Plasma versus tissue tumor mutational burden as biomarkers of durvalumab plus tremelimumab response in patients with metastatic colorectal cancer in the CO.26 trial.

PURPOSE: Tissue derived tumor mutation burden (TMB) of ≥10 mutations/Mb is a histology agnostic biomarker for the immune checkpoint inhibitor (ICI) pembrolizumab. However, the dataset on which this was validated lacked colorectal cancers (CRCs), and there is limited evidence for immunotherapy benefit in CRC using this threshold. PATIENTS AND METHODS: CO.26 was a randomized phase II study of 180 patients comparing durvalumab and tremelimumab (D+T, n=119 patients) versus best supportive care (BSC, n=61 patients). ctDNA sequencing was available for 168 patients (n=118 D+T, n=50), of which 165 had evaluable plasma TMB (pTMB). Tissue sequencing was available for 108 patients. Optimal thresholds for stratifying patients based on overall survival were determined using a minimal p-value approach. This report includes the final overall survival analysis. RESULTS: Tissue TMB ≥10 mutations/Mb was not predictive of benefit from D+T compared to BSC in microsatellite stable (MSS) metastatic CRC (HR 0.71 [95% CI:0.28-1.80], p=0.47). No tissue TMB threshold could identify a high TMB group that benefited from ICI. In contrast, plasma TMB (pTMB) ≥28 mutations/Mb was predictive of benefit from D+T (HR=0.34 [95%CI:0.13-0.85], p=0.022), as was clonal pTMB ≥10.6 mutations/Mb (HR=0.10 [95%CI:0.014-0.79], p=0.029) and subclonal pTMB ≥25.9/Mb (HR=0.20 [95% CI:0.061-0.69], p=0.010). Higher pTMB was associated with length of time on cytotoxic agents (p=0.021) and prior anti-EGFR exposure (p=2.44x10-06). CONCLUSION: pTMB derived from either clonal or subclonal mutations may identify a group more likely to benefit from immunotherapy, though validation is required. Tissue TMB provided no predictive utility for immunotherapy in this trial.

Potential limitations of micro-dystrophin gene therapy for Duchenne muscular dystrophy.

Clinical trials delivering high doses of adeno-associated viruses (AAVs) expressing truncated dystrophin molecules (micro-dystrophins) are underway for individuals with Duchenne muscular dystrophy (DMD). We examined the efficiency and efficacy of this strategy with four micro-dystrophin constructs (three in clinical trials and a variant of the largest clinical construct), in a severe mouse model of DMD, using doses of AAV comparable to those used in the clinical trials. We achieved high levels of micro-dystrophin expression in striated muscle with cardiac expression ~10 fold higher than that observed in skeletal muscle. Significant, albeit incomplete, correction of the skeletal muscle disease was observed. Surprisingly, a lethal acceleration of cardiac disease progression occurred with two of the micro-dystrophins. The detrimental impact on the heart appears to be caused by the high levels of micro-dystrophin resulting in variable competition (dependent on the design of the micro-dystrophin) between micro-dystrophin and utrophin at the cardiomyocyte membrane. There may also be a contribution from an overloading of protein degradation. The significance of these observations for patients currently being treated with AAV-micro-dystrophin therapies is unclear since the levels of expression being achieved in the DMD hearts are unknown. However, it suggests that micro-dystrophin treatments need to avoid excessively high levels of expression in the heart and cardiac function should be carefully monitored in these patients.

Complement receptor 4 mediates the clearance of extracellular tau fibrils by microglia.

