A bifunctional MoS2/SGCN nanocatalyst for the electrochemical detection and degradation of hazardous 4-nitrophenol.

Herein, we reported the dual functions of molybdenum disulfide/sulfur-doped graphitic carbon nitride (MoS2/SGCN) composite as a sensing material for electrochemical detection of 4-NP and a catalyst for 4-NP degradation. The MoS2 nanosheet, sulfur-doped graphitic carbon nitride (SGCN) and MoS2/SGCN were characterized using field emission scanning electron microscopy (FESEM), X-ray diffraction (XRD) spectroscopy and X-ray photoelectron spectroscopy (XPS). Electrochemical characterization of these materials with electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV) in 1 mM K4[Fe(CN)6]3-/4- show that the composite has the lowest charge transfer resistance and the best electrocatalytic activity. The limit of detection (LOD) and the linear range of 4-nitrophenol at MoS2/SGCN modified glassy carbon electrode (MoS2/SGCN/GCE) were computed as 12.8 nM and 0.1 - 2.6 µM, respectively. Also, the percentage recoveries of 4-NP in spiked tap water samples ranged from 97.8 - 99.1 %. The electroanalysis of 4-NP in the presence of notable interferons shows that the proposed electrochemical sensor features outstanding selectivity toward 4-NP. Additionally, the results of the catalytic degradation of 4-NP at MoS2/SGCN show that the nanocatalyst catalyzed the transformation of 4-NP to 4-aminophenol (4-AP) with a first-order rate constant (k) estimated to be 4.2 ×10-2 s-1. The results of this study confirm that the MoS2/SGCN nanocatalyst is a useful implement for electroanalytical monitoring and catalytic degradation of the hazardous 4-NP in water samples.

Combined clinical, structural, and cellular studies discriminate pathogenic and benign TRPV4 variants.

Dominant mutations in the calcium-permeable ion channel TRPV4 (transient receptor potential vanilloid 4) cause diverse and largely distinct channelopathies, including inherited forms of neuromuscular disease, skeletal dysplasias, and arthropathy. Pathogenic TRPV4 mutations cause gain of ion channel function and toxicity that can be rescued by small molecule TRPV4 antagonists in cellular and animal models, suggesting that TRPV4 antagonism could be therapeutic for patients. Numerous variants in TRPV4 have been detected with targeted and whole exome/genome sequencing, but for the vast majority, their pathogenicity remains unclear. Here, we used a combination of clinical information and experimental structure-function analyses to evaluate 30 TRPV4 variants across various functional protein domains. We report clinical features of seven patients with TRPV4 variants of unknown significance and provide extensive functional characterization of these and an additional 17 variants, including structural position, ion channel function, subcellular localization, expression level, cytotoxicity, and protein-protein interactions. We find that gain-of-function mutations within the TRPV4 intracellular ankyrin repeat domain target charged amino acid residues important for RhoA interaction, whereas ankyrin repeat domain residues outside of the RhoA interface have normal or reduced ion channel activity. We further identify a cluster of gain-of-function variants within the intracellular intrinsically disordered region that may cause toxicity via altered interactions with membrane lipids. In contrast, assessed variants in the transmembrane domain and other regions of the intrinsically disordered region do not cause gain of function and are likely benign. Clinical features associated with gain of function and cytotoxicity include congenital onset of disease, vocal cord weakness, and motor predominant disease, whereas patients with likely benign variants often demonstrated late-onset and sensory-predominant disease. These results provide a framework for assessing additional TRPV4 variants with respect to likely pathogenicity, which will yield critical information to inform patient selection for future clinical trials for TRPV4 channelopathies.

Comparative analysis of reduced toxicity conditioning regimens between fludarabine plus melphalan and fludarabine plus busulfex in adult patients with acute lymphoblastic leukemia.

