Efficacy of a real-time intelligent quality-control system for the detection of early upper gastrointestinal neoplasms: a multicentre, single-blinded, randomised controlled trial.

Background: Oesophagogastroduodenoscopy (OGD) quality and identification of the early upper gastrointestinal (UGI) neoplasm play an important role in detecting the UGI neoplasm. However, the optimal method for quality control in daily OGD procedures is currently lacking. We aimed to evaluate the efficacy of a real-time intelligent quality-control system (IQCS), which combines OGD quality control with lesion detection of early UGI neoplasms. Methods: We performed a multicentre, single-blinded, randomised controlled trial at 6 hospitals in China. Patients aged 40-80 years old who underwent painless OGD were screened for enrolment in this study. Patients with a history of advanced UGI cancer, stenosis, or obstruction in UGI tract were excluded. Eligible subjects were randomly assigned (1:1) to either the routine or IQCS group to undergo standard OGD examination and OGD examination aided by IQCS, respectively. Patients were masked to the randomisation status. The primary outcome was the detection of early UGI neoplasms. All analyses were done on a per-protocol basis. This trial is registered with ClinicalTrials.gov, NCT04720924. Findings: Between January 16, 2021 and December 23, 2022, 1840 patients were randomised (IQCS group: 919, routine group: 921). The full analysis set consisted of 914 in the IQCS group and 915 in the routine group. The early UGI neoplasms detection rate in the IQCS group (6.1%, 56/914) was significantly higher than in the routine group (2.3%, 21/915; P = 0.0001). The IQCS group had fewer blind spots (2.3 vs. 6.2, P < 0.0001). The IQCS group had higher stomach cleanliness on cardia or fundus (99.5% vs. 87.9%, P < 0.0001), body (98.9% vs. 88.0%, P < 0.0001), angulus (99.8% vs. 88.4%, P < 0.0001) and antrum or pylorus (100.0% vs. 87.4%, P < 0.0001). The inspection time (576.2 vs. 574.5s, P = 0.91) and biopsy rate (57.2% vs. 56.6%, P = 0.83) were not different between the groups. The early UGI neoplasms detection rate in the IQCS group increased in both non-academic centres (RR = 3.319, 95% CI 1.277-9.176; P = 0.0094) and academic centres (RR = 2.416, 95% CI 1.301-4.568; P = 0.0034). The same improvements were observed for both less-experienced endoscopists (RR = 2.650, 95% CI 1.330-5.410; P = 0.0034) and experienced endoscopists (RR = 2.710, 95% CI 1.226-6.205; P = 0.010). No adverse events or serious adverse events were reported in the two groups. Interpretation: The IQCS improved the OGD quality and increased early UGI neoplasm detection in different hospital types and endoscopist experiences. IQCS could play an important role in primary basic hospitals and non-expert endoscopists to improve the diagnostic accuracy of early UGI neoplasms. The effectiveness of IQCS in real-world clinical settings needs a larger population validation. Funding: Key R&D Program of Shandong Province, China (Major Scientific and Technological Innovation Project), National Natural Science Foundation of China, the Taishan Scholars Program of Shandong Province, the National Key Research and Development Program of China, and the Shandong Provincial Natural Science Foundation.

Exploration of the Muribaculaceae Family in the Gut Microbiota: Diversity, Metabolism, and Function.

The gut microbiota are mainly composed of Bacteroidetes and Firmicutes and are crucial for metabolism and immunity. Muribaculaceae are a family of bacteria within the order Bacteroidetes. Muribaculaceae produce short-chain fatty acids via endogenous (mucin glycans) and exogenous polysaccharides (dietary fibres). The family exhibits a cross-feeding relationship with probiotics, such as Bifidobacterium and Lactobacillus. The alleviating effects of a plant-based diet on inflammatory bowel disease, obesity, and type 2 diabetes are associated with an increased abundance of Muribaculaceae, a potential probiotic bacterial family. This study reviews the current findings related to Muribaculaceae and systematically introduces their diversity, metabolism, and function. Additionally, the mechanisms of Muribaculaceae in the alleviation of chronic diseases and the limitations in this field of research are introduced.

miR-340-3p-modified bone marrow mesenchymal stem cell-derived exosomes inhibit ferroptosis through METTL3-mediated m6A modification of HMOX1 to promote recovery of injured rat uterus.

