Early Stages Of Treatment Research Articles

Force-Encoding DNA Nanomachines for Simultaneous and Direct Detection of Multiple Pathogenic Bacteria in Blood.

Pathogen detection is growing in importance in the early stages of bacterial infection and treatment due to the significant morbidity and mortality associated with bloodstream infections. Although various diagnostic approaches for pathogen detection have been proposed, most of them are time-consuming, with insufficient sensitivity and limited specificity and multiplexing capability for clinical use. Here, we report a force-encoding DNA nanomachine for simultaneous and high-throughput detection of multiple pathogens in blood through force-induced remnant magnetization spectroscopy (FIRMS). The force-encoding DNA nanomachines coupled with DNA walkers enable analytical sensitivity down to a single bacterium via a cascade signal amplification strategy. More importantly, it allows for rapid and specific profiling of various pathogens directly in blood samples, without being affected by factors such as light color and solution properties. We expect that this magnetic sensing platform holds great promise for various applications in biomedical research and clinical diagnostics.

Impact of harmful algal bloom severity on bacterial communities in a full-scale biological filtration system for drinking water treatment

The occurrence of harmful algal blooms (HABs) in freshwater environments has been expanded worldwide with growing frequency and severity. HABs can pose a threat to public water supplies, raising concerns about safety of treated water. Many studies have provided valuable information about the impacts of HABs and management strategies on the early-stage treatment processes (e.g., pre-oxidation and coagulation/flocculation) in conventional drinking water treatment plants (DWTPs). However, the potential effect of HAB-impacted water in the granular media filtration has not been well studied. Biologically-active filters (BAFs), which are used in drinking water treatment and rely largely on bacterial community interactions, have not been examined during HABs in full-scale DWTPs. In this study, we assessed the bacterial community structure of BAFs, functional profiles, assembly processes, and bio-interactions in the community during both severe and mild HABs. Our findings indicate that bacterial diversity in BAFs significantly decreases during severe HABs due to the predominance of bloom-associated bacteria (e.g., Spingopyxis, Porphyrobacter, and Sphingomonas). The excitation-emission matrix combined with parallel factor analysis (EEM-PARAFAC) confirmed that filter influent affected by the severe HAB contained a higher portion of protein-like substances than filter influent samples during a mild bloom. In addition, BAF community functions showed increases in metabolisms associated with intracellular algal organic matter (AOM), such as lipids and amino acids, during severe HABs. Further ecological process and network analyses revealed that severe HAB, accompanied by the abundance of bloom-associated taxa and increased nutrient availability, led to not only strong stochastic processes in the assembly process, but also a bacterial community with lower complexity in BAFs. Overall, this study provides deeper insights into BAF bacterial community structure, function, and assembly in response to HABs.

Extracellular vesicles derived from mesenchymal stem cells mediate extracellular matrix remodeling in osteoarthritis through the transport of microRNA-29a.

Knee osteoarthritis (KOA) is a common orthopedic condition with an uncertain etiology, possibly involving genetics and biomechanics. Factors like changes in chondrocyte microenvironment, oxidative stress, inflammation, and immune responses affect KOA development. Early-stage treatment options primarily target symptom relief. Mesenchymal stem cells (MSCs) show promise for treatment, despite challenges. Recent research highlights microRNAs (miRNAs) within MSC-released extracellular vesicles that can potentially promote cartilage regeneration and hinder KOA progression. This suggests exosomes (Exos) as a promising avenue for future treatment. While these findings emphasize the need for effective KOA progression management, further safety and efficacy validation for Exos is essential. To explore miR-29a's role in KOA, we'll create miR-29a-loaded vesicles, testing for early treatment in rat models. Extraction of bone marrow MSC-derived extracellular vesicles, preparation of engineered vesicles loaded with miR-29a using ultrasonication, and identification using quantitative reverse transcription polymerase chain reaction; after establishing a rat model of KOA, rats were randomly divided into three groups: Blank control group injected with saline, normal extracellular vesicle group injected with normal extracellular vesicle suspension, and engineered extracellular vesicle group injected with engineered extracellular vesicle suspension. The three groups were subjected to general behavioral observation analysis, imaging evaluation, gross histological observation evaluation, histological detection, and immunohistochemical detection to compare and evaluate the progress of various forms of arthritis. General behavioral observation results showed that the extracellular vesicle group and engineered extracellular vesicle group had better performance in all four indicators of pain, gait, joint mobility, and swelling compared to the blank control group. Additionally, the engineered extracellular vesicle group had better pain relief at 4 wk and better knee joint mobility at 8 wk compared to the normal extracellular vesicle group. Imaging examination results showed that the blank control group had the fastest progression of arthritis, the normal extracellular vesicle group had a relatively slower progression, and the engineered extracellular vesicle group had the slowest progression. Gross histological observation results showed that the blank control group had the most obvious signs of arthritis, the normal extracellular vesicle group showed signs of arthritis, and the engineered extracellular vesicle group showed no significant signs of arthritis. Using the Pelletier gross score evaluation, the engineered extracellular vesicle group had the slowest progression of arthritis. Results from two types of staining showed that the articular cartilage of rats in the normal extracellular vesicle and engineered extracellular vesicle groups was significantly better than that of the blank control group, and the engineered extracellular vesicle group had the best cartilage cell and joint surface condition. Immunohistochemical detection of type II collagen and proteoglycan showed that the extracellular matrix of cartilage cells in the normal extracellular vesicle and engineered extracellular vesicle groups was better than that of the blank control group. Compared to the normal extracellular vesicle group, the engineered extracellular vesicle group had a better regulatory effect on the extracellular matrix of cartilage cells. Engineered Exos loaded with miR-29a can exert anti-inflammatory effects and maintain extracellular matrix stability, thereby protecting articular cartilage, and slowing the progression of KOA.