Reduced-toxicity conditioning (RTC) regimens aim to mitigate regimen-related toxicity while maintaining anti-leukemic efficacy in allogeneic hematopoietic stem cell transplantation (allo-HSCT). We assessed outcomes of RTC regimens utilizing melphalan versus intravenous busulfan combined with fludarabine in adult acute lymphoblastic leukemia (ALL) patients. A retrospective analysis was conducted with 149 consecutive adult ALL patients (median age 51, range 18-60) in remission undergoing allo-HSCT. Patients received either fludarabine 150 mg/BSA plus 2 days of melphalan 70 mg/BSA (FM140, n = 76) from 2009 to 2015 or fludarabine plus 3 days of busulfan 3.2 mg/kg (FB9.6, n = 73) from 2016 to 2021. At 5 years post-HSCT, FM140 demonstrated superior disease-free survival (53.4% vs. 30.5%, p = 0.007) and lower cumulative relapse (27.4% vs. 46.8%, p = 0.026) than FB9.6. Five-year overall survival and non-relapse mortality did not significantly differ. FM140 exhibited a higher incidence of acute graft-versus-host disease (GVHD) grades II-IV (49.3% vs. 30.3%, p = 0.016), though rates of acute GVHD grades III-IV and chronic GVHD were similar. Multivariate analysis identified Philadelphia chromosome and minimal residual disease positive status, and FB9.6 conditioning as predictors of increased relapse and poorer disease-free survival. FM140 RTC regimen displayed significantly reduced relapse and superior disease-free survival compared to FB9.6 in ALL patients undergoing allo-HSCT, highlighting its current clinical utility.

Risk of Cardiovascular Events Associated with Chronic Obstructive Pulmonary Disease and/or Metabolic Syndrome: A Large-Scale Nationwide Population-Based Cohort Study.

Purpose: Chronic obstructive pulmonary disease (COPD) and metabolic syndrome (MetS) are among the most prevalent conditions that might predispose individuals to life-threatening events. We aimed to examine their associations with cardiovascular (CV) events and mortality using a large-scale population dataset from the National Health Information Database in Korea. Patients and Methods: This population-based cohort study enrolled adults aged ≥40 years who had undergone more than two health examinations between 2009 and 2011. They were divided into four groups based on the presence of COPD and MetS. Analysis of the outcomes and CV events or deaths was performed from 2014 to 2019. We compared CV event incidence and mortality rates using a multivariate Cox proportional hazards model and Kaplan-Meier curves. Results: Totally, 5,101,810 individuals were included, among whom 3,738,458 (73.3%) had neither COPD nor MetS, 1,193,014 (23.4%) had only MetS, 125,976 (2.5%) had only COPD, and 44,362 (0.9%) had both. The risk of CV events was significantly higher in individuals with both COPD and MetS than in those with either COPD or MetS alone (HRs: 2.4 vs 1.6 and 1.8, respectively; all P <0.001). Similarly, among those with both COPD and MetS, all-cause and CV mortality risks were also elevated (HRs, 2.9 and 3.0, respectively) compared to the risks in those with either COPD (HRs, 2.6 and 2.1, respectively) or MetS (HRs, 1.7 and 2.1, respectively; all P <0.001). Conclusion: The comorbidity of MetS in patients with COPD increases the incidence of CV events and all-cause and cardiovascular mortality rates.

Population pharmacokinetic modeling of sufentanil in adult Korean patients undergoing cardiopulmonary bypass surgery.

