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In this multicentre study, sera from 803 retransplant candidates, including 775 kidney transplant recipients, were analysed with regard to the presence and specificity of anti- HLA alloantibodies of the Ig A isotype using a modified microsphere-based platform. Of the kidney recipients, nearly one-third ( n = 237, 31%) had Ig A alloantibodies. Mostly, these antibodies were found in sera that also harboured Ig G alloantibodies that could be found in a total of 572 (74%) of patients. Interestingly, Ig A anti- HLA antibodies were preferentially targeting HLA class I antigens in contrast to those of the Ig G isotype, which targeted mostly both HLA class I and II antigens. Donor specificity of the Ig A alloantibodies could be established for over half of the 237 patients with Ig A alloantibodies ( n = 124, 52%). A further 58 patients had specificities against HLA- C or HLA- DP, for which no information regarding donor typing was available. In summary, these data showed in a large cohort of retransplant candidates that Ig A alloantibodies occur in about one-third of patients, about half of these antibodies being donor specific. [ABSTRACT FROM AUTHOR]

Abstract This report describes the clinical courses of two acute myeloid leukemia patients. Both had MLL translocations, the first a t(10;11)(p11.2;q23) with MLL-AF10 and the second a t(11;19)(q23;p13.1) with MLL-ELL fusion. They achieved a clinical remission under conventional chemotherapy but relapsed shortly after end of therapy. Both had a history of invasive mycoses (one had possible pulmonary mycosis, one systemic candidiasis). Because no HLA-identical donor was available, a haploidentical transplantation was performed in both cases. Using a specially designed PCR method for the assessment of minimal residual disease (MRD), based on the quantitative detection of the individual chromosomal breakpoint in the MLL gene, both patients achieved complete and persistent molecular remission after transplantation. The immune reconstitution after transplantation is described in terms of total CD3+/CD4+, CD3+/CD8+, CD19+, and CD16+/CD56+ cell numbers over time. The KIR and HLA genotypes of donors and recipients are reported and the possibility of a KIR-mediated alloreactivity is discussed. This report illustrates that haploidentical transplantation may offer a chance of cure without chronic graft-versus-host disease in situations where no suitable HLA-identical donor is available even in a high-risk setting and shows the value of MRD monitoring in the pre- and posttransplant setting.

Nanoparticles have proven to be attractive carriers in therapeutic drug delivery since they can encapsulate, protect and stabilize a plethora of different drugs, thereby improving therapeutic efficacy and reducing side effects. However, specific targeting of drug-loaded nanoparticles to the tissue of interest and a timely and spatially controlled release of drugs on demand still represent a challenge. Recently, gas-filled microparticles, so-called antibubbles, have been developed which can efficiently encapsulate liquid drug droplets. Here, we show that antibubbles are efficiently taken up by macrophages in vitro and are stably maintained for more than 48 h without compromising antibubble integrity and macrophage viability. We show that application of diagnostic ultrasound induces the disintegration of both antibubbles and carrier cells while not affecting non-loaded macrophages. Using 4-hydroxytamoxifen as a model drug, we show ultrasound-mediated drug release upon adoptive transfer of antibubble-loaded macrophages in mice. Together with the ability of macrophages to accumulate in inflamed tissues, antibubble-loaded macrophages represent an attractive tool for targeted delivery of drugs and its ultrasound-mediated spatial and temporal drug release, highlighting the therapeutic perspective of this strategy., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Hypothesis: Donor-derived cell-free DNA (dd-cfDNA) shows good diagnostic performance for the detection of antibody-mediated rejection (AMR) in kidney transplant recipients (KTR). However, the clinical benefits of dd-cfDNA monitoring need to be established. Early diagnosis of AMR at potentially reversible stages may be increasingly important due to emerging treatment options for AMR.We hypothesized that monitoring dd-cfDNA in KTR with de novo donor-specific anti-HLA antibodies (dnDSA) and performing kidney biopsy in case of increased dd-cfDNA may reduce time to AMR diagnosis in comparison to clinical indication biopsy., Methods: In this diagnostic, single-center, open-label, randomized clinical trial, we assigned 40 KTR with prevalent dnDSA and estimated glomerular filtration rate ≥20 mL/min/1.73m2, but without previous biopsy-proven AMR, to either dd-cfDNA-guided biopsy (intervention group) or clinician-guided biopsy (control group) over a 12-months period. In both groups, dd-cfDNA was assessed at inclusion and 1, 3, 6, 9, and 12 months. In the intervention group, dd-cfDNA > 50cp/mL indicated a biopsy. Biopsies for clinical indication could be performed at any point during the study period in both groups. A protocol biopsy was scheduled after 12 months for patients without dd-cfDNA-guided biopsy or clinical indication biopsy until study completion. The primary endpoint was time from study inclusion to diagnosis of active or chronic active AMR., Results: 39/40 patients had functioning grafts at study completion. From these, 26 patients underwent biopsy, 13 in each group. AMR was diagnosed earlier in the intervention group than in the control group (median 2.8 months, IQR 1.7-5.3 vs. median 14.5 months, IQR 13.3-16.7, p = 0.003). Longitudinal dd-cfDNA monitoring had 77% positive predictive value and 85% negative predictive value for AMR., Conclusions: Dd-cfDNA-guided biopsy in KTR with prevalent dnDSA can reduce the time to AMR diagnosis and hereby expedite therapy initiation. (NCT04897438)., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Systemic lupus erythematosus (SLE) is an autoimmune disease, the pathophysiology and genetic basis of which are incompletely understood. Using a forward genetic screen in multiplex families with SLE, we identified an association between SLE and compound heterozygous deleterious variants in the non-receptor tyrosine kinases (NRTKs) ACK1 and BRK . Experimental blockade of ACK1 or BRK increased circulating autoantibodies in vivo in mice and exacerbated glomerular IgG deposits in an SLE mouse model. Mechanistically, NRTKs regulate activation, migration, and proliferation of immune cells. We found that the patients' ACK1 and BRK variants impair efferocytosis, the MERTK-mediated anti-inflammatory response to apoptotic cells, in human induced pluripotent stem cell (hiPSC)-derived macrophages, which may contribute to SLE pathogenesis. Overall, our data suggest that ACK1 and BRK deficiencies are associated with human SLE and impair efferocytosis in macrophages., Competing Interests: SG, TL, NJ, BB, MT, BC, TZ, CN, RB, HY, FR, RF, SD, DI, DD, NL, OE, AV, NS, LA, SN, MH, WM, JC, FG No competing interests declared, (© 2024, Guillet, Lazarov et al.)

