Laser-responsive erastin-loaded chondroitin sulfate nanomedicine targeting CD44 and system xc- in liver cancer: A non-ferroptotic approach.

Erastin, a ferroptosis-inducing system xc- inhibitor, faces clinical challenges due to suboptimal physicochemical and pharmacokinetic properties, as well as relatively low potency and off-target toxicity. Addressing these, we developed ECINs, a novel laser-responsive erastin-loaded nanomedicine utilizing indocyanine green (ICG)-grafted chondroitin sulfate A (CSA) derivatives. Our aim was to improve erastin's tumor targeting via CSA-CD44 interactions and enhance its antitumor efficacy through ICG's photothermal and photodynamic effects in the laser-on state while minimizing off-target effects in the laser-off state. ECINs, with their nanoscale size of 186.7 ±â€¯1.1 nm and high erastin encapsulation efficiency of 93.0 ±â€¯0.8 %, showed excellent colloidal stability and sustained drug release up to 120 h. In vitro, ECINs demonstrated a mechanism of cancer cell inhibition via G1-phase cell cycle arrest, indicating a non-ferroptotic action. In vivo biodistribution studies in SK-HEP-1 xenograft mice revealed that ECINs significantly enhanced tumor distribution of erastin (1.9-fold greater than free erastin) while substantially reducing off-target accumulation in the lungs and spleen by 203-fold and 19.1-fold, respectively. Combined with laser irradiation, ECINs significantly decreased tumor size (2.6-fold, compared to free erastin; 2.4-fold, compared to ECINs without laser irradiation) with minimal systemic toxicity. This study highlights ECINs as a dual-modality approach for liver cancer treatment, demonstrating significant efficacy against tumors overexpressing CD44 and system xc-.

Mass spectrometry (MS)-based metabolomics of plasma and urine in dry eye disease (DED)-induced rat model.

Dry eye disease (DED) is an ophthalmic disease associated with poor quality and quantity of tears, and the number of patients is steadily increasing. The aim of this study was to determine plasma and urine metabolites obtained from DED scopolamine animal model where dry eye conditions (DRY) are induced. It was also of interest to examine whether DED (scopolamine) rat model was exacerbated by treatment with benzalkonium chloride (BAC). Subsequently, plasma and urine metabolites were analyzed using liquid chromatography (LC) and gas chromatography (GC)-mass spectrometry (MS), respectively. Data demonstrated that DED indicators such as tear volume, tear breakup time (TBUT), and corneal damage in the DED groups (DRY and BAC group) differed from those of control (CON). Similar results were noted in inflammatory factors such as interleukin (IL-1ß), IL-6, and tumor necrosis factor (TNF)-α. In the partial least squares-discriminant analysis (PLS-DA) score plots, the three groups were distinctly separated from each other. In addition, the related metabolites were also associated with these distinct separations as evidenced by 9 and 14 in plasma and urine, respectively. Almost all of the selected metabolites were decreased in the DRY group compared to CON, and the BAC group was lower than the DRY. In plasma and urine, lysophosphatidylcholine/lysophosphatidylethanolamine, organic acids, amino acids, and sugars varied between three groups, and these metabolites were related to inflammation and oxidative stress. Data suggest that treatment with scopolamine with/without BAC-induced DED and affected the level of systemic metabolites involved in inflammation and oxidative stress.

Central Role of Hypothalamic Circuits for Acupuncture's Anti-Parkinsonian Effects.

Despite clinical data stretching over millennia, the neurobiological basis of the effectiveness of acupuncture in treating diseases of the central nervous system has remained elusive. Here, using an established model of acupuncture treatment in Parkinson's disease (PD) model mice, we show that peripheral acupuncture stimulation activates hypothalamic melanin-concentrating hormone (MCH) neurons via nerve conduction. We further identify two separate neural pathways originating from anatomically and electrophysiologically distinct MCH neuronal subpopulations, projecting to the substantia nigra and hippocampus, respectively. Through chemogenetic manipulation specifically targeting these MCH projections, their respective roles in mediating the acupuncture-induced motor recovery and memory improvements following PD onset are demonstrated, as well as the underlying mechanisms mediating recovery from dopaminergic neurodegeneration, reactive gliosis, and impaired hippocampal synaptic plasticity. Collectively, these MCH neurons constitute not only a circuit-based explanation for the therapeutic effectiveness of traditional acupuncture, but also a potential cellular target for treating both motor and non-motor PD symptoms.