Sufentanil is frequently used as an anesthetic agent in cardiac surgery owing to its cardiovascular safety and favorable pharmacokinetics. However, the pharmacokinetics profiles of sufentanil in patients undergoing cardiopulmonary bypass (CPB) surgery remain less understood, which is crucial for achieving the desired level of anesthesia and mitigating surgical complications. Therefore, this study aimed to develop a population pharmacokinetic model of sufentanil in patients undergoing CPB surgery and elucidate the clinical factors affecting its pharmacokinetic profile. Adult patients who underwent cardiac surgery with CPB and were administered sufentanil for anesthesia were enrolled. Arterial blood samples were collected to quantify plasma concentrations of sufentanil and clinical laboratory parameters, including inflammatory cytokines. A population pharmacokinetic model was established using nonlinear mixed-effects modeling. Simulations were performed using the pharmacokinetic parameters of the final model. Overall, 20 patients were included in the final analysis. Sufentanil pharmacokinetics were modeled using a two-compartment model, accounting for CPB effects. Sufentanil clearance increased 2.80-fold during CPB and warming phases, while the central compartment volume increased 2.74-fold during CPB. CPB was a significant covariate affecting drug clearance and distribution volume. No other significant covariates were identified despite increased levels of the inflammatory cytokines, including IL-6, IL-8, and TNF-α during CPB. The simulation indicated a 30 µg loading dose and 40 µg/h maintenance infusion for target-controlled infusion. Additionally, a bolus dose of 60 µg was added at CPB initiation to adjust for exposure changes during this phase. Considering the target sufentanil concentrations, a uniform dosing regimen was acceptable for effective analgesia.

Risk of lung diseases in patients with previous carbon monoxide poisoning: a nationwide population-based cohort study in the Republic of Korea.

INTRODUCTION: Carbon monoxide poisoning is associated with severe damage to various organs. In this study, we aimed to determine if previous carbon monoxide poisoning was associated with an increased risk of lung diseases. METHODS: The study population was derived from the National Health Insurance Service database of Korea between 1 January 2002 and 31 December 2021. Adults with carbon monoxide poisoning, with at least one visit to medical facilities between 2002 and 2021, were included. For comparison, an equal number of matched controls with the same index date were selected from the database. RESULTS: A total of 28,618 patients with carbon monoxide poisoning and 28,618 matched controls were included in this study. Approximately 42.8 per cent of the patient and control groups were female, with a mean age of 51.3 years. In patients with carbon monoxide poisoning, there was a significant increase in the risk of lung cancer (adjusted hazard ratio, 1.84; 95 per cent confidence interval, 1.42-2.39; P < 0.001), chronic obstructive pulmonary disease (adjusted hazard ratio, 1.60; 95 per cent confidence interval, 1.36-1.89; P < 0.001), pulmonary tuberculosis (adjusted hazard ratio, 1.46; 95 per cent confidence interval, 1.13-1.88; P = 0.003), and non-tuberculous mycobacterial infection (adjusted hazard ratio, 1.54; 95 per cent confidence interval, 1.01-2.36; P = 0.047). DISCUSSION: In this retrospective cohort study, previous carbon monoxide poisoning was associated with an increased risk of lung cancer, chronic obstructive pulmonary disease, pulmonary tuberculosis, and non-tuberculous mycobacterial infection. Further studies are needed to confirm such an association in other populations and the risk of lung diseases due to the toxic effect of carbon monoxide from different sources. CONCLUSIONS: Previous carbon monoxide poisoning was associated with an increased risk of lung diseases, but the relative importance of the causes and sources of exposure was not known. The long-term management of survivors of acute carbon monoxide poisoning should include monitoring for lung cancer, chronic obstructive pulmonary disease, pulmonary tuberculosis, and non-tuberculous mycobacterial infection.

Monolithic DNApatite: An Elastic Apatite with Sub-Nanometer Scale Organo-Inorganic Structures.

Hydroxyapatite (HA) exhibits outstanding biocompatibility, bioactivity, osteoconductivity, and natural anti-inflammatory properties. Pure HA, ion-doped HA, and HA-polymer composites are investigated, but critical limitations such as brittleness remain; numerous efforts are being made to address them. Herein, the novel self-crystallization of a polymeric single-stranded deoxyribonucleic acid (ssDNA) without additional phosphate ions for synthesizing deoxyribonucleic apatite (DNApatite) is presented. The synthesized DNApatite, DNA1Ca2.2(PO4)1.3OH2.1, has a repetitive dual phase of inorganic HA crystals and amorphous organic ssDNA at the sub-nm scale, forming nanorods. Its mechanical properties, including toughness and elasticity, are significantly enhanced compared with those of HA nanorod, with a Young's modulus similar to that of natural bone.