Acne and sensitive skin can take a profound toll on patients' well-being, which can be exacerbated if the conditions are experienced together. This narrative review aims to identify appropriate treatments to facilitate a holistic management approach to acne (One Acne™), sensitive skin, and acne-induced sequelae and describe the role of treatments in improving skin quality. Topical retinoids are considered the preferred first-line option for acne treatment by dermatologists, either as monotherapy or in combination with other treatments, because of their ability to target various aspects of the disease. Tretinoin, trifarotene, adapalene, and tazarotene have all been assessed in clinical studies for managing acne-associated scarring, with varying success, with the latter three reported to improve skin quality. Moreover, some corrective procedures, e.g., injectable non-animal stabilized hyaluronic acid (NASHA) fillers, have proven effective for treating acne scarring. Both treatment types may complement each other to provide optimal treatment outcomes and patient satisfaction, as observed in several patients receiving concomitant treatment with NASHA fillers/topical trifarotene. Adjunctive use of cleansers, moisturizers, and photoprotection-containing ingredients such as vitamin B3, glycerin, or pro-vitamin B3 may also complement drug/corrective treatments to reduce skin irritation and risk of scarring, as well as improve skin hydration, tone, and overall appearance. This narrative review highlights that comprehensive skincare regimens should be used throughout acne patients' journeys to reduce treatment-related irritation, improve treatment outcomes, adherence, and satisfaction, and enhance overall skin quality. Patients with sensitive skin should choose tailored skincare products to maintain skin barrier integrity and restore skin function., (© 2024 Galderma and The Author(s). International Journal of Dermatology published by Wiley Periodicals LLC on behalf of the International Society of Dermatology.)

Introduction: Cystic fibrosis (CF) is a hereditary autosomal recessive disease driven by deleterious variants of the CFTR gene, leading, among other symptoms, to increased lung infection susceptibility. Mucus accumulation in the CF lung is, as of yet, considered as one important factor contributing to its colonization by opportunistic pathogens such as Pseudomonas aeruginosa . However, in recent years evidence was provided that alveolar macrophages, which form the first line of defense against airborne pathogens, seem to be intrinsically defective with regard to bactericidal functionality in the CF lung. To assess the impact of CFTR deficiency in human macrophages only insufficient systems are available., Methods: To address this problem and to evaluate the role of CFTR in human macrophages, we successfully differentiated human induced pluripotent stem cells (iPSC) from a CF p.Phe508del homozygous individual and a healthy donor into primitive macrophages (iMac ΔF508 and iMac WT ), respectively, and compared the bactericidal functionality in the relevant cell type., Results: iMac ΔF508 showed impaired P. aeruginosa clearance and intracellular killing capacity in comparison to iMac WT . Furthermore, iMac ΔF508 exhibited a less acidic lysosomal pH, and upon P. aeruginosa infection, there were signs of mitochondrial fragmentation and autophagosome formation together with a hyperinflammatory phenotype and deficient type I interferon response., Conclusion: In summary, we present a defective phenotype in iMac ΔF508 upon P. aeruginosa infection, which will constitute an ideal platform to further study the role of macrophages in the context of CF., Competing Interests: Author MM was employed by the company Colzyx AB. 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Rodriguez Gonzalez, Basílio-Queirós, Neehus, Merkert, Tschritter, Ünal, Hegermann, Mörgelin, Bustamante, Nietert, Martin, Tümmler, Munder and Lachmann.)

