Non-treated Group Research Articles

Real-World Effectiveness of Nirmatrelvir in Protecting Long COVID for Outpatient Adult Patients - A Large-Scale Observational Cohort Study from the RECOVER Initiative.

Paxlovid has been approved for use in patients who are at high risk for severe acute COVID-19 illness. Evidence regarding whether Paxlovid protects against Post-Acute Sequelae of SARS-CoV-2 infection (PASC), or Long COVID, is mixed in high-risk patients and lacking in low-risk patients. With a target trial emulation framework, we evaluated the association of Paxlovid treatment within 5 days of SARS-CoV-2 infection with incident Long COVID and hospitalization or death from any cause in the post-acute period (30-180 days after infection) using electronic health records from the Patient-Centered Clinical Research Networks (PCORnet) RECOVER repository. The study population included 497,499 SARS-CoV-2 positive patients between March 1, 2022, to February 1, 2023, and among which 165,256 were treated with Paxlovid within 5 days since infection and 307,922 were not treated with Paxlovid or other COVID-19 treatments. Compared with the non-treated group, Paxlovid treatment was associated with reduced risk of Long COVID with a Hazard Ratio (HR) of 0.88 (95% CI, 0.87 to 0.89) and absolute risk reduction of 2.99 events per 100 persons (95% CI, 2.65 to 3.32). Paxlovid treatment was associated with reduced risk of all-cause death (HR, 0.53, 95% CI 0.46 to 0.60; risk reduction 0.23 events per 100 persons, 95% CI 0.19 to 0.28) and hospitalization (HR, 0.70, 95% CI 0.68 to 0.73; risk reduction 2.37 events per 100 persons, 95% CI 2.19 to 2.56) in the post-acute phase. For those without documented risk factors, the associations (HR, 1.03, 95% CI 0.95 to 1.11; risk increase 0.80 events per 100 persons, 95% CI -0.84 to 2.45) were inconclusive. Overall, high-risk, nonhospitalized adult patients with COVID-19 who were treated with Paxlovid within 5 days of SARS-CoV-2 infection had a lower risk of Long COVID and all-cause hospitalization or death in the post-acute period. However, Long COVID risk reduction with Paxlovid was not observed in low-risk patients.

In Vitro Human Endometrial Cells and In Vivo Rat Model Studies Suggest That Ulipristal Acetate Impacts Endometrial Compatibility for Embryo Implantation

Ulipristal acetate (UPA) and levonorgestrel are used as emergency hormonal contraceptives. Although both are highly effective in preventing pregnancy, UPA shows efficacy even when taken up to 120 h after unprotected sexual intercourse. To investigate whether the mechanism of UPA's contraceptive action involves post-fertilization effects. In vitro and in vivo studies using cultured human endometrial cells and a pre-clinical rat model. Endometrial cells treated with UPA showed changes in the expression of receptivity gene markers and a significant decrease in trophoblast spheroids attached to the cultured cells. In addition, administration of UPA to female unmated rats decreased the expression of implantation-related genes in the endometrium and inhibited the number of implantation sites in the mated group compared to the non-treated group. These results support that UPA as an emergency contraceptive might have post-fertilization effects that may affect embryo implantation.

Development of PSL-Loaded PLGA Nanoparticles for the Treatment of Allergic Contact Dermatitis

Allergic contact dermatitis (ACD) can easily develop once sensitization is established by exposure to small amounts of antigen, and steroids are used for treatment. In this study, we evaluated the therapeutic efficacy of prednisolone (PSL)-loaded poly(DL-lactide-co-glycolide) (PLGA) nanoparticles (NPs) on a mouse model of contact dermatitis (CHS). Nanoparticles were prepared using a poor solvent diffusion method, and particle size distribution and mean particle size were measured using dynamic light scattering. Treatment experiments with PSL-loaded PLGA NPs were performed before and after sensitization with 1-fluoro-2,4-dinitrobenzene (DNFB), and evaluation was performed by quantifying intracutaneous IL-4 and TNF-α levels in a mouse model of CHS using ELISA. When PSL-loaded PLGA NPs were administered before sensitization, IL-4 expression was significantly decreased, and TNF-α tended to decrease in the group treated with PSL-loaded PLGA NPs compared to the non-treated group. When PSL-loaded PLGA NPs were administered after sensitization, IL-4 expression was significantly decreased in the group treated with PSL-loaded PLGA NPs compared to the non-treated group. In both cases, there were no significant differences between the PSL-loaded PLGA NP treatment group and the PSL-containing ointment group. These results suggest that, in the treatment of CHS, PSL-loaded PLGA NPs show a certain therapeutic effect when preadministration.