Tauopathies exhibit a characteristic accumulation of misfolded tau aggregates in the brain. Tau pathology shows disease-specific spatiotemporal propagation through intercellular transmission, which is closely correlated with the progression of clinical manifestations. Therefore, identifying molecular mechanisms that prevent tau propagation is critical for developing therapeutic strategies for tauopathies. The various innate immune receptors, such as complement receptor 3 (CR3) and complement receptor 4 (CR4), have been reported to play a critical role in the clearance of various extracellular toxic molecules by microglia. However, their role in tau clearance has not been studied yet. In the present study, we investigated the role of CR3 and CR4 in regulating extracellular tau clearance. We found that CR4 selectively binds to tau fibrils but not to tau monomers, whereas CR3 does not bind to either of them. Inhibiting CR4, but not CR3, significantly reduces the uptake of tau fibrils by BV2 cells and primary microglia. By contrast, inhibiting CR4 has no effect on the uptake of tau monomers by BV2 cells. Furthermore, inhibiting CR4 suppresses the clearance of extracellular tau fibrils, leading to more seed-competent tau fibrils remaining in the extracellular space relative to control samples. We also provide evidence that the expression of CR4 is upregulated in the brains of human Alzheimer's disease patients and the PS19 mouse model of tauopathy. Taken together, our data strongly support that CR4 is a previously undescribed receptor for the clearance of tau fibrils in microglia and may represent a novel therapeutic target for tauopathy.

The ICL1 and MLS1 Genes, Integral to the Glyoxylate Cycle, are Essential and Specific for Caloric Restriction-Mediated Extension of Lifespan in Budding Yeast.

The regulation of complex energy metabolism is intricately linked to cellular energy demands. Caloric restriction (CR) plays a pivotal role in modulating the expression of genes associated with key metabolic pathways, including glycolysis, the tricarboxylic acid (TCA) cycle, and the glyoxylate cycle. In this study, the chronological lifespan (CLS) of 35 viable single-gene deletion mutants under both non-restricted and CR conditions, focusing on genes related to these metabolic pathways is evaluated. CR is found to increase CLS predominantly in mutants associated with the glycolysis and TCA cycle. However, this beneficial effect of CR is not observed in mutants of the glyoxylate cycle, particularly those lacking genes for critical enzymes like isocitrate lyase 1 (icl1Δ) and malate synthase 1 (mls1Δ). This analysis revealed an increase in isocitrate lyase activity, a key enzyme of the glyoxylate cycle, under CR, unlike the activity of isocitrate dehydrogenase, which remains unchanged and is specific to the TCA cycle. Interestingly, rapamycin, a compound known for extending lifespan, does not increase the activity of the glyoxylate cycle enzyme. This suggests that CR affects lifespan through a distinct metabolic mechanism.

Preoperative smoking and robot-assisted radical cystectomy outcomes & complications in multicenter KORARC database.

To investigate the influence of preoperative smoking history on the survival outcomes and complications in a cohort from a large multicenter database. Many patients who undergo radical cystectomy (RC) have a history of smoking; however, the direct association between preoperative smoking history and survival outcomes and complications in patients with muscle-invasive bladder cancer (MIBC) who undergo robot-assisted radical cystectomy (RARC) remains unexplored. We conducted a retrospective analysis using data from 749 patients in the Korean Robot-Assisted Radical Cystectomy Study Group (KORARC) database, with an average follow-up duration of 30.8 months. The cohort was divided into two groups: smokers (n = 351) and non-smokers (n = 398). Propensity score matching was employed to address differences in sample size and baseline demographics between the two groups (n = 274, each). Comparative analyses included assessments of oncological outcomes and complications. After matching, smoking did not significantly affect the overall complication rate (p = 0.121). Preoperative smoking did not significantly increase the occurrence of complications based on complication type (p = 0.322), nor did it increase the readmission rate (p = 0.076). There were no perioperative death in either group. Furthermore, preoperative smoking history showed no significant impact on overall survival (OS) [hazard ratio (HR) = 0.87, interquartile range (IQR): 0.54-1.42; p = 0.589] and recurrence-free survival (RFS) (HR = 1.12, IQR: 0.83-1.53; p = 0.458) following RARC for MIBC. The extent of preoperative smoking (≤ 10, 10-30, and ≥ 30 pack-years) had no significant influence on OS and RFS in any of the categories (all p > 0.05). Preoperative smoking history did not significantly affect OS, RFS, or complications in patients with MIBC undergoing RARC.

