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Torque Teno virus (TTV) is nonpathogenic, highly prevalent, and reflects the immune status of its host. Thus, TTV plasma load was suggested for the guidance of immunosuppression post solid organ transplantation. The present study was designed to determine the kinetics of TTV following changes in calcineurin inhibitor (CNI) dose. A total of 48 adult recipients of a kidney graft transplanted at the Medical University of Vienna between 2018 and 2019 with isolated changes in CNI dose were selected from the prospective TTV-POET trial. TTV plasma load was quantified by in-house PCR. At Day 30 following CNI dose adaptation (median 33% of daily dose) no changes in TTV load were noted. However, at Day 60, following CNI dose reduction a lower TTV load of 6.4 log 10 c/mL (median; interquartile range [IQR] 4.9-8.1) compared with the baseline of 7.1 log 10 c/mL (IQR 5.3-8.9) was noted (p = 0.001); there was also a trend toward a higher TTV load following CNI increase (6.6 log 10 c/mL, IQR 4.1-9.7 vs. 5.2 log 10 c/mL, IQR 4.5-6.8; p = 0.09). The data suggested that TTV load changes become noticeable only 2 months after CNI dose adaptation, which might be the ideal time point for TTV load monitoring., (© 2024 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Competing Interests: G.B. received a payment from bioMerieux for the preparation of an information brochure on TTV R-GENE for an invited talk on TTV at a scientific conference. F.H. declares no conflicts of interest.

Introduction: Earlier reports suggest that patients after ABO-incompatible kidney transplantation (ABOi) are at enhanced risk of developing BK-virus (BKV, also known as BK polyomavirus [BKPyV]) nephropathy (BKPyVAN). It remains elusive whether this is a result of more intense immunosuppression or an ABOi-associated "intrinsic attribute." To address this question, we measured Torque Teno virus (TTV) loads as a quantitative proxy for immunosuppressive depth in ABOi recipients and compared them to human leukocyte antigen-incompatible (HLAi, i.e. pretransplant donor-specific antibody-positive) and standard-risk transplant recipients., Methods: Our retrospective study screened 2256 consecutive kidney transplantations performed between 2007 and 2020 at the Medical University of Vienna. Out of 629 in-principle eligible transplantations, we were able to include 465 patients: 42 ABOi, 106 HLAi, and 317 control recipients. Longitudinal TTV- polymerase chain reaction (PCR) and BKV-PCR was carried out at predefined timepoints and ranged from pretransplant until month 24 posttransplantation. TTV loads and immunosuppression were evaluated in the context of BKV-associated complications., Results: ABOi recipients had a higher TTV load compared to HLAi and controls both at month 3 (median 1.5 × 10 9 vs. 2.4 × 10 8 vs. 9.1 × 10 7 ; P  = 0.010) and at month 6 (3.1 × 10 9 vs. 1.4 × 10 7 vs. 6.4 × 10 7 ; P  = 0.014) posttransplantation. Tacrolimus exposure was significantly higher in ABOi patients compared to HLAi and control patients (ABOi vs. HLAi: P  = 0.007; ABOi vs. controls: P  < 0.0001). Biopsy-proven BKPyVAN was more frequent in ABOi recipients when compared to HLAi and control recipients (11.9% vs. 2.8% vs. 4.1%; P  = 0.046)., Conclusion: Our data support the assumption that ABOi patients are indeed at higher risk to develop BKPyVAN. A higher TTV load and immunosuppressive burden suggest that intense immunosuppression, rather than an "intrinsic attribute" conferred by ABOi, may contribute to this finding., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

Background: Immunosuppression after kidney transplantation is mainly guided via plasma tacrolimus trough level, which cannot sufficiently predict allograft rejection and infection. The plasma load of the non-pathogenic and highly prevalent torque teno virus (TTV) is associated with the immunosuppression of its host. Non-interventional studies suggest the use of TTV load to predict allograft rejection and infection. The primary objective of the current trial is to demonstrate the safety, tolerability and preliminary efficacy of TTV-guided immunosuppression., Methods: For this purpose, a randomised, controlled, interventional, two-arm, non-inferiority, patient- and assessor-blinded, investigator-driven phase II trial was designed. A total of 260 stable, low-immunological-risk adult recipients of a kidney graft with tacrolimus-based immunosuppression and TTV infection after month 3 post-transplantation will be recruited in 13 academic centres in six European countries. Subjects will be randomised in a 1:1 ratio (allocation concealment) to receive tacrolimus either guided by TTV load or according to the local centre standard for 9 months. The primary composite endpoint includes the occurrence of infections, biopsy-proven allograft rejection, graft loss, or death. The main secondary endpoints include estimated glomerular filtration rate, graft rejection detected by protocol biopsy at month 12 post-transplantation (including molecular microscopy), development of de novo donor-specific antibodies, health-related quality of life, and drug adherence. In parallel, a comprehensive biobank will be established including plasma, serum, urine and whole blood. The date of the first enrolment was August 2022 and the planned end is April 2025., Discussion: The assessment of individual kidney transplant recipient immune function might enable clinicians to personalise immunosuppression, thereby reducing infection and rejection. Moreover, the trial might act as a proof of principle for TTV-guided immunosuppression and thus pave the way for broader clinical applications, including as guidance for immune modulators or disease-modifying agents., Trial Registration: EU CT-Number: 2022-500024-30-00., (© 2023. The Author(s).)

