An exercise-inducible metabolite that suppresses feeding and obesity.

Exercise confers protection against obesity, type 2 diabetes and other cardiometabolic diseases1-5. However, the molecular and cellular mechanisms that mediate the metabolic benefits of physical activity remain unclear6. Here we show that exercise stimulates the production of N-lactoyl-phenylalanine (Lac-Phe), a blood-borne signalling metabolite that suppresses feeding and obesity. The biosynthesis of Lac-Phe from lactate and phenylalanine occurs in CNDP2+ cells, including macrophages, monocytes and other immune and epithelial cells localized to diverse organs. In diet-induced obese mice, pharmacological-mediated increases in Lac-Phe reduces food intake without affecting movement or energy expenditure. Chronic administration of Lac-Phe decreases adiposity and body weight and improves glucose homeostasis. Conversely, genetic ablation of Lac-Phe biosynthesis in mice increases food intake and obesity following exercise training. Last, large activity-inducible increases in circulating Lac-Phe are also observed in humans and racehorses, establishing this metabolite as a molecular effector associated with physical activity across multiple activity modalities and mammalian species. These data define a conserved exercise-inducible metabolite that controls food intake and influences systemic energy balance.

RSV Prefusion F Protein-Based Maternal Vaccine - Preterm Birth and Other Outcomes.

BACKGROUND: Vaccination against respiratory syncytial virus (RSV) during pregnancy may protect infants from RSV disease. Efficacy and safety data on a candidate RSV prefusion F protein-based maternal vaccine (RSVPreF3-Mat) are needed. METHODS: We conducted a phase 3 trial involving pregnant women 18 to 49 years of age to assess the efficacy and safety of RSVPreF3-Mat. The women were randomly assigned in a 2:1 ratio to receive RSVPreF3-Mat or placebo between 24 weeks 0 days and 34 weeks 0 days of gestation. The primary outcomes were any or severe medically assessed RSV-associated lower respiratory tract disease in infants from birth to 6 months of age and safety in infants from birth to 12 months of age. After the observation of a higher risk of preterm birth in the vaccine group than in the placebo group, enrollment and vaccination were stopped early, and exploratory analyses of the safety signal of preterm birth were performed. RESULTS: The analyses included 5328 pregnant women and 5233 infants; the target enrollment of approximately 10,000 pregnant women and their infants was not reached because enrollment was stopped early. A total of 3426 infants in the vaccine group and 1711 infants in the placebo group were followed from birth to 6 months of age; 16 and 24 infants, respectively, had any medically assessed RSV-associated lower respiratory tract disease (vaccine efficacy, 65.5%; 95% credible interval, 37.5 to 82.0), and 8 and 14, respectively, had severe medically assessed RSV-associated lower respiratory tract disease (vaccine efficacy, 69.0%; 95% credible interval, 33.0 to 87.6). Preterm birth occurred in 6.8% of the infants (237 of 3494) in the vaccine group and in 4.9% of those (86 of 1739) in the placebo group (relative risk, 1.37; 95% confidence interval [CI], 1.08 to 1.74; P = 0.01); neonatal death occurred in 0.4% (13 of 3494) and 0.2% (3 of 1739), respectively (relative risk, 2.16; 95% CI, 0.62 to 7.56; P = 0.23), an imbalance probably attributable to the greater percentage of preterm births in the vaccine group. No other safety signal was observed. CONCLUSIONS: The results of this trial, in which enrollment was stopped early because of safety concerns, suggest that the risks of any and severe medically assessed RSV-associated lower respiratory tract disease among infants were lower with the candidate maternal RSV vaccine than with placebo but that the risk of preterm birth was higher with the candidate vaccine. (Funded by GlaxoSmithKline Biologicals; ClinicalTrials.gov number, NCT04605159.).

Applying interpretable machine learning in computational biology-pitfalls, recommendations and opportunities for new developments.

Recent advances in machine learning have enabled the development of next-generation predictive models for complex computational biology problems, thereby spurring the use of interpretable machine learning (IML) to unveil biological insights. However, guidelines for using IML in computational biology are generally underdeveloped. We provide an overview of IML methods and evaluation techniques and discuss common pitfalls encountered when applying IML methods to computational biology problems. We also highlight open questions, especially in the era of large language models, and call for collaboration between IML and computational biology researchers.