Applications of artificial intelligence in urologic oncology.

PURPOSE: With the recent rising interest in artificial intelligence (AI) in medicine, many studies have explored the potential and usefulness of AI in urological diseases. This study aimed to comprehensively review recent applications of AI in urologic oncology. MATERIALS AND METHODS: We searched the PubMed-MEDLINE databases for articles in English on machine learning (ML) and deep learning (DL) models related to general surgery and prostate, bladder, and kidney cancer. The search terms were a combination of keywords, including both "urology" and "artificial intelligence" with one of the following: "machine learning," "deep learning," "neural network," "renal cell carcinoma," "kidney cancer," "urothelial carcinoma," "bladder cancer," "prostate cancer," and "robotic surgery." RESULTS: A total of 58 articles were included. The studies on prostate cancer were related to grade prediction, improved diagnosis, and predicting outcomes and recurrence. The studies on bladder cancer mainly used radiomics to identify aggressive tumors and predict treatment outcomes, recurrence, and survival rates. Most studies on the application of ML and DL in kidney cancer were focused on the differentiation of benign and malignant tumors as well as prediction of their grade and subtype. Most studies suggested that methods using AI may be better than or similar to existing traditional methods. CONCLUSIONS: AI technology is actively being investigated in the field of urological cancers as a tool for diagnosis, prediction of prognosis, and decision-making and is expected to be applied in additional clinical areas soon. Despite technological, legal, and ethical concerns, AI will change the landscape of urological cancer management.

The impact of maxillary dimensions on determining surgical approach of fungal ball in the maxillary sinus.

Endoscopic middle meatal antrostomy (MMA) is commonly used for maxillary sinus (MS) fungal ball removal. For challenging cases involving anterior or inferior recess, an additional inferior meatal approach (IMA) might be needed. We analyzed the differences in MS dimensions on CT scans according to the surgical approach to suggest preoperative variables that could facilitate an additional IMA. CT scans of 281 adult patients who underwent ESS for the MS fungal ball (139 MMA, 62 MMA & IMA) were evaluated for comparative analysis of 8 MS measurements based on the surgical approach. Complete removal was achieved in all cases. Age and sex didn't differ significantly (p > 0.05). The maximum distances between the anterior-posterior walls, the inferior ostium border to the lateral recess, and the ostium to the inferior wall of the MS were statistically greater in the MMA & IMA group compared to the MMA group (p = 0.003, p = 0.005, and p = 0.010, respectively), especially among females. This study underscores the clinical importance of specific measurements-anterior to posterior wall, medial wall to lateral recess, and ostium to inferior wall of the maxillary sinus-for guiding optimal surgical approaches in MS lesions.

A multimodal machine learning model for predicting dementia conversion in Alzheimer's disease.

Alzheimer's disease (AD) accounts for 60-70% of the population with dementia. Mild cognitive impairment (MCI) is a diagnostic entity defined as an intermediate stage between subjective cognitive decline and dementia, and about 10-15% of people annually convert to AD. We aimed to investigate the most robust model and modality combination by combining multi-modality image features based on demographic characteristics in six machine learning models. A total of 196 subjects were enrolled from four hospitals and the Alzheimer's Disease Neuroimaging Initiative dataset. During the four-year follow-up period, 47 (24%) patients progressed from MCI to AD. Volumes of the regions of interest, white matter hyperintensity, and regional Standardized Uptake Value Ratio (SUVR) were analyzed using T1, T2-weighted-Fluid-Attenuated Inversion Recovery (T2-FLAIR) MRIs, and amyloid PET (αPET), along with automatically provided hippocampal occupancy scores (HOC) and Fazekas scales. As a result of testing the robustness of the model, the GBM model was the most stable, and in modality combination, model performance was further improved in the absence of T2-FLAIR image features. Our study predicts the probability of AD conversion in MCI patients, which is expected to be useful information for clinician's early diagnosis and treatment plan design.

Adaptable Self-Assembly of a PEG Dendrimer-Coiled Coil Conjugate.

