Serum bile acid and unsaturated fatty acid profiles of non-alcoholic fatty liver disease in type 2 diabetic patients.

BACKGROUND: The understanding of bile acid (BA) and unsaturated fatty acid (UFA) profiles, as well as their dysregulation, remains elusive in individuals with type 2 diabetes mellitus (T2DM) coexisting with non-alcoholic fatty liver disease (NAFLD). Investigating these metabolites could offer valuable insights into the pathophy-siology of NAFLD in T2DM. AIM: To identify potential metabolite biomarkers capable of distinguishing between NAFLD and T2DM. METHODS: A training model was developed involving 399 participants, comprising 113 healthy controls (HCs), 134 individuals with T2DM without NAFLD, and 152 individuals with T2DM and NAFLD. External validation encompassed 172 participants. NAFLD patients were divided based on liver fibrosis scores. The analytical approach employed univariate testing, orthogonal partial least squares-discriminant analysis, logistic regression, receiver operating characteristic curve analysis, and decision curve analysis to pinpoint and assess the diagnostic value of serum biomarkers. RESULTS: Compared to HCs, both T2DM and NAFLD groups exhibited diminished levels of specific BAs. In UFAs, particular acids exhibited a positive correlation with NAFLD risk in T2DM, while the ω-6:ω-3 UFA ratio demonstrated a negative correlation. Levels of α-linolenic acid and γ-linolenic acid were linked to significant liver fibrosis in NAFLD. The validation cohort substantiated the predictive efficacy of these biomarkers for assessing NAFLD risk in T2DM patients. CONCLUSION: This study underscores the connection between altered BA and UFA profiles and the presence of NAFLD in individuals with T2DM, proposing their potential as biomarkers in the pathogenesis of NAFLD.

CBX1 is involved in hepatocellular carcinoma progression and resistance to sorafenib and lenvatinib via IGF-1R/AKT/SNAIL signaling pathway.

BACKGROUND: Chromobox Homolog 1 (CBX1) plays a crucial role in the pathogenesis of numerous diseases, including the evolution and advancement of diverse cancers. The role of CBX1 in pan-cancer and its mechanism in hepatocellular carcinoma (HCC), however, remains to be further investigated. METHODS: Bioinformatics approaches were harnessed to scrutinize CBX1's expression profile, its association with tumor staging, and its potential impact on patient outcomes across various cancers. Single-cell RNA sequencing data facilitated the investigation of CBX1 expression patterns at the individual cell level. The CBX1 expression levels in HCC and adjacent non-tumor tissues were quantified through Real-Time Polymerase Chain Reaction (RT-PCR), Western Blotting (WB), and Immunohistochemical analyses. A tissue microarray was employed to explore the relationship between CBX1 levels, patient prognosis, and clinicopathological characteristics in HCC. Various in vitro assays-including CCK-8, colony formation, Transwell invasion, and scratch tests-were conducted to assess the proliferative and motility properties of HCC cells upon modulation of CBX1 expression. Moreover, the functional impact of CBX1 on HCC was further discerned through xenograft studies in nude mice. RESULTS: CBX1 was found to be upregulated in most cancer forms, with heightened expression correlating with adverse patient prognoses. Within the context of HCC, elevated levels of CBX1 were consistently indicative of poorer clinical outcomes. Suppression of CBX1 through knockdown methodologies markedly diminished HCC cell proliferation, invasive capabilities, migratory activity, Epithelial-mesenchymal transition (EMT) processes, and resistance to Tyrosine kinase inhibitors (TKIs). Contrastingly, CBX1 augmentation facilitated the opposite effects. Subsequent investigative efforts revealed CBX1 to be a promoter of EMT and a contributor to increased TKI resistance within HCC cells, mediated via the IGF-1R/AKT/SNAIL signaling axis. The oncogenic activities of CBX1 proved to be attenuable either by AKT pathway inhibition or by targeted silencing of IGF-1R. CONCLUSIONS: The broad overexpression of CBX1 in pan-cancer and specifically in HCC positions it as a putative oncogenic entity. It is implicated in forwarding HCC progression and exacerbating TKI resistance through its interaction with the IGF-1R/AKT/SNAIL signaling cascade.