Long-Term Care Insurance for Older Adults in Terms of Community Care in South Korea: Using the Framework Method.

This study aimed to analyze the long-term care insurance for older adults in South Korea in terms of community care. An analytical framework was designed for the study, focusing on comprehensiveness, adequacy, and integration. The findings suggest that Korean LTCI is significantly limited for the development of community care. First, in terms of comprehensiveness, the use of visiting nurses and the availability of short-stay services have been significantly reduced, and the supporting services for informal caregivers are at the beginning stage of their introduction. Second, in terms of adequacy, the quantity of benefits, such as three to four hours of care a day, are insufficient to meet older adults' substantial needs. Furthermore, the overall quality of home care services is low, particularly with regard to short-stay services and welfare equipment. Finally, in terms of integration, basic linkage of organizations has not been properly conducted in local areas, and there remains an absence of care managers in the LTCI system. To cope with these challenging issues, the following policy measures are suggested: the activation of rehabilitation services, the expansion of benefit quantities, the improvement of service quality, and the creation of organizational linkages through local authorities and long-term care centers.

Enhanced efficacy of glycoengineered rice cell-produced trastuzumab.

For several decades, a plant-based expression system has been proposed as an alternative platform for the production of biopharmaceuticals including therapeutic monoclonal antibodies (mAbs), but the immunogenicity concerns associated with plant-specific N-glycans attached in plant-based biopharmaceuticals has not been completely solved. To eliminate all plant-specific N-glycan structure, eight genes involved in plant-specific N-glycosylation were mutated in rice (Oryza sativa) using the CRISPR/Cas9 system. The glycoengineered cell lines, PhytoRice®, contained a predominant GnGn (G0) glycoform. The gene for codon-optimized trastuzumab (TMab) was then introduced into PhytoRice® through Agrobacterium co-cultivation. Selected cell lines were suspension cultured, and TMab secreted from cells was purified from the cultured media. The amino acid sequence of the TMab produced by PhytoRice® (P-TMab) was identical to that of TMab. The inhibitory effect of P-TMab on the proliferation of the BT-474 cancer cell line was significantly enhanced at concentrations above 1 µg/mL (****P < 0.0001). P-TMab bound to a FcγRIIIa variant, FcγRIIIa-F158, more than 2.7 times more effectively than TMab. The ADCC efficacy of P-TMab against Jurkat cells was 2.6 times higher than that of TMab in an in vitro ADCC assay. Furthermore, P-TMab demonstrated efficient tumour uptake with less liver uptake compared to TMab in a xenograft assay using the BT-474 mouse model. These results suggest that the glycoengineered PhytoRice® could be an alternative platform for mAb production compared to current CHO cells, and P-TMab has a novel and enhanced efficacy compared to TMab.

Cinnamaldehyde-Treated Bone Marrow Mesenchymal-Stem-Cell-Derived Exosomes via Aqueous Two-Phase System Attenuate IL-1ß-Induced Inflammation and Catabolism via Modulation of Proinflammatory Signaling Pathways.

