Dopaminergic REST/NRSF is protective against manganese-induced neurotoxicity in mice.

Chronic exposure to elevated levels of manganese (Mn) may cause a neurological disorder referred to as manganism. The transcription factor REST is dysregulated in several neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. REST upregulated tyrosine hydroxylase and induced protection against Mn toxicity in neuronal cultures. In the present study, we investigated if dopaminergic REST plays a critical role in protecting against Mn-induced toxicity in vivo using dopaminergic REST conditional knockout (REST-cKO) mice and REST loxP mice as wild-type (WT) controls. Restoration of REST in the substantia nigra (SN) with neuronal REST AAV vector infusion was performed to further support the role of REST in Mn toxicity. Mice were exposed to Mn (330 µg, intranasal, daily for 3 weeks), followed by behavioral tests and molecular biology experiments. Results showed that Mn decreased REST mRNA/protein levels in the SN-containing midbrain, as well as locomotor activity and motor coordination in WT mice, which were further decreased in REST-cKO mice. Mn-induced mitochondrial insults, such as impairment of fission/fusion and mitophagy, apoptosis, and oxidative stress, in the midbrain of WT mice were more pronounced in REST-cKO mice. However, REST restoration in the SN of REST-cKO mice attenuated Mn-induced neurotoxicity. REST's molecular target for its protection is unclear, but REST attenuated Mn-induced mitochondrial dysregulation, indicating that it is a primary intracellular target for both Mn and REST. These novel findings suggest that dopaminergic REST in the nigrostriatal pathway is critical in protecting against Mn toxicity, underscoring REST as a potential therapeutic target for treating manganism.

Epigenetic Mechanisms of Aluminum-Induced Neurotoxicity and Alzheimer's Disease: A Focus on Non-Coding RNAs.

Aluminum (Al) is known to induce neurotoxic effects, potentially contributing to Alzheimer's disease (AD) pathogenesis. Recent studies suggest that epigenetic modification may contribute to Al neurotoxicity, although the mechanisms are still debatable. Therefore, the objective of the present study was to summarize existing data on the involvement of epigenetic mechanisms in Al-induced neurotoxicity, especially AD-type pathology. Existing data demonstrate that Al exposure induces disruption in DNA methylation, histone modifications, and non-coding RNA expression in brains. Alterations in DNA methylation following Al exposure were shown to be mediated by changes in expression and activity of DNA methyltransferases (DNMTs) and ten-eleven translocation proteins (TETs). Al exposure was shown to reduce histone acetylation by up-regulating expression of histone deacetylases (HDACs) and impair histone methylation, ultimately contributing to down-regulation of brain-derived neurotrophic factor (BDNF) expression and activation of nuclear factor κB (NF-κB) signaling. Neurotoxic effects of Al exposure were also associated with aberrant expression of non-coding RNAs, especially microRNAs (miR). Al-induced patterns of miR expression were involved in development of AD-type pathology by increasing amyloid ß (Aß) production through up-regulation of Aß precursor protein (APP) and ß secretase (BACE1) expression (down-regulation of miR-29a/b, miR-101, miR-124, and Let-7c expression), increasing in neuroinflammation through NF-κB signaling (up-regulation of miR-9, miR-125b, miR-128, and 146a), as well as modulating other signaling pathways. Furthermore, reduced global DNA methylation, altered histone modification, and aberrant miRNA expression were associated with cognitive decline in Al-exposed subjects. However, further studies are required to evaluate the contribution of epigenetic mechanisms to Al-induced neurotoxicity and/or AD development.

The Impact of Real-Time Documentation of In-Hospital Medication Changes on Preventing Undocumented Discrepancies at Discharge and Improving Physician-Pharmacist Communication: A Retrospective Cohort Study and Survey.

