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We present a novel 2D oscillator with an asymmetric design and investigate its stable vibration utilizing the Ms-DTM method. Initially, we obtain the equations of motion for the proposed system. Subsequently, by employing Taylor expansion of s i n h z and c o s h z , the derived nonlinear equations are transformed into linear ones, which we solve analytically using the eigenvalues-eigenfunctions technique. Additionally, we solve the obtained nonlinear system using the Ms-DTM method. Lastly, we examine the stability of the nonlinear system by visualizing the closed nature of the phase portrait. [ABSTRACT FROM AUTHOR]

Aim: COVID-19 has been associated with cardiovascular complications including ventricular arrhythmias (VA) and an increased number of out-of-hospital cardiac arrests. Nevertheless, several authors described a decrease of VA burden in patients with an implantable defibrillator (ICD) during the first wave of the COVID-19 pandemic. The objective of this study was to determine if these observations could be transferred to later periods of the pandemic as well., Methods: We retrospectively analyzed a total of 1674 patients with an ICD presenting in our outpatient clinic during the second wave of the COVID-19 pandemic and during a control period for the occurrence of VA requiring ICD interventions., Results: Seven hundred ninety-five patients with an ICD had a device interrogation in our ambulatory clinic during the second wave of the COVID-19 pandemic compared to eight hundred seventy-nine patients in the control period. There was significant higher amount of adequate ICD therapies in the course of the COVID-19 period. Thirty-six patients (4.5%) received in total eighty-five appropriate ICD interventions during COVID-19, whereas only sixteen patients (1.8%) had sustained VA in the control period (p = 0.01)., Conclusion: In contrast to the first wave of COVID-19, which was characterized by a decrease or least stable number of ICD therapies in several centers, we found a significant increase of VA in ICD patients during the second wave of COVID-19. Possible explanations for this observation include higher infectious rates, potential cardiac side effects of the vaccination as well as personal behavioral changes, or reduced utilization of medical services., (© 2023. The Author(s).)

Atrial fibrillation (AF) is common in patients with chronic kidney disease (CKD) undergoing hemodialysis and in this patient population, management in terms of oral anticoagulation (OAC) presents unique challenges due to the increased risk of both thromboembolic events and bleeding complications. The attributable risk of AF for stroke may differ from patients without CKD, raising the question if OAC is indicated at all. Historically, vitamin K antagonists (VKA) have been the standard treatment for anticoagulation in AF; however, direct oral anticoagulants (DOACs) have emerged as an alternative therapeutic option, whereby data from prospective randomised trials with hemodialysis patients is limited resulting in great variability of practice and guideline recommendations. This review summarizes existing data sources regarding the use and benefit of oral anticoagulation with VKA and DOAC in hemodialysis patients., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: In orthopaedic research, it is crucial to determine changes that are statistically significant and clinically meaningful. One approach to accomplish this is by calculating the Minimal Clinically Important Difference (MCID), the Clinically Important Differences (CID), the Minimum Detectable Change (MDC), the Minimal Important Change (MIC), and the Patient Acceptable Symptom State (PASS) values. These tools assist medical professionals in comprehending the patient's viewpoint, enabling them to establish treatment objectives that align with patients' desires and expectations. The present systematic review investigated the MCID, MIC, CID, MDC, and PASS of the most used PROMs to assess patients who have undergone THA., Methods: This systematic review followed the 2020 PRISMA guidelines. Web of Science, Embase, and PubMed were accessed in March 2024 without time constraints or additional filters. All the clinical investigations which evaluated data tools (MCID, MIC, CID, MDC, and PASS) to assess the clinical relevance of PROMs in THA were accessed. Articles in Spanish, Italian, German, and English were eligible. Studies with levels of evidence I to III were eligible., Results: Data from 100,824 patients were collected. All relevant demographic data were analysed and summarised. In addition, the MCID, MIC, CID, MDC and PASS of the COMI, HOOS, SF-36, OHS, Oxford-12, PROMIS-PF, SF-12, and WOMAC scores for THA were determined., Conclusion: Current evidence recommends to collect MCIDs based on anchors routinely. These values should be used as complementary tools to determine the clinical effectiveness of a treatment instead of solely relying on statistically significant improvements., Level of Evidence: Level IV, systematic review and meta-analysis., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aseptic loosening is a feared and not yet fully-understood complication of total knee arthroplasty (TKA). Hypersensitivity reactions may be the underlying cause within some susceptible patients. Metal-free implants have been developed as a possible solution. The aim of this prospective, observational long-term study was the assessment of a completely metal-free ceramic knee replacement system compared to its identical metal counterpart 8 years after implantation, conducted as a follow-up of a previous report. A total of 88 patients (mean age 69 years) were enrolled in this prospective, observational long-term 8-year follow-up study. The "ceramic group" with a completely metal-free total knee replacement system was compared to the "conventional group" with an identical metal TKA system at the final follow-up. Clinical assessment included Knee Society Score (KSS), Oxford Knee Score (OKS), European Quality of Life 5 Dimensions 3 Level Version (EQ-5D-L), European Quality of Life 5 Dimension Visual Analogue Scale (EQ-VAS) and High Activity Arthroplasty Score (HAAS) as well as perioperative or postoperative complications and need for revision. The tibial/femoral positioning, signs of periprosthetic fissures/fractures or radiolucent lines were documented radiographically. All postoperative clinical scores in the ceramic group primarily improved from baseline to 4-year follow-up, but then decreased at the final 8-year follow-up. At the final follow-up, statistically non-significant differences were found in comparison of both groups for the KSS (ceramic: 166 ± 31, conventional: 162 ± 29; p > 0.05), OKS (ceramic: 37, conventional: 39; p > 0.05), EQ-VAS (ceramic: 77 ± 17, conventional: 72 ± 18; p > 0.05), and HAAS (ceramic: 8.29 ± 3.32, conventional: 9.28 ± 4.44; p > 0.05). A significant difference was found for EQ-5D-L (ceramic: 0.819 ± 0.284, conventional: 0.932 ± 0.126; p ≤ 0.05). Progressive radiolucent lines have been found around the uncemented tibial stem (0.8 mm at initial diagnosis (mean 19 months); 1.3 mm at 4-year follow-up; 1.6 mm at 8-year follow-up) without any clinical signs of loosening. One revision surgery was performed after a traumatic polyethylene inlay-breakage. No allergic reactions could be detected. The used ceramic TKA system meets the functional performance standards of an established identical metal TKA system after an 8-year follow-up period, offering a safe option for patients with prior hypersensitivity reactions to metallic materials. Full cementation of ceramic components is recommended., (© 2024. The Author(s).)