TM4SF19 controls GABP-dependent YAP transcription in head and neck cancer under oxidative stress conditions.

Tobacco and alcohol are risk factors for human papillomavirus-negative head and neck squamous cell carcinoma (HPV- HNSCC), which arises from the mucosal epithelium of the upper aerodigestive tract. Notably, despite the mutagenic potential of smoking, HPV- HNSCC exhibits a low mutational load directly attributed to smoking, which implies an undefined role of smoking in HPV- HNSCC. Elevated YAP (Yes-associated protein) mRNA is prevalent in HPV- HNSCC, irrespective of the YAP gene amplification status, and the mechanism behind this upregulation remains elusive. Here, we report that oxidative stress, induced by major risk factors for HPV- HNSCC such as tobacco and alcohol, promotes YAP transcription via TM4SF19 (transmembrane 4 L six family member 19). TM4SF19 modulates YAP transcription by interacting with the GABP (Guanine and adenine-binding protein) transcription factor complex. Mechanistically, oxidative stress induces TM4SF19 dimerization and topology inversion in the endoplasmic reticulum membrane, which in turn protects the GABPß1 subunit from proteasomal degradation. Conversely, depletion of TM4SF19 impairs the survival, proliferation, and migration of HPV- HNSCC cells, highlighting the potential therapeutic relevance of targeting TM4SF19. Our findings reveal the roles of the key risk factors of HPV- HNSCC in tumor development via oxidative stress, offering implications for upcoming therapeutic approaches in HPV- HNSCC.

High-performance and low-power source-gated transistors enabled by a solution-processed metal oxide homojunction.

Cost-effective fabrication of mechanically flexible low-power electronics is important for emerging applications including wearable electronics, artificial intelligence, and the Internet of Things. Here, solution-processed source-gated transistors (SGTs) with an unprecedented intrinsic gain of ~2,000, low saturation voltage of +0.8 ± 0.1 V, and a ~25.6 µW power consumption are realized using an indium oxide In2O3/In2O3:polyethylenimine (PEI) blend homojunction with Au contacts on Si/SiO2. Kelvin probe force microscopy confirms source-controlled operation of the SGT and reveals that PEI doping leads to more effective depletion of the reverse-biased Schottky contact source region. Furthermore, using a fluoride-doped AlOx gate dielectric, rigid (on a Si substrate) and flexible (on a polyimide substrate) SGTs were fabricated. These devices exhibit a low driving voltage of +2 V and power consumption of ~11.5 µW, yielding inverters with an outstanding voltage gain of >5,000. Furthermore, electrooculographic (EOG) signal monitoring can now be demonstrated using an SGT inverter, where a ~1.0 mV EOG signal is amplified to over 300 mV, indicating significant potential for applications in wearable medical sensing and human-computer interfacing.

Infective endocarditis.

First described more than 350 years ago, infective endocarditis represents a global health concern characterised by infections affecting the native or prosthetic heart valves, the mural endocardium, a septal defect, or an indwelling cardiac device. Over recent decades, shifts in causation and epidemiology have been observed. Echocardiography remains pivotal in the diagnosis of infective endocarditis, with alternative imaging modalities gaining significance. Multidisciplinary management requiring expertise of cardiologists, cardiovascular surgeons, infectious disease specialists, microbiologists, radiologists and neurologists, is imperative. Current recommendations for clinical management often rely on observational studies, given the limited number of well conducted randomised controlled trials studying infective endocarditis due to the rarity of the disease. In this Seminar, we provide a comprehensive overview of optimal clinical practices in infective endocarditis, highlighting key aspects of pathophysiology, pathogens, diagnosis, management, prevention, and multidisciplinary approaches, providing updates on recent research findings and addressing remaining controversies in diagnostic accuracy, prevention strategies, and optimal treatment.

Efficacy of Endovascular Thrombectomy in Acute Basilar Artery Occlusion with Low PC-ASPECTS: A Nationwide Prospective Registry-Based Study.