Osteoarthritis (OA) is a degenerative joint disorder that is distinguished by inflammation and chronic cartilage damage. Interleukin-1ß (IL-1ß) is a proinflammatory cytokine that plays an important role in the catabolic processes that underlie the pathogenesis of OA. In this study, we investigate the therapeutic efficacy of exosomes derived from untreated bone-marrow-derived mesenchymal stem cells (BMMSC-Exo) and those treated with cinnamaldehyde (BMMSC-CA-Exo) for preventing the in vitro catabolic effects of IL-1ß on chondrocytes. We stimulated chondrocytes with IL-1ß to mimic the inflammatory microenvironment of OA. We then treated these chondrocytes with BMMSC-Exo and BMMSC-CA-Exo isolated via an aqueous two-phase system and evaluated their effects on the key cellular processes using molecular techniques. Our findings revealed that treatment with BMMSC-Exo reduces the catabolic effects of IL-1ß on chondrocytes and alleviates inflammation. However, further studies directly comparing treatments with BMMSC-Exo and BMMSC-CA-Exo are needed to determine if CA preconditioning can provide additional anti-inflammatory benefits to the exosomes beyond those of CA preconditioning or treatment with regular BMMSC-Exo. Through a comprehensive molecular analysis, we elucidated the regulatory mechanisms underlying this protective effect. We found a significant downregulation of proinflammatory signaling pathways in exosome-infected chondrocytes, suggesting the potential modulation of the NF-κB and MAPK signaling cascades. Furthermore, our study identified the molecular cargo of BMMSC-Exo and BMMSC-CA-Exo, determining the key molecules, such as anti-inflammatory cytokines and cartilage-associated factors, that may contribute to their acquisition of chondroprotective properties. In summary, BMMSC-Exo and BMMSC-CA-Exo exhibit the potential as therapeutic agents for OA by antagonizing the in vitro catabolic effects of IL-1ß on chondrocytes. The regulation of the proinflammatory signaling pathways and bioactive molecules delivered by the exosomes suggests a multifaceted mechanism of action. These findings highlight the need for further investigation into exosome-based therapies for OA and joint-related diseases.

A clinical application for arterial coupling and histomorphometric comparison of internal mammary and thoracodorsal arteries for safe use.

BACKGROUND: In breast reconstruction, arterial coupling has been reported to be more favorable in the thoracodorsal artery (TDA) than the internal mammary artery (IMA). This technique may help overcome anastomosis in a small, deep space. Understanding the arteries' mechanical properties is crucial for breast reconstruction's safety and success. METHODS: Abdominal-based free flap breast reconstructions performed by a single surgeon between 2020 and 2022 were retrospectively analyzed. The patients were classified by microanastomosis technique (handsewn and coupler device) to compare the rate of vascular revision. Histomorphometric analysis of arterial coupling in TDA and IMA was performed in 10 fresh cadavers for comparing wall thickness and composition, including densities of elastic fiber, smooth muscle, and collagen. RESULTS: A total of 309 patients (339 reconstructed breasts) were included. There were 29 patients in the TDA handsewn group (A), 38 patients in the TDA coupler group (B), and 242 patients in the IMA handsewn group (C). The rates of arterial revision in groups A, B, and C were 0.00% (95%CI: 0.00%-11.03%), 2.5% (95%CI: 0.44%-12.88%), and 1.49% (95%CI: 0.58%-3.77%), respectively, with no statistically significant differences (p-value = .694). Histologically, the thickness of the tunica media and adventitia between IMA and TDA showed no significant difference. The density of elastic fiber was significantly higher in IMA (16.70%) than in TDA (0.79%) (p-value <.001). CONCLUSION: The histologic characteristics of TDA are more favorable for arterial coupling than those of IMA. Arterial coupling is a safe option in situations where TDA anastomosis must be performed through a narrow and deep incision.

Metabolic regulation of preimplantation embryo development in vivo and in vitro: Molecular mechanisms and insights.

Understanding of embryonic development has led to the clinical application of Assisted Reproductive technologies (ART), with the resulting birth of millions of children. Recent developments in metabolomics, proteomics, and transcriptomics have brought to light new insights into embryonic growth dynamics, with implications spanning reproductive medicine, stem cell research, and regenerative medicine. The review explores the key metabolic processes and molecular pathways active during preimplantation embryo development, including PI3K-Akt, mTOR, AMPK, Wnt/ß-catenin, TGF-ß, Notch and Jak-Stat signaling pathways. We focused on analyzing the differences occurring in vitro as opposed to in vivo development and we discussed significant physiological and clinical implications.