Case report: Acquired resistance to crizotinib from a MET Y1230H mutation in a patient with non-small cell lung cancer and KIF5B-MET fusion.

Background: The c-met proto-oncogene (MET) serves as a significant primary oncogenic driver in non-small cell lung cancer (NSCLC) and has the potential to fuse with other genes, such as KIF5B, although it occurs infrequently. Only a limited number of reported cases have examined the clinical efficacy of crizotinib in patients with KIF5B-MET gene fusion, with no known data regarding acquired resistance to crizotinib and its potential mechanisms. In this report, we present the clinical progression of a female patient diagnosed with NSCLC and harboring a KIF5B-MET gene fusion. Case description: The patient initially exhibited partial response to first-line crizotinib treatment, albeit for a short duration and with limited efficacy. Subsequent disease progression revealed the emergence of a secondary MET mutation, specifically MET Y1230H, leading to acquired resistance to crizotinib. Conclusion: The reporting of this case is imperative for informing clinical practice, given the uncommon occurrence of NSCLC with MET fusion, displaying responsiveness to MET tyrosine kinase inhibitor therapy, as well as the emergence of the secondary Y1230H alteration as a potential resistance mechanism.

Med rec double check: Inpatient psychiatry medication errors identified on admission using Medicaid Web portals and electronic pharmaceutical claims data.

Introduction: The role of pharmacists during medication reconciliation (MR) is well established, with a number of reports describing this in the context of psychiatric hospitalizations. However, medication errors (MEs) are common during transitions of care, with no exception during psychiatric hospitalizations. Our institution uses pharmacy-performed MR processes using patient interviews and reviewing objective sources, such as electronic pharmaceutical claims data (EPCD), which includes Medicaid Web portals. The inpatient psychiatric pharmacist reviews EPCD sources against previously pharmacy-completed MRs for new admissions, where if discrepancies are found, the patient is reinterviewed to identify and correct MEs. Methods: We performed a prospective quality improvement project during 28 days to evaluate the quantity and classification of MEs upon admission to a 22-bed inpatient psychiatry unit. Results: Of 52 included patients, where a cumulative 426 medications were reviewed, a total of 29 MEs in 16 patients were identified. Eight patients had discrepancies on their home medication lists when compared to EPCD, where 7 of these had at least 1 ME due to inaccurate MR. Discussion: Of all the MEs identified, the greatest quantity was found secondary to the EPCD "double-check" method. The most common MEs in all patients were the omission of home medications (34%), wrong frequency (28%), and ordering medication the patient is not taking (10%). All patients admitted on long-acting injection antipsychotics had errors in last dose received. No MEs resulted in patient harm, and they were identified and corrected by the psychiatric pharmacist 97% of the time.

Exosomes regulate doxorubicin resistance in breast cancer via miR-34a-5p/NOTCH1.

Breast cancer (BRCA) is the most common cancer among women. Adriamycin (ADR), also known as doxorubicin (Dox), is a commonly used chemotherapeutic agent for BRCA patients, however, the susceptibility of tumor cells to develop resistance to Dox has severely limited its clinical use. One new promising therapeutic target for breast cancer patients is exosomes. The objective of this study was to investigate the role of exosomes in regulating Dox resistance in BRCA. In this study, the exosomes from both types of cells were extracted by differential centrifugation. The effect of exosomes on drug resistance was assessed by laser confocal microscopy, MTT assay, and qRT-PCR. The miRNA was transfected into cells using Lipofectamine 2000, which was then evaluated for downstream genes and changes in drug resistance. Exosomes from MCF-7 cells (MCF-7/exo) and MCF-7/ADR cells (ADR/exo) were effectively extracted in this study. The ADR/exo was able to endocytose MCF-7 cells and make them considerably more resistant to Dox. Moreover, we observed a significant difference in miR-34a-5p expression in MCF-7/ADR and ADR/exo compared to MCF-7 and MCF-7/exo. Among the miR-34a-5p target genes, NOTCH1 displayed a clear change with a negative correlation. In addition, when miR-34a-5p expression was elevated in MCF-7/ADR cells, the expression of miR-34a-5p in ADR/exo was also enhanced alongside NOTCH1, implying that exosomes may carry miRNA into and out of cells and perform their function. In conclusion, exosomes can influence Dox resistance in breast cancer cells by regulating miR-34a-5p/NOTCH1. These findings provide novel insights for research into the causes of tumor resistance and the enhancement of chemotherapy efficacy in breast cancer.

