Novel magnetic compression technique for the treatment of postoperative anastomotic stenosis in rectal cancer: A case report.

BACKGROUND: The treatment of postoperative anastomotic stenosis after excision of rectal cancer is challenging. Endoscopic balloon dilation and radial incision are not effective in all patients. We present a new endoscopy-assisted magnetic compression technique (MCT) for the treatment of rectal anastomotic stenosis. We successfully applied this MCT to a patient who developed an anastomotic stricture after radical resection of rectal cancer. CASE SUMMARY: A 50-year-old man had undergone laparoscopic radical rectal cancer surgery at a local hospital 5 months ago. A colonoscopy performed 2 months ago indicated that the rectal anastomosis was narrow due to which ileostomy closure could not be performed. The patient came to the Magnetic Surgery Clinic of the First Affiliated Hospital of Xi'an Jiaotong University after learning that we had successfully treated patients with colorectal stenosis using MCT. We performed endoscopy-assisted magnetic compression surgery for rectal stenosis. The magnets were removed 16 d later. A follow-up colonoscopy performed after 4 months showed good anastomotic patency, following which, ileostomy closure surgery was performed. CONCLUSION: MCT is a simple, non-invasive technique for the treatment of anastomotic stricture after radical resection of rectal cancer. The technique can be widely used in clinical settings.

Magnetic compression anastomosis to restore biliary tract continuity after obstruction following major abdominal trauma: A case report.

BACKGROUND: The combination of magnetic compression anastomosis (MCA) and endoscopy has been used to treat biliary stricture after liver transplantation. However, its use for the treatment of complex biliary obstruction after major abdominal trauma has not been reported. This case report describes the successful use of MCA for the treatment of biliary obstruction resulting from major abdominal trauma. CASE SUMMARY: A 23-year-old man underwent major abdominal surgery (repair of liver rupture, right half colon resection, and ileostomy) following a car accident one year ago. The abdominal drainage tube, positioned at the Winslow foramen, was draining approximately 600-800 mL of bile per day. During the two endoscopic retrograde cholangiopancreatography procedures, the guide wire was unable to enter the common bile duct, which prevented placement of a biliary stent. MCA combined with endoscopy was used to successfully achieve magnetic anastomosis of the peritoneal sinus tract and duodenum, and then a choledochoduodenal stent was placed. Finally, the external biliary drainage tube was removed. The patient achieved internal biliary drainage leading to the removal of the external biliary drainage tube, which improved the quality of life. CONCLUSION: Magnetic compression technique can be used for the treatment of complex biliary obstruction with minimal operative trauma.

Hospital-Treated Infections and Risk of Disability Worsening in Multiple Sclerosis.

OBJECTIVE: To investigate the association between infections and disability worsening in people with multiple sclerosis (MS) treated with either B-cell depleting therapy (rituximab) or interferon-beta/glatiramer acetate (IFN/GA). METHODS: This cohort study spanned from 2000 to 2021, using data from the Swedish MS Registry linked to national health care registries, comprising 8,759 rituximab and 7,561 IFN/GA treatment episodes. The risk of hospital-treated infection was estimated using multivariable Cox models. The association between infections and increase in Expanded Disability Status Scale (EDSS) scores was assessed using a doubly robust generalized estimating equations model. Additionally, a piece-wise exponential model analyzed events of increased disability beyond defined cut-off values, controlling for relapses, and MRI activity. RESULTS: Compared with IFN/GA, rituximab displayed increased risk of both inpatient- and outpatient-treated infections (hazard ratio [HR], 2.08; 95% confidence interval [CI], 1.50-2.90 and HR, 1.37; 95% CI, 1.13-1.67, respectively). An inpatient-treated infection was associated with a 0.19-unit increase in EDSS (95% CI, 0.12-0.26). Degree of worsening was greatest for progressive MS, and under IFN/GA treatment, which unlike rituximab, was more commonly associated with MRI activity. After controlling for relapses and MRI activity, inpatient-treated infections were associated with disability worsening in people with relapsing-remitting MS treated with IFN/GA (HR, 2.01; 95% CI, 1.59-2.53), but not in those treated with rituximab. INTERPRETATION: Compared to IFN/GA, rituximab doubled the infection risk, but reduced the risk of subsequent disability worsening. Further, the risk of worsening after hospital-treated infection was greater with progressive MS than with relapsing-remitting MS. Infection risk should be considered to improve long term outcomes. ANN NEUROL 2024.

