Design, synthesis and bioactivity evaluation of 4-hydroxycoumarin derivatives as potential anti-inflammatory agents against acute lung injury and colitis.

Acute lung injury (ALI) and inflammatory bowel disease (IBD) are common inflammatory illnesses that seriously affect people's health. Herein, a series of 4-hydroxylcoumarin (4-HC) derivatives were designed and synthesized. The inhibitory effects of these compounds on LPS-induced interleukin-6 (IL-6) release from J774A.1 cells were then screened via ELISA assay, compound B8 showed 3 times more active than the lead compound 4-HC. The most active compound B8 had the IC50 values of 4.57 µM and 6.51 µM for IL-6 release on mouse cells J774A.1 and human cells THP-1, respectively. Furthermore, we also found that B8 could act on the MAPK pathway. Based on the target prediction results of computer virtual docking, kinase inhibitory assay was carried out, and it revealed that targeting IRAK1 was a key mechanism for B8 to exert anti-inflammatory activity. Moreover, B8 exerted a good therapeutic effect on the dextran sulfate sodium (DSS)-induced colitis model and liposaccharide (LPS)-induced ALI mouse models. The acute toxicity experiments indicated that high-dose B8 caused no adverse reactions in mice, confirming its safety in vivo. Additionally, the preliminary pharmacokinetic (PK) parameters of B8 in SD rats were also examined, revealing a bioavailability (F) of 28.72 %. In conclusion, B8 is a potential candidate of drug for the treatment of ALI and colitis.

Impact of temperature-controlled endobiliary radiofrequency ablation for inoperable hilar cholangiocarcinoma: A propensity score-matched analysis.

Background and study aims Endobiliary radiofrequency ablation (RFA) can be an effective palliative treatment, but few studies have evaluated its outcomes for malignant obstruction in the hilar bile duct, which has a thin wall and complex duct-vascular contacts. We evaluated the efficacy and safety of temperature-controlled endobiliary RFA, which can reduce the risk of unintentional thermal injury by maintaining the temperature of the ablation segment, in the treatment of inoperable hilar cholangiocarcinoma (CCA). Patients and methods After propensity score matching, 64 patients with inoperable hilar CCA were categorized to the RFA + stent group (endobiliary RFA with stenting; n=32) or stent-only group (stenting only; n=32). The evaluated outcomes were the median time to recurrent biliary obstruction (RBO), overall survival (OS), and adverse events (AEs). Results Technical success was achieved in all patients. The clinical success rate was 93.8% in the RFA + stent group and 87.5% in the stent-only group ( P =0.672). The median time to RBO was 242 days in the RFA + stent group and 168 days in the stent-only group ( P =0.031). The median OS showed a non-significant tendency to be higher in the RFA + stent group (337 versus 296 days; P =0.260). Overall AE rates were comparable between the two groups (12.5% vs 9.4%, P =1.000). Conclusions Temperature-controlled endobiliary RFA resulted in favorable stent patency without increasing the rate of AEs but it did not significantly increase OS in patients with inoperable hilar CCA (Clinical trial registration number: KCT0008576).

The activin/BMP-2 chimera AB204 promotes periodontal tissue regeneration in a buccal dehiscence model: a pilot study.

PURPOSE: A combination of activin and bone morphogenetic protein-2 (BMP-2), termed AB204, has been shown to improve osteogenic potential with fewer side effects than BMP-2 alone. This study was performed to evaluate the effect of AB204 on periodontal tissue regeneration in a dog buccal dehiscence model. METHODS: Buccal dehiscence defects were created on the maxillary premolars (P1, P2, and P3) of 6 mongrel dogs. After 5 weeks, the dogs were randomly assigned to 1 of 3 groups: the control, collagen matrix (CM), and CM/AB204 groups. Grafting procedures were then performed. The dogs were sacrificed 8 weeks after the grafting procedure, and volumetric and histological analyses were conducted. RESULTS: The thickness of the buccal gingiva in the CM/AB204 group was greater than those in the other groups at 2 weeks (P<0.05). The ridge width in the AB204/CM group exceeded the width in the other groups at 4 and 8 weeks; however, the difference was not statistically significant. Histological analysis revealed that the CM/AB204 group demonstrated the formation of new bone surrounded by newly formed periodontal ligament and cementum (P=0.035). CONCLUSIONS: The combined application of CM and AB204 shows promise in facilitating the regeneration of periodontal attachment, including the formation of new bone, cementum, and periodontal ligament.

