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Wound healing requires a delicate balance between cellular and molecular factors, all affected by reactive oxygen species (ROS). While ROS decontaminate, they also might lead to impaired wound healing, as evident in radiation-exposed skin and in venous insufficiency. Human alpha-1 antitrypsin (hAAT) is a circulating antiprotease that is anti-inflammatory and tissue-protective. Accordingly, tissue repair is enhanced in hAAT-rich conditions. hAAT undergoes oxidative modification in high-ROS environments, which alters its functional properties. While its antiprotease function is lost, the consequences of oxidation on its anti-inflammatory and tissue-protective properties are still under investigation. To explore this, excisional skin wound closure rates were first examined on irradiated skin and then tested using an iron-loading venous insufficiency model. The former was tested on hAAT transgenic mice, the latter on wild-type mice using topical clinical-grade hAAT. In-vitro, hAAT was oxidized using H 2 O 2 (0.5, 5 and 25 mM), then tested for elastase inhibition and added to an in-vitro A549 epithelial cell gap closure assay and a RAW 264.7 macrophage cell response assay. ROS levels, inflammatory responses and NRF2/ARE activation were determined. Results demonstrated wound closure was impaired in wild-type mice by both radiation and iron. In contrast, hAAT-transgenic mice exhibited accelerated wound closure in both normal and irradiated skin, and topical hAAT improved wound healing in the venous insufficiency model. hAAT OX lacked elastase inhibition across the three oxidation levels, yet highly oxidized hAAT (hAAT OX 25mM ) impaired epithelial gap closure and weakly oxidized hAAT (hAAT OX 0.5mM ) enhanced gap closure. All forms of hAAT OX elevated ROS in macrophages, as well as the expression of iNOS and catalase, IL-1β, TNFα and CXCL-1. Unexpectedly, the NRF2/ARE pathway was activated by hAAT OX 25mM and suppressed by hAAT OX 0.5mM , and hAAT OX 0.5 mM induced IL-1 receptor antagonist expression. In conclusion, oxidation levels of hAAT modify its effects on inflammation and tissue repair. While protease inhibition is lost, anti-inflammatory and repair attributes are maintained under low oxidative conditions, suggesting a molecular profile that is physiologically attuned to local signals. Considering its safety record, the study proposes that hAAT therapy is poised for trials in the context of defective tissue repair under oxidative conditions.

Impaired wound healing is a major cause of morbidity among patients with diabetes. Human α1-antitrypsin (hAAT) promotes the resolution of injured tissues. In hyperglycemic conditions, circulating hAAT is likely to undergo glycation, yet it is unknown whether its reparative properties are preserved. We hypothesized that clinical-grade hAAT treatment, but not deliberately glycated hAAT (gly-hAAT), would promote wound repair under hyperglycemic conditions. Mice were rendered hyperglycemic, excisional wounding was performed, and wounds were treated with topical albumin or hAAT every three days. The wound area was assessed, and samples were collected for histology and gene expression analysis. Gly-hAAT was generated from clinical-grade hAAT, after which in vitro RAW 264.7 macrophage responses and re-epithelialization of A549 cells were assessed. Gap closure was further assessed using sera from a human cohort (prospective samples from 10 patients with poorly controlled diabetes at Soroka University Medical Center, Beer-Sheva, Israel, 2018). Group comparisons were performed using one-way ANOVA with Tukey’s post hoc test. hAAT accelerated in vivo wound closure and in vitro A549 cell gap closure, accompanied by an anti-inflammatory IL-1Ra/IL-1β gene expression profile. In contrast, gly-hAAT inhibited normoglycemic mouse wound closure, evoked an inflammatory response in macrophages, and interfered with A549 cell gap closure; concomitant hAAT treatment improved gap closure. Similarly, patient serum inhibited A549 gap closure, and concomitant hAAT treatment improved gap closure. Importantly, inferential statistical analysis was not performed on this outcome due to the small and heterogeneous human cohort. In conclusion, hAAT accelerated wound closure in hyperglycemic mice and in A549 cells, whereas gly-hAAT promoted inflammatory responses and impaired wound closure, a trend reversed by native hAAT. These findings support the concept that glycation undermines the beneficial functions of circulating hAAT and provides a mechanistic insight into the pathophysiology of diabetic wound healing. Further studies are warranted to evaluate clinical-grade hAAT as a potential therapeutic for hyperglycemia-associated impaired wound healing.