Aortic valve replacement through right anterior mini-thoracotomy in patients with chronic severe aortic regurgitation: a retrospective single-center study.

Background: Aortic valve replacement (AVR) has recently been performed at many centers using a minimally invasive approach to reduce postoperative mortality, morbidity, and pain. Most previous reports on minimally invasive AVR (MiAVR) have mainly focused on aortic stenosis, and those exclusively dealing with aortic regurgitation (AR) are few. The purpose of this study was to investigate early surgical results and review our experience with patients with chronic severe AR who underwent AVR via right anterior mini-thoracotomy (RAT). Methods: Data were retrospectively collected in this single-center study. Eight patients who underwent RAT AVR between January 2020 and January 2024 were enrolled. Short-term outcomes, including the length of hospital stay, in-hospital mortality, postoperative complications, and echocardiographic data, were analyzed. Results: No in-hospital mortalities were observed. Postoperative atrial fibrillation occurred temporarily in three patients (37.5%). However, none required permanent pacemaker implantation or renal replacement therapy. The median values of ventilator time, length of intensive care unit stay, and hospital stay were 17 hours, 34.5 hours, and 9 days, respectively. Preoperative and postoperative measurements of left ventricular ejection fraction were similar. However, the left ventricular end systolic and diastolic diameters significantly decreased postoperatively from 42 mm to 35.5 mm (p=0.018) and 63 mm to 51 mm (p=0.012), respectively. Conclusion: MiAVR via RAT is a safe and reproducible procedure with acceptable morbidity and complication rates in patients with chronic severe AR. Despite some limitations such as a narrow surgical field and demanding learning curve, MiAVR is a competent method for AR.

Impact of an antimicrobial stewardship programme on antibiotic utilization and resistance burden in patients with acute leukaemia: an 11-year longitudinal cohort study using interrupted time-series analysis.

BACKGROUND: Antimicrobial resistance (AMR), driven by inappropriate and overuse of antibiotics, poses a significant threat, especially to patients with acute leukaemia. OBJECTIVES: To evaluate the impact of antimicrobial stewardship programmes (ASPs) on antibiotic use and analyse temporal changes in bloodstream infections (BSI) caused by AMR organisms. METHODS: We performed a retrospective, interventional, longitudinal cohort study spanning an 11-year period. ASPs included optimizing antibiotic use, enhancing tracking and reporting systems and delineating leadership and accountability. A segmented regression model of interrupted time series was used to evaluate the trend of antibiotic consumption and BSI with AMR organisms after the interventions. RESULTS: A total of 3296 BSI episodes with 454 419 days of therapy (DOT) from 7754 patients were obtained. ASPs were significantly associated with an immediate reduction [-70.03 DOT/1000 patient-days (PD), P = 0.036] and a decreasing trend (-11.65 DOT/1000 PD per quarter, P < 0.001) in overall antibiotic use. The increasing incidence of BSI with AMR before ASP intervention was notably curbed and revealed a decreasing trend (slope change: -0.06 BSI/1000 PD per quarter, P = 0.002). The decreasing trend was more significant for Enterobacterales: ciprofloxacin-resistant and ESBL-producing isolates showed a slope change of -0.06 BSI/1000 PD and -0.08 BSI/1000 PD per quarter, respectively (all P < 0.05). However, Pseudomonas aeruginosa BSI increased. CONCLUSIONS: Multidimensional ASPs effectively reduced both the immediate and trends in overall antibiotic usage even in patients with acute leukaemia. Additionally, there was a notable decrease in the incidence of BSI caused by AMR organisms, particularly among Enterobacterales.

Treatment of chronic mini-thoracotomy wound pain and lung herniation with intercostal cryoablation and surgical mesh repair: a case report.

