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(1) Background: CMV infections remain a problem after kidney transplantation, particularly if patients are refractory or resistant (r/r) to treatment with valganciclovir (VGCV) or ganciclovir (GCV). (2) Methods: In a single-center retrospective study, kidney transplant recipients (KTR) receiving letermovir (LTV) as rescue therapy for VGCV-/GCV-r/r CMV disease were analyzed regarding CMV history, immunosuppression, and outcomes. (3) Results: Of 201 KTR treated for CMV between 2017 and 2022, 8 patients received LTV following treatment failure with VGCV/GCV. All patients received CMV prophylaxis with VGCV according to the center's protocol, and 7/8 patients had a high-risk (D+/R−) CMV constellation. In seven of eight cases, rising CMV levels occurred during prophylaxis. In seven of eight patients, a mutation in UL97 associated with a decreased response to VGCV/GCV was detected. In four of eight patients, LTV resulted in CMV clearance after 24 ± 10 weeks (16–39 weeks), two of eight patients stabilized at viral loads <2000 cop/mL (6–20 weeks), and two of eight patients developed LTV resistance (range 8–10 weeks). (4) Conclusion: LTV, which is currently evaluated for CMV prophylaxis in kidney transplantation, also shows promising results for the treatment of patients with VGCV/GCV resistance despite the risk of developing LTV resistance. Additional studies are needed to further define its role in the treatment of patients with CMV resistance. [ABSTRACT FROM AUTHOR]

The identification and location of critical defects inside battery cells before the performance decreases or safety issues arise remain a challenge. This study compares two nondestructive testing methods for the 3D visualization of defects at different depths inside a pouch battery cell: scanning acoustic microscopy (SAM) and X‐ray computed tomography (CT). A manufactured pouch cell with eight electrode sheets is used for this investigation. SAM using a 15 MHz transducer in reflection mode can detect defects at depths of up to four electrode sheets with a lateral resolution of 150 μm in 2 min. CT can locate defects on all eight stacked electrode sheets inside the pouch cell. The CT measurements take about 12.5 h. Both methods can complement each other in detecting defects inside thin pouch cells as an end‐of‐line test after the production or for qualifying individual battery cells for second‐life applications. As an in‐line quality check, SAM has proven to be a cost‐effective and efficient method for detecting defects such as misalignment on stacked electrodes. Both methods have the potential to expand the portfolio of nondestructive quality assurance tests in the production of lithium‐ion battery cells. This contributes to increasing the safety and productivity of battery technology. [ABSTRACT FROM AUTHOR]

Introduction: Antibody mediated rejection (ABMR) is the most common cause of long-term allograft loss in kidney transplantation (KT). Therefore, a low human leukocyte antigen (HLA) mismatch (MM) load is favorable for KT outcomes. Hitherto, serological or low-resolution molecular HLA typing have been adapted in parallel. Here, we aimed to identify previously missed HLA mismatches and corresponding antibodies by high resolution HLA genotyping in a living-donor KT cohort. Methods: 103 donor/recipient pairs transplanted at the University of Leipzig Medical Center between 1998 and 2018 were re-typed using next generation sequencing (NGS) of the HLA loci -A, -B, -C, -DRB1, -DRB345, -DQA1, -DQB1, -DPA1, and -DPB1. Based on these data, we compiled HLA MM counts for each pair and comparatively evaluated genomic HLA-typing with pre-transplant obtained serological/low-resolution HLA (=one-field) typing results. NGS HLA typing (=two-field) data was further used for reclassification of de novo HLA antibodies as “donor-specific”. Results: By two-field HLA re-typing, we were able to identify additional MM in 64.1% (n=66) of cases for HLA loci -A, -B, -C, -DRB1 and -DQB1 that were not observed by one-field HLA typing. In patients with biopsy proven ABMR, two-field calculated MM count was significantly higher than by one-field HLA typing. For additional typed HLA loci -DRB345, -DQA1, -DPA1, and -DPB1 we observed 2, 26, 3, and 23 MM, respectively. In total, 37.3% (69/185) of de novo donor specific antibodies (DSA) formation was directed against these loci (DRB345 ➔ n=33, DQA1 ➔ n=33, DPA1 ➔ n=1, DPB1 ➔ n=10). Conclusion: Our results indicate that two-field HLA typing is feasible and provides significantly more sensitive HLA MM recognition in living-donor KT. Furthermore, accurate HLA typing plays an important role in graft management as it can improve discrimination between donor and non-donor HLA directed cellular and humoral alloreactivity in the long range. The inclusion of additional HLA loci against which antibodies can be readily detected, HLA-DRB345, -DQA1, -DQB1, -DPA1, and -DPB1, will allow a more precise virtual crossmatch and better prediction of potential DSA. Furthermore, in living KT, two-field HLA typing could contribute to the selection of the immunologically most suitable donors. [ABSTRACT FROM AUTHOR]