Background: Torque Teno virus (TTV) is non-pathogenic, highly prevalent and reflects the immune status of its host. TTV plasma load was suggested for risk stratification of graft rejection and infection post kidney-transplantation, for which most studies applied an in-house PCR. Recently, a commercial PCR was CE-certified for clinical use. The present study was designed to assess the performance of TTV load as quantified by the commercial PCR in the prediction of graft rejection and infection., Methods: Patients and events were selected from the prospective TTV-POET trial, including 683 consecutive adult recipients of a kidney-graft transplanted at the Medical University Vienna, 2016-2020. TTV was quantified in plasma drawn in Months 4-12 post-transplant by in-house and commercial PCR and associated with consecutive infections and graft rejections until Month 12 post-transplantation., Results: A total of 342 samples from 314 patients with 85 biopsies (rejection, n = 18) and 79 infectious events were assessed. The two PCRs were highly associated (estimate 0.91, 95%CI 0.89-0.93), with a mean difference of 1.38 log 10 copies/mL (95%CI 1.46-1.30). The risk of rejection decreased by 25% with every log 10 increase in TTV load as quantified by commercial PCR (RR 0.75, 95%CI 0.67-0.85), and the risk of infection increased by 6% (RR 1.06, 95%CI 1.00-1.12)., Conclusion: These data support the value of TTV quantification by commercial PCR for the risk stratification of graft rejection and infection in the first year post kidney-transplantation. The test performance determined within this study may serve to design clinical trials and subsequently, support application in clinical routine., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Fanny Gelas, Dorian Kulifaj and Ludovic Brossault are employees of bioMérieux., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Pretransplant kidney graft biopsies have been suggested for organ quality assessment. Data on the association between donor proteinuria and organ quality of deceased donors are not available., Methods: In this prospective study, we analyzed 147 pretransplant kidney biopsies from 88 deceased adult donors procured and transplanted consecutively at the Medical University Vienna between July 2017 and May 2020. Lesions in each renal compartment were scored from 0 to 5 with each ascending score representing a 20% increase in organ damage. A chronic lesions score was calculated including glomerulosclerosis, intima fibrosis, hyalinosis, interstitial fibrosis, and tubular atrophy., Results: The median chronic lesion score was 2 (interquartile range [IQR] 1-4) and the median donor urinary protein to creatinine ratio (UPCR) was 382 mg/dL (IQR 222-703). There was a positive correlation between UPCR and number of chronic lesions (β 0.15, 95% confidence interval, 0.03-0.28; P = 0.019). Biopsies with 2 or more lesions had a median UPCR of 486 mg/dL (IQR 251-717) compared with 274 mg/dL (IQR 211-556; P = 0.016) in biopsies with <2 lesions. The risk for detection of 2 or more lesions rose by 18% for every log increase in UPCR (risk ratio 1.18, 95% confidence interval, 1.03-1.25; P = 0.017). Multivariable and sensitivity analysis revealed an independent and robust association between chronic lesions and UPCR., Conclusions: Donor UPCR is associated with chronic lesions in pretransplant deceased donor kidney graft biopsies. This finding justifies further investigation of donor proteinuria for the assessment of organ quality and outcome., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Obesity affects a rising proportion of the population and is an important risk factor for unfavorable outcomes in viral disease including severe acute respiratory syndrome coronavirus 2- associated diseases. Torque Teno virus (TTV) is a ubiquitous and apathogenic virus which reflects the immune function of its host. The aim of this study was to investigate the association between obesity and TTV load - an indirect marker of compromised viral immune response., Methods: TTV was quantified by TTV R-GENE ® PCR in a total of 89 participants of which 30 were lean (BMI <25 kg/m 2 ) and 59 were obese (BMI >30 kg/m 2 ). For 38 subjects, follow-up was available after bariatric surgery., Results: TTV load was higher in individuals with obesity (median 2.39, IQR: 1.69-3.33 vs. 1.88, IQR 1.08-2.43 log10 copies/mL; p = 0.027). Multivariable linear modeling revealed an independent association between TTV load and obesity. TTV was positively correlated with waist-to-hip ratio and inversely with 25OH vitamin D levels. Interleukin 6 and fasting insulin resistance were confounders of the association between TTV and obesity, while age was an effect modifier. TTV load increased by 87% (95% CI 2-243%) in the year following bariatric surgery., Discussion: A higher TTV load in obese individuals may reflect compromised immune function and thus might serve for risk stratification of unfavorable outcomes during infectious disease, including coronavirus disease 2019, in this population. Our data warrant further analysis of TTV-based risk assessment in obese individuals in the context of infectious disease-associated outcomes., Competing Interests: DK and FG are employees of bioMérieux SA. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Herz, Kulterer, Kulifaj, Gelas, Franzke, Haupenthal, Prager, Langer, Marculescu, Haug, Kiefer and Bond.)