BACKGROUND: Ferroptosis is associated with the pathological progression of hemorrhagic injury and ischemia-reperfusion injury. According to our previous study, exosomes formed through bone marrow mesenchymal stem cells modified with miR-340-3p (MB-exos) can restore damaged endometrium. However, the involvement of ferroptosis in endometrial injury and the effect of MB-exos on ferroptosis remain elusive. METHODS: The endometrial injury rat model was developed. Exosomes were obtained from the supernatants of bone marrow mesenchymal stromal cells (BMSCs) and miR-340/BMSCs through differential centrifugation. We conducted RNA-seq analysis on endometrial tissues obtained from the PBS and MB-exos groups. Ferroptosis was induced in endometrial stromal cells (ESCs) by treating them with erastin or RSL3, followed by treatment with B-exos or MB-exos. We assessed the endometrial total m6A modification level after injury and subsequent treatment with B-exos or MB-exos by methylation quantification assay. We performed meRIP-qPCR to analyze m6A modification-regulated endogenous mRNAs. RESULTS: We reveal that MB-exos facilitate the injured endometrium to recover by suppressing ferroptosis in endometrial stromal cells. The injured endometrium showed significantly upregulated N6-methyladenosine (m6A) modification levels; these levels were attenuated by MB-exos through downregulation of the methylase METTL3. Intriguingly, METTL3 downregulation appears to repress ferroptosis by stabilizing HMOX1 mRNA, thereby potentially elucidating the mechanism through which MB-exos inhibit ferroptosis in ESCs. We identified YTHDF2 as a critical m6A reader protein that contributes to HMOX1 mRNA degradation. YTHDF2 facilitates HMOX1 mRNA degradation by identifying the m6A binding site in the 3'-untranslated regions of HMOX1. In a rat model, treatment with MB-exos ameliorated endometrial injury-induced fibrosis by inhibiting ferroptosis in ESCs. Moreover, METTL3 short hairpin RNA-mediated inhibition of m6A modification enhanced the inhibitory effect of MB-exos on ferroptosis in endometrial injury. CONCLUSIONS: Thus, these observations provide new insights regarding the molecular mechanisms responsible for endometrial recovery promotion by MB-exos and highlight m6A modification-dependent ferroptosis inhibition as a prospective therapeutic target to attenuate endometrial injury.

Identification, screening and molecular mechanisms of natural stable angiotensin-converting enzyme (ACE) inhibitory peptides from foxtail millet protein hydrolysates: a combined in silico and in vitro study.

The stability of bioactive peptides under various food processing conditions is the basis for their use in industrial manufacturing. This study aimed to identify natural ACE inhibitors with excellent stability and investigate their physicochemical properties and putative molecular mechanisms. Five novel ACE inhibitory peptides (QDPLFPL, FPGVSPF, SPAQLLPF, LVPYRP, and WYWPQ) were isolated and identified using RP-HPLC and Nano LC-MS/MS with foxtail millet protein hydrolysates as the raw material. These peptides are non-toxic and exhibit strong ACE inhibitory activity in vitro (IC50 values between 0.13 mg mL-1 and 0.56 mg mL-1). In addition to QDPLFPL, FPGVSPF, SPAQLLPF, LVPYRP, and WYWPQ have excellent human intestinal absorption. Compared to FPGVSPF and SPAQLLPF, the stable helical structure of LVPYRP and WYWPQ allows them to maintain high stability under conditions that mimic gastrointestinal digestion and various food processing (temperatures, pH, sucrose, NaCl, citric acid, sodium benzoate, Cu2+, Zn2+, K+, Mg2+, Ca2+). The results of molecular docking and molecular dynamics simulation suggest that LVPYRP has greater stability and binding capacity to ACE than WYWPQ. LVPYRP might attach to the active pockets (S1, S2, and S1') of ACE via hydrogen bonds and hydrophobic interactions, then compete with Zn2+ in ACE to demonstrate its ACE inhibitory activity. The binding of LVPYRP to ACE enhances the rearrangement of ACE's active structural domains, with electrostatic and polar solvation energy contributing the most energy to the binding. Our findings suggested that LVPYRP derived from foxtail millet protein hydrolysates has the potential to be incorporated into functional foods to provide antihypertensive benefits.

Adverse events following immunization of co- and separate administration of DTaP-IPV/Hib vaccines: A real-world comparative study.

