Potential Interventions Research Articles

ProkDBP: Toward more precise identification of prokaryotic DNA binding proteins.

Prokaryotic DNA binding proteins (DBPs) play pivotal roles in governing gene regulation, DNA replication, and various cellular functions. Accurate computational models for predicting prokaryotic DBPs hold immense promise in accelerating the discovery of novel proteins, fostering a deeper understanding of prokaryotic biology, and facilitating the development of therapeutics targeting for potential disease interventions. However, existing generic prediction models often exhibit lower accuracy in predicting prokaryotic DBPs. To address this gap, we introduce ProkDBP, a novel machine learning-driven computational model for prediction of prokaryotic DBPs. For prediction, a total of nine shallow learning algorithms and five deep learning models were utilized, with the shallow learning models demonstrating higher performance metrics compared to their deep learning counterparts. The light gradient boosting machine (LGBM), coupled with evolutionarily significant features selected via random forest variable importance measure (RF-VIM) yielded the highest five-fold cross-validation accuracy. The model achieved the highest auROC (0.9534) and auPRC (0.9575) among the 14 machine learning models evaluated. Additionally, ProkDBP demonstrated substantial performance with an independent dataset, exhibiting higher values of auROC (0.9332) and auPRC (0.9371). Notably, when benchmarked against several cutting-edge existing models, ProkDBP showcased superior predictive accuracy. Furthermore, to promote accessibility and usability, ProkDBP (https://iasri-sg.icar.gov.in/prokdbp/) is available as an online prediction tool, enabling free access to interested users. This tool stands as a significant contribution, enhancing the repertoire of resources for accurate and efficient prediction of prokaryotic DBPs.

Effects of clamshell exercises in terminal extension lag after ACL reconstruction

BackgroundTerminal extension lag (TEL) is common following anterior cruciate ligament reconstruction (ACLR). Clamshell exercises have been suggested as a potential intervention to address TEL, but limited research has been conducted in this area. ObjectiveThis study aimed to determine the effects of Clamshell exercises in terminal extension lag after anterior cruciate ligament reconstruction. MethodsThis randomized controlled trial included 40 participants with a history of ACLR between 1 and 3 years prior. Participants were randomly assigned to either the experimental group (Group A) or the control group (Group B). Group A received conventional exercises along with isolated hip strengthening rehabilitation, while Group B received conventional exercises without specific hip strengthening. The primary outcomes were pain levels (Numeric Pain Rating Scale), knee function (International Knee Documentation Committee scores, (IKDC)), range of motions (goniometer) and strength (sphygmomanometer). ResultsIn between the group comparison shows that all outcome measures (NPRS, IKDC, Goniometer, Sphygmomanometer) show significant results (p < 0.05). Within-group comparisons (paired sample t-test) show that there was a significant difference (p < 0.05) in all outcome measures of both groups. ConclusionThe addition of Clamshell exercises to the rehabilitation program resulted in a significantly greater reduction in TEL compared to the control group. These findings suggest that Clamshell exercises were found to be an effective intervention for addressing TEL after ACLR.

Retinotopic cortical mapping in objective functional monitoring of macular therapy

Background/AimsTo determine the suitability of functional MRI (fMRI) as an objective measure of macular function following therapeutic intervention; conventional psychophysical measures rely heavily on patient compliance.MethodsTwenty patients with neovascular age-related...

Analysis of evidence on nutraceutical interventions for Peyronie's disease: a guideline-based critical review.

The management of Peyronie's disease (PD) is a challenge for the clinician. Despite the lack of etiologic therapy, different nonsurgical approaches have often been empirically proposed. The most used treatment is based on nutraceutical drugs with antioxidant activity, although such an intervention remains controversial. We reviewed the evidence from the randomized controlled trials included in the recommendations of the American Urological Association (AUA), Canadian Urological Association (CUA), European Association of Urology, and International Society for Sexual Medicine. We searched PubMed, Scopus, Web of Science, and Cochrane Library for randomized controlled trials, reviews, and guidelines on nutraceutical interventions for PD. Our analysis provides detailed information on potential interventions, underlying the inconsistent evidence. Acetyl esters of carnitine, although not recommended by any of the available guidelines, showed potential benefit in some selected studies. Omega-3 fatty acids are not recommended due to withdrawn study evidence. The CUA and AUA were the only societies to consider the use of coenzyme Q10. While the CUA suggested that it might be offered as a treatment option, the AUA refrained from taking a definitive stance due to insufficient evidence. Similarly, conflicting recommendations have been produced on potassium para-aminobenzoate. While the CUA considers potassium para-aminobenzoate potentially useful in slowing PD progression, the AUA deems the evidence insufficient. Conversely, both the International Society for Sexual Medicine and European Association of Urology do not recommend its use. This critical comparative analysis of the most recent guidelines produced by the leading scientific societies highlights some inconsistencies in the recommendations on nutraceutical intervention for PD, even within a background of overall ineffectiveness of this treatment approach.