DIPG-13. TIM-3 TARGETED APTAMER IN COMBINATION WITH LOCO-REGIONAL RADIOTHERAPY IMPROVES SURVIVAL BY MODULATING THE IMMUNE INFILTRATION IN DIFFUSE MIDLINE GLIOMA MODELS

Abstract BACKGROUND Diffuse midline gliomas (DMG) are the most aggressive pediatric brain tumors. Their meager survival has not changed in the last decades emphasizing the urgent need for effective treatments. TIM-3 has emerged as a new target expressed in multiple immune cell types, regulating adaptive and innate immunity. In this work, we used an aptamer against TIM-3 to modify the tumor microenvironment and enhance the antitumor effect. METHODS For in vivo experiments, DMG murine cells were injected orthotopically into the pons of mice using a screw-guided system. The aptamer was administered intracranially (380pmol) on day 5 with the same system and three times intravenous (320pmol/mouse) 8-11-14 days after tumor implantation. In the radiotherapy experiments, 6Gy was given on day 7. Tumor and immune populations were analyzed by flow cytometry. RESULTS TIM-3 aptamer as monotherapy increases immune infiltration and elicits a specific immune response with a modest tendency to improve overall survival. Interestingly, we observed that radiotherapy, DMG standard of care, significantly induced TIM-3 expression in tumor and immune cells in the tumor microenvironment (TME). The combination of TIM-3 aptamer with radiotherapy increased the overall survival (3-fold), led to long-term survivors (30-50%), and generated immune memory in three different glioma models. Importantly, combination treatment significantly increases the infiltration of immune cells (3-fold) in the TME compared with the control groups. Radiotherapy and TIM-3 Apt treatment significantly increased the number and proliferative state of microglia, dendritic, NK, CD4, and CD8 T-cells. Interestingly, TIM-3 aptamer decreased the number and proliferative state of Tregs increasing the pro-inflammatory ratio of CD8: Tregs in the TME compared to non-treated groups after radiotherapy. CONCLUSIONS In conclusion, we provide evidence that combining radiotherapy with a TIM-3 aptamer increases overall survival, leads to the expansion of myeloid and T-cells in the TME, and generates immune memory in DMG models.

Tolerability and outcomes with rollout of tixagevimab-cilgavimab in patients with common variable immunodeficiency

Tixagevimab-cilgavimab is a combination of 2 mAbs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In December 2021, the Food and Drug Administration issued Emergency Use Authorization for intramuscular injection of tixagevimab-cilgavimab for prophylaxis against SARS-CoV-2 in immunocompromised patients. Shortly thereafter, our clinic distributed tixagevimab-cilgavimab to patients with common variable immunodeficiency. We sought to evaluate the effectiveness and tolerability of tixagevimab-cilgavimab in a common variable immunodeficiency clinic. A retrospective chart review from February 1, 2022, to August 1, 2022, of 47 patients with common variable immunodeficiency who were offered tixagevimab-cilgavimab was carried out. Comparative outcomes of treatment and nontreatment groups examined the occurrence of SARS-CoV-2 infection, severity of SARS-CoV-2 infection, and other non-SARS-CoV-2 infections. Seventy percent of the patients were female; mean age was 49 years. Twenty-three patients received tixagevimab-cilgavimab, and 24 did not receive prophylaxis. In the tixagevimab-cilgavimab group, all were vaccinated for SARS-CoV-2 and 22 were receiving immunoglobulin replacement. One patient was infected with SARS-CoV-2, no patients required emergency care, and 7 patients had non-SARS-CoV-2 infection. In the cohort that did not receive prophylaxis, 21 were vaccinated, and all received immunoglobulin replacement. Two patients tested positive for SARS-CoV-2, 1 patient required emergency care due to SARS-CoV-2 disease severity, and 4 patients had a non-SARS-CoV-2 infection. None of the results showed statistical significance. Although there is evidence that tixagevimab-cilgavimab can be protective against SARS-CoV-2 in immunocompromised individuals, our data suggest that this benefit may be blunted in patients with common variable immunodeficiency on immunoglobulin replacement. The additional benefit of tixagevimab-cilgavimab in immunocompromised patients already receiving replacement therapy requires further exploration.