Self-assembly of designed molecules has enabled the construction of a variety of functional nanostructures. Specifically, adaptable self-assembly has demonstrated several advantageous features for smart materials. Here, we demonstrate that an α-helical coiled coil conjugated with a dendrimer can adapt to spatial restriction due to the strong steric repulsion between dendrimer chains. The adaptable transformation of a tetrameric coiled coil to a trimeric coiled coil can be confirmed using analytical ultracentrifugation upon conjugation of the dendrimer to the coiled coil-forming building block. Interestingly, circular dichroism spectroscopy analysis of the dendrimer conjugate revealed an unconventional trend: the multimerization of the coiled coil is inversely dependent on concentration. This result implies that the spatial crowding between the bulky dendritic chains is significantly stronger than that between linear chains, thereby affecting the overall assembly process. We further illustrated the application potential by decorating the surface of gold nanorods (AuNRs) with the adaptable coiled coil. The dendrimer-coiled coil peptide conjugate can be utilized to fabricate organic-inorganic nanohybrids with enhanced colloidal and thermal stabilities. This study demonstrates that the coiled coil can engage in the adaptable mode of self-assembly with the potential to form dynamic peptide-based materials.

Heat-treated Limosilactobacillus fermentum LM1020 with menthol, salicylic acid, and panthenol promotes hair growth and regulates hair scalp microbiome balance in androgenetic alopecia: A double-blind, randomized and placebo-controlled clinical trial.

BACKGROUND: Androgenetic alopecia (AGA) is a common and chronic problem characterized by hair follicle miniaturization. AIMS: In this study, heat-treated Limosilactobacillus fermentum LM1020 (HT-LM1020) was investigated in human follicle dermal papilla cell (HFDPC), scalp tissue, and clinical trials for patients with AGA. PATIENTS/METHODS: Cell proliferation and the expression of cyclins and cyclin-dependent kinases (CDKs) were measured in HFDPC. The relative gene expression of 5α-reductase and growth factors were investigated in hair scalp. This double-blind, randomized, placebo-controlled clinical trial was conducted over 24 weeks. Primary efficacy was evaluated by measuring hair density, and secondary efficacy was assessed by experts and self-assessment. Changes in the microbiota of the hair scalps were analyzed using 16S metagenome amplicon sequencing. RESULTS: HT-LM1020 promoted cell growth (p < 0.001) and cyclin B1 expression, and it reduced 5α-reductase and induced fibroblast growth factor 7 (FGF7), FGF10, and epithelial growth factor7 (EGF7) (p < 0.001). In the clinical trial, the experimental group demonstrated an increase in hair density from 133.70 to 148.87 n/cm2 at Week 24 (p < 0.001), while also expressing satisfaction with their hair density, reduced hair loss, and hairline. At Week 24, the total ratio of lactic acid bacteria operational taxonomic unit (OTU) in the scalp increased from 6.65% to 26.19%. At the same period, placebo-controlled group decreased Staphylococcus caprae OTU from 77.95% to 14.57% while experimental group decreased from 65.80% to 41.02%. CONCLUSIONS: These present results showed that HT-LM1020 was a co-effector of ingredients for anti-hair loss contributing to cell proliferation and the expression of CDKs.

Quality of Life and Nutritional Outcomes of Stomach-Preserving Surgery for Early Gastric Cancer: A Secondary Analysis of the SENORITA Randomized Clinical Trial.