Introduction: An online interactive repository of available medication adherence technologies may facilitate their selection and adoption by different stakeholders. Developing a repository is among the main objectives of the European Network to Advance Best practices and technoLogy on medication adherencE (ENABLE) COST Action (CA19132). However, meeting the needs of diverse stakeholders requires careful consideration of the repository structure., Methods and Analysis: A real-time online Delphi study by stakeholders from 39 countries with research, practice, policy, patient representation and technology development backgrounds will be conducted. Eleven ENABLE members from 9 European countries formed an interdisciplinary steering committee to develop the repository structure, prepare study protocol and perform it. Definitions of medication adherence technologies and their attributes were developed iteratively through literature review, discussions within the steering committee and ENABLE Action members, following ontology development recommendations. Three domains ( product and provider information (D1), medication adherence descriptors (D2) and evaluation and implementation (D3 )) branching in 13 attribute groups are proposed: product and provider information, target use scenarios, target health conditions, medication regimen, medication adherence management components, monitoring/measurement methods and targets, intervention modes of delivery, target behaviour determinants, behaviour change techniques, intervention providers, intervention settings, quality indicators and implementation indicators . Stakeholders will evaluate the proposed definition and attributes' relevance, clarity and completeness and have multiple opportunities to reconsider their evaluations based on aggregated feedback in real-time. Data collection will stop when the predetermined response rate will be achieved. We will quantify agreement and perform analyses of process indicators on the whole sample and per stakeholder group., Ethics and Dissemination: Ethical approval for the COST ENABLE activities was granted by the Malaga Regional Research Ethics Committee. The Delphi protocol was considered compliant regarding data protection and security by the Data Protection Officer from University of Basel. Findings from the Delphi study will form the basis for the ENABLE repository structure and related activities., Competing Interests: Competing interests: SPG is a research team member for ExpertLens (an online platform and methodology for conducting modified-Delphi studies). SPG's spouse is a salaried employee of, and owns stock in, Eli Lilly and Company., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Nonpathogenic torque teno viruses (TTVs) are highly prevalent in transplant recipients and associated with immunosuppression. Studies in kidney transplant patients have proposed assessment of TTV load for risk stratification of clinically overt graft rejection. The value of TTV quantification in the context of subclinical rejection has not been evaluated., Methods: In this prospective trial, 307 consecutive kidney transplant recipients were subjected to per-protocol monitoring of plasma TTV. TTV was analyzed in the context of protocol biopsies (n = 82), scheduled 1 year posttransplantation., Results: TTV load at the time of biopsy was lower in recipients with rejection (n = 19; according to Banff, including borderline changes suspicious for acute T cell-mediated rejection) than those without rejection (n = 63) whereby each log increase in TTV copies/mL decreased the risk for rejection by 9% (risk ratio 0.91, 95% confidence interval, 0.85-0.97; P = 0.004). Development of chronic lesions (cg, cv, ci, ct, ah, ptcml) was associated with the number of days with a TTV load <1 × 106 copies/mL between months 3 and 12 posttransplant (β 0.07, 95% confidence interval, 0.01-0.14; P = 0.02)., Conclusions: This trial demonstrates an association between TTV and subclinical graft rejection in kidney transplant recipients. A TTV load <1 × 106 copies/mL suggests suboptimal immunosuppression., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

The nonpathogenic and ubiquitous torque teno virus (TTV) is associated with immunosuppression in solid organ transplant recipients. Studies in kidney transplant patients proposed TTV quantification for risk stratification of graft rejection and infection. In this prospective trial (DRKS00012335) 386 consecutive kidney transplant recipients were subjected to longitudinal per-protocol monitoring of plasma TTV load by polymerase chain reaction for 12 months posttransplant. TTV load peaked at the end of month 3 posttransplant and reached steady state thereafter. TTV load after the end of month 3 was analyzed in the context of subsequent rejection diagnosed by indication biopsy and infection within the first year posttransplant, respectively. Each log increase in TTV load decreased the odds for rejection by 22% (odds ratio [OR] 0.78, 95% confidence interval [CI] 0.62-0.97; P = .027) and increased the odds for infection by 11% (OR 1.11, 95% CI 1.06-1.15; P < .001). TTV was quantified at a median of 14 days before rejection was diagnosed and 27 days before onset of infection, respectively. We defined a TTV load between 1 × 10 6 and 1 × 10 8 copies/mL as optimal range to minimize the risk for rejection and infection. These data support the initiation of an interventional trial assessing the efficacy of TTV-guided immunosuppression to reduce infection and graft rejection in kidney transplant recipients., (© 2020 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Torque Teno Virus (TTV) is a non-pathogenic anellovirus, highly prevalent in healthy populations. Variations in its viral load have been associated with states of diminished immunity, as occurs after organ transplantation. It is hypothesized that TTV-load might be used as a diagnostic tool to guide prescription and dosing of immunosuppressive drugs. Not much is known about the effects of combined immunosuppressive drugs on TTV replication in renal transplantation. Belatacept was introduced to counter side-effects of calcineurin inhibitors (CNI). It was never widely adopted, mainly because its association with increased risk of rejection. To investigate the differential effects of a regimen based on calcineurin inhibitors versus belatacept on TTV-loads, we measured TTV-levels in 105 patients from two randomized controlled trials in kidney transplant recipients (KTRs). We observed that time after transplantation was inversely related to TTV-levels of patients that remained on a CNI-containing regime, whereas this decline over time was diminished after conversion to belatacept. In addition, a correlation with tacrolimus-trough levels and age were found. Our study is the first report on the impact of conversion from CNI to belatacept on TTV-levels in KTR. In conclusion, the time-related decline in TTV-levels is mitigated after conversion from CNI to belatacept., (© 2024 The Author(s). Journal of Medical Virology published by Wiley Periodicals LLC.)