OBJECTIVE: We evaluated the efficacy of endovascular thrombectomy (EVT) on the functional outcome of patients with acute basilar artery occlusion and low posterior circulation acute stroke prognosis early computed tomography score (PC-ASPECTS). METHODS: We identified patients with acute ischemic stroke due to basilar artery occlusion and PC-ASPECTS of 6 or less, presenting within 24 h between August 2008 and April 2022. The primary outcome was a favorable functional outcome, defined as a modified Rankin Scale (mRS) score of 0-3 at 90 days. The secondary outcomes included an mRS score of 0-2, a favorable shift in the ordinal mRS scale, the occurrence of symptomatic intracranial hemorrhage (sICH), and mortality at 90 days. We compared the outcome of patients treated with EVT and those without EVT, using the inverse probability of treatment weighting methods. RESULTS: Out of 566 patients, 55.5% received EVT. In the EVT group, 106 (33.8%) achieved favorable outcomes, compared to 56 patients (22.2%) in the conservative group. EVT significantly increased the likelihood of achieving a favorable outcome compared to conservative treatment (relative risk [RR] 1.39, 95% confidence interval [CI], 1.11-1.74, p = 0.004). EVT was associated with a favorable shift in the mRS (RR 1.85, 95% CI, 1.49-2.29, p < 0.001) and reduced mortality without an increase in the risk of sICH. It did not have an impact on achieving an mRS score of 0-2. INTERPRETATION: Patients with acute basilar artery occlusion and a PC-ASPECTS of 6 or less might benefit from EVT without an increasing sICH. ANN NEUROL 2024;95:788-799.

Potential Use of Extracellular Vesicles for the HER2 Status Assessment in Breast Cancer Patients.

Human epithelial growth factor receptor 2 (HER2)-targeted therapies are effective in patients with HER2-positive breast cancer. Recent advances have shown that HER2-targeted therapies can also be of benefit when treating tumors expressing low levels of HER2, highlighting the importance of identifying the HER2-low subgroup. This clinical trend has opened new therapeutic avenues for patients who were previously ineligible for HER2-targeted therapies. Thus, the development of new diagnostic methods for real-time HER2 profiling is crucial for accurately tailoring the treatment for these patients. We hypothesized that tumor-derived extracellular vesicles (TEVs) could reflect the HER2 profiles of primary tumors and potentially serve as diagnostic tools for HER2 status. This approach was validated using six breast cancer cell lines, which confirmed that the TEVs accurately reflected the HER2 profiles of the tumor cells. TEVs were isolated using an immunoaffinity method, and copy number variation (CNV) in the ERBB2/EIF2C ratio was assessed using droplet digital PCR of DNA from these vesicles. Clinical validation using plasma samples from 33 breast cancer patients further reinforced the diagnostic potential of our method. Pearson's correlation coefficient analysis of the flow cytometry results demonstrated that TEVs reflected HER2 expression in primary cells. To distinguish between HER2-negative and HER2-low patients, the area under the curve (AUC) of the ROC curve in our method was 0.796, with a sensitivity of 53.8% and a specificity of 100%. These findings suggest the clinical utility of extracellular vesicles derived from plasma and emphasize the need for further research to distinguish HER2-negative from HER2-low patients.

Phase 3 Study Assessing Lot-to-lot Consistency of RSVPreF3 Vaccine and its Immune Response, Safety, and Reactogenicity When Co-administered with FLU-D-QIV.