Importance: The Sentinel Node Oriented Tailored Approach (SENORITA) randomized clinical trial evaluated quality of life (QoL) and nutritional outcomes between the laparoscopic sentinel node navigation surgery (LSNNS) and laparoscopic standard gastrectomy (LSG). However, there has been no report on the QoL and nutritional outcomes of patients who underwent stomach-preserving surgery among the LSNNS group. Objective: To compare long-term QoL and nutritional outcomes between patients who underwent stomach-preserving surgery and those who underwent standard gastrectomy and to identify factors associated with poor QoL outcomes in patients who underwent stomach-preserving surgery. Design, Setting, and Participants: This study is a secondary analysis of the SENORITA trial, a randomized clinical trial comparing LSNNS with LSG. Patients from 7 tertiary or general hospitals across the Republic of Korea were enrolled from March 2013 to December 2016, with follow-up through 5 years. Data were analyzed between August and September 2022. Among trial participants, patients who underwent actual laparoscopic standard gastrectomy in the LSG group and those who underwent stomach-preserving surgery in the LSNNS group were included. Patients who did not complete the baseline or any follow-up questionnaire were excluded. Intervention: Stomach-preserving surgery vs standard gastrectomy. Main Outcomes and Measures: Overall European Organization for Research and Treatment of Cancer QoL Questionnaire Core 30 (EORTC QLQ-C30) and stomach module (STO22) scores, body mass index, hemoglobin, protein, and albumin levels. Results: A total of 194 and 257 patients who underwent stomach-preserving surgery and standard gastrectomy, respectively, were included in this study (mean [SD] age, 55.6 [10.6] years; 249 [55.2%] male). The stomach-preserving group had better QoL scores at 3 months postoperatively in terms of physical function (87.2 vs 83.9), dyspnea (5.9 vs 11.2), appetite loss (13.1 vs 19.4), dysphagia (8.0 vs 12.7), eating restriction (10.9 vs 18.2), anxiety (29.0 vs 35.2), taste change (7.4 vs 13.0), and body image (19.5 vs 27.2). At 1 year postoperatively, the stomach-preserving group had significantly higher body mass index (23.9 vs 22.1, calculated as weight in kilograms divided by height in meters squared) and hemoglobin (14.3 vs 13.3 g/dL), albumin (4.3 vs 4.25 g/dL), and protein (7.3 vs 7.1 g/dL) levels compared to the standard group. Multivariable analyses showed that tumor location (greater curvature, lower third) was favorably associated with global health status (ß, 10.5; 95% CI, 3.2 to 17.8), reflux (ß, -8.4; 95% CI, -14.7 to -2.1), and eating restriction (ß, -5.7; 95% CI, -10.3 to -1.0) at 3 months postoperatively in the stomach-preserving group. Segmental resection was associated with risk of diarrhea (ß, 40.6; 95% CI, 3.1 to 78.1) and eating restriction (ß, 15.1; 95% CI, 1.1 to 29.1) at 3 years postoperatively. Conclusions and Relevance: Stomach-preserving surgery after sentinel node evaluation was associated with better long-term QoL and nutritional outcomes than standard gastrectomy. These findings may help facilitate decision-making regarding treatment for patients with early-stage gastric cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT01804998.

Energy deprivation affects nitrogen assimilation and fatty acid biosynthesis leading to leaf chlorosis under waterlogging stress in the endangered Abies koreana.

Energy deprivation triggers various physiological, biochemical and molecular changes in plants under abiotic stress. We investigated the oxidative damages in the high altitude grown conifer Abies koreana exposed to waterlogging stress. Our experimental results showed that waterlogging stress led to leaf chlorosis, 35 days after treatment (DAT). A significant decrease in leaf fresh weight, chlorophyll, and sugar content supported this phenotypic change. Biochemical analysis showed a significant increase in leaf proline, lipid peroxidase and DPPH free radical content of waterlogged plants. To elucidate the molecular mechanisms, we conducted RNA-sequencing and de novo assembly. Using RNA-Seq analysis approach and filtering (P < 0.05 and FDR < 0.001), we obtained 134 unigenes upregulated and 574 unigenes downregulated. GO and KEGG pathway analysis, placed the obtained differentially expressed unigenes (DEGs) in α-linoleic pathway, fatty acid degradation, glycosis, glycolipid metabolism and oligosaccharide biosynthesis process. Mapping of unigenes with Arabidopsis using BLASTn tool, showed several critical genes in photosynthesis and carbon metabolism downregulated. Following this, we found the repression of multiple nitrogen (N) assimilation and nucleotide biosynthesis genes including purine metabolism. In addition, waterlogging stress reduced the levels of polyunsaturated fatty acids with a concomitant increase only in myristic acid. Together, our results indicate that the prolonged snowmelt may cause inability of Abies koreana seedlings to lead the photosynthesis normally, due to the lack of root intercellular oxygen and emphasizes a detrimental effect on the N metabolic pathway, compromising this endangered tree's ability to be fully functional under waterlogging stress.

