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Abstract Background In epilepsy patients, SISCOM or subtraction ictal single photon emission computed tomography co-registered to magnetic resonance imaging has become a routinely used, non-invasive technique to localize the ictal onset zone (IOZ). Thresholding of clusters with a predefined number of standard deviations from normality (z-score) is generally accepted to localize the IOZ. In this study, we aimed to assess the robustness of this parameter in a group of patients with well-characterized drug-resistant epilepsy in whom the exact location of the IOZ was known after successful epilepsy surgery. Eighty patients underwent preoperative SISCOM and were seizure free in a postoperative period of minimum 1 year. SISCOMs with z-threshold 2 and 1.5 were analyzed by two experienced readers separately, blinded from the clinical ground truth data. Their reported location of the IOZ was compared with the operative resection zone. Furthermore, confidence scores of the SISCOM IOZ were compared for the two thresholds. Results Visual reporting with a z-score threshold of 1.5 and 2 showed no statistically significant difference in localizing correspondence with the ground truth (70 vs. 72% respectively, p = 0.17). Interrater agreement was moderate (κ = 0.65) at the threshold of 1.5, but high (κ = 0.84) at a threshold of 2, where also reviewers were significantly more confident (p

Abstract Background Epilepsy surgery often causes changes in cognition and cerebral glucose metabolism. Our aim was to explore relationships between pre- and postoperative cerebral metabolism as measured with 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) and neuropsychological test scores in patients with left mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS), who were rendered seizure-free after epilepsy surgery. Results Thirteen patients were included. All had neuropsychological testing and an interictal FDG-PET scan of the brain pre- and postoperative. Correlations between changes in neuropsychological test scores and metabolism were examined using statistical parametric mapping (SPM). There were no significant changes in the neuropsychological test scores pre- and postoperatively at the group level. Decreased metabolism was observed in the left mesial temporal regions and occipital lobe. Increased metabolism was observed in the bi-frontal and right parietal lobes, temporal lobes, occipital lobes, thalamus, cerebellum, and vermis. In these regions, we did not find a correlation between changes in metabolism and neuropsychological test scores. A significant negative correlation, however, was found between metabolic changes in the precuneus and Boston Naming Test (BNT) scores. Conclusions There are significant metabolic decreases in the left mesial temporal regions and increases in the bi-frontal lobes; right parietal, temporal, and occipital lobes; right thalamus; cerebellum; and vermis in patients with left MTLE-HS who were rendered seizure-free after epilepsy surgery. We could not confirm that these changes translate into significant cognitive changes. A significant negative correlation was found between changes in confrontation naming and changes in metabolism in the precuneus. We speculate that the precuneus may play a compensatory role in patients with postoperative naming difficulties after left TLE surgery. Understanding of these neural mechanisms may aid in designing cognitive rehabilitation strategies.

Infections with multidrug-resistant bacteria pose a major healthcare problem which urges the need for novel treatment options. Besides its potent antiplatelet properties, ticagrelor has antibacterial activity against Gram-positive bacteria, including methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA and VRSA). Several retrospective studies in cardiovascular patients support an antibacterial effect of this drug which is not related to its antiplatelet activity. We investigated the mechanism of action of ticagrelor in Staphylococcus aureus and model Bacillus subtilis, and assessed cross-resistance with two conventional anti-MRSA antibiotics, vancomycin and daptomycin. Bacillus subtilis bioreporter strains revealed ticagrelor-induced cell envelope-related stress responses. Sub-inhibitory drug concentrations caused membrane depolarization, impaired positioning of both the peripheral membrane protein MinD and the peptidoglycan precursor lipid II, and it affected cell shape. At the MIC, ticagrelor destroyed membrane integrity, indicated by the influx of membrane impermeable dyes, and lipid aggregate formation. Whole-genome sequencing of in vitro -generated ticagrelor-resistant MRSA clones revealed mutations in genes encoding ClpP, ClpX, and YjbH. Lipidomic analysis of resistant clones displayed changes in levels of the most abundant lipids of the Staphylococcus aureus membrane, for example, cardiolipins, phosphatidylglycerols, and diacylglycerols. Exogeneous cardiolipin, phosphatidylglycerol, or diacylglycerol antagonized the antibacterial properties of ticagrelor. Ticagrelor enhanced MRSA growth inhibition and killing by vancomycin and daptomycin in both exponential and stationary phases. Finally, no cross-resistance was observed between ticagrelor and daptomycin, or vancomycin. Our study demonstrates that ticagrelor targets multiple lipids in the cytoplasmic membrane of Gram-positive bacteria, thereby retaining activity against multidrug-resistant staphylococci including daptomycin- and vancomycin-resistant strains.IMPORTANCEInfections with multidrug-resistant bacteria pose a major healthcare problem with an urgent need for novel treatment options. The antiplatelet drug ticagrelor possesses antibacterial activity against Gram-positive bacteria including methicillin-resistant and vancomycin-resistant Staphylococcus aureus strains. We report a unique, dose-dependent, antibacterial mechanism of action of ticagrelor, which alters the properties and integrity of the bacterial cytoplasmic membrane. Ticagrelor retains activity against multidrug-resistant staphylococci, including isolates carrying the most common in vivo selected daptomycin resistance mutations and vancomycin-intermediate Staphylococcus aureus . Our data support the use of ticagrelor as adjunct therapy against multidrug-resistant strains. Because of the presence of multiple non-protein targets of this drug within the bacterial membrane, resistance development is expected to be slow. All these findings corroborate the accumulating observational clinical evidence for a beneficial anti-bacterial effect of ticagrelor in cardiovascular patients in need of such treatment.