Background: Implantable loop recorder (ILR) allows rhythm-monitoring up to 3 years. They are recommended in patients with recurrent syncope and for the detection of atrial fibrillation (AF) in patients with cryptogenic thromboembolic events. AF and syncope occur more often in elderly patients. However, data in this cohort is limited., Methods and Results: All patients ≥ 80 years undergoing ILR-implantation between 2011 and 2022 in our center were included. Permanent pacemaker implantation (PPI) and oral anticoagulation due AF were defined as primary endpoints. Forty-five patients ≥ 80 years were included, 33 because of recurrent syncope and 12 because of suspected AF. The average follow up (FU) was 17.6 months. Overall in 22 patients, ILR-implantation led to a therapeutic consequence (48.9%). In the 12 patients who underwent ILR-implantation for detection of AF, AF was detected in nine patients (75%). In the 33 elderly patients who received ILR-implantation after syncope, 11 underwent PPI during FU (33.3%). One patient accidentally removed the ILR himself via the implantation-wound, and no other ILR-related complications were observed., Conclusion: ILR are effective and safe in elderly patients. AF was often found in patients with suspected AF, especially in patients after catheter ablation of only documented atrial flutter (AFlu). PPI-rate was high in patients with recurrent syncope and ILR-implantation. Further investigations are necessary to determine whether PPI may be considered in elderly patients with syncope even in the absence of a bifascicular block., (© 2024 The Author(s). Pacing and Clinical Electrophysiology published by Wiley Periodicals LLC.)

Objective and Background:  Data on incidence of in-hospital pulmonary embolisms (PE) after catheter ablation (CA) are scarce. To gain further insights, we sought to provide new findings through case-based analyses of administrative data., Methods:  Incidences of PE after CA of supraventricular tachycardias (SVT), atrial fibrillation (AF), atrial flutter (AFlu), and ventricular tachycardias (VT) in three German tertiary centers between 2005 and 2020 were determined and coded by the G-DRG (German Diagnosis Related Groups System) and OPS (German Operation and Procedure Classification) systems. An administrative search was performed with a consecutive case-based analysis., Results:  Overall, 47,344 ablations were analyzed (10,037 SVT; 28,048 AF; 6,252 AFlu; 3,007 VT). PE occurred in 14 (0.03%) predominantly female ( n  = 9; 64.3%) patients with a mean age of 55.3 ± 16.9 years, body mass index 26.2 ± 5.1 kg/m 2 , and left ventricular ejection fraction of 56 ± 13.6%. PE incidences were 0.05% ( n  = 5) for SVT, 0.02% ( n  = 5) for AF, and 0.13% ( n  = 4) for VT ablations. No patient suffered PE after AFlu ablation. Five patients (35.7%) with PE after CA had no prior indication for oral anticoagulation (OAC). Preprocedural international normalized ratio in PE patients was 1.2 ± 0.5. Most patients with PE following CA presented with symptoms the day after the procedure ( n  = 9) after intraprocedural heparin application of 12,943.2 ± 5,415.5 IU. PE treatment included anticoagulation with either phenprocoumon ( n  = 5) or non-vitamin K-dependent OAC ( n  = 9). Two patients with PE died after VT/AF ablation, respectively. The remaining patients were discharged without sequels., Conclusion:  Over a 15-year period, incidence of PE after ablation is low, particularly low in patients with ablation for AF/AFlu. This is most likely due to stricter anticoagulation management in these patients compared with those receiving SVT/VT ablation procedures and could argue for continuation of OAC prior to ablation. Optimizing periprocedural anticoagulation management should be subject of further prospective trials., Competing Interests: None declared., (Thieme. All rights reserved.)