BACKGROUND: A single-dose investigational respiratory syncytial virus (RSV) vaccine, RSV prefusion protein F3 (RSVPreF3), was co-administered with a single-dose quadrivalent influenza vaccine (FLU-D-QIV) in a phase 3, randomized, controlled, multicenter study in healthy, non-pregnant women aged 18-49 years. METHODS: The study was observer-blind to evaluate the lot-to-lot consistency of RSVPreF3, and single-blind to evaluate the immune response, safety, and reactogenicity of RSVPreF3 co-administered with FLU-D-QIV. RESULTS: A total of 1415 participants were included in the per-protocol set. There was a robust immune response at day 31 across each of the 3 RSVPreF3 vaccine lots; adjusted geometric mean concentration ratios (95% confidence interval [CI]) were 1.01 (0.91, 1.12), 0.93 (0.84, 1.03), and 0.92 (0.83, 1.02) for RSV1/RSV2, RSV1/RSV3, and RSV2/RSV3, respectively. For FLU-D-QIV co-administered with RSVPreF3, versus FLU-D-QIV alone at day 31, noninferiority was satisfied for 3 of 4 strains assessed, with the lower limit of the 95% CI for geometric mean ratio >0.67. CONCLUSIONS: Immunogenic consistency was demonstrated for 3 separate lots of RSVPreF3. Immunogenic noninferiority was demonstrated when comparing FLU-D-QIV administered alone, versus co-administered with RSVPreF3, for 3 strains of FLU-D-QIV. Co-administration was well tolerated, and both vaccines had clinically acceptable safety and reactogenicity profiles. CLINICAL TRIALS REGISTRATION: NCT05045144; EudraCT, 2021-000357-26.

This was a phase 3 study that compared antibodies against respiratory syncytial virus (or RSV for short) between women who were given 3 different production batches of RSV prefusion protein F3 (known as RSVPreF3) vaccine. The study also compared the antibodies between women who received either an RSV vaccine together with a flu vaccine (known as FLU-D-QIV), or a flu vaccine alone. The flu vaccine contained 4 different strains of flu virus. The study involved 1415 healthy, non-pregnant women aged 18­49 years. The antibodies checked after 31 days showed strong immune responses for all 3 RSV vaccine production batches, and similar immune responses between each of the 3 RSV vaccine production batches. The immune response of 3 of the 4 flu strains was not less when the flu vaccine was given together with the RSV vaccine than the immune response when flu vaccine was given alone and both vaccines were well tolerated.

Safety and Immunogenicity of Respiratory Syncytial Virus Prefusion Maternal Vaccine Coadministered With Diphtheria-Tetanus-Pertussis Vaccine: A Phase 2 Study.

BACKGROUND: Respiratory syncytial virus (RSV) fusion protein stabilized in the prefusion conformation (RSVPreF3) was under investigation as a maternal vaccine. METHODS: This phase 2, randomized, placebo-controlled, single-dose, multicenter study enrolled healthy, nonpregnant women, randomized 1:1:1:1:1 to 5 parallel groups studying RSVPreF3 (60 or 120 µg) coadministered with diphtheria, tetanus, and acellular pertussis vaccine (dTpa) or placebo, and dTpa coadministered with placebo. Safety and humoral immune responses were assessed. An extension phase also assessed a RSVPreF3 120 µg vaccination 12-18 months after first vaccination. RESULTS: The safety profile of RSVPreF3 was unaffected by dose or dTpa coadministration. Solicited and unsolicited adverse events (AEs) were evenly distributed across study groups. Injection-site pain was higher following the second vaccination versus the first vaccination. Medically attended AEs were rare (<5% overall). Both RSVPreF3 dose levels (alone and with dTpa) were immunogenic, increasing levels of RSV-A neutralizing antibody ≥8-fold and anti-RSVPreF3 IgG antibody ≥11-fold at 1 month postvaccination, which persisted at 12-18 months postvaccination; modest 2-fold increases were observed with a second RSVPreF3 vaccination. CONCLUSIONS: This study indicates RSVPreF3 coadministration with dTpa induces robust immune responses and is well tolerated, regardless of the RSVPreF3 dose level used. CLINICAL TRIALS REGISTRATION: NCT04138056.

Automated Prediction of Proximal Middle Cerebral Artery Occlusions in Noncontrast Brain Computed Tomography.