Competing Interests: The authors declare no funding or conflicts of interest.

Kidney transplantation (KT) is the best treatment for patients with kidney failure, associated with improved survival and quality of life compared with maintenance dialysis. However, despite constant improvements in the assessment and management of the alloimmune response, KT patients frequently demonstrate a reduced estimated glomerular filtration rate. Therefore, the usual complications of chronic kidney disease (CKD), such as anemia, hypertension, metabolic acidosis, hyperkalemia, or persistent secondary hyperparathyroidism, are highly prevalent after KT. However, their underlying mechanisms are different in the transplant setting (compared with the nontransplanted CKD population), and management recommendations are based on relatively poor-quality data. In recent years, new therapies have emerged, significantly improving kidney and cardiovascular outcomes of non-KT patients with CKD. Whether those new drugs could improve the outcomes of KT patients has largely been under investigated so far. In this review, we will address the challenges of the management of a KT patient with a reduced estimated glomerular filtration rate, cover the published evidence, and highlight the critical knowledge gaps., Competing Interests: T.D. reports research support from the Fonds National de Recherche Scientifique – FNRS (F.R.S.-FNRS) as well as travel support from Organ Recovery Systems, Diegem, Belgium. E.G. reports research support from Baxter Healthcare, conference support from Baxter Healthcare, Fresenius, Nx Stage, Dirinco, and AstraZeneca; and consulting fees from Amgen, Astellas, AstraZeneca, Bayer, Baxter Healthcare, Fresenius, NxStage, and Dirinco. M.J. reports research support from AstraZeneca, speaker fees from AstraZeneca, Bayer, Boehringer-Ingelheim, and Menarini; consulting fees from Astellas, AstraZeneca, Bayer, Boehringer-Ingelheim, Cardiorenal, CSL Vifor, GlaxoSmithKline, Stada-Eurogenerics, and Vertex; and other: co-chair of Kidney Disease Improving Global Outcomes (KDIGO) since January 2019. A.D. reports consultancy fees from Alnylam and Merck. E.V.R. reports support from CSL Vifor and Pharmacosmos; speaker fees from Baxter Healthcare, Astellas, and Bayer; and consulting fees from Bayer. N.K. reports consulting fees from Hansa Biopharm. The other authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Transfer RNA dynamics contribute to cancer development through regulation of codon-specific messenger RNA translation. Specific aminoacyl-tRNA synthetases can either promote or suppress tumourigenesis. Here we show that valine aminoacyl-tRNA synthetase (VARS) is a key player in the codon-biased translation reprogramming induced by resistance to targeted (MAPK) therapy in melanoma. The proteome rewiring in patient-derived MAPK therapy-resistant melanoma is biased towards the usage of valine and coincides with the upregulation of valine cognate tRNAs and of VARS expression and activity. Strikingly, VARS knockdown re-sensitizes MAPK-therapy-resistant patient-derived melanoma in vitro and in vivo. Mechanistically, VARS regulates the messenger RNA translation of valine-enriched transcripts, among which hydroxyacyl-CoA dehydrogenase mRNA encodes for a key enzyme in fatty acid oxidation. Resistant melanoma cultures rely on fatty acid oxidation and hydroxyacyl-CoA dehydrogenase for their survival upon MAPK treatment. Together, our data demonstrate that VARS may represent an attractive therapeutic target for the treatment of therapy-resistant melanoma., (© 2024. The Author(s).)

Introduction: Etelcalcetide is an i.v. calcimimetic agent, effectively reducing parathyroid hormone levels in patients on maintenance hemodialysis (HD). The clinical impact of discontinuing etelcalcetide at the time of kidney transplantation is unknown., Methods: We retrospectively reviewed all patients on HD meeting predefined criteria who received a kidney transplant at our institution between January 1, 2015, and December 12, 2022. The incidence of parathyroidectomy and the evolution of calcium, phosphate, and intact parathyroid hormone (iPTH) levels after transplantation was analyzed according to the type of calcimimetic treatment before transplantation (cinacalcet vs. etelcalcetide vs. none)., Results: Overall, 372 patients (aged 53 years; interquartile range [IQR]: 42-62 years) were included. At the time of transplantation, 35, 75, and 262 patients were under etelcalcetide, cinacalcet, or no calcimimetic, respectively. After 1064 (IQR: 367-1658) days, the incidences of parathyroidectomy in the etelcalcetide, cinacalcet, no calcimimetic groups were 29%, 12%, and 1%, respectively ( P  < 0.001). Etelcalcetide was associated with an increased incidence of parathyroidectomy after adjustment for age, sex, and HD vintage (hazard ratio [HR]: 97.0, 95% confidence interval [CI]: 19.1-493.9, P  < 0.001). The incidence of parathyroidectomy was related to etelcalcetide dosage (6/11 [54.6%] in patients with ≥ 10 mg vs. 4/24 [16.7%] in patients with < 10 mg, P  = 0.02). Moreover, peak calcium levels were higher ( P  < 0.001) and parathyroidectomy was performed earlier (median 80 vs. 480 days, P  < 0.001) in the etelcalcetide compared with the cinacalcet group. Long-term graft function, graft loss, and mortality were similar., Conclusion: Etelcalcetide use during maintenance HD is associated with an increased incidence of early parathyroidectomy after transplantation compared to cinacalcet or no calcimimetic., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