Background and Objectives: The coexistence of major depressive disorder (MDD) and metabolic illness could culminate in an aberrant metabolic profile. Individuals with MDD and type 2 diabetes mellitus (T2DM) are more likely to have impaired metabolic indicators. Effective antidepressant therapy can alleviate depressive symptoms and metabolic abnormalities. We focused on the effects of vilazodone, escitalopram, and vortioxetine on metabolic indices. Our research aimed to examine changes after 16 weeks of intervention in the glycemic indices, serum creatinine, lipid profile, hepatic parameters, and the Hamilton Depression Rating Scale (HDRS) 17-item version., Methods: A three-arm, randomized, open-label trial with 96 MDD patients was executed. Participants were divided into three distinct groups in a 1:1:1 ratio for 16 weeks and issued tablets of vilazodone (20-40 mg/day), escitalopram (10-20 mg/day), or vortioxetine (5-20 mg/day). Vilazodone and vortioxetine were the two test medications, while escitalopram served as the control. We stratified the participants as non-diabetics and diabetics. Follow-up appointments were slated four weeks after the initial visit. HDRS scores and other metabolic indicators were assessed at each visit in the per-protocol (PP) population. After 12 weeks, glycated hemoglobin (HbA 1c ) levels were measured. Lower HDRS scores indicated that depression-related symptoms had improved. We investigated the relationship between the 16-week differences in the fasting blood sugar (FBS) and HDRS scores. The Kruskal-Wallis test, Bonferroni correction, and Pearson correlation were all used in our analysis. We registered our trial prospectively in the Clinical Trial Registry of India (CTRI) (2022/07/043808)., Results: Of the 134 people we screened, 119 (81.34%) were deemed eligible. The PP population included 96 (88.07%) of those who completed the 16-week study. The population's average age was 46.3 ± 6.2 years. Across all study groups, the median baseline HDRS score was 30.0 (p = 0.964). At 16 weeks, the equivalent scores dropped to 15.0, 14.0, and 13.0 (p = 0.002). The median FBS levels at baseline and 16 weeks were 100.5, 104.0, and 98.0 (p = 0.491) and 91.5, 98.5, and 91.5 (p = 0.561), respectively. The post hoc analysis manifested no statistically significant changes between any parameters. Except for the reductions in glycemic indices in diabetic patients, no other data differed significantly. There was a positive relationship between FBS and HDRS scores., Conclusion: Irrespective of the diabetic situation, all three drugs substantially lowered HDRS scores. People with diabetes experienced noticeable declines in glycemic indices. Despite this, the patients' other metabolic indicators showed no significant alterations. We urge additional research with a larger sample size to investigate these medications' long-term impact on various metabolic indicators., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Institutional Research & Ethics Committee, Veer Surendra Sai Institute of Medical Sciences & Research issued approval 029-2022/I-S-T/03. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Santi et al.)

Despite advancements in antifibrotic therapy, idiopathic pulmonary fibrosis (IPF) remains a medical condition with unmet needs. Single-cell RNA sequencing (scRNA-seq) has enhanced our understanding of IPF but lacks the cellular tissue context and gene expression localization that spatial transcriptomics provides. To bridge this gap, we profiled IPF and control patient lung tissue using spatial transcriptomics, integrating the data with an IPF scRNA-seq atlas. We identified three disease-associated niches with unique cellular compositions and localizations. These include a fibrotic niche, consisting of myofibroblasts and aberrant basaloid cells, located around airways and adjacent to an airway macrophage niche in the lumen, containing SPP1 + macrophages. In addition, we identified an immune niche, characterized by distinct lymphoid cell foci in fibrotic tissue, surrounded by remodeled endothelial vessels. This spatial characterization of IPF niches will facilitate the identification of drug targets that disrupt disease-driving niches and aid in the development of disease relevant in vitro models.

