Mitochondrial translocation of TFEB regulates complex I and inflammation.

TFEB is a master regulator of autophagy, lysosome biogenesis, mitochondrial metabolism, and immunity that works primarily through transcription controlled by cytosol-to-nuclear translocation. Emerging data indicate additional regulatory interactions at the surface of organelles such as lysosomes. Here we show that TFEB has a non-transcriptional role in mitochondria, regulating the electron transport chain complex I to down-modulate inflammation. Proteomics analysis reveals extensive TFEB co-immunoprecipitation with several mitochondrial proteins, whose interactions are disrupted upon infection with S. Typhimurium. High resolution confocal microscopy and biochemistry confirms TFEB localization in the mitochondrial matrix. TFEB translocation depends on a conserved N-terminal TOMM20-binding motif and is enhanced by mTOR inhibition. Within the mitochondria, TFEB and protease LONP1 antagonistically co-regulate complex I, reactive oxygen species and the inflammatory response. Consequently, during infection, lack of TFEB specifically in the mitochondria exacerbates the expression of pro-inflammatory cytokines, contributing to innate immune pathogenesis.

Interaction between overconfidence effects and training formats in nurses' education in hand hygiene.

BACKGROUND: Undergraduate training in hand hygiene is a keystone of infection control. Several studies have shown overconfidence effects in hand hygiene practices, which can impair metacognition. We hypothesized that overconfidence might be prevalent in the early education stages of nursing students and that these effects could be reduced through frequent interactive learning formats, such as learning groups. METHODS: We conducted a multicenter cross-sectional questionnaire with 196 German nursing students, including general, surgical, and anesthetic nursing specializations. RESULTS: Overconfidence was observed in nursing students across all specialties and years of education. The cluster analyses showed three different types of learners: two characterized by overconfidence and one demonstrating justifiable confidence. Furthermore, the moderation analysis indicated that providing feedback and promoting metacognition regarding students' learning achievements could mitigate overplacement, particularly through the frequent implementation of interactive teaching formats. DISCUSSION: Despite some limitations, these findings highlight the prevalence of overconfidence effects in nursing students, the presence of different learning profiles, and the importance of incorporating feedback within interactive learning formats concerning hand hygiene. Accordingly, educators need to be trained and supervised to deliver these learning formats and provide feedback to students effectively.

Utilizing the Perfluoronaphthalene Radical Cation as a Selective Deelectronator to Access a Variety of Strongly Oxidizing Reactive Cations.

A selective deelectronation reagent with very high potential of +2.00 (solution)/+2.41 V (solid-state) vs. Fc+/0 and based on a room temperature stable perfluoronaphthalene (naphthaleneF) radical cation salt was developed and applied. The solid-state deelectronation of commercial naphthaleneF with [NO]+[F{Al(ORF)3}2]- generates [naphthaleneF]+⋅[F{Al(ORF)3}2]- (ORF=OC(CF3)3) in gram scale. Thermochemical analysis unravels the solid-state deelectronation potential of the starting [NO]+-reagent to be +2.34 V vs. Fc+/0 with [F{Al(ORF)3}2]- counterion, but only +1.14 V vs. Fc+/0 with the small [SbF6]- ion. Selective reactions demonstrate the selectivity of [naphthaleneF]+⋅ for deelectronation of a multitude of organ(ometall)ic molecules and elements in solution: providing the molecular structures of the acene dications [tetracene]2+, [pentacene]2+ or spectroscopic evidence for the carbonyl complex of the ferrocene dication [Fc(CO)]2+, the [P9]+ cation from white phosphorus, the solvent-free copper(I) salt starting from copper metal and the dicationic Fe(IV)-scorpionate complex [Fe(sc)2]2+.

Pushing redox potentials to highly positive values using inert fluorobenzenes and weakly coordinating anions.

While the development of weakly coordinating anions (WCAs) received much attention, the progress on weakly coordinating and inert solvents almost stagnated. Here we study the effect of strategic F-substitution on the solvent properties of fluorobenzenes C6FxH6-x (xFB, x = 1-5). Asymmetric fluorination leads to dielectric constants as high as 22.1 for 3FB that exceeds acetone (20.7). Combined with the WCAs [Al(ORF)4]- or [(FRO)3Al-F-Al(ORF)3]- (RF = C(CF3)3), the xFB solvents push the potentials of Ag+ and NO+ ions to +1.50/+1.52 V vs. Fc+/Fc. The xFB/WCA-system has electrochemical xFB stability windows that exceed 5 V for all xFBs with positive upper limits between +1.82 V (1FB) and +2.67 V (5FB) vs. Fc+/Fc. High-level ab initio calculations with inclusion of solvation energies show that these high potentials result from weak interactions of the ions with solvent and counterion. To access the available positive xFB potential range with stable reagents, the innocent deelectronator salts [anthraceneF]+∙[WCA]- and [phenanthreneF]+∙[WCA]- with potentials of +1.47 and +1.89 V vs. Fc+/Fc are introduced.