The synthesis and biological evaluation on AMPA and kainate receptors of new examples of 3,4-dihydro-2H-1,2,4-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxides is described. The introduction of a cyclopropyl chain instead of an ethyl chain at the 4-position of the thiadiazine ring was found to dramatically improve the potentiator activity on AMPA receptors, with compound 32 (BPAM395) expressing in vitro activity on AMPARs (EC2x = 0.24 μM) close to that of the reference 4-cyclopropyl-substituted benzothiadiazine dioxide 10 (BPAM344). Interestingly, the 4-allyl-substituted thienothiadiazine dioxide 27 (BPAM307) emerged as the most promising compound on kainate receptors being a more effective potentiator than the 4-cyclopropyl-substituted thienothiadiazine dioxide 32 and supporting the view that the 4-allyl substitution of the thiadiazine ring could be more favorable than the 4-cyclopropyl substitution to induce marked activity on kainate receptors versus AMPA receptors. The thieno-analogue 36 (BPAM279) of the clinically tested S18986 (11) was selected for in vivo evaluation in mice as a cognitive enhancer due to a safer profile than 32 after massive per os drug administration. Compound 36 was found to increase the cognition performance in mice at low doses (1 mg/kg) per os suggesting that the compound was well absorbed after oral administration and able to reach the central nervous system. Finally, compound 32 was selected for co-crystallization with the GluA2-LBD (L504Y,N775S) and glutamate to examine the binding mode of thienothiadiazine dioxides within the allosteric binding site of the AMPA receptor. At the allosteric site, this compound established similar interactions as the previously reported BTD-type AMPA receptor modulators., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Pirotte Bernard reports financial support was provided by Servier Laboratories Suresnes. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Introduction: Cotrimoxazole (CTX) 800/160 mg daily or thrice-weekly is recommended as prophylaxis of Pneumocystis jirovecii pneumonia in kidney transplant recipients. Cotrimoxazole 800/160 daily elevates plasma creatinine and potassium levels but whether the thrice-weekly regimen does so is unknown., Methods: Medical records of 225 kidney transplant recipients at Cliniques Universitaires Saint-Luc were analyzed retrospectively. All received thrice-weekly CTX 800/160 for 6 months after transplantation. Monthly laboratory results, co-medications, and tacrolimus trough levels were compared. Standard statistical tests were used., Results: One month after CTX stop, creatinine level decreased by 0.11 mg/dl (8%, p = 0.029). This contrasts with its stability in previous and subsequent months. No co-medication change accounted for this decrease. The decrease averaged 0.17 mg/dl (p < 0.01) in the highest initial creatinine tertile. The higher the initial creatinine level, the greater the decrease after CTX stop (p < 0.001), and urea levels remained stable after CTX stop. Potassium levels decreased by 0.09 mmol/L (p = 0.021) one month after CTX stop, and decreased by 0.23 mmol/L (p < 0.01) in the highest initial potassium level tertile., Conclusions: Our study pinpoints the impact of CTX 800/160 thrice-weekly on creatinine and potassium levels in kidney transplant recipients. This should be considered when interpreting the evolution of plasma creatinine over time, especially in patients with graft dysfunction. Thus, creatinine levels of cohorts with 6 months versus lifelong CTX require different interpretations., (© 2023. The Author(s) under exclusive licence to Italian Society of Nephrology.)

Background: Rapid progression of aortic stenosis (AS) has been observed in patients undergoing dialysis, but existing cross-sectional evidence is contradictory in non-dialysis-dependent chronic kidney disease (CKD). The present study sought to evaluate whether CKD is associated with the progression of AS over time in a large cohort of patients with AS., Methods: We retrospectively studied all consecutive patients diagnosed with AS [peak aortic jet velocity (Vmax) ≥2.5 m/s] and left ventricular ejection fraction ≥50% in the echocardiography laboratories of two tertiary centers between 2000 and 2018. The estimated glomerular filtration rate (eGFR) (mL/min/1.73 m2) was calculated from serum creatinine values. Patients were divided into five CKD stages according to the baseline eGFR. Annual rates of change in the aortic valve area (AVA) were determined by a linear mixed-effects model., Results: Among the 647 patients included, 261 (40%) had CKD. After a median follow-up of 2.9 (interquartile range 1.8-4.8) years, the mean overall rate of change in AVA was -0.077 (95% confidence interval -0.082; -0.073) cm2/year. There was an inverse relationship between the progression rate and kidney function. The more severe the CKD stage, the greater the AVA narrowing (P < .001). By multivariable linear regression analysis, the eGFR was also negatively associated (P < .001) with AS progression. An eGFR strata below 45 mL/min/1.73 m2 was associated with higher odds of rapid progression of AS than normal kidney function. During the clinical follow-up, event-free survival (patients free of aortic valve replacement or death) decreased as CKD progressed. Rapid progression of AS in patients with kidney dysfunction was associated with worse outcomes., Conclusions: Patients with CKD exhibit more rapid progression of AS over time and require close monitoring. The link between kidney dysfunction and rapid progression of AS is still unknown and requires further research., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

The development of effective and flexible vaccine platforms is a major public health challenge, especially in the context of influenza vaccines that have to be renewed every year. Adenoviruses (AdVs) are easy to produce and have a good safety and efficacy profile when administered orally, as demonstrated by the long-term use of oral AdV-4 and -7 vaccines in the U.S. military. These viruses therefore appear to be the ideal backbone for the development of oral replicating vector vaccines. However, research into these vaccines is limited by the ineffectiveness of human AdV replication in laboratory animals. The use of mouse AdV type 1 (MAV-1) in its natural host allows infection to be studied under replicating conditions. Here, we orally vaccinated mice with a MAV-1 vector expressing influenza hemagglutinin (HA) to assess the protection conferred against an intranasal challenge of influenza. We showed that a single oral immunization with this vaccine generates influenza-specific and -neutralizing antibodies and completely protects mice against clinical signs and viral replication, similar to traditional inactivated vaccines. IMPORTANCE Given the constant threat of pandemics and the need for annual vaccination against influenza and possibly emerging agents such as SARS-CoV-2, new types of vaccines that are easier to administer and therefore more widely accepted are a critical public health need. Here, using a relevant animal model, we have shown that replicative oral AdV vaccine vectors can help make vaccination against major respiratory diseases more available, better accepted, and therefore more effective. These results could be of major importance in the coming years in the fight against seasonal or emerging respiratory diseases such as COVID-19., Competing Interests: The authors declare no conflict of interest.