Background: This study evaluated the osseointegration potential of functionalised high-performance oxide ceramics (HPOC) in isolation or coated with BMP-2 or RGD peptides in 36 New Zeeland female rabbits using micro-computed tomography (micro CT). The primary outcomes of interest were to assess the amount of ossification evaluating the improvement in the bone volume/ total volume (BV/TV) ratio and trabecular thickness at 6 and 12 weeks. The second outcome of interest was to investigate possible differences in osteointegration between the functionalised silanised HPOC in isolation or coated with Bone Morphogenetic Protein 2 (BMP-2) or RGD peptides., Methods: 36 adult female New Zealand white rabbits with a minimum weight of three kg were used. One-third of HPOCs were functionalised with silicon suboxide (SiOx), a third with BMP-2 (sHPOC-BMP2), and another third with RGD (sHPOC-RGD). All samples were scanned with a high-resolution micro CT (U-CTHR, MILabs B.V., Houten, The Netherlands) with a reconstructed voxel resolution of 10 µm. MicroCT scans were reconstructed in three planes and processed using Imalytics Preclinical version 2.1 (Gremse-IT GmbH, Aachen, Germany) software. The total volume (TV), bone volume (BV) and ratio BV/TV were calculated within the coating area., Results: BV/TV increased significantly from 6 to 12 weeks in all HPOCs: silanised (P = 0.01), BMP-2 (P < 0.0001), and RGD (P < 0.0001) groups. At 12 weeks, the BMP-2 groups demonstrated greater ossification in the RGD (P < 0.0001) and silanised (P = 0.008) groups. Trabecular thickness increased significantly from 6 to 12 weeks (P < 0.0001). At 12 weeks, BMP-2 promoted greater trabecular thickness compared to the silanised group (P = 0.07), although no difference was found with the RGD (P = 0.1) group., Conclusion: Sinalised HPOC in isolation or functionalised with BMP-2 or RGD promotes in vivo osteointegration. The sinalised HOPC functionalised with BMP-2 demonstrated the greatest osseointegration., (© 2024. The Author(s).)

Antiviral therapies for treatment of COVID-19 may be associated with significant proarrhythmic potential. In the present study, the potential cardiotoxic side effects of these therapies were evaluated using a Langendorff model of the isolated rabbit heart. 51 hearts of female rabbits were retrogradely perfused, employing a Langendorff-setup. Eight catheters were placed endo- and epicardially to perform an electrophysiology study, thus obtaining cycle length-dependent action potential duration at 90% of repolarization (APD 90 ), QT intervals and dispersion of repolarization. After generating baseline data, the hearts were assigned to four groups: In group 1 (HXC), hearts were treated with 1 µM hydroxychloroquine. Thereafter, 3 µM hydroxychloroquine were infused additionally. Group 2 (HXC + AZI) was perfused with 3 µM hydroxychloroquine followed by 150 µM azithromycin. In group 3 (LOP) the hearts were perfused with 3 µM lopinavir followed by 5 µM and 10 µM lopinavir. Group 4 (REM) was perfused with 1 µM remdesivir followed by 5 µM and 10 µM remdesivir. Hydroxychloroquine- and azithromycin-based therapies have a significant proarrhythmic potential mediated by action potential prolongation and an increase in dispersion. Lopinavir and remdesivir showed overall significantly less pronounced changes in electrophysiology. In accordance with the reported bradycardic events under remdesivir, it significantly reduced the rate of the ventricular escape rhythm., (© 2024. The Author(s).)