Glutaminase-1 inhibition alleviates senescence of Wharton's jelly-derived mesenchymal stem cells via senolysis.

Replicative senescence of mesenchymal stem cells (MSCs) caused by repeated cell culture undermines their potential as a cell therapy because of the reduction in their proliferation and therapeutic potential. Glutaminase-1 (GLS1) is reported to be involved in the survival of senescent cells, and inhibition of GLS1 alleviates age-related dysfunction via senescent cell removal. In the present study, we attempted to elucidate the association between MSC senescence and GLS1. We conducted in vitro and in vivo experiments to analyze the effect of GLS1 inhibition on senolysis and the therapeutic effects of MSCs. Inhibition of GLS1 in Wharton's jelly-derived MSCs (WJ-MSCs) reduced the expression of aging-related markers, such as p16, p21, and senescence-associated secretory phenotype genes, by senolysis. Replicative senescence-alleviated WJ-MSCs, which recovered after short-term treatment with bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide 3 (BPTES), showed increased proliferation and therapeutic effects compared to those observed with senescent WJ-MSCs. Moreover, compared to senescent WJ-MSCs, replicative senescence-alleviated WJ-MSCs inhibited apoptosis in serum-starved C2C12 cells, enhanced muscle formation, and hindered apoptosis and fibrosis in mdx mice. These results imply that GLS1 inhibition can ameliorate the therapeutic effects of senescent WJ-MSCs in patients with muscle diseases such as Duchenne muscular dystrophy. In conclusion, GLS1 is a key factor in modulating the senescence mechanism of MSCs, and regulation of GLS1 may enhance the therapeutic effects of senescent MSCs, thereby increasing the success rate of clinical trials involving MSCs.

Astrocytic autophagy plasticity modulates Aß clearance and cognitive function in Alzheimer's disease.

BACKGROUND: Astrocytes, one of the most resilient cells in the brain, transform into reactive astrocytes in response to toxic proteins such as amyloid beta (Aß) in Alzheimer's disease (AD). However, reactive astrocyte-mediated non-cell autonomous neuropathological mechanism is not fully understood yet. We aimed our study to find out whether Aß-induced proteotoxic stress affects the expression of autophagy genes and the modulation of autophagic flux in astrocytes, and if yes, how Aß-induced autophagy-associated genes are involved Aß clearance in astrocytes of animal model of AD. METHODS: Whole RNA sequencing (RNA-seq) was performed to detect gene expression patterns in Aß-treated human astrocytes in a time-dependent manner. To verify the role of astrocytic autophagy in an AD mouse model, we developed AAVs expressing shRNAs for MAP1LC3B/LC3B (LC3B) and Sequestosome1 (SQSTM1) based on AAV-R-CREon vector, which is a Cre recombinase-dependent gene-silencing system. Also, the effect of astrocyte-specific overexpression of LC3B on the neuropathology in AD (APP/PS1) mice was determined. Neuropathological alterations of AD mice with astrocytic autophagy dysfunction were observed by confocal microscopy and transmission electron microscope (TEM). Behavioral changes of mice were examined through novel object recognition test (NOR) and novel object place recognition test (NOPR). RESULTS: Here, we show that astrocytes, unlike neurons, undergo plastic changes in autophagic processes to remove Aß. Aß transiently induces expression of LC3B gene and turns on a prolonged transcription of SQSTM1 gene. The Aß-induced astrocytic autophagy accelerates urea cycle and putrescine degradation pathway. Pharmacological inhibition of autophagy exacerbates mitochondrial dysfunction and oxidative stress in astrocytes. Astrocyte-specific knockdown of LC3B and SQSTM1 significantly increases Aß plaque formation and GFAP-positive astrocytes in APP/PS1 mice, along with a significant reduction of neuronal marker and cognitive function. In contrast, astrocyte-specific overexpression of LC3B reduced Aß aggregates in the brain of APP/PS1 mice. An increase of LC3B and SQSTM1 protein is found in astrocytes of the hippocampus in AD patients. CONCLUSIONS: Taken together, our data indicates that Aß-induced astrocytic autophagic plasticity is an important cellular event to modulate Aß clearance and maintain cognitive function in AD mice.

