Long-term Safety Research Articles

Long-term efficacy and safety of stapokibart for moderate-to-severe atopic dermatitis: 52-week results from a phase 3 trial.

Management of moderate-to-severe atopic dermatitis (AD) needs long-term therapy. Stapokibart is a humanized monoclonal antibody targeting interleukin-4 receptor α subunit (IL-4Rα), a shared receptor for IL-4 and IL-13 which are key pathogenic drivers of AD. In a pivotal phase 3 trial (NCT05265923), significant higher proportions of adult AD patients receiving stapokibart than placebo achieved ≥75% improvement from baseline in Eczema Area and Severity Index (EASI-75; 66.9% vs. 25.8%) and Investigator's Global Assessment (IGA) score of 0/1 with ≥2-point reduction (44.2% vs. 16.1%) at Week 16. Herein, we report long-term (52 weeks) efficacy and safety of stapokibart from this trial. After 16-week double-blind treatment completed, patients in both stapokibart and placebo groups entered a 36-week maintenance treatment period and received stapokibart 300 mg every 2 weeks. Concomitant use of topical medications for AD was permitted throughout the maintenance period. Of 476 patients entering maintenance period, 430 completed the treatment. At Week 52, EASI-75 was achieved in 92.5% of patients continuing stapokibart and 88.7% of those switching from placebo to stapokibart, respectively; an IGA score of 0 or 1 with a ≥2-point reduction was achieved in 67.3% and 64.2% of patients, respectively; a ≥4-point reduction in weekly average of daily Peak Pruritus Numerical Rating Scale (PP-NRS) was achieved in 67.3% and 60.5% of patients, respectively. Over the 52-week treatment period, 88.1% of patients reported treatment-emergent adverse events, most were mild or moderate. Long-term treatment with stapokibart demonstrated a sustained efficacy and favorable safety profile in adults with moderate-to-severe AD.

Prediction of Scour Depth for Diverse Pier Shapes Utilizing Two-Dimensional Hydraulic Engineering Center’s River Analysis System Sediment Model

Examining scouring around bridge piers is crucial for ensuring water-related infrastructure’s long-term safety and stability. Accurate forecasting models are essential for addressing scour, especially in complex water systems where traditional methods fall short. This study investigates the application of the HEC-RAS 2D sedimentation model, which has recently become available for detailed sediment analysis, to evaluate its effectiveness in predicting scoring around various pier shapes and under different water conditions. This study offers a comprehensive assessment of the model’s predictive capabilities by focusing on variables such as water velocity, shear stress, and riverbed changes. Particular attention was paid to the influence of factors like floating debris and different pier geometries on scour predictions. The results demonstrate that while the HEC-RAS 2D model generally provides accurate predictions for simpler pier shapes—achieving up to 85% precision—it shows varied performance for more complex designs and debris-influenced scenarios. Specifically, the model overpredicted scouring depths by approximately 20% for diamond-shaped piers and underpredicted by 15% for square piers in debris conditions. Elliptical piers, in contrast, experienced significantly less erosion, with scour depths up to 30% shallower compared to other shapes. This study highlights the novel application of the HEC-RAS 2D model in this context and underscores its strengths and limitations. Identified issues include difficulties in modeling water flow and debris-induced bottlenecks. This research points to the improved calibration of sediment movement parameters and the development of advanced computational techniques to enhance scour prediction accuracy in complex environments. This work contributes valuable insights for future research and practical applications in civil engineering, especially where traditional scour mitigation methods, such as apron coverings, are not feasible.

A Retrospective Study on Endoscopic Surgery for the Treatment of Paravertebral Abscess in Spinal Tuberculosis Patients.