In vitro effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on the expression of genes related to sperm motility and energy metabolism and intracytoplasmic sperm injection outcomes in obstructive azoospermic patients.

The presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and its receptor in various testicular cells and spermatozoa suggests a potential role in enhancing spermatogonial and postmeiotic cell development. Moreover, GM-CSF activates the pivotal pathways implicated in sperm motility regulation and glucose metabolism. However, the impact of GM-CSF on testicular biopsies from patients with obstructive azoospermia (OA) remains unexplored. Therefore, this study aimed to investigate the in vitro effects of GM-CSF on the expression of genes related to glucose transporters and signaling pathways, sperm motility, and viability in testicular biopsies. Following testicular sperm extraction from 20 patients diagnosed with OA, each sample was divided into two parts: the experimental samples were incubated with medium containing 2ng/ml GM-CSF at 37°C for 60min, and the control samples were incubated with medium without GM-CSF. Subsequently, the oocytes retrieved from the partner were injected with sperm from the treatment and control groups. The sperm parameters (motility and viability), the expression levels of sperm motility-related genes (PIK3R1, PIK3CA, and AKT1), and the expression levels of sperm energy metabolism-related genes (GLUT1, GLUT3, and GLUT14) were assessed. Furthermore, the fertilization and day 3 embryo development rate and embryo quality were evaluated. Compared with those in the nontreated group, the motility parameters and the mRNA expression levels of PIK3R1, AKT1, and GLUT3 in testicular sperm supplemented with GM-CSF were significantly greater (p < 0.05). However, no significant differences in the mRNA expression of PIK3CA, GLUT1, or GLUT14 were detected. According to the ICSI results, compared with the control group, the GM-CSF treatment group exhibited significantly greater fertilization rates (p = 0.027), Day 3 embryo development rate (p = 0.001), and proportions of good-quality embryos (p = 0.002). GM-CSF increased the expression of genes related to motility and the energy metabolism pathway and effectively promoted the motility of testis-extracted spermatozoa, consequently yielding positive clinical outcomes.

Dexamethasone-Induced Insulin Resistance Attenuation by Oral Sulfur-Oxidovanadium(IV) Complex Treatment in Mice.

Vanadium compounds are known to exert insulin-enhancing activity, normalize elevated blood glucose levels in diabetic subjects, and show significant activity in models of insulin resistance (IR). Faced with insulin resistance, the present work investigates the antidiabetic performance of a known oxidovanadium(IV)-based coordination compound-[VIVO(octd)]-and effects associated with glucocorticoid-induced insulin resistance in mice. The effects of [VIVO(octd)] were evaluated in a female Swiss mice model of insulin resistance induced by seven days of dexamethasone treatment in comparison with groups receiving metformin treatment. Biological assays such as hematological, TyG index, hepatic lipids, glycogen, oxidative stress in the liver, and oral glucose tolerance tests were evaluated. [VIVO(octd)] was characterized with 51V NMR, infrared spectroscopy (FTIR), electron paramagnetic resonance (EPR), electronic absorption spectroscopy, and mass spectrometry (ESI-FT-MS). The [VIVO(octd)] oral treatment (50 mg/kg) had an antioxidant effect, reducing 50% of fast blood glucose (p < 0.05) and 25% of the TyG index, which is used to estimate insulin resistance (p < 0.05), compared with the non-treated group. The oxidovanadium-sulfur compound is a promising antihyperglycemic therapeutic, including in cases aggravated by insulin resistance induced by glucocorticoid treatment.

Efficacy and Safety Evaluation of Tacrolimus-Eluting Stent in a Porcine Coronary Artery Model.