Background: Transitional medication safety is crucial, as miscommunication about medication changes can lead to significant risks. Unclear or incomplete documentation during care transitions can result in outdated or incorrect medication lists at discharge, potentially causing medication errors, adverse drug events, and inadequate patient education. These issues are exacerbated by extended hospital stays and multiple care events, making accurate medication recall challenging at discharge. Objective: Thus, we aimed to investigate how real-time documentation of in-hospital medication changes prevents undocumented medication changes at discharge and improves physician-pharmacist communication. Methods: We conducted a retrospective cohort study in a tertiary hospital. Two pharmacists reviewed medical records of patients admitted to the acute medical unit from April to June 2020. In-hospital medication discrepancies were determined by comparing preadmission and hospitalization medication lists and it was verified whether the physician's intent of medication changes was clarified by documentation. By a documentation rate of medication changes of 100% and <100%, respectively, fully documented (FD) and partially documented (PD) groups were defined. Any undocumented medication changes at discharge were considered a "documentation error at discharge". Pharmacists' survey was conducted to assess the impact of appropriate documentation on the pharmacists. Results: After reviewing 400 medication records, patients were categorized into FD (61.3%) and PD (38.8%) groups. Documentation errors at discharge were significantly higher in the PD than in the FD group. Factors associated with documentation errors at discharge included belonging to the PD group, discharge from a non-hospitalist-managed ward, and having three or more intentional discrepancies. Pharmacists showed favorable attitudes towards physician's documentation. Conclusion: Appropriate documentation of in-hospital medication changes, facilitated by free-text communication, significantly decreased documentation errors at discharge. This analysis underlines the importance of communication between pharmacists and hospitalists in improving patient safety during transitions of care.

During transitions of care, communication failures among healthcare professionals can lead to medication errors. Therefore, effective sharing of information is essential, especially when intentional changes in prescription orders are made. Documenting medication changes facilitates real-time communication, potentially improving medication reconciliation and reducing discrepancies. However, inadequate documentation of medication changes is common in clinical practice. This retrospective cohort study underlines the importance of real-time documentation of in-hospital medication changes. There was a significant reduction in documentation errors at discharge in fully documented group, where real-time documentation of medication changes was more prevalent. Pharmacists showed favorable attitudes toward the physician's real-time documenting of medication changes because it provided valuable information on understanding the physician's intent and improving communication and also saved time for pharmacists. This study concludes that physicians' documentation on medication changes may reduce documentation errors at discharge, meaning that proper documentation of medication changes could enhance patient safety through effective communication.

Intermittent Fasting Attenuates Obesity-Induced Triple-Negative Breast Cancer Progression by Disrupting Cell Cycle, Epithelial-Mesenchymal Transition, Immune Contexture, and Proinflammatory Signature.

Obesity is associated with one-fifth of cancer deaths, and breast cancer is one of the obesity-related cancers. Triple-negative breast cancer (TNBC) lacks estrogen and progesterone receptors and human epidermal growth factor receptor 2, leading to the absence of these therapeutic targets, followed by poor overall survival. We investigated if obesity could hasten TNBC progression and intermittent fasting (IF) could attenuate the progression of obesity-related TNBC. Our meta-analysis of the TNBC outcomes literature showed that obesity led to poorer overall survival in TNBC patients. Fasting-mimicking media reduced cell proliferation disrupted the cell cycle, and decreased cell migration and invasion. IF decreased body weight in obese mice but no change in normal mice. Obese mice exhibited elevated plasma glucose and cholesterol levels, increased tumor volume and weight, and enhanced macrophage accumulation in tumors. The obesity-exacerbated TNBC progression was attenuated after IF, which decreased cyclin B1 and vimentin levels and reduced the proinflammatory signature in the obesity-associated tumor microenvironment. IF attenuated obesity-induced TNBC progression through reduced obesity and tumor burdens in cell and animal experiments, supporting the potential of a cost-effective adjuvant IF therapy for TNBC through lifestyle change. Further evidence is needed of these IF benefits in TNBC, including from human clinical trials.

Microglial Sp1 induced LRRK2 upregulation in response to manganese exposure, and 17ß-estradiol afforded protection against this manganese toxicity.