Background and objectives The quality of life declines with the growing severity of major depressive disorder (MDD). In depressed people, medication adherence and the quality of life are mutually corrosive. These concerns spurred the investigation of relationships between treatment outcomes and adherence levels. Limited studies are looking at how vortioxetine, escitalopram, and vilazodone affect these parameters. We aimed to detect how the Short Form-36 (SF-36) had changed 16 weeks after the baseline. The connection between treatment results (as expressed by the Hamilton Depression Rating Scale or HDRS) and medication adherence (as reflected by the Morisky Medication Adherence Scale-8 or MMAS-8) was also explored. Methods An open-label, randomized, three-arm trial with 96 MDD patients was conducted. For 16 weeks, the participants were put into three groups per a 1:1:1 ratio and administered tablets of vilazodone (20-40 mg/day), escitalopram (10-20 mg/day), or vortioxetine (5-20 mg/day). There were two test drugs: vilazodone and vortioxetine; the control was escitalopram. Four weeks apart, follow-up appointments were set after the baseline visit. The HDRS, mental and physical components of SF-36, and MMAS-8 scores were evaluated in the per-protocol (PP) population. Reduced HDRS scores were indicative of improved depression symptoms. Higher MMAS-8 and SF-36 scores indicated high drug adherence and enhanced quality of life. Our analysis used the Kruskal-Wallis test, the Bonferroni correction, and the Sankey diagram. In the Clinical Trial Registry-India (CTRI), we recorded this study prospectively (2022/07/043808). Results One hundred nine (81.34%) of the 134 individuals we examined were eligible. The PP population consisted of 96 (88.07%) of them who wrapped up the 16-week study. The mean age of the group was 46.3 ± 6.2 years. For each of the three groups, the SF-36 physical component scores revealed a median difference of 24.5 (23.8-26.0), 24.0 (22.8-25.3), and 27.0 (25.0-29.0) (p = 0.001). Accordingly, the mental components of their SF-36 scores showed a median difference of 32.0 (31.0-33.3), 31.0 (29.8-34.3), and 36.0 (33.0-38.0) (p = 0.001). A median difference of -15.0 (-16.0 to -14.0), -16.0 (-17.0 to -15.0), and -16.0 (-17.0 to -15.8) was observed in the HDRS scores after 16 weeks, with respect to the baseline (p < 0.001). The median MMAS-8 scores at 16 weeks were 6.0 (6.0-7.0), 6.8 (6.0-7.0), and 7.5 (6.5-8.0) (p = 0.031). The Sankey diagram illustrated the connection between better treatment results, increased medication compliance, and decreased symptoms of depression. Conclusion In comparison to vilazodone and escitalopram, vortioxetine demonstrated a statistically significant decrease in HDRS scores and an improvement in the physical and mental component scores of the SF-36. Clinical improvements were evident in the individuals' drug adherence levels. Larger-scale studies are advised to investigate the effects of these medications on the quality of life, medication adherence, and treatment outcomes., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. The Institutional Research and Ethics Committee of Veer Surendra Sai Institute of Medical Sciences and Research issued approval 029-2022/I-S-T/03, dated 17/05/2022. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Santi et al.)

Introduction: Only a few anatomic studies have described an isolated rectus femoris tendon autograft for anterior cruciate ligament (ACL) reconstruction. This study aims to demonstrate a new surgical technique utilising the rectus femoris tendon for ACL reconstruction. This study hypothesises that the rectus tendon autograft will yield satisfying postoperative outcomes in terms of stability, with minimal complications at the harvest site., Methods: This retrospective study investigated the outcomes of 28 revision ACL reconstructions using a rectus tendon autograft with a mean follow-up of 41.7 (range, 24.0-64.8) months. A 3 cm longitudinal incision was used to harvest the rectus tendon with an open tendon stripper. Intraoperative collected data included the length of the tendon and thickness of a 4-fold graft. Further outcome parameters include anterior cruciate ligament stability and range of motion. Additionally, postoperative complications, especially donor site morbidity, were documented in type and frequency., Results: The mean tendon length measured 32.4 cm (range, 30-35 cm). After preparing a 4-fold graft, the mean diameter was 9.2 mm (range, 8.0-10 mm) at the tibial and 9.0 mm (range, 7.5-10 mm) at the femoral end. Stability evaluated by the Lachman test improved significantly from 2 (Interquartile range (IQR), 2-3) preoperatively to 0 (IQR, 0-1) postoperatively (p < .001). Rerupture of the anterior cruciate ligament graft was observed in 2 patients (7.1%). Four patients showed a persistent extension deficit of about 5 degrees postoperatively. Two of them underwent revision surgery due to a Cyclops lesion. Only one patient complained of prolonged pain at the harvest site (3.6%)., Conclusion: The 4-fold rectus tendon represents a novel autograft technique in revision ACL reconstruction. This study provides evidence of appropriate graft dimensions and satisfying postoperative outcomes regarding stability. The technique is associated with a low complication rate at the harvest site., Study Design: Case series; Level of evidence, IV., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Objectives: The majority of mainstream antidepressants lack the promise of complete amelioration of symptoms. Other pitfalls include the latency period and side effects. These issues prompted investigations concerning the various roles of serotonin (5-HT) neurotransmissions in the etiology of depression. In this study, each study participant received vilazodone, vortioxetine, and escitalopram monotherapy for major depressive disorder (MDD) for 16 weeks. After that, the subject's scores on the Hamilton Depression Rating Scale (HDRS)-17 item version and the Montgomery Åsberg Depression Rating Scale (MADRS) were evaluated. In the study population, we kept track of the incidence of adverse events., Methods: Ninety-six patients with MDD participated in this open-label, randomized, three-arm study. Participants were allotted into three groups according to a 1:1:1 ratio and given vilazodone (20-40 mg/day), vortioxetine (5-20 mg/day), or escitalopram (10-20 mg/day) for 16 weeks. Vortioxetine and vilazodone are test medications, with escitalopram serving as the control. After the baseline visit, follow-up appointments were scheduled every four weeks. Per-protocol (PP) and intent-to-treat (ITT) populations served as means for efficacy and safety evaluations, respectively. We prospectively registered this research in the Clinical Trial Registry, India (CTRI) (2022/07/043808)., Results: Out of the 134 patients we screened, 109 (81.34%) were eligible. Ninety-six (88.07%) of them completed the 16-week trial. In the PP population (n = 96), we analyzed efficacy. They had a mean age of 46.3 ± 6.2 years. At baseline, each group's median HDRS score was 30.0 (p = 0.964). Following 16 weeks of antidepressant therapy, these scores dropped to 15.0, 14.0, and 13.0 (p = 0.002). Baseline MADRS scores for all groups were 36.0 (p = 0.741). They had corresponding values of 20.0, 18.0, and 17.0 at 16 weeks (p < 0.001). Regarding both efficacy endpoints, the post-hoc analysis with the Bonferroni correction demonstrated statistically significant differences (p < 0.001). We performed the safety assessments within our ITT population (n = 109). Ninety-six adverse events were recorded. Nonetheless, none of them seemed serious. Still, five participants opted out because of their side effects. Vomiting and nausea were the most frequent side effects., Conclusion: Compared to escitalopram and vilazodone, vortioxetine demonstrated a statistically significant reduction in HDRS and MADRS scores. It also had fewer and milder side effects . We recommend conducting studies involving a broader population to investigate the antidepressant effects of these medications further., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Santi et al.)