The interplay of mitophagy, autophagy, and apoptosis in cisplatin-induced kidney injury: involvement of ERK signaling pathway

AKI induced by CP chemotherapy remains an obstacle during patient treatments. Extracellular signal-regulated protein kinases 1/2 (ERK), key participants in CP-induced nephrotoxicity, are suggested to be involved in the regulation of mitophagy, autophagy, and apoptosis. Human renal proximal tubular cells (HK-2) and BALB/cN mice were used to determine the role of ERK in CP-induced AKI. We found that active ERK is involved in cell viability reduction during apoptotic events but exerts a protective role in the early stages of treatment. Activation of ERK acts as a maintainer of the mitochondrial population and is implicated in mitophagy initiation but has no significant role in its conduction. In the late stages of CP treatment when ATP is deprived, general autophagy that requires ERK activation is initiated as a response, in addition to apoptosis activation. Furthermore, activation of ERK is responsible for the decrease in reserve respiratory capacity and controls glycolysis regulation during CP treatment. Additionally, we found that ERK activation is also required for the induction of NOXA gene and protein expression as well as FoxO3a nuclear translocation, but not for the regular ERK-induced phosphorylation of FoxO3a on Ser294. In summary, this study gives detailed insight into the involvement of ERK activation and its impact on key cellular processes at different time points during CP-induced kidney injury. Inhibitors of ERK activation, including Mirdametinib, are important in the development of new therapeutic strategies for the treatment of AKI in patients receiving CP chemotherapy.

Асциминиб у больных хроническим миелолейкозом, не имеющих альтернативных методов лечения: результаты исследования в рамках программы расширенного доступа МАР (Managed Access Program, NCT04360005) в России

Aim. To assess the efficacy and tolerability of asciminib in chronic myeloid leukemia (CML) patients after failure of ≥ 2 lines of tyrosine kinase inhibitors (TKIs) therapy under the МАР (Managed Access Program, NCT04360005) in Russia. Materials & Methods. The study enrolled 68 patients with Ph-positive CML chronic phase (CF), over 18 years of age, after failure of ≥ 2 lines of TKI therapy. The analysis was conducted on data from 50 patients who were followed-up for at least 3 months and did not undergo allo-HSCT. Dosing regimens were prescribed depending on T315I mutation. Asciminib 200 mg per os was administered twice a day to 20 patients with this mutation, and asciminib 40 mg per os was administered twice a day to 30 patients without this mutation. By the time of admission into the MAP, there were 42 (82 %) CF CML patients as well as 8 patients with second CF after accelerated phase (AF, n = 7) and myeloid blast crisis (BC, n = 1). None of them could be treated with any therapeutic alternative. 92 % of patients had received ≥ 3 lines of prior TKI therapy. Overall survival (OS) and discontinuation-free survival were estimated by the Kaplan-Meier method. A cumulative incidence function (CIF) was used to calculate the probability of achieving response. Multivariate analysis was based on Cox regression model. Results. The median asciminib treatment duration was 11 months (range 4–30 months). The probable 2-year OS was 96 %. After 12 and 24 months, discontinuation-free survival was 92 % and 70 %, respectively. On asciminib therapy, complete cytogenetic (CCyR/МR2), major molecular (MMR), and deep molecular (MR4) responses were achieved in 17 (42 %), 14 (30 %), and 9 (19 %) patients who had not responded to prior treatment at the point of enrollment. After completing the 12- and 24-month therapy, the probability of CCyR/МR2 achievement was 44 % and 62 %, that of MMR achievement was 32 % and 40 %, and that of MR4 achievement was 26 % and 37 %, respectively. The patients treated with different doses did not significantly differ in achieving either CCyR/МR2 or MMR. By multivariate analysis, the independently significant factor impacting the probability of achieving MMR on asciminib treatment was the best MR (BCR::ABL1 < 1 % vs. 1–10 % vs. ≥ 10 %) after prior TKI therapy (hazard ratio 7.5873; p = 0.0072). In 22 (44 %) patients, adverse events (AEs) of all grades were observed, and 8 (16 %) patients showed AEs grade 3/4 (predominantly thrombocythemia and neutropenia). None of the patients discontinued asciminib treatment due to AEs. Conclusion. Asciminib demonstrated highly promising efficacy in previously TKI-treated patients with T315I mutation (200 mg BID) and without it (40 mg BID). Asciminib can be regarded as therapeutic option after failure of other TKIs. Different doses of asciminib were equally well tolerated, which makes it applicable for patients with intolerance to other TKIs and also provides ground for considering dose increases in non-responders. Good prospects are also expected for studying asciminib efficacy at earlier treatment stages (in first or second lines) as well as in combination with ATP-binding TKIs in CML patients with insufficient response to TKI treatment.