Mucin phenotype and microvessels in early gastic cancer: Magnifying endoscopy with narrow band imaging.

Backgrounds: In order to detect early gastric cancer (EGC), this research sought to assess the diagnostic utility of magnifying endoscopy (ME) as well as the significance of mucin phenotype and microvessel features. Methods: 402 individuals with an EGC diagnosis underwent endoscopic submucosal dissection (ESD) at the Department of ME between 2012 and 2020. After adjusting for image distortion, high-magnification endoscopic pictures were taken and examined to find microvessels in the area of interest. The microvessel density was measured as counts per square millimeter (counts/mm2) after segmentation, and the vascular bed's size was computed as a percentage of the area of interest. To identify certain properties of the microvessels, such as end-points, crossing points, branching sites, and connection points, further processing was done using skeletonized pixels. Results: According to the research, undifferentiated tumors often lacked the MS pattern and showed an oval and tubular microsurface (MS) pattern, but differentiated EGC tumors usually lacked the MS pattern and presented a corkscrew MV pattern. Submucosal invasion was shown to be more strongly associated with the destructive MS pattern in differentiated tumors as opposed to undifferentiated tumors. While lesions with a corkscrew MV pattern and an antrum or body MS pattern revealed greater MUC5AC expression, lesions with a loop MV pattern indicated higher MUC2 expression. Furthermore, CD10 expression was higher in lesions with a papillary pattern and an antrum or body MS pattern. Conclusion: These results imply that evaluating mucin phenotype and microvessel features in conjunction with magnifying endoscopy (ME) may be a useful diagnostic strategy for early gastric cancer (EGC) detection. Nevertheless, further investigation is required to confirm these findings and identify the best course of action for EGC diagnosis.

Efficient and rapid digestion of proteins with a dual-enzyme microreactor featuring 3-D pores formed by dopamine/polyethyleneimine/acrylamide-coated KIT-6 molecular sieve.

The microreactor with two types of immobilized enzymes, exhibiting excellent orthogonal performance, represents an effective approach to counteract the reduced digestion efficiency resulting from the absence of a single enzyme cleavage site, thereby impacting protein identification. In this study, we developed a hydrophilic dual-enzyme microreactor characterized by rapid mass transfer and superior enzymatic activity. Initially, we selected KIT-6 molecular sieve as the carrier for the dual-IMER due to its three-dimensional network pore structure. Modification involved co-deposition of polyethyleneimine (PEI) and acrylamide (AM) as amine donors, along with dopamine to enhance material hydrophilicity. Remaining amino and double bond functional groups facilitated stepwise immobilization of trypsin and Glu-C. Digestion times for bovine serum albumin (BSA) and bovine hemoglobin (BHb) on the dual-IMER were significantly reduced compared to solution-based digestion (1 min vs. 36 h), resulting in improved sequence coverage (91.30% vs. 82.7% for BSA; 90.24% vs. 89.20% for BHb). Additionally, the dual-IMER demonstrated excellent durability, retaining 96.08% relative activity after 29 reuse cycles. Enhanced protein digestion efficiency can be attributed to several factors: (1) KIT-6's large specific surface area, enabling higher enzyme loading capacity; (2) Its three-dimensional network pore structure, facilitating faster mass transfer and substance diffusion; (3) Orthogonality of trypsin and Glu-C enzyme cleavage sites; (4) The spatial effect introduced by the chain structure of PEI and glutaraldehyde's spacing arm, reducing spatial hindrance and enhancing enzyme-substrate interactions; (5) Mild and stable enzyme immobilization. The KIT-6-based dual-IMER offers a promising technical tool for protein digestion, while the PDA/PEI/AM-KIT-6 platform holds potential for immobilizing other proteins or active substances.

Portable spirometer-based pulmonary function test willingness in China: A nationwide cross-sectional study from the "Happy Breathing Program".