BACKGROUND: Early identification of large vessel occlusion (LVO) in patients with ischemic stroke is crucial for timely interventions. We propose a machine learning-based algorithm (JLK-CTL) that uses handcrafted features from noncontrast computed tomography to predict LVO. METHODS: We included patients with ischemic stroke who underwent concurrent noncontrast computed tomography and computed tomography angiography in seven hospitals. Patients from 5 of these hospitals, admitted between May 2011 and March 2015, were randomly divided into training and internal validation (9:1 ratio). Those from the remaining 2 hospitals, admitted between March 2021 and September 2021, were designated for external validation. From each noncontrast computed tomography scan, we extracted differences in volume, tissue density, and Hounsfield unit distribution between bihemispheric regions (striatocapsular, insula, M1-M3, and M4-M6, modified from the Alberta Stroke Program Early Computed Tomography Score). A deep learning algorithm was used to incorporate clot signs as an additional feature. Machine learning models, including ExtraTrees, random forest, extreme gradient boosting, support vector machine, and multilayer perceptron, as well as a deep learning model, were trained and evaluated. Additionally, we assessed the models' performance after incorporating the National Institutes of Health Stroke Scale scores as an additional feature. RESULTS: Among 2919 patients, 83 were excluded. Across the training (n=2463), internal validation (n=275), and external validation (n=95) datasets, the mean ages were 68.5±12.4, 67.6±13.8, and 67.9±13.6 years, respectively. The proportions of men were 57%, 53%, and 59%, with LVO prevalences of 17.0%, 16.4%, and 26.3%, respectively. In the external validation, the ExtraTrees model achieved a robust area under the curve of 0.888 (95% CI, 0.850-0.925), with a sensitivity of 80.1% (95% CI, 72.0-88.1) and a specificity of 88.6% (95% CI, 84.7-92.5). Adding the National Institutes of Health Stroke Scale score to the ExtraTrees model increased sensitivity (from 80.1% to 92.1%) while maintaining specificity. CONCLUSIONS: Our algorithm provides reliable predictions of LVO using noncontrast computed tomography. By enabling early LVO identification, our algorithm has the potential to expedite the stroke workflow.

Secular Trends in Outcomes and Impact of Novel Oral Anticoagulants in Atrial Fibrillation-Related Acute Ischemic Stroke.

BACKGROUND: Novel oral anticoagulants (NOACs) are currently recommended for the secondary prevention of stroke in patients with acute ischemic stroke (AIS) accompanied by atrial fibrillation (AF). However, the impact of NOACs on clinical outcomes in real-world practice remains ambiguous. This study analyzes the trend of clinical events in patients with AF-related AIS and determines how much the introduction of NOACs has mediated this trend. METHODS: We identified patients with AIS and AF between January 2011 and December 2019 using a multicenter stroke registry. Annual rates of NOAC prescriptions and clinical events within 1 year were evaluated. The primary outcome was a composite of recurrent stroke, myocardial infarction, and all-cause mortality. To assess the mediation effect of NOACs on the relationship between the calendar year and these outcomes, we used natural effect models and conducted exposure-mediator, exposure-outcome, and mediator-outcome analyses using multivariable regression models or accelerated failure time models, adjusting for potential confounders. RESULTS: Among the 12 977 patients with AF-related AIS, 12 500 (average age: 74.4 years; 51.3% male) were analyzed after excluding cases of valvular AF. Between 2011 and 2019, there was a significant decrease in the 1-year incidence of the primary composite outcome from 28.3% to 21.7%, while the NOAC prescription rate increased from 0% to 75.6%. A 1-year increase in the calendar year was independently associated with delayed occurrence of the primary outcome (adjusted time ratio, 1.10 [95% CI, 1.07-1.14]) and increased NOAC prescription (adjusted odds ratio, 2.20 [95% CI, 2.14-2.27]). Increased NOAC prescription was associated with delayed occurrence of the primary outcome (adjusted time ratio, 3.82 [95% CI, 3.17 to 4.61]). Upon controlling for NOAC prescription (mediator), the calendar year no longer influenced the primary outcome (adjusted time ratio, 0.97 [95% CI, 0.94-1.00]). This suggests that NOAC prescription mediates the association between the calendar year and the primary outcome. CONCLUSIONS: Our study highlights a temporal reduction in major clinical events or death in Korean patients with AF-related AIS, mediated by increased NOAC prescription, emphasizing NOAC use in this population.

