and improved ECM remodeling. Histological and molecular analyses revealed elevated levels of MMPs, interleukins, collagen, fibronectin, FGF2, and TGF-β1, supporting regenerative healing without excessive fibrosis. These findings demonstrate that multispectral pulsed photobiomodulation enhances diabetic wound healing through focal adhesion-mediated cell migration and ECM remodeling, offering a cost-effective and clinically translatable approach for chronic wound therapy. Full article

Background/Objectives: Pain remains as a prevailing cause, prompting patients to seek medical attention, comprising approximately 40% of all emergency department (ED) visits annually. Timely and effective pain management is crucial for patient comfort, satisfaction, and optimal recovery. However, there is increasing evidence highlighting the concern that patients often receive inadequate pain management in both emergency departments and prehospital settings. Despite the simplicity and potential for the repetitive use of pain scales throughout a patient’s stay, it appears that a greater emphasis is often placed on monitoring hypotension or low saturation values rather than addressing pain levels above 7 on the numeric rating pain scale. Methods: This article represents an ambitious attempt to implement process improvement methodologies such as Lean Management and SixSigma, both which have been well established in service and industrial fields, within the hospital environment to improve the process of pain management in the emergency department. Results: The implementation of pain management improvement processes in the emergency department led to a statistically significant but clinically modest increase in the administration of analgesics and improved pain reporting practices. The percentage of patients receiving no analgesia decreased from 96.6% to 94.8% (p = 0.008), and the documentation of pain characteristics during triage improved. However, the escalation of pain therapy remained limited, and strong analgesics were still underutilized. Conclusions: Despite partial improvements, the lean management-based interventions did not sufficiently address the problem of oligoanalgesia in the emergency setting. Sustainable change requires enhanced clinical engagement, ongoing staff training, and the broader adoption of structured analgesia protocols across prehospital and hospital care. Full article

Background and Clinical Significance: Fulminant pulmonary embolism (PE) leading to an out-of-hospital cardiac arrest (OHCA) is associated with a high mortality rate and cardiopulmonary resuscitation (CPR) frequently failing to achieve return of spontaneous circulation (ROSC). Extracorporeal CPR (eCPR) has emerged as a potential life-saving intervention. Case Presentation: A 66-year-old woman suffered an OHCA due to massive PE, presenting with pulseless electrical activity (PEA). After 90 min of pre- and in-hospital CPR without sustained ROSC, venoarterial extracorporeal membrane oxygenation (va-ECMO) was initiated as eCPR upon arrival at the hospital. Even after implantation of the va-ECMO, there was initially a pronounced acidosis (pH 6.9) with a high elevated lactate level (>30 mmol/L); these factors, together with the prolonged low-flow period, indicated a poor prognosis. Further diagnostic tests revealed intracranial hemorrhage (subdural hematoma), and systemic lysis was not possible. With persistent right heart failure, surgical thrombectomy was performed during hospitalization. Intensive multidisciplinary management finally led to successful therapy and weaning from mechanical ventilation, as well as to complete neurological recovery (CPC-Score 1-2). Conclusions: This case illustrates that eCPR can facilitate survival with good favorable neurological outcomes despite initially poor prognostic predictors. It underscores the importance of refining patient selection criteria and optimizing management strategies for eCPR in refractory cardiac arrest secondary to PE. Full article