Bone regeneration using activin A/BMP2 chimera (AB204) with collagen membrane in rats with calvarial defects.

PURPOSE: Collagen has long been recognized as an excellent carrier for growth factors, and membrane-type collagen has been widely applied in dentistry for guided bone regeneration. This study was conducted to examine the effects of an activin A/BMP2 chimera (AB204) combined with a collagen membrane (CM) on bone repair in a rat calvarial defect model. METHODS: A unilateral calvarial defect measuring 5.0 mm was surgically created in 32 Sprague-Dawley rats. The rats were then randomly assigned to 1 of 4 groups, each consisting of 8 animals: control (untreated), CM (treated with a CM only), CM/bone morphogenetic protein 2 (BMP2) (treated with a CM and 1.0 µg of BMP2), and CM/AB204 (treated with a CM and 1.0 µg of AB204). Bone regeneration was evaluated using micro-computed tomography (CT) and histological analysis at 2 and 4 weeks following surgery. RESULTS: Micro-CT analysis revealed that bone formation in the CM/BMP2 and CM/AB204 groups was superior to that observed in the control and CM groups at both 2 and 4 weeks postoperatively. BMP2 induced greater bone regeneration than AB204 at 2 weeks; however, AB204 resulted in a greater bone volume at 4 weeks, achieving the highest values recorded. No significant differences were found between the CM/BMP2 and CM/AB204 groups at either time point (P>0.05). On histological examination, new bone formation was evident in both CM/BMP2 and CM/AB204 groups. CONCLUSIONS: Within the limitations of this study, the findings indicate that AB204 may enhance osteogenic potential when used in combination with CM for bone regeneration.

Perspectives on Electronic Nicotine Delivery System Use Cessation Among Adults in Rural Areas: Implications for Future Studies.

INTRODUCTION: More young adults (age 18-24 years) in rural areas versus urban areas use electronic nicotine delivery systems (ENDS) - also known as e-cigarettes. Little is known about young adults' perceptions toward ENDS use and cessation. The objective of this study was to examine barriers and facilitators to ENDS use cessation among young adults living in rural areas, as well as their perceptions about ENDS use and cessation and to determine implications for future cessation studies. METHODS: We administered cross-sectional online surveys to young adults living in rural Midwestern counties. A total of 100 individuals responded to the surveys. Descriptive statistics were used to report their perceptions of ENDS use as well as barriers and facilitators to ENDS use cessation. The content analysis method was used to analyze the answers to an open-ended question regarding perceptions about the ENDS use cessation in the context of rural areas. RESULTS: Barriers to ENDS use cessation included perceived advantages to ENDS use, high nicotine dependence, and the perception that ENDS use was less harmful cigarettes. Facilitators to ENDS use cessation included cost of ENDS use, perceived harm, and high confidence in ability to quit. Participants' perceptions about ENDS use cessation in the context of rural areas were conceptualized under the themes of (1) exposure to and initiation of ENDS use, (2) continuation of ENDS use, and (3) prevention and cessation of ENDS use. CONCLUSIONS: Health care providers, tobacco control researchers, and public health advocates should be aware of barriers and facilitators to ENDS use cessation among young adults for future cessation intervention studies relevant specifically to rural areas.

Comparison of disposable digital single-operator cholangioscopy versus direct peroral cholangioscopy for the diagnosis of intraductal superficial lesions of the bile duct.

BACKGROUND AND AIMS: Disposable digital single-operator cholangioscopy (D-SOC) and direct peroral cholangioscopy (D-POC) using an ultraslim endoscope are established POC modalities for the diagnosis and treatment of various biliary diseases. We compared the usefulness of D-SOC and D-POC for the diagnosis of intraductal superficial lesions of the bile duct (ISL-Bs). METHODS: In total, 38 consecutive patients with suspected biliary diseases who underwent both D-SOC and D-POC were enrolled. The primary outcome was the detection rate of the ISL-Bs, and the secondary outcomes were the technical success of POC and POC-guided forceps biopsy sampling (POC-FB), procedure time, visualization quality, and tissue adequacy. RESULTS: D-SOC had a higher technical success rate than D-POC but without a statistically significant difference (100% vs. 92.1%, P = 0.248). D-POC had a marginally higher ISL-B detection rate (34.2% vs. 28.9%, P = 0.683) and significantly higher visualization quality (P = 0.033). The mean procedure time was significantly shorter with D-SOC (11.00 ± 1.34 vs. 19.03 ± 2.95 min, P < 0.001). The technical success rate of POC-FB and tissue adequacy did not differ between the two techniques (D-SOC vs. D-POC: 81.8% vs. 84.6%, P = 0.693 and 77.8% vs. 90.9%, P = 0.566). CONCLUSIONS: Our results demonstrate that both POC systems are safe and useful for the detection, characterization, and diagnosis of minute ISL-Bs. While D-SOC displayed a shorter procedure time and a tendency for higher technical success rate, D-POC provided superior visualization quality, allowing detailed observation of the surface structure and microvascular patterns.