Development of a Risk Prediction Model for Adverse Skin Events Associated with TNF-α Inhibitors in Rheumatoid Arthritis Patients.

Background: Rheumatoid arthritis (RA) is a chronic inflammatory disorder primarily targeting joints, significantly impacting patients' quality of life. The introduction of tumor necrosis factor-alpha (TNF-α) inhibitors has markedly improved RA management by reducing inflammation. However, these medications are associated with adverse skin reactions, which can vary greatly among patients due to genetic differences. Objectives: This study aimed to identify risk factors associated with skin adverse events by TNF-α in RA patients. Methods: A cohort study was conducted, encompassing patients with RA who were prescribed TNF-α inhibitors. This study utilized machine learning algorithms to analyze genetic data and identify markers associated with skin-related adverse events. Various machine learning algorithms were employed to predict skin and subcutaneous tissue-related outcomes, leading to the development of a risk-scoring system. Multivariable logistic regression analysis identified independent risk factors for skin and subcutaneous tissue-related complications. Results: After adjusting for covariates, individuals with the TT genotype of rs12551103, A allele carriers of rs13265933, and C allele carriers of rs73210737 exhibited approximately 20-, 14-, and 10-fold higher incidences of skin adverse events, respectively, compared to those with the C allele, GG genotype, and TT genotype. The machine learning algorithms used for risk prediction showed excellent performance. The risk of skin adverse events among patients receiving TNF-α inhibitors varied based on the risk score: 0 points, 0.6%; 2 points, 3.6%; 3 points, 8.5%; 4 points, 18.9%; 5 points, 36.7%; 6 points, 59.2%; 8 points, 90.0%; 9 points, 95.7%; and 10 points, 98.2%. Conclusions: These findings, emerging from this preliminary study, lay the groundwork for personalized intervention strategies to prevent TNF-α inhibitor-associated skin adverse events. This approach has the potential to improve patient outcomes by minimizing the risk of adverse effects while optimizing therapeutic efficacy.

ER-to-lysosome Ca2+ refilling followed by K+ efflux-coupled store-operated Ca2+ entry in inflammasome activation and metabolic inflammation.

We studied lysosomal Ca2+ in inflammasome. Lipopolysaccharide (LPS) + palmitic acid (PA) decreased lysosomal Ca2+ ([Ca2+]Lys) and increased [Ca2+]i through mitochondrial ROS, which was suppressed in Trpm2-KO macrophages. Inflammasome activation and metabolic inflammation in adipose tissue of high-fat diet (HFD)-fed mice were ameliorated by Trpm2 KO. ER→lysosome Ca2+ refilling occurred after lysosomal Ca2+ release whose blockade attenuated LPS + PA-induced inflammasome. Subsequently, store-operated Ca2+entry (SOCE) was activated whose inhibition suppressed inflammasome. SOCE was coupled with K+ efflux whose inhibition reduced ER Ca2+ content ([Ca2+]ER) and impaired [Ca2+]Lys recovery. LPS + PA activated KCa3.1 channel, a Ca2+-activated K+ channel. Inhibitors of KCa3.1 channel or Kcnn4 KO reduced [Ca2+]ER, attenuated increase of [Ca2+]i or inflammasome activation by LPS + PA, and ameliorated HFD-induced inflammasome or metabolic inflammation. Lysosomal Ca2+ release induced delayed JNK and ASC phosphorylation through CAMKII-ASK1. These results suggest a novel role of lysosomal Ca2+ release sustained by ER→lysosome Ca2+ refilling and K+ efflux through KCa3.1 channel in inflammasome activation and metabolic inflammation.

Association between uterine artery embolization for postpartum hemorrhage and second delivery on maternal and offspring outcomes: a nationwide cohort study.

