lncRNA Oip5-as1 inhibits excessive mitochondrial fission in myocardial ischemia/reperfusion injury by modulating DRP1 phosphorylation.

BACKGROUND: Aberrant mitochondrial fission, a critical pathological event underlying myocardial ischemia/reperfusion (MI/R) injury, has emerged as a potential therapeutic target. The long non-coding RNA (lncRNA) Oip5-as1 is increasingly recognized for its regulatory roles, particularly in MI/R injury. However, its precise mechanistic role in modulating mitochondrial dynamics remains elusive. This study aims to elucidate the mechanistic role of Oip5-as1 in regulating mitochondrial fission and evaluate its therapeutic potential against MI/R injury. METHODS: To simulate in vitro MI/R injury, HL-1 cardiomyocytes were subjected to hypoxia/reoxygenation (H/R). Lentiviral vectors were employed to achieve overexpression or knockdown of Oip5-as1 in HL-1 cells by expressing Oip5-as1 or shRNA targeting Oip5-as1, respectively. The impact of Oip5-as1 on mitochondrial dynamics in HL-1 cells was assessed using CCK-8 assay, flow cytometry, immunofluorescence staining, and biochemical assays. MI/R injury was induced in mice by ligating the left anterior descending coronary artery. Conditional knockout mice for Oip5-as1 were generated using the CRISPR/Cas9 genome editing technology, while overexpression of Oip5-as1 in mice was achieved via intramyocardial administration of AAV9 vectors. In mice, the role of Oip5-as1 was evaluated through echocardiographic assessment, histopathological staining, and transmission electron microscopy. Furthermore, Western blotting, RNA pull-down, RNA immunoprecipitation, and co-immunoprecipitation assays were conducted to investigate Oip5-as1's underlying mechanisms. RESULTS: The expression levels of Oip5-as1 are significantly decreased in MI/R-injured HL-1 cells and myocardium. In HL-1 cells undergoing H/R injury, overexpression of Oip5-as1 attenuated excessive mitochondrial fission, preserved mitochondrial functionality, and reduced cellular apoptosis, while knockdown of Oip5-as1 exhibited the opposite effects. Furthermore, in a mouse model of MI/R injury, overexpression of Oip5-as1 diminished mitochondrial fission, myocardial infarct size and improved cardiac function. However, knockout of Oip5-as1 exacerbated myocardial injury and cardiac dysfunction, which were significantly reversed by treatment with a mitochondrial division inhibitor-1 (Mdivi-1). Mechanistically, Oip5-as1 selectively interacts with AKAP1 and CaN proteins, inhibiting CaN activation and subsequent DRP1 dephosphorylation at Ser637, thereby constraining DRP1's translocation to the mitochondria and its involvement in mitochondrial fission. CONCLUSIONS: Our study underscores the pivotal role of Oip5-as1 in mitigating excessive mitochondrial fission during MI/R injury. The findings not only enhance our comprehension of the molecular mechanisms underlying MI/R injury but also identify Oip5-as1 as a potential therapeutic target for ameliorating MI/R injury.

m6A-methylated Lonp1 drives mitochondrial proteostasis stress to induce testicular pyroptosis upon environmental cadmium exposure.