Dynamic changes in cardiac biomarkers in radiotherapy for oesophageal cancer and their correlations with cardiac radiation dosimetry

Background and purposeTo investigate the dynamic changes in cardiac enzymes, high-sensitivity troponin T (hs-TnT), pro-brain natriuretic peptide (pro-BNP) and left ventricular ejection fraction (LVEF) during radiotherapy (RT) and 6 months after RT for oesophageal squamous cell carcinoma (ESCC) in the middle and lower locations and to analyse the correlations between these indicators and cardiac radiation dosimetry parameters. MethodsFor 35 patients with ESCC in the middle and lower locations receiving radical concurrent chemoradiotherapy (cCRT), intensity-modulated RT was performed at 1.8 Gy or 2.0 Gy per day, and the totle dose was 50.4 Gy or 60 Gy. Serum creatine kinase (CK), creatine kinase isoenzyme (CK-MB), lactate dehydrogenase (LDH), alpha-hydroxybutyrate dehydrogenase (α-HBDH), hs-TnT, pro-BNP and LVEF were measured before, during, and at the end of RT and 1, 3 and 6 months after RT, and correlations of these indicators with mean heart dose (MHD) and heart V5-V50 were analysed. Resultshs-TnT during, at the end and 6 months after RT for oesophageal cancer showed increasing trends, however, LVEF showed a downward trend. pro-BNP showed an increasing trend during RT and gradually returned to normal after RT. CK and CK-MB showed decreasing trends during RT and continued until one month after RT and then gradually returned to normal. Compared with the low-dose group (MHD < 2000 cGy), the high-dose group (MHD ≥ 2000 cGy) had larger increases in hs-TnT and pro-BNP, a more significant decrease in LVEF, and a longer recovery time for these indicators. MHD and V35 were positively correlated with dynamic changes in hs-TnT. ConclusionsCardiac injury caused by cCRT for ESCC in the middle and lower locations led to increased hs-TnT and pro-BNP levels and a decrease in LVEF in the early stage of treatment, effects that were more pronounced in the high-dose group. MHD and V35 may be potential indicators to predict the degree of cardiac damage. hs-TnT and pro-BNP are sensitive indicators reflecting cardiac injury in RT for oesophageal cancer. Continuous dynamic monitoring of these markers can provide a reference for cardiac protection in clinical RT.

Revolutionizing Early-Stage Cervical Cancer Treatment: A Comprehensive Review of Radical Trachelectomy as a Minimally Invasive Approach.

This comprehensive review explores the transformative potential of radical trachelectomy as a minimally invasive approach to early-stage cervical cancer treatment. Cervical cancer, a significant global health concern, necessitates innovative strategies for effective intervention, particularly in its early stages. The review begins by providing a background on cervical cancer, emphasizing the pressing need for early-stage treatment options. The focal point is the meticulous examination of radical trachelectomy, a surgical technique that addresses the oncological aspects of treatment and preserves fertility. The conclusion encapsulates vital findings, highlighting this approach's dual benefits and challenges. Furthermore, the implications for clinical practice underscore the paradigm shift that radical trachelectomy brings, urging healthcare professionals to consider its integration into personalized treatment plans. The review concludes with a compelling call to action for further research, emphasizing the importance of refining surgical techniques and fostering interdisciplinary collaboration to ensure the seamless implementation of radical trachelectomy. Overall, this review sets the stage for a transformative shift in the approach to early-stage cervical cancer, presenting radical trachelectomy as a promising frontier in the quest for effective and patient-centered interventions.

Level of Distress Experienced by Glioblastoma Multiforme Patients and Caregivers in Relation to their Medical Education Background: A Qualitative Study

BACKGROUND: Glioblastoma multiforme (GBM) is a primary brain tumor with extensive infiltration of surrounding brain tissue and a high rate of recurrence, with an average survival of 13–16 months. Due to the rapid course of the disease, multimodality treatment, and poor prognosis, both the patients and their caregivers will face significant psychological distress. Identification of the types and severity of distress is crucial to control morbidity during treatment. AIM: This study aims to define the level of distress experienced by patients and their caregivers during the treatment period by considering their medical education background. At the time of publication, this type of study is unique and has never been done before. MATERIALS AND METHODS: This study was conducted at the Neurosurgery Outpatient Department of Mochtar Riady Comprehensive Cancer Center Siloam Hospital Jakarta. Patients with GBM and their caregivers were recruited during the early stages of radiation treatment (T1) and the follow-up chemotherapy (T2) and were assessed using the distress thermometer (DT) and National Comprehensive Cancer Network (NCCN) problem checklist followed by in-depth interviews. Participants were divided into two groups based on medical education background. Significant distress is defined as DT score &gt;4. RESULTS: Data from four pairs of patient-caregivers are collected during the early stages of T1. Two pairs of Patient-Caregivers without medical educational background (P-C non-D) are included later during T2. From T1, patients and caregivers with medical education (P-D) are higher than those without medical education (P-D &gt; P-non D; C-D &gt; C-non D). Another comparison shows that P-D is higher than C-D. In contrast, P-non D is lower than C-non D. Based on the time data collected, it shows DT: P-non D T2 &gt; P-non D T1, but there is no difference between T2 and T1 in the caregiver’s group: C-non D T1 = C- non D T2. From the NCCN problem checklist, it is known that they attribute their distress mostly to physical problems. CONCLUSION: The physical and mental changes experienced by patients cause distress for patients and their caregivers. Knowledge of disease and treatment possessed by patients or caregivers helps them deal with GBM and the entire course of treatment.