Objective: Evidence regarding the role of cellular immunity in protecting against COVID-19 is emerging. To better assess immune status, simple and robust assays measuring specific T-cell responses associated with humoral responses are needed. We aimed to evaluate the Quan-T-Cell SARS-CoV-2 test for measuring cellular immune responses in vaccinated healthy and immunosuppressed subjects., Methods: T-cell responses were assessed in healthy vaccinated and unvaccinated and unexposed healthcare workers to determine the sensitivity and specificity of the EUROIMMUN SARS-CoV-2 Quan-T-Cell IGRA test performed on vaccinated kidney transplant recipients (KTRs)., Results: The EUROIMMUN SARS-CoV-2 Quan-T-Cell IGRA test showed good sensitivity (87.2%) and specificity (92.3%) at the calculated 147 mIU/mL cutoff, with an 88.33% accuracy. In KTRs, specific cellular immunity was lower than the antibody response; however, those with a positive IGRA result produced as much IFN-γ as healthy individuals., Conclusions: The EUROIMMUN SARS-CoV-2 Quan-T-Cell IGRA test showed good sensitivity and specificity for the detection of specific T-cell responses against the SARS-CoV-2 spike protein. These results present an additional tool for better management of COVID-19, especially in vulnerable populations., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

In addition to its potent antiplatelet activity, ticagrelor possesses antibacterial properties against gram-positive bacteria. We wondered whether the typical clinical dosage of ticagrelor could prevent the development of infective endocarditis caused by highly virulent Staphylococcus aureus . Ticagrelor prevented vegetation formation in a mouse model of inflammation-induced endocarditis. The dosage achieved in patients under ticagrelor therapy altered bacterial toxin production and adherence on activated endothelial cells, thereby mitigating bacterial virulence. Besides the previously described bactericidal activity at high doses, ticagrelor at typical clinical doses possesses antivirulence activity against S aureus . Ticagrelor antiplatelet activity further interferes with the interplay between platelets and bacteria., Competing Interests: Dr Oury. is Research Director at the Belgium National Funds for Scientific Research (F.R.S.-FNRS). Research from the University of Liège (ULiège) is funded by F.R.S.-FNRS (grant number PDR T.0190.20) to Dr Oury; ULiège internal Fund grant numbers FSR-S-SS-19/18 and FSR-S-SS-21/41 to Dr Oury; and European Research Council Consolidator grant (grant number 647197) to Dr Lancellotti. Dr Meyers is a fellow of the Fonds Wetenschappelijk Onderzoek Vlaanderen (FWO) (1S77119N). Research from the group at the University of Leuven is funded by FWO research grants 1514518N and 1525319N, KU Leuven Internal Fund Starting Grant number STG/18/048 to Dr Martinod; FWO research project number G066021N to Drs Verhamme and Vanassche; and KU Leuven Internal Fund grant number C24M/20/056 to Drs Verhamme and Vanassche. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Positive allosteric modulators of the AMPA receptors (AMPAR PAMs) have been proposed as new drugs for the management of various neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, attention deficit hyperactivity disorder, depression, and schizophrenia. The present study explored new AMPAR PAMs belonging to 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides (BTDs) characterized by the presence of a short alkyl substituent at the 2-position of the heterocycle and by the presence or absence of a methyl group at the 3-position. The introduction of a monofluoromethyl or a difluoromethyl side chain at the 2-position instead of the methyl group was examined. 7-Chloro-4-cyclopropyl-2-fluoromethyl-3,4-dihydro-4H-1,2,4-benzothiadiazine 1,1-dioxide (15e) emerged as the most promising compound associating high in vitro potency on AMPA receptors, a favorable safety profile in vivo and a marked efficacy as a cognitive enhancer after oral administration in mice. Stability studies in aqueous medium suggested that 15e could be considered, at least in part, as a precursor of the corresponding 2-hydroxymethyl-substituted analogue and the known AMPAR modulator 7-chloro-4-cyclopropyl-3,4-dihydro-4H-1,2,4-benzothiadiazine 1,1-dioxide (3) devoid of an alkyl group at the 2-position., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Pirotte Bernard reports financial support was provided by Laboratoires Servier. Pirotte Bernard reports a relationship with Laboratoires Servier that includes: funding grants., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Background: The clinical course of COVID-19 in peritoneal dialysis (PD) patients has so far only been analysed in relatively small, often single-centre case series. Therefore, we studied patient- and disease-related characteristics and outcomes of COVID-19 in a larger European cohort of PD patients., Methods: We used data from the European Renal Association COVID-19 Database (ERACODA) on PD and haemodialysis (HD) patients with COVID-19 (presentation between February 2020 and April 2021). Hazard ratios (HR) for mortality at 3 months were calculated using Cox proportional-hazards regression. In addition, we examined functional and mental health status among survivors at this time point as determined by their treating physician., Results: Of 216 PD patients with COVID-19, 80 (37%) were not hospitalised and 136 (63%) were hospitalised, of whom 19 (8.8%) were admitted to an intensive care unit. Mortality at 3 months for these subgroups was 18%, 40%, and 37%, respectively ( p = 0.0031). Compared with HD patients, PD patients had higher mortality (crude HR: 1.49; 95% CI: 1.33-1.66), even when adjusted for patient characteristics and disease severity (adjusted HR: 1.56; 95% CI: 1.39-1.75). Follow-up data on 67 of 146 patients who survived COVID-19 showed functional recovery to pre-COVID-19 levels in 52 (78%) and mental recovery in 58 patients (87%) at 3 months after the COVID-19 diagnosis., Conclusion: The mortality rate in the first 3 months after presentation with COVID-19 is high, especially among PD patients who were hospitalised. PD patients with COVID-19 had a higher mortality risk than HD patients. The majority of surviving patients recovered both functionally and mentally from COVID-19 within 3 months.