To fully understand the safety of DTaP-IPV/Hib vaccination, we evaluated the differences between DTaP-IPV/Hib co-administration and separate administration of the DTaP, IPV and Hib vaccines (DTaP+IPV+Hib) based on adverse events following immunization (AEFI). All AEFI reported in Hebei Province, China, between 2020 and 2022 were included in this study. The risk difference (RD%), relative risk (RR), and Chi-square value were used to compare the differences in reported rates of AEFI between the DTaP-IPV/Hib and DTaP+IPV+Hib groups. From 2020 to 2022, 130 AEFI cases were reported in Hebei Province after DTaP-IPV/Hib vaccination, corresponding to an AEFI reported rate of 66.9/million doses, which was significantly lower than that for DTaP+IPV+Hib (9836 AEFI with a reported rate of 637.8/million doses). The overall reported rate of non-severe AEFI for DTaP+IPV+Hib vaccines was 9.5 times that of DTaP-IPV/Hib vaccination [95% confidence interval (CI): 8.0, 11.3]. Meanwhile, the reported rate of AEFI among infants aged 0-1 y was 9.8 times higher for DTaP+IPV+Hib than for DTaP-IPV/Hib (95% CI: 8.2, 11.7). DTaP+IPV+Hib vaccination also resulted in higher risks of high fever, localized redness and swelling, localized induration, and allergic rash compared with DTaP-IPV/Hib vaccination. The risk of AEFI, which were mostly mild reaction, was higher after vaccination with DTaP+IPV+Hib than after DTaP-IPV/Hib vaccination.

Diagnostic value of the pepsin concentration in saliva and induced sputum for gastroesophageal reflux-induced chronic cough: a prospective clinical study.

Background: Finding a simple, effective and rapid diagnostic method to improve the diagnosis of gastroesophageal reflux-induced chronic cough (GERC) is indicated. Our objective was to determine the diagnostic value of the pepsin concentration in saliva and induced sputum for GERC. Methods: 171 patients with chronic cough were enrolled. The diagnosis and treatment followed the chronic cough diagnosis and treatment protocol. Saliva and induced sputum were collected, and the pepsin concentration was determined using Peptest. A Gastroesophageal Reflux Diagnostic Questionnaire (GerdQ) was completed. The diagnostic value of the pepsin concentration in saliva and induced sputum for GERC was analysed and compared. Results: The salivary pepsin concentration predicted GERC with an area under the receiver operating characteristic curve (AUC) of 0.845. The optimal cut-off value was 76.10 ng·mL-1, the sensitivity was 83.58% and the specificity was 82.69%. The pepsin concentration in the induced sputum supernatant for GERC had an AUC of 0.523. When GerdQ was used for GERC diagnosis, the AUC was 0.670 and the diagnostic value of salivary pepsin was better compared to GerdQ (DeLong test, p=0.0008). Salivary pepsin had a comparable diagnostic value to GerdQ (AUC 0.779 versus 0.826; p=0.4199) in acidic GERC. Salivary pepsin had superior diagnostic value compared to GerdQ (AUC 0.830 versus 0.533; p<0.0001) in non-acidic GERC. Conclusions: A salivary pepsin concentration >76.10 ng·mL-1 is of good diagnostic value for GERC, especially in non-acidic GERC. The pepsin concentration in induced sputum has a low diagnostic value.

Mining Bovine Milk Proteins for DPP-4 Inhibitory Peptides Using Machine Learning and Virtual Proteolysis.

Dipeptidyl peptidase-IV (DPP-4) enzyme inhibitors are a promising category of diabetes medications. Bioactive peptides, particularly those derived from bovine milk proteins, play crucial roles in inhibiting the DPP-4 enzyme. This study describes a comprehensive strategy for DPP-4 inhibitory peptide discovery and validation that combines machine learning and virtual proteolysis techniques. Five machine learning models, including GBDT, XGBoost, LightGBM, CatBoost, and RF, were trained. Notably, LightGBM demonstrated superior performance with an AUC value of 0.92 ± 0.01. Subsequently, LightGBM was employed to forecast the DPP-4 inhibitory potential of peptides generated through virtual proteolysis of milk proteins. Through a series of in silico screening process and in vitro experiments, GPVRGPF and HPHPHL were found to exhibit good DPP-4 inhibitory activity. Molecular docking and molecular dynamics simulations further confirmed the inhibitory mechanisms of these peptides. Through retracing the virtual proteolysis steps, it was found that GPVRGPF can be obtained from ß-casein through enzymatic hydrolysis by chymotrypsin, while HPHPHL can be obtained from κ-casein through enzymatic hydrolysis by stem bromelain or papain. In summary, the integration of machine learning and virtual proteolysis techniques can aid in the preliminary determination of key hydrolysis parameters and facilitate the efficient screening of bioactive peptides.

Microbiota and metabolite alterations in pancreatic head and body/tail cancer patients.