Overexpression of wild-type HRAS drives non-alcoholic steatohepatitis to hepatocellular carcinoma in mice.

Hepatocellular carcinoma (HCC), a prevalent solid carcinoma of significant concern, is an aggressive and often fatal disease with increasing global incidence rates and poor therapeutic outcomes. The etiology and pathological progression of non-alcoholic steatohepatitis (NASH)-related HCC is multifactorial and multistage. However, no single animal model can accurately mimic the full NASH-related HCC pathological progression, posing considerable challenges to transition and mechanistic studies. Herein, a novel conditional inducible wild-type human HRAS overexpressed mouse model (HRAS-HCC) was established, demonstrating 100% morbidity and mortality within approximately one month under normal dietary and lifestyle conditions. Advanced symptoms of HCC such as ascites, thrombus, internal hemorrhage, jaundice, and lung metastasis were successfully replicated in mice. In-depth pathological features of NASH- related HCC were demonstrated by pathological staining, biochemical analyses, and typical marker gene detections. Combined murine anti-PD-1 and sorafenib treatment effectively prolonged mouse survival, further confirming the accuracy and reliability of the model. Based on protein-protein interaction (PPI) network and RNA sequencing analyses, we speculated that overexpression of HRAS may initiate the THBS1-COL4A3 axis to induce NASH with severe fibrosis, with subsequent progression to HCC. Collectively, our study successfully duplicated natural sequential progression in a single murine model over a very short period, providing an accurate and reliable preclinical tool for therapeutic evaluations targeting the NASH to HCC continuum.

Bifonazole caffeate: The first molecular salt of bifonazole with enhanced biopharmaceutical property based on experiments and quantum chemistry research.

In order to make novel breakthroughs in molecular salt studies of BCS class-IV antifungal medication bifonazole (BIF), a salification-driven strategy towards ameliorating attributes and aiding augment efficiency is raised. This strategy fully harnesses structural characters together attributes and benefits of caffeic acid (CAF) to concurrently enhance dissolvability and permeability of BIF by introducing the two ingredients into the identical molecular salt lattice through the salification reaction, which, coupled with the aroused potential activity of CAF significantly amplifies the antifungal efficacy of BIF. Guided by this route, the first BIF-organic molecular salt, BIF-CAF, is directionally designed and synthesized with satisfactorily structural characterizations and integrated theoretical and experimental explorations on the pharmaceutical properties. Single-crystal X-ray diffraction resolving confirms that there is a lipid-water amphiphilic sandwich structure constructed by robust charge-assistant hydrogen bonds in the salt crystal, endowing the molecular salt with the potential to enhance both dissolvability and permeability relative to the parent drug, which is validated by experimental evaluations. Remarkably, the comprehensive DFT-based theoretical investigations covering frontier molecular orbital, molecular electrostatic potential, Hirshfeld surface analysis, reduced density gradient, topology, sphericity and planarity analysis strongly support these observations, thereby allowing some positive relationships between macroscopic properties and microstructures of the molecular salt can be made. Intriguingly, the optimal properties, together with the stimulated activity of CAF markedly augment in vitro antifungal ability of the molecular salt, with magnifying inhibition zones and reducing minimum inhibitory concentrations. These findings fill in the gaps on researches of BIF-organic molecular salt, and adequately exemplify the feasibility and validity by integrating theoretical and experimental approaches to resolve BIF's problems via the salification-driven tactic.

