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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.)

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.

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.)

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.)

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.)

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.