Cadmium (Cd) is a widely distributed typical environmental pollutant and one of the most toxic heavy metals. It is well-known that environmental Cd causes testicular damage by inducing classic types of cell death such as cell apoptosis and necrosis. However, as a new type of cell death, the role and mechanism of pyroptosis in Cd-induced testicular injury remain unclear. In the current study, we used environmental Cd to generate a murine model with testicular injury and AIM2-dependent pyroptosis. Based on the model, we found that increased cytoplasmic mitochondrial DNA (mtDNA), activated mitochondrial proteostasis stress occurred in Cd-exposed testes. We used ethidium bromide to generate mtDNA-deficient testicular germ cells and further confirmed that increased cytoplasmic mtDNA promoted AIM2-dependent pyroptosis in Cd-exposed cells. Uracil-DNA glycosylase UNG1 overexpression indicated that environmental Cd blocked UNG-dependent repairment of damaged mtDNA to drive the process in which mtDNA releases to cytoplasm in the cells. Interestingly, we found that environmental Cd activated mitochondrial proteostasis stress by up-regulating protein expression of LONP1 in testes. Testicular specific LONP1-knockdown significantly reversed Cd-induced UNG1 protein degradation and AIM2-dependent pyroptosis in mouse testes. In addition, environmental Cd significantly enhanced the m6A modification of Lonp1 mRNA and its stability in testicular germ cells. Knockdown of IGF2BP1, a reader of m6A modification, reversed Cd-induced upregulation of LONP1 protein expression and pyroptosis activation in testicular germ cells. Collectively, environmental Cd induces m6A modification of Lonp1 mRNA to activate mitochondrial proteostasis stress, increase cytoplasmic mtDNA content, and trigger AIM2-dependent pyroptosis in mouse testes. These findings suggest that mitochondrial proteostasis stress is a potential target for the prevention of testicular injury.

GrapeMOTS: UAV vineyard dataset with MOTS grape bunch annotations recorded from multiple perspectives for enhanced object detection and tracking.

Object Detection and Tracking have provided a valuable tool for many tasks, mostly time-consuming and prone-to-error jobs, including fruit counting while in the field, among others. Fruit counting can be a challenging assignment for humans due to the large quantity of fruit available, which turns it into a mentally-taxing operation. Hence, it is relevant to use technology to ease the task of farmers by implementing Object Detection and Tracking algorithms to facilitate fruit counting. However, those algorithms suffer undercounting due to occlusion, which means that the fruit is hidden behind a leaf or a branch, complicating the detection task. Consequently, gathering the datasets from multiple viewing angles is essential to boost the likelihood of recording the images and videos from the most visible point of view. Furthermore, the most critical open-source datasets do not include labels for certain fruits, such as grape bunches. This study aims to unravel the scarcity of public datasets, including labels, to train algorithms for grape bunch Detection and Tracking by considering multiple angles acquired with a UAV to overcome fruit occlusion challenges.

Single-site iron-anchored amyloid hydrogels as catalytic platforms for alcohol detoxification.

Constructing effective antidotes to reduce global health impacts induced by alcohol prevalence is a challenging topic. Despite the positive effects observed with intravenous applications of natural enzyme complexes, their insufficient activities and complicated usage often result in the accumulation of toxic acetaldehyde, which raises important clinical concerns, highlighting the pressing need for stable oral strategies. Here we present an effective solution for alcohol detoxification by employing a biomimetic-nanozyme amyloid hydrogel as an orally administered catalytic platform. We exploit amyloid fibrils derived from ß-lactoglobulin, a readily accessible milk protein that is rich in coordinable nitrogen atoms, as a nanocarrier to stabilize atomically dispersed iron (ferrous-dominated). By emulating the coordination structure of the horseradish peroxidase enzyme, the single-site iron nanozyme demonstrates the capability to selectively catalyse alcohol oxidation into acetic acid, as opposed to the more toxic acetaldehyde. Administering the gelatinous nanozyme to mice suffering from alcohol intoxication significantly reduced their blood-alcohol levels (decreased by 55.8% 300 min post-alcohol intake) without causing additional acetaldehyde build-up. Our hydrogel further demonstrates a protective effect on the liver, while simultaneously mitigating intestinal damage and dysbiosis associated with chronic alcohol consumption, introducing a promising strategy in effective alcohol detoxification.

Quantitation of Enterovirus A71 Empty and Full Particles by Sedimentation Velocity Analytical Ultracentrifugation.