BACKGROUND: Understanding willingness to undergo pulmonary function tests (PFTs) and the factors associated with poor uptake of PFTs is crucial for improving early detection and treatment of chronic obstructive pulmonary disease (COPD). This study aimed to understand willingness to undergo PFTs among high-risk populations and identify any barriers that may contribute to low uptake of PFTs. METHODS: We collected data from participants in the "Happy Breathing Program" in China. Participants who did not follow physicians' recommendations to undergo PFTs were invited to complete a survey regarding their willingness to undergo PFTs and their reasons for not undergoing PFTs. We estimated the proportion of participants who were willing to undergo PFTs and examined the various reasons for participants to not undergo PFTs. We conducted univariable and multivariable logistic regressions to analyze the impact of individual-level factors on willingness to undergo PFTs. RESULTS: A total of 8475 participants who had completed the survey on willingness to undergo PFTs were included in this study. Out of these participants, 7660 (90.4%) were willing to undergo PFTs. Among those who were willing to undergo PFTs but actually did not, the main reasons for not doing so were geographical inaccessibility (n = 3304, 43.1%) and a lack of trust in primary healthcare institutions (n = 2809, 36.7%). Among the 815 participants who were unwilling to undergo PFTs, over half (n = 447, 54.8%) believed that they did not have health problems and would only consider PFTs when they felt unwell. In the multivariable regression, individuals who were ≤54 years old, residing in rural townships, with a secondary educational level, with medical reimbursement, still working, with occupational exposure to dust, and aware of the abbreviation "COPD" were more willing to undergo PFTs. CONCLUSIONS: Willingness to undergo PFTs was high among high-risk populations. Policymakers may consider implementing strategies such as providing financial incentives, promoting education, and establishing community-based programs to enhance the utilization of PFTs.

Effect of esketamine on haemodynamic fluctuations in patients undergoing hysteroscopic surgery: A prospective, double-blind randomized clinical trial.

AIMS: We explored whether esketamine anesthesia during hysteroscopic surgery can reduce intraoperative hemodynamic fluctuations and improve patient benefit. METHODS: A total of 170 patients undergoing hysteroscopic surgery were enrolled, and 151 patients were finally included in the analysis, among which 19 used vasoactive drugs during surgery. Patients were randomly assigned to either the esketamine anesthesia group (E group) or the sufentanil anesthesia group (S group). The primary outcomes were blood pressure and heart rate during the surgery. Secondary outcomes included resistance to laryngeal mask insertion, demand for propofol and remifentanil, nausea and vomiting, Richmond Agitation and Sedation Scale (RASS), dizziness and pain intensity after resuscitation, vasoactive medication treatment, hospitalization time and expenses. RESULTS: E group had a more stable heart rate, systolic blood pressure, diastolic blood pressure and mean blood pressure than the S group (p < 0.001). Patients in E group had a higher demand for propofol (p < 0.001) but better RASS scores (p < 0.001) after resuscitation. The incidence of intraoperative vasoactive medication use was higher in the S group (18.4% vs. 6.7%, p = 0.029). There were no statistically significant differences in terms of resistance to laryngeal mask insertion, remifentanil demand, time required for resuscitation, postoperative pain, dizziness, nausea or vomiting. CONCLUSIONS: Compared with sufentanil, esketamine-induced anesthesia during hysteroscopic surgery can reduce intraoperative hemodynamic fluctuations and the incidence of intraoperative vasoactive medication. Although esketamine-induced anesthesia may increase the demand for propofol during surgery, it does not affect the anesthesia recovery time and the quality of patient recovery is better.

Targeting delivery of miR-146a via IMTP modified milk exosomes exerted cardioprotective effects by inhibiting NF-κB signaling pathway after myocardial ischemia-reperfusion injury.