STUDY QUESTION: What are the maternal and neonatal outcomes of second delivery in women who underwent uterine artery embolization (UAE) during their first delivery? SUMMARY ANSWER: Women who underwent UAE during their first delivery exhibited higher risks of placental problems, preterm births, and postpartum hemorrhage (PPH) in second delivery and the second offspring also showed increased risk of major congenital malformations, admission to the neonatal intensive care units (NICU), necrotizing enterocolitis, intraventricular hemorrhage, and bronchopulmonary dysplasia. WHAT IS KNOWN ALREADY: UAE is a minimally invasive procedure used as an alternative to hysterectomy for managing severe PPH. However, recent studies have raised concerns about potential obstetric complications, including recurrent PPH, placenta accreta spectrum (PAS), and fetal growth restriction in subsequent delivery following UAE. STUDY DESIGN SIZE DURATION: This was a nationwide retrospective cohort study using the Korean National Health Insurance Service (K-NHIS) database, covering 50 million individuals from 2004 to 2020. The cohort included 3 616 923 women with live births between 1 January 2005 and 31 December 2019 with follow-up data extending to 31 December 2020. PARTICIPANTS/MATERIALS SETTING METHODS: The study included women who had their first live birth between 2005 and 2019, excluding those who underwent hysterectomy (without UAE = 3 612 389, UAE = 4534). Among them, we selected women who had single gestation secondary delivery (without UAE = 1 694 600, UAE = 1146). Propensity score matching was used to control for confounding factors, resulting in 11 184 women without UAE and 1119 women with UAE for subsequent analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Women in the UAE group had significantly higher risks of PAS (odds ratio (OR) = 38.91, 95% CI = 18.61-81.34), placenta previa (OR = 6.98, 95% CI = 5.57-8.75), and preterm birth (OR = 2.23, 95% CI = 1.71-2.90) during their second delivery. The risk of recurrent PPH was also significantly higher (OR = 8.94, 95% CI = 7.19-11.12). Their second offspring were more likely to have major congenital malformations (OR = 1.62, 95% CI = 1.25-2.11) and adverse neonatal outcomes, including NICU admissions (OR = 1.83, 95% CI = 1.48-2.25). Long-term outcomes showed a higher risk of attention-deficit/hyperactivity disorder (hazard ratio = 1.64, 95% CI = 1.03-2.63) but were otherwise comparable to those in the without UAE group. LIMITATIONS REASONS FOR CAUTION: Retrospective nature of the study may have introduced exposure and outcome misclassifications, despite the reliability of the K-NHIS database. Unmeasured confounders and selection bias due to only including live births could also have influenced the results. WIDER IMPLICATIONS OF THE FINDINGS: Women with a history of UAE require meticulous prenatal care and close monitoring during subsequent deliveries due to increased risks of complications. Counseling and referral to high-risk medical centers may improve outcomes. Further research is needed to understand the mechanisms of complications in both mothers and offspring at sequential delivery, as well as to refine UAE procedures. STUDY FUNDING/COMPETING INTERESTS: This study supported by Patient-Centered Clinical Research Coordinating Center (PACEN) funded by the Ministry of Health & Welfare, Republic of Korea (HC21C0123). This study was funded by S.-Y.O. The authors of this manuscript declare no relationships with any companies whose products or services may be related to the subject matter of the article. TRIAL REGISTRATION NUMBER: N/A.

Improving Accuracy and Reliability of Hearing Tests: Measurement Standards for Audiometric Devices.

Pure-tone audiometry, using an audiometer, is the fundamental hearing test for diagnosing hearing loss. The requirements of the devices and the detailed process for calibrating the related equipment are described in international standards. However, traceable calibration and uncertainty evaluation processes are not widely accepted or applied to the qualification and maintenance of audiometric equipment. Here, we briefly review standard measurement systems for audiometric devices and introduce their calibration procedures. The uncertainty of each calibration process was investigated, and its impact on hearing test results was considered. Our findings show that the traceability of each procedure can be secured, satisfying the uncertainty requirement and being sufficiently smaller than the permissible deviation from the audiometer requirement. To guarantee the objectivity and reliability of hearing tests and maintain low uncertainty, close cooperation and mutual understanding between the metrology field and the medical community are necessary.