Unhealthy Weight Control Behaviors according to the Status of Combustible Cigarette and Noncombustible Nicotine or Tobacco Product Use among Korean Adolescents with Experience Attempting to Reduce or Maintain Their Body Weight: The 15th Korea Youth Risk Behavior Survey, 2019.

Background: Noncombustible nicotine or tobacco product (NNTP) use, and cigarette smoking are associated with a high likelihood of unhealthy weight control behaviors (UWCBs) among adolescents. However, no study has addressed the differences in UWCBs among non-users, single users of combustible cigarettes (CCs) or NNTPs and dual users. This study compared the frequencies of weight control behaviors according to the status of CC and NNTP use among Korean adolescents. Methods: This was a cross-sectional study of 25,094 adolescents who had attempted to reduce or maintain their body weight during the past 30 days, using data from the 15th Korea Youth Risk Behavior Survey, 2019. Data on the status of CC and NNTP use, weight status, and weight control behaviors were obtained using self-report questionnaires. Subjects were categorized into four groups: non-users, cigarette-only users, NNTP-only users, and dual users. Results: Among boys and girls, current smokers and NNTP users were 8.9%±0.3% and 5.5%±0.3%, and 4.2%±0.2% and 1.7%±0.1%, respectively. Among boys, NNTP-only users were more likely to engage in extreme weight control behaviors than non-users. Among girls, users of either CCs or NNTPs were more likely to engage in extreme weight control behaviors and less extreme weight control behaviors than non-users. Conclusion: This study shows that users of either CCs or NNTPs are more likely to engage in UWCBs, and NNTP-only users are the most likely to do so.

Adipocyte-Specific Disruption of the BBSome Causes Metabolic and Autonomic Dysfunction.

Obesity is a major public health issue due to its association with type 2 diabetes, hypertension, and other cardiovascular risks. The BBSome, a complex of 8 conserved Bardet-Biedl Syndrome (BBS) proteins, has emerged as a key regulator of energy and glucose homeostasis as well as cardiovascular function. However, the importance of adipocyte BBSome in controlling these physiological processes is not clear. Here, we show that adipocyte-specific constitutive disruption of the BBSome through selective deletion of the Bbs1 gene (AdipoCre/Bbs1fl/fl mice) does not affect body weight under normal chow or high fat & high sucrose diet (HFHSD). However, constitutive BBSome defiency caused impairment in glucose tolerance and insulin sensitivity. Similar phenotypes were observed after inducible adipocyte-specific constitutive disruption of the BBSome (AdipoCreERT2/Bbs1fl/fl mice). Interestingly, a significant increase in renal sympathetic nerve activity, measured using multifiber recording in the conscious state, was observed in AdipoCre/Bbs1fl/fl mice on both chow and HFHSD. A significant increase in tail-cuff arterial pressure was also observed in chow-fed AdipoCre/Bbs1fl/fl mice, but this was not reproduced when arterial pressure was measured by radiotelemetry. Moreover, AdipoCre/Bbs1fl/fl mice had no significant alterations in vascular reactivity. On the other hand, AdipoCre/Bbs1fl/fl mice displayed impaired baroreceptor reflex sensitivity when fed HFHSD, but not on normal chow. Taken together, these data highlight the relevance of the adipocyte BBSome for the regulation of glucose homeostasis, sympathetic traffic. The BBSome also contribute to baroreflex sensitivity under HFHSD, but not normal chow.

Clinical Portrait of Cochlear Implantation in Patients With CHARGE Syndrome.