Spinal tuberculosis (TB) remains a significant global health concern, necessitating the development of innovative treatment strategies. This clinical study aimed to evaluate the efficacy and safety of endoscopic debridement as a minimally invasive approach for treating paravertebral abscesses in patients with spinal tuberculosis. A total of 52 patients diagnosed with paravertebral tuberculosis abscesses were enrolled in this retrospective study. Patients were assigned to two groups: the endoscopic debridement group (n = 30) and the conventional open surgery group (n = 22), based on the type of surgery they received. Clinical outcomes were assessed at baseline, post-treatment, and follow-up visits at regular intervals, including surgery time, intraoperative blood loss, total hospital stay duration, pain relief, and neurological improvement. The results of this study demonstrate that endoscopic debridement is a highly effective treatment for paravertebral abscesses in patients with spinal TB. Patients in the endoscopic debridement group experienced significant improvements in surgery time, intraoperative blood loss, total hospital stay duration, pain relief, and neurological improvement compared to those in the conventional open surgery group. Additionally, the endoscopic approach resulted in fewer complications, such as wound infections and postoperative instability, with no cases of recurrence observed during the follow-up period. Therefore, this clinical study highlights the potential of endoscopic debridement as a safe and effective treatment modality for spinal tuberculosis. The technique not only effectively eliminates infected tissue but also ensures faster patient recovery and reduces postoperative complications. Additional research and long-term follow-up studies are necessary to confirm the long-term effectiveness and safety of endoscopic debridement as the standard treatment for spinal tuberculosis.

Efficacy and safety of thalidomide in patients with β-thalassemia intermedia and major.

To investigate the short-term and long-term efficacy and safety of thalidomide in the treatment of intermediate and severe β-thalassemia. We analyzed patients with intermediate and severe β-thalassemia treated at our hospital from February 2019 to February 2024. Patients who received treatment for more than 3 months were included. The efficacy of thalidomide was assessed by comparing changes in hemoglobin (Hb), ferritin, bilirubin, and Hb electrophoresis before and after treatment. Adverse drug reactions during treatment were also recorded. A total of 42 β-thalassemia patients were included, with thalidomide dosages ranging from 75 to 150 mg/d. The response rates at 1, 3, and 6 months of treatment were 73.8% (31/42), 75.0% (24/32), and 94.7% (18/19), respectively. The increase in Hb levels was primarily attributed to fetal hemoglobin (HbF). After 1 month of treatment, the HbF percentage increased from a baseline of 34.04 ± 27.58% to 56.25 ± 28.40% (P < .001). At 3 and 6 months, HbF further increased to 67.21 ± 27.12% (P < .001) and 73.93 ± 22.96% (P < .001), respectively. The average duration of thalidomide treatment was 25.3 ± 9.2 months (range: 4-60 months), with 6 patients treated for over 60 months and 18 patients for over 48 months. Two homozygous patients who failed thalidomide treatment achieved Hb levels above 100 g/L and discontinued transfusion therapy after 3 months of hydroxyurea treatment. The most common adverse reaction was somnolence, which was mild and tolerable. Thalidomide demonstrates significant and sustained therapeutic effects in β-thalassemia patients. The adverse reactions are mild and tolerable, allowing patients to continue treatment.

Chimeric antigen receptor T-cell therapy in patients with malignant glioma-From neuroimmunology to clinical trial design considerations.

Clinical trials evaluating chimeric antigen receptor (CAR) T-cell therapy in patients with malignant gliomas have shown some early promise in pediatric and adult patients. However, the long-term benefits and safety for patients remain to be established. The ultimate success of CAR T-cell therapy for malignant glioma will require the integration of an in-depth understanding of the immunology of the central nervous system (CNS) parenchyma with strategies to overcome the paucity and heterogeneous expression of glioma-specific antigens. We also need to address the cold (immunosuppressive) microenvironment, exhaustion of the CAR T-cells, as well as local and systemic immunosuppression. Here, we discuss the basics and scientific considerations for CAR T-cell therapies and highlight recent clinical trials. To help identify optimal CAR T-cell administration routes, we summarize our current understanding of CNS immunology and T-cell homing to the CNS. We also discuss challenges and opportunities related to clinical trial design and patient safety/monitoring. Finally, we provide our perspective on future prospects in CAR T-cell therapy for malignant gliomas by discussing combinations and novel engineering strategies to overcome immuno-regulatory mechanisms. We hope this review will serve as a basis for advancing the field in a multiple discipline-based and collaborative manner.