Estimating insulin sensitivity and ß-cell function from the oral glucose tolerance test: validation of a new insulin sensitivity and secretion (ISS) model.

Efficient and accurate methods to estimate insulin sensitivity (SI) and ß-cell function (BCF) are of great importance for studying the pathogenesis and treatment effectiveness of type 2 diabetes (T2D). Existing methods range in sensitivity, input data, and technical requirements. Oral glucose tolerance tests (OGTTs) are preferred because they are simpler and more physiological than intravenous methods. However, current analytical methods for OGTT-derived SI and BCF also range in complexity; the oral minimal models require mathematical expertise for deconvolution and fitting differential equations, and simple algebraic surrogate indices (e.g., Matsuda index, insulinogenic index) may produce unphysiological values. We developed a new insulin secretion and sensitivity (ISS) model for clinical research that provides precise and accurate estimates of SI and BCF from a standard OGTT, focusing on effectiveness, ease of implementation, and pragmatism. This model was developed by fitting a pair of differential equations to glucose and insulin without need of deconvolution or C-peptide data. This model is derived from a published model for longitudinal simulation of T2D progression that represents glucose-insulin homeostasis, including postchallenge suppression of hepatic glucose production and first- and second-phase insulin secretion. The ISS model was evaluated in three diverse cohorts across the lifespan. The new model had a strong correlation with gold-standard estimates from intravenous glucose tolerance tests and insulin clamps. The ISS model has broad applicability among diverse populations because it balances performance, fidelity, and complexity to provide a reliable phenotype of T2D risk.NEW & NOTEWORTHY The pathogenesis of type 2 diabetes (T2D) is determined by a balance between insulin sensitivity (SI) and ß-cell function (BCF), which can be determined by gold standard direct measurements or estimated by fitting differential equation models to oral glucose tolerance tests (OGTTs). We propose and validate a new differential equation model that is simpler to use than current models and requires less data while maintaining good correlation and agreement with gold standards. Matlab and Python code is freely available.

TAAR8 Mediates Increased Migrasome Formation by Cadaverine in RPE Cells.

Migrasomes, the newly discovered cellular organelles that form large vesicle-like structures on the retraction fibers of migrating cells, are thought to be involved in communication between neighboring cells, cellular content transfer, unwanted material shedding, and information integration. Although their formation has been described previously, the molecular mechanisms of migrasome biogenesis are largely unknown. Here, we developed a cell line that overexpresses GFP-tetraspanin4, enabling observation of migrasomes. To identify compounds that regulate migrasome activity in retinal pigment epithelial (RPE) cells, we screened a fecal chemical library and identified cadaverine, a biogenic amine, as a potent migrasome formation inducer. Compared with normal migrating cells, those treated with cadaverine had significantly more migrasomes. Putrescine, another biogenic amine, also increased migrasome formation. Trace amine-associated receptor 8 (TAAR8) depletion inhibited migrasome increase in cadaverine-treated RPE cells, and cadaverine also inhibited protein kinase A phosphorylation. In RPE cells, cadaverine triggers migrasome formation via a TAAR8-mediated protein kinase A signaling pathway.

YAP1 regulates esophageal stem cells' self-renewal and differentiation.

Esophageal epithelium is one of the most proliferative and regenerative epithelia in our body, indicating robust stem cell activity. However, the underlying mechanisms regulating the self-renewal and differentiation of esophageal stem cells need to be more elucidated. Here, we identify the role of YAP1 in esophageal stem cells. YAP1 is differentially expressed in the nuclei of esophageal basal cells. Furthermore, the treatment of verteporfin, a YAP1 inhibitor, interfered with esophageal organoid formation. Consistently, YAP1 deletion decreased esophageal organoid formation and the expression of basal genes while increasing the expression of suprabasal genes. Finally, global transcriptomic analysis revealed that YAP1 inhibition induced a significant enrichment of gene sets related to keratinization and cornification, while depleting gene sets related to DNA repair and chromosome maintenance. Our data uncover a novel regulatory mechanism for esophageal stem cells, which could provide a potential strategy for esophageal regenerative medicine.

BEOL-Compatible 4F2 Oscillator Using Vertical InGaAs Biristor for Highly Scalable Monolithic 3D Ising Solver.