Chronic exposure to elevated levels of manganese (Mn) causes a neurological disorder referred to as manganism, presenting symptoms similar to those of Parkinson's disease (PD), yet the mechanisms by which Mn induces its neurotoxicity are not completely understood. 17ß-estradiol (E2) affords neuroprotection against Mn toxicity in various neural cell types including microglia. Our previous studies have shown that leucine-rich repeat kinase 2 (LRRK2) mediates Mn-induced inflammatory toxicity in microglia. The LRRK2 promoter sequences contain three putative binding sites of the transcription factor (TF), specificity protein 1 (Sp1), which increases LRRK2 promoter activity. In the present study, we tested if the Sp1-LRRK2 pathway plays a role in both Mn toxicity and the protection afforded by E2 against Mn toxicity in BV2 microglial cells. The results showed that Mn induced cytotoxicity, oxidative stress, and tumor necrosis factor-α production, which were attenuated by an LRRK2 inhibitor, GSK2578215A. The overexpression of Sp1 increased LRRK2 promoter activity, mRNA and protein levels, while inhibition of Sp1 with its pharmacological inhibitor, mithramycin A, attenuated the Mn-induced increases in LRRK2 expression. Furthermore, E2 attenuated the Mn-induced Sp1 expression by decreasing the expression of Sp1 via the promotion of the ubiquitin-dependent degradation pathway, which was accompanied by increased protein levels of RING finger protein 4, the E3-ligase of Sp1, Sp1 ubiquitination, and SUMOylation. Taken together, our novel findings suggest that Sp1 serves as a critical TF in Mn-induced LRRK2 expression as well as in the protection afforded by E2 against Mn toxicity through reduction of LRRK2 expression in microglia.

Retinal toxicity of heavy metals and its involvement in retinal pathology.

The objective of the present review is to discuss epidemiological evidence demonstrating the association between toxic metal (Cd, Pb, Hg, As, Sn, Ti, Tl) exposure and retinal pathology, along with the potential underlying molecular mechanisms. Epidemiological studies demonstrate that Cd, and to a lesser extent Pb exposure, are associated with age-related macular degeneration (AMD), while the existing evidence on the levels of these metals in patients with diabetic retinopathy is scarce. Epidemiological data on the association between other toxic metals and metalloids including mercury (Hg) and arsenic (As), are limited. Clinical reports and laboratory in vivo studies have shown structural alterations in different layers of retina following metal exposure. Examination of retina samples demonstrate that toxic metals can accumulate in the retina, and the rate of accumulation appears to increase with age. Experimental studies in vivo and in vitro studies in APRE-19 and D407 cells demonstrate that toxic metal exposure may cause retinal damage through oxidative stress, apoptosis, DNA damage, mitochondrial dysfunction, endoplasmic reticulum stress, impaired retinogenesis, and retinal inflammation. However, further epidemiological as well as laboratory studies are required for understanding the underlying molecular mechanisms and identifying of the potential therapeutic targets and estimation of the dose-response effects.

Correction: LRRK2 kinase plays a critical role in manganese-induced inflammation and apoptosis in microglia.

[This corrects the article DOI: 10.1371/journal.pone.0210248.].

Health-related quality of life in long-term early-stage breast cancer survivors compared to general population in Korea.

PURPOSE: This study assessed health-related quality of life (HRQoL) of long-term breast cancer (BC) survivors diagnosed at early stages and compare with cancer-free, age-matched women. METHODS: The study population included BC survivors diagnosed with ductal carcinoma in situ (DCIS) or breast cancer stages I-II, who had undergone lumpectomy/mastectomy, with time since diagnosis ranging from 9 to 16 years. Survey was conducted at two tertiary hospitals in 2020. Data for cancer-free female controls was randomly drawn from a population-based survey and age-, education-matched with 1 case: 3 controls ratio. Self-reported HRQoL was assessed using EQ-5D with five dimentions. EQ-5D utility index score was calculated. Difference in EQ-5D score was evaluated using the Tobit regression model with adjustment for other covariates. RESULTS: Of 273 survivors. 88% and 12% underwent mastectomy and lumpectomy, respectively. The mean (standard deviation, SD) age at survey was 57.3 (8.5) years old. BC survivors reported significantly more problems performing daily activities (11% vs. 5%, p < 0.001), pain/discomfort (46% vs. 23%, p < 0.001), and anxious/depressed feelings (44% vs. 8%, p < 0.001) relative to the controls. Difference in EQ-5D score between BC survivors and the general population was higher in older age groups. The overall EQ-5D score of BC survivors was statistically lower than that of the control subjects (adjusted [Formula: see text]=0.117, p < 0.001). CONCLUSION: Long-term BC survivors who survived beyond ten years post-diagnosis experience more pain, anxiety, and distress, leading to an overall poorer HRQoL. IMPLICATIONS FOR CANCER SURVIVORS: This study suggest the importance of follow-up care, particularly focusing on pain, anxiety, and distress management to enhance the HRQoL of long-term BC survivors.