Pancreatic head cancer (PHC) and pancreatic body/tail cancer (PBTC) have distinct clinical and biological behaviors. The microbial and metabolic differences in PHC and PBTC have not been studied. The pancreatic microbiota and metabolome of 15 PHC and 8 PBTC tissues and their matched nontumor tissues were characterized using 16S rRNA amplicon sequencing and untargeted metabolomics. At the genus level, Bradyrhizobium was increased while Corynebacterium and Ruminococcus were decreased in the PHC tissues (Head T) compared with the matched nontumor tissues (Head N) significantly. Shuttleworthia, Bacillus, and Bifidobacterium were significantly decreased in the PBTC tissues (Body/Tail T) compared with the matched nontumor tissues (Body/Tail N). Significantly, Ileibacterium was increased whereas Pseudoxanthomonas was decreased in Head T and Body/Tail T, and Lactobacillus was increased in Head T but decreased in Body/Tail T. A total of 102 discriminative metabolites were identified between Head T and Head N, which were scattered through linoleic acid metabolism and purine metabolism pathways. However, there were only four discriminative metabolites between Body/Tail T and Body/Tail N, which were related to glycerophospholipid metabolism and autophagy pathways. The differential metabolites in PHC and PBTC were commonly enriched in alpha-linolenic acid metabolism and choline metabolism in cancer pathways. Eubacterium decreased in Head T was positively correlated with decreased linoleic acid while negatively correlated with increased arachidyl carnitine and stearoylcarnitine. Bacillus decreased in Body/Tail T was negatively correlated with increased L-carnitine. These microbiota and metabolites deserve further investigations to reveal their roles in the pathogenesis of PHC and PBTC, providing clues for future treatments.

A comparison between a gastroesophageal reflux disease questionnaire-based algorithm and multichannel intraluminal impedance-pH monitoring for the treatment of gastroesophageal reflux-induced chronic cough.

BACKGROUND: Empiric therapy with multichannel intraluminal impedance-pH monitoring (MII-pH) has been used for the initial treatment of gastroesophageal reflux-induced chronic cough (GERC). However, an algorithm based on the gastroesophageal reflux disease questionnaire (GerdQ) has the potential to achieve a simple, structured, and effective treatment approach for patients with GERC. OBJECTIVES: This study compared the efficacy of anti-reflux therapy based on GerdQ (new structured pathway, NSP) with medical treatment after MII-pH examination (ordinary clinical pathway, OCP) in the management of GERC. DESIGN: For the NSP, we adapted the GerdQ score to establish the basis for a treatment algorithm. For the OCP, treatment was determined using the MII-pH examination results. METHODS: The non-inferiority (NI) hypothesis was used to evaluate NSP versus OCP. RESULTS: Overall, the NSP and OCP-based therapeutic algorithms have similar efficacy for GERC [NI analysis: 95% confidence interval (CI), -4.97 to 17.73, p = 0.009; superiority analysis: p = 0.420]. Moreover, the cough symptom scores and cough threshold improved faster in the NSP group than in the OCP group at week 8 (p < 0.05). In the subgroup analyses using the GerdQ and GerdQ impact scale (GIS) scores, patients with low-likelihood GERC (GerdQ < 8) were more likely to benefit from OCP (NI analysis: 95% CI, -19.73 to 18.02, p = 0.213). On the other hand, in patients with high-likelihood and low-reflux impact GERC patients (GerdQ > 8 and GIS < 4), the NSP arm was not inferior to the standard treatment of OCP (NI analysis: 95% CI, -8.85 to 28.21%, p = 0.04; superiority analysis: p = 0.339), indicating that GerdQ- and GIS-guided diagnosis and management of patients with GERC could be an alternative to MII-pH management, especially in settings with reduced medical resources. CONCLUSIONS: The use of the GerdQ algorithm should be considered when handling patients with GERC in the primary care setting. TRIAL REGISTRATION: This research was registered in the Chinese Clinical Trials Registry (ChiCTR-ODT-12001899).

Post-reflux swallow-induced peristaltic wave index: a new parameter for the identification of non-acid gastroesophageal reflux-related chronic cough.