A drug-eluting stent (DES) is a highly beneficial medical device used to widen or unblock narrowed blood vessels. However, the drugs released by the implantation of DES may hinder the re-endothelialization process, increasing the risk of late thrombosis. We have developed a tacrolimus-eluting stent (TES) that as acts as a potent antiproliferative and immunosuppressive agent, enhancing endothelial regeneration. In addition, we assessed the safety and efficacy of TES through both in vitro and in vivo tests. Tacrolimus and Poly(lactic-co-glycolic acid) (PLGA) were applied to the metal stent using electrospinning equipment. The surface morphology of the stent was examined before and after coating using a scanning electron microscope (SEM) and energy dispersive X-rays (EDX). The drug release test was conducted through high-performance liquid chromatography (HPLC). Cell proliferation and migration assays were performed using smooth muscle cells (SMC). The stent was then inserted into the porcine coronary artery and monitored for a duration of 4weeks. SEM analysis confirmed that the coating surface was uniform. Furthermore, EDX analysis showed that the surface was coated with both polymer and drug components. The HPCL analysis of TCL at a wavelength of 215nm revealed that the drug was continuously released over a period of 4weeks. Smooth muscle cell migration was significantly decreased in the tacrolimus group (54.1% ± 11.90%) compared to the non-treated group (90.1% ± 4.86%). In animal experiments, the stenosis rate was significantly reduced in the TES group (29.6% ± 7.93%) compared to the bare metal stent group (41.3% ± 10.18%). Additionally, the fibrin score was found to be lower in the TES group compared to the group treated with a sirolimus-eluting stent (SES). Similar to SES, TES reduces neointimal proliferation in a porcine coronary artery model, specifically decreasing the fibrins score. Therefore, tacrolimus could be considered a promising drug for reducing restenosis and thrombosis.

Response of Tahitian Bridal Veil (Gibasis pellucida) and Small-Leaf Spiderwort (Tradescantia fluminensis) to Postemergence Herbicides under Greenhouse Conditions.

Tahitian bridal veil (Gibasis pellucida) and small-leaf spiderwort (Tradescantia fluminensis) are both invasive species in natural areas throughout Florida. However, very little is known regarding herbicide control. To provide land managers with herbicidal control options for both species, postemergence herbicides were evaluated for efficacy in a greenhouse to identify herbicide options that control both species under similar settings. Four herbicides, including triclopyr acid, triclopyr amine + 2,4-D amine, triclopyr amine, and glufosinate were applied at standard label rates and compared to a non-treated control group for efficacy. Visual control ratings were taken at 2, 4, and 8 weeks after treatment (WAT), and shoot dry weights (WAT 8) and regrowth dry weights (WAT 12) were determined. Triclopyr (acid and amine) generally provided the most consistent control of both species as evidenced by the visual control ratings and shoot dry weight data which showed reductions of 76% to 89% in shoot biomass at trial conclusion. Triclopyr + 2,4-D reduced shoot dry weights by 52% to 54% and was the least effective when considering the control of both species.

Synergistic efficacy of ultrasound and ammonium persulfate in inactivating Escherichia coli O157:H7 in buffered peptone water and orange juice

This study investigated the synergistic effects of ammonium persulfate (PS) and ultrasound (US) on the inactivation of Escherichia coli O157:H7 in buffered peptone water (BPW) and orange juice products. A comprehensive assessment of PS concentrations ranging from 1 to 300 mM, considering not only the statistical significance but also the reliability and stability of the experimental outcomes, showed that 150 mM was the optimal PS concentration for the inactivation of E. coli O157:H7. Additionally, US output intensities varying from 30 % to 60 % of the maximum US intensity were evaluated, and 50 % US amplitude was found to be the optimal US condition. A 50 % amplitude setting on the sonicator corresponds to half of its maximum displacement, approximately 60 μm, based on a maximum amplitude of 120 μm. The inactivation level of E. coli O157:H7 was significantly enhanced by the combined treatment of PS and US, compared to each treatment of PS and US alone. In the BPW, a 10-min treatment with the combination of PS and US resulted in a significant synergistic inactivation, achieving up to a log reduction of 3.86 log CFU/mL. Similarly, in orange juice products, a 5-min treatment with the combination of PS and US yielded a significant synergistic inactivation, with a reduction reaching 5.90 log CFU/mL. Although the treatment caused a significant color change in the sample, the visual differences between the treated and non-treated groups were not pronounced. Furthermore, the combined treatment in orange juice demonstrated significantly enhanced antimicrobial efficacy relative to BPW. Despite identical 5-min treatment periods, the application in orange juice resulted in a substantially higher log reduction of E. coli O157:H7, achieving 7.16 log CFU/mL at a reduced PS concentration of 30 mM, whereas the same treatment in BPW yielded only a 2.89 log CFU/mL reduction at a PS concentration of 150 mM, thereby highlighting its significantly superior antimicrobial performance in orange juice. The mechanism underlying microbial inactivation, induced by the combined treatment of PS and US, was identified as significant cell membrane damage. This damage is mediated by sulfate radicals, generated through the sono-activation of persulfate. In addition, the low pH of orange juice, measured at 3.7, is likely to have further deteriorated the E. coli O157:H7 cells compared to BPW (pH 7.2), by disrupting their cell membranes, proton gradients, and energy metabolism. These findings underscore the effectiveness of PS and US integration as a promising approach for non-thermal pasteurization in the food industry. Further research is needed to optimize treatment parameters and fully explore the practical application of this technique in large-scale food processing operations. Sensory evaluation and nutritional assessment are also necessary to address the limitations of PS.