Reperfusion therapy is critical for saving heart muscle after myocardial infarction, but the process of restoring blood flow can itself exacerbate injury to the myocardium. This phenomenon is known as myocardial ischemia-reperfusion injury (MIRI), which includes oxidative stress, inflammation, and further cell death. microRNA-146a (miR-146a) is known to play a significant role in regulating the immune response and inflammation, and has been studied for its potential impact on the improvement of heart function after myocardial injury. However, the delivery of miR-146a to the heart in a specific and efficient manner remains a challenge as extracellular RNAs are unstable and rapidly degraded. Milk exosomes (MEs) have been proposed as ideal delivery platform for miRNA-based therapy as they can protect miRNAs from RNase degradation. In this study, the effects of miR-146a containing MEs (MEs-miR-146a) on improvement of cardiac function were examined in a rat model of MIRI. To enhance the targeting delivery of MEs-miR-146a to the site of myocardial injury, the ischemic myocardium-targeted peptide IMTP was modified onto the surfaces, and whether the modified MEs-miR-146a could exert a better therapeutic role was examined by echocardiography, myocardial injury indicators and the levels of inflammatory factors. Furthermore, the expressions of miR-146a mediated NF-κB signaling pathway-related proteins were detected by western blotting and qRT-PCR to further elucidate its mechanisms. MiR-146 mimics were successfully loaded into the MEs by electroporation at a square wave 1000 V voltage and 0.1 ms pulse duration. MEs-miR-146a can be up-taken by cardiomyocytes and protected the cells from oxygen glucose deprivation/reperfusion induced damage in vitro. Oral administration of MEs-miR-146a decreased myocardial tissue apoptosis and the expression of inflammatory factors and improved cardiac function after MIRI. The miR-146a level in myocardium tissues was significantly increased after the administration IMTP modified MEs-miR-146a, which was higher than that of the MEs-miR-146a group. In addition, intravenous injection of IMTP modified MEs-miR-146a enhanced the targeting to heart, improved cardiac function, reduced myocardial tissue apoptosis and suppressed inflammation after MIRI, which was more effective than the MEs-miR-146a treatment. Moreover, IMTP modified MEs-miR-146a reduced the protein levels of IRAK1, TRAF6 and p-p65. Therefore, IMTP modified MEs-miR-146a exerted their anti-inflammatory effect by inhibiting the IRAK1/TRAF6/NF-κB signaling pathway. Taken together, our findings suggested miR-146a containing MEs may be a promising strategy for the treatment of MIRI with better outcome after modification with ischemic myocardium-targeted peptide, which was expected to be applied in clinical practice in future.

High-Entropy Metal Nitride Embedded in Concave Porous Carbon Enabling Polysulfide Conversion in Lithium-Sulfur Batteries.

The practical implementation of lithium-sulfur batteries is severely hindered by the rapid capacity fading due to the solubility of the intermediate lithium polysulfides (LiPSs) and the sluggish redox kinetics. Herein, high-entropy metal nitride nanocrystals (HEMN) embedded within nitrogen-doped concave porous carbon (N-CPC) polyhedra are rationally designed as a sulfur host via a facile zeolitic imidazolate framework (ZIF)-driven adsorption-nitridation process toward this challenge. The configuration of high-entropy with incorporated metal manganese (Mn) and chromium (Cr) will optimize the d-band center of active sites with more electrons occupied in antibonding orbitals, thus promoting the adsorption and catalytic conversion of LiPSs. While the concave porous carbon not only accommodates the volume change upon the cycling processes but also physically confines and exposes active sites for accelerated sulfur redox reactions. As a result, the resultant HEMN/N-CPC composites-based sulfur cathode can deliver a high specific capacity of 1274 mAh g-1 at 0.2 C and a low capacity decay rate of 0.044% after 1000 cycles at 1 C. Moreover, upon sulfur loading of 5.0 mg cm-2, the areal capacity of 5.0 mAh cm-2 can still be achieved. The present work may provide a new avenue for the design of high-performance cathodes in Li-S batteries.

Exploring the Correlation Between Varied Serum Iodine Nutritional Levels and Anti-Thyroglobulin Antibodies.

Iodine deficiency results in elevated thyroglobulin (Tg) concentrations, with high iodine Tg being more immunogenic than low iodine Tg. The study investigated the correlation between serum iodine concentration and thyroglobulin autoantibody (TgAb) levels across diverse iodine nutritional statuses as determined by urine iodine concentration (UIC). Demographic information was collected from 1,482 participants through a questionnaire. Blood and spot urine were collected to measure thyroid-stimulating hormone (TSH), TgAb, thyroid anti-peroxidase antibody (TPOAb), serum iodine (SIC), serum non-protein-bound iodine (snPBI), urine iodine (UIC), creatinine (UCr). The median UIC and SIC were 146.5 µg/L and 74.9 µg/L, respectively. A linear relationship was observed between SIC, snPBI, and serum-protein-bound iodine (sPBI) (P < 0.001). The 90% reference intervals for SIC, snPBI, and sPBI were 50.7-120.7 µg/L, 21.9-52.9 µg/L, and 19.7-77.9 µg/L, respectively. The prevalence of elevated TgAb levels was significantly higher in women than in men (P < 0.001). Both low and high levels of snPBI and sPBI were associated with an increased risk of elevated TgAb levels. In women, the risk of positive TgAb in the group below the reference value of snPBI (OR = 2.079, 95%CI: 1.166, 3.705) and sPBI (OR = 2.578, 95%CI: 1.419, 4.684) was higher. In men, the risk of positive TgAb in the group below the reference value of SIC was higher (OR = 3.395, 95%CI: 1.286, 8.962). Iodine might exert an influence on TgAb levels through its binding to proteins, primarily Tg, thereby altering the iodine content of Tg. The interplay of gender factors further enhanced the risk of TgAb emergence.