The enterovirus A71 (EV71) inactivated vaccine is an effective intervention to control the spread of the virus and prevent EV71-associated hand, foot, and mouth disease (HFMD). It is widely administered to infants and children in China. The empty particles (EPs) and full particles (FPs) generated during production have different antigenic and immunogenic properties. However, the antigen detection methods currently used were established without considering the differences in antigenicity between EPs and FPs. There is also a lack of other effective analytical methods for detecting the different particle forms, which hinders the consistency between batches of products. In this study, we analyzed the application of sedimentation velocity analytical ultracentrifugation (SV-AUC) in characterizing the EPs and FPs of EV71. Our results showed that the proportions of the two forms could be quantified simultaneously by SV-AUC. We also determined the repeatability and accuracy of this method and found that both parameters were satisfactory. We assessed SV-AUC for bulk vaccine quality control, and our findings indicated that SV-AUC can be used effectively to analyze the percentage of EPs and FPs and monitor the consistency of the process to ensure the quality of the vaccine.

Clinical Benefit from Docetaxel +/- Ramucirumab Is Not Associated with Mutation Status in Metastatic Non-Small-Cell Lung Cancer Patients Who Progressed on Platinum Doublets and Immunotherapy.

Docetaxel +/- ramucirumab remains the standard-of-care therapy for patients with metastatic non-small-cell lung cancer (NSCLC) after progression on platinum doublets and immune checkpoint inhibitors (ICIs). The aim of our study was to investigate whether the cancer gene mutation status was associated with clinical benefits from docetaxel +/- ramucirumab. We also investigated whether platinum/taxane-based regimens offered a better clinical benefit in this patient population. A total of 454 patients were analyzed (docetaxel +/- ramucirumab n=381; platinum/taxane-based regimens n=73). Progression-free survival (PFS) and overall survival (OS) were compared among different subpopulations with different cancer gene mutations and between patients who received docetaxel +/- ramucirumab versus platinum/taxane-based regimens. Among patients who received docetaxel +/- ramucirumab, the top mutated cancer genes included TP53 (n=167), KRAS (n=127), EGFR (n=65), STK11 (n=32), ERBB2 (HER2) (n=26), etc. None of these cancer gene mutations or PD-L1 expression was associated with PFS or OS. Platinum/taxane-based regimens were associated with a significantly longer mQS (13.00 m, 95% Cl: 11.20-14.80 m versus 8.40 m, 95% Cl: 7.12-9.68 m, LogRank P=0.019) than docetaxel +/- ramcirumab. Key prognostic factors including age, histology, and performance status were not different between these two groups. In conclusion, in patients with metastatic NSCLC who have progressed on platinum doublets and ICIs, the clinical benefit from docetaxel +/- ramucirumab is not associated with the cancer gene mutation status. Platinum/taxane-based regimens may offer a superior clinical benefit over docetaxel +/- ramucirumab in this patient population.

Prognostic value of tumor volume doubling time in lung-metastatic adenoid cystic carcinoma.

OBJECTIVES: Lung metastases in adenoid cystic carcinoma (ACC) usually have indolent growth and the optimal timing to start systemic therapy is not established. We assessed ACC lung metastasis tumor growth dynamics and compared the prognostic value of time to progression (TTP) and tumor volume doubling time (TVDT). METHODS: The study included ACC patients with ≥1 pulmonary metastasis (≥5 mm) and at least 2 chest computed tomography scans. Radiology assessment was performed from the first scan showing metastasis until treatment initiation or death. Up to 5 lung nodules per patient were segmented for TVDT calculation. To assess tumor growth rate (TGR), the correlation coefficient (r) and coefficient of determination (R2) were calculated for measured lung nodules. TTP was assessed per RECIST 1.1; TVDT was calculated using the Schwartz formula. Overall survival was analyzed using the Kaplan-Meier method. RESULTS: The study included 75 patients. Sixty-seven patients (89%) had lung-only metastasis on first CT scan. The TGR was overall constant (median R2 = 0.974). Median TTP and TVDT were 11.2 months and 7.5 months. Shorter TVDT (<6 months) was associated with poor overall survival (HR = 0.48; p = 0.037), but TTP was not associated with survival (HR = 1.02; p = 0.96). Cox regression showed that TVDT but not TTP significantly correlated with OS. TVDT calculated using estimated tumor volume correlated with TVDT obtained by segmentation. CONCLUSION: Most ACC lung metastases have a constant TGR. TVDT may be a better prognostic indicator than TTP in lung-metastatic ACC. TVDT can be estimated by single longitudinal measurement in clinical practice.