Regulation of inflammation and re-epithelialization are critical for efficient wound healing. This study explores the role of human α1-antitrypsin (hAAT), an immunomodulatory protein, in modulating inflammation and promoting re-epithelialization across various epithelial cell types. , epithelial gap closure and migration assays were performed using two human epithelial cell lines-HaCaT and A549 cells with and without mitomycin C treatment. These cell lines were also used in an gel-directed epithelial migration assay. Cells were treated with hAAT, and the gap area was measured using image analysis. Gene expression of inflammatory markers (IL-1β, IL-6, and TNFα) and adhesion molecules (desmoglein-1, plectin, and integrin α6β4) were analyzed using qPCR. , corneal abrasions were induced in C57BL/6 mice using an Ophthalmic Burr. Mice received topical hAAT treatment immediately after injury and every 6 hours thereafter. Wound closure was assessed by applying the standard ophthalmic staining technique, fluorescein, and image analysis. Inflammatory markers and adhesion molecule expression were evaluated using qPCR and immunohistochemistry. , hAAT accelerated epithelial gap closure and increased migration distance, independent of cell proliferation. hAAT-treated cells also exhibited earlier peak expressions of IL-1β and IL-6. , hAAT treatment accelerated corneal wound closure and resulted in a preference for IL-1Ra over IL-1β expression. hAAT also enhanced the expression of desmoglein-1, plectin, and integrin α6β4, both and , and increased desmoglein-1 expression in the epithelial migration zone of mouse cornea. hAAT enhances re-epithelialization by modulating inflammation, promoting epithelial cell migration, and regulating expression of adhesion molecules.

Background: Blood stream infections are a significant cause of morbidity and mortality in burns, and pathogen identification is important for treatment. This study aims to characterize the microbiology of these infections and the association between the infecting pathogen and the hospitalization course. Methods: We conducted a cohort study that included records of burn patients treated at the Soroka University Medical Center between 2007–2020. Statistical analysis of demographic and clinical data was performed to explore relationships between burn characteristics and outcomes. Patients with positive blood cultures were divided into four groups: Gram-positive, Gram-negative, mixed-bacterial, and fungal. Results: Of the 2029 burn patients hospitalized, 11.7% had positive blood cultures. The most common pathogens were Candida and Pseudomonas. We found significant differences in ICU admission, need for surgery, and mortality between the infected and non-infected groups (p < 0.001). Pathogen groups differed significantly mean TBSA, ICU admission, need for surgery, and mortality (p < 0.001). Multivariate analysis showed flame (OR 2.84) and electric burns (OR 4.58) were independent risk factors for ICU admission and surgical intervention (p < 0.001). Gram-negative bacterial infection was found to be an independent predictor of mortality (OR = 9.29, p < 0.001). Conclusions: Anticipating specific pathogens which are associated with certain burn characteristics may help guide future therapy.