Clinical effects of dexmedetomidine on patients with sepsis and myocardial injury.

This study aimed to explore the organ-protective effects of dexmedetomidine in patients with sepsis combined with myocardial injury. From December 2021 to December 2023, 263 sepsis patients with myocardial injury were included based on inclusion and exclusion criteria. They were divided into an experimental group (n = 122), who had previously received dexmedetomidine, and a control group (n = 141), who had received midazolam. After matching baseline characteristics, the treatment outcomes between the 2 groups were compared. In a propensity score-matched cohort of 263 patients, each group had 62 individuals with balanced baseline characteristics. The experimental group showed significantly lower heart rates on days 1, 3, and 7 compared to the control (P < .05). Biomarkers high-sensitivity troponin I and creatine kinase-MB decreased significantly by days 3 and 7, with lower levels in the experimental group. B-type natriuretic peptide levels were also lower in the experimental group on days 3 and 7. Heart function improved in both groups, with the experimental group showing better outcomes. Inflammatory markers decreased significantly after 7 days, with the experimental group having lower levels. Hospitalization duration was similar between groups. Dexmedetomidine reduces heart rate and inflammatory markers, protects myocardial cells, and improves cardiac function in patients with sepsis and myocardial injury. It shows potential as a treatment option, with future research needed to assess its long-term efficacy and safety.

Justification of an innovative system for the complete burial of solid, high-level radioactive waste (HLW) in spent open-pit mines

The object of research is the spent open-pit mines themselves where the proposed system could be applied. The primary reason for this studying is the following circumstance: up to the present time period, in all countries of the world, no methods of HLW disposal in a storage facility has been identified that is absolutely safe for any length of time, taking into account the impact of catastrophic natural emergencies and man-made emergencies. The research was conducted to address the problem of safely managing and storing HLW, leveraging the unique characteristics of spent open-pit mines, such as their large volume and geological stability, to prevent environmental contamination and ensure long-term safety. In the article has been justified a novel approach to the burial of sarcophagus containers with solid HLW in exhausted mining pits and studied the usabilities of the basalt sarcofagous container. Robust materials and advanced robotic systems proposed in the article aims to address the challenges associated with long-term radioactive waste disposal effectively. The robotic systems transfer the basalt container with HLW, ensuring personnel safety by minimizing human presence near radioactive materials. In the article have been established the distribution of temperature into the multi-layered composite structure of the basalt sarcophagous with HLW from 300 °C into the inner space to 50 °C onto on the its outer suffer where the thickness of each layers (from inner to outer radius) was respectively: for lead matrix: from r1=0.1 m to r2=0.2 m; for clay layer: from r2=0.2 m to r3=0.3 m; for basalt block: from r3=0.3 m to r4=0.4 m. The findings on temperature distribution are crucial as they directly affect the performance and longevity of the basalt containment system

A long-term follow-up study of gastric peroral endoscopic myotomy (G-POEM) in a large cohort of patients with postsurgical gastroparesis.