Analysis of trends in radiofrequency ablation in a tertiary care center practice.

Radiofrequency ablation (RFA) for thyroid nodules has recently been introduced into the United States healthcare system landscape. Little is known about the process of incorporating this procedure into existing clinical practice. A retrospective chart review of a single institution was conducted to examine referral patterns and decision-making after the introduction of RFA into an endocrine surgery-focused practice. Patient demographics and thyroid-specific data were recorded. Two reviewers abstracted and coded reasons for the noncompletion of RFA. Two-sample t tests were used to compare groups; linear regression was used to assess trends and practice patterns. Chart review identified 451 patients referred for consideration of RFA from January 2020 to December 2022. Only 255 (56.5%) went on to receive the treatment. There was no significant difference in nodule volume between treated and nontreated groups (18.5 vs. 14.9 cm3, p = 0.07). Concern for malignancy on genetic testing, size (too large/too small), recommendation for Ethanol ablation, and multinodular disease without target nodules were the most common reasons for physician deferral. Of patients who declined to proceed, 46% opted to undergo surgical excision. Linear regression showed that referral numbers significantly increased with time; however, the proportion of patients receiving treatment decreased yearly, primarily because of higher rates of physician deferral. This study reflects the complex decision-making in offering minimally invasive thyroid nodule ablation. Despite a greater number of referrals over time, physician criteria became increasingly selective. Optimal candidacy in RFA is an evolving determination requiring patient and physician input to guide ideal practice patterns.

Effect of mTOR inhibitors on the mortality and safety of patients with lymphangioleiomyomatosis on the lung transplantation waitlist: A retrospective cohort study

BackgroundAlthough lung transplantation (LTx) is the last resort for patients with end-stage lymphangioleiomyomatosis (LAM), the high waitlist mortality is a source of concern in Japan. Discontinuation of mechanistic target of rapamycin (mTOR) inhibitors prior to LTx is recommended due to the incidence of severe adverse events. Therefore, we hypothesized that mTOR inhibitors may affect the mortality of patients with LAM on the LTx waitlist. MethodsWe retrospectively compared the characteristics of consecutive patients with LAM on the LTx waitlist who were and were not receiving mTOR inhibitors. ResultsTwenty-nine consecutive patients with LAM who listed our center between January 2004 and December 2021 were selected from the database and enrolled in the present study. Seventeen patients (58.6%) were receiving a mTOR inhibitor, sirolimus (treatment group). During a median listing period of 1277 days, 12 patients (41.4%) were hospitalized, six patients (20.7%) died from disease before LTx, and 15 patients underwent LTx. Among the deceased patients, four patients (66.6%) had pneumothoraces. The waitlist mortality in the treatment group was significantly lower than that in the non-treatment group (p = 0.03). Among the six patients who discontinued sirolimus in the treatment group, four patients (66.6%) were hospitalized with respiratory complications after the discontinuation of sirolimus. No mTOR inhibitor-related complications arose in the treatment group undergoing LTx (n = 7), including those on a reduced sirolimus dose. ConclusionsAdministration of an mTOR inhibitor until LTx may decrease waitlist mortality. Due to life-threatening events after discontinuing sirolimus pre-LTx, a reduced dose until LTx is permissible.