Epilepsy is one of the most common chronic neurological diseases. It is characterized by recurrent epileptic seizures, where one-third of patients are refractory to existing treatments. Evidence revealed the association between neuroinflammation and increased susceptibility to seizures since there is a pronounced increase in the expression of key inflammatory mediators, such as prostaglandin E 2 (PGE 2 ), during seizures. The purpose of this study was to investigate whether PGE 2 increases susceptibility to pentylenetetrazol-induced (PTZ) seizures. Subsequently, we evaluated if the flavonoid isolated from the plant Piper aleyreanum (galangin) presented any anticonvulsive effects. Our results demonstrated that the group treated with PGE 2 increased susceptibility to PTZ and caused myoclonic and generalized seizures, which increased seizure duration and electroencephalographic wave amplitudes. Furthermore, treatment with PGE 2 and PTZ increased IBA-1 (microglial marker), GFAP (astrocytic marker), 4-HNE (lipid peroxidation marker), VCAM-1 (vascular cell adhesion molecule 1), and p-PKAIIα (phosphorylated cAMP-dependent protein kinase) immunocontent. Indeed, galangin prevented behavioral and electroencephalographic seizures, reactive species production, decreased microglial and astrocytic immunocontent, as well as decreased VCAM-1 immunocontent and p-PKA/PKA ratio induced by PGE 2 /PTZ. Therefore, this study suggests galangin may have an antagonizing role on PGE 2 -induced effects, reducing cerebral inflammation and protecting from excitatory effects evidenced by administrating PGE 2 and PTZ. However, further studies are needed to investigate the clinical implications of the findings and their underlying mechanisms., (Copyright © 2019. Published by Elsevier Ltd.)

Trichothiodystrophy is a rare condition associated with autosomal recessive or X-linked dominant variants in the ERCC2, ERCC3, GTF2H5, MPLKIP, RNF113A or GTF2E2 genes. The genes associated to photosensitive trichothiodystrophy encode subunits of transcription factor IIH, involved in the nucleotide excision repair pathway. The disease is characterised by cysteine-deficient brittle hair along with other neuroectodermal abnormalities. It has a variable clinical expression and some cases might be associated with photosensitivity, resulting in the acronym PIBIDS ( photosensitivity , ichthyosis , brittle hair , intellectual impairment , decreased fertility and short stature ). We report clinical findings of two siblings diagnosed with trichothiodystrophy associated with marked photosensitivity., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

Optimization of individual immunosuppression, which reduces the risks of both graft loss and patients' death, is considered the best approach to improve long-term outcomes of renal transplantation. Torque Teno Virus (TTV) DNAemia has emerged as a potential biomarker reflecting the depth of therapeutic immunosuppression during the initial year post-transplantation. However, its efficacy in long-term monitoring remains uncertain. In a cohort study involving 34 stable kidney transplant recipients and 124 healthy volunteers, we established lower and upper TTV DNAemia thresholds (3.75-5.1 log10 cp/mL) correlating with T-cell activatability, antibody response against flu vaccine, and risk for subsequent serious infections or cancer over 50 months. Validation in an independent cohort of 92 recipients confirmed that maintaining TTV DNAemia within this range in >50% of follow-up time points was associated with reduced risks of complications due to inadequate immunosuppression, including de novo DSA, biopsy-proven antibody-mediated rejection, graft loss, infections, or cancer. Multivariate analysis highlighted "in-target" TTV DNAemia as the sole independent variable significantly linked to decreased risk for long-term complications due to inadequate immunosuppression (odds ratio [OR]: 0.27 [0.09-0.77]; p = 0.019). Our data suggest that the longitudinal monitoring of TTV DNAemia in kidney transplant recipients could help preventing the long-term complications due to inadequate immunosuppression., (© 2024 Wiley Periodicals LLC.)

Background: Long-term outcomes in pediatric kidney transplantation remain suboptimal, largely related to chronic rejection. Creatinine is a late marker of renal injury, and more sensitive, early markers of allograft injury are an active area of current research., Methods: This is an educational review summarizing existing strategies for monitoring for rejection in kidney transplant recipients., Results: We summarize supporting currently available clinical tests, including surveillance biopsy, donor specific antibodies, and donor-derived cell free DNA, as well as the potential limitations of these studies. In addition, we review the current avenues of active research, including transcriptomics, proteomics, metabolomics, and torque tenovirus levels., Conclusion: Advancing the use of noninvasive immune monitoring will depend on well-designed multicenter trials that include patients with stable graft function, include biopsy results on all patients, and can demonstrate both association with a patient-relevant clinical endpoint such as graft survival or change in glomerular filtration rate and a potential timepoint for intervention., (© 2024 The Authors. Pediatric Transplantation published by Wiley Periodicals LLC.)

Background: In the lipofilling procedures used in breast reconstruction, there is an unpredictability in the rate of reabsorption of the grafted fat. The objective of this study was to analyze the effect of tamoxifen, a medication commonly prescribed for patients with breast cancer, as a possible alternative to reduce the rate of autologous fat graft resorption., Methods: The fatty cushion of the inguinal region of 20 female adult Wistar rats was removed and then autografted, using a standard volume of 0.2 ml in the subfascial plane of the dorsal region. The subject animals were randomized into two groups, the control and study groups. The study group animals were administered 20 mg/kg/day of tamoxifen citrate over a period of 21 days, by means of gavage. At the end of the experiment, the animals were killed and the grafts underwent morphologic and histopathologic analysis, with emphasis on the predominant inflammatory response pattern and collagen maturation., Results: The rats undergoing treatment with tamoxifen (study group) presented higher values in relation to the weight and volume of fat grafts compared with the initial values and the control group. Histologic analysis using hematoxylin and eosin staining showed that resolution of the inflammatory process was faster in the control group. Analysis using the picrosirius method demonstrated higher percentages of immature collagen versus mature collagen., Conclusion: Use of tamoxifen reduced the rates of resorption and fibrosis of the injected fat, resulting in better integration of the autologous fat graft.