Gut microbial change after administration of Lacticaseibacillus paracasei AO356 is associated with anti-obesity in a mouse model.

Introduction: The status of an impaired gut microbial community, known as dysbiosis, is associated with metabolic diseases such as obesity and insulin resistance. The use of probiotics has been considered an effective approach for the treatment and prevention of obesity and related gut microbial dysbiosis. The anti-obesity effect of Lacticaseibacillus paracasei AO356 was recently reported. However, the effect of L. paracasei AO356 on the gut microbiota has not yet been identified. This study aimed to elucidate the effect of L. paracasei AO356 on gut microbiota and ensure its safety for use as a probiotic. Methods: Oral administration of L. paracasei AO356 (107 colony-forming units [CFU]/mg per day, 5 days a week, for 10 weeks) to mice fed a high-fat diet significantly suppressed weight gain and fat mass. We investigated the composition of gut microbiota and explored its association with obesity-related markers. Results: Oral administration of L. paracasei AO356 significantly changed the gut microbiota and modified the relative abundance of Lactobacillus, Bacteroides, and Oscillospira. Bacteroides and Oscillospira were significantly related to the lipid metabolism pathway and obesity-related markers. We also confirmed the safety of L. paracasei AO356 using antibiotics resistance, hemolysis activity, bile salt hydrolase activity, lactate production, and toxicity tests following the safety assessment guidelines of the Ministry of Food and Drug Safety (MFDS). Discussion: This study demonstrated that L. paracasei AO356 is not only associated with an anti-obesity effect but also with changes in the gut microbiota and metabolic pathways related to obesity. Furthermore, the overall safety assessment seen in this study could increase the potential use of new probiotic materials with anti-obesity effects.

Effective Atomic N Doping on CeO2 Nanoparticles by Environmentally Benign Urea Thermolysis and Its Significant Effects on the Scavenging of Reactive Oxygen Radicals.

Atomic nitrogen doping on CeO2 nanoparticles (NPs) by an efficient and environmentally benign urea thermolysis approach is first studied, and its effects on the intrinsic scavenging activity of the CeO2 NPs for reactive oxygen radicals are investigated. The N-doped CeO2 (N-CeO2) NPs, characterized by X-ray photoelectron and Raman spectroscopy analyses, showed considerably high levels of N atomic doping (2.3-11.6%), accompanying with an order of magnitude increase of the lattice oxygen vacancies on the CeO2 crystal surface. The radical scavenging properties of the N-CeO2 NPs are characterized by applying Fenton's reaction with collective and quantitative kinetic analysis. The results revealed that the significant increase of surface oxygen vacancies is the leading cause for the enhancements of radical scavenging properties by the N doping of CeO2 NPs. Enriched with abundant surface oxygen vacancies, the N-CeO2 NPs prepared by urea thermolysis provided about 1.4-2.5 times greater radical scavenging properties than the pristine CeO2. The collective kinetic analysis revealed that the surface-area-normalized intrinsic radical scavenging activity of the N-CeO2 NPs is about 6- to 8-fold greater than that of the pristine CeO2 NPs. The results suggest the high effectiveness of the N doping of CeO2 by the environmentally benign urea thermolysis approach to enhance the radical scavenging activity of CeO2 NPs for extensive applications such as that in polymer electrolyte membrane fuel cells.

The role of microglial LRRK2 kinase in manganese-induced inflammatory neurotoxicity via NLRP3 inflammasome and RAB10-mediated autophagy dysfunction.