Maternal prednisone exposure during pregnancy elevates susceptibility to osteoporosis in female offspring: The role of mitophagy/FNDC5 alteration in skeletal muscle.

Maternal exposure to glucocorticoids has been associated with adverse outcomes in offspring. However, the consequences and mechanisms of gestational exposure to prednisone on susceptibility to osteoporosis in the offspring remain unclear. Here, we found that gestational prednisone exposure enhanced susceptibility to osteoporosis in adult mouse offspring. In a further exploration of myogenic mechanisms, results showed that gestational prednisone exposure down-regulated FNDC5/irisin protein expression and activation of OPTN-dependent mitophagy in skeletal muscle of adult offspring. Additional experiments elucidated that activated mitophagy significantly inhibited the expression of FNDC5/irisin in skeletal muscle cells. Likewise, we observed delayed fetal bone development, downregulated FNDC5/irisin expression, and activated mitophagy in fetal skeletal muscle upon gestational prednisone exposure. In addition, an elevated total m6A level was observed in fetal skeletal muscle after gestational prednisone exposure. Finally, gestational supplementation with S-adenosylhomocysteine (SAH), an inhibitor of m6A activity, attenuated mitophagy and restored FNDC5/irisin expression in fetal skeletal muscle, which in turn reversed fetal bone development. Overall, these data indicate that gestational prednisone exposure increases m6A modification, activates mitophagy, and decreases FNDC5/irisin expression in skeletal muscle, thus elevating osteoporosis susceptibility in adult offspring. Our results provide a new perspective on the earlier prevention and treatment of fetal-derived osteoporosis.

Environmental cadmium inhibits testicular testosterone synthesis via Parkin-dependent MFN1 degradation.

Low testosterone (T) levels are associated with many common diseases, such as obesity, male infertility, depression, and cardiovascular disease. It is well known that environmental cadmium (Cd) exposure can induce T decline, but the exact mechanism remains unclear. We established a murine model in which Cd exposure induced testicular T decline. Based on the model, we found Cd caused mitochondrial fusion disorder and Parkin mitochondrial translocation in mouse testes. MFN1 overexpression confirmed that MFN1-dependent mitochondrial fusion disorder mediated the Cd-induced T synthesis suppression in Leydig cells. Further data confirmed Cd induced the decrease of MFN1 protein by increasing ubiquitin degradation. Testicular specific Parkin knockdown confirmed Cd induced the ubiquitin-dependent degradation of MFN1 protein through promoting Parkin mitochondrial translocation in mouse testes. Expectedly, testicular specific Parkin knockdown also mitigated testicular T decline. Mito-TEMPO, a targeted inhibitor for mitochondrial reactive oxygen species (mtROS), alleviated Cd-caused Parkin mitochondrial translocation and mitochondrial fusion disorder. As above, Parkin mitochondrial translocation induced mitochondrial fusion disorder and the following T synthesis repression in Cd-exposed Leydig cells. Collectively, our study elucidates a novel mechanism through which Cd induces T decline and provides a new treatment strategy for patients with androgen disorders.

Multigenerational paternal obesity enhances the susceptibility to male subfertility in offspring via Wt1 N6-methyladenosine modification.

There is strong evidence that obesity is a risk factor for poor semen quality. However, the effects of multigenerational paternal obesity on the susceptibility to cadmium (a reproductive toxicant)-induced spermatogenesis disorders in offspring remain unknown. Here, we show that, in mice, spermatogenesis and retinoic acid levels become progressively lower as the number of generations exposed to a high-fat diet increase. Furthermore, exposing several generations of mice to a high fat diet results in a decrease in the expression of Wt1, a transcription factor upstream of the enzymes that synthesize retinoic acid. These effects can be rescued by injecting adeno-associated virus 9-Wt1 into the mouse testes of the offspring. Additionally, multigenerational paternal high-fat diet progressively increases METTL3 and Wt1 N6-methyladenosine levels in the testes of offspring mice. Mechanistically, treating the fathers with STM2457, a METTL3 inhibitor, restores obesity-reduced sperm count, and decreases Wt1 N6-methyladenosine level in the mouse testes of the offspring. A case-controlled study shows that human donors who are overweight or obese exhibit elevated N6-methyladenosine levels in sperm and decreased sperm concentration. Collectively, these results indicate that multigenerational paternal obesity enhances the susceptibility of the offspring to spermatogenesis disorders by increasing METTL3-mediated Wt1 N6-methyladenosine modification.