Postoperative gastroparesis occurs after surgeries which affect the upper digestive tract. Gastric peroral endoscopic myotomy (G-POEM) is a treatment for postoperative gastroparesis. The present study boasts the long-term efficacy and safety of G-POEM in a large cohort of patients. Gastroparesis Cardinal Symptom Index (GCSI) and Gastroesophageal Reflux Disease Questionnaire (GERDQ) were utilized for the assessment of postsurgical gastroparesis symptoms. Gastroscope was used to observe the anastomotic site. Three-dimensional ultrasound was used to measure the morphological structure of the gastric antrum and pylorus tube. Gastric emptying time was calculated by analyzing the volume change of gastric antrum. Significant clinical effectiveness of G-POEM was observed. The GCSI score, including each subscale score, showed significant decrease after G-POEM. Before G-POEM, there was a negative correlation between GCSI score and the inner diameter of pylorus, as well as a positive correlation with the length of pyloric tube. The similar results were found in the scores of nausea/vomiting and postprandial fullness/early satiety subscales. No correlation was observed between GCSI score and the emptying time, nor between the emptying time and the parameters of antrum morphology. After G-POEM, no correlation was found between GCSI (including subscales) score, the emptying time, and the parameters of antrum morphology. Patients who exhibited as clinical non-responders often accompanied with GERD symptoms. After G-POEM, the score of GERDQ decreased significantly. Either before or after G-POEM, no correlation was noticed between GERDQ scores, the emptying time and the parameters of antrum morphology. The technique of G-POEM was demonstrated as a minimally invasive approach with the long-term efficacy and safety in therapying postoperative gastroparesis.

Long-term Effectiveness and Safety of Risankizumab in Patients with Crohn’s Disease from a Large Tertiary Center

Background and AimsRisankizumab is a selective IL23 inhibitor approved for the treatment of Crohn’s disease (CD). We report a large long-term real-world experience with risankizumab in CD. MethodsWe performed a prospective monitoring of clinical outcomes in patients in our center who started treatment with risankizumab. Patients with active luminal disease who had at least 12 weeks of follow-up were included in the effectiveness analysis. Harvey-Bradshaw Index (HBI) as well as C-reactive protein (CRP) and fecal calprotectin (FCP) were used to monitor disease activity. Primary outcomes were clinical remission and steroid-free clinical remission rates at weeks 12, 26, and 52. Univariate analysis followed by a multivariate analysis using a logistic regression model was performed to identify predictors of steroid-free clinical remission at one year. All patients who started treatment with risankizumab for any indication were included in the safety analysis. Results134 patients were included in the effectiveness analysis. 70 (52%) were ustekinumab-experienced. Clinical remission rates were 69%, 64%, and 54% at weeks 12, 26, and 52, respectively. Steroid-free clinical remission rates at 12, 26, and 52 weeks were 58%, 58%, and 50% respectively. Remission rates in ustekinumab-experienced patients were not statistically lower compared to naïve patients, and in a multivariate analysis, prior ustekinumab treatment was not associated with lower odds of achieving steroid-free clinical remission at one year. Adverse effects were assessed in 243 patients and were consistent with previous literature. ConclusionsThis large real-world experience with risankizumab with long-term follow-up demonstrates effectiveness and safety in patients with CD; there was comparable effectiveness in ustekinumab-naïve and ustekinumab-experienced patients.

A web-based safety management platform to enhance safety for Chinese migrant construction workers

Over the past decade, existing research has investigated various solutions to enhance safety management on construction sites. Among the many solutions, developing a web-based safety platform has increasingly become a key element in safety improvement strategies. International research shows that safety management platforms improve migrant workers’ safety, but evidence for such interventions in New Zealand, especially for Chinese migrant construction workers, remains limited. This study built a web prototype catering to Chinese migrant construction workers in New Zealand. The data collection method was semi-structured interviews, and the effectiveness of the novel web prototype was validated based on respondents’ feedback. Results show that this safety web prototype can effectively improve the safety knowledge and safety awareness of Chinese migrant construction workers by providing local safety policies and conducting multi-frequency long-term safety training tests. The incentive function in this web prototype can motivate Chinese migrant construction workers to use this application and enhance their safety compliance. The limitations of this research include geographical restrictions and a small sample size to evaluate the effectiveness of the prototype. Future research should incorporate a larger, cross-sectional sample to assess the effectiveness of web-based safety awareness solutions, enabling more generalizable conclusions for construction workers of diverse nationalities and regions.

Long-term safety and efficacy of endovascular ultrasound renal denervation in resistant hypertension: 8-year results from the ACHIEVE study.