"Medical scientists" are postgraduate investigators who are engaged in biomedical research, and either hold a biomedical PhD or are qualified in medicine but do not participate in patient care. Medical scientists constitute ~40% of staff at medical faculties and >90% at nonuniversity medical research institutions in Germany. However, medical scientists in Germany face limited long-term career prospects and a lack of dedicated training and support programmes. They also face time limits on their career progression arising from national academic employment legislation, and imminent reforms by the German government are likely to make this worse. Nevertheless, recent developments in the educational landscape including the introduction of increasingly focused MSc, pre-PhD, and doctoral programmes to train medically aware basic scientists, as well as improved general recognition of the roles and relevance of medical scientists in health research, are encouraging. Physiologists have taken essential steps to improve the recognition of medical scientists in Germany by introducing a "specialist physiologist" qualification; this initiative could be applied to support medical scientists in other fields and countries. In this review, we describe the particular challenges facing medical scientists in Germany and make recommendations that may apply to other academic systems., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Background: Patients with autosomal dominant polycystic kidney disease (ADPKD) represent >10% of patients awaiting kidney transplantation. These patients are prone to potentially severe urinary tract (UTI) and liver cyst infections after transplantation. Whether such infections compromise outcome is unclear., Methods: Between 2000 and 2017 we performed 193 kidney transplantations in patients with ADPKD. In 189 patients, we assessed the occurrence, frequency, and severity of infection episodes requiring inpatient treatment and their impact on graft and patient outcomes compared with 189 matched controls. Risk factors were analyzed by uni- and multivariable analyses., Results: During a mean observation period of 77 months UTIs occurred more frequently in ADPKD patients (39.1% vs. 26.7%, P  = .022; 0.8 ± 1.4 vs. 0.5 ± 1.1 episodes, P  < .001). Eight ADPKD patients suffered from 19 episodes of liver cyst infection. Steroid medication (RR 3.04; P  < .001) and recipient age (RR 1.05; P  = .003) increased the risk for UTI/urosepsis, while nephrectomy reduced it (unilateral, RR 0.60; P  = .088; bilateral, RR 0.45; P  = .020). Patient survival was similar in both groups. The risk of graft failure was lower in ADPKD patients [hazard ratio (HR) 0.67; P  = .047] due to a lower risk of death-censored graft loss (HR 0.47; P  = .014). Donor age (HR 1.34; P  = .002) and rejection (HR 8.47; P  < .001) were risk factors for death-censored graft loss., Conclusions: ADPKD patients are at increased risk of UTI and liver cyst infection after transplantation. Steroid medication and recipient age seem to increase the risk of UTI/urosepsis, while nephrectomy seems to reduce it. Nevertheless, patient survival was similar compared to non-ADPKD patients and death-censored graft survival even better., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Introduction: The immune response after transplantation depends on recipient/donor HLA allele mismatches. To enhance our understanding of the relations of HLA alleles in terms of amino-acid polymorphisms and shared epitopes, we assessed pairwise sequence difference between HLA-alleles., Methods: We translated amino-acid sequences of confirmed eplets into an atlas of HLA class I and II antigens, followed by visualization of the pairwise allele distances by means of antigen-specific disparity graphs in differential amino-acid space. We obtained an overview of relationships of all alleles of an antigen, corresponding similarity/dissimilarity structures, outliers, alleles with similarity to different antigen groups. Additionally, we calculated prevalence of the amino-acids for each polymorphic sequence position and visualized them in amino-acid motif plots of all alleles belonging to an antigen., Results: Our visualizations show strongly varying intra-group heterogeneity of HLA class I and II alleles, as well as shared inter-group and inter-locus eplets and epitopes, indicating a benefit of epitope-based transplant matching: Single allele recipient/donor mismatches potentially refer to identical eplets, or to a set of multiple mismatched eplets., Discussion: This data reveals inconsistencies in the HLA group nomenclature and consequently adds a new level of quality to allocation, motivating the definition of tolerable or taboo mismatches., Competing Interests: The 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Doxiadis, Lehmann, Lachmann and Loeffler-Wirth.)