A survey of gastrointestinal helminth infestation in smallholder backyard pigs and the first molecular identification of the two zoonotic helminths Ascaris suum and Trichuris suis in Myanmar.

BACKGROUND: Parasitic infestations have a substantial economic impact on pig production. This study aimed to investigate the gastrointestinal (GI) helminths in pigs and to molecularly characterise two important nematodes, Ascaris and Trichuris species. MATERIALS AND METHODS: A total of 500 pig faecal samples were collected from small holder backyard pig farms in five townships within Nay Pyi Taw, Myanmar. Microscopic examination was conducted to estimate the prevalence of GI helminth infestation in the pigs. DNA extraction and PCR were performed on faecal samples that were morphologically positive for Ascaris and Trichuris eggs. Molecular analysis was then conducted to characterise A. suum and T. suis, the most common and zoonotic helminths. RESULTS: According to microscopic examination, 69.2% (346/500) were positive for GI helminth eggs. The GI helminth species observed were A. suum, Strongyle, Strongyloides spp., T. suis, Metastrongylus spp., Hyostrongylus spp., Fasciolopsis spp., Paragonimus spp., and Schistosoma spp., with occurrences of 34.8%, 29.6%, 21.4%, 20.0%, 4.0%, 1.6%, 1.0%, 1.0%, and 0.4%, respectively. Mixed infections of GI helminths were noted in 31.0% of the samples. Overall, sampled pigs excreted mostly low levels (< 100 EPG) or moderate levels (> 100-500 EPG) of GI helminth eggs. The highest mean EPG for each parasite species was noted in A. suum. The presence of A. suum and T. suis was confirmed molecularly. The sequences of the internal transcribed spacer 1 (ITS1) region of A. suum showed high similarity with previously reported sequences. Likewise, the sequences of T. suis exhibited high similarity with the sequences reported from humans and pigs. Age was noted as an associated factor (P < 0.05) for GI helminth infection status. CONCLUSIONS: In this report, A. suum and T. suis were molecularly identified for the first time in Myanmar. It is important to extend the information among the farmers to be aware of the necessity of preventing zoonotic parasites by practicing regular deworming, proper use of anthelmintics and maintaining hygienic conditions in their pig farms.

Healthcare providers' perceived barriers to providing breastfeeding support in Northwest rural China.

BACKGROUND: Healthcare providers play important roles in supporting breastfeeding. Although there has been insufficient actual breastfeeding support from healthcare providers in China, little research has been conducted to understand Chinese healthcare providers' perceived barriers to providing breastfeeding support, especially in rural China. This study aims to identify these perceived barriers to providing breastfeeding support in Northwestern rural China. METHODS: This study was conducted during the period from March 2018 to December 2018. Forty-one healthcare providers were recruited through purposive sampling in two rural counties in Northwest China that are in close proximity to each other and share similar demographic features. Participants included obstetrician-gynecologists, midwives, nurses, "village doctors", and township and village maternal and child health workers. Qualitative data were collected through one-on-one in-depth semi-structured interviews and focus group discussions. Transcripts were thematically analyzed. RESULTS: Analysis of interview data resulted in four themes that the participants perceived as barriers to supporting breastfeeding: (1) lack of medical resources, within which inadequate staffing, and lack of financial incentives were discussed, (2) lack of clear and specific responsibility assignment, within which no one takes the lead, and mutual buck-passing were discussed, (3) healthcare providers' lack of relevant expertise, within which lack of knowledge and skills, and low prestige of village healthcare providers were discussed, (4) difficulties in accessing mothers, within which medical equipment shortages reduce services utilization, mothers' housing situation, mothers' mobility, and cultural barriers were discussed. CONCLUSIONS: The study identified HCPs perceived barriers to providing breastfeeding support. Unique to China's Tri-Level Healthcare System, challenges like staffing and financial incentives are hard to swiftly tackle. Recommendations include mHealth enhancement and clarified responsibilities with incentives and tailored training. Further research is crucial to evaluate these strategies in rural Northwestern China and comparable underdeveloped areas nationwide.