Ultrasound renal sympathetic denervation (uRDN) reduces blood pressure (BP) in the absence and presence of antihypertensive treatment at 2months. Beyond 3years, there is a lack of follow-up data. This study investigated the long-term safety and efficacy of uRDN. This prospective observational study recruited patients previously included in the international multicenter ACHIEVE study, with office systolic blood pressure (SBP) ≥160 mmHg, 24h ambulatory SBP ≥130mmHg, ≥3 antihypertensive drugs and estimated Glomerular Filtration Rate (eGFR) ≥45 ml/min/1.73m2 undergoing uRDN. The primary efficacy outcome was 24h ambulatory SBP, adjusted for the number of defined daily dosages (DDD) of antihypertensive drugs. Statistical analyses were performed using linear mixed-effects models and inverse probability weighting. A total of 27 out of the initially enrolled 96 patients underwent prospective follow-up at a median of 8.2 [7.6-8.9]years. Mean age was 62.6±9.3years (37.0% female). Preprocedural 24h ambulatory BP was 151.9/84.1±11.5/11.1 mmHg and the median number of DDDs was 5.0 [4.3-7.0]. At 8years after uRDN, the change in 24h ambulatory SBP was -19.5 [95%CI -26.7,-12.4] mmHg (p<0.001). The 8-year change in the number of DDDs was -1.7 [-2.8,-0.6] (p = 0.003). The 8-year decline in eGFR was -8.9 [-13.2,-4.7] ml/min/1.73m2 (p<0.001). Clinical event data were available for all 96 patients (median follow-up 3.5 [1.0-8.0]years). Renal failure occurred in one patient and no cases of renal artery stenosis were detected. A significant BP reduction was observed up until 8years following uRDN in parallel to a decrease in drug burden over time, in the absence of procedure-related adverse events.

Long-term management of moderate-to-severe atopic dermatitis with lebrikizumab and concomitant topical corticosteroids: a 68-week, randomized, double-blind, placebo-controlled phase III trial in Japan (ADhere-J).

Moderate-to-severe atopic dermatitis (AD) impacts patients' quality of life (QOL). More treatment options are urgently needed to manage this chronic disease. Lebrikizumab is a monoclonal antibody that binds to IL-13, a key mediator in AD pathogenesis. In Japanese patients, lebrikizumab has been evaluated through week (W) 16 in the randomized, placebo-controlled, phase III ADhere-J study. To evaluate long-term efficacy and safety of lebrikizumab in combination with topical corticosteroids (TCS) in the ADhere-J study. Patients aged ≥12 years and weighing ≥40 kg with moderate-to-severe AD, and receiving either subcutaneous lebrikizumab 250 mg every 2 weeks (Q2W)/every 4 weeks (Q4W) or placebo during the 16-week induction period, were evaluated during the long-term maintenance period from W16 to W68. Responders achieved co-primary endpoints at W16: Investigator's Global Assessment score of 0 or 1 (IGA [0,1]) with ≥2-point improvement from baseline, and/or ≥75% improvement from baseline in Eczema Area and Severity Index (EASI 75). In this analysis, W16 responders received lebrikizumab 250 mg Q2W or Q4W combined with TCS during the maintenance period (maintenance primary population; MPP); W16 per-protocol nonresponders received lebrikizumab Q2W with TCS (maintenance escape population; MEP). Major endpoints included IGA (0,1) with ≥2-point improvement from baseline and EASI 75 through W68. Other outcomes included QOL, itch, and serum thymus and activation-regulated chemokine. At W68, 66-81% of 103 patients in the MPP and 32-38% of 168 patients in the MEP achieved IGA (0,1) with ≥2-point improvement from baseline. EASI 75 was maintained by 83-89% of patients in the MPP, while 71-80% of patients in the MEP achieved this outcome by W68. Across treatment arms, patients in the MPP tended to maintain improvements recorded at W16, while patients in the MEP steadily improved across the maintenance period. No new safety signals were reported, and most treatment-emergent adverse events were mild or moderate in severity in both populations. Safety outcomes were consistent with previous reports for lebrikizumab treatment in global studies. These results support the use of lebrikizumab in combination with TCS for moderate-to-severe AD in the Japanese population over the long term. ClinicalTrials.gov (NCT04760314).