Upregulation of Neuroinflammation-Associated Genes in the Brain of SARS-CoV-2-Infected Mice.

Neurological manifestations are a significant complication of coronavirus disease 2019 (COVID-19), but the underlying mechanisms are yet to be understood. Recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced neuroinvasion and encephalitis were observed in K18-hACE2 mice, leading to mortality. Our goal in this study was to gain insights into the molecular pathogenesis of neurological manifestations in this mouse model. To analyze differentially expressed genes (DEGs) in the brains of mice following SARS-CoV-2 infection, we performed NanoString gene expression analysis using three individual animal samples at 1, 3, and 6 days post-infection. We identified the DEGs by comparing them to animals that were not infected with the virus. We found that genes upregulated at day 6 post-infection were mainly associated with Toll-like receptor (TLR) signaling, RIG-I-like receptor (RLR) signaling, and cell death pathways. However, downregulated genes were associated with neurodegeneration and synaptic signaling pathways. In correlation with gene expression profiles, a multiplexed immunoassay showed the upregulation of multiple cytokines and chemokines involved in inflammation and cell death in SARS-CoV-2-infected brains. Furthermore, the pathway analysis of DEGs indicated a possible link between TLR2-mediated signaling pathways and neuroinflammation, as well as pyroptosis and necroptosis in the brain. In conclusion, our work demonstrates neuroinflammation-associated gene expression profiles, which can provide key insight into the severe disease observed in COVID-19 patients.

Complete Obstruction, a Real Risk Factor: A Comprehensive Study on Obstruction in Stage IIA Colon Cancer With Propensity Score Matching Analysis.

MICROABSTRACT: This study evaluates the prognostic significance of obstructions in stage IIA colon cancer, distinguishing between partial and complete obstructions. It employs a retrospective review of 1914 patients with propensity score matching to analyze oncologic outcomes. Findings reveal complete obstruction as a significant risk factor for poorer outcomes, emphasizing the necessity for further research to refine treatment strategies, particularly regarding the efficacy of adjuvant chemotherapy across obstruction types. BACKGROUND: This study examined the prognostic impact of obstructions in stage IIA colon cancer. The analysis specifically differentiated partial and complete obstructions, analyzing their distinct influences of both on oncologic outcomes. MATERIALS AND METHODS: A retrospective review was conducted of stage IIA colon cancer cases with the presence of an obstruction. Patients were stratified by whether it was partial or complete based on the severity of obstruction. Propensity score matching was employed to control for confounders. RESULTS: Among 1914 consecutive patients diagnosed with stage IIA colon cancer, 758 patients (597 patients with partial obstruction, 161 patients with complete obstruction) exhibited obstruction, while 1156 patients had no obstruction. The median follow-up period was 126 months. Complete obstruction was associated with poorer disease-free survival (Hazard ratio (HR) = 1.785, P < .001) and overall survival (HR = 1.853, P = .001). This trend persisted after propensity score matching, patients with complete obstruction showing a worsened disease-free survival (HR = 1.666, P = .028) and overall survival (HR = 1.732, P = .041). Adjuvant chemotherapy showed improved outcomes overall, but its efficacy varied across obstruction types. CONCLUSION: Differentiating between complete and partial obstructions in stage IIA colon cancer is an important clinical distinction, as our findings suggest that complete obstruction is a significant risk factor for poorer oncologic outcomes. While adjuvant chemotherapy generally improves prognosis in stage IIA colon cancer, the correlation of obstruction type with its efficacy remains uncertain, necessitating further research to refine treatment strategies.

The influence of advanced maternal age on congenital malformations, short- and long-term outcomes in offspring of nulligravida: a Korean National Cohort Study over 15 years.