Early effectiveness and safety analysis of belimumab in addition to standard treatment in patients with systemic lupus erythematosus.

This study aimed to evaluate the early effectiveness and safety of belimumab in addition to standard therapy in patients with systemic lupus erythematosus (SLE) for 24 weeks. This retrospective study was conducted with 60 adult patients with active SLE between June 2020 and August 2022. The patients either received intravenous belimumab in addition to standard therapy (n=31; 24 females, 7 males; mean age: 33.7±14.1 years; range, 18 to 52 years) or only standard therapy (n=29; 22 females, 7 males; mean age: 34.1±13.4 years; range, 19 to 66 years) for 24 weeks. Outcome measures, including safety and effectiveness (Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index [SELENA-SLEDAI]), changes in biomarkers (double-stranded DNA [deoxyribonucleic acid]), serum complement levels, and immunoglobin G (IgG) were recorded. Adverse events were recorded. Baseline demographic and clinical characteristics were similar between the two groups. More patients in the belimumab group achieved a reduction of ≥4 points in SELENA-SLEDAI at weeks 12 and 24 (week 12, 77.4% vs. 41.4%, p=0.008; week 24, 87.1% vs. 48.3%, p=0.002). The mean score of SELENA-SLEDAI was significantly lower in the belimumab group compared to the standard therapy group at week 12. However, a significant difference was not reached at week 24. Moreover, mean levels of serum C3 and C4 in the belimumab group were significantly higher than those in the standard therapy group at weeks 12 and 24. A higher proportion of patients in the belimumab group had a normal C3 level than in the standard therapy group. In addition, belimumab treatment resulted in a significant decrease in IgG levels at both weeks 12 and 24. At week 24, the belimumab group had a higher reduction in prednisone dose than the standard therapy group. Furthermore, the percentages of patients with more than 50% reduction in prednisone over baseline were significantly greater for belimumab versus standard therapy at week 12 (p=0.002). The occurrence of adverse events was similar between the two groups (standard therapy group, 44.8%; belimumab group, 51.6%). Intravenous belimumab was well tolerated and significantly improved disease activity in Chinese patients with SLE at the early stage of treatment. More importantly, belimumab treatment could result in a rapid reduction in prednisone dose as early as week 12.

Detection of renal cell hydronephrosis in ultrasound kidney images: a study on the efficacy of deep convolutional neural networks

In the realm of medical imaging, the early detection of kidney issues, particularly renal cell hydronephrosis, holds immense importance. Traditionally, the identification of such conditions within ultrasound images has relied on manual analysis, a labor-intensive and error-prone process. However, in recent years, the emergence of deep learning-based algorithms has paved the way for automation in this domain. This study aims to harness the power of deep learning models to autonomously detect renal cell hydronephrosis in ultrasound images taken in close proximity to the kidneys. State-of-the-art architectures, including VGG16, ResNet50, InceptionV3, and the innovative Novel DCNN, were put to the test and subjected to rigorous comparisons. The performance of each model was meticulously evaluated, employing metrics such as F1 score, accuracy, precision, and recall. The results paint a compelling picture. The Novel DCNN model outshines its peers, boasting an impressive accuracy rate of 99.8%. In the same arena, InceptionV3 achieved a notable 90% accuracy, ResNet50 secured 89%, and VGG16 reached 85%. These outcomes underscore the Novel DCNN’s prowess in the realm of renal cell hydronephrosis detection within ultrasound images. Moreover, this study offers a detailed view of each model’s performance through confusion matrices, shedding light on their abilities to categorize true positives, true negatives, false positives, and false negatives. In this regard, the Novel DCNN model exhibits remarkable proficiency, minimizing both false positives and false negatives. In conclusion, this research underscores the Novel DCNN model’s supremacy in automating the detection of renal cell hydronephrosis in ultrasound images. With its exceptional accuracy and minimal error rates, this model stands as a promising tool for healthcare professionals, facilitating early-stage diagnosis and treatment. Furthermore, the model’s convergence rate and accuracy hold potential for enhancement through further exploration, including testing on larger and more diverse datasets and investigating diverse optimization strategies.