Risk Factors for Infectious Complications following Endoscopic Retrograde Cholangiopancreatography in Liver Transplant Patients: A Single-Center Study.

Background: Liver transplant recipients often require endoscopic retrograde cholangiopancreatography (ERCP) for biliary complications, which can lead to infections. This retrospective single-center study aimed to identify risk factors for infectious complications following ERCP in liver transplant patients. Methods: A retrospective analysis was conducted on 285 elective ERCP interventions performed in 88 liver transplant patients at a tertiary care center. The primary endpoint was the occurrence of an infection following ERCP. Univariable and multivariable regression analyses, Cox regression, and log-rank tests were employed to assess the influence of various factors on the incidence of infectious complications. Results: Among the 285 ERCP interventions, isolated anastomotic stenosis was found in 175 cases, ischemic type biliary lesion (ITBL) in 103 cases, and choledocholithiasis in seven cases. Bile duct interventions were performed in 96.9% of all ERCPs. Infections after ERCP occurred in 46 cases (16.1%). Independent risk factors for infection included male sex (OR 24.19), prednisolone therapy (OR 4.5), ITBL (OR 4.51), sphincterotomy (OR 2.44), cholangioscopy (OR 3.22), dilatation therapy of the bile ducts (OR 9.48), and delayed prophylactic antibiotic therapy (>1 h after ERCP) (OR 2.93). Additionally, infections following previous ERCP interventions were associated with an increased incidence of infections following future ERCP interventions (p < 0.0001). Conclusion: In liver transplant patients undergoing ERCP, male sex, prednisolone therapy, and complex bile duct interventions independently raised infection risks. Delayed antibiotic treatment further increased this risk. Patients with ITBL were notably susceptible due to incomplete drainage. Additionally, a history of post-ERCP infections signaled higher future risks, necessitating close monitoring and timely antibiotic prophylaxis.

Immunomonitoring via ELISPOT Assay Reveals Attenuated T-Cell Immunity to CMV in Immunocompromised Liver-Transplant Patients.

Assessing immune responses to cytomegalovirus (CMV) after liver transplant in patients on immunosuppressive therapy remains challenging. In this study, employing ELISPOT assays, 52 liver-transplant recipients were evaluated for antiviral T-cell activity in peripheral blood mononuclear cells (PBMCs), measuring interferon-γ (IFN-γ) secretion upon stimulation with CMV-specific peptides (CMV peptide pool, CMV IE-1, and pp65 antigens). Parameters such as stimulation index, mean spot size, and mean spot count were measured. The study found that heightened immunosuppression, especially with prednisolone in triple therapy, significantly dampened CMV-specific immune responses. This was demonstrated by decreased IFN-γ production by CMV-specific T-cells (CMV peptide pool: p = 0.036; OR = 0.065 [95% CI: 0.005-0.840], pp65 antigen: p = 0.026; OR = 0.048 [95% CI: 0.003-0.699]). Increased immunosuppression correlated with reduced IFN-γ secretion per cell, reflected in smaller mean spot sizes for the CMV peptide pool (p = 0.019). Notably, shorter post-transplant intervals correlated with diminished antiviral T-cell IFN-γ release at two years (CMV peptide pool: p = 0.019; IE antigen: p = 0.010) and five years (CMV peptide pool: p = 0.0001; IE antigen: p = 0.002; pp65 antigen: p = 0.047), as did advancing age (pp65 antigen: p = 0.016, OR = 0.932, 95% CI: 0.881-0.987). Patients with undetectable CMV antigens had a notably higher risk of CMV reactivation within six months from blood collection, closely linked with triple immunosuppression and prednisolone use. These findings highlight the intricate interplay between immunosuppression, immune response dynamics, and CMV reactivation risk, emphasizing the necessity for tailored immunosuppressive strategies to mitigate CMV reactivation in liver-transplant recipients. It can be concluded that, particularly in the early months post-transplantation, the use of prednisolone as a third immunosuppressant should be critically reconsidered. Additionally, the use of prophylactic antiviral therapy effective against CMV in this context holds significant importance.