Introduction: The efficacy of nirmatrelvir-ritonavir (NR; Paxlovid, Pfizer, New York, NY) to decrease the risk of progression to severe COVID-19 in high-risk patients has been demonstrated. However, evidence in infected kidney transplant recipients (KTRs) is lacking. Moreover, NR has significant and potentially harmful interactions with calcineurin inhibitors (CNIs)., Methods: In this single-center retrospective study, we included all KTRs treated with NR from April 28 to June 3, 2022. A standard management strategy of CNI dose adaptation (discontinuation of tacrolimus 12 hours before the start of NR and administration of 20% of the cyclosporine dose) and laboratory follow-up was applied., Results: A total of 14 patients were included. Compared with day-0 (day before NR initiation), day-7 plasma creatinine concentrations and SARS-CoV-2 viral loads were similar ( P  = 0.866) and decreased ( P  = 0.002), respectively. CNI trough concentrations at the end of the treatment were satisfactory, nonetheless, with high individual variability. After a median follow-up time of 34 days, no death or viral pneumonia were observed. Nevertheless, 2 patients experienced early SARS-CoV-2 infection relapses (at day-10 and day-21) associated with an increase in SARS-CoV-2 viral loads., Conclusion: NR can be used in KTRs but requires a strict protocol of drug adaptation. We observed 2 cases of early relapse after NR treatment that need further investigations., (© 2022 International Society of Nephrology. Published by Elsevier Inc.)

Background: The aim of this study was to evaluate the effect of a recipient's obesity on posttransplant complications and patient and graft survival., Methods: A single-institution, retrospective study was performed on obese renal transplant recipients (BMI ≥ 30 kg/m 2 , n = 102) from January 2010 to December 2018, matched with non-obese recipients (BMI < 30 kg/m 2 , n = 204). For comparison, for every obese patient we selected 2 nonobese patients with a similar age, sex, and period of transplantation. The comparative analysis included patient and graft survival as primary outcomes and graft function and postoperative complications as a secondary outcome., Results: Recipient demographics were comparable in both groups except for diabetic nephropathy in obese patients (P = .0006). Obesity was strongly related to a poorer patient survival (risk ratio [RR] = 2.83 confidence interval [CI] 95% 1.14-7.04; P = .020) but there was no observed difference in graft survival (P = .6). While early graft function was inferior in the obese population (RR = 2.41; CI 95% 1.53-3.79; P = .00016), during late follow-up, no statistically significant differences were observed between both groups (P = .36). Obese recipients had a significantly higher risk of delayed graft function (RR = 1.93; CI 95% (1.19-3.1), P = .0077), heart infarction (RR = 7; CI 95% 1.68-29.26; P = .0042), wound infections (RR = 8; CI 95% 1.96-32.87; P = .0015), diabetes aggravation (RR = 3.13; CI 95% 1.29-7.6; P = .011), and surgical revision for eventration (RR = 8; CI 95% 1.22-52.82; P = .026) when compared with nonobese recipients., Conclusions: Despite the inferior early kidney graft function in obese recipients, there was no difference observed at the long-term follow-up. However, recipient obesity demonstrated a negative effect on patient survival and postoperative complications., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Canine Distemper Virus (CDV) is a fatal and highly contagious pathogen of multiple carnivores. While injectable vaccines are very effective in protecting domestic animals, their use in the wild is unrealistic. Alternative vaccines are therefore needed. Adenovirus (AdV) vectors are popular vaccine vectors due to their capacity to elicit potent humoral and cellular immune responses against the antigens they carry. In parallel, vaccines based on live human AdV-4 and -7 have been used in U.S. army for several decades as replicative oral vaccines against respiratory infection with the same viruses. Based on these observations, the use of oral administration of replication competent AdV-vectored vaccines has emerged as a promising tool especially for wildlife vaccination. Developing this type of vaccine is not easy, however, given the high host specificity of AdVs and their very low replication in non-target species. To overcome this problem, the feasibility of this approach was tested using mouse adenovirus 1 (MAV-1) in mice as vaccine vectors. First, different vaccine vectors expressing the entire or part H or F proteins of CDV were constructed. These different strains were then used as oral vaccines in BALB/c mice and the immune response to CDV was evaluated. Only the strain expressing the full length CDV H protein generated a detectable and neutralizing immune response to CDV. Secondly, using this strain, we were able to show that although this type of vaccine is sensitive to pre-existing immunity to the vector, a second oral administration of the same vaccine is able to boost the immune response against CDV. Overall, this study demonstrates the feasibility of using replicating AdVs as oral vaccine vectors to immunize against CDV in wildlife carnivores.