Background: Quantification of torque teno virus (TTV) has been proposed as a surrogate parameter to monitor immunocompetence in kidney transplant recipients (KTRs) early after transplantation. However, its use in monitoring short-term changes of immunosuppression in KTRs late after transplantation requires further investigation., Methods: In this post hoc analysis, we quantified TTV load in sera of 76 KTRs, with 43 pausing mycophenolic acid (MPA) 1 wk before to 4 wk after COVID-19 vaccination to increase vaccine response. TTV load was quantified before, 4 wk, and 3 mo postvaccination. Results were compared to 33 KTRs with continued standard immunosuppressive therapy and with 18 hemodialysis as well as 18 healthy control subjects., Results: TTV load before vaccination was with a median (interquartile range) of 1.39 × 10 4 copies/milliliter (c/mL) (9.17 × 10 1 -2.66 × 10 5 c/mL) highest in KTRs compared to 1.73 × 10 3 c/mL (1.07 × 10 3 -1.31 × 10 4 c/mL) in hemodialysis patients and 1.53 × 10 2 c/mL (6.38-1.29 × 10 3 c/mL) in healthy controls. In KTRs with MPA withdrawal, TTV load decreased significantly from a median (interquartile range) of 1.11 × 10 4 c/mL (4.75 × 10 2 -1.92 × 10 5 c/mL) to 5.24 × 10 3 c/mL (6.92 × 10 2 -6.91 × 10 4 c/mL) 4-5 wk after initiation of MPA withdrawal ( P = 0.003). In patients with MPA withdrawal, TTV load was significantly inversely correlated with COVID-19 or SARS-CoV-2-specific antibodies 4 wk and 3 mo postvaccination ( P = 0.009 and P = 0.004)., Conclusions: TTV load reflects changes in immunosuppressive therapy even late after transplantation, supporting its use to monitor immunocompetence in KTRs., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Torque Teno virus (TTV) load is linked with the functionality of its host's immune system and has been proposed as a potential monitoring tool for immune-modulating therapy. However, the immunological mechanisms of TTV control are incompletely understood. To assess the effect of the classical complement pathway on TTV, 64 healthy volunteers and 10 kidney transplant recipients treated with the anti-C1s antibody sutimlimab were analyzed for serum TTV copy numbers (c/mL) by qPCR. Overall, a correlation was observed between the decrease in complement activity caused by sutimlimab and the TTV load increase (ρ = -0.367, p < 0.001). Subgroup analysis indicated a trend toward TTV load increase in healthy volunteers following the highest sutimlimab dose compared to baseline (100 mg/kg body weight; median 3.5 log 10 c/mL, interquartile range [IQR] 2.8-4.4 vs. 2.9 log 10 c/mL, 0.8-3.5; p = 0.063). Administering multiple lower doses (30 mg/kg) also showed a trend toward TTV load increase in healthy volunteers (1.8 log 10 c/mL, 0-2.3 vs. 1.9, 1.3-2.8; p = 0.054) and a significant increase in transplant recipients (3.5 log 10 c/mL, 3.0-6.1 vs. 4.1, 3.5-6.4; p = 0.004). This report suggests a role for the classical complement pathway in controlling TTV load., (© 2024 The Author(s). Journal of Medical Virology published by Wiley Periodicals LLC.)

Energy-coupling factor transporters (ECFTs) are membrane-bound ATP-binding cassette (ABC) transporters in prokaryotes that are found in pathogens against which novel antibiotics are urgently needed. To date, just 54 inhibitors of three molecular-structural classes with mostly weak inhibitory activity are known. Target repurposing is a strategy that transfers knowledge gained from a well-studied protein family to under-studied targets of phylogenetic relation. Forty-eight human ABC transporters are known that may harbor structural motifs similar to ECFTs to which particularly multitarget compounds may bind. We assessed 31 multitarget compounds which together target the entire druggable human ABC transporter proteome against ECFTs, of which nine showed inhibitory activity (hit rate 29.0%) and four demonstrated moderate to strong inhibition of an ECFT (IC 50 values between 4.28 and 50.2 µM) as well as antibacterial activity against ECFT-expressing Streptococcus pneumoniae. Here, ivermectin was the most potent candidate (MIC 95 : 22.8 µM), and analysis of five ivermectin derivatives revealed moxidectin as one of the most potent ECFT-targeting antibacterial agents (IC 50 : 2.23 µM; MIC 95 : 2.91 µM). Distinct molecular-structural features of avermectins and derivatives as well as the differential biological response of the hit compounds in general provided first indications with respect to the structure-activity relationships and mode of action, respectively., (© 2024 The Authors. Archiv der Pharmazie published by Wiley‐VCH GmbH on behalf of Deutsche Pharmazeutische Gesellschaft.)

The last decade has seen an explosion in clinical research focusing on the use of noninvasive biomarkers in kidney transplantation. Much of the published literature focuses on donor-derived cell-free DNA (dd-cfDNA). Although initially studied as a noninvasive means of identifying acute rejection, it is now clear that dd-cfDNA is more appropriately described as a marker of severe injury and irrespective of the etiology, elevated dd-cfDNA ≥0.5% portends worse graft outcomes. Blood gene expression profiling is also commercially available and has mostly been studied in the context of early identification of subclinical rejection, although additional data is needed to validate these findings. Torque teno virus, a ubiquitous DNA virus, has emerged as a biomarker of immunosuppression exposure as peripheral blood Torque teno virus copy numbers might mirror the intensity of host immunosuppression. Urinary chemokine tests including C-X-C motif chemokine ligand 9 and C-X-C motif chemokine ligand 10 have recently been assessed in large clinical trials and hold promising potential for early diagnosis of both subclinical and acute rejection, as well as, for long-term prognosis. Urinary cellular messenger RNA and exosome vesicular RNA based studies require additional validation. Although current data does not lend itself to conclusion, future studies on multimodality testing may reveal the utility of serial surveillance for individualization of immunosuppression and identify windows of opportunity to intervene early and before the irreversible allograft injury sets in., Competing Interests: G.G. has received honoraria from Alexion, CareDx, and Natera; he has served on the Scientific Advisory Board for Alexion, CareDx, Natera, and Veloxis; he has received research funding from Gilead and Merck; he is the national Primary Investigator for the Natera Multi-organ Transplant Registry (MOTR) study; and he is a co-investigator of an investigator-initiated trial with support from Eurofins Viracor. The other authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