Treatment of lung cancer by acupuncture combined with medicine based on pathophysiological mechanism: A review.

Lung cancer is one of the most frequently diagnosed cancers in the world. There are an estimated 2.2 million new cases and 1.79 million deaths each year. Over the past 2 decades, our understanding of disease biology, the use of predictive biomarkers, and improvements in therapeutic approaches have made significant progress and transformed the outcomes of many patients. Treatment is determined by the subtype and stage of the cancer; however, the effect of personalized treatment remains unsatisfactory. The use of Chinese medicines has attracted increasing attention worldwide. Chinese medicine treatment of lung cancer has few side effects, which can effectively prolong the survival expectation of patients and improve their quality of life, and has attracted increasing attention. Based on the pathophysiological mechanism of lung cancer reported in modern medical research, this article explores the efficacy and safety of acupuncture combined with medicine in the treatment of lung cancer.

Vitamin D binding protein (VDBP) hijacks twist1 to inhibit vasculogenic mimicry in hepatocellular carcinoma.

Rationale: Vitamin D (VD) has been suggested to have antitumor effects, however, research on the role of its transporter vitamin D-binding protein (VDBP, gene name as GC) in tumors is limited. In this study, we demonstrated the mechanism underlying the inhibition of vasculogenic mimicry (VM) by VDBP in hepatocellular carcinoma (HCC) and proposed an anti-tumor strategy of combining anti-PD-1 therapy with VD. Methods: Three-dimensional cell culture models and mice with hepatocyte-specific GC deletion were utilized to study the correlation between VDBP expression and VM. A patient-derived tumor xenograft (PDX) model was further applied to validate the therapeutic efficacy of VD in combination with an anti-PD-1 drug. Results: The study revealed that VDBP expression is negatively correlated with VM in HCC patients and elevated VDBP expression is associated with a favorable prognosis. The mechanism studies suggested VDBP hindered the binding of Twist1 on the promoter of VE-cadherin by interacting with its helix-loop-helix DNA binding domain, ultimately leading to the inhibition of VM. Furthermore, VD facilitated the translocation of the vitamin D receptor (VDR) into the nucleus where VDR interacts with Yin Yang 1 (YY1), leading to the transcriptional activation of VDBP. We further demonstrated that the combination of VD and anti-PD-1 led to an improvement in the anti-tumor efficacy of an anti-PD-1 drug. Conclusion: Collectively, we identified VDBP as an important prognostic biomarker in HCC patients and uncovered it as a therapeutic target for enhancing the efficacy of immune therapy.

Exploring China's water scarcity incorporating surface water quality and multiple existing solutions.

Water scarcity has threatened the sustainability of human life, ecosystem evolution, and socio-economic development. However, previous studies have often lacked a comprehensive consideration of the impact of water quality and existing solutions, such as inter-basin water transfer and unconventional water resources, on water scarcity. In this paper, an improved approach was proposed to quantify water scarcity levels by comprehensively considering surface water quality and multiple solutions. China's water scarcity was first assessed at a high spatial resolution on a monthly basis over the 5-year period from 2014 to 2018. Then, the driving factors including water quality and solutions were identified by a geographic detector model. Finally, an in-depth investigation was conducted to unravel the effects of water quantity solutions (i.e., inter-basin water transfer and unconventional water use), and water quality solutions (i.e., improving surface water quality) on alleviating water scarcity. Based on monthly assessments considering water quality and multiple existing solutions, the results showed that over half of the national population (∼777 million) faced water scarcity for at least one month of the year. Agricultural water use and inadequate water quality were the main driving factors responsible for China's water scarcity. Over four-fifths of the national population (∼1.10 billion) could benefit from alleviated water scarcity through a combination of water quantity and quality solutions. However, the existing solutions considered were insufficient to completely resolve water scarcity in China, especially in Northern China, persisting as a challenging issue. The results obtained from this study provided a better understanding of China's water scarcity, which could contribute to guiding future efforts aimed at alleviating water scarcity and ensuring water security in China.