Nursing home (NH) residents and staff have been severely affected by the COVID-19 pandemic. The aim of this study was to examine the use of weekly saliva RT-qPCR testing for SARS-CoV-2 detection among NH workers as a strategy to control disease transmission within NHs in Belgium. From 16 November to 27 December 2020, a voluntary and anonymous weekly screening was implemented in a cohort of 50,000 workers across 572 NHs in the Walloon region of Belgium to detect asymptomatic cases of SARS-CoV-2 via saliva RT-qPCR testing and using the Diagenode saliva sample collection device. Positive workers were isolated to avoid subsequent infections in residents and other staff. RT-qPCR testing was based on pooled saliva sampling techniques from three workers, followed by individual testing of each positive or inconclusive pool. The majority of NHs (85%) and 55% of their workers participated. Pooling did not affect sensitivity as it only induced a very decrease in sensitivity estimated as 0.33%. Significant decreases in the prevalence (34.4-13.4%) and incidence of NHs with either single (13.8-2%) or multiple positive workers (3.7-0%) were observed over time. In addition, deaths among NH residents and NH worker absences decreased significantly over time. Weekly saliva RT-qPCR testing for SARS-CoV-2 demonstrated large-scale feasibility and efficacy in disrupting the chain of transmission. Implementation of this testing strategy in NHs could also be extended to other settings with the aim to control viral transmission for maintaining essential activities., (© 2021 Wiley-VCH GmbH.)

Background: Home hemodialysis (HHD) remains underused in patients with kidney failure. Current literature on HHD mostly originates from non-European countries, making generalization difficult. The present study describes patients' profile and practice patterns from a Belgian HHD center, and assesses patient and technique survival and complications associated with HHD., Methods: We analyzed data from all our incident patients during a 6-year period. The patient's characteristics were summarized using descriptive statistics. Transition to another therapeutic modality, estimated using a risk model with death and transplantation as competing events, episodes of respite cares and hospitalizations, and access complications were analyzed., Results: Eighty patients (mean age: 47 years; male: 64%) met the inclusion criteria. Fifty-one percent of patients initiated dialysis with a central venous catheter (CVC) and 96% were not assisted. Arterio-venous fistula (AVF) cannulation was performed using buttonhole technique. Standard-frequent HD (47%) and short-frequent low-flow dialysate HD (34%) were mostly used at HHD initiation. Cumulative incidences of technique failure and death were 15%, 24%, and 32% at 1, 2, and 5 years. Incidence rates for respite dialysis and hospitalizations were 2.39 and 0.54 per patient-year of HHD. In comparison with AVF, incidence rate ratios of overall access complications and access-related infections for CVC were 4.3 (95% CI: 3.1-6, p < 0.01) and 4.4 (95% CI: 2.1-10, p < 0.01), respectively. Buttonhole cannulation was complicated by 0.26 (95% CI: 0.15-0.46) infections per 1000 AVF-days., Conclusions: This present study provides important information about patient's profile and practice patterns and safety in a cohort of 80 incident Belgian HHD patients, with encouraging techniques and patient survival., (© 2022 International Society for Hemodialysis.)

Rationale & Objective: Neutralizing monoclonal antibody treatments have shown promising preliminary results in kidney transplant recipients infected with severe acute respiratory syndrome coronavirus 2. However, their efficacy in kidney transplant recipients infected with the Omicron variant has not been reported yet., Study Design: Single-center retrospective study., Setting & Participants: We included all consecutive kidney transplant recipients treated with monoclonal antibodies for severe acute respiratory syndrome coronavirus 2 infections (positive polymerase chain reaction on nasopharyngeal swab) between June 10, 2021, and January 14, 2022. Forty-seven kidney transplant recipients were included. All patients had symptoms evolving for ≤7 days and no oxygen therapy need at monoclonal antibody infusion., Results: Symptoms at diagnosis were mainly cough (n = 25; 53%) and fever (n = 15; 32%). Eighty-three percent of the cohort (n = 39) had been vaccinated with at least 2 doses before infection, of whom 30 (77%) had demonstrated a vaccine-induced humoral response. They were treated with either casirivimab-imdevimab (n = 16; 34%) or sotrovimab (n = 31; 66%) a median of 2 days (range, 0-6 days) after the onset of symptoms. Except for 1 mild allergic reaction during casirivimab-imdevimab infusion, no side effects were reported. The median viral loads at admission (day 0) and 7 days after monoclonal antibody infusion were 2,110,027 copies/mL (range, 1,000-153,798,962 copies/mL) and 1,000 copies/mL (range, 0-10,000,000 copies/mL), respectively. Genotypes were available for 22 kidney transplant recipients (47%). Omicron, Delta, and Gamma variants were identified in 13 (59%), 8 (36%), and 1 (5%) patients, respectively. In kidney transplant recipients infected with the Omicron variant, the median viral loads at day 0 and day 7 were 752,789 copies/mL (range, 4,000-12,859,300 copies/mL) and 1,353 copies/mL (range, 0-1,211,163 copies/mL), respectively. 2 kidney transplant recipients required hospitalization immediately after sotrovimab perfusion for oxygen therapy that was weaned in 3 days, allowing patients' discharge. None were admitted to the intensive care unit or died., Limitations: Small sample size, no control group., Conclusions: Neutralizing monoclonal antibody therapy is associated with positive outcomes in kidney transplant recipients with mild coronavirus disease 2019, including those infected with the Omicron variant., (© 2022 The Authors.)