Perinatal depression and risk of maternal cardiovascular disease: a Swedish nationwide study.

BACKGROUND AND AIMS: Increasing evidence suggests that some reproductive factors/hazards are associated with a future risk of cardiovascular disease (CVD) in women. While major (non-perinatal) depression has consistently been associated with CVD, the long-term risk of CVD after perinatal depression (PND) is largely unknown. METHODS: A nationwide population-based matched cohort study involving 55 539 women diagnosed with PND during 2001-14 in Sweden and 545 567 unaffected women individually matched on age and year of conception/delivery was conducted. All women were followed up to 2020. Perinatal depression and CVD were identified from Swedish national health registers. Using multivariable Cox models, hazard ratios (HR) of any and type-specific CVD according to PND were estimated. RESULTS: The mean age at the PND diagnosis was 30.8 [standard deviation (SD) 5.6] years. During the follow-up of up to 20 years (mean 10.4, SD 3.6), 3533 (6.4%) women with PND (expected number 2077) and 20 202 (3.7%) unaffected women developed CVD. Compared with matched unaffected women, women with PND had a 36% higher risk of developing CVD [adjusted HR = 1.36, 95% confidence interval (CI): 1.31-1.42], while compared with their sisters, women with PND had a 20% higher risk of CVD (adjusted HR = 1.20, 95% CI 1.07-1.34). The results were most pronounced in women without a history of psychiatric disorder (P for interaction < .001). The association was observed for all CVD subtypes, with the highest HR in the case of hypertensive disease (HR = 1.50, 95% CI: 1.41-1.60), ischaemic heart disease (HR = 1.37, 95% CI: 1.13-1.65), and heart failure (HR 1.36, 95% CI: 1.06-1.74). CONCLUSIONS: Women with PND are at higher risk of CVD in middle adulthood. Reproductive history, including PND, should be considered in CVD risk assessments of women.

A theoretical explanation for how a nutrition counseling and medically tailored meal delivery program benefitted participants living with lung cancer.

PURPOSE: The purpose of this study was to assess participants' perceptions and experiences while participating in a Food is Medicine medically tailored meal plus intensive nutrition counseling intervention to create a theoretical explanation about how the intervention worked. METHODS: This interpretive qualitative study included the use of semi-structured interviews with active participants in a randomized controlled trial aimed at understanding how a medically tailored meal plus nutrition counseling intervention worked for vulnerable individuals with lung cancer treated at four cancer centers across the USA. During the 8-month long study, participants in the intervention arm were asked to be interviewed, which were recorded, transcribed verbatim, and analyzed using conventional content analysis with principles of grounded theory. RESULTS: Twenty individuals participated. Data analysis resulted in a theoretical explanation of the intervention's mechanism of action. The explanatory process includes three linked and propositional categories leading to patient resilience: engaging in treatment, adjusting to diagnosis, and active coping. The medically tailored meals plus nutrition counseling engaged participants throughout treatment, which helped participants adjust to their diagnosis, leading to active coping through intentional self-care, behavior change, and improved quality of life. CONCLUSIONS: These findings provide evidence that a Food is Medicine intervention may buffer some of the adversity related to the diagnosis of lung cancer and create a pathway for participants to experience post-traumatic growth, develop resilience, and change behaviors to actively cope with lung cancer. Medically tailored meals plus intensive nutrition counseling informed by motivational interviewing supported individuals' adjustment to their diagnosis and resulted in perceived positive behavior change.

Evaluating the role of DNA methyltransferases in trophoblast fusion and preeclampsia development: Insights from methylation-regulated genes.