OBJECTIVE: To assess the influence of advanced maternal age on congenital malformations, short- and long-term outcomes in offspring of nulligravida. METHODS: A retrospective study was conducted using the Korean National Health Insurance Service database spanning from January 2005 to December 2019. All live-born offspring of nulligravida (n=3,685,817) were included. The maternal age was subdivided into the following subgroups: <25 years (n=153,818), 25-29 years (n=845,355), 30-34 years (n=1,738,299), 35-39 years (n=787,530), 40-44 years (n=151,519), and >44 years (n=9,296). Outcomes were assessed based on International Classification of Diseases-10 codes. Adjusted odds ratios (aOR) were calculated with the group of 25-29 years as a reference. RESULT: Most congenital malformations showed an age dependent increase, but cleft lip and abdominal wall defect exhibited a U-shape curve, indicating an increase even in those <25 years old. Similarly, various disorders included in the neonatal composite outcomes from short-term outcomes showed aged dependent escalation. However, the preterm birth from the short-term outcome and most of the long-term developmental outcomes, except for motor developmental delay and Tics, showed a U-shaped pattern. The aOR of autism and cerebral palsy, showing the most obvious U-shaped curved in the long-term outcomes, was 1.50 (95% confidence interval [CI], 1.24-1.82) and 1.54 (95% CI, 1.17-2.03), respectively in the group >44 years old and 1.18 (95% CI, 1.11-1.25) and 1.19 (95% CI, 1.09-1.30) in <25 years old group. CONCLUSION: Overall, an advanced maternal age has an age-dependent correlation with most congenital malformations and shortand long-term outcomes of neonates.

Postpartum Maternal Anxiety Affects the Development of Food Allergy Through Dietary and Gut Microbial Diversity During Early Infancy.

PURPOSE: We aimed to investigate the mediating factors between maternal anxiety and the development of food allergy (FA) in children until 2 years from birth. METHODS: In this longitudinal cohort of 122 mother-child dyads from pregnancy to 24 months of age, we regularly surveyed maternal psychological states, infant feeding data, and allergic symptoms and collected stool samples at 6 months of age for microbiome analysis. Considering the temporal order of data collection, we investigated serial mediating effects and indirect effects among maternal anxiety, dietary diversity (DD), gut microbial diversity, and FA using structural equation modeling. RESULTS: Among the 122 infants, 15 (12.3%) were diagnosed with FA. Increased maternal anxiety between 3 and 6 months after delivery was associated with a lower DD score. Infants with low DD at 4 months showed low gut microbial richness, which was associated with FA development. When the infants were grouped into 4 subtypes, using consensus clustering of 13 gut bacteria significantly associated with maternal anxiety and DD, Prevotella, Eubacterium, Clostridiales and Lachnospiraceae were more abundant in the group with lower FA occurrence. CONCLUSIONS: Postpartum maternal anxiety, mediated by reduced DD and gut microbial diversity, may be a risk factor for the development of FA in infants during the first 2 years of life.

The role of astrocytic γ-aminobutyric acid in the action of inhalational anesthetics.

BACKGROUND: Inhalational anesthetics target the inhibitory extrasynaptic γ-aminobutyric acid type A (GABAA) receptors. Both neuronal and glial GABA mediate tonic inhibition of the extrasynaptic GABAA receptors. However, the role of glial GABA during inhalational anesthesia remains unclear. This study aimed to evaluate whether astrocytic GABA contributes to the action of different inhalational anesthetics. METHODS: Gene knockout of monoamine oxidase B (MAOB) was used to reduce astrocytic GABA levels in mice. The hypnotic and immobilizing effects of isoflurane, sevoflurane, and desflurane were assessed by evaluating the loss of righting reflex (LORR) and tail-pinch withdrawal response (LTWR) in MAOB knockout and wild-type mice. Minimum alveolar concentration (MAC) for LORR, time to LORR, MAC for LTWR and time to LTWR of isoflurane, sevoflurane, and desflurane were assessed. RESULTS: Time to LORR and time to LTWR with isoflurane were significantly longer in MAOB knockout mice than in wild-type mice (P < 0.001 and P = 0.032, respectively). Time to LORR with 0.8 MAC of sevoflurane was significantly longer in MAOB knockout mice than in wild-type mice (P < 0.001), but not with 1.0 MAC of sevoflurane (P=0.217). MAC for LTWR was significantly higher in MAOB knockout mice exposed to sevoflurane (P < 0.001). With desflurane, MAOB knockout mice had a significantly higher MAC for LORR (P = 0.003) and higher MAC for LTWR (P < 0.001) than wild-type mice. CONCLUSIONS: MAOB knockout mice showed reduced sensitivity to the hypnotic and immobilizing effects of isoflurane, sevoflurane, and desflurane. Behavioral tests revealed that the hypnotic and immobilizing effects of inhalational anesthetics would be mediated by astrocytic GABA.