O EMPREGO DO CANABIDIOL NA TERAPÊUTICA DO TRANSTORNO DO ESPECTRO AUTISTA: REVISÃO SISTEMÁTICA

Objective: To analyze the applicability of cannabidiol in the complementary treatment of Autism Spectrum Disorder. Methods: The present work is characterized as a systematic literature review, which was carried out by searching for studies available in the Google Scholar, MedLine, PubMed and SciELO indexers. Results: 163 articles were found on the researched platforms, of which 19 were included for full reading and 11 were chosen to be part of the literature review. Conclusion: The effectiveness of cannabidiol as a complementary therapy for ASD is concluded, as long as it is indicated and monitored by a medical professional. However, it appears that drugs derived from Cannabis are not free from adverse effects, requiring assessment of their long-term safety profile.

The renoprotective efficacy and safety of genetically-engineered human bone marrow-derived mesenchymal stromal cells expressing anti-fibrotic cargo

BackgroundKidney fibrosis is a hallmark of chronic kidney disease (CKD) and compromises the viability of transplanted human bone marrow-derived mesenchymal stromal cells (BM-MSCs). Hence, BM-MSCs were genetically-engineered to express the anti-fibrotic and renoprotective hormone, human relaxin-2 (RLX) and green fluorescent protein (BM-MSCs-eRLX + GFP), which enabled BM-MSCs-eRLX + GFP delivery via a single intravenous injection.MethodsBM-MSCs were lentiviral-transduced with human relaxin-2 cDNA and GFP, under a eukaryotic translation elongation factor-1α promoter (BM-MSCs-eRLX + GFP) or GFP alone (BM-MSCs-eGFP). The ability of BM-MSCs-eRLX + GFP to differentiate, proliferate, migrate, produce RLX and cytokines was evaluated in vitro, whilst BM-MSC-eRLX + GFP vs BM-MSCs-eGFP homing to the injured kidney and renoprotective effects were evaluated in preclinical models of ischemia reperfusion injury (IRI) and high salt (HS)-induced hypertensive CKD in vivo. The long-term safety of BM-MSCs-RLX + GFP was also determined 9-months after treatment cessation in vivo.ResultsWhen cultured for 3- or 7-days in vitro, 1 × 106 BM-MSCs-eRLX + GFP produced therapeutic RLX levels, and secreted an enhanced but finely-tuned cytokine profile without compromising their proliferation or differentiation capacity compared to naïve BM-MSCs. BM-MSCs-eRLX + GFP were identified in the kidney 2-weeks post-administration and retained the therapeutic effects of RLX in vivo. 1–2 × 106 BM-MSCs-eRLX + GFP attenuated the IRI- or therapeutically abrogated the HS-induced tubular epithelial damage and interstitial fibrosis, and significantly reduced the HS-induced hypertension, glomerulosclerosis and proteinuria. This was to an equivalent extent as RLX and BM-MSCs administered separately but to a broader extent than BM-MSCs-eGFP or the angiotensin-converting enzyme inhibitor, perindopril. Additionally, these renoprotective effects of BM-MSCs-eRLX + GFP were maintained in the presence of perindopril co-treatment, highlighting their suitability as adjunct therapies to ACE inhibition. Importantly, no major long-term adverse effects of BM-MSCs-eRLX + GFP were observed.ConclusionsBM-MSCs-eRLX + GFP produced greater renoprotective and therapeutic efficacy over that of BM-MSCs-eGFP or ACE inhibition, and may represent a novel and safe treatment option for acute kidney injury and hypertensive CKD.

Complication rate across the minimally invasive surgical treatments (MISTs): where do we stand? A systematic review of the literature.