The etiology of preeclampsia (PE), a complex and multifactorial condition, remains incompletely understood. DNA methylation, which is primarily regulated by three DNA methyltransferases (DNMTs), DNMT1, DNMT3A, and DNMT3B, plays a vital role in early embryonic development and trophectoderm differentiation. Yet, how DNMTs modulate trophoblast fusion and PE development remains unclear. In this study, we found that the DNMTs expression was downregulated during trophoblast cells fusion. Downregulation of DNMTs was observed during the reconstruction of the denuded syncytiotrophoblast (STB) layer of placental explants. Additionally, overexpression of DNMTs inhibited trophoblast fusion. Conversely, treatment with the DNA methylation inhibitor 5-aza-CdR decreased the expression of DNMTs and promoted trophoblast fusion. A combined analysis of DNA methylation data and gene transcriptome data obtained from the primary cytotrophoblasts (CTBs) fusion process identified 104 potential methylation-regulated differentially expressed genes (MeDEGs) with upregulated expression due to DNA demethylation, including CD59, TNFAIP3, SDC1, and CDK6. The transcription regulation region (TRR) of TNFAIP3 showed a hypomethylation with induction of 5-aza-CdR, which facilitated CREB recruitment and thereby participated in regulating trophoblast fusion. More importantly, clinical correlation analysis of PE showed that the abnormal increase in DNMTs may be involved in the development of PE. This study identified placental DNA methylation-regulated genes that may contribute to PE, offering a novel perspective on the role of epigenetics in trophoblast fusion and its implication in PE development.

Lifestyle and medical conditions in relation to ALS risk and progression-an introduction to the Swedish ALSrisc Study.

BACKGROUND: This study was an introduction to the Swedish ALSrisc Study and explored the association of lifestyle and medical conditions, with risk and progression of amyotrophic lateral sclerosis (ALS). METHODS: We included 265 newly diagnosed ALS patients during 2016-2022 in Stockholm and 207 ALS-free siblings and partners of the patients as controls. Information on body mass index (BMI), smoking, and history of head injuries, diabetes mellitus, hypercholesterolemia, and hypertension was obtained through the Euro-MOTOR questionnaire at recruitment. Patients were followed from diagnosis until death, invasive ventilation, or November 30, 2022. RESULTS: Higher BMI at recruitment was associated with lower risk for ALS (OR 0.89, 95%CI 0.83-0.95), especially among those diagnosed after 65 years. One unit increase in the average BMI during the 3 decades before diagnosis was associated with a lower risk for ALS (OR 0.94, 95%CI 0.89-0.99). Diabetes was associated with lower risk of ALS (OR 0.38, 95%CI 0.16-0.90), while hypercholesterolemia was associated with higher risk of ALS (OR 2.10, 95%CI 1.13-3.90). Higher BMI at diagnosis was associated with lower risk of death (HR 0.91, 95%CI 0.84-0.98), while the highest level of smoking exposure (in pack-years) (HR 1.90, 95%CI 1.20-3.00), hypercholesterolemia (HR 1.84, 95%CI 1.06-3.19), and hypertension (HR 1.76, 95%CI 1.03-3.01) were associated with higher risk of death, following ALS diagnosis. CONCLUSIONS: Higher BMI and diabetes were associated with lower risk of ALS. Higher BMI was associated with lower risk of death, whereas smoking (especially in high pack-years), hypercholesterolemia, and hypertension were associated with higher risk of death after ALS diagnosis.

Testosterone supplementation increases red blood cell susceptibility to oxidative stress, decreases membrane deformability, and decreases survival after cold storage and transfusion.