Ising solvers are important for efficiently addressing non-deterministic polynomial-time (NP)-hard combinatorial optimization problems (COPs), where scalability and compactness are crucial for practical applications. In this study, an experimental demonstration of an oscillator-based Ising solver employing a highly scalable 4F2 InGaAs bi-stable resistor (biristor) is presented. It is first explored the oscillation behavior of the InGaAs biristor, establishing that classical Ising spins can be emulated using the sub-harmonic injection locking (SHIL) technique. Furthermore, capacitive and resistive coupling between two coupled InGaAs biristors is demonstrated, leading to out-of-phase and in-phase coupling, respectively. Employing this foundational technology, it is experimentally achieved a solution to the MaxCUT problem with the InGaAs biristor-based Ising solver, supplemented by simulation-based behavior evaluations. This emerging device architecture offers a viable pathway to surmount the scaling limitations faced by present hardware-based Ising solvers, representing a significant step forward in the development of efficient, scalable solutions for complex optimization challenges.

Prevalence of Mutations in Mendelian Stroke Genes in Early Onset Stroke Patients.

OBJECTIVE: Heritability of stroke is assumed not to be low, especially in the young stroke population. However, most genetic studies have been performed in highly selected patients with typical clinical or neuroimaging characteristics. We investigated the prevalence of 15 Mendelian stroke genes and explored the relationships between variants and the clinical and neuroimaging characteristics in a large, unselected, young stroke population. METHODS: We enrolled patients aged ≤55 years with stroke or transient ischemic attack from a prospective, nationwide, multicenter stroke registry. We identified clinically relevant genetic variants (CRGVs) in 15 Mendelian stroke genes (GLA, NOTCH3, HTRA1, RNF213, ACVRL1, ENG, CBS, TREX1, ABCC6, COL4A1, FBN1, NF1, COL3A1, MT-TL1, and APP) using a customized, targeted next generation sequencing panel. RESULTS: Among 1,033 patients, 131 (12.7%) had 28 CRGVs, most frequently in RNF213 (n = 59), followed by ABCC6 (n = 53) and NOTCH3 (n = 15). The frequency of CRGVs differed by ischemic stroke subtypes (p < 0.01): the highest in other determined etiology (20.1%), followed by large artery atherosclerosis (13.6%). It also differed between patients aged ≤35 years and those aged 51 to 55 years (17.1% vs 9.3%, p = 0.02). Only 27.1% and 26.7% of patients with RNF213 and NOTCH3 variants had typical neuroimaging features of the corresponding disorders, respectively. Variants of uncertain significance (VUSs) were found in 15.4% patients. INTERPRETATION: CRGVs in 15 Mendelian stroke genes may not be uncommon in the young stroke population. The majority of patients with CRGVs did not have typical features of the corresponding monogenic disorders. Clinical implications of having CRGVs or VUSs should be explored. ANN NEUROL 2023;93:768-782.

Drug-resistant profiles of extracellular vesicles predict therapeutic response in TNBC patients receiving neoadjuvant chemotherapy.

BACKGROUND: Predicting tumor responses to neoadjuvant chemotherapy (NAC) is critical for evaluating prognosis and designing treatment strategies for patients with breast cancer; however, there are no reliable biomarkers that can effectively assess tumor responses. Therefore, we aimed to evaluate the clinical feasibility of using extracellular vesicles (EVs) to predict tumor response after NAC. METHODS: Drug-resistant triple-negative breast cancer (TNBC) cell lines were successfully established, which developed specific morphologies and rapidly growing features. To detect resistance to chemotherapeutic drugs, EVs were isolated from cultured cells and plasma samples collected post-NAC from 36 patients with breast cancer. RESULTS: Among the differentially expressed gene profiles between parental and drug-resistant cell lines, drug efflux transporters such as MDR1, MRP1, and BCRP were highly expressed in resistant cell lines. Drug efflux transporters have been identified not only in cell lines but also in EVs released from parental cells using immunoaffinity-based EV isolation. The expression of drug resistance markers in EVs was relatively high in patients with residual disease compared to those with a pathological complete response. CONCLUSIONS: The optimal combination of drug-resistant EV markers was significantly efficient in predicting resistance to NAC with 81.82% sensitivity and 92.86% specificity.