BACKGROUND: The incidence of minimally invasive heart surgery via mini-thoracotomy (MT; right anterior thoracotomy) is on the rise, accompanied by an increase in post-MT intercostal nerve neuralgia and the risk of lung herniation through the incision site. While various methods have been proposed to address these issues, none have been commonly effective. In this case report, we attempted to simultaneously address these problems by performing intercostal cryoablation (IC) and mesh repair. CASE PRESENTATION: A 43-year-old male was referred to our hospital for chronic post-thoracotomy neuralgia following heart surgery via MT, involving patch closure of an atrial septal defect and tricuspid annuloplasty. He presented with intercostal nerve neuralgia and lung herniation accompanied by severe pain. Despite medication and lidocaine injections, there was no relief. Consequently, he underwent surgical treatment with IC for chronic MT wound pain and simultaneously underwent mesh repair for a lung hernia. He was discharged from hospital free of complications. Subsequently, he no longer required further pain medication and experienced a favorable recovery. CONCLUSION: Our findings suggest that concurrent IC and mesh repair can effectively relieve chronic post-MT intercostal nerve neuralgia and severe lung herniation pain in patients who underwent MT surgery, leading to a decrease in opioid medication usage.

Ultrasonographic evaluation of nail matrix topography for preservative nail surgery of nail unit melanoma.

Recently, functional or preservative surgery has been preferred for nail unit melanoma; however, complete resection of the nail unit, particularly the matrix, is challenging because of its complex structure. This study aims to measure the distance of important nail structures through ultrasonography. Herein, 14 patients without nail deformity were included. The length from the nail cuticle to the distal interphalangeal joint (distance X), to the attachment part of the extensor muscle (distance A), to the median proximal end of the nail matrix (distance B), and to the lateral proximal end of the nail matrix (distance C) were measured. In the axial plane, the length from the highest point of the nail plate to the bottom of the distal phalanx (distance Y) and to the lateral tip of the nail plate (distance D) were measured. On the first fingernail, third fingernail, first toenail, and third toenail, the mean ratio A:X, ratio B:X, ratio C:X, and ratio D:Y were 78.6%, 44.3%, 57.2%, 40.1%, and 84.6%; 55.9%, 64.9%, 40.2%, and 66.4%; 35.6%, 50.8%, 34.3%, and 81.9%; and 57.2%, 59.6%, and 31.7%, respectively. Nail units are often invisible to the naked eye; thus, this study will help identify the approximate scope of excision.

Development of a natural product optimization strategy for inhibitors against MraY, a promising antibacterial target.

MraY (phospho-N-acetylmuramoyl-pentapeptide-transferase) inhibitory natural products are attractive molecules as candidates for a new class of antibacterial agents to combat antimicrobial-resistant bacteria. Structural optimization of these natural products is required to improve their drug-like properties for therapeutic use. However, chemical modifications of these natural products are painstaking tasks due to complex synthetic processes, which is a bottleneck in advancing natural products to the clinic. Here, we develop a strategy for a comprehensive in situ evaluation of the build-up library, which enables us to streamline the preparation of the analogue library and directly assess its biological activities. We apply this approach to a series of MraY inhibitory natural products. Through construction and evaluation of the 686-compound library, we identify promising analogues that exhibit potent and broad-spectrum antibacterial activity against highly drug-resistant strains in vitro as well as in vivo in an acute thigh infection model. Structures of the MraY-analogue complexes reveal distinct interaction patterns, suggesting that these analogues represent MraY inhibitors with unique binding modes. We further demonstrate the generality of our strategy by applying it to tubulin-binding natural products to modulate their tubulin polymerization activities.

The effect of preoperative botulinum toxin a injection on traction force during hernia repair: a prospective, single-blind study, intra-patient comparison using contralateral side as a control.