Over the past decade, the range of surgical options to benign prostatic obstruction (BPO) has expanded significantly with the advent of minimally invasive surgical therapies (MISTs). Nevertheless, the available evidence in the field is heterogeneous. Efficacy and safety thresholds are yet to be determined. To evaluate perioperative and long-term complications after MISTs - including Aquablation, steam injection (Rezūm), Transperineal laser ablation of the prostate (TPLA), implantation of a prostatic urethral lift (PUL) and temporary implantable nitinol device (iTIND) - in patients with lower urinary tract symptoms due to BPO. A systematic literature search was conducted in January 2024 using Medline (via PubMed), Embase (via Ovid), Scopus, and Web of Science. The search strategy used PICO criteria (Patients, Interventions, Comparisons, Outcomes) [1], focusing specifically on patients with BPH-associated LUTS who underwent MIST or other comparative treatments, aiming to assess both perioperative and long-term safety outcomes. Article selection was conducted in accordance with the PRISMA guidelines. The risk of bias and the quality of the articles included were assessed. A dedicated data extraction form was used to collect the data of interest. The initial electronic search identified 3660 records, of which 24 ultimately met the inclusion criteria and were included in the analysis. Overall, Aquablation was associated with a higher major complications rate of 14% (IQR 6-22), particularly in the case of patients with prostates <70 ml. PUL showed a higher early postoperative acute urinary retention rate (10.9%, IQR 9.2-12.3%), while 1.4% of patients treated with iTIND experienced major perioperative complications. Urinary tract infections were mostly reported in series assessing TPLA and Rezūm. The adoption of MISTs for LUTS due to BPH is associated with a varied spectrum of perioperative and long-term complications. Our findings showed an acceptable safety profile with specific complications dependent on the type of MIST performed, highlighting the importance of individualized patient selection and procedure-specific considerations.

Olokizumab plus methotrexate: safety and efficacy over 106 weeks of treatment

ObjectiveTo report long-term safety and tolerability of olokizumab (OKZ) in combination with methotrexate (MTX) in subjects with active rheumatoid arthritis (RA), using pooled data from three randomised clinical trials (RCT)...

Evolution of carbides and Charpy toughness in a low alloy bainitic steel during step-up aging process

The low alloy bainitic steel used in reactor pressure vessels deteriorates during thermal service while the macroscopic thermodynamic parameters that cause thermal aging remains unknown. In this work, a thermal aging restructuring scheme was proposed by step-up aging the steel from 350 °C to 490 °C, with a total duration of 7500 hours. Samples from varied thickness of the steel were characterized in terms of carbides evolution and Charpy impact toughness at 20 °C. The carbide size and its fraction were statistically analyzed showing partial coarsening and dissolution during aging, while the carbide fraction was found linearly correlated with the impact energy for the first time. The critical transition temperature parameter of the aging process was found to be 470 °C for the steel. The macroscopic thermodynamic parameters, including the thermal aging time and temperature, facilitate a comprehensive understanding of the material degradation mechanism and provide a basis for long-term safety of equipment.

Zinc oxide nanoparticle biofortification of lentil seedlings enhances plant growth and zinc bioavailability in rats