BACKGROUND: The current available diagnostic criteria for gastroesophageal reflux-related chronic cough (GERC) dominated by non-acid reflux is imperfect. The post-reflux swallow-induced peristaltic wave index (PSPWI) is a parameter reflecting esophageal clearance function. OBJECTIVES: This study aims to investigate its diagnostic value for non-acid GERC. DESIGN: This study sought to compare the diagnostic value of PSPWI in different types of GERC, particularly non-acid GERC, and explore the clinical significance of PSPWI in the diagnosis of non-acid GERC through diagnostic experiments. METHODS: A retrospective analysis was performed based on 223 patients with suspected GERC who underwent multichannel intraluminal impedance-pH monitoring (MII-pH) in the outpatient clinic of our department from August 2016 to June 2021. Their clinical information, laboratory test results, and treatment responses were assessed and the underlying etiologies of chronic cough were categorized. The predictive value of the PSPWI in diagnosing different types of GERC, especially non-acid GERC, was analyzed and compared. RESULTS: A total of 195 patients with chronic cough who met the inclusion criteria underwent MII-pH monitoring. 143 patients had a definitive diagnosis of GERC, including 98 with acid GERC and 45 with non-acid GERC. The diagnostic value of PSPWI alone was moderate for GERC with an area under the working curve (AUC) 0.760, but poor for non-acid GERC with an AUC of 0.569. However, PSPWI < 39.8% combining with acid exposure time (AET) ⩽ 6.2% demonstrated a moderate diagnostic value for non-acid GERC, with an AUC of 0.722. When PSPWI < 39.8% combined with a non-acid reflux ratio >68.75%, the diagnostic value for non-acid GERC was improved (AUCROC = 0.80 versus AUCROC = 0.722, p < 0.05), which was significantly superior to non-acid symptom index (AUCROC = 0.804 versus AUCROC = 0.550, p < 0.05) and non-acid symptom association probability (AUCROC = 0.804 versus AUCROC = 0.571, p < 0.05). CONCLUSION: PSPWI < 39.8% and AET ⩽ 6.2% have demonstrated good diagnostic value for non-acid GERC. The diagnostic value was further improved when combined with non-acid reflux ratio >68.75%.

Identification and molecular binding mechanism of novel pancreatic lipase and cholesterol esterase inhibitory peptides from heat-treated adzuki bean protein hydrolysates.

Heat-treated adzuki bean protein hydrolysates exhibit lipid-reducing properties; however, few studies have reported pancreatic lipase (PL) and cholesterol esterase (CE) inhibitory effects and elucidated the underlying mechanisms. In this study, we accomplished the identification of antiobesity peptides through peptide sequencing, virtual screening, and in vitro experiments. Furthermore, the mechanisms were investigated via molecular docking. The findings reveal that the action of pepsin and pancreatin resulted in the transformation of intact adzuki bean protein into smaller peptide fragments. The < 3 kDa fraction exhibited a high proportion of hydrophobic amino acids and displayed superior inhibitory properties for both PL and CE. Five novel antiobesity peptides (LLGGLDSSLLPH, FDTGSSFYNKPAG, IWVGGSGMDM, YLQGFGKNIL, and IFNNDPNNHP) were identified as PL and CE inhibitors. Particularly, IFNNDPNNHP exhibited the most robust biological activity. These peptides exerted their inhibitory action on PL and CE by occupying catalytic or substrate-binding sites through hydrogen bonds, hydrophobic interactions, salt bridges, and π-π stacking.

New Insights Into Refractory Chronic Cough and Unexplained Chronic Cough: A 6-Year Ambispective Cohort Study.

PURPOSE: Only limited studies have depicted the unique features and management of refractory chronic cough (RCC) and unexplained chronic cough (UCC). These led to the initiation of this study, which reported the demographic characteristics, manifestations, and long-term outcomes on a large series of consecutive RCC/UCC patients, providing a guideline-led real-world clinical experience. METHODS: Retrospective baseline information was obtained from Clinical Research Database (January 2016 to May 2021). At least 6 months after the last clinic visit, included subjects were prospectively followed up. RESULTS: Three hundred and sixty-nine RCC and UCC patients (199 females, 53.9%) were analyzed. The median cough duration was 24.0 (12.0-72.0) months. Laryngeal symptoms were reported in 95.9% of the patients. The common triggers for coughing were talking (74.9%), pungent odors (47.3%), eating (45.5%), and cold air (42.8%). RCC was considered in 38.2%, and the remainder of 228 patients had UCC, with an equal sex distribution (P = 0.66). Among the 141 RCCs, 90.8% (128) had refractory reflux cough, which was more responsive to current treatments (P < 0.01). Although most features and test results between RCC and UCC were similar, UCC was more commonly inappropriately treated (P < 0.01). Nineteen (7.7-41.1) months after the final clinic visit, 31.2% still coughed persistently, while 68.8% reported cough improvement or remission. RCC reported more favorable treatment outcomes (including cough improvement, control, and spontaneous remission) than UCC (P < 0.01). Coughs with long duration before the initial cough clinic visit (P < 0.01), frequent urinary incontinence (P < 0.01), and being sensitive to "talking" (P < 0.01) or "cold air" (P < 0.01) were less likely to be solved. CONCLUSIONS: The current treatments only improve cough symptoms in two-thirds of patients. Clinical indicators for treatment failure were those coughing for long duration and being sensitive to "talking" or "cold air."

N6-methyladenosine-modified oncofetal lncRNA MIR4435-2HG contributed to stemness features of hepatocellular carcinoma cells by regulating rRNA 2'-O methylation.