Background: The lack of space, as an indication for a native unilateral nephrectomy for positioning a future kidney graft in the absence of other autosomal dominant polycystic kidney disease-related symptoms, remains controversial., Aim: To evaluate the surgical comorbidity and the impact on graft survival of an associated ipsilateral native nephrectomy during isolated kidney transplantation in patients with autosomal dominant polycystic kidney disease., Methods: One hundred and fifty-four kidney transplantations performed between January 2007 and January 2019 of which 77 without (kidney transplant alone (KTA) group) and 77 with associated ipsilateral nephrectomy (KTIN group), were retrospectively reviewed. Demographics and surgical variables were analyzed and their respective impact on surgical comorbidity and graft survival., Results: Creation of space for future graft positioning was the main reason ( n = 74, 96.1%) for associated ipsilateral nephrectomy. No significant difference in surgical comorbidity (lymphocele, wound infection, incisional hernia, wound hematoma, urinary infection, need for blood transfusion, hospitalization stay, Dindo Clavien classification and readmission rate) was observed between the two study groups. The incidence of primary nonfunction and delayed graft function was comparable in both groups [0% and 2.6% ( P = 0.497) and 9.1% and 16.9% ( P = 0.230), respectively, in the KTA and KTIN group]. The 1- and 5-year graft survival were 94.8% and 90.3%, and 100% and 93.8%, respectively, in the KTA and KTIN group ( P = 0.774). The 1- and 5-year patient survival were 96.1% and 92.9%, and 100% and 100%, respectively, in the KTA and KTIN group ( P = 0.168)., Conclusion: Simultaneous ipsilateral native nephrectomy to create space for graft positioning during kidney transplantation in patients with autosomal dominant polycystic kidney disease does not negatively impact surgical comorbidity and short- and long-term graft survival., Competing Interests: Conflict-of-interest statement: All the authors have no conflict of interest related to the manuscript., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Pregnancies in women who underwent kidney transplants are at high risk compared with the general population., Methods: In this study, we aimed to retrospectively assess the obstetrical complications, delivery outcomes, and impact of pregnancy on kidney allograft function in a single-center cohort of kidney transplant recipients (KTRs). We provide data regarding the long-term evolution of children., Results: Thirty-two KTRs underwent a total of 57 pregnancies between 1994 and 2010. Fourteen pregnancies (24 %) did not survive caused by miscarriages (n = 9), stillborn (n = 1), ectopic pregnancies (n = 2), and medical abortion (n = 2). Live birth occurred in 76% of pregnancies. Delivery was by cesarean in 66%. The mean gestational age was 30.45 ± 11.3 weeks and 65% of newborns were premature. A low birth weight <2500g was noted in 46%. Obstetric complications were de novo hypertension in 4%, pre-eclampsia in 9%, and gestational diabetes in 2%. The 5- and 10-year post-delivery death-censored graft loss rates were 3.1% and 12.5%, respectively. Data on 21 children were collected via a self-questionnaire. After a median follow-up time of 17 years, they appeared in good medical and psychological health. None of them suffered from chronic disease (especially uronephrological condition) or was taking chronic medication., Conclusions: Long-term evolution of children born to women who underwent kidney transplants seems favorable. Pregnancies in KTRs are successful in two-thirds of cases but are at increased risk of prematurity, delivery by cesarean, and low birth weight., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Kidney transplant recipients (KTRs) infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may have an increased risk of mortality compared with the general population and hemodialysis patients. As these patients are immunosuppressed, it might seem obvious to attribute this excess mortality to the impaired immunity induced by immunosuppression. In line with this reasoning is the low immune response, both cellular and humoral, that KTRs mount in response to the anti-SARS-CoV-2 vaccine; however, acute respiratory distress syndrome associated with coronavirus disease 2019 is triggered by a state of inflammation and cytokine release syndrome that lead to pulmonary damage and increased mortality. In that context, immunosuppressive treatment dampening the immune response could, in theory, be potentially beneficial. This review aims at analyzing the current knowledge on the impact of immunosuppressive treatment on mortality in SARS-CoV-2-infected KTRs, the optimal management of immunosuppression in the coronavirus disease 2019 era, and the vaccine response and management in immunosuppressed KTRs., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2022 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Background: Nursing home (NH) residents have been severely affected during the COVID-19 pandemic because of their age and underlying comorbidities. Infection and outbreaks in NHs are most likely triggered by infected workers. Screening for asymptomatic NH workers can prevent risky contact and viral transmission to the residents. This study examined the effect of the BNT162b2 mRNA COVID‑19 (Comirnaty ® ; BioNTech and Pfizer) vaccination on the saliva excretion of SARS-CoV-2 among NH workers, through weekly saliva RT-qPCR testing., Methods: A 2-month cohort study was conducted among 99 NHs in the Walloon region (Belgium), at the start of February 2021. Three groups of workers, i.e., non-vaccinated ( n  = 1618), one-dosed vaccinated ( n  = 1454), and two-dosed vaccinated ( n  = 2379) of BNT162b2 mRNA COVID‑19 vaccine, were followed-up weekly. Their saliva samples were used to monitor the shedding of SARS-CoV-2. All positive samples were sequenced and genotyped to identify the circulating wild-type virus or variants of concern., Results: The protection fraction against the excretion of the SARS-CoV-2 in the saliva samples of the workers after the second dose is estimated at 0.90 (95% CI: 0.18; 0.99) at 1 week and 0.83 (95% CI: 0.54; 0.95) at 8 weeks. We observe more circulating SARS-CoV-2 and a greater variability of viral loads in the unvaccinated group compared to those of the vaccinated group., Conclusions: This field cohort study advances our knowledge of the efficacy of the mRNA BNT162b2 COVID-19 vaccine on the viral shedding in the saliva specimens of vaccinated NH workers, contributing to better decision-making in public health interventions and management., Competing Interests: Competing interestsF.B. and L.G. are the inventors of the device used in the saliva collection kit. This device was patented (EP20186086.3) and produced by Diagenode (Seraing, Belgium) under a commercial agreement with the University of Liège. This does not alter the adherence to all journal policies on sharing data and materials, as detailed online in the Author Guide. All other authors do not have competing interests., (© The Author(s) 2022.)