Background: With the recent developments in automated tools, smaller and cheaper machines for lung ultrasound (LUS) are leading us toward the potential to conduct POCUS tele-guidance for the early detection of pulmonary congestion. This study aims to evaluate the feasibility and accuracy of a self-lung ultrasound study conducted by hemodialysis (HD) patients to detect pulmonary congestion, with and without artificial intelligence (AI)-based automatic tools. Methods: This prospective pilot study was conducted between November 2020 and September 2021. Nineteen chronic HD patients were enrolled in the Soroka University Medical Center (SUMC) Dialysis Clinic. First, we examined the patient’s ability to obtain a self-lung US. Then, we used interrater reliability (IRR) to compare the self-detection results reported by the patients to the observation of POCUS experts and an ultrasound (US) machine with an AI-based automatic B-line counting tool. All the videos were reviewed by a specialist blinded to the performer. We examined their agreement degree using the weighted Cohen’s kappa (Kw) index. Results: A total of 19 patients were included in our analysis. We found moderate to substantial agreement between the POCUS expert review and the automatic counting both when the patient performed the LUS (Kw = 0.49 [95% CI: 0.05–0.93]) and when the researcher performed it (Kw = 0.67 [95% CI: 0.67–0.67]). Patients were able to place the probe in the correct position and present a lung image well even weeks from the teaching session, but did not show good abilities in correctly saving or counting B-lines compared to an expert or an automatic counting tool. Conclusions: Our results suggest that LUS self-monitoring for pulmonary congestion can be a reliable option if the patient’s count is combined with an AI application for the B-line count. This study provides insight into the possibility of utilizing home US devices to detect pulmonary congestion, enabling patients to have a more active role in their health care.

Anti-boycott laws are more popular and pervasive today than ever before. More than half of U.S. states have \"anti-BDS laws\" that prohibit recipients of public contracts and state investment from boycotting the State of Israel. And almost as many have proposed or passed \"anti-ESG\" rules that restrict boycotts of fossil fuels, firearms, and other contested industries in similar ways. These controversial rules have triggered a fierce debate-and nationwide litigation-over whether the First Amendment includes a \"right to boycott. \" This Article is the first to take up the question from a historical standpoint. Examining the boycott's constitutional status from before the Founding to the present era, we find that state actors have consistently treated the boycott as economic conduct subject to governmental control, and not as expression presumptively immune from state interference. Before the Founding, the colonists mandated a strict boycott of Britain, which local governmental bodies enforced through trial proceedings and economic punishments. At common law, courts used the doctrine of conspiracy to enjoin \"unjustified\" boycotts and hold liable their perpetrators. And in the modern era, state and federal officials have consistently compelled participation in the boycotts they approved, while prohibiting participation in the ones they opposed. The Article concludes that modern anti-boycott laws not only fit within, but improve upon, this constitutional tradition. As the Supreme Court's 1982 decision in NAACP v. Claiborne Hardware illustrates, the common-law approach risks violating the Pirst Amendment if applied to restrict not only the act of boycotting or refusing to deal, but also the expressive activities that accompany such politically motivated refusals. Modern anti-boycott laws minimize that problem by surgically targeting the act of boycotting while leaving regulated entities free to say whatever they please. Hence, from the standpoint of history, these laws reflect First Amendment progress, not decay.

Dysregulation of the nucleus accumbens (NAc) is implicated in numerous neuropsychiatric disorders. Treatments targeting this area directly (e.g. deep brain stimulation) demonstrate variable efficacy, perhaps owing to non-specific targeting of a functionally heterogeneous nucleus. Here we provide support for this notion, first observing disparate behavioral effects in response to direct simulation of different locations within the NAc in a human patient. These observations motivate a segmentation of the NAc into subregions, which we produce from a diffusion-tractography based analysis of 245 young, unrelated healthy subjects. We further explore the mechanism of these stimulation-induced behavioral responses by identifying the most probable subset of axons activated using a patient-specific computational model. We validate our diffusion-based segmentation using evidence from several modalities, including MRI-based measures of function and microstructure, human post-mortem immunohistochemical staining, and cross-species comparison of cortical-NAc projections that are known to be conserved. Finally, we visualize the passage of individual axon bundles through one NAc subregion in a post-mortem human sample using CLARITY 3D histology corroborated by 7T tractography. Collectively, these findings extensively characterize human NAc subregions and provide insight into their structural and functional distinctions with implications for stereotactic treatments targeting this region. •Tractography can subdivide the Human Nucleus Accumbens into 2 subregions.•Subregions closely match regions demarcated by immunohistochemistry.•Effects of electrical stimulation of the Accumbens vary by location.•Activation of Insula-NAc projections may mediate effects of stimulation.•Subregions may have asymmetric structural connectivity.