OBJECTIVE: To examine the clinical characteristics and auditory performance of patients with CHARGE syndrome following cochlear implantation (CI), as well as the prognostic factors affecting auditory outcomes. STUDY DESIGN: Retrospective cohort. SETTING: Tertiary academic center. METHODS: A retrospective chart review was performed in patients with CHARGE syndrome who underwent CI from 2007 to 2022. The category of auditory performance (CAP) score was used to assess the CI outcomes, and factors that may affect the speech outcomes were also evaluated. RESULTS: In 14 children with CHARGE syndrome, 22 CIs were performed, 6 unilaterally and 8 bilaterally. The mean age at CI was 25.9 months (range: 10-62). All patients had ear abnormalities and developmental delays, and cochlear nerve deficiency (CND) was present in all ears. At the last follow-up (mean: 49.6 months), the mean CAP score improved significantly compared to the preoperative measure (from 0.36 ± 0.81 to 3.21 ± 1.70, P = .001), with 6 patients (42.9%) achieving a CAP score of 4 points or higher. However, between the unilateral and bilateral CI groups, the final CAP score or change in CAP score was similar. Factors including age, coloboma, and CND did not significantly affect speech outcomes (all P > .05). CONCLUSION: Even though CHARGE syndrome features challenging anomalies, CI can be conducted safely and can offer effective contribution to significant speech improvement. Patients with CHARGE syndrome should be given the opportunity to undergo CI to maximize their audiological progress.

Status and perception of point-of-care ultrasound education in Korean medical schools: A national cross-sectional study.

As point-of-care ultrasound (POCUS) is increasingly being used in clinical settings, ultrasound education is expanding into student curricula. We aimed to determine the status and awareness of POCUS education in Korean medical schools using a nationwide cross-sectional survey. In October 2021, a survey questionnaire consisting of 20 questions was distributed via e-mail to professors in the emergency medicine (EM) departments of Korean medical schools. The questionnaire encompassed 19 multiple-choice questions covering demographics, current education, perceptions, and barriers, and the final question was an open-ended inquiry seeking suggestions for POCUS education. All EM departments of the 40 medical schools responded, of which only 13 (33%) reported providing POCUS education. The implementation of POCUS education primarily occurred in the third and fourth years, with less than 4 hours of dedicated training time. Five schools offered a hands-on education. Among schools offering ultrasound education, POCUS training for trauma cases is the most common. Eight schools had designated professors responsible for POCUS education and only 2 possessed educational ultrasound devices. Of the respondents, 64% expressed the belief that POCUS education for medical students is necessary, whereas 36%, including those with neutral opinions, did not anticipate its importance. The identified barriers to POCUS education included faculty shortages (83%), infrastructure limitations (76%), training time constraints (74%), and a limited awareness of POCUS (29%). POCUS education in Korean medical schools was limited to a minority of EM departments (33%). To successfully implement POCUS education in medical curricula, it is crucial to clarify learning objectives, enhance faculty recognition, and improve the infrastructure. These findings provide valuable insights for advancing ultrasound training in medical schools to ensure the provision of high-quality POCUS education for future healthcare professionals.

Eosinophilia is a favorable marker for pneumonia in chronic obstructive pulmonary disease.

Background: Patients with chronic obstructive pulmonary disease (COPD) expressing eosinophilia experience slightly fewer episodes of community-acquired pneumonia (CAP) than those without eosinophilia. However, the severity and burden of hospitalized pneumonia patients with COPD concerning eosinophilia have not been assessed. Methods: We evaluated the differences in clinical characteristics between patients with CAP and COPD with or without eosinophilia by a post-hoc analysis of a prospective, multi-center, cohort study data. Results: Of 349 CAP patients with COPD, 45 (12.9%) had eosinophilia (blood eosinophil ≥ 300 cells/µL). Patients with eosinophilia had a lower sputum culture percentile (8.1% vs. 23.4%, P < 0.05), a lower percentile of neutrophils (70.3% vs 80.2%, P<0.05), reduced C-reactive protein levels (30.6 mg/L vs 86.6 mg/L, P<0.05), and a lower pneumonia severity index score (82.5 vs. 90.0, P < 0.05) than those without eosinophilia. The duration of antibiotic treatment (8.0 days vs. 10.0 days, P < 0.05) and hospitalization (7.0 days vs. 9.0 days, P < 0.05) were shorter in eosinophilic patients. The cost of medical care per day (256.4 US$ vs. 291.0 US$, P < 0.05), cost for the medication (276.4 US$ vs. 349.9 US$, P < 0.05), and cost for examination (685.5 US$ vs 958.1 US$, P<0.05) were lower in patients with eosinophilia than those without eosinophilia. Conclusion: Eosinophilia serves as a favorable marker for severity of pneumonia, health-care consumption, and cost of medical care in patients with CAP and COPD.