BACKGROUND: Blood collection from donors on testosterone therapy (TT) is restricted to red blood cell (RBC) concentrates to avoid patient exposure to supraphysiological testosterone (T). The objective of this study was to identify TT-related changes in RBC characteristics relevant to transfusion effectiveness in patients. STUDY DESIGN: This was a two-part study with cohorts of patients and blood donors on TT. In part 1, we conducted longitudinal evaluation of RBCs collected before and at three time points after initiation of T. RBC assays included storage and oxidative hemolysis, membrane deformability (elongation index), and oximetry. In part 2, we evaluated the fate of transfused RBCs from TT donors in immunodeficient mice and by retrospective analyses of NIH's vein-to-vein databases. RESULTS: TT increased oxidative hemolysis (1.45-fold change) and decreased RBC membrane deformability. Plasma free testosterone was positively correlated with oxidative hemolysis (r = .552) and negatively correlated with the elongation index (r = -.472). Stored and gamma-irradiated RBCs from TT donors had lower posttransfusion recovery in mice compared to controls (41.6 ± 12 vs. 55.3 ± 20.5%). Recipients of RBCs from male donors taking T had 25% lower hemoglobin increments compared to recipients of RBCs from non-TT male donors, and had increased incidence (OR, 1.80) of requiring additional RBC transfusions within 48 h of the index transfusion event. CONCLUSIONS: TT is associated with altered RBC characteristics and transfusion effectiveness. These results suggest that clinical utilization of TT RBCs may be less effective in recipients who benefit from longer RBC survival, such as chronically transfused patients.

Deucravacitinib and shikonin combination therapy ameliorates imiquimod-induced psoriasis in mice.

INTRODUCTION: TYK2 inhibitors and traditional natural drugs as promising drugs for psoriasis therapy are receiving increasing attention. They both affect different molecules of JAK/STAT pathway, but it is currently unclear whether their combination will enhance the effect on psoriasis. In this study, we used imiquimod (IMQ)-induced psoriasis mouse model to investigate the therapeutic effects of the combined administration of deucravacitinib (TYK2 inhibitor) and shikonin. METHODS: Aldara cream containing 5% IMQ was used to topically treat the dorsal skin of each mouse for a total of six consecutive days to induce psoriasis. The psoriasis area and severity index (PASI) scores were recorded every day. On the 7th day, skin tissues were taken for histopathological examination and the content of cytokines in skin were evaluated. The frequency of immune cells in peripheral blood, spleen and skin were detected through flow cytometry. RESULTS: Compared to the vehicle control group, the psoriasis symptoms and immune disorder improved significantly in the combination therapy group and deucravacitinib treatment group on the 7th day, and the expressions of p-STAT3 and Ki67 in skin were reduced as well. Moreover, the combined treatment of deucravacitinib and shikonin for psoriasis was superior to the monotherapy group, especially in inhibiting abnormal capillaries proliferation, reducing immune cells infiltration and decreasing the concentration of IL-12p70 in skin. CONCLUSION: The combination of deucravacitinib and shikonin is a promising clinical application.

Application and prospect of microfluidic devices for rapid assay of cell activities in the tumor microenvironment.

The global impact of cancer on human health has raised significant concern. In this context, the tumor microenvironment (TME) plays a pivotal role in the tumorigenesis and malignant progression. In order to enhance the accuracy and efficacy of therapeutic outcomes, there is an imminent requirement for in vitro models that can accurately replicate the intricate characteristics and constituents of TME. Microfluidic devices exhibit notable advantages in investigating the progression and treatment of tumors and have the potential to become a novel methodology for evaluating immune cell activities in TME and assist clinicians in assessing the prognosis of patients. In addition, it shows great advantages compared to traditional cell experiments. Therefore, the review first outlines the applications and advantages of microfluidic chips in facilitating tumor cell culture, constructing TME and investigating immune cell activities. Second, the roles of microfluidic devices in the analysis of circulating tumor cells, tumor prognosis, and drug screening have also been mentioned. Moreover, a forward-looking perspective is discussed, anticipating the widespread clinical adoption of microfluidic devices in the future.

Phase I Study of Fianlimab, a Human Lymphocyte Activation Gene-3 (LAG-3) Monoclonal Antibody, in Combination With Cemiplimab in Advanced Melanoma.