For many clinically prevalent severe injuries, the inherent regenerative capacity of skeletal muscle remains inadequate. Skeletal muscle tissue engineering (SMTE) seeks to meet this clinical demand. With continuous progress in biomedicine and related technologies including micro/nanotechnology and 3D printing, numerous studies have uncovered various intrinsic mechanisms regulating skeletal muscle regeneration and developed tailored biomaterial systems based on these understandings. Here, the skeletal muscle structure and regeneration process are discussed and the diverse biomaterial systems derived from various technologies are explored in detail. Biomaterials serve not merely as local niches for cell growth, but also as scaffolds endowed with structural or physicochemical properties that provide tissue regenerative cues such as topographical, electrical, and mechanical signals. They can also act as delivery systems for stem cells and bioactive molecules that have been shown as key participants in endogenous repair cascades. To achieve bench-to-bedside translation, the typical effect enabled by biomaterial systems and the potential underlying molecular mechanisms are also summarized. Insights into the roles of biomaterials in SMTE from cellular and molecular perspectives are provided. Finally, perspectives on the advancement of SMTE are provided, for which gene therapy, exosomes, and hybrid biomaterials may hold promise to make important contributions., (© 2024 Wiley‐VCH GmbH.)

Solid organ transplantation is a life-saving intervention for individuals with end-stage organ failure. Despite the effectiveness of immunosuppressive therapy, the risk of graft rejection persists in all viable transplants between individuals. The risk of rejection may vary depending on the degree of compatibility between the donor and recipient for both human leucocyte antigen (HLA) and non-HLA gene-encoded products. Monitoring the status of the allograft is a critical aspect of post-transplant management, with invasive biopsies being the standard of care for detecting rejection. Non-invasive biomarkers are increasingly being recognized as valuable tools for aiding in the detection of graft rejection, monitoring graft status and evaluating the efficacy of immunosuppressive therapy. Here, we focus on the importance of molecular biomarkers in solid organ transplantation and their potential role in clinical practice. Conventional molecular biomarkers used in transplantation include HLA typing, detection of anti-HLA antibodies, killer cell immunoglobulin-like receptor genotypes, and anti-MHC class 1-related chain A antibodies, which are important for assessing the compatibility of the donor and recipient. Emerging molecular biomarkers include the detection of donor-derived cell-free DNA, microRNAs (regulation of gene expression), exosomes (small vesicles secreted by cells), and kidney solid organ response test, in the recipient's blood for early signs of rejection. This review highlights the strengths and limitations of these molecular biomarkers and their potential role in improving transplant outcomes., (© 2024 John Wiley & Sons Ltd.)

Quantification of Torque teno virus (TTV) load emerged as a marker of immunosuppression. Associations of TTV load with complications and survival after allogeneic hematopoietic cell transplantation (allo-HCT) were controversial in published studies. In this prospective study, we aimed to identify factors influencing TTV load after allo-HCT and to determine whether the TTV load is associated with complications or outcomes. Seventy allo-HCT recipients were included. TTV DNA load was quantified in 469 plasma samples of 70 patients from Day (D) 15 before D120 after transplantation. The influence of transplant characteristics on TTV load and the associations of TTV load with viral infections, acute graft versus host disease, mortality, and relapse were analyzed. More than 80% of patients were TTV DNA positive from D30 after transplantation onwards. Median TTV load increased between D30 and D60 post-transplantation. Patients with lymphoid malignancies had higher TTV load than those with myeloid malignancies. Myeloablative conditioning was associated with higher TTV loads. Patients with no measurable residual disease at transplant had higher TTV loads. High TTV load at D90 post-transplantation was associated with lower overall survival and at D120 post-transplantation was associated with higher relapse rate. In conclusion, TTV load at time points later than D90 after allo-HCT may be useful to assess prognosis., (Journal of Medical Virology© 2024 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Objectives: Regarding the relationship between donor kidney quality and renal graft function after deceased kidney transplantation (KTx) following donation after cardiac death (DCD), the evaluation timing varies depending on the study. Evaluation of histology and changes in long-term renal graft function is limited., Methods: A retrospective single-center study included 71 recipients who underwent 0-hour biopsy for KTx from DCD. The recipients were divided into two groups to evaluate factors related to renal graft function (study1). The two groups were categorized as stable graft function and poor graft function with the change of estimated glomerular filtration rate (eGFR) after KTx. The recipients were then divided into four groups to assess whether the factors identified in study1 were related to the change in long-term renal graft function (study2). They were categorized as follows: Improved, Stable, Deteriorated, and Primary non-function with the change of eGFR after KTx., Results: In study1, donor age ≥ 50 years (29.5% vs. 65.2%; p = 0.09), banff arteriolar hyalinosis (ah) score (0.66 ± 0.78 vs. 1.2 ± 1.0; p = 0.018), and presence of glomerulosclerosis (43.2% vs. 76.2%; p = 0.017) were significant risk factors for poor long-term graft function. When the recipients were divided into four groups, the severity of ah correlated well with changes in long-term renal function., Conclusions: We can predict the shift in long-term renal graft function after KTx from DCD according to the severity of ah by 0-hour biopsy., (© 2023 The Japanese Urological Association.)