Recent Advances of Green Electricity Generation: Potential in Solar Interfacial Evaporation System.

Solar-driven interfacial evaporation (SDIE) has played a pivotal role in optimizing water-energy utilization, reducing conventional power costs, and mitigating environmental impacts. The increasing emphasis on the synergistic cogeneration of water and green electricity through SDIE is particularly noteworthy. However, there is a gap of existing reviews that have focused on the mechanistic understanding of green power from water-electricity cogeneration (WEC) systems, the structure-activity relationship between efficiency of green energy utilization in WEC and material design in SDIE. Particularly, it lacks a comprehensive discussion to address the challenges faced in these areas along with potential solutions. Therefore, this review aims to comprehensively assess the progress and future perspective of green electricity from WEC systems by investigating the potential expansion of SDIE. First, it provides a comprehensive overview about material rational design, thermal management, and water transportation tunnels in SDIE. Then, it summarizes diverse energy sources utilized in the SDIE process, including steaming generation, photovoltaics, salinity gradient effect, temperature gradient effect, and piezoelectric effect. Subsequently, it explores factors that affect generated green electricity efficiency in WEC. Finally, this review proposes challenges and possible solution in the development of WEC.

Single-Atom Site SERS Chip for Rapid, Ultrasensitive, and Reproducible Direct-Monitoring of RNA Binding.

Ribonucleic acids (RNA) play active roles within cells or viruses by catalyzing biological reactions, controlling gene expression, and communicating responses to cellular signals. Rapid monitoring RNA variation has become extremely important for appropriate clinical decisions and frontier biological research. However, the most widely used method for RNA detection, nucleic acid amplification, is restricted by a mandatory temperature cycling period of ≈1 h required to reach target detection criteria. Herein, a direct detection approach via single-atom site integrated surface-enhanced Raman scattering (SERS) monitoring nucleic acid pairing reaction, can be completed within 3 min and reaches high sensitivity and extreme reproducibility for COVID-19 and two other influenza viruses' detection. The mechanism is that a single-atom site on SERS chip, enabled by positioning a single-atom oxide coordinated with a specific complementary RNA probe on chip nanostructure hotspots, can effectively bind target RNA analytes to enrich them at designed sites so that the binding reaction can be detected through Raman signal variation. This ultrafast, sensitive, and reproducible single-atom site SERS chip approach paves the route for an alternative technique of immediate RNA detection. Moreover, single-atom site SERS is a novel surface enrichment strategy for SERS active sites for other analytes at ultralow concentrations.

FeNi decorated nitrogen-doped hollow carbon spheres as ultra-stable bifunctional oxygen electrocatalyst for rechargeable zinc-air battery with 2.7% decay after 300 hours cycling.

Research on non-noble metal bifunctional electrocatalysts with high efficiency and long-lasting stability is crucial for many energy storage devices such as zinc-air batteries. In this report, nitrogen-doped porous hollow carbon spheres with a size of about 300 nm were fabricated using a modified Stöber method and decorated with an FeNi alloy through a pyrolytic reduction process, resulting in a promising bifunctional electrocatalyst for both the oxygen evolution reaction and oxygen reduction reaction. The as-prepared FeNi@NHCS electrocatalyst exhibits excellent bifunctional activity in KOH electrolyte, attributed to its mesoporous structure, large specific surface area, and the strong coupling between the FeNi nanoalloy and nitrogen-doped carbon carriers. The electrocatalyst demonstrates excellent ORR performance with E1/2 = 0.828 V and OER activity with Ej=10 mA = 1.51 V. A zinc-air battery using FeNi@NHCS as the air electrode achieves an open-circuit voltage of 1.432 V and a maximum power density of 181.8 mW cm-2. After 300 h of galvanostatic charge-discharge cycles, the charge-discharge voltage gap (ΔU) of the battery had only decayed by 2.7%, demonstrating superior cycling stability.