Substance P’s Impact on Chronic Pain and Psychiatric Conditions—A Narrative Review

Substance P (SP) plays a crucial role in pain modulation, with significant implications for major depressive disorder (MDD), anxiety disorders, and post-traumatic stress disorder (PTSD). Elevated SP levels are linked to heightened pain sensitivity and various psychiatric conditions, spurring interest in potential therapeutic interventions. In chronic pain, commonly associated with MDD and anxiety disorders, SP emerges as a key mediator in pain and emotional regulation. This review examines SP’s impact on pain perception and its contributions to MDD, anxiety disorders, and PTSD. The association of SP with increased pain sensitivity and chronic pain conditions underscores its importance in pain modulation. Additionally, SP influences the pathophysiology of MDD, anxiety disorders, and PTSD, highlighting its potential as a therapeutic target. Understanding SP’s diverse effects provides valuable insights into the mechanisms underlying these psychiatric disorders and their treatment. Further research is essential to explore SP modulation in psychiatric disorders and develop more effective treatment strategies.

Pathological Changes and Metabolic Adaptation in the Myocardium of Rats in Response to Chronic Variable Mild Stress

Chronic variable mild stress (CVS) in rats is a well-established paradigm for inducing depressive-like behaviors and has been utilized extensively to explore potential therapeutic interventions for depression. While the behavioral and neurobiological effects of CVS have been extensively studied, its impact on myocardial function remains largely unexplored. To induce the CVS model, rats were exposed to various stressors over 40 days. Behavioral assessments confirmed depressive-like behavior. Biochemical analyses revealed alterations in myocardial metabolism, including changes in NAD+ and NADP+, and NADPH concentrations. Free amino acid analysis indicated disturbances in myocardial amino acid metabolism. Evaluation of oxidative DNA damage demonstrated an increased number of abasic sites in the DNA of rats exposed to CVS. Molecular analysis showed significant changes in gene expression associated with glucose metabolism, oxidative stress, and cardiac remodeling pathways. Histological staining revealed minor morphological changes in the myocardium of CVS-exposed rats, including increased acidophilicity of cells, collagen deposition surrounding blood vessels, and glycogen accumulation. This study provides novel insights into the impact of chronic stress on myocardial function and metabolism, highlighting potential mechanisms linking depression and cardiovascular diseases. Understanding these mechanisms may aid in the development of targeted therapeutic strategies to mitigate the adverse cardiovascular effects of depression.

Protocol for a multicentre prospective exploratory mixed-methods study investigating the modifiable psychosocial variables influencing access to and outcomes after kidney transplantation in children and young people in the UK

IntroductionKidney transplantation is the preferred therapy for children with stage 5 chronic kidney disease (CKD-5). However, there is a wide variation in access to kidney transplantation across the UK for...

The Syvn1 inhibits neuronal cell ferroptosis by activating Stat3/Gpx4 axis in rat with spinal cord injury.