Background: In nephrotic range proteinuria of adult-onset, kidney biopsy is the diagnostic gold standard in determining the underlying cause of disease. However, in low grade or subnephrotic proteinuria the diagnostic value of kidney biopsy as first-line diagnostics is less well established. Methods: We conducted a retrospective analysis of all native kidney biopsies at our institution (n = 639) between 01/2012 and 05/2021 for comparison of histological diagnoses and clinical outcomes stratified by amount of proteinuria at the time of kidney biopsy: A: <300mg/g creatinine (low grade), B: 300-3500mg/g creatinine (subnephrotic), C >3500mg/g creatinine (nephrotic). Results: Nephrotic range proteinuria was associated with the highest frequency (49.3%) of primary glomerulopathies followed by subnephrotic (34.4%) and low grade proteinuria (37.7%). However, within the subnephrotic group, the amount of proteinuria at kidney biopsy was linearly associated with renal and overall survival (HR 1.05 per Δ100mg protein/g creatinine (95% CI: 1.02–1.09, p = 0.001)) independent of present histological diagnoses and erythrocyturia. Conclusion: Frequency of primary glomerulopathies supports to perform kidney biopsy in patients with subnephrotic proteinuria. These patients have a substantial risk of ESKD and death upon follow-up. Therefore, diagnostic accuracy including histopathology is essential to guide personalized treatment and avert detrimental courses. [ABSTRACT FROM AUTHOR]

The fate of matter forming a black hole is still an open problem, although models of quantum gravity corrected black holes are available. In loop quantum gravity (LQG) models were presented, which resolve the classical singularity in the centre of the black hole by means of a black-to-white hole transition, but neglect the collapse process. The situation is similar in other quantum gravity approaches, where eternal non-singular models are available. In this paper, a strategy is presented to generalise these eternal models to dynamical collapse models by surface matching. Assuming (1) the validity of a static quantum black hole spacetime outside the collapsing matter, (2) homogeneity of the collapsing matter, and (3) differentiability at the surface of the matter fixes the dynamics of the spacetime uniquely. It is argued that these assumptions resemble a collapse of pressure-less dust and thus generalises the Oppenheimer–Snyder–Datt model, although no precise model of the matter has to be assumed. Hawking radiation is systematically neglected in this approach. The junction conditions and the spacetime dynamics are discussed generically for bouncing black hole spacetimes, as proposed by LQG, although the scheme is approach independent. Further, the equations are explicitly solved for the recent model Bodendorfer et al (2019 Class. Quantum Grav. 36 195015) and a global spacetime picture of the collapse is achieved. The causal structure is discussed in detail and the Penrose diagram is constructed. The trajectory of the collapsing matter is completely constructed from an inside and outside observer point of view. The general analysis shows that the matter is collapsing and re-expanding and crosses the Penrose diagram diagonally. This way the infinite tower of Penrose diagrams, as proposed by several LQG models, is generically not cut out. Questions about different timescales of the collapse for in- and outside observers can be answered. [ABSTRACT FROM AUTHOR]

Background: Autosomal polycystic kidney disease is distinguished into dominant (ADPKD) and recessive (ARPKD) inheritance usually caused by either monoallelic (PKD1 / PKD2) or biallelic (PKHD1) germline variation. Clinical presentations are genotype-dependent ranging from fetal demise to mild chronic kidney disease (CKD) in adults. Additionally, exemptions from dominant and recessive inheritance have been reported in both disorders resulting in respective phenocopies. Here, we comparatively report three young adults with microcystic-hyperechogenic kidney morphology based on unexpected genetic alterations beyond typical inheritance. Methods: Next-generation sequencing (NGS)-based gene panel analysis and multiplex ligation-dependent probe amplification (MLPA) of PKD-associated genes, familial segregation analysis, and reverse phenotyping. Results: Three unrelated individuals presented in late adolescence for differential diagnosis of incidental microcystic-hyperechogenic kidneys with preserved kidney and liver function. Upon genetic analysis, we identified a homozygous hypomorphic PKHD1 missense variant causing pseudodominant inheritance in a family, a large monoallelic PKDH1 -deletion with atypical transmission, and biallelic PKD1 missense hypomorphs with recessive inheritance. Conclusion: By this report, we illustrate clinical presentations associated with atypical PKD-gene alterations beyond traditional modes of inheritance. Large monoallelic PKHD1 -alterations as well as biallelic hypomorphs of both PKD1 and PKHD1 may lead to mild CKD in the absence of prominent macrocyst formation and functional liver impairment. The long-term renal prognosis throughout life, however, remains undetermined. Increased detection of atypical inheritance challenges our current thinking of disease ontology not only in PKD but also in Mendelian disorders in general. [ABSTRACT FROM AUTHOR]