This study aimed to evaluate the potential of zinc oxide nanoparticles (ZnO NPs) in the biofortification of lentil seedlings and subsequently improve the Zn status in rats. In the first phase of the study, the effects of various ZnO NPs concentrations (0, 10, 20, 40, 80, and 160 ppm) on the lentil growth, Zn accumulation, and other physiological parameters were investigated. Subsequently, the rats were fed ZnO NP-biofortified lentil seedlings (20 and 160 ppm) to assess their impact on animal health and Zn status. The results highlighted a concentration-dependent response of lentil seedlings to ZnO NPs, with optimal growth observed at 20 ppm, whereas higher concentrations inhibited lentil growth. Pigment and biochemical analyses revealed a complex interplay between chlorophyll, carotenoids, soluble sugars, and proteins with distinct responses to nanoparticle concentrations. Elevated levels of hydrogen peroxide and malondialdehyde of lentil seedlings at high concentrations of ZnO NPs suggest oxidative stress, countered by the upregulation of antioxidant enzymes and increased phenolic compounds. On the other hand. animal studies have showed that ZnO NP-biofortified lentil seedlings enhance serum zinc and magnesium levels in rats without affecting body weight. While serum triglyceride levels of rats decreased in both treatment groups, an elevation in creatinine and a marked increase in aspartate aminotransferase (AST) levels were observed at a higher ZnO NP concentration (160 ppm), indicative of potential kidney and liver stress. Paradoxically, serum iron levels were lower in all groups consuming lentil seedlings than in the control group, suggesting a potential interaction between lentil components and iron metabolism. These findings suggest that ZnO NP-biofortified lentils may be a promising approach to enhance Zn nutrition; however, further investigation is needed to optimize ZnO NPs concentration and assess long-term safety.

Intraventricular baclofen for intractable spasticity and secondary dystonia: a frame-based stereotactic approach and case series

ObjectiveIntraventricular baclofen has been reported as an alternative to intrathecal baclofen for managing refractory spasticity and dystonia in some circumstances. In this report, we described a frame-based stereotactic approach for precisely positioning of the infusion catheter into the third ventricle.Material and methodsHigh resolution contrast-enhanced anatomical MR sequences was acquired prior to surgery for pre-planning. Catheter trajectory was planned to pass from the lateral ventricle to the third ventricle through the Foramen of Monro. The surgical procedure was adapted from the frame-based deep brain stimulation surgery. The Touch-Loc kit (SceneRay, China) was used to temporarily secure the catheter in place during the surgery. From July 2022 to December 2022, three patients suffering from intractable spasticity and/or secondary dystonia received IVB successfully using the described technique.ResultsNo severe adverse events, including death, intracranial hemorrhage, infection, catheter migration or fracture, were documented at the last follow-up (range: 12‒24 months). Transient side effects included mild nausea following the initiation of infusion or the increase in infusion rate. All three patients responded to the IVB.ConclusionsThe described frame-based stereotactic technique for IVB catheter implant is feasible and could be quickly mastered by neurosurgeons in related fields. Larger prospective cohorts with longer follow-up periods are necessary to further evaluate the long-term safety and efficacy of this procedure.

Recent Progress of Antisense Oligonucleotide Therapy for Superoxide-Dismutase-1-Mutated Amyotrophic Lateral Sclerosis: Focus on Tofersen.

Amyotrophic lateral sclerosis (ALS) is a refractory neurodegenerative disease characterized by the degeneration and loss of motor neurons, typically resulting in death within five years of onset. There have been few effective treatments, making the development of robust therapies an urgent challenge. Genetic mutations have been identified as contributors to ALS, with mutations in superoxide dismutase 1 (SOD1), which neutralizes the harmful reactive oxygen species superoxide, accounting for approximately 2% of all ALS cases. To counteract the toxic gain of function caused by SOD1 mutations, therapeutic strategies aimed at suppressing SOD1 gene expression have shown promise. Antisense oligonucleotide (ASO) is an artificially synthesized, short, single-stranded DNA/RNA molecule that binds to target RNA to alter gene expression, representing a next-generation therapeutic approach. In 2023, tofersen became the first ASO drug approved by the FDA for ALS. Administered intrathecally, tofersen specifically binds to SOD1 mRNA, inhibiting the production of toxic SOD1 protein, thereby improving biomarkers of ALS. The long-term efficacy and safety of tofersen require further validation, and the development of more optimized treatment protocols is essential. A series of studies and therapeutic developments related to SOD1 mutations have advanced the understanding of ALS pathophysiology and significantly contributed to treatment strategies for central nervous system disorders. This review focuses on an overview of SOD1 mutations and the development process of tofersen, aiming to deepen the understanding of advancements in ALS research and discuss future challenges and directions for ASO therapy.