Background Facial nerve paralysis, leading to the loss of facial expression, poses significant discomfort to patients. While most individuals exhibit a favorable response to treatment, a subset experiences enduring facial deformities without clearly defined etiology. This study aimed to identify prognostic factors influencing outcomes and quality of life in facial nerve palsy patients, contributing to enhanced clinical management. Methods A prospective observational study was conducted in the Otorhinolaryngology Department of Maharaja Krishna Chandra Gajapati Medical College and Hospital, a tertiary care hospital. We included patients presenting with any clinical variety of facial nerve palsy, irrespective of age and gender. Only moribund and noncompliant cases were excluded. Patients underwent clinical assessment using the House-Brackmann (HB) grading at presentation and were subsequently monitored at three weeks, three months, and six months post-onset to assess recovery. Results Out of 66 patients, 18 (27.27%) fully recovered at three weeks, 50 (75.76%) recovered at three months, and 54 (81.82%) at six-month follow-up. Incomplete recovery was observed in 13 (19.69%) patients. Factors associated with favorable outcomes included younger age of onset (p = 0.003), lower baseline HB grade (IV or less) (p = 0.001), Electroneurography Degeneration Index (ENoG DI) of <70% (p < 0.0001), early initiation of treatment (within five days of onset) (p = 0.0003), and absence of comorbid conditions (p = 0.03). Gender and affected side (left or right) did not influence the outcome. Conclusion In summary, age, associated comorbid conditions, baseline HB grade, and extent of facial nerve degeneration are crucial predictors of outcomes in facial nerve palsy. This knowledge can guide clinicians in optimizing treatment strategies for improved patient care., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Misra et al.)

Pancreatic cancer has a dismal prognosis due to late detection and lack of efficient therapies. The Kirsten rat sarcoma virus (KRAS) oncogene is mutated in up to 90% of all pancreatic ductal adenocarcinomas (PDACs) and constitutes an attractive target for therapy. However, the most common KRAS mutations in PDAC are G12D (44%), G12V (34%) and G12R (20%) that are not amenable to treatment by KRAS G12C-directed cysteine-reactive KRAS inhibitors such as Sotorasib and Adagrasib that exhibit clinical efficacy in lung cancer. KRAS G12C mutant pancreatic cancer has been treated with Sotorasib but this mutation is detected only in 2%-3% of PDAC. Recently, the KRAS G12D-directed MRTX1133 inhibitor has entered clinical trials and more of such inhibitors are in development. The other KRAS mutations may be targeted indirectly via inhibition of the cognate guanosine exchange factor (GEF) Son of Sevenless 1 that drives KRAS. These agents seem to provide the means to target the most frequent KRAS mutations in PDAC and to improve patient outcomes., Competing Interests: All authors declared that there are no conflicts of interest., (© 2024 Stickler, Rath and Hamilton.)