Overprescribing of potentially harmful medication: an observational study in England's general practice.

BACKGROUND: Overprescribing of potentially harmful medication in UK general practice has a complex association with socioeconomic deprivation. AIM: To assess trends in general practice prescribing of five high-risk medications and their relationship to deprivation. DESIGN & SETTING: We conducted an observational study using general practice data from three English regions with varied socio-demographic factors: West Yorkshire and Harrogate (WY), Black Country and West Birmingham (BC), and Surrey and East Sussex (SE). METHOD: Practice-level prescribing data was obtained from 2016-2021 for five drug classes: opioids, hypnotics, gabapentinoids, non-steroidal anti-inflammatory drugs (NSAIDs) and antibacterials. Prescribing trends were demonstrated using a linear model. RESULTS: Reduction in NSAID, Opioid, Hypnotic and Antibacterial prescriptions, and the increase in gabapentinoid prescriptions, were significant at each financial-year time period. Index of Multiple Deprivation (IMD) was positively associated with all drug classes except antibacterials, which showed a positive association when incorporating the interaction term between IMD and age.When adjusting for IMD and population, region was independently associated with prescribing rate. Compared to WY, IMD had a smaller association with prescribing in BC for NSAIDs (Coefficient -0.01578, P=0.004) and antibacterials (Coefficient -0.02769, P=0.007), whereas IMD had a greater association with prescribing in SE for NSAIDs (Coefficient 0.02443, P<.001), opioids (Coefficient 0.08919 p<.001), hypnotics (Coefficient 0.09038 p<.001), gabapentinoids (Coefficient 0.1095, P<.001) and antibacterials (Coefficient 0.01601, P=0.19). CONCLUSION: The association of socioeconomic deprivation with overprescribing of high-risk medication in general practice varies by region and drug type. Geographical location is associated with overprescribing, independent of socioeconomic status.

PD-1/PD-L1 governed cross-talk of exhausted CD8+ T and memory B cells in systemic lupus erythematosus.

BACKGROUND: Indeterminate readout of the quantitative interferon-γ release test (QFT) for Mycobacterium tuberculosis screening is a specific laboratory finding for systemic lupus erythematosus (SLE), which may be due to T-cell exhaustion and abnormal programmed death receptor 1 (PD-1)/programmed death-ligand 1 (PD-L1) signalling. METHODS: We enrolled 104 patients with SLE and 225 with other rheumatic musculoskeletal diseases (RMDs) who presented to the outpatient clinic between 2020 and 2023. Twenty healthy donors served as the controls. The QFT was performed in all participants, and those with indeterminate results were compared among the groups. Immunophenotyping and functional assays were performed using blood mononuclear cells. Interferon (IFN)-γ was detected in vitro and ex vivo in patients with SLE with indeterminate or negative QFT results, before or after rituximab therapy. RESULTS: 104 patients with SLE had a significantly higher rate of indeterminate QFT results was significantly higher (17.31%) than that of 225 patients with RMD (3.56%). Patients with SLE with indeterminate QFT had more active disease (SLEDAI-2K, mean 10.94 vs 4.02, p<0.0001), including a higher incidence of active nephritis (55.56% vs 29.07%). Indeterminate QFT in SLE is mainly caused by an insufficient IFN-γ response in CD8+T cells with exhausted immunophenotypes. The abnormal interaction between exhausted PD-1 high CD8+ T cells and activated PD-L1 low memory B cells in SLE can be reversed with a PD-1 agonist or increased PD-L1 expression. Rituximab treatment indirectly reversed this IFN-γ response. CONCLUSION: The PD-1/PD-L1 signalling pathway, which governs the crosstalk between exhausted CD8+ T cells and activated memory B cells, is a mechanistic explanation for insufficient interferon-γ response in patients with SLE.