Multicentric reticulohistiocytosis post-COVID-19: a case report.

Background: Multicentric reticulohistiocytosis (MRH) stands as a rare and challenging systemic granulomatous disease characterized by its predilection for skin and joint involvement, confounding clinicians with its infrequent presentation and systemic manifestations. Case Description: This compelling case presentation unravels the intricate complexity of MRH, exemplifying its unique clinical course. Following mild upper respiratory coronavirus disease 2019 (COVID-19) symptoms, the patient manifested purplish-pink papular lesions on both the skin and mucosa, accompanied by debilitating arthralgias. A diagnostic skin biopsy, a pivotal tool in MRH diagnosis, confirmed the presence of this granulomatous disorder, underlining its systemic impact. Strategic therapeutic intervention involving a combination of steroids and methotrexate demonstrated remarkable efficacy, culminating in the resolution of symptoms within 3-month. The absence of malignancy upon thorough screening further amplifies the perplexing nature of MRH. Conclusions: This seminal case not only bridges the realms of rare systemic disorders but also marks the first known instance of MRH emerging post-COVID-19. It underscores the imperative consideration of MRH in analogous scenarios and provides invaluable insights into the nuanced interplay of MRH symptoms, diagnosis, and therapeutic strategies following viral triggers. This comprehensive exploration enriches our scientific understanding, offering nuanced perspectives on the manifestations and intricate dynamics of MRH in the context of post-viral sequelae.

CerviLearnNet: Advancing cervical cancer diagnosis with reinforcement learning-enhanced convolutional networks.

Women tend to face many problems throughout their lives; cervical cancer is one of the most dangerous diseases that they can face, and it has many negative consequences. Regular screening and treatment of precancerous lesions play a vital role in the fight against cervical cancer. It is becoming increasingly common in medical practice to predict the early stages of serious illnesses, such as heart attacks, kidney failure, and cancer, using machine learning-based techniques. To overcome these obstacles, we propose the use of auxiliary modules and a special residual block, to record contextual interactions between object classes and to support the object reference strategy. Unlike the latest state-of-the-art classification method, we create a new architecture called the Reinforcement Learning Cancer Network, "RL-CancerNet", which diagnoses cervical cancer with incredible accuracy. We trained and tested our method on two well-known publicly available datasets, SipaKMeD and Herlev, to assess it and enable comparisons with earlier methods. Cervical cancer images were labeled in this dataset; therefore, they had to be marked manually. Our study shows that, compared to previous approaches for the assignment of classifying cervical cancer as an early cellular change, the proposed approach generates a more reliable and stable image derived from images of datasets of vastly different sizes, indicating that it will be effective for other datasets.

Long-term follow-up results of facial nerve schwannoma with good facial nerve function: a multicenter study.

PURPOSE: Facial nerve schwannomas (FNSs) are rare intracranial tumors, and the optimal management of these tumors remains unclear. We investigated the long-term follow-up results of FNS with good facial nerve function. METHODS: At nine medical centers in the Korean Facial Nerve Study Group, 43 patients undergoing observation periods longer than 12 months for FNS with good facial nerve function (House-Brackmann grade ≤ II) were enrolled, and clinical and radiographic data were obtained for these cases. RESULTS: The mean follow-up period was 63 months. In the majority of cases, tumors involved multiple segments (81.4%) and only eight cases were confined to a single site. There were no cases where the tumor was confined to the extratemporal region. Tumor size increased slightly, with an average estimated change of 0.48 mm/year. Twenty (46.5%) of 43 patients showed no change in tumor size. Seven patients (16.3%) showed worsening House-Brackmann (H-B) grade, of which two patients deteriorated from H-B grade I to II, four worsened to grade III, and one deteriorated to grade IV. The remaining 36 patients (83.7%) showed no change in facial nerve function. There was no difference in H-B grade according to tumor size at the time of diagnosis or change in tumor size. CONCLUSION: We conducted a large-scale observational study of FNS with good facial nerve function. Our study showed that many patients maintained facial nerve function during long-term follow-up. Conservative management with regular examination and imaging can be an appropriate option for managing FNS with good facial nerve function.