Erratum: Favorable efficacy and reduced acute neurotoxicity by antisense oligonucleotides with 2',4' -BNA/LNA with 9-(aminoethoxy)phenoxazine.

[This corrects the article DOI: 10.1016/j.omtn.2024.102161.].

Adult pancreatoblastoma with atypical histological morphology combined with familial adenomatous polyposis: a rare case report.

Pancreatoblastoma (PB) is a rare malignant pancreatic epithelial tumor that mostly occurs in children and occasionally occurs in adults. The tumor has acinar cell differentiation and squamous corpuscles/squamous epithelial islands, which are frequently separated by fibrous bundles. Familial adenomatous polyposis (FAP) is an autosomal dominant inherited disease characterized by the presence of numerous adenomatous polyps in the colon and rectum. Cases of pancreatoblastoma combined with familial adenomatous polyposis (FAP) are rarely reported. A review of a rare case of adult pancreatoblastoma with atypical histological morphology combined with familial adenomatous polyposis is presented herein. In this case, the patient was first diagnosed with familial adenomatous polyposis and subsequently found to have pancreatoblastoma 1 year and 3 months later. This suggests pancreatoblastoma may occur in patients with familial adenomatous polyposis or a family history of the condition, indicating a possible association between the two tumors. Therefore, pancreatoblastoma should be included in a differential diagnosis for FAP patients with a pancreatic mass. The final diagnosis of pancreatoblastoma depends on the pathological diagnosis. Acinar-like cells and squamous corpuscles/squamous epithelial cell islands under light microscopy are the key diagnostic points. This case report also can improve the awareness of clinicians, radiologists, and pathologists on the presence of rare tumor-adult pancreatoblastoma in patients with familial adenomatous polyposis.

An analysis of E-governance in Pakistan from the lens of the Chinese governance model.

In this era of digitalization, the role of information and communication technology (ICT) has significantly increased. The integration of ICT into the government system has improved efficiency and working processes. Some countries such as China have successfully integrated ICT into their governance system. However, many other countries especially the developing world are yet to effectively utilize the role of ICT in their governance structure and these countries are struggling to produce a better governance system. It is, therefore, imperative for the developing world to learn from successful nations and devise their governance systems so that ICT can be fully utilized and produce good governance. However, such comparative analyses are not done as such to bring strengths and weaknesses in the integration of ICT into the governance system especially in developing countries' governance systems. This study contributes by conducting a comparative study on the China-Pakistan e-government progress. China has widely implemented e-government, which has helped the country to ensure good governance. Pakistan, on the other hand, is also moving towards digitalization and making efforts to implement e-government. This research examines the United Nations' E-Government Development Index (EGDI) reports and rankings. The findings of our research show that China has significantly improved its ranking, whereas Pakistan's ranking has indicated a gradual decline except for the year 2008. This happened because of a lack of investment in infrastructure, scarcity of financial resources, weak institutional capabilities, and limited access to advanced technologies. Moreover, there is a big gap between public policy and public implementation in Pakistani scenarios. However, it has been dug out in this study that employing the Chinese model and seeking cooperation with China can improve e-governance ranking and overall governance in Pakistan. The study advances the understanding of e-governance and its challenges in Pakistan and the findings of the study will assist researchers, policymakers, and officials in the implementation and development of e-projects in Pakistan.

Secondary metabolites and their bioactivities from Paecilomyces gunnii YMF1.00003.