Aims: The present study aimed at characterizing the impact of the presence or absence of fluorine atoms on the phenyl and benzopyran rings of 4-phenyl(thio)ureido-substituted 2,2- dimethylchromans on their ability to inhibit insulin release from pancreatic β-cells or to relax vascular smooth muscle cells., Methods: Most compounds were found to inhibit insulin secretion and to provoke a marked myorelaxant activity., Results: The lack of a fluorine or chlorine atom at the 6-position of the 2,2-dimethylchroman core structure reduced the inhibitory activity on the pancreatic endocrine tissue. One of the most active compounds on both tissues, compound 11h (BPDZ 678), was selected for further pharmacological investigations., Conclusion: The biological data suggested that 11h mainly expressed the profile of a KATP channel opener on pancreatic β-cells, although a calcium entry blockade effect was also observed. On vascular smooth muscle cells, 11h behaved as a calcium entry blocker., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Coronavirus disease 2019 (COVID-19) has exposed haemodialysis (HD) patients and kidney transplant (KT) recipients to an unprecedented life-threatening infectious disease, raising concerns about kidney replacement therapy (KRT) strategy during the pandemic. This study investigated the association of the type of KRT with COVID-19 severity, adjusting for differences in individual characteristics., Methods: Data on KT recipients and HD patients diagnosed with COVID-19 between 1 February 2020 and 1 December 2020 were retrieved from the European Renal Association COVID-19 Database. Cox regression models adjusted for age, sex, frailty and comorbidities were used to estimate hazard ratios (HRs) for 28-day mortality risk in all patients and in the subsets that were tested because of symptoms., Results: A total of 1670 patients (496 functional KT and 1174 HD) were included; 16.9% of KT and 23.9% of HD patients died within 28 days of presentation. The unadjusted 28-day mortality risk was 33% lower in KT recipients compared with HD patients {HR 0.67 [95% confidence interval (CI) 0.52-0.85]}. In a fully adjusted model, the risk was 78% higher in KT recipients [HR 1.78 (95% CI 1.22-2.61)] compared with HD patients. This association was similar in patients tested because of symptoms [fully adjusted model HR 2.00 (95% CI 1.31-3.06)]. This risk was dramatically increased during the first post-transplant year. Results were similar for other endpoints (e.g. hospitalization, intensive care unit admission and mortality >28 days) and across subgroups., Conclusions: KT recipients had a greater risk of a more severe course of COVID-19 compared with HD patients, therefore they require specific infection mitigation strategies., (© The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA.)

Background: Variability in ultrafiltration influences prescriptions and outcomes in patients with kidney failure who are treated with peritoneal dialysis. Variants in AQP1 , the gene that encodes the archetypal water channel aquaporin-1, may contribute to that variability., Methods: We gathered clinical and genetic data from 1851 patients treated with peritoneal dialysis in seven cohorts to determine whether AQP1 variants were associated with peritoneal ultrafiltration and with a risk of the composite of death or technique failure (i.e., transfer to hemodialysis). We performed studies in cells, mouse models, and samples obtained from humans to characterize an AQP1 variant and investigate mitigation strategies., Results: The common AQP1 promoter variant rs2075574 was associated with peritoneal ultrafiltration. Carriers of the TT genotype at rs2075574 (10 to 16% of patients) had a lower mean (±SD) net ultrafiltration level than carriers of the CC genotype (35 to 47% of patients), both in the discovery phase (506±237 ml vs. 626±283 ml, P = 0.007) and in the validation phase (368±603 ml vs. 563±641 ml, P = 0.003). After a mean follow-up of 944 days, 139 of 898 patients (15%) had died and 280 (31%) had been transferred to hemodialysis. TT carriers had a higher risk of the composite of death or technique failure than CC carriers (adjusted hazard ratio, 1.70; 95% confidence interval [CI], 1.24 to 2.33; P = 0.001), as well as a higher risk of death from any cause (24% vs. 15%, P = 0.03). In mechanistic studies, the rs2075574 risk variant was associated with decreases in AQP1 promoter activity, aquaporin-1 expression, and glucose-driven osmotic water transport. The use of a colloid osmotic agent mitigated the effects of the risk variant., Conclusions: A common variant in AQP1 was associated with decreased ultrafiltration and an increased risk of death or technique failure among patients treated with peritoneal dialysis. (Funded by the Swiss National Science Foundation and others.)., (Copyright © 2021 Massachusetts Medical Society.)

An expansion of the structure-activity relationship study of CXCR4 antagonists led to the synthesis of a series of isoquinolines, bearing a tetrahydroquinoline or a 3-methylpyridinyl moiety as head group. All compounds were investigated for CXCR4 affinity and antagonism in competition binding and calcium mobilization assays, respectively. In addition, the anti-HIV activity of all analogues was determined. All compounds showed excellent activity, with compound 24c being the most promising one, since it displayed consistently low nanomolar activity in the various assays.