Perspectives on improving photosynthesis to increase crop yield.

Improving photosynthesis, the fundamental process by which plants convert light energy into chemical energy, is a key area of research with great potential for enhancing sustainable agricultural productivity and addressing global food security challenges. This perspective delves into the latest advancements and approaches aimed at optimizing photosynthetic efficiency. Our discussion encompasses the entire process, beginning with light harvesting and its regulation and progressing through the bottleneck of electron transfer. We then delve into the carbon reactions of photosynthesis, focusing on strategies targeting the enzymes of the Calvin-Benson-Bassham (CBB) cycle. Additionally, we explore methods to increase CO2 concentration near the Rubisco, the enzyme responsible for the first step of CBB cycle, drawing inspiration from various photosynthetic organisms, and conclude this section by examining ways to enhance CO2 delivery into leaves. Moving beyond individual processes, we discuss two approaches to identifying key targets for photosynthesis improvement: systems modeling and the study of natural variation. Finally, we revisit some of the strategies mentioned above to provide a holistic view of the improvements, analyzing their impact on nitrogen use efficiency and on canopy photosynthesis.

Computational drug repositioning with attention walking.

Drug repositioning aims to identify new therapeutic indications for approved medications. Recently, the importance of computational drug repositioning has been highlighted because it can reduce the costs, development time, and risks compared to traditional drug discovery. Most approaches in this area use networks for systematic analysis. Inferring drug-disease associations is then defined as a link prediction problem in a heterogeneous network composed of drugs and diseases. In this article, we present a novel method of computational drug repositioning, named drug repositioning with attention walking (DRAW). DRAW proceeds as follows: first, a subgraph enclosing the target link for prediction is extracted. Second, a graph convolutional network captures the structural features of the labeled nodes in the subgraph. Third, the transition probabilities are computed using attention mechanisms and converted into random walk profiles. Finally, a multi-layer perceptron takes random walk profiles and predicts whether a target link exists. As an experiment, we constructed two heterogeneous networks with drug-drug similarities based on chemical structures and anatomical therapeutic chemical classification (ATC) codes. Using 10-fold cross-validation, DRAW achieved an area under the receiver operating characteristic (ROC) curve of 0.903 and outperformed state-of-the-art methods. Moreover, we demonstrated the results of case studies for selected drugs and diseases to further confirm the capability of DRAW to predict drug-disease associations.

Novel strategies for modulating the gut microbiome for cancer therapy.

Recent advancements in genomics, transcriptomics, and metabolomics have significantly advanced our understanding of the human gut microbiome and its impact on the efficacy and toxicity of anti-cancer therapeutics, including chemotherapy, immunotherapy, and radiotherapy. In particular, prebiotics, probiotics, and postbiotics are recognized for their unique properties in modulating the gut microbiota, maintaining the intestinal barrier, and regulating immune cells, thus emerging as new cancer treatment modalities. However, clinical translation of microbiome-based therapy is still in its early stages, facing challenges to overcome physicochemical and biological barriers of the gastrointestinal tract, enhance target-specific delivery, and improve drug bioavailability. This review aims to highlight the impact of prebiotics, probiotics, and postbiotics on the gut microbiome and their efficacy as cancer treatment modalities. Additionally, we summarize recent innovative engineering strategies designed to overcome challenges associated with oral administration of anti-cancer treatments. Moreover, we will explore the potential benefits of engineered gut microbiome-modulating approaches in ameliorating the side effects of immunotherapy and chemotherapy.

Impact of IL-1ß on lung pathology caused by Mycobacterium abscessus infection and its association with IL-17 production.