BACKGROUND: The unique expression pattern endows oncofetal genes with great value in cancer diagnosis and treatment. However, only a few oncofetal genes are available for clinical use and the underlying mechanisms that drives the fetal-like reprogramming of cancer cells remain largely unknown. METHODS: Microarray assays and bioinformatic analyses were employed to screen for potential oncofetal long non-coding RNAs (lncRNAs) in hepatocellular carcinoma (HCC). The expression levels of MIR4435-2HG, NOP58 ribonucleoprotein (NOP58), insulin like growth factor 2 mRNA binding protein 1 (IGF2BP1) and stem markers were detected by quantitative polymerase chain reaction. The 2'-O-methylation (2'-O-Me) status of rRNA were detected through reverse transcription at low dNTP concentrations followed by PCR. The regulation of MIR4435-2HG by IGF2BP1 was explored by RNA immunoprecipitation (RIP), methylated RIP (MeRIP) and dual-luciferase assays. The interaction between MIR4435-2HG and NOP58 was investigated by RNA Pulldown, RIP and protein stability assays. In vitro and in vivo function assays were performed to detect the roles of MIR4435-2HG/NOP58 in HCC. RESULTS: MIR4435-2HG was an oncofetal lncRNA associated with poor prognosis in HCC. Functional experiments showed that overexpression of MIR4435-2HG remarkably enhanced the stem-cell properties of HCC cells, promoting tumorigenesis in vitro and in vivo. Mechanically, MIR4435-2HG directly bound NOP58 and IGF2BP1. IGF2BP1 upregulated MIR4435-2HG expression in HCC through N6-methyladenosine (m6A) modification. Moreover, MIR4435-2HG protected NOP58 from degradation, which raised rRNA 2'-O-Me levels and promoted internal ribosome entry site (IRES)-dependent translation of oncogenes. CONCLUSIONS: This study identified an oncofetal lncRNA MIR4435-2HG, characterized the role of MIR4435-2HG/NOP58 in stemness maintenance and proliferation of HCC cells, and confirmed m6A as a 'driver' that reactivated MR4435-2HG expression in HCC.

A multi-omics study to investigate the progression of the Correa pathway in gastric mucosa in the context of cirrhosis.

BACKGROUND: Patients with liver cirrhosis (LC) are prone to gastric mucosa damage. We investigated the alterations of gastric mucosa in LC patients and their possible mechanisms through multi-omics. RESULTS: We observed significant gastric mucosa microbial dysbiosis in LC subjects. Gastric mucosal microbiomes of LC patients contained a higher relative abundance of Streptococcus, Neisseria, Prevotella, Veillonella, and Porphyromonas, as well as a decreased abundance in Helicobacter and Achromobacter, than control subjects. The LC patients had higher levels of bile acids (BAs) and long-chain acylcarnitines (long-chain ACs) in serum. The gastric mucosal microbiomes were associated with serum levels of BAs and long-chain ACs. Transcriptome analyses of gastric mucosa revealed an upregulation of endothelial cell specific molecule 1, serpin family E member 1, mucin 2, caudal type homeobox 2, retinol binding protein 2, and defensin alpha 5 in LC group. Besides, the bile secretion signaling pathway was significantly upregulated in the LC group. CONCLUSIONS: The alterations in the gastric mucosal microbiome and transcriptome of LC patients were identified. The impaired energy metabolism in gastric mucosal cells and bile acids might aggravate the inflammation of gastric mucosa and even exacerbate the Correa's cascade process. The gastric mucosal cells might reduce bile acid toxicity by bile acid efflux and detoxification. TRIAL REGISTRATION: ChiCTR2100051070.

A randomized, double-blinded, placebo-controlled clinical trial of duloxetine hydrochloride enteric-coated tablets in the treatment of refractory chronic cough.