Spinal cord injury (SCI) leads to secondary neuronal death, which severely impedes recovery of motor function. Therefore, prevention of neuronal cell death after SCI is an important strategy. Ferroptosis, a new form of cell death discovered in recent years, has been shown to be involved in the regulation of SCI. However, the role and potential mechanisms of ferroptosis in secondary SCI are not fully understood. In this study, we report that the E3 ubiquitin ligase Syvn1 suppresses ferroptosis and promotes functional recovery from SCI in vitro and in vivo. Mechanistically, screened with bioinformatics, immunoprecipitation, and mass spectrometry, we identified Stat3, a transcription factor that induces the expression of the ferroptosis inhibitor Gpx4, as a substrate of Syvn1. Furthermore, we identified neurons as the primary cellular source of Syvn1 signalling. Moreover, we determined the binding domains of Syvn1 and Stat3 in HEK 293 T cells using full-length proteins and a series of truncated Flag-tagged and Myc-tagged fragments. Furthermore, we created the cell and animal models with silencing or overexpression of Syvn1 and Stat3 and found that Syvn1 inhibits neuronal ferroptosis by stabilizing Stat3, which subsequently activates the ferroptosis regulator Gpx4 in SCI. In summary, the Syvn1-mediated Stat3/Gpx4 signalling axis attenuates neuronal ferroptosis, reduces neuronal death, and promotes SCI repair. Therefore, our findings provide potential new targets and intervention strategies for the treatment of SCI.

Exploring the molecular mechanisms of ferroptosis-related genes in periodontitis: a multi-dataset analysis

PurposeThis study aims to elucidate the biological functions of ferroptosis-related genes in periodontitis, along with their correlation to tumor microenvironment (TME) features such as immune infiltration. It aims to provide potential diagnostic markers of ferroptosis for clinical management of periodontitis.MethodsUtilizing the periodontitis-related microarray dataset GSE16134 from the Gene Expression Omnibus (GEO) and a set of 528 ferroptosis-related genes identified in prior studies, this research unveils differentially expressed ferroptosis-related genes in periodontitis. Subsequently, a protein–protein interaction network was constructed. Subtyping of periodontitis was explored, followed by validation through immune cell infiltration and gene set enrichment analyses. Two algorithms, randomForest and SVM(Support Vector Machine), were employed to reveal potential ferroptosis diagnostic markers for periodontitis. The diagnostic efficacy, immune correlation, and potential transcriptional regulatory networks of these markers were further assessed. Finally, potential targeted drugs for differentially expressed ferroptosis markers in periodontitis were predicted.ResultsA total of 36 ferroptosis-related genes (30 upregulated, 6 downregulated) were identified from 829 differentially expressed genes between 9 periodontitis samples and the control group. Subsequent machine learning algorithm screening highlighted 4 key genes: SLC1A5(Solute Carrier Family 1 Member 5), SLC2A14(Solute Carrier Family 1 Member 14), LURAP1L(Leucine Rich Adaptor Protein 1 Like), and HERPUD1(Homocysteine Inducible ER Protein With Ubiquitin Like Domain 1). Exploration of these 4 key genes, supported by time-correlated ROC analysis, demonstrated reliability, while immune infiltration results indicated a strong correlation between key genes and immune factors. Furthermore, Gene Set Enrichment Analysis (GSEA) was conducted for the four key genes, revealing enrichment in GO/KEGG pathways that have a significant impact on periodontitis. Finally, the study predicted potential transcriptional regulatory networks and targeted drugs associated with these key genes in periodontitis.ConclusionsThe ferroptosis-related genes identified in this study, including SLC1A5, SLC2A14, LURAP1L, and HERPUD1, may serve as novel diagnostic and therapeutic targets for periodontitis. They are likely involved in the occurrence and development of periodontitis through mechanisms such as immune infiltration, cellular metabolism, and inflammatory chemotaxis, potentially linking the ferroptosis pathway to the progression of periodontitis. Targeted drugs such as flurofamide, L-733060, memantine, tetrabenazine, and WAY-213613 hold promise for potential therapeutic interventions in periodontitis associated with these ferroptosis-related genes.

Upregulated Palmitoleate and Oleate Production in Escherichia coli Promotes Gentamicin Resistance

Metabolic reprogramming mediates antibiotic efficacy. However, metabolic adaptation of microbes evolving from antibiotic sensitivity to resistance remains undefined. Therefore, untargeted metabolomics was conducted to unveil relevant metabolic reprogramming and potential intervention targets involved in gentamicin resistance. In total, 61 metabolites and 52 metabolic pathways were significantly altered in gentamicin-resistant E. coli. Notably, the metabolic reprogramming was characterized by decreases in most metabolites involved in carbohydrate and amino acid metabolism, and accumulation of building blocks for nucleotide synthesis in gentamicin-resistant E. coli. Meanwhile, fatty acid metabolism and glycerolipid metabolism were also significantly altered in gentamicin-resistant E. coli. Additionally, glycerol, glycerol-3-phosphate, palmitoleate, and oleate were separately defined as the potential biomarkers for identifying gentamicin resistance in E. coli. Moreover, palmitoleate and oleate could attenuate or even abolished killing effects of gentamicin on E. coli, and separately increased the minimum inhibitory concentration of gentamicin against E. coli by 2 and 4 times. Furthermore, palmitoleate and oleate separately decreased intracellular gentamicin contents, and abolished gentamicin-induced accumulation of reactive oxygen species, indicating involvement of gentamicin metabolism and redox homeostasis in palmitoleate/oleate-promoted gentamicin resistance in E. coli. This study identifies the metabolic reprogramming, potential biomarkers and intervention targets related to gentamicin resistance in bacteria.

Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy

Cancer of the colon and rectum (CRC) has been identified among the three most prevalent types of cancer and cancer-related deaths for both sexes. Even though significant progress in surgical and chemotherapeutic techniques has markedly improved disease-free and overall survival rates in contrast to those three decades ago, recent years have seen a stagnation in these improvements. This underscores the need for new therapies aiming to augment patient outcomes. A number of emerging strategies, such as immune checkpoint inhibitors (ICIs) and adoptive cell therapy (ACT), have exhibited promising outcomes not only in preclinical but also in clinical settings. Additionally, a thorough appreciation of the underlying biology has expanded the scope of research into potential therapeutic interventions. For instance, the pivotal role of altered telomere length in early CRC carcinogenesis, leading to chromosomal instability and telomere dysfunction, presents a promising avenue for future treatments. Thus, this review explores the advancements in CRC immunotherapy and telomere-targeted therapies, examining potential synergies and how these novel treatment modalities intersect to potentially enhance each other’s efficacy, paving the way for promising future therapeutic advancements.

Trauma in Schools: A Review of the Impact of Childhood Trauma and Assessment of a Potential Intervention

According to the National Survey of Children’s Health (NSCH), nearly 30 million children in the United States have experienced one or more types of significant childhood trauma. In the average public school, this statistic translates to as many as half of the students in a given teacher’s classroom. Children exposed to the toxic stress of trauma often experience negative consequences that affect their academic, psychological, socioemotional, and behavioral health. To aid educators in addressing this reality, trauma-informed care practices have increasingly begun to be translated into professional development opportunities for educators. Using the theoretical frameworks of trauma theory and transformational learning theory, this review of the literature provides a brief overview of trauma theory, the short- and long-term effects on children, the mechanisms involved in how trauma affects developmental outcomes, and the relevance of trauma in an educational setting. It also reviews the implementation of trauma-informed care as professional development in educational settings, examines research on educators’ awareness of beliefs and attitudes, and reviews how/whether knowledge and change in attitudes affect behavioral change.

A SARS-CoV-2 outbreak in a public order and safety training facility in England, June 2021.

The public order and safety (POS) sector remains susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreaks, as workplace attendance is typically compulsory and close physical contact is often needed. Here, we report on a SARS-CoV-2 outbreak with an attack rate of 39% (9/23), which occurred between 19 and 29 June 2021 among a cohort of new POS recruits participating in a mandatory 18-week training programme in England. The COVID-OUT (COVID-19 Outbreak investigation to Understand Transmission) study team undertook a multidisciplinary outbreak investigation, including viral surface sampling, workplace environmental assessment, participant viral and antibody testing, and questionnaires, at the two associated training facilities between 5 July and 24 August 2021. Environmental factors, such as ventilation, were deemed inadequate in some areas of the workplace, with carbon dioxide (CO2) levels exceeding 1,500ppm on multiple occasions within naturally ventilated classrooms. Activities during safety training required close contact, with some necessitating physical contact, physical exertion, and shouting. Furthermore, most participants reported having physical contact with colleagues (67%) and more than one close work contact daily (97%). Our investigation suggests that site- and activity-specific factors likely contributed to the transmission risks within the POS trainee cohort. Potential interventions for mitigating SARS-CoV-2 transmission in this POS training context could include implementing regular rapid lateral flow testing, optimizing natural ventilation, using portable air cleaning devices in classrooms, and expanding use of well-fitted FFP2/FFP3 respirators during activities where prolonged close physical contact is required.