The temporal progression of retinal degeneration and early-stage idebenone treatment in the Pde6brd1/rd1 mouse model of retinal dystrophy

Photoreceptor cell death, primarily through apoptosis, related to retinal disorders like retinitis pigmentosa (RP), would result in vision loss. The pathological processes and crucial mutant conditions preceding photoreceptor cell demise are not well understood. This study aims to conduct an in-depth examination of early-stage changes in the widely utilized Pde6brd1/rd1 (rd1) mouse model, which has Pde6b gene mutations representing autosomal recessive RP disorder. We investigated the morphology and ultrastructure of retinal cells, including second-order neurons, during the initial phase of disease progression. Our findings revealed that mitochondrial alterations in rod photoreceptors were present as a predeath mutant state as early as postnatal day 3 (P3). The bipolar and horizontal cells from the rd1 mouse retina exhibited significant morphological changes in response to loss of photoreceptor cells, indicating that second-order neurons rely on these cells for their structures. Subsequent oral administration of idebenone, a mitochondria-protective agent, enhanced retinal function and promoted both photoreceptor cell survival and inner retinal second-order synaptogenesis in rd1 mice at P14. Our findings offer a mechanistic framework, suggesting that mitochondrial damage acts as an early driver for photoreceptor cell death in retinal degeneration.

Clinical presentation and outcome of invasive mould disease in paediatric patients with acute lymphoblastic leukaemia

BackgroundChildhood acute lymphoblastic leukaemia (ALL) cure rates have improved, but invasive mould disease (IMD) remains a life-threatening complication. Here, we evaluate the epidemiology, clinical presentation, treatment and outcome of IMD in paediatric patients with ALL. MethodsPatients (1–18 years) treated according to the Dutch Childhood Oncology Group (DCOG) ALL-11 protocol from 2012–2021 were analysed for probable and proven IMD. Data was extracted from the Dutch national registry and the electronic health care system. ResultsAmong 643 patients with ALL, 47 (7.3%) were diagnosed with a probable (n = 29) or proven (n = 18) IMD. Aspergillosis was diagnosed in 42 (89%) patients. Forty-one episodes (87%) occurred during the induction (n = 20) and first consolidation (n = 21) course. The median age at ALL diagnosis was 5 years [IQR 3–10] in the overall group versus 14 years [IQR 7–16] in the IMD group. Two-third of the patients did not receive mould-active prophylaxis. The most prevalent clinical symptoms at presentation were persistent fever and respiratory symptoms. The lungs were the most common site of infection with involvement in 44 (94%) patients, followed by the CNS in 16 (34%) patients. The 6-week and 12-week mortality rate after IMD diagnosis was 10.6% and 14.9%, respectively. Discussion and conclusionIn our paediatric cohort a notable incidence of probable and proven IMD was observed during the early stages of treatment. Remarkable is the high frequency of CNS involvement. These findings highlight the importance of effective prophylactic strategies and warrant early brain imaging.

Extracorporeal Methods of Hemocorrection in Patients with Abdominal Sepsis

BACKGROUND. Theoretical data convincingly support the use of extracorporeal hemocorrection (ECHC) methods in the treatment of sepsis. However, a large number of researchers have still not been able to convincingly prove the advantage of ECHC methods; there is no unanimity of opinion. We tried to analyze our own experience in using ECHC methods in the treatment of abdominal sepsis over the past 3 years. AIM OF STUDY. To analyze the use of ECHC methods in the early stages of treatment of abdominal sepsis, to determine whether their use had an advantage for survival. STUDY DESIGN. Prospective cohort. DESCRIPTION OF THE METHOD. In 50 cases (group 1), ECHC was performed early after surgery. The median time from admission to the intensive care unit after surgery to the start of ECHC was 25.3 (17.7; 36.5) hours. When determining the ECHC modality, we were guided by the individual approach and clinical experience of the ECHC specialist. Apheresis methods alone were performed in 8 % of patients (4/50), a combination of apheresis methods and renal replacement therapy was performed in 40 % (20/50), renal replacement therapy (RRT) methods were performed in 98 % (46/50), plasmapheresis/plasma exchange/selective plasma filtration were performed in 30 % (15/50), selective hemosorption of cytokines was performed in 4 % (2/50), selective hemosorption lipopolysaccharides was performed in 24 % (12/50). We analyzed outcomes, assessments of the severity of functional disorders and sepsis-associated organ dysfunction according to the APACHE scales II and SOFA and their dynamics, probabilities of outcomes depending on the scores on the indices (logistic regression); life times, cumulative survival rate (Kaplan-Meier method). SAMPLE CHARACTERISTICS. There were 113 patients after emergency laparotomy due to widespread peritonitis, abdominal sepsis, aged from 23 to 90 years. 67 men, 46 women. In 50 cases of observation (group 1), ECHC was performed in the early stages ; in 63 cases, methods of active hemocorrection were not used (group 2). In group 1 there were 35 patients with septic shock and 15 patients with stable hemodynamics (subgroup 1/shock and subgroup 1/sepsis). In group 2 there were 20 patients with shock and 43 with stable hemodynamics (subgroup 2/shock and subgroup 2/sepsis). RESEARCH RESULTS ECHC. Methods allowed survival of patients with more severe APACHE scores II and SOFA: in survivors in subgroup 1/shock Me 29 (24; 31) versus 23 (14; 26) in the subgroup 2/shock and 8 (4; 10) versus 4 (2; 6) points, p=0.048 and p = 0.010; with stable hemodynamics in survivors in subgroup 1/sepsis Me 20 (17; 22) versus 15 (11; 19) in subgroup 2/sepsis, p=0.016. ECHC changed the survival threshold in favor of more severe patients from 29 to 33 points; reduced the likelihood of an unfavorable outcome 1.2-fold for each point on the APACHE scale II and 1,276 times over the entire range of estimates; prolonged survival time in hemodynamically unstable patients at a significance level of p = 0.083, shifting the first quartile of survival from 1 to 12 days, the median from 12 to 20, the third quartile from 27 to 45 days. When performing ECHC, the cumulative survival rate was higher throughout the entire hospital observation period: 0.886 (95 % CI 0.780–0.939) in 2 days versus 0.700 (95 % CI 0.499–0.802); 0.800 (95 % CI 0.667–0.868) in 10 days versus 0.545 (95 % CI 0.325–0.658); 0.653 (95 % CI 0.494–0.734) in 14 days versus 0.416 (95 % CI 1.185–0.533). Overall mortality from all causes was 35.4 % (40/113), 67.3 (37/55) with shock, 5.2 % (3/58) with stable hemodynamics. The maximum risk of an unfavorable outcome occurred in the early stages: 30 % (12/40) of all deaths occurred in the first 4 days after surgery, 20 % (8/40) in the first 24 hours. In shock patients, 10-day mortality was lower when performing ECHC: 20.0 % (7/35) versus 45.0 % (9/20), p = 0.050, 1st stage. Fisher’s test, P = 0.38 insufficient. Hospital mortality in the shock subgroups was equal, all the advantages of ECHC achieved in the early stages were lost; although in most late outcomes the peritonitis was relieved; which was confirmed during the section. CONCLUSIONS. The power of the study was sufficient to identify statistically significant advantages of extracorporeal hemocorrection in the treatment of abdominal sepsis based on APACHE index estimates II and SOFA. For the Kaplan–Meier method, differences were obtained for shock patients at a significance level of 0.083; the number of observations must be doubled to detect statistically significant differences. The final results of hospital mortality require additional in-depth analysis, since in the later stages many deaths were not associated with abdominal sepsis and occurred with already resolved peritonitis. It is necessary to understand to what extent they were associated with experienced sepsis, and to what extent with comorbid pathology; whether there was an association with methods of extracorporeal hemocorrection.