INTRODUCTION: Refractory cough, a chronic cough with an unclear diagnosis or poor treatment response. The symptoms are often stubborn and persistent, causing serious complications and lowering the patient's quality of life. Cough hypersensitivity syndrome (CHS) is proposed as a potential cause, and reducing sensory nerve hyperresponsiveness is suggested as an effective treatment. However, current drugs have low efficacy and benefit rates and numerous side effects. This trail proposes using duloxetine, a selective 5-HT and norepinephrine reuptake inhibitor, as a potential treatment for refractory cough, which has shown promise in treating pain and depression. Duloxetine may inhibit pain conduction and oxidative stress in peripheral nerves by inhibiting the activity of TRPV1 channels, which play an important role in the peripheral afferent pathway of refractory cough. Meanwhile, the antidepressant effects of duloxetine may also play a role in the treatment of refractory cough. METHODS AND ANALYSIS: This is a single-center, prospective, randomized, double-blind, and controlled trial. A total of 98 individuals will be randomized in a 1:1 ratio to duloxetine group and placebo control group (starting with 20 mg QD, increasing 20 mg daily until 20 mg TID). After a screening period, the second stage runs from baseline to the 42nd (last) day of treatment, with follow-up visits on the 3rd, 7th, 14th, 21st, 28th, 35th, 42nd and 49th days. The main end-stage observation indicators include objective cough frequency, cough visual analog scale (VAS), cough symptom score, Leicester Cough Questionnaire (LCQ), and cough evaluation test (CET); the secondary end-stage observation indicators include capsaicin cough sensitivity, Patient Health Questionnaire-9 (PHQ-9), Major Depression Inventory (MDI), the Generalized Anxiety Disorder-7 scale (GAD-7), Life Events Scale (LES-32), induced sputum supernatant. The safety measures will be AEs/SAEs, vital signs, liver and kidney function, fecal occult blood test. DISCUSSION: This study is the first randomized, double-blind, and controlled clinical trial investigating the use of duloxetine in the treatment of refractory coughs. The study aims to provide a high-quality basis for evaluating the efficacy and safety of duloxetine for this condition. TRIAL REGISTRATION: Our study was registered in the Chinese Clinical Trials Register ( www.chictr.org.cn/ ) (ChiCTR2000037429) in 28/08/2020.

MicroRNA-144-3p protects against chemotherapy-induced apoptosis of ovarian granulosa cells and activation of primordial follicles by targeting MAP3K9.

Premature ovarian failure (POF) is defined by amenorrhea, ovarian atrophy, hypoestrogenism, elevated gonadotropin level, and infertility under the age of 40. POF is frequently induced by chemotherapeutic agents. However, the underlying mechanisms regarding chemotherapy-mediated damage to ovarian function are unclear. In this study, enhanced apoptosis of granulosa cells (GCs) and aberrant activation of primordial follicles were observed in a POF mouse model induced by cisplatin. We subsequently observed significant downregulation of miR-144-3p and upregulation of mitogen-activated protein kinase kinase kinase 9 (MAP3K9) in primary ovarian GCs from POF mice, as revealed by microarrays. Furthermore, MAP3K9 expression was higher in human ovarian granulosa cells (COV434) treated with cisplatin and was identified as a novel target of miR-144-3p. Functional analysis revealed that miR-144-3p attenuated cisplatin induced apoptosis of GCs via silencing MAP3K9 expression, which suppressed the activity of the downstream p38 mitogen activated protein kinase (MAPK) pathway. Meanwhile, miR-144-3p prevented premature primordial follicle depletion in cisplatin-induced POF mice through targeting Map3k9, which led to a decline in the phosphorylation and activation of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase b (AKT) pathway. Taken together, this study revealed the protective effects of miR-144-3p on ovarian function and shed light on the epigenetic regulatory mechanism in the development of POF, which might provide new biomarkers for the ovarian reserve.

Psychological morbidity and chronic cough: which is predominant? A comparison of clinical characteristics.

Background: The clinical characteristics of chronic cough with pre-existing psychological co-morbidity (PCC) and chronic cough with secondary anxiety and depression (SCC) were compared to provide a basis for diagnosing and treating psychological co-morbidities in people with chronic cough. Methods: A prospective study was conducted to analyze the general clinical data between the PCC, SCC, and the chronic cough without anxiety and depression (CC) groups. A total of 203 patients with chronic cough were enrolled in the study. The final diagnosis was made in all cases using a combination of psychosomatic and respiratory diagnoses. The three groups' general clinical data, capsaicin cough sensitivity, cough symptom score, Leicester cough questionnaire (LCQ), and psychosomatic scale scores were compared among the three groups. The diagnostic value of the patient health questionnaire (PHQ)-9 and general anxiety disorder (GAD)-7 in patients with PCC and the follow-up information were analyzed. Results: Compared with the SCC group, the duration of cough in the PCC group was shorter (H = -3.54, p = 0.001), the night cough symptoms were milder (H = -4.60, p < 0.001), the total LCQ score was lower (H = -2.97, p = 0.009), and the PHQ-9 (H = 2.90, p = 0.011) and GAD-7 scores (H = 2.71, p = 0.002) were higher. When using PHQ-9 and GAD-7 scores for the combined prediction and diagnosis of PCC, the area under the curve (AUC) was 0.88, and the sensitivity and specificity were 90.0% and 73.85%, respectively. After 8 weeks of psychosomatic treatment, cough symptoms improved in the PCC group, but the psychological improvement was not significant. The psychological status of the SCC group improved after cough symptoms were ameliorated by etiologic or empirical treatment. Conclusion: The clinical characteristics of patients with PCC and SCC are different. The evaluation of psychosomatic scales is of value to distinguish between the two groups. Chronic cough patients with psychological co-morbidity benefit from the combined diagnosis of psychosomatic medicine in a timely fashion. PCC requires more attention in psychological therapy, but for SCC, targeting etiological treatment of the cough is preferred. Trial registration: The protocol was registered in the Chinese Clinical Trials Register (http://www.chictr.org.cn/) [ChiCTR2000037429].