Comparison of analgesic effects between programmed intermittent epidural boluses and continuous epidural infusion after cesarean section: a randomized controlled study.

BACKGROUND: This study aimed to compare the analgesic effects of programmed intermittent epidural boluses (PIEB) and continuous epidural infusion (CEI) for postoperative analgesia after elective cesarean section (CS). METHODS: Seventy-four women who underwent elective CS were randomized to receive either PIEB or CEI. The PIEB group received 4 ml-intermittent boluses of 0.11% ropivacaine every hour at a rate of 120 ml/h. The CEI group received a constant rate of 4 ml/h of 0.11% ropivacaine. The primary outcome was the pain score at rest at 36 h after CS. Secondary outcomes included the pain scores during mobilization, time-weighted pain scores, the incidence of motor blockade, and complications-related epidural analgesia during 36 h after CS. RESULTS: The pain score at rest at 36 h after CS was significantly lower in the PIEB group compared with that in the CEI group (3.0 vs. 0.0; median difference: 2, 95% CI [1, 2], P < 0.001). The mean time-weighted pain scores at rest and during mobilizations were also significantly lower in the PIEB group than in the CEI group (pain at rest; mean difference [MD]: 37.5, 95% CI [24.6, 50.4], P < 0.001/pain during mobilization; MD: 56.6, 95% CI [39.8, 73.5], P < 0.001). The incidence of motor blockade was significantly reduced in the PIEB group compared with that in the CEI group (P < 0.001). CONCLUSIONS: PIEB provides superior analgesia with less motor blockade than CEI in postpartum women after CS, without any apparent adverse events.

Skin biomarkers predict the development of food allergy in early life.

BACKGROUND: Food allergy (FA) often occurs in early childhood with and without atopic dermatitis (AD). FA can be severe and even fatal. For primary prevention, it is important to find early biomarkers to predict the future onset of FA before any clinical manifestations. OBJECTIVE: Our aim was to find early predictors of future onset of FA in the stratum corneum (SC). METHODS: Skin tape strips were collected from the forearm of newborns (n = 129) at age 2 months, before any signs of clinical FA or AD. Children were clinically monitored until they reached age 2 years to confirm the presence or absence of FA and AD. Skin tape strips were subjected to lipidomic analyses by liquid chromatography-tandem mass spectrometry and cytokine determination by Meso Scale Discovery U-Plex assay. RESULTS: Overall, 9 of 129 infants (7.0%) developed FA alone and 9 of 129 infants (7.0%) developed FA concomitantly with AD. In the stratum corneum of children with future FA and concomitant AD and FA, absolute amounts of unsaturated (N24:1)(C18-sphingosine)ceramide and (N26:1)(C18-sphingosine)ceramide and their relative percentages within the molecular group were increased compared with the amounts and percentages in healthy children, with P values ranging from less than .01 to less than .05 according to ANOVA. The children with future AD had normal levels of these molecules. IL-33 level was upregulated in those infants with future FA but not in those with future AD, whereas thymic stromal lymphopoietin was upregulated in those with future AD but not in those with future FA. Logistic regression analysis revealed strong FA predicting power for the combination of dysregulated lipids and cytokines, with an odds ratio reaching 101.4 (95% CI = 5.4-1910.6). CONCLUSION: Noninvasive skin tape strip analysis at age 2 months can identify infants at risk of FA in the future.

Indigenous data governance approaches applied in research using routinely collected health data: a scoping review.