Mycobacterium abscessus (MAB), a non-tuberculous mycobacterium (NTM), causes chronic pulmonary inflammation in humans. The NLRP3 inflammasome is a multi-protein complex that triggers IL-1ß maturation and pyroptosis through the cleavage of caspase-1. In this study, we investigated the roles of NLRP3 and IL-1ß in the host's defense against MAB. The IL-1ß production by MAB was completely abolished in NLRP3, but not NLRC4, deficient macrophages. The NLRP3 inflammasome components, which are ASC and caspase-1 were also found to be essential for IL-1ß production in response to MAB. NLRP3 and IL-1ß deficiency did not affect the intracellular growth of MAB in macrophages, and the bacterial burden in lungs of NLRP3- and IL-1ß-deficient mice was also comparable to the burden observed in WT mice. In contrast, IL-1ß deficiency ameliorated lung pathology in MAB-infected mice. Notably, the lung homogenates of IL-1ß-deficient mice had reduced levels of IL-17, but not IFN-γ and IL-4 when compared with WT counterparts. Furthermore, in vitro co-culture analysis showed that IL-1ß signaling was essential for IL-17 production in response to MAB. Finally, we observed that the anti-IL-17 antibody administration moderately mitigated MAB-induced lung pathology. These findings indicated that IL-1ß production contribute to MAB-induced lung pathology via the elevation of IL-17 production.

Sleep duration, sleep efficiency, and amyloid ß among cognitively healthy later-life adults: a systematic review and meta-analysis.

BACKGROUND: Abnormal amyloid ß (Aß) deposits in the brain are a hallmark of Alzheimer's disease (AD). Insufficient sleep duration and poor sleep quality are risk factors for developing AD. Sleep may play a role in Aß regulation, but the magnitude of the relationship between sleep and Aß deposition remains unclear. This systematic review examines the relationship between sleep (i.e., duration and efficiency) with Aß deposition in later-life adults. METHODS: A search of PubMed, CINAHL, Embase, and PsycINFO generated 5,005 published articles. Fifteen studies met the inclusion criteria for qualitative syntheses; thirteen studies for quantitative syntheses related to sleep duration and Aß; and nine studies for quantitative syntheses related to sleep efficiency and Aß. RESULTS: Mean ages of the samples ranged from 63 to 76 years. Studies measured Aß using cerebrospinal fluid, serum, and positron emission tomography scans with two tracers: Carbone 11-labeled Pittsburgh compound B or fluorine 18-labeled. Sleep duration was measured subjectively using interviews or questionnaires, or objectively using polysomnography or actigraphy. Study analyses accounted for demographic and lifestyle factors. Based on 13 eligible articles, our synthesis demonstrated that the average association between sleep duration and Aß was not statistically significant (Fisher's Z = -0.055, 95% CI = -0.117 ~ 0.008). We found that longer self-report sleep duration is associated with lower Aß (Fisher's Z = -0.062, 95% CI = -0.119 ~ -0.005), whereas the objectively measured sleep duration was not associated with Aß (Fisher's Z = 0.002, 95% CI = -0.108 ~ 0.113). Based on 9 eligible articles for sleep efficiency, our synthesis also demonstrated that the average association between sleep efficiency and Aß was not statistically significant (Fisher's Z = 0.048, 95% CI = -0.066 ~ 0.161). CONCLUSION: The findings from this review suggest that shorter self-reported sleep duration is associated with higher Aß levels. Given the heterogeneous nature of the sleep measures and outcomes, it is still difficult to determine the exact relationship between sleep and Aß. Future studies with larger sample sizes should focus on comprehensive sleep characteristics and use longitudinal designs to better understand the relationship between sleep and AD.

Ketonuria as an Indicator of Improvement of Renal Function in Patients with Type 2 Diabetes Receiving SGLT2 Inhibitor Treatment.

We investigated the potential association between ketonuria during treatment with sodium-glucose cotransporter-2 (SGLT2) inhibitors and its renoprotective effect in patients with type 2 diabetes. We included 192 patients who had received SGLT2 inhibitors for more than 6 months. After propensity score matching, 52 patients each were allocated into groups with or without ketonuria, respectively. The estimated glomerular filtration rate exhibited a significant improvement only in subjects with ketonuria (without ketonuria: mean difference, -0.02 mL/min/1.73 m2 [95% confidence interval (CI), -3.87 to 3.83 mL/min/1.73 m2] vs. with ketonuria: mean difference, 6.81 mL/min/1.73 m2 [95% CI, 3.16 to 10.46 mL/min/1.73 m2]; P<0.001). Improvement in estimated glomerular filtration rate at 6 months was associated with female sex and lower baseline body weight, blood pressure, and triglyceride levels in patients with ketonuria. In conclusion, the presence of ketonuria was associated with the renoprotective effect of SGLT2 inhibitors, and female sex and the absence of metabolic syndrome components may serve as additional indicators of these medications' substantial renoprotective effects in individuals with ketonuria.