Torque Teno Virus (TTV) is a single-stranded circular DNA virus which has been identified as a surrogate marker of immune competence in transplantation. In this study we investigated the dynamics of plasma TTV DNAemia in 79 adult patients undergoing chimeric antigen receptor T-cell (CAR-T) therapy for relapsed or refractory large B-cell lymphoma, also evaluating the impact of TTV on immunotoxicities, response and survival outcomes. After lymphodepleting therapy, TTV DNA load was found to decrease slightly until reaching nadir around day 10, after which it increased steadily until reaching maximum load around day 90. TTV DNA load < 4.05 log10 copies/ml at immune effector cell-associated neurotoxicity syndrome (ICANS) onset identified patients at risk of progressing to severe forms of ICANS (OR 16.68, P = 0.048). Finally, patients who experienced falling or stable TTV DNA load between lymphodepletion and CAR-T infusion had better progression-free survival than those with ascending TTV DNA load (HR 0.31, P = 0.006). These findings suggest that TTV monitoring could serve as a surrogate marker of immune competence, enabling predictions of CAR-T efficacy and toxicity. This could pave the way for the development of TTV-guided therapeutic strategies that modulate clinical patient management based on plasma TTV load, similar to suggested strategies in solid organ transplant recipients., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Accurate prediction of COVID-19 severity remains a challenge. Torque teno virus (TTV), recognized as a surrogate marker of functional immunity in solid organ transplant recipients, holds the potential for assessing infection outcomes. We investigated whether quantifying TTV in nasopharyngeal samples upon emergency department (ED) admission could serve as an early predictor of COVID-19 severity. Retrospective single-center study in the ED of Saint-Louis Hospital in Paris, France. TTV DNA was quantified in nasopharyngeal swab samples collected for SARS-CoV-2 testing. Among 295 SARS-CoV-2 infected patients, 92 returned home, 160 were admitted to medical wards, and 43 to the intensive care unit (ICU). Elevated TTV loads were observed in ICU patients (median: 3.02 log copies/mL, interquartile range [IQR]: 2.215-3.825), exceeding those in discharged (2.215, [0; 2.962]) or hospitalized patients (2.24, [0; 3.29]) (p = 0.006). Multivariate analysis identified diabetes, obesity, hepatitis, fever, dyspnea, oxygen requirement, and TTV load as predictors of ICU admission. A 2.91 log 10 copies/mL TTV threshold independently predicted ICU admission. Nasopharyngeal TTV quantification in SARS-CoV-2 infected patients is linked to the likelihood of ICU admission and might reflect respiratory immunosuppression., (© 2023 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Among genodermatoses, trichothiodystrophies (TTDs) are a rare genetically heterogeneous group of syndromic conditions, presenting with skin, hair, and nail abnormalities. An extra-cutaneous involvement (craniofacial district and neurodevelopment) can be also a part of the clinical picture. The presence of photosensitivity describes three forms of TTDs: MIM#601675 (TTD1), MIM#616390 (TTD2) and MIM#616395 (TTD3), that are caused by variants afflicting some components of the DNA Nucleotide Excision Repair (NER) complex and with more marked clinical consequences. In the present research, 24 frontal images of paediatric patients with photosensitive TTDs suitable for facial analysis through the next-generation phenotyping (NGP) technology were obtained from the medical literature. The pictures were compared to age and sex-matched to unaffected controls using 2 distinct deep-learning algorithms: DeepGestalt and GestaltMatcher (Face2Gene, FDNA Inc., USA). To give further support to the observed results, a careful clinical revision was undertaken for each facial feature in paediatric patients with TTD1 or TTD2 or TTD3. Interestingly, a distinctive facial phenotype emerged by the NGP analysis delineating a specific craniofacial dysmorphic spectrum. In addition, we tabulated every single detail within the observed cohort. The novelty of the present research includes the facial characterization in children with the photosensitive types of TTDs through the 2 different algorithms. This result can become additional criteria for early diagnosis, and for subsequent targeted molecular investigations as well as a possible tailored multidisciplinary personalized management., (© 2023. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Torque teno virus (TTV) is a promising novel marker for quantifying the immune function in solid organ recipients, whose diagnostic accuracy of acute rejection (AR) and infection after kidney transplantation (KT) has not been evaluated. We performed a systematic review and meta-analysis to evaluate the diagnostic accuracy of TTV for discriminating AR and infection after KT. Eleven studies were included in the meta-analysis. Seven studies focused on the diagnostic accuracy of TTV for AR, and the pooled analysis indicated patients who developed AR had a significant lower TTV viral DNA load (log 10 copies/mL, MD: -0.74, p < 0.01). The pooled sensitivity, specificity, and area under the receiver operating characteristics curve for TTV in AR differentiation were 0.61 (0.36-0.82), 0.81 (0.64-0.91), and 0.79 (0.75-0.82), respectively. The overall diagnostic odds ratio (DOR) was 6.74 (2.60-17.50), positive likelihood ratio (PLR) was 3.22 (1.75-5.95), and negative likelihood ratio (NLR) was 0.48 (0.27-0.84), respectively. Similarly, seven studies investigated the infection discrimination and found that patients who subsequently developed posttransplant infection had higher plasma TTV DNA loads (log 10 copies/mL, MD: 0.65; p < 0.01) than those remaiing infection-free. Pooled sensitivity, specificity, and area under the receiver operating characteristics curve for TTV in infection differentiation were 0.72 (0.39-0.91), 0.57 (0.30-0.80), and 0.68 (0.64-0.72), respectively. The overall DOR was 3.28 (95% confidence interval [CI]: 2.08-5.17), the pooled PLR and NLR were 1.65 (95% CI: 1.25-2.18) and 0.50 (95% CI: 0.29-0.86), respectively. TTV might be a modest indicator for risk stratification of AR after KT, but it is a poor to discriminate posttransplant infection., (© 2023 Wiley Periodicals LLC.)