PURPOSE: Coblockade of lymphocyte activation gene-3 (LAG-3) and PD-1 receptors could provide significant clinical benefit for patients with advanced melanoma. Fianlimab and cemiplimab are high-affinity, human, hinge-stabilized IgG4 monoclonal antibodies, targeting LAG-3 and PD-1, respectively. We report results from a first-in-human phase-I study of fianlimab and cemiplimab safety and efficacy in various malignancies including advanced melanoma. METHODS: Patients with advanced melanoma were eligible for enrollment into four cohorts: three for patients without and one for patients with previous anti-PD-1 therapy in the advanced disease setting. Patients were treated with fianlimab 1,600 mg and cemiplimab 350 mg intravenously once every 3 weeks for up to 51 weeks, with an optional additional 51 weeks if clinically indicated. The primary end point was objective response rate (ORR) per RECIST 1.1 criteria. RESULTS: ORRs were 63% for patients with anti-PD-1-naïve melanoma (cohort-6; n = 40; median follow-up 20.8 months), 63% for patients with systemic treatment-naïve melanoma (cohort-15; n = 40; 11.5 months), and 56% for patients with previous neo/adjuvant treatment melanoma (cohort-16; n = 18, 9.7 months). At a median follow-up of 12.6 months for the combined cohorts (6 + 15 + 16), the ORR was 61.2% and the median progression-free survival (mPFS) 13.3 months (95% CI, 7.5 to not estimated [NE]). In patients (n = 13) with previous anti-PD-1 adjuvant therapy, ORR was 61.5% and mPFS 12 months (95% CI, 1.4 to NE). ORR in patients with previous anti-PD-1 therapy for advanced disease (n = 15) was 13.3% and mPFS 1.5 months (95% CI, 1.3 to 7.7). Treatment-emergent and treatment-related adverse events ≥grade 3 (G3) were observed in 44% and 22% of patients, respectively. Except for increased incidence of adrenal insufficiency (12%-G1-4, 4%-G3-4), no new safety signals were recorded. CONCLUSION: The current results show a promising benefit-risk profile of fianlimab/cemiplimab combination for patients with advanced melanoma, including those with previous anti-PD-1 therapy in the adjuvant, but not advanced, setting.

Evaluating the link between immune characteristics and attention deficit hyperactivity disorder through a bi-directional Mendelian randomization study.

Context: Despite the recognition of attention deficit hyperactivity disorder (ADHD) as a multifaceted neurodevelopmental disorder, its core causes are still ambiguous. The objective of this study was to explore if the traits of circulating immune cells contribute causally to susceptibility to ADHD. Methods: By employing a unified GWAS summary data covering 731 immune traits from the GWAS Catalog (accession numbers from GCST0001391 to GCST0002121), our analysis focused on the flow cytometry of lymphocyte clusters, encompassing 3,757 Sardinians, to identify genetically expected immune cells. Furthermore, we obtained summarized GWAS statistics from the Psychiatric Genomics Consortium to evaluate the genetic forecasting of ADHD. The studies employed ADHD2019 (20,183 cases and 35,191 controls from the 2019 GWAS ADHD dataset) and ADHD2022 (38,691 cases and 275,986 controls from the 2022 GWAS ADHD dataset). Through the examination of genome-wide association signals, we identified shared genetic variances between circulating immune cells and ADHD, employing the comprehensive ADHD2022 dataset. We primarily utilized inverse variance weighted (IVW) and weighted median methods in our Mendelian randomization research and sensitivity assessments to evaluate diversity and pleiotropy. Results: After adjusting for false discovery rate (FDR), three distinct immunophenotypes were identified as associated with the risk of ADHD: CD33 in Im MDSC (OR=1.03, CI: 1.01~1.04, P=3.04×10-5, PFDR =0.015), CD8br NKT %T cell (OR=1.08, 95%CI: 1.04~1.12, P=9.33×10-5, PFDR =0.023), and CD8br NKT %lymphocyte (OR=1.08, 95%CI: 1.03~1.12, P=3.59×10-4, PFDR =0.066). Furthermore, ADHD showed no statistical effects on immunophenotypes. It's worth noting that 20 phenotypes exist where ADHD's appearance could diminish 85% of immune cells, including FSC-A in myeloid DC (ß= -0.278, 95% CI: 0.616~0.931, P=0.008), CD3 in CD45RA- CD4+ (ß= -0.233, 95% CI: 0.654~0.960, P=0.017), CD62L- monocyte AC (ß=0.227, 95% CI: 0.038~1.518, P=0.019), CD33 in CD33br HLA DR+ CD14dim (ß= -0.331, 95% CI: 0.543~0.950, P=0.020), and CD25 in CD39+ resting Treg (ß=0.226, 95% CI: 1.522, P=0.022), and FSC-A in monocytes (ß= -0.255, 95% CI: 0.621~0.967, P=0.234), among others. Conclusion: Studies indicate that the immune system's response influences the emergence of ADHD. The findings greatly improve our understanding of the interplay between immune responses and ADHD risk, aiding in the development of treatment strategies from an immunological perspective.