Delivery of Eicosapentaenoic acid-loaded cellulose nanocrystal alleviates liver fibrosis via modulating phospholipids and apoptotic regulators

Liver fibrosis is a chronic liver condition that can eventually lead to cirrhosis. Eicosapentaenoic acid (EPA, C20:5n-3), has shown promise in alleviating liver injury. However, its delivery to the liver can be challenging. In this study, we aimed to prepare EPA-loaded cellulose nanocrystal (CNC) with high entrapment efficiency and sustained release of EPA and tested its potential therapeutic effect on a murine Diethylnitrosamine (DEN)-induced fibrosis model. The results demonstrated that EPA, either in its free form or encapsulated, was effective in ameliorating liver fibrosis and reducing collagen deposition compared to the non-treated group. Specifically, the encapsulated form of EPA was highly effective in reducing oxidative markers such as Malondialdehyde (MDA) and Advanced Oxidation Protein Products (AOPP), as well as the fibrosis-related biomarker Alpha-Fetoprotein (AFP). Additionally, the administration of EPA to the DEN-induced fibrosis groups resulted in a significant modulation in membrane phospholipids, potentially improving membrane stability and function. Our findings reveal that EPA may be effective in reducing fibrosis development by targeting various molecular pathways. This includes reducing the expression of β-catenin, CD95, and Bcl-2 and downregulating miR-221, which is involved in fibrosis progression. This study highlights the potential of EPA-encapsulated CNC as a safe and effective approach for managing liver fibrosis.

Effectiveness of a tissue conditioner containing antifungals in a rat model of denture stomatitis.

This study investigated the effectiveness of a drug-modified tissue conditioner in an animal model of denture stomatitis. Wistar rats wore a Candida albicans-contaminated palatal device for 4 days. Next, nystatin (Nys) or chlorhexidine (Chx) were added to a tissue conditioner in their raw or β-cyclodextrin-complexed (βCD) forms at their minimum inhibitory concentrations. As controls, one group was not subjected to any procedure (NC), one group used sterile devices, one group had denture stomatitis but was not treated (DS), and another had the devices relined with the tissue conditioner without the addition of any drug (Soft). After 4 days of treatment, treatment effectiveness was assessed visually, histologically, and through CFU count, and myeloperoxidase (MPO) and N-acetylglucosaminidase (NAG) assays. Rats from the Soft, Nys, Nys:βCD, and Chx groups presented a significant decrease in the microbial load compared with the untreated group. Treatment groups showed lower MPO and NAG activity compared to the non-treated group. The addition of antifungals to a soft tissue conditioner can be a promising approach for denture stomatitis treatment.

Effect of drug therapies on self‐reported chemosensory outcomes after COVID‐19

AbstractObjectiveThe aim of this study was to assess the relative efficacy of medications used following severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection on self‐reported alterations in taste and/or smell function.MethodsSeven hundred and fourteen persons with self‐reported postcoronavirus disease 2019 (post‐COVID‐19) chemosensory disorders were personally interviewed regarding specific medications they were administered following the acute phase of the disease. The dependent measure—self‐reported total recovery of chemosensory symptoms—was subjected to stepwise logistic regression. Independent predictors included demographic and clinical variables, in addition to specific medications used to mitigate disease symptoms (i.e., systemic corticosteroids, oseltamivir, vitamin C, ibuprofen, hydroxychloroquine, azithromycin, ivermectin, nitazoxanide, anticoagulants, and zinc).ResultsThe median time between COVID‐19 symptom onset and the interviews was 81 days (interquartile range: 60–104). Of the 714 subjects, 249 (34.9%) reported total recovery of their chemosensory function; 437 (61.2%) had at least one treatment since the beginning of the disease. Women and those with more comorbidities had undergone more treatments. The recovery rates of the treated and nontreated groups did not differ significantly. Nonetheless, respondents who had used nitazoxanide tended to have a higher rate of self‐reported taste or smell recovery. Those who took oral zinc were less likely to improve.ConclusionsNo medication employed during the first months after SARS‐CoV‐2 infection had a clear positive effect on returning self‐reported smell or taste function to normal, although nitrazoxide trended in a positive direction. Oral zinc had a negative effect on the reported recovery of these senses.