The long-term effects of the fenestration in patients with extracardiac Fontan circulation-a multicenter Korean cohort study based on national Fontan registry.

Introduction: The long-term effects of fenestration in patients with Fontan circulation remain unclear. We aim to evaluate the fenestration impact on early and late outcomes in patients with extracardiac Fontan (ECF) using a propensity score matching analysis. Methods: We performed an extensive retrospective multicenter clinical data review of the Korean Fontan registry and included 1,233 patients with surgical ECF (779 fenestrated, 454 non-fenestrated). Demographics, baseline, and follow-up data were collected and comprehensively analyzed. Patients were divided into two groups according to the baseline presence or absence of surgical fenestration. Subsequently, patients were sub-divided according to the fenestration status at the last follow-up. Propensity-score matching was performed to account for collected data between the 2 groups using a multistep approach. The primary outcomes were survival and freedom from Fontan failure (FFF). We also looked at postoperative hemodynamics, cardiopulmonary exercise test results, oxygen saturations, and functional status. Results: After propensity-score matching (454 matched pairs), there was no difference in survival or FFF between the 2 groups. However, ECF patients with baseline fenestration had significantly lower oxygen saturation (p = 0.001) and lower functional status (p < 0.001). Patients with fenestration had significantly longer bypass times, higher postoperative central venous pressure, higher postoperative left atrial pressure, and less prolonged pleural effusion in the early postoperative period. The propensity score matching according to the fenestration status at the last follow-up (148 matched pairs) showed that patients with a persistent fenestration had significantly lower oxygen saturation levels (p < 0.001). However there were no intergroup differences in the functional status, survival and FFF. Conclusions: Our results showed no long-term benefits of the Fenestration in terms of survival and FFF. Patients with persistent fenestration showed oxygen desaturation but no difference in exercise intolerance was shown between the 2 groups.

Synthesis and characterization of nitrogen-doped-MWCNT@cobalt oxide for nerve agent simulant detection.

Organophosphorus nerve agents are toxic compounds that disrupt neuromuscular transmission by inhibiting the neurotransmitter enzyme, acetylcholinesterase, leading to rapid death. A hybrid composite was synthesized using a hydrothermal process for the early detection of dimethyl methyl phosphonate (DMMP), a simulant of the G-series nerve agent, sarin. Quartz crystal microbalance (QCM) and surface acoustic wave (SAW) sensors were used as detectors. Nitrogen-doped multiwalled carbon nanotubes (N-MWCNTs), cobalt oxide (Co3O4), and N-MWCNT@Co3O4 were compared to detect DMMP concentrations of 25-150 ppm. At 25 ppm, the differential frequencies (Δf) of the N-MWCNT, Co3O4, and N-MWCNT@Co3O4 sensors were 5.8, 2.3, and 99.5 Hz, respectively. The selectivity results revealed a preference for the DMMP rather than potential interference. The coefficients of determination (R2) of the N-MWCNT, Co3O4, and N-MWCNT@Co3O4 sensors for detecting 25-150 ppm DMMP were 0.983, 0.986, and 0.999, respectively. The response times of the N-MWCNT, Co3O4, and N-MWCNT@Co3O4 sensors for detecting 100 ppm DMMP were 25, 27, and 34 s, respectively, while the corresponding recovery times were 85, 105, and 181 s. The repeatability results revealed the reversible adsorption and desorption phenomena for the fixed DMMP concentration of 100 ppm. These unique findings show that synthesized materials can be used to detect organophosphorus nerve agents.

Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome Knowledge and Attitude among Myanmar Women.