Chronic manganese (Mn) exposure can lead to manganism, a neurological disorder sharing common symptoms with Parkinson's disease (PD). Studies have shown that Mn can increase the expression and activity of leucine-rich repeat kinase 2 (LRRK2), leading to inflammation and toxicity in microglia. LRRK2 G2019S mutation also elevates LRRK2 kinase activity. Thus, we tested if Mn-increased microglial LRRK2 kinase is responsible for Mn-induced toxicity, and exacerbated by G2019S mutation, using WT and LRRK2 G2019S knock-in mice and BV2 microglia. Mn (30 mg/kg, nostril instillation, daily for 3 weeks) caused motor deficits, cognitive impairments, and dopaminergic dysfunction in WT mice, which were exacerbated in G2019S mice. Mn induced proapoptotic Bax, NLRP3 inflammasome, IL-1ß, and TNF-α in the striatum and midbrain of WT mice, and these effects were more pronounced in G2019S mice. BV2 microglia were transfected with human LRRK2 WT or G2019S, followed by Mn (250 µM) exposure to better characterize its mechanistic action. Mn increased TNF-α, IL-1ß, and NLRP3 inflammasome activation in BV2 cells expressing WT LRRK2, which was elevated further in G2019S-expressing cells, while pharmacological inhibition of LRRK2 mitigated these effects in both genotypes. Moreover, the media from Mn-treated G2019S-expressing BV2 microglia caused greater toxicity to the cath.a-differentiated (CAD) neuronal cells compared to media from microglia expressing WT. Mn-LRRK2 activated RAB10 which was exacerbated in G2019S. RAB10 played a critical role in LRRK2-mediated Mn toxicity by dysregulating the autophagy-lysosome pathway and NLRP3 inflammasome in microglia. Our novel findings suggest that microglial LRRK2 via RAB10 plays a critical role in Mn-induced neuroinflammation.

The role of microglial LRRK2 in manganese-induced inflammatory neurotoxicity via NLRP3 inflammasome and RAB10-mediated autophagy dysfunction.

Chronic exposure to manganese (Mn) can lead to manganism, a neurological disorder sharing common symptoms with Parkinson's disease (PD). Studies have shown that Mn can increase the expression and activity of leucine-rich repeat kinase 2 (LRRK2), leading to inflammation and toxicity in microglia. LRRK2 G2019S mutation also elevates LRRK2 kinase activity. Thus, we tested if Mn-increased microglial LRRK2 kinase is responsible for Mn-induced toxicity, and exacerbated by G2019S mutation, using WT and LRRK2 G2019S knock-in mice, and BV2 microglia. Mn (30 mg/kg, nostril instillation, daily for 3 weeks) caused motor deficits, cognitive impairments, and dopaminergic dysfunction in WT mice, which were exacerbated in G2019S mice. Mn induced proapoptotic Bax, NLRP3 inflammasome, IL-1ß and TNF-α in the striatum and midbrain of WT mice, and these effects were exacerbated in G2019S mice. BV2 microglia were transfected with human LRRK2 WT or G2019S, followed by Mn (250 µM) exposure to better characterize its mechanistic action. Mn increased TNF-α, IL-1ß, and NLRP3 inflammasome activation in BV2 cells expressing WT LRRK2, which was exacerbated in G2019S-expressing cells, while pharmacological inhibition of LRRK2 mitigated these effects in both genotypes. Moreover, the media from Mn-treated BV2 microglia expressing G2019S caused greater toxicity to cath.a-differentiated (CAD) neuronal cells compared to media from microglia expressing WT. Mn-LRRK2 activated RAB10, which was exacerbated in G2019S. RAB10 played a critical role in LRRK2-mediated Mn toxicity by dysregulating the autophagy-lysosome pathway, and NLRP3 inflammasome in microglia. Our novel findings suggest that microglial LRRK2 via RAB10 plays a critical role in Mn-induced neuroinflammation.

Modulation of gut microbiota by rice starch enzymatically modified using amylosucrase from Deinococcus geothermalis.