Confirmed bacteriological diagnosis and cure of nonsevere gram-positive clinical mastitis cases enrolled in a randomized clinical trial based on results of on-farm culture

Our objectives were to describe the confirmed bacteriological diagnosis of mastitis pathogens cultured from cases of nonsevere clinical mastitis (CM) identified as gram-positive (GP) using on-farm culture and to compare differences in bacteriological cure (BC) based on antimicrobial (AM) therapy. Cows that developed nonsevere CM in a single quarter were enrolled in a randomized clinical trial based on microbial growth on GP selective agars. Cows were randomly assigned to receive a once-daily intramammary treatment: 3 d hetacillin (n = 69), 3 d ceftiofur (n = 69), 8 d ceftiofur (n = 70), or to a nontreated group (n = 32). Etiologies were confirmed with MALDI-TOF using frozen duplicate milk samples. The crude proportion of BC was determined using milk samples collected at 14, 21, and 28 d after enrollment for cases caused by streptococci, NAS, Streptococcus-like organisms (consisting of Enterococcus and Lactococcus; SLO), and Staphylococcus aureus. Multivariable models were used to determine the effect of AM treatment on BC cure at d 21 for a subset of cases that had complete data for all covariates (n = 88). Growth on GP agar resulted in enrollment of 240 cases with confirmed etiologies distributed as Streptococcus spp. (21.7%; n = 52), Lactococcus spp. (19.2%; n = 46), NAS (16.3%; n = 39), Staph. aureus (6.3%; n = 16), Enterococcus spp. (5.0%; n = 12), and others (10%; n = 24). Thirty-five (14.5%) duplicate milk samples collected from enrolled cows had no significant growth in the laboratory and 16 (6.7%) were contaminated. Among sampling dates, combined crude BC for cases caused by target pathogens ranged from 68% to 71%. Crude BC ranged from 58% to 73% for the small group of nontreated cases (n = 12) and 69% to 71% for the combined group of cases that received intramammary AM (n = 113). Among all groups and all follow-up dates, crude BC was least for cases caused by Staph. aureus (ranging from 33% to 43%), followed by cases caused by SLO (58%–67%), NAS (79%–80%), and Streptococcus spp. (81%–91%). The proportion of BC at 21 d (LSM ± SE) did not vary between all cases that received AM (0.77 ± 0.06) and cases in the nontreated group (0.73 ± 0.16). The odds of BC at 21 d was about 5× greater for cases that occurred in primiparous as compared with multiparous cows and decreased 1.3-fold for each 1 log unit increase in SCC before the case. While this study does not have sufficient power to detect small differences in BC among pathogen groups or treatments, our results demonstrate that CM is caused by a wide diversity of GP bacteria with varying ranges of BC. These results provide justification for inclusion of negative control groups in future studies and confirm that important characteristics such as parity and history of subclinical mastitis influence the probability of BC.

Electron Beam-Supported Fabrication of Biocompatible Silver/iota-Carrageenan for Wound Healing Application.

Silver nanoparticles (AgNPs) are a potent antibacterial agent, especially when used to treat bacteria that are multidrug resistant. However, it is challenging to eliminate the hazardous reducing agents that remain in AgNPs produced by the conventional chemical reduction process. To overcome these challenges, the presented research demonstrates the fabrication of AgNPs using iota-carrageenan (ι-carra) as a carbohydrate polymer using electron beam (EB) irradiation. Well-characterized ι-carra@AgNPs have a face-centered cubic (FCC) structure with spherical morphology and an average size of 26 nm. Herein we explored the approach for fabricating ι-carra@AgNPs that is suitable for scaling up the production of nanoparticles that exhibit excellent water stability. Further, the optimized ι-carra@AgNPs exhibited considerable antibacterial activity of 40% and 30% inhibition when tested with Gram-negative Escherichia coli ATCC 43895 and Gram-positive Staphylococcus aureus (S. aureus) (ATCC 6538), respectively, and low cytotoxicity at 10-50 μg/mL. To establish the potential biomedical application, as proof of the concept, the ι-carra@AgNPs showed significant antibiofilm activity at 20 μg/mL and also showed 95% wound healing abilities at 50 μg/mL compared to the nontreated control groups. Electron beam assisted ι-carra@AgNPs showed significant beneficial effects against specific bacterial strains and may provide a guide for the development of new antibacterial materials for wound dressing for large-scale production for biomedical applications.