The global challenge posed by the human immunodeficiency virus (HIV) and its manifestation as acquired immunodeficiency syndrome (AIDS) is underscored by the prevalence of 5.9 million people living with HIV in the Asia-Pacific region in 2018. Myanmar, among Asian nations, faces a particularly high burden with a prevalence of 0.7% among adults aged 15-49. Despite the disproportionate impact on at-risk populations, including injection drug users and commercial sex workers, there is a scarcity of data on public awareness of HIV/AIDS in Myanmar. This study utilizes the 2015-2016 Myanmar Demographic Health Survey to assess the impact of socioeconomic factors on the knowledge and attitudes of women toward HIV/AIDS. The analysis encompasses 12,885 respondents, revealing that while 91.6% were aware of AIDS, <60% possessed accurate knowledge of HIV transmission. The study identifies significant variations in knowledge and attitudes based on age, region, residence type, education, wealth index, and media exposure. Notably, younger women aged 15-19 exhibited the lowest HIV/AIDS knowledge scores. Wealth and education emerged as key determinants influencing both knowledge and attitudes. The findings emphasize the need for tailored public health interventions to address the knowledge gap among women in different settings in Myanmar. However, it is crucial to acknowledge the temporal limitation of the study, as the data were collected in 2015-2016. Caution is advised in generalizing the results to the present day, emphasizing the necessity for ongoing research to capture the evolving landscape of HIV/AIDS awareness. This study contributes valuable insights that can inform targeted interventions, promoting awareness and prevention strategies in Myanmar's dynamic public health context.

The role of glial and neuronal Eph/ephrin signaling in Drosophila mushroom body development and sleep and circadian behavior.

The Eph receptor, a prototypically large receptor protein tyrosine kinase, interacts with ephrin ligands, forming a bidirectional signaling system that impacts diverse brain functions. Eph receptors and ephrins mediate forward and reverse signaling, affecting neurogenesis, axon guidance, and synaptic signaling. While mammalian studies have emphasized their roles in neurogenesis and synaptic plasticity, the Drosophila counterparts are less studied, especially in glial cells, despite structural similarities. Using RNAi to modulate Eph/ephrin expression in Drosophila neurons and glia, we studied their roles in brain development and sleep and circadian behavior. Knockdown of neuronal ephrin disrupted mushroom body development, while glial knockdown had minimal impact. Surprisingly, disrupting ephrin in neurons or glial cells altered sleep and circadian rhythms, indicating a direct involvement in these behaviors independent from developmental effects. Further analysis revealed distinct sleep phenotypes between neuronal and glial knockdowns, underscoring the intricate interplay within the neural circuits that govern behavior. Glia-specific knockdowns showed altered sleep patterns and reduced circadian rhythmicity, suggesting an intricate role of glia in sleep regulation. Our findings challenge simplistic models of Eph/ephrin signaling limited to neuron-glia communication and emphasize the complexity of the regulatory networks modulating behavior. Future investigations targeting specific glial subtypes will enhance our understanding of Eph/ephrin signaling's role in sleep regulation across species.

The design and implementation of a multi-center, pragmatic, individual-level randomized controlled trial to evaluate Baby2Home, an mHealth intervention to support new parents.

BACKGROUND: Becoming a parent is a transformative experience requiring multiple transitions, including the need to navigate several components of health care, manage any mental health issues, and develop and sustain an approach to infant feeding. Baby2Home (B2H) is a digital intervention built on the collaborative care model (CCM) designed to support families during these transitions to parenthood. OBJECTIVES: We aim to investigate the effects of B2H on preventive healthcare utilization for the family unit and patient-reported outcomes (PROs) trajectories with a focus on mental health. We also aim to evaluate heterogeneity in treatment effects across social determinants of health including self-reported race and ethnicity and household income. We hypothesize that B2H will lead to optimized healthcare utilization, improved PROs trajectories, and reduced racial, ethnic, and income-based disparities in these outcomes as compared to usual care. METHODS: B2H is a multi-center, pragmatic, individual-level randomized controlled trial. We will enroll 640 families who will be randomized to: [1] B2H + usual care, or [2] usual care alone. Preventive healthcare utilization is self-reported and confirmed from medical records and includes attendance at the postpartum visit, contraception use, depression screening, vaccine uptake, well-baby visit attendance, and breastfeeding at 6 months. PROs trajectories will be analyzed after collection at 1 month, 2 months, 4 months, 6 months and 12 months. PROs include assessments of stress, depression, anxiety, self-efficacy and relationship health. IMPLICATIONS: If B2H proves effective, it would provide a scalable digital intervention to improve care for families throughout the transition to new parenthood.