Real-world clinical characteristics and treatment patterns among people with hepatocellular carcinoma in the United States (US) treated with resection or ablation.

436 Background: Treatment guidelines for early-stage hepatocellular carcinoma (eHCC) include therapies with curative intent comprising three primary strategies: liver transplantation, surgical resection, or ablation (for small lesions). However, many people experience HCC recurrence, with recurrence rates of up to approximately 80% within 5 years after resection. Furthermore, contemporary insights into the eHCC treatment landscape and post-recurrence treatment patterns in the real-world setting are lacking. This study was designed to assess demographic and clinical characteristics and treatment patterns for people with HCC who received resection or ablation as a proxy for defining early-stage disease. Methods: This was a retrospective observational cohort study of adults with HCC treated with resection or ablation in the US, conducted using linked electronic health records and healthcare claims from Optum’s de-identified Market Clarity Data. Index date was the date of the first observed resection or ablation between July 2016 and March 2021. Baseline characteristics were assessed in the 6-month period prior to index, and patients (pts) were followed until end of continuous enrolment in a medical and pharmacy plan, death, or data cut-off (September 2022), whichever occurred first. Demographic and clinical characteristics and treatment patterns, including subsequent treatments, were described. Results: A total of 649 pts met the study criteria and were included in the analyses. The median duration of follow-up was 23.0 months (range: 0.03–74.55 months). The mean age at index was 64.1 years (median 64.0 years), with a majority male gender (72.9%) and White race (65.5%). A total of 385 pts (59.3%) underwent ablation only, 242 pts (37.3%) underwent resection only, and 22 pts (3.4%) underwent both procedures at index. Transarterial embolization alone was received by 57 (8.8%) pts and was the most common embolization procedure received during follow-up, followed by transarterial chemoembolization alone in 46 (7.1%) pts and transarterial radioembolization in 46 (7.1%) pts. A total of 88 (13.6%) pts received systemic therapies for HCC (tyrosine kinase inhibitors, programmed cell death protein-1/programmed cell death-ligand 1/cytotoxic T-lymphocyte-associated antigen 4 inhibitors, or angiogenesis inhibitors) during follow-up. Conclusions: In this real-world cohort, ablation was the most received curative intent therapy for HCC. Among treatments received during follow-up, locoregional therapies were used most often, followed by systemic therapies. Although limited by its retrospective, observational nature, short duration of follow-up, and availability of data in the database, the results of this analysis provide a contemporary landscape of early-stage treatments for HCC in the real-world setting.