Amylosucrase can increase the amount of resistant starch (RS) in starch by transferring glucose from sucrose to amylopectin. Here, rice starch was modified using amylosucrase from Deinococcus geothermalis (DgAS). DgAS-modified rice starch (DMRS) increased the side-chain length of amylopectin and appeared in the form of B-type crystals. In vitro digestion analyses revealed that DMRS had a higher RS contents and lower digestion rate than native rice starch. When high-fat diet (HFD)-induced C57BL/6 mice were orally administered DMRS, body weight and white fat tissues of DMRS-fed HFD mice were not significantly different. However, serum leptin and glucose levels were significantly decreased and serum glucagon like peptide-1was increased in these mice. The cecal microbiome in DMRS-fed HFD mice was identified to investigate the role of DMRS in gut microbiota regulation. DMRS supplementation increased the relative abundance of Bacteroides, Faecalibaculum, and Ruminococcus in mouse gut microbiota. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-022-01238-1.

Complete genome sequence of a tentative novel capillovirus isolated from Gerbera jamesonii.

The currently named gerbera virus A (GeVA) has been shown to be a novel capillovirus with a complete genome of 6929 nucleotides (nt) (GenBank accession no. OM525829.1). GeVA was detected in Gerbera jamesonii using high-throughput RNA sequencing analysis. The GeVA genome is a single linear RNA with two open reading frames (ORF), similar to those of other capilloviruses. The larger ORF encodes a polyprotein containing four domains, while the smaller ORF encodes a movement protein. The complete genome had 41.0-54.9% nt sequence identity to other those of capilloviruses, while the polyprotein and the movement protein had 26.5-36.4% and 13.1-32.2% amino acid (aa) sequence identity, respectively. Two UUAGGU promoters for subgenomic RNA (sgRNA) transcription were also identified in this study. BLAST analysis demonstrated that the GeVA genome shared the highest sequence similarity with rubber tree capillovirus 1 (MN047299.1) (complete nucleotide sequence identity, 68.54%; polyprotein amino acid sequence identity, 44.53%). Phylogenetic analysis based on complete genome and replication protein sequences placed GeVA alongside other members of the genus Capillovirus in the family Betaflexiviridae. These data suggest that GeVA is a new member of the genus Capillovirus.

Role of Astrocytes in Parkinson's Disease Associated with Genetic Mutations and Neurotoxicants.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons and the aggregation of Lewy bodies in the basal ganglia, resulting in movement impairment referred to as parkinsonism. However, the etiology of PD is not well known, with genetic factors accounting only for 10-15% of all PD cases. The pathogenetic mechanism of PD is not completely understood, although several mechanisms, such as oxidative stress and inflammation, have been suggested. Understanding the mechanisms of PD pathogenesis is critical for developing highly efficacious therapeutics. In the PD brain, dopaminergic neurons degenerate mainly in the basal ganglia, but recently emerging evidence has shown that astrocytes also significantly contribute to dopaminergic neuronal death. In this review, we discuss the role of astrocytes in PD pathogenesis due to mutations in α-synuclein (PARK1), DJ-1 (PARK7), parkin (PARK2), leucine-rich repeat kinase 2 (LRRK2, PARK8), and PTEN-induced kinase 1 (PINK1, PARK6). We also discuss PD experimental models using neurotoxins, such as paraquat, rotenone, 6-hydroxydopamine, and MPTP/MPP+. A more precise and comprehensive understanding of astrocytes' modulatory roles in dopaminergic neurodegeneration in PD will help develop novel strategies for effective PD therapeutics.

Current Status of Outpatient Parenteral Antimicrobial Therapy in Korea: Experience of a Single University-Affiliated Acute-Care Hospital.