PURPOSE: Ventral hernias are a common complication of laparotomy, posing challenges particularly when primary fascial closure is unattainable. Although chemical component separation using preoperative botulinum toxin A (BTX) injections has emerged as a promising adjunct, objective evidence of its efficacy remains limited. This study aimed to objectively assess the effect of preoperative BTX on traction force during ventral hernia repair. METHODS: A prospective, single-blind study was conducted on patients with midline incisional hernias following liver transplantation. BTX was administered unilaterally, and the traction force required to medially advance the anterior rectus sheath was measured intraoperatively. Pre- and post-injection CT scans were analyzed for changes in hernia size and LAW muscle measurements. Statistical analyses were performed to evaluate traction force differences between BTX-injected and uninjected sides. RESULTS: Ten patients underwent hernia repair with primary fascial closure achieved in all cases. Comparison of pre- and post-injection CT scans showed no significant changes in hernia size. LAW muscle length increased by 1.8 cm, while thickness decreased by 0.2 cm. Intraoperative traction force measurements revealed a significant reduction on the BTX-injected side compared to the uninjected side (p < 0.0001). The traction force ratio on the BTX-injected to the uninjected side averaged 57%, indicating the efficacy of BTX in reducing tension. CONCLUSION: Preoperative BTX significantly reduces traction force during ventral hernia repair, highlighting its potential as an adjunctive therapy in complex cases. While challenges remain in patient selection and outcome assessment, BTX offers a promising avenue for enhancing abdominal wall reconstruction outcomes and reducing surgical complications.

Lipedema associated with Skin Hypoperfusion and Ulceration: Soft Tissue Debulking Improving Skin Perfusion.

Lipedema is a progressive connective tissue disease with enlargement of adipose tissue, fibrosis, fluid collection, and dermal thickening. Herein, we present a case of lipedema associated with skin hypoperfusion and ulceration in which soft tissue debulking with liposuction improved patients' symptoms. A 39-year-old female presented with asymmetric progressive initially unilateral lower limb swelling with severe pain with subsequent skin ulceration. Conservative management failed to improve her condition. After excluding other causes and detailed radiologic investigation, lipedema was diagnosed with an associated impaired skin perfusion. Trial of local wound care and compression therapy failed to improve the condition. Subsequent soft tissue debulking with circumferential liposuction and ulcer debridement and immediate compression showed dramatic improvement of the symptoms and skin perfusion. The unique nature of this case sheds light on lipedema as a loose connective tissue disease. Inflammation and microangiopathies explain the associated pain with hypoperfusion and ulceration being quite atypical and in part might be related to the large buildups of matrix proteins and sodium contents leading to fragility in microvessels with frequent petechiae and hematoma and subsequent tissue ischemia. Conservative measures like compression therapy plays a significant role in disease course. Surgical debulking with liposuction was shown to be efficacious in reducing the soft tissue load with improvement in limb pain, edema, circumference, and skin perfusion that was seen in our patient. Lipedema is a frequently misdiagnosed condition with disabling features. Skin involvement in lipedema with potential hypoperfusion was shown and it requires further investigation.

The ion channel TRPA1 is a modulator of the cocaine reward circuit in the nucleus accumbens.

Drug addiction therapies commonly fail because continued drug use promotes the release of excessive and pleasurable dopamine levels. Because the connection between pleasure and drug use becomes hard-wired in the nucleus accumbens (NAc), which interfaces motivation, effective therapies need to modulate this mesolimbic reward system. Here, we report that mice with knockdown of the cation channel TRPA1 (transient receptor potential ankyrin 1) were resistant to the drug-seeking behavior and reward effects of cocaine compared to their wildtype litter mates. In our study, we demonstrate that TRPA1 inhibition in the NAc reduces cocaine activity and dopamine release, and conversely, that TRPA1 is critical for cocaine-induced synaptic strength in dopamine receptor 1-expressing medium spiny neurons. Taken together, our data support that cocaine-induced reward-related behavior and synaptic release of dopamine in the NAc are controlled by TRPA1 and suggest that TRPA1 has therapeutic potential as a target for drug misuse therapies.