Effects of ultrasonic cavitation on microstructure and surface properties of Mn–Cu alloy

In the presented study, the effects of ultrasonic vibration on microstructure and surface properties of Mn–Cu alloy were investigated. At the early stage of ultrasonic cavitation treatment, grains of Mn–Cu alloy are refined, nanocrystals and amorphous bands are produced. As the ultrasonic cavitation treatment proceeds, the face-centered cubic structure is transformed into the body-centered tetragonal structure, and the martensitic phase transformation arises. The transformation is accompanied by plastic deformation and the formation of dislocations. The generation of martensite is caused by the stress and strain. Due to grain refinement, dislocations, and generation of martensite, the surface hardness of Mn–Cu alloy is enhanced, and the friction coefficient decreases. The resistance to wear is thereby improved.

Gynecological cancer during pregnancy-From a gyne-oncological perspective.

Gynecological cancer diagnosed during pregnancy requires accurate diagnosis and staging to determine optimal treatment based on gestational age. Cervical and ovarian cancers are the most common and multidisciplinary team collaboration is pivotal. Magnetic resonance imaging and ultrasound can be used without causing fetal harm. In cervical cancer, early-stage treatments can often be delayed until fetal lung maturation and cesarean section is recommended if disease prevails, in combination with a simple/radical hysterectomy and lymphadenectomy. Chemoradiotherapy, the recommended treatment for advanced stages, is not compatible with pregnancy preservation. Most gestational ovarian cancers are diagnosed at an early stage and consist of nonepithelial cancers or borderline tumors. Removal of the affected adnexa during pregnancy is often necessary for diagnosis, though staging can be performed after delivery. In selected cases of advanced cervical and ovarian cancers, neoadjuvant chemotherapy may be an option to allow gestational advancement but only after thorough multidisciplinary discussions and counseling.

Biomarkers in the early stage of PD-1 inhibitor treatment have shown superior predictive capabilities for immune-related thyroid dysfunction.

Hematological indicators in the early stage of PD-1 inhibitor treatment may show superior predictive ability of the occurrence of immune related adverse event (irAE) compared to the pre-treatment indicators, as the immune response is modulated during the PD-1 inhibitor treatment. The objective of this study was to investigate the predictive capabilities of biomarkers in the early treatment stage for immune related thyroid dysfunction (irTD), and explore the potential predictive cytokines. Medical records and blood test results of cancer patients treated with PD-1 inhibitor at a certain medical institution were collected. Logistic regression analysis was utilized to identify the predictive factors of irTD, ROC curves were plotted and the area under the curves (AUC) was calculated. Serum samples were collected before and during early treatment phase, cytokine detection was performed to explore potential predictive cytokines. A total of 264 patients were enrolled, 58 developed irTD (21.97%), including 31 patients with thyrotoxicosis and 27 with hypothyroidism. There were no significant differences in demographic characteristics, tumor types and PD-1 inhibitors between patients with and without irTD. Multivariate logistic analysis showed that anti-thyroglobulin antibody (TgAb) (OR=2.831, 95%CI: 1.077-7.443, P=0.035) and anti-thyroperoxidase antibody (TPOAb) (OR=9.565, 95%CI: 3.399-26.921, P=0.000) in the early treatment phase were independent predictive factors for irTD, the AUC of early-stage biomarkers was larger than that of pre-treatment (0.655 vs 0.571); low level of TSH at the early stage (OR=0.162, 95%CI: 0.077-0.341, P=0.000) was significantly correlated with thyrotoxicosis; female (OR=3.889, 95%CI: 1.457-10.380, P=0.007) and positive TPOAb (OR=8.678, 95%CI: 2.656-28.357, P=0.000) at the early stage were significantly correlated with hypothyroidism. The AUCs of early-stage biomarkers were larger than that of pre-treatment both in thyrotoxicosis (0.812 vs 0.637) and hypothyroidism patients (0.728 vs 0.710). The increase of IL-16 (adjusted P=0.004), IL-12p70 (adjusted P=0.014), IL-17 (adjusted P=0.014), CCL-15 (adjusted P=0.014) and IL-1a (adjusted P=0.021) in the early treatment phase were positively correlated with irTD. Biomarkers at the early stage of PD-1 inhibitor treatment could predict irTD, and demonstrated stronger predictive ability compared to pre-treatment biomarkers. IL-16, IL-12p70, IL-17, CCL-15 and IL-1a could serve as potential predictive biomarkers for irTD.

Racial Disparities in Surgical Management For Early-Stage Laryngeal Squamous Cell Carcinoma and Recurrent Dysplasia.

The aim of this study is to evaluate the association between race and the treatment of laryngeal dysplasia and early-stage laryngeal squamous cell carcinoma (LSCC). Retrospective Cohort Study. Large multispecialty academic medical center. Patients were treated for laryngeal dysplasia or LSCC between September 2019 and September 2022. A retrospective chart review was conducted to collect demographic and clinical information. Two-sample t tests, chi-square tests, and linear regression models were used to compare characteristics (α = 0.05). Analyses were performed in STATA 17. Sixty-fivepatients were identified that underwent potassium titanyl phosphate (KTP) transoral laser microsurgery for management of early-stage LSCC (n = 29) or dysplasia (n = 36). The cohort consisted of 23 Black and 42 White patients. No significant difference was found in age, alcohol or tobacco use, rate of adjuvant radiotherapy, stage of disease, nor insurance status between the 2 groups. White patients underwent more procedures to address initial disease and subsequent recurrent dysplasia on average than Black patients (2.52 vs 1.52, P = .02). This remained true after adjusting for demographic and clinical characteristics and insurance status in a linear regression model. While Black patients were more likely to be lost to follow-up than White patients (30.4% vs 9.5%, P = .03), the average number of procedures between the groups still differed significantly (2.63 vs 1.56, P = .04) when controlling for those lost to follow-up. The findings presented here highlight potential inequities that exist for racial minorities at early stages of treatment and in addressing premalignant conditions, which may contribute to the known downstream disparities in laryngeal cancer outcomes.