Background: Cardiac autonomic neuropathy (CAN) is a common yet frequently underdiagnosed complication of diabetes. While our previous study demonstrated the utility of multiscale cross-approximate entropy (MS-CXApEn) in detecting early CAN, the present study further investigates the use of frequency-domain coherence analysis between systolic blood pressure (SBP) and R-R intervals (RRI) and evaluates the effects of insulin treatment on autonomic function in diabetic rats. Methods: At the onset of diabetes induced by streptozotocin (STZ), rats were assessed for cardiovascular autonomic function both before and after insulin treatment. Spectral and coherence analyses were performed to evaluate baroreflex function and autonomic regulation. Parameters assessed included low-frequency power (LFP) and high-frequency power (HFP) of heart rate variability, coherence between SBP and RRI at low and high-frequency bands (LF_Coh and HF_Coh), spontaneous and phenylephrine-induced baroreflex sensitivity (BRS_spn and BRS_phe), HRV components derived from fast Fourier transform, and MS-CXApEn at multiple scales. Results: Compared to normal controls (LF_Coh: 0.14 ± 0.07, HF_Coh: 0.19 ± 0.06), early diabetic rats exhibited a significant reduction in both LF_Coh (0.08 ± 0.04, p < 0.05) and HF_Coh (0.16 ± 0.10, p > 0.05), indicating impaired autonomic modulation. Insulin treatment led to a recovery of LF_Coh (0.11 ± 0.04) and HF_Coh (0.24 ± 0.12), though differences remained statistically insignificant (p > 0.05 vs. normal). Additionally, low-frequency LFP increased at the onset of diabetes and decreased after insulin therapy in most rats significantly, while MS-CXApEn at all scale levels increased in the early diabetic rats, and MS-CXApEn_large declined following hyperglycemia correction. The BRS_spn and BRS_phe showed no consistent trend. Conclusions: Coherence analysis provides valuable insights into autonomic dysfunction in early diabetes. The significant reduction in LF_Coh in early diabetes supports its role as a potential marker for CAN. Although insulin treatment partially improved coherence, the lack of full recovery suggests persistent autonomic impairment despite glycemic correction. These findings underscore the importance of early detection and long-term management strategies for diabetic CAN. Full article

Background: Tendinopathy is a challenging condition associated with high treatment costs, prolonged dysfunction, and lower quality of life. Current treatment strategies aim to accelerate healing by modulating the healing phases. Phototherapy and growth factor-based modalities have shown promising outcomes in promoting tendon healing. A two-factor experimental design investigates the therapeutic efficacy of conditioning a partially tenotomized rat Achilles tendon model with low concentrations of collagenase, followed by platelet-rich plasma and/or light-emitting diode treatments. Methods: Forty-six adult male Wistar rats (284.8g ± 6.8) were randomly assigned to nine groups (G1 (n = 6), G2–G9; n = 5 per group) based on the treatment applied upon a partially incised rat’s hind-limb Achilles tendon model for three weeks. On day 21, blood samples were collected for hematological and biochemical analyses and tendon explants were harvested and subjected to histology. Results: Observational findings support the safety and validity of the model with insignificant weight gain. Hematological measures revealed no significant differences, except WBC, which was affected by phototherapy (p = 0.037). Blood biochemical measures of creatinine and AST levels were significantly affected by collagenase, while both treatments significantly influence CPK levels (p < 0.001). Histological scores revealed no significant main or interaction effect of both treatment modalities. Effect size estimates for biochemical variables were strong effects while hematological and histological variables demonstrated weak effects. Conclusions: Preconditioning a partially incised tendon with low collagenase and combined with PRP and/or LED therapy may offer therapeutic benefits by enhancing the remodeling phase of tendon repair. Study results validated the rat model, which could be a reliable model for future research to refine treatment as well as the investigational tools protocols. Full article

Fibromyalgia syndrome is a chronic pain condition involving altered nociceptive processing, which requires multidisciplinary management. Photobiomodulation therapy (PBMT) has recently emerged as a promising non-pharmacological approach, but its clinical effectiveness and optimal application methods remain unclear. This systematic review evaluated the efficacy of PBMT in managing Fibromyalgia symptoms, including pain, physical function, sleep quality, and overall well-being, while comparing localized and whole-body delivery. A systematic review was conducted in accordance with the PRISMA guidelines and previously registered on PROSPERO (CRD42024626368). Literature searches were performed across MEDLINE ((PubMed)), PEDro, SPORTDiscus, Scopus, Elsevier (ScienceDirect), and Web of Science (WOS), identifying 17 eligible studies (n = 857 participants). PBMT was applied via low-level laser, infrared, or LED-based devices, delivered either locally or to the whole body. The methodological quality of the studies was assessed using the PEDro scale, and the risk of bias was evaluated using the RoB 2.0 tool. PBMT showed significant clinical benefits, including reduced pain intensity, improved physical function, decreased fatigue, and enhanced quality of life. Whole-body PBMT showed greater and more sustained effects than localized applications, likely due to its systemic modulation of nociceptive pathways and autonomic regulation. Improvements were also observed in terms of psychological well-being, sleep quality, and reduced kinesiophobia. In conclusion, PBMT appears to be an effective therapeutic option for Fibromyalgia syndrome, with whole-body applications offering superior benefits. However, the variability in treatment parameters and study methodologies underscores the need for standardized protocols and high-quality clinical trials to support its integration into multidisciplinary pain management strategies. Full article