Globally, there is a growing acknowledgment of Indigenous Peoples' rights to control data related to their communities. This is seen in the development of Indigenous Data Governance standards. As health data collection increases, it's crucial to apply these standards in research involving Indigenous communities. Our study, therefore, aims to systematically review research using routinely collected health data of Indigenous Peoples, understanding the Indigenous Data Governance approaches and the associated advantages and challenges. We searched electronic databases for studies from 2013 to 2022, resulting in 85 selected articles. Of these, 65 (77%) involved Indigenous Peoples in the research, and 60 (71%) were authored by Indigenous individuals or organisations. While most studies (93%) provided ethical approval details, only 18 (21%) described Indigenous guiding principles, 35 (41%) reported on data sovereignty, and 28 (33%) addressed consent. This highlights the increasing focus on Indigenous Data Governance in utilising health data. Leveraging existing data sources in line with Indigenous data governance principles is vital for better understanding Indigenous health outcomes.

Preparation of human astrocytes with potent therapeutic functions from human pluripotent stem cells using ventral midbrain patterning.

INTRODUCTION: Astrocytes are glial-type cells that protect neurons from toxic insults and support neuronal functions and metabolism in a healthy brain. Leveraging these physiological functions, transplantation of astrocytes or their derivatives has emerged as a potential therapeutic approach for neurodegenerative disorders. METHODS: To substantiate the clinical application of astrocyte-based therapy, we aimed to prepare human astrocytes with potent therapeutic capacities from human pluripotent stem cells (hPSCs). To that end, we used ventral midbrain patterning during the differentiation of hPSCs into astrocytes, based on the roles of midbrain-specific factors in potentiating glial neurotrophic/anti-inflammatory activity. To assess the therapeutic effects of human midbrain-type astrocytes, we transplanted them into mouse models of Parkinson's disease (PD) and Alzheimer's disease (AD). RESULTS: Through a comprehensive series of in-vitro and in-vivo experiments, we were able to establish that the midbrain-type astrocytes exhibited the abilities to effectively combat oxidative stress, counter excitotoxic glutamate, and manage pathological protein aggregates. Our strategy for preparing midbrain-type astrocytes yielded promising results, demonstrating the strong therapeutic potential of these cells in various neurotoxic contexts. Particularly noteworthy is their efficacy in PD and AD-specific proteopathic conditions, in which the midbrain-type astrocytes outperformed forebrain-type astrocytes derived by the same organoid-based method. CONCLUSION: The enhanced functions of the midbrain-type astrocytes extended to their ability to release signaling molecules that inhibited neuronal deterioration and senescence while steering microglial cells away from a pro-inflammatory state. This success was evident in both in-vitro studies using human cells and in-vivo experiments conducted in mouse models of PD and AD. In the end, our human midbrain-type astrocytes demonstrated remarkable effectiveness in alleviating neurodegeneration, neuroinflammation, and the pathologies associated with the accumulation of α-synuclein and Amyloid ß proteins.

Guide to Rho(D) Immune Globulin in Women With Molecularly Defined Asian-type DEL (c.1227G>A).

Rh hemolytic disease of the fetus and newborn is a potential risk for D-negative mothers who produce anti-D during pregnancy, which can lead to morbidity and mortality in subsequent pregnancies. To prevent this hemolytic disease, Rho(D) immune globulin (RhIG) is generally administered to D-negative mothers without anti-D at 28 weeks of gestation and shortly after delivery. However, current guidelines suggest that pregnant mothers with molecularly defined weak D types 1, 2, 3, 4.0, and 4.1 do not need RhIG as they are unlikely to produce alloanti-D when exposed to fetuses with D-positive red cells. This issue and the necessity of RHD genotyping have been extensively discussed in Western countries, where these variants are relatively common. Recent evidence indicates that women with Asian-type DEL (c.1227G>A) also do not form alloanti-D when exposed to D-positive red cells. We report that mothers with molecularly defined Asian-type DEL, similar to those with weak D types 1, 2, 3, 4.0, and 4.1, do not require RhIG before and after delivery. Collectively, this review could pave the way for the revision of international guidelines to include the selective use of RhIG based on specific genotypes, particularly in women with the Asian-type DEL.