Liver injury due to endothelin receptor antagonists: a real-world study based on post-marketing drug monitoring data.

Liver injury is the hallmark adverse reaction of endothelin receptor antagonist (ERA). Since the first drug, bosentan has been widely used in clinical practice, hepatotoxicity has been accompanied by the history of ERA. The new ERA has been proven to have a lower liver risk but the current research findings are inconsistent. ERA-based targeted drug combinations are commonly used in the treatment of pulmonary arterial hypertension, where the risk of liver injury is difficult to estimate. This study aimed to compare the correlation between ERA and different ERA combination regimens with liver injury in the real world. This is a retrospective study using data from the Adverse Event Reporting System (Food and Drug Administration AERS, FAERS). The study used proportional imbalance and Bayesian analysis to mine FAERS data from January 2004 to December 2022 to determine the association of three ERAs with liver injury and to further mine the risk of liver injury due to the combination of ERAs with other targeted drugs. In addition, we analyzed the onset time, mortality, and hospitalization rate of liver injury caused by different ERA combination regimens. We screened out 3581 ERA-related liver injury events, of which bosentan (59.82%) had the largest number of cases. The patients with liver injury were mainly female (60.63%), and the age was concentrated between 61 and 75 years (26.75%). According to different signal mining methods, reporting odds ratio (ROR; 3.38, 95% confidence interval = 3.23-3.53), proportional reporting ratio (PRR; 3.22, χ2 = 37.84), Bayesian confidence propagation neural network (BCPNN; 1.68, 95% confidence interval = 1.61), multi-item gamma Poisson shrinker (MGPS; 3.21, 95% confidence interval = 3.09), bosentan had the strongest association with liver injury compared to ambrisentan and macitentan. Furthermore, bosentan + sildenafil [ROR (2.52, 95% confidence interval = 2.23-2.84), PRR (2.44, χ2 = 15.92), BCPNN (1.29, 95% confidence interval = 1.14), MGPS (2.44, 95% confidence interval = 2.21)], bosentan + epoprostenol [ROR (5.39, 95% confidence interval = 4.29-6.77), PRR (4.94, χ2 = 65.18), BCPNN (2.30, 95% confidence interval = 1.83), MGPS (4.94, 95% confidence interval = 4.08)], bosentan + iloprost [ROR (2.70, 95% confidence interval = 2.11-3.45), PRR (2.61, χ2 = 31.03), BCPNN (1.38, 95% confidence interval = 1.08), MGPS (2.61, 95% confidence interval = 2.12)] had a higher risk of liver injury caused by the three ERA combination regimens. The median time to onset of hepatotoxicity associated with all ERA combination regimens was 259 days (interquartile range: 58-716.5 days). Finally, the hospitalization rate for patients experiencing hepatotoxicity with ERA combination regimens was 47.86% and the mortality rate was 12.67%. By mining the FAERS, we analyzed and compared the risk of liver injury related to different ERA and ERA combination regimens, and the onset time and adverse reaction outcomes of all ERA combination regimens. According to the results of the study, bosentan had the highest risk of liver injury and the combination regimens bosentan + sildenafil, bosentan + epoprostenol, and bosentan + iloprost had a stronger risk of liver injury. From the early stages of treatment, we need to regularly monitor the liver function of patients, especially for females and the elderly, and discontinue the suspected drug as soon as the liver injury occurs.

Updates on altered signaling pathways in tumor drug resistance

Curing cancer has always presented a formidable clinical challenge. Among the various treatment strategies for combating tumors, the combination of targeted therapy and immunotherapy has recently assumed significant importance. Regrettably, while targeted drugs demonstrate efficiency in the early stages of cancer treatment, patients inevitably develop drug resistance as treatment progresses, ultimately resulting in treatment failure and death. Currently, effective countermeasures against drug-resistant tumor cells remain limited, and research into the mechanisms of drug resistance continues to garner profound interest. The current understanding of drug resistance primarily focuses on two aspects: intrinsic or primary drug resistance, and acquired or secondary drug resistance. Further explanations delve into molecular mechanisms, including acquired gene mutations, epigenetic modifications, the plasticity of cancer stem cells, and the mediation of exosomes. With the advancement of single-cell analysis, our understanding of these potential mechanisms has become more comprehensive. In this review, we initially explore classical signaling pathways related to tumorigenesis and cancer cell progression. Additionally, we summarize recent findings regarding gene mutations and modifications related to drug resistance in cancer. Finally, we discuss the plasticity of cancer stem cells and the latest research on exosome-mediated tumor drug resistance.