Association of Pain, Analgesic, Psychological, and Socioeconomic Factors With Subacute Pain After Childbirth: A Prospective Cohort Study

(J Clin Anesth. 2022;83:110978 | https://doi.org/10.1016/j.jclinane.2022.110978|) Persistent postpartum pain poses significant societal and health care challenges. It is defined by the International Association for the Study of Pain as pain lasting beyond 3 months after tissue injury, affecting up to 30% of postpartum women. Research primarily focuses on risk factors for persistent pain, including severe acute postpartum pain, psychological factors, and social deprivation. However, there is a lack of investigation into subacute pain after childbirth (lasting 4 wk to 3 mo). A previous study identified some risk factors for subacute pain, but the relationship between acute postpartum pain and subacute pain remains unexplored. This study aims to investigate these associations and explore potential interventions by anesthesiologists.

Promoting planting in front gardens: a systematic approach to intervention development

Planting in front gardens is associated with a range of human and environmental health benefits. Effective interventions aimed at cultivating this practice are, however, hampered by the paucity of theory- and evidence-based behavioural research in this context. This study aims to systematically determine a set of behaviour change interventions likely to be effective at promoting planting in front gardens amongst UK householders. The Behaviour Change Wheel framework was applied. Behavioural systems mapping was used to identify community actors relevant to front gardening. Potential behavioural influences on householders’ front gardening were identified using the Capability, Opportunity, Motivation, Behaviour model. Using peer-reviewed scientific findings as evidence, behavioural influences were systematically linked to potential intervention strategies, behaviour change techniques and real-world implementation options. Finally, intervention recommendations were refined through expert evaluations and local councillor and public stakeholder feedback, evaluating them against the Acceptability, Practicability, Effectiveness, Affordability, Side effects and Equity criteria in a UK implementation context. This study formulated 12 intervention recommendations, implementable at a community level, to promote front gardening. Stakeholder feedback revealed a preference for educational and supportive (social and practical) strategies (e.g., community gardening workshops, front gardening ‘starter kits’) over persuasive and motivational approaches (e.g., social marketing, motivational letters from the council to householders). Householders’ front gardening behaviour is complex and influenced by the behaviour of many other community actors. It also needs to be understood as a step in a continuum of other behaviours (e.g., clearing land, gardening, waste disposal). This study demonstrates the application of behavioural science to an understudied implementation context, that is, front gardening promotion, drawing on a rigorous development process promoting a transparent approach to intervention design. Stakeholder consultation allowed relevance, feasibility and practical issues to be considered. These improve the likely effectiveness of interventions in practice. The next steps include evaluating the proposed interventions in practice.

Renal artery stenosis increases the risk of incident atrial fibrillation and cardiovascular events incorporating death

Abstract Background Renal artery stenosis (RAS) remains an under-recognized clinical risk factor for cardiovascular complications. Its long-term impact on AF arrhythmogenesis is unclear. Objective To investigate the role of RAS on incident AF and related adverse cardiovascular events Methods We performed a retrospective cohort study that comprised 100 patients with ultrasonographically-confirmed atherosclerotic RAS, and 50 age- and sex-matched controls who were healthy renal transplant donors (age 52.6 ±5.6 vs 50.1 ±10.7years, women 59% vs 70%). Incident AF was ascertained from clinical records. Primary endpoint was defined as the composite of incident AF, myocardial infarction, unstable angina, heart failure, ischemic stroke, peripheral arterial disease, end-stage renal failure, and cardiovascular death. Results Over a follow-up duration of 4818 ± 2751 days, RAS was significantly associated with incident AF (9.4% versus 0%, P=0.025). Kaplan-Meier analyses showed that RAS was associated with reduced incident AF event-free survival (Log-rank Mantel-Cox=4.6 P=0.032, Figure). Multivariable logistic regression showed that after adjustment for potential confounders (including age, sex, smoking, alcohol use, history of hypertension, diabetes mellitus, myocardial infarction, heart failure, ischemic stroke, renal function and serum low-density lipoprotein level), RAS was independently associated with substantially increased risk of the primary endpoint (OR=27.8, 95%CI [2.3 – 333.9], P=0.009), Conclusions RAS is an important and under-recognized independent risk factor for AF and cardiovascular events incorporating death. Its pathophysiological implications with a view to potential interventions need to be further explored.