Four new polyketides (1-4) and seven known compounds (5-11) including three polyketides and four sterols were isolated from the fermented extracts of Paecilomyces gunnii YMF1.00003. The new chemical structures were determined through the analysis of the nuclear magnetic resonance and high-resolution electrospray ionization mass spectrometry, and their configurations were subsequently confirmed by nuclear overhauser effect spectroscopy, the calculated electronic circular dichroism (ECD) spectra, and quantum chemical calculations of the NMR data (qcc NMR). Based on the results of pre-activity screening and compound structure target prediction, certain metabolites were assayed to evaluate their cytotoxic and protein kinase Cα inhibitory activities. Results indicated that 3ß-hydroxy-7α-methoxy-5α,6α-epoxy-8(14),22E-dien-ergosta (8) exhibited potent cytotoxic activity, with half-maximal inhibitory concentration values of 3.00 ± 0.27 to 15.69 ± 0.61 µM against five tumor cells, respectively. The new compound gunniiol A (1) showed weak cytotoxic activity at a concentration of 40 µM. At a concentration of 20 µg/mL, compounds 1, 6, and 7 exhibited protein kinase Cα inhibition by 43.63, 40.93, and 57.66%, respectively. This study is the first to report steroids demonstrating good cytotoxicity and polyketides exhibiting inhibitory activity against protein kinase Cα from the extracts of P. gunnii.

TGR5-mediated lateral hypothalamus-dCA3-dorsolateral septum circuit regulates depressive-like behavior in male mice.

Although bile acids play a notable role in depression, the pathological significance of the bile acid TGR5 membrane-type receptor in this disorder remains elusive. Using depression models of chronic social defeat stress and chronic restraint stress in male mice, we found that TGR5 in the lateral hypothalamic area (LHA) predominantly decreased in GABAergic neurons, the excitability of which increased in depressive-like mice. Upregulation of TGR5 or inhibition of GABAergic excitability in LHA markedly alleviated depressive-like behavior, whereas down-regulation of TGR5 or enhancement of GABAergic excitability facilitated stress-induced depressive-like behavior. TGR5 also bidirectionally regulated excitability of LHA GABAergic neurons via extracellular regulated protein kinases-dependent Kv4.2 channels. Notably, LHA GABAergic neurons specifically innervated dorsal CA3 (dCA3) CaMKIIα neurons for mediation of depressive-like behavior. LHA GABAergic TGR5 exerted antidepressant-like effects by disinhibiting dCA3 CaMKIIα neurons projecting to the dorsolateral septum (DLS). These findings advance our understanding of TGR5 and the LHAGABA→dCA3CaMKIIα→DLSGABA circuit for the development of potential therapeutic strategies in depression.

Effects of alcohol on the composition and metabolism of the intestinal microbiota among people with HIV: a cross-sectional study.

OBJECTIVES: Alcohol consumption is not uncommon among people with HIV (PWH) and may exacerbate HIV-induced intestinal damage, and further lead to dysbiosis and increased intestinal permeability. This study aimed to determine the changes in the faecal microbiota and its association with alcohol consumption in HIV-infected patients. METHODS: A cross-sectional survey was conducted between November 2021 and May 2022, and 93 participants were recruited. To investigate the alterations of alcohol misuse on fecal microbiology in HIV-infected individuals, we performed 16s rDNA gene sequencing on fecal samples from the low to moderate drinking (n=21) and non-drinking (n=72) groups. RESULTS: Comparison between groups using alpha and beta diversity showed that the diversity of stool microbiota in the low to moderate drinkinge group did not differ from that of the non-drinking group (all P>0.05). The Linear discriminant Analysis effect size (LEfSe) algorithm was to determine the bacterial taxa associated with alcohol consumption, and the results showed altered fecal bacterial composition in HIV-infected patients who consumed alcohol, with Coprobacillus, Pseudobutyrivibrio and Peptostreptococcaceae enriched, and Pasteurellaceae and Xanthomonadaceae were depleted. In addition, by using the Kyoto Encyclopedia of Genes and Genomes (KEGG) functional microbiome features were also found to be altered in the low to moderate drinking group, showing a reduction in metabolic pathways (P=0.036) and cardiovascular disease pathway (P=0.006). CONCLUSION: Low to moderate drinking will change the composition, metabolism and cardiovascular disease pathway of the gut microbiota of HIV-infected patients.

Glia-derived adenosine in the ventral hippocampus drives pain-related anxiodepression in a mouse model resembling trigeminal neuralgia.