Platelet-to-lymphocyte ratio as a biomarker of systemic inflammation in systemic lupus erythematosus: A meta-analysis and systematic review.

OBJECTIVE: The objective of this study was to evaluate the relationship between the platelet-to-lymphocyte ratio (PLR) and systemic lupus erythematosus (SLE). Additionally, the study aimed to establish an association between PLR and SLE disease activity, specifically lupus nephritis (LN). METHODS: We conducted a comprehensive search across Medline, Embase, and Cochrane databases to identify relevant articles. Subsequently, we performed meta-analyses to compare PLR between SLE patients and controls, as well as active and inactive SLE cases, along with LN and non-LN groups. Furthermore, a meta-analysis was conducted on correlation coefficients between PLR and various parameters in SLE patients, including the SLE Disease Activity Index (SLEDAI), C3, C4, anti-dsDNA, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). RESULTS: In total, fifteen studies comprising 1,522 SLE patients and 1,424 controls were eligible for inclusion. The meta-analysis demonstrated a significant elevation of PLR in the SLE group compared to the control group (Standardized Mean Difference [SMD] = 0.604, 95% Confidence Interval [CI] = 0.299-0.909, p < 0.001). Upon stratification by ethnicity, an elevated PLR was observed in the SLE group among both Asian and Arab populations. Subgroup analysis based on sample size revealed consistently higher PLR in both small (n < 200) and large sample (n ≥ 200) SLE groups. Moreover, when considering disease activity, there was a noteworthy trend of increased PLR in the active disease group compared to the inactive group (SMD = 0.553, 95% CI = 0.000-1.106, p = 0.050). However, the meta-analysis did not demonstrate a significant distinction in PLR between the LN and non-LN groups. Notably, a positive association was established between PLR and SLEDAI (correlation coefficient = 0.325, 95% CI = 0.176-0.459, p < 0.001). Furthermore, PLR exhibited positive correlations with ESR, CRP, proteinuria, C3, and anti-dsDNA antibody levels. CONCLUSIONS: The outcomes of this meta-analysis underscored the elevated PLR in SLE patients, suggesting its potential as a biomarker for gauging systemic inflammation in SLE. Additionally, PLR exhibited correlations with SLEDAI, as well as with key indicators such as ESR, CRP, proteinuria, C3, and anti-dsDNA antibody levels.

Childcare sharing and family happiness: analyzing parental and child well-being in the actor-partner interdependence model.

Introduction: The exploration of the relationship between parental and child happiness, particularly in the context of shared childcare responsibilities, has not been examined in Korean families. Methods: Using a two-wave longitudinal design and data from 1,403 families from the Panel Study on Korean Children, this study employed the actor-partner interdependence model to examine the dynamics of childcare sharing between mothers and fathers in South Korea. Results: Mothers' childcare sharing was found to have no significant impact on their own and their partner's happiness, reflecting traditional gender norms that undervalue mothers' contributions. In contrast, fathers' childcare sharing had a positive impact on their own and their spouse's happiness, suggesting a growing recognition of fathers' involvement. Furthermore, fathers' active participation in childcare was found to promote their children's happiness through their own happiness. Discussion: This study reflects the complexity of evolving family roles and the covert persistence of traditional gender roles in modern Korean parenting. It suggests the importance of work and family policies that support changes in family dynamics by providing a more nuanced understanding of how changing family roles and responsibilities can enhance overall family well-being.