The Effect of Type 2 Resistant Starch and Indole-3-Propionic Acid on Ameliorating High-Fat-Diet-Induced Hepatic Steatosis and Gut Dysbiosis

Owing to the interplay of genetic and environmental factors, obesity has emerged as a significant global public health concern. To gain enhanced control over obesity, we examined the effects of type 2 resistant starch (RS2) and its promoted microbial-derived metabolite, indole-3-propionic acid (IPA), on hepatic steatosis, antioxidant activity, and gut microbiota in obese mice. Neither RS2 nor low-dose IPA (20 mg kg−1) exhibited a reduction in body weight or improved glucose and lipid metabolism in post-obesity state mice continuously fed the high-fat diet (HFD). However, both interventions improved hepatic steatosis, with RS2 being more effective in all measured parameters, potentially due to changes in gut microbiota and metabolites not solely attributed to IPA. LC-MS/MS analysis revealed increased serum IPA levels in both RS2 and IPA groups, which positively correlated with Bifidobacterium and Clostridium. Moreover, RS2 exhibited a more significant restoration of gut dysbiosis by promoting the abundance of health-promoting bacteria including Faecalibaculum and Bifidobacterium. These findings suggest that the regulatory role of RS2 on tryptophan metabolism only partially explains its prebiotic activity. Future studies should consider increasing the dose of IPA and combining RS2 and IPA to explore their potential interventions in obesity.

#1801 Gut dysbiosis contributes to TMAO accumulation in CKD

Abstract Background and Aims Chronic kidney disease (CKD) patients face a substantial morbidity risk, especially related to cardiovascular complications. The imbalance of circulating metabolites influences inter-organ crosstalk and disease pathophysiology. In this regard, metabolites of microbial origin have gained increasing attention. Trimethylamine N-oxide (TMAO) originates from microbial Trimethylamine (TMA) metabolism and is found at high concentrations in the blood of CKD patients. A high TMAO concentration is known to be an independent risk factor for cardiovascular disease. This study aims to investigate the extent to which high concentrations of TMAO in the blood are due to increased bacterial production or are mainly a consequence of impaired renal clearance. Methods We used existing biomaterials and clinical data of a pediatric CKD cohort, consisting of patients enrolled at CKD stage G3-5, including G5 patients treated with hemodialysis (HD), as well as patients after kidney transplantation (KT) and individuals with normal kidney function. We analyzed TMAO in plasma and urine samples using LC-MS/MS and developed a novel gene targeting assay (GTA) that quantifies the abundance of the bacterial target genes (CutC, CntA) encoding for the key enzymes of microbial TMA synthesis in each fecal sample. Results Plasma TMAO levels were stage-dependently elevated in CKD, with HD patients showing the highest levels (75 ± 46 µmol/l). While urinary TMAO levels were lower in the CKD groups, TMAO/creatinine ratios and fractional excretion were not significantly different in CKD compared to controls. Fecal microbial gene abundance of both CutC and CntA genes was elevated across CKD stages and correlated with both plasma TMAO levels and eGFR. Although KT patients exhibited an eGFR range comparable to controls, they still showed higher plasma TMAO levels and elevated TMAO-associated gene abundances. In a regression analysis, this gene abundance was associated with plasma TMAO independent of eGFR in a model adjusted for age, sex, and BMI. Using a likelihood ratio test, we showed that adding fecal microbial gene abundance to the model provided a significantly better fit compared to only eGFR, age, sex, and BMI. Conclusion Our data indicate that the production of TMA by intestinal bacteria contributes significantly to the accumulation of TMAO in patients with CKD and after kidney transplantation. This finding opens the possibility for new potential interventions in the management of patients with CKD.

#569 Proenkephalin A 119-159 (penKid) for the early identification and risk stratification of delayed graft function following kidney transplantation