In the past years, black holes and the fate of their singularity have been heavily studied within loop quantum gravity. Effective spacetime descriptions incorporating quantum geometry corrections are provided by the so-called polymer models. Despite the technical differences, the main common feature shared by these models is that the classical singularity is resolved by a black-to-white hole transition. In a recent paper (Bodendorfer et al 2019 Class. Quantum Grav. 36 195015), we discussed the existence of two Dirac observables in the effective quantum theory respectively corresponding to the black and white hole mass. Physical requirements about the onset of quantum effects then fix the relation between these observables after the bounce, which in turn corresponds to a restriction on the admissible initial conditions for the model. In the present paper, we discuss in detail the role of such observables in black hole polymer models. First, we revisit previous models and analyse the existence of the Dirac observables there. Observables for the horizons or the masses are explicitly constructed. In the classical theory, only one Dirac observable has physical relevance. In the quantum theory, we find a relation between the existence of two physically relevant observables and the scaling behaviour of the polymerisation scales under fiducial cell rescaling. We present then a new model based on polymerisation of new variables which allows to overcome previous restrictions on initial conditions. Quantum effects cause a bound of a unique Kretschmann curvature scale, independently of the relation between the two masses. [ABSTRACT FROM AUTHOR]

Purpose Autosomal dominant polycystic kidney disease (ADPKD), caused by pathogenic variants of either PKD1 or PKD2, is characterised by wide interfamilial and intrafamilial phenotypic variability. This study aimed to determine the molecular basis of marked clinical variability in ADPKD family members and sought to analyse whether alterations of WT1 (Wilms tumour 1), encoding a regulator of gene expression, may have an impact on renal cyst formation. Methods ADPKD family members underwent clinical and molecular evaluation. Functionally, Pkd1 mRNA and protein expression upon Wt1 knockdown was evaluated in mouse embryonic kidneys and mesonephric M15 cells. Results By renal gene panel analysis, we identified two pathogenic variants in an individual with maternal history of ADPKD, however, without cystic kidneys but polycystic liver disease: a known PKD1 missense variant (c.8311G>A, p.Glu2771Lys) and a known de novo WT1 splice site variant (c.1432+4C>T). The latter was previously associated with imbalanced +/-KTS isoform ratio of WT1. In ex vivo organ cultures from mouse embryonic kidneys, Wt1 knockdown resulted in decreased Pkd1 expression on mRNA and protein level. Conclusion While the role of WT1 in glomerulopathies has been well established, this report by illustrating genetic interaction with PKD1 proposes WT1 as potential modifier in ADPKD. [ABSTRACT FROM AUTHOR]

A common strategy to investigate the fate of gravitational singularities in asymptotically AdS spacetimes is to translate the question from the gravitational side to a dual field theory using the gauge/gravity correspondence and to do a field theory computation. Given recent progress in singularity resolution via non-perturbative quantum gravity, it is natural to now turn the question around and to ask about field theory signatures of resolved singularities. An investigation along this line has been initiated in a companion paper, where a finite-distance pole exhibited by the two-point correlator in the dual field theory, which has previously been linked directly to the gravitational bulk singularity, has been resolved in this way. In order to perform analytic computations, some simplifications were necessary. In this paper, we lift these restrictions by tackling the problem numerically. Our analysis shows that the pole in the two-point correlator gets resolved in the same manner as before. [ABSTRACT FROM AUTHOR]

Atypical haemolytic uraemic syndrome (aHUS) may clinically present as acute renal graft failure resulting from excessive activation of the complement cascade. While mutations of complement-encoding genes predispose for aHUS, it is generally thought to require an additional insult (e.g. drugs) to trigger and manifest the full-blown clinical syndrome. Calcineurin inhibitors (CNIs) used for immunosuppression act as potential triggers, especially in the post-transplantation setting. Therefore, CNI-free immunosuppressive regimens may be beneficial. We report on a 58-year-old woman who developed aHUS with acute graft failure within 20 days after renal transplantation. Genetic investigation revealed a homozygous deletion of the CFH-related 1 (CFHR1) and CFHR3 genes in addition to the presence of autoantibodies against complement factor H (CFH). The patient was treated with plasmapheresis and administration of the complement component 5 (C5) antibody eculizumab, and her immunosuppressive regimen was switched from CNI (tacrolimus) to the cytotoxic T-lymphocyteassociated protein 4 (CTLA-4) inhibitor belatacept. Renal graft function recovered and stabilized over an 18-month followup period. We describe the successful management of post-transplant aHUS using a CNI-free immunosuppressive regimen based on eculizumab and belatacept. Ideally, adequate molecular diagnostics, performed prior to transplantation, can identify relevant genetic risk factors for graft failure and help to select patients for individualized immunosuppressive regimens [ABSTRACT FROM AUTHOR]