BACKGROUND: Systematic protocols for the management of outpatient parenteral antimicrobial therapy (OPAT) and information on the current status of a prescription of parenteral antibiotics for outpatients and referred patients are lacking in the Korea. This study aimed to describe the current status of OPAT at a tertiary care hospital in Korea. MATERIALS AND METHODS: This was a retrospective study of outpatients and referral patients who were prescribed parenteral antibiotics from July to December 2019. We reviewed the prescribed antimicrobials, indications for antimicrobial therapy, institution administering the antimicrobial injections, and pre- and post-prescription management. RESULTS: Of the 577 prescriptions assessed in this study, 399 (69.2%) and 178 (30.8%) were delivered using the referral and outpatient models, respectively. About 70% of OPATs were prescribed in the pulmonology, infectious diseases, orthopedics, gastroenterology, and hematology departments. Five antibiotics (ertapenem [26.0%], ceftriaxone [12.8%], kanamycin [11.8%], amikacin [10.1%], and cefazolin [8.5%]) accounted for 69.2% of the total OPATs. Urinary tract (27.3%), respiratory (20.8%), and intra-abdominal (15.9%) infections were the most frequent indications for OPAT. After prescription, there were 295 (73.9%) and 150 (84.3%) follow-up visits in the referral and outpatient models, respectively (P <0.05). Laboratory tests necessary for monitoring were fully performed for 274 (47.5%) prescriptions. CONCLUSION: We found that a significant number of OPATs were prescribed, follow-up visits were not performed in the case of about a quarter of prescriptions, and laboratory monitoring was not fully conducted in more than half of the cases. Therefore, it is necessary to establish an appropriate management program for OPAT. Considering the limited resources and the distribution of OPAT prescriptions, an effective strategy may be to select the frequently-used antibiotics or frequently-prescribing departments and start the program with them.

Long-term trajectory of postoperative health-related quality of life in young breast cancer patients: a 15-year follow-up study.

PURPOSE: Breast cancer (BC) patients often experience various long-term sequelae due to aggressive treatment. We analyzed and illustrated long-term trajectory during different phases of treatment and survivorship. METHODS: Data were obtained from a cohort of 298 BC patients diagnosed between 2004 and 2006 and were followed up until 2020. We measured HRQoL using EORTC QLQ-C30, QLQ-BR23, and EuroQoL-5D questionnaires and conducted eight assessments right after initial diagnosis, during treatment, post-treatment, and during survivorship phases. Linear mixed model was used to assess changes in HRQoL. Overall HRQoL measured by EQ-5D index of long-term BC survivors were further compared with that of the age-matched general population. RESULTS: Of 298 participants, 246 women survived and 124 participated in the long-term follow-up survey (LTFU). Overall, HRQoL functions deteriorated during treatment but gradually improved between 1- and 3-year post-diagnosis and stabilized over LTFU measure. Significant recovery was observed in physical, role, emotional, social functions, and future perspectives (p < 0.05). Treatment-related acute symptoms were reported in the first year but diminished afterward, and treatment-related financial difficulties lessened. At LTFU, BC survivors reported a high level of insomnia, fatigue, and pain and appeared to have poorer overall HRQoL than the general population (mean difference, EQ-5D index: 0.073, p < 0.001). CONCLUSIONS: Through 15-year survivorship, BC survivors showed improvement in many aspects of HRQoL. However, some inferior aspects remain relevant for long-term survivors. Ongoing supportive programs concentrating on pain management, persistent cancer-related fatigue, and sleeping problems might aid enhance their HRQoL.

Astrocytic Yin Yang 1 is critical for murine brain development and protection against apoptosis, oxidative stress, and inflammation.

The transcription factor Yin Yang 1 (YY1) is ubiquitously expressed in mammalian cells, regulating the expression of a variety of genes involved in proliferation, differentiation, and apoptosis in a context-dependent manner. While it is well-established that global YY1 knockout (KO) leads to embryonic death in mice and that YY1 deletion in neurons or oligodendrocytes induces impaired brain function, the role of astrocytic YY1 in the brain remains unknown. We investigated the role of astrocytic YY1 in the brain using a glial fibrillary acidic protein (GFAP)-specific YY1 conditional KO (YY1 cKO) mouse model to delete astrocytic YY1. Astrocytic YY1 cKO mice were tested for behavioral phenotypes, such as locomotor activity, coordination, and cognition, followed by an assessment of relevant biological pathways using RNA-sequencing analysis, immunoblotting, and immunohistochemistry in the cortex, midbrain, and cerebellum. YY1 cKO mice showed abnormal phenotypes, movement deficits, and cognitive dysfunction. At the molecular level, astrocytic YY1 deletion altered the expression of genes associated with proliferation and differentiation, p53/caspase apoptotic pathways, oxidative stress response, and inflammatory signaling including NF-κB, STAT, and IRF in all regions. Astrocytic YY1 deletion significantly increased the expression of GFAP as astrocytic activation and Iba1 as microglial activation, indicating astrocytic YY1 deletion activated microglia as well. Accordingly, multiple inflammatory cytokines and chemokines including TNF-α and CXCL10 were elevated. Combined, these novel findings suggest that astrocytic YY1 is a critical transcription factor for normal brain development and locomotor activity, motor coordination, and cognition. Astrocytic YY1 is also essential in preventing pathological oxidative stress, apoptosis, and inflammation.