Abstract Background and Aims Delayed graft function (DGF) frequently occurs following kidney transplantation, and prolonged duration of DGF adversely affects 1-year graft function and long-term graft survival. Recently, Proenkephalin A 119-159 (penKid) was shown to reflect kidney function and predict acute kidney injury (AKI) in critically ill patients. Given the similarities between DGF in transplanted and AKI in native kidneys, we hypothesized that penKid may aid in identifying and risk-stratifying DGF post-transplantation. Method In a prospective study of 159 consecutive kidney transplant recipients at Heidelberg University Hospital from November 2021 to July 2023, penKid was quantified using an immunoluminometric assay until patient discharge. DGF was primarily defined as the necessity for dialysis within 7 days post-transplant. Additionally, penKid was examined in the context of DGF severity, discriminating the different durations of post-transplant dialysis treatment. Similarly, penKid was assessed to differentiate uptake of graft function, defined as slow or immediate by a serum creatinine reduction ratio of pre-transplant and 7 days post-transplant levels of &amp;lt;0.7 and ≥0.7, respectively. Results DGF, defined as the need for dialysis within the first week post-transplant, occurred in 53/159 (33.3%) patients. penKid enabled the differentiation of patients with and without DGF from the first day post-transplant onward (P &amp;lt; 0.001, Fig. 1), and consistently outperformed SCr in discriminating DGF from no DGF at all time points studied (P &amp;lt; 0.001). Additionally, penKid allowed identification of DGF severity from the first day post-transplant (P &amp;lt; 0.001) and early differentiation between slow and delayed graft function (AUC 0.79 [95% CI 0.68-0.90]). In a multivariate model, delta penKid from pre-transplant to the first day post-transplant emerged as the strongest predictor for DGF (C index = 0.88). On the first day post-transplant, penKid, with a cut-off at 300 pmol/L, discriminated DGF from no DGF with a sensitivity of 95.1% (95% CI 83.9–98.7) and a specificity of 56.5% (95% CI 46.3–66.2). Conclusion penKid is a promising biomarker shown to accurately differentiate DGF from no DGF as early as the first day post-transplant and to predict DGF severity, allowing for earlier intervention in these at-risk patients. Due to its high discriminatory power to identify and predict DGF post-transplantation, penKid shows great potential to accompany future studies examining the occurrence of DGF in transplant programs, where DCD is introduced into practice, machine perfusion techniques are assessed, or in trials that assess potential therapeutic interventions in patients with DGF.

Agrin-Lrp4 pathway in hippocampal astrocytes restrains development of temporal lobe epilepsy through adenosine signaling

BackgroundHuman patients often experience an episode of serious seizure activity, such as status epilepticus (SE), prior to the onset of temporal lobe epilepsy (TLE), suggesting that SE can trigger the development of epilepsy. Yet, the underlying mechanisms are not fully understood. The low-density lipoprotein receptor related protein (Lrp4), a receptor for proteoglycan-agrin, has been indicated to modulate seizure susceptibility. However, whether agrin-Lrp4 pathway also plays a role in the development of SE-induced TLE is not clear.MethodsLrp4f/f mice were crossed with hGFAP-Cre and Nex-Cre mice to generate brain conditional Lrp4 knockout mice (hGFAP-Lrp4−/−) and pyramidal neuron specific knockout mice (Nex-Lrp4−/−). Lrp4 was specifically knocked down in hippocampal astrocytes by injecting AAV virus carrying hGFAP-Cre into the hippocampus. The effects of agrin-Lrp4 pathway on the development of SE-induced TLE were evaluated on the chronic seizure model generated by injecting kainic acid (KA) into the amygdala. The spontaneous recurrent seizures (SRS) in mice were video monitored.ResultsWe found that Lrp4 deletion from the brain but not from the pyramidal neurons elevated the seizure threshold and reduced SRS numbers, with no change in the stage or duration of SRS. More importantly, knockdown of Lrp4 in the hippocampal astrocytes after SE induction decreased SRS numbers. In accord, direct injection of agrin into the lateral ventricle of control mice but not mice with Lrp4 deletion in hippocampal astrocytes also increased the SRS numbers. These results indicate a promoting effect of agrin-Lrp4 signaling in hippocampal astrocytes on the development of SE-induced TLE. Last, we observed that knockdown of Lrp4 in hippocampal astrocytes increased the extracellular adenosine levels in the hippocampus 2 weeks after SE induction. Blockade of adenosine A1 receptor in the hippocampus by DPCPX after SE induction diminished the effects of Lrp4 on the development of SE-induced TLE.ConclusionThese results demonstrate a promoting role of agrin-Lrp4 signaling in hippocampal astrocytes in the development of SE-induced development of epilepsy through elevating adenosine levels. Targeting agrin-Lrp4 signaling may serve as a potential therapeutic intervention strategy to treat TLE.