Background: Patients on renal replacement therapy are often unaware of their underlying condition and hence suffer from so-called end-stage renal disease (ESRD) of unknown origin. However, an exact diagnosis is not only important for better estimating the prognosis, but also when preparing for kidney transplantation. Whilst patients with FSGS without a confirmed genetic cause have a high recurrence rate in the transplanted organ, patients with a mutation generally exhibit no recurrence and have a good prognosis. Furthermore, renal biopsy, which may be helpful for differential diagnosis, is usually contraindicated in end-stage kidneys. We here present the case of familial ESRD of unknown origin, which could be resolved by targeted genetic testing prior to planning of kidney transplantation. Case presentation: A 32-year-old female with ESRD and nephrotic range proteinuria was admitted to our clinic. Family-history revealed that both mother and maternal grandmother had ESRD of unknown origin. As renal biopsy was impossible due to atrophic kidneys, we performed mutation analysis of genes known for dominant forms of FSGS and found a novel heterozygous mutation of INF2 (c.485 T > C, p.Leu162Pro). The same mutation could be detected in the index patient’s mother (ESRD at age 50) and three brothers with normal serum-creatinine but mid or low range proteinuria. Conclusions: Genetic testing is warranted in families with ESRD of unknown origin and may provide a robust diagnosis even without kidney biopsy. It will help detecting relatives at risk who have to be excluded from potential kidney donation and who may benefit from timely initiation of protective measures in order to slow down disease progression. [ABSTRACT FROM AUTHOR]

While common obesity accounts for an increasing global health burden, its monogenic forms have taught us underlying mechanisms via more than 20 single-gene disorders. Among these, the most common mechanism is central nervous system dysregulation of food intake and satiety, often accompanied by neurodevelopmental delay (NDD) and autism spectrum disorder. In a family with syndromic obesity, we identified a monoallelic truncating variant in POU3F2 (alias BRN2) encoding a neural transcription factor, which has previously been suggested as a driver of obesity and NDD in individuals with the 6q16.1 deletion. In an international collaboration, we identified ultra-rare truncating and missense variants in another ten individuals sharing autism spectrum disorder, NDD, and adolescent-onset obesity. Affected individuals presented with low-to-normal birth weight and infantile feeding difficulties but developed insulin resistance and hyperphagia during childhood. Except for a variant leading to early truncation of the protein, identified variants showed adequate nuclear translocation but overall disturbed DNA-binding ability and promotor activation. In a cohort with common non-syndromic obesity, we independently observed a negative correlation of POU3F2 gene expression with BMI, suggesting a role beyond monogenic obesity. In summary, we propose deleterious intragenic variants of POU3F2 to cause transcriptional dysregulation associated with hyperphagic obesity of adolescent onset with variable NDD. [Display omitted] Monogenic forms of obesity have taught us about central nervous system dysregulation of food intake as a disease mechanism. We associate ultra-rare variants in POU3F2 , encoding a central nervous system transcription factor, with syndromic obesity and neurodevelopmental delay in 12 individuals. Additionally, we demonstrate variant pathogenicity through in vitro analysis. [ABSTRACT FROM AUTHOR]

Quantum gravity effects in effective models of loop quantum gravity, such as loop quantum cosmology, are encoded in the choice of so-called polymerisation schemes. Physical viability of the models, such as an onset of quantum effects at curvature scales near the Planck curvature, severely restricts the possible choices. An alternative point of view on the choice of polymerisation scheme is to choose adapted variables so that the scheme is the simplest possible one, known as μ 0 -scheme in loop quantum cosmology. There, physically viable models with μ 0 -scheme polymerise the Hubble rate b that is directly related to the Ricci scalar and the matter energy density on-shell. Consequently, the onset of quantum effects depends precisely on those parameters. In this letter, we construct similar variables for black to white hole transitions modelled using the description of the Schwarzschild interior as a Kantowski-Sachs cosmology. The resulting model uses the μ 0 -scheme and features sensible physics for a broad range of initial conditions (= choices of black and white hole masses) and favours symmetric transitions upon invoking additional qualitative arguments. The resulting Hamiltonian is very simple and at most quadratic in its arguments, allowing for a straightforward quantisation. [ABSTRACT FROM AUTHOR]