Background/aim: Osteosarcoma at an advanced stage has a poor outcome, and novel targeted therapies are needed, especially for metastatic disease. Bromodomain inhibitors (BETi) are epigenetic modulators that broadly impair the expression of oncogenic proteins and exert antitumor effects. BETi can be combined with chemotherapeutics to increase therapeutic responses with superior effects in the form of proteolysis targeting chimeras (PROTACs) that degrade proteins of interest (POI) in multiple cycles. This work aimed to investigate the efficacy of BETi, such as JQ1, dBET57, and MZ1 PROTACs in combination with cytotoxic drugs against osteosarcoma cell lines., Materials and Methods: Chemosensitivity of the osteosarcoma cell lines HOS, Saos-2, MG-63, and G292 were tested with BET-directed agents alone or in combination with cytotoxic drugs comprising cisplatin, doxorubicin, topotecan, and gemcitabine using cell viability assays., Results: The BET degraders exhibited highest toxicity to HOS cells and showed synergistic activity in combination with the chemotherapeutics, except for the degrader - topotecan/gemcitabine combinations. Highest synergy between BET agents and chemotherapeutics were found for the more chemoresistant Saos-2 cells and potentiation of toxicity in MG-63 cells for the BET agents - doxorubicin combinations and the MZ1-topotecan pair. HOS and Saos-2 cell lines had reduced protein expression of AXL, BCL-X, e-cadherin, CAIX, EpCAM, ErbB2, and vimentin in response to JQ1, MZ1, and BET57., Conclusion: The study suggests that the application of novel BET PROTACs in combination with chemotherapeutics could represent a new therapeutic option to improve the therapy of osteosarcomas. First orally available PROTACs have reached clinical trials., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The use of SGLT-2 inhibitors has revolutionized heart failure therapy. Evidence suggests a reduced incidence of ventricular and atrial arrhythmias in patients with dapagliflozin or empagliflozin treatment. It is unclear to what extent the reduced arrhythmia burden is due to direct effects of the SGLT2 inhibitors or is solely a marker of improved cardiac function., Methods: One hundred five rabbit hearts were allocated to eight groups and retrogradely perfused, employing a Langendorff setup. Action potential duration at 90% of repolarization (APD 90 ), QT intervals, effective refractory periods, conduction velocity, and dispersion of repolarization were obtained with monophasic action potential catheters. A model for tachyarrhythmias was established with the I Kr blocker erythromycin for QT prolongation associated proarrhythmia as well as the potassium channel opener pinacidil for a short-QT model. An atrial fibrillation (AF) model was created with isoproterenol and acetylcholine. With increasing concentrations of both SGLT2 inhibitors, reductions in QT intervals and APD 90 were observed, accompanied by a slight increase in ventricular arrhythmia episodes. During drug-induced proarrhythmia, empagliflozin succeeded in decreasing QT intervals, APD 90 , and VT burden whereas dapagliflozin demonstrated no significant effects. In the presence of pinacidil induced arrhythmogenicity, neither SGLT2 inhibitor had a significant impact on cardiac electrophysiology. In the AF setting, perfusion with dapagliflozin showed significant suppression of AF in the course of restitution of electrophysiological parameters whereas empagliflozin showed no significant effect on atrial fibrillation incidence., Conclusion: In this model, empagliflozin and dapagliflozin demonstrated opposite antiarrhythmic properties. Empagliflozin reduced ventricular tachyarrhythmias whereas dapagliflozin showed effective suppression of atrial arrhythmias., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Wolfes, Uphoff, Kemena, Wegner, Rath, Eckardt, Frommeyer and Ellermann.)

Background: Small cell lung cancer (SCLC) is a neuroendocrine aggressive tumor with a dismal prognosis due to the lack of curative therapeutic modalities. Approximately 11% of these patients show a malignant pleural effusion (MPE) that increase in frequency with progression of the disease. In MPE, fluid accumulates due to leaky vessels and mesothelial surfaces as well as impaired removal of fluid due to impaired drainage., Methods: For this investigation, three SCLC MPE samples and supernatants of the corresponding isolated cell lines were analyzed for the content of 105 cytokines, chemokines, and growth factors. Overexpressed pathways including these cytokines were identified using Reactome analysis tools., Results: A large range of cytokines, including vascular endothelial growth factor A ( VEGFA ), were found to be expressed in the MPEs and conditioned media of the corresponding cell line. These mediators are involved in pathways such as interleukin ( IL ) signaling, growth factor stimulation, modulation of cell adhesion molecules and proliferative cell signaling. Cytokine expression by the corresponding SCLC cell lines revealed the specific contributions of the tumor cells and included high expression of VEGFA , tumor-promoting factors and mediators exerting immunosuppressive and protumor effects. MPEs used here showed marked stimulation of the proliferation of four permanent SCLC cell lines., Conclusions: MPEs comprise a large number of cytokines with mixed activities on tumor cells and the invading SCLC cells release a number of protumor mediators and induce an immunosuppressive pleural environment., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-569/coif). G.H. serves as an unpaid editorial board member of Translational Lung Cancer Researchfrom September 2023 to August 2025. The other authors have no conflicts of interest to declare., (2024 Translational Lung Cancer Research. All rights reserved.)