Potent immunosuppressive drugs have been introduced into clinical care for solid organ transplant recipients. It is now time to guide these drugs on an individual level to optimize their efficacy. An ideal tool simultaneously detects overimmunosuppression and underimmunosuppression, is highly standardized, and is straightforward to implement into routine. Randomized controlled interventional trials are crucial to demonstrate clinical value. To date, proposed assays have mainly focused on the prediction of rejection and were based on the assessment of few immune compartments. Recently, novel tools have been introduced based on a more integrated approach to characterize the immune function and cover a broader spectrum of the immune system. In this respect, the quantification of the plasma load of a highly prevalent and apathogenic virus that might reflect the immune function of its host has been proposed: the torque teno virus (TTV). Although TTV control is driven by T cells, other major immune compartments might contribute to the hosts' response. A standardized in-house polymerase chain reaction and a conformité européenne-certified commercially available polymerase chain reaction are available for TTV quantification. TTV load is associated with rejection and infection in solid organ transplant recipients, and cutoff values for risk stratification of such events have been proposed for lung and kidney transplantation. Test performance of TTV load does not allow for the diagnosis of rejection and infection but is able to define at-risk patients. Hitherto TTV load has not been used in interventional settings, but two interventional randomized controlled trials are currently testing the safety and efficacy of TTV-guided immunosuppression., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Thiophene, as a member of the group of five-membered heterocycles containing one heteroatom, is one of the simplest heterocyclic systems. Many synthetic strategies allow the accurate positioning of various functionalities onto the thiophene ring. This review provides a comprehensive, systematic and detailed account of the developments in the field of antimicrobial compounds featuring at least one thiophene ring in their structure, over the last decade., (© 2022 Deutsche Pharmazeutische Gesellschaft.)

New reliable biomarkers are needed to improve individual risk assessment for post-transplant infection, acute graft rejection and other immune-related complications after solid organ transplantation (SOT) and allogeneic hematopoietic stem cell transplantation (allo-HSCT). One promising strategy relies on the monitoring of replication kinetics of virome components as functional surrogate for the net state of immunosuppression. Torque Teno Virus (TTV) is a small, non-enveloped, circular, single-stranded DNA anellovirus with no attributable pathological effects. A major component of the human blood virome, TTV exhibits various features that facilitate its application as immune biomarker: high prevalence rates, nearly ubiquitous distribution, stable viral loads with little intra-individual variability, insensitivity to antiviral drugs, and availability of commercial PCR assays for DNA quantification. The present review summarizes the available studies supporting the use of post-transplant TTV viremia to predict patient and graft outcomes after SOT and allo-HSCT. Taken together, this evidence suggests that high or increasing TTV DNA levels precede the occurrence of infectious complications in the SOT setting, whereas low or decreasing viral loads are associated with the development of acute rejection. The interpretation in allo-HSCT recipients is further complicated by complex interplay with the underlying disease, conditioning regimen, and timing of recovery of lymphocyte counts, although TTV kinetics may act as a marker of immunological reconstitution at the early post-transplant period. The standardization of PCR methods and reporting units for TTV DNAemia and the results from ongoing interventional trials evaluating a TTV load-guided strategy to adjust immunosuppressive therapy are achievements expected in the coming years., (© 2021 Wiley Periodicals LLC.)

Improved long-term kidney allograft survival is largely related to better outcomes at 12 months, in association with declining acute rejection rates and more efficacious immunosuppression. Finding the right balance between under- and overimmunosuppression or rejection versus immunosuppression toxicity remains one of transplant's holy grails. In the absence of precise measures of immunosuppression burden, transplant clinicians rely on nonspecific, noninvasive tests and kidney allograft biopsy generally performed for cause. This review appraises recent advances of conventional monitoring strategies and critically examines the plethora of emerging tests utilizing tissue, urine, and blood samples to improve upon the diagnostic precision of allograft surveillance., (Copyright © 2021 by the American Society of Nephrology.)

Natural polyphenols are being tested both in preclinical and clinical settings for the treatment of different neurological disorders. The article describes the outcome of three polyphenols, resveratrol, epigallocatechin gallate, and quercetin, in preclinical animal models of epilepsy (both acute and chronic) and epileptogenesis. In theory, the antioxidant and neuroprotective properties of these natural polyphenols might be valuable in the management of acute seizures and the prevention of epileptogenesis. It is fascinating to observe that these polyphenols have a capacity to alter various signaling processes involved in the pathogenesis of epilepsy. The antiepileptic or antiseizure potential with these molecules delivers a mixed outcome. Some studies have demonstrated the usefulness of these molecules in preclinical models of epilepsy; however, contrary to the findings also exist. These molecules have poor bioavailability that may remain as the limiting factor in their clinical effects. The use of nanotechnology and other techniques have been tested to enhance bioavailability and brain penetration. There are no randomized double-blinded clinical studies establishing their antiepileptic effects in humans. It is concluded that more preclinical mechanism-based studies are needed to deliver a more certain picture regarding the use of natural polyphenols in the treatment of epilepsy., (© 2020 John Wiley & Sons, Ltd.)