Correction: Heat-treated foxtail millet protein delayed the development of pre-diabetes to diabetes in mice by altering gut microbiota and metabolomic profiles.

Correction for 'Heat-treated foxtail millet protein delayed the development of pre-diabetes to diabetes in mice by altering gut microbiota and metabolomic profiles' by Han Wang et al., Food Funct., 2023, 14, 4866-4880, https://doi.org/10.1039/D3FO00294B.

Heat-treated foxtail millet protein delayed the development of pre-diabetes to diabetes in mice by altering gut microbiota and metabolomic profiles.

Millet protein has gained much attention for its beneficial effects in mitigating metabolic diseases. However, most individuals pass through a prediabetic phase before developing full-blown diabetes, and whether millet protein has hypoglycemic effects on prediabetic mice remains unclear. In the present study, heat-treated foxtail millet protein (HMP) supplementation significantly decreased fasting blood glucose and serum insulin levels, alleviated insulin resistance, and improved impaired glucose tolerance in prediabetic mice. In addition, HMP altered the intestinal flora composition, as evidenced by the reduction in the abundance of Dubosiella and Marvinbryantia and the increase in the content of Lactobacillus, Bifidobacterium, and norank_f_Erysipelotrichaceae. Moreover, HMP supplementation dramatically regulated the levels of serum metabolites (i.e., LysoPCs, 11,14,17-eicosatrienoic acid, and sphingosine) and related metabolic pathways, such as sphingolipid metabolism and pantothenate and CoA biosynthesis. In conclusion, the improvement of gut microbiota and serum metabolic profiles was related to the hypoglycemic potential of HMP in prediabetes.

Antitussive efficacy of the current treatment protocol for refractory chronic cough: our real-world experience in a retrospective cohort study.

BACKGROUND: The management of refractory chronic cough (RCC) is a great challenge. Neuromodulators have long been used for RCC with imperfect efficacy. OBJECTIVES: We summarized the outcomes of the current treatments used at our specialist cough clinic, which provides a guideline-led service and real-world experience for the future management of RCC. DESIGN: This is a single-centre retrospective observational cohort study. METHODS: Consecutive RCC patients (the first clinic visit between January 2016 and May 2021) were included into this observational cohort study. Medical records in the Chronic Cough Clinical Research Database were fully reviewed using uniform criteria. The included subjects were followed-up for at least 6 months after the final clinic visit via instant messages with the link to self-scaled cough-associated questionnaires. RESULTS: Overall, 369 RCC patients were analysed with a median age of 46.6 years and a cough duration of 24.0 months. A total of 10 different treatments were offered. However, 96.2% of patients had been prescribed at least one neuromodulator. One-third of patients had alternative treatments prescribed given the poor response to the initial therapy and 71.3% favourably responded to at least one of the treatments. Gabapentin, deanxit, and baclofen had comparable therapeutic efficacy (56.0%, 56.0%, and 62.5% respectively; p = 0.88) and overall incidences of adverse effects (28.3%, 22.0%, and 32.3% respectively; p = 0.76). However, 19.1 (7.7-41.8) months after the last clinic visit, 65.0% reported improvement (24.9%) or control of their cough (40.1%); 3.8% reported a spontaneous remission and 31.2% still had a severe cough. Both HARQ (n = 97; p < 0.001) and LCQ (n = 58; p < 0.001) demonstrated marked improvement. CONCLUSION: Trying different neuromodulators is a pragmatic strategy for RCC, which helped around two-thirds of patients. Relapse is common on withdrawal or reduction of dosage. Novel medication for RCC is an urgent clinical need. PLAIN LANGUAGE SUMMARY: This is the first report that fully represented a guideline-led treatment protocol for refractory chronic cough (RCC) based on a large series of patients, which evaluated the short- and long-term effects of the currently available treatments for RCC. We found that the therapeutic trial of different neuromodulators is a pragmatic strategy, which helped around two-thirds of patients. Gabapentin, deanxit (flupentixol/melitracen), and baclofen had similar therapeutic outcomes. This study may offer real-world experience for the future management of RCC.