Sialylated IVIg promotes clinical improvements in a rabbit dry eye model by regulating inflammatory cytokines.

Dry eye disease (DED) is caused by a loss of homeostasis of the tear film, which results in visual disturbance, ocular surface inflammation and damage, and neurosensory abnormalities. Although it is prevalent in 5-50% of the global population, there are limited clinical options for its treatment. This study explored the potential use of human intravenous immunoglobulin (IVIg) and its enriched fractions of sialylation, sialylated IVIg (sIVIg), as a treatment for DED. Fifteen female New Zealand white rabbits were topically instilled with 0.2% benzalkonium chloride (BAC) twice daily for five consecutive days to induce experimental dry eye. Saline, 0.4% IVIg, or 0.04% sIVIg eye drops were instilled twice daily for 20 consecutive days. Clinical evaluations, such as non-invasive tear break-up time (NIBUT) and corneal fluorescein staining (CFS), were conducted. mRNA levels of mucin 4, mucin 16, TNF-α, IL-1ß, MMP9, IL-10, TGF-ß, and CD209 in rabbit conjunctival tissues were examined using reverse transcription polymerase chain reaction (RT-PCR) or quantitative RT-PCR (qRT-PCR). The relationships between CD209 family members in rabbits and various mammalian species were analyzed using a phylogenetic tree. IVIg or sIVIg treatment resulted in clinical improvements in the rabbit DED model. The inflammatory cytokines, TNF-α and IL-1ß, were increased and mucin 4 and mucin 16, cell surface-associated mucins, were decreased in BAC-induced dry eye. Following IVIg or sIVIg treatment, inflammatory cytokines decreased, whereas the anti-inflammatory cytokine, IL-10, increased substantially. Moreover, a 10-fold lower sIVIg treatment dose resulted in prolonged IL-10 production, representing a significantly improved DED compared to IVIg. Furthermore, the expression of rabbit CD209 mRNA in the rabbit conjunctiva and its close relationship with primate homologs suggest that it may interact with IVIg or sIVIg to promote IL-10 expression, as previously described in humans. At a lower dosage, sIVIg showed a more efficient improvement in DED, making it a promising new candidate medication for DED.

Evaluating the Efficacy of a Novel Hemostatic Powder Compared to Traditional Treatments in Non-Variceal Upper Gastrointestinal Bleeding: A Multicenter, Randomized Non-inferiority Study.

BACKGROUND AND AIMS: Hemostatic powders have been rapidly developed and used to treat gastrointestinal bleeding. We aimed to investigate the non-inferiority of the newly developed hemostatic powder (CEGP-003) compared to conventional endoscopic treatments for non-variceal upper gastrointestinal bleeding (NVUGIB). METHODS: This prospective, multicenter, randomized, open-label, controlled trial was conducted at four referral institutions. We enrolled consecutive patients who underwent emergency endoscopy for NVUGIB. The patients were randomly assigned to either the CEGP-003 or the conventional treatment group. In the CEGP-003 group, the hemostatic powder was applied as a spray. Conventional endoscopic treatments included electrical coagulation and hemoclipping. RESULTS: Between November 2019 and June 2022, 218 patients were enrolled (CEGP-003, 108; conventional, 110). Initial hemostasis was achieved in 104 of 108 patients (96.3%) in the CEGP-003 group and 101 of 110 patients (91.8%) in the conventional treatment group. The CEGP-003 group exhibited a significantly higher re-bleeding rate than the conventional treatment group. Multivariate analysis that age, duodenum and middle 1/3 of stomach, and CEGP-003 use as the initial hemostatic treatment were independent risk factors for re-bleeding. No adverse events were associated with CEGP-003. CONCLUSIONS: CEGP-003 demonstrates promise as an initial endoscopic therapy for NVUGIB, however close monitoring is warranted due to the risk of re-bleeding (Cris.nih.go.kr, number: KCT0004655).