Real-world efficacy of adjuvant therapy for totally resected stage I lung adenocarcinoma patients with pathological high-risk factors: propensity score analysis

BackgroundWe investigated the real-world efficacy of adjuvant therapy for stage I lung adenocarcinoma patients with pathological high-risk factors.MethodsStudy participants were enrolled from November 1, 2016 and December 31, 2020. Clinical bias was balanced by propensity score matching. Disease-free survival (DFS) outcomes were compared by Kaplan–Meier analysis. The Cox proportional hazards regression was used to identify survival-associated factors. p ≤ 0.05 was the threshold for statistical significance.ResultsA total of 454 patients, among whom 134 (29.5%) underwent adjuvant therapy, were enrolled in this study. One hundred and eighteen of the patients who underwent adjuvant therapy were well matched with non-treatment patients. Prognostic outcomes of the treatment group were significantly better than those of the non-treatment group, as revealed by Kaplan-Meier analysis after PSM. Differences in prevention of recurrence or metastasis between the targeted therapy and chemotherapy groups were insignificant. Adjuvant therapy was found to be positive prognostic factors, tumor size and solid growth patterns were negative.ConclusionsAdjuvant therapy significantly improved the DFS for stage I lung adenocarcinoma patients with high-risk factors. Larger prospective clinical trials should be performed to verify our findings.

Exogenous Thyroxine Increases Cardiac AS160 Phosphorylation in Insulin Resistant OLETF Rats

Thyroxine (T4) is the most abundant thyroid hormone secreted by thyroid gland and contributes to glucose metabolism via both insulin and non-insulin dependent pathways. Akt substrate 160 (AS160) is a Rab-GDP activating protein and a downstream effector of protein kinase B (Akt) required for glucose transport and upregulation of GLUT4 activating vesicle (GSV). The phosphorylation of AS160 (p-AS160) is required for the regulation of GLUT4 translocation to the membrane. It is also involved in insulin-mediated traffcking of GLUT4 in skeletal muscle and adipose tissues. The accumulation of AS160 has also been implicated in promoting cardiac hypertrophy, which is commonly associated with the metabolic syndrome (MetS). This study explores how thyroid hormones can affect the phosphorylation status of cardiac AS160 during insulin resistance. Under normal conditions, AS160 is phosphorylated by Akt to upregulate GSV, allowing glucose to cross the cell membrane through GLUT4. We hypothesize that exogenous T4 increases cardiac phosphorylation of AS160 expression during insulin resistance. Insulin resistant, Otsuka Long Evans Tokushima Fatty (OLETF) rats were used to assess the effects of exogenous thyroxine (T4) on cardiac p-AS160. Rats were assigned to four groups: (1) lean, Long Evans Tokushima Otsuka (LETO; n=6), (2) LETO + T4 (8 μg/100g BM/d × 5 wks; n=7), (3) untreated OLETF (n=6), and (4) OLETF + T4 (n=7). Exogenous T4 did not significantly alter native AS160 protein expression among all four groups. However, p-AS160 was reduced in the non-treated OLETF group by 61% (p&lt;0.01) compared to healthy LETO control group. Exogenous T4 increased p-AS160 by 16% (p&lt;0.05) compared to non-treated OLETF group and by 36% (p&lt;0.05) in treated LETO compared to control LETO group. We have previously demonstrated that exogenous T4 increased the translocation of cardiac GLUT4 and the present findings suggest that this increased translocation is mediated by activation of AS160, resulting in improved glucose metabolism in the heart during insulin resistance. American Heart Association. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Lacticaseibacillus rhamnosus TOM 22.8 (DSM 33500) is an effective strategy for managing vaginal dysbiosis, rising the lactobacilli population.

The present study is a single-centre, randomized, controlled clinical trial aimed to evaluate the effectiveness of the probiotic Lacticaseibacillus rhamnosus TOM 22.8 (DSM 33500) strain, orally administrated, to treat vaginal dysbiosis. Overall, 80 women, with signs and symptoms of vaginal dysbiosis, were enrolled and allocated to the treatment group (A, n=60), who took 1 capsule of the probiotic strain for 10 consecutive days, or the non-treatment group (B, n=20), who did not receive any treatment. Clinical (vaginal signs and symptoms; pH of the vaginal fluid; Amsel criteria; Nugent score; Lactobacillary grade) and microbiological examinations were performed at baseline (T0), 10 days (T1), and 30 (T2) days after the oral administration of the probiotic TOM 22.8 strain. The latter resulted in a restoration of the physiological pH, accompanied by remission or attenuation of clinical signs and symptoms as well as the improvement of the quality of life (QoL). Microbiological data revealed a significant reduction of potentially pathogenic bacteria. The administration of the L. rhamnosus TOM 22.8 probiotic strain could be proposed as an effective strategy for the treatment of vaginal dysbiosis.