Glial activation and dysregulation of adenosine triphosphate (ATP)/adenosine are involved in the neuropathology of several neuropsychiatric illnesses. The ventral hippocampus (vHPC) has attracted considerable attention in relation to its role in emotional regulation. However, it is not yet clear how vHPC glia and their derived adenosine regulate the anxiodepressive-like consequences of chronic pain. Here, we report that chronic cheek pain elevates vHPC extracellular ATP/adenosine in a mouse model resembling trigeminal neuralgia (rTN), which mediates pain-related anxiodepression, through a mechanism that involves synergistic effects of astrocytes and microglia. We found that rTN resulted in robust activation of astrocytes and microglia in the CA1 area of the vHPC (vCA1). Genetic or pharmacological inhibition of astrocytes and connexin 43, a hemichannel mainly distributed in astrocytes, completely attenuated rTN-induced extracellular ATP/adenosine elevation and anxiodepressive-like behaviors. Moreover, inhibiting microglia and CD39, an enzyme primarily expressed in microglia that degrades ATP into adenosine, significantly suppressed the increase in extracellular adenosine and anxiodepressive-like behaviors. Blockade of the adenosine A2A receptor (A2AR) alleviated rTN-induced anxiodepressive-like behaviors. Furthermore, interleukin (IL)-17A, a pro-inflammatory cytokine probably released by activated microglia, markedly increased intracellular calcium in vCA1 astrocytes and triggered ATP/adenosine release. The astrocytic metabolic inhibitor fluorocitrate and the CD39 inhibitor ARL 67156, attenuated IL-17A-induced increases in extracellular ATP and adenosine, respectively. In addition, astrocytes, microglia, CD39, and A2AR inhibitors all reversed rTN-induced hyperexcitability of pyramidal neurons in the vCA1. Taken together, these findings suggest that activation of astrocytes and microglia in the vCA1 increases extracellular adenosine, which leads to pain-related anxiodepression via A2AR activation. Approaches targeting astrocytes, microglia, and adenosine signaling may serve as novel therapies for pain-related anxiety and depression.

Association of farmers' knowledge, attitude and practices with bovine brucellosis seroprevalence in Myanmar.

OBJECTIVE: This study aimed to identify the relationship between bovine brucellosis prevalence, farmers' knowledge, attitude, practice (KAP), and social factors on migratory draft cattle and smallholder dairy farms in the central dry zone of Myanmar. METHODS: This cross-sectional study was conducted on 54 migratory and 38 dairy cattle farms between August 2020 and February 2021. A structured questionnaire was used to identify farmers' behaviors. Bulk milk was sampled and tested using indirect enzyme-linked immunosorbent assay (I-ELISA). STATA 17 was used for all the analyses. RESULTS: Migratory cattle farms had a higher farm level brucellosis prevalence (14.8%) than dairy farms (2.6%; χ2 = 3.75; df = 1; p = 0.05). Only 2.8% of the farmers had knowledge about brucellosis, while 39.1% and 41.6% had attitudes and farm practices with respect to brucellosis, respectively in the study area. Socio-economic attribute of training in animal husbandry (p<0.01), raising system (p<0.01), practice of separating the aborted cow (p<0.01) were negatively associated to brucellosis. The overall farm level brucellosis prevalence was strongly associated with cattle herd size (p = 0.01), free movement grazing practices (p<0.01), practice of self-removal of placental debris without using personal protective equipment (p<0.01) and farmers' attitudes towards eating cow placenta debris (p<0.01). CONCLUSION: Farmers had little knowledge of brucellosis. Attitudes and practices differed significantly between migratory and dairy farmers. Training and extension programs are necessary to make farmers aware of their KAP situation since livestock migration and the custom of eating cow placental debris contribute to the spread of brucellosis. Persistent efforts are required to reduce the adverse effects of brucellosis. Therefore, the study suggests that a feasible control intervention and public awareness campaigns need to be conducted regarding methods of preventing human exposure to brucellosis.

Corticotropin-releasing hormone neurons control trigeminal neuralgia-induced anxiodepression via a hippocampus-to-prefrontal circuit.