Chronic burn wounds are frequently characterised by a prolonged and dysregulated inflammatory phase that is mediated by over-activation of NF-κB p65. Synthetic wound healing drugs used for treatment of inflammation are primarily associated with several shortcomings which reduce their therapeutic index. In this scenario, phytoconstituents that exhibit multifaceted biological activities including anti-inflammatory effects have emerged as a promising therapeutic alternative. However, identification and isolation of phytoconstituents from medicinal herbs is a cumbersome method that is linked to profound uncertainty. Hence, present study aimed to identify prospective phytoconstituents as inhibitors of RHD of NF-κB p65 by utilizing in silico approach. Virtual screening of 2821 phytoconstituents was performed against protein model. Out of 2821 phytoconstituents, 162 phytoconstituents displayed a higher binding affinity (≤ -8.0 kcal/mol). These 162 phytoconstituents were subjected to ADMET predictions, and 15 of them were found to satisfy Lipinski's rule of five and showed favorable pharmacokinetic properties. Among these 15 phytoconstituents, 5 phytoconstituents with high docking scores i.e. silibinin, bismurrayaquinone A, withafastuosin B, yuccagenin, (+)-catechin 3-gallate were selected for molecular dynamics (MD) simulation analysis. Results of MD simulation indicated that withafastuosin B, (+)-catechin 3-gallate and yuccagenin produced a compact and stable complex with protein without significant variations in conformation. Relative binding energy analysis of best hit molecules indicate that withafastuosin B, and (+)-catechin 3-gallate exhibit high binding affinity with target protein among other lead molecules. Findings of study suggest that these phytoconstituents could serve as promising anti-inflammatory agents for treatment of burn wounds by inhibiting the RHD of NF-κB p65.Communicated by Ramaswamy H. Sarma.

Consideration of the individual carpal bone characteristics of the wrist plays a key role in well-functioning biomedical devices and successful surgical procedures. Although geometric differences and individual bone sizes have been analyzed in the literature, detailed morphologic descriptions and correlations covering the entire wrist reported in a clinical context are lacking. This study aimed to perform a comprehensive and automatic analysis of the wrist morphology using the freely available "Open Source Carpal Database" (OSCD). We quantified the size of each of the individual carpal bones and their combination. These sizes were extracted in n = 117 datasets of the wrist of the OSCD in anatomical directions and analyzed using descriptive statics and correlation analysis to investigate the morphological characteristics under sex-specific aspects and to provide regression plots and equations to predict individual carpal bone sizes from the proximal and distal row dimensions. The correlations in the proximal row were higher compared to the distal row. We established comprehensive size correlations and size rations and found that there exist statistical differences between sex, particularly of the scaphoid. The regression plots and equations we provided will assist surgeons in a more accurate preoperative morphological evaluation for therapy planning and may be used for future anatomically inspired orthopedic biomedical device designs.

Small cell lung cancer (SCLC) has a dismal prognosis. In addition to the inactivation of the tumor suppressors TP53 and RB1, tumor-promoting MYC and paralogs are frequently overexpressed in this neuroendocrine carcinoma. SCLC exhibits high resistance to second-line chemotherapy and all attempts of novel drugs and targeted therapy have failed so far to achieve superior survival. MYC and paralogs have key roles in the oncogenic process, orchestrating proliferation, apoptosis, differentiation, and metabolism. In SCLC, MYC-L and MYC regulate the neuroendocrine dedifferentiation of SCLC cells from Type A (ASCL1 expression) to the other SCLC subtypes. Targeting MYC to suppress tumor growth is difficult due to the lack of suitable binding pockets and the most advanced miniprotein inhibitor Omomyc exhibits limited efficacy. MYC may be targeted indirectly via the bromodomain (BET) protein BRD4, which activates MYC transcription, by specific BET inhibitors that reduce the expression of this oncogenic driver. Here, novel BET-directed Proteolysis Targeting Chimeras (PROTACs) are discussed that show high antiproliferative activity in SCLC. Particularly, ARV-825, targeting specifically BRD4, exhibits superior cytotoxic effects on SCLC cell lines and may become a valuable adjunct to SCLC combination chemotherapy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)