Survival of women with pregnancy-associated breast cancer according to clinical characteristics: A propensity score matching study.

In recent years, postponing childbearing has increased the prevalence of pregnancy-associated breast cancer (PABC). PABC has a poorer prognosis than breast cancer not associated with pregnancy (non-PABC) due to delayed diagnosis and aggressive subtype. Additionally, pregnancy itself predicts a poor prognosis; but, this is a subject of debate. Thus, we analyzed the effects of known prognostic factors and pregnancy on the prognosis of PABC. We retrospectively analyzed women aged 20 to 49 years who were diagnosed with breast cancer (BC) between 1989 and 2014. Patients were distributed into PABC and non-PABC groups, and 1:4 propensity score matching was performed to adjust for baseline characteristics. Primary endpoints were overall survival (OS) and BC-specific survival (BCSS). Secondary endpoint was the difference in prognosis according to BC subtype. Of the 34,970 recruited patients with BC, 410 (1.2%) had PABC. Patients with PABC were younger and tended to have triple-negative BC (TNBC) subtype than non-PABC patients. The 1640 matched non-PABC patients showed a significantly worse mean survival rate than the unmatched non-PABC patients. Patients with PABC had a significantly worse OS and BCSS than those with non-PABC. In multivariate analyses, patients with PABC of luminal B (Ki-67 ≥14.0%) and TNBC subtypes had worse OS and BCSS than patients with non-PABC. Patients with PABC had poorer prognosis than non-PABC patients after adjusting for several prognostic factors. This difference was particularly significant in patients with the luminal B and TNBC subtypes.

Effect of Early Nutritional Support on Clinical Outcomes of Critically Ill Patients with Sepsis and Septic Shock: A Single-Center Retrospective Study.

The initial nutritional delivery policy for patients with sepsis admitted to the intensive care unit (ICU) has not been fully elucidated. We aimed to determine whether an initial adequate nutrition supply and route of nutrition delivery during the first week of sepsis onset improve clinical outcomes of critically ill patients with sepsis. We reviewed adult patients with sepsis and septic shock in the ICU in a single tertiary teaching hospital between 31 November 2013 and 20 May 2017. Poisson log-linear and Cox regressions were performed to assess the relationships between clinical outcomes and sex, modified nutrition risk in the critically ill score, sequential organ failure assessment score, route of nutrition delivery, acute physiology and chronic health evaluation score, and daily energy and protein delivery during the first week of sepsis onset. In total, 834 patients were included. Patients who had a higher protein intake during the first week of sepsis onset had a lower in-hospital mortality (adjusted hazard ratio (HR), 0.55; 95% confidence interval (CI), 0.39−0.78; p = 0.001). A higher energy intake was associated with a lower 30-day mortality (adjusted HR, 0.94; 95% CI, 0.90−0.98; p = 0.003). The route of nutrition delivery was not associated with 1-year mortality in the group which was underfed; however, in patients who met > 70% of their nutritional requirement, enteral feeding (EN) with supplemental parenteral nutrition (PN) was superior to only EN (p = 0.016) or PN (p = 0.042). In patients with sepsis and septic shock, a high daily average protein intake may lower in-hospital mortality, and a high energy intake may lower the 30-day mortality, especially in those with a high modified nutrition risk in the critically ill scores. In patients who receive adequate energy, EN with supplemental PN may be better than only EN or PN, but not in underfed patients.