Anxiety and depression are frequently observed in patients suffering from trigeminal neuralgia (TN), but neural circuits and mechanisms underlying this association are poorly understood. Here, we identified a dedicated neural circuit from the ventral hippocampus (vHPC) to the medial prefrontal cortex (mPFC) that mediates TN-related anxiodepression. We found that TN caused an increase in excitatory synaptic transmission from vHPCCaMK2A neurons to mPFC inhibitory neurons marked by the expression of corticotropin-releasing hormone (CRH). Activation of CRH+ neurons subsequently led to feed-forward inhibition of layer V pyramidal neurons in the mPFC via activation of the CRH receptor 1 (CRHR1). Inhibition of the vHPCCaMK2A-mPFCCRH circuit ameliorated TN-induced anxiodepression, whereas activating this pathway sufficiently produced anxiodepressive-like behaviors. Thus, our studies identified a neural pathway driving pain-related anxiodepression and a molecular target for treating pain-related psychiatric disorders.

Metabolomic profiles, polygenic risk scores and risk of rheumatoid arthritis: a population-based cohort study in the UK Biobank.

OBJECTIVE: To investigate the relationship between metabolomic profiles, genome-wide polygenic risk scores (PRSs) and risk of rheumatoid arthritis (RA). METHODS: 143 nuclear magnetic resonance-based plasma metabolic biomarkers were measured among 93 800 participants in the UK Biobank. The Cox regression model was used to assess the associations between these metabolic biomarkers and RA risk, and genetic correlation and Mendelian randomisation analyses were performed to reveal their causal relationships. Subsequently, a metabolic risk score (MRS) comprised of the weighted sum of 17 clinically validated metabolic markers was constructed. A PRS was derived by assigning weights to genetic variants that exhibited significant associations with RA at a genome-wide level. RESULTS: A total of 620 incident RA cases were recorded during a median follow-up time of 8.2 years. We determined that 30 metabolic biomarkers were potentially associated with RA, while no further significant causal associations were found. Individuals in the top decile of MRS had an increased risk of RA (HR 3.52, 95% CI: 2.80 to 4.43) compared with those below the median of MRS. Further, significant gradient associations between MRS and RA risk were observed across genetic risk strata. Specifically, compared with the low genetic risk and favourable MRS group, the risk of incident RA in the high genetic risk and unfavourable MRS group has almost elevated by fivefold (HR 6.10, 95% CI: 4.06 to 9.14). CONCLUSION: Our findings suggested the metabolic profiles comprising multiple metabolic biomarkers contribute to capturing an elevated risk of RA, and the integration of genome-wide PRSs further improved risk stratification.

Association of age-related hearing loss with cognitive impairment and dementia: an umbrella review.

Background: Hearing loss, cognitive impairment and dementia have become common problems for older adults. Currently, systematic reviews and meta-analyses of the association between age-related hearing loss (ARHL) with cognitive impairment and dementia may have inconsistent results. To explore and validate the association between ARHL with cognitive impairment and dementia through summarizing and evaluating existing evidence. Methods: From inception to February 01, 2023, PubMed, Web of Science, Embase, and Cochrane Library databases were systematically searched. AMSTAR 2 was used to evaluate methodological quality and GRADE system was used to evaluate evidence quality. We summarized the basic characteristics of the included studies and extracted effect data for ARHL with cognitive impairment and dementia. Forest plots were used to describe the relative risk associated with ARHL and cognitive impairment, and the relative risk associated with ARHL and dementia, respectively. Results: A total of 11 systematic reviews and meta-analyses met the inclusion criteria. Overall, the methodological quality of the included SRs/MAs was moderate and the quality of the evidence was low. The combined results found that the pooled risk ratio of ARHL and cognitive impairment was 1.30 (random-effects; 95% CI 1.16 to 1.45), and the pooled risk ratio of ARHL and dementia was 1.59 (random-effects; 95% CI 1.34 to 1.90). Conclusion: Based on the evidence reported in this umbrella review, age-related hearing loss is significantly associated with cognitive impairment and dementia. Hearing loss may be a high risk factor for cognitive impairment and dementia in older adults.