North Macedonia interprofessional dementia care (NOMAD) - personalized care plans for people with dementia and caregiver psychoeducation delivered at home by interprofessional teams.

Introduction: The increasing number of people living with dementia and its burden on families and systems particularly in low- and middle-income countries require comprehensive and efficient post-diagnostic management. This study aimed to explore the acceptability and efficacy of a multi-professional case management and psychoeducation model (North Macedonia Interprofessional Dementia Care, or NOMAD) delivered by mobile teams for people with dementia and their caregivers in North Macedonia. Method: We conducted a two-arm randomized controlled trial comparing the intervention with treatment as usual. Participants were recruited from 12 general practitioner (GP) offices in the Skopje region. The NOMAD intervention included the delivery of a personalized care plan over four home visits to dyads of people with dementia and their caregivers by a team including a dementia nurse and a social worker, in collaboration with GPs and dementia experts, and the introduction of a caregiver manual. We assessed caregivers' depressive symptoms, burden, and quality of life and the neuropsychiatric symptoms, daily living activities, and service utilization of people with dementia at baseline and follow-up; we also assessed the acceptability of the intervention by analyzing case notes and attendance rates. Results: One hundred and twenty dyads were recruited and randomized to either the control (n = 60) or the intervention group (n = 60). At follow-up, caregivers in the intervention group had, on average, scores that were 2.69 lower for depressive symptoms (95% CI [-4.75, -0.62], p = 0.012), and people with dementia had, on average, 11.32 fewer neuropsychiatric symptoms (95% CI [-19.74, -2.90], p = 0.009) and used, on average, 1.81 fewer healthcare services (95% CI [-2.61, -1.00], p < 0.001) compared to the control group. The completion of the home visits was 100%, but the intervention's acceptability was underpinned by relationship building, GP competencies, and resources to support families with dementia. There were no differences in the caregivers' quality of life and burden levels or daily living activities in people with dementia. NOMAD is the first case management, non-pharmacological, and multi-professional intervention tested in North Macedonia. Discussion: The trial showed that it is effective in reducing caregivers' depressive symptoms and neuropsychiatric symptoms in people with dementia and the burden on health and social care services, and it is acceptable for families. Implementing NOMAD in practice will require building primary care capacity and recognizing dementia as a national priority.

Terlipressin therapy is associated with increased risk of colonisation with multidrug-resistant bacteria in patients with decompensated cirrhosis.

BACKGROUND: Patients with cirrhosis are susceptible to develop bacterial infections that trigger acute decompensation (AD) and acute-on-chronic liver failure (ACLF). Infections with multidrug-resistant organisms (MDRO) are associated with deleterious outcome. MDRO colonisation frequently proceeds MDRO infections and antibiotic therapy has been associated with MDRO colonisation. AIM: The aim of the study was to assess the influence of non-antibiotic medication contributing to MDRO colonisation. METHODS: Three hundred twenty-four patients with AD and ACLF admitted to the ICU of Frankfurt University Hospital with MDRO screening were included. Regression models were performed to identify drugs associated with MDRO colonisation. Another cohort (n = 129) from Barcelona was included to validate. A third multi-centre cohort (n = 203) with metagenomic sequencing data of stool was included to detect antibiotic resistance genes. RESULTS: A total of 97 patients (30%) were identified to have MDRO colonisation and 35 of them (11%) developed MDRO infection. Patients with MDRO colonisation had significantly higher risk of MDRO infection than those without (p = 0.0098). Apart from antibiotic therapy (odds ratio (OR) 2.91, 95%-confidence interval (CI) 1.82-4.93, p < 0.0001), terlipressin therapy in the previous 14 days was the only independent covariate associated with MDRO colonisation in both cohorts, the overall (OR 9.47, 95%-CI 2.96-30.23, p < 0.0001) and after propensity score matching (OR 5.30, 95%-CI 1.22-23.03, p = 0.011). In the second cohort, prior terlipressin therapy was a risk factor for MDRO colonisation (OR 2.49, 95% CI 0.911-6.823, p = 0.075) and associated with risk of MDRO infection during follow-up (p = 0.017). The validation cohort demonstrated that antibiotic inactivation genes were significantly associated with terlipressin administration (p = 0.001). CONCLUSIONS: Our study reports an increased risk of MDRO colonisation in patients with AD or ACLF, who recently received terlipressin therapy, while other commonly prescribed non-antibiotic co-medications had negligible influence. Future prospective trials are needed to confirm these results.