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Aim: The aim of this study was to investigate the relationship between handgrip strength and phalangeal bone mineral density (BMD) and to evaluate the confounding factors in highly trained male athletes. Material and Methods: A total of 57 highly trained athletes; with a mean age of 23.5±4.1 (17-37) years were included in the study. Age, smoking status, alcohol consumption, medications, previous fractures, calcium intake, the duration of sports participation, weekly training time, height and weight of the subjects were recorded. Handgrip strength was measured by a hand-held dynamometer and BMD was measured with radiographic absorbtiometry in both hands. Results: Significant positive correlations were found between BMD and handgrip strength, age, weight and height (p<0.01). When stepwise regression analysis was performed, two variables were found to be significantly related to BMD: handgrip strength and weight. R2 value was 0.29 (F=8.71, p=0.001). To eliminate the effect of body weight on BMD we compared BMD and grip strength in the dominant and non-dominant hands. Bone mineral density, t-scores and the handgrip strength were significantly higher in the dominant hand (p<0.05). Conclusion: Handgrip strength is an independent predictor of phalangeal bone mineral density in highly trained male athletes. [ABSTRACT FROM AUTHOR]

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Abstract: A molecular modeling analysis was performed via density functional theory (DFT), using B3LYP/6–31++G(d,p) basis set on Zn(PM)2Cl2, PM-Al(OH)3 and PM-(Al(OH)3)2 complexes (PM: Pyrimidine) in order to investigate monodentate and bidentate coordination effects on pyrimidine vibrational wavenumbers. The Zn(PM)2Cl2 complex was synthesized and the FT-IR and FT-Ra spectra were recorded which, when compared to the calculated wavenumbers of the model mono- and bidentate Al(OH)3 complexes, showed that pyrimidine behaved as a monodentate ligand. Anharmonic corrections to the calculated wavenumbers of the Zn(PM)2Cl2 complex were done and the results led to a good overall agreement with the observed wavenumbers. A complete assignment of the fundamentals was proposed based on the internal mode analysis done by Gaussian03 programme. [Copyright &y& Elsevier]

Objective: Droopy shoulder syndrome [DSS] is classified as a small subgroup of disputed neurogenic thoracic outlet syndrome and characterized by drooping of the shoulders which leads to traction on the brachial plexus. The effect of exercise seems controversial in DSS. The aim of this study is to evaluate the effect of exercise both on clinical and radiological outcome in DSS. Methods: Thirty-four patients referred to the physical medicine and rehabilitation outpatient clinic with DSS were included in this prospective follow-up study. Of these patients, five were lost to follow-up All patients were given home exercises and followed up for 13.7 +/- 5.0 months. The patients were divided into two groups with regard to their adherence to exercise programs as regular and irregular exercise groups. The clinical outcome was assessed on the basis of pain with visual analog scale, patient's response to treatment, and radiographic changes. Results: At the end of the treatment when the two groups were compared, the patients doing regular exercise had a better improvement in pain scores [P = 0.002] and radiographic findings [P = 0.05] than the irregular exercisers. They also said they were much more satisfied with the treatment [P = 0.04]. Conclusion: Regular exercise improves outcome in DSS. Unlike previous reports, radiographic improvement can also be achieved if the objective evaluation is performed. [ABSTRACT FROM AUTHOR]

In order to compare the prevalence of antibiotic resistance in different geographical areas, it is necessary to ensure agreement between laboratories on the assignment of strains to 'susceptible' and 'resistant' categories. An international quality assessment was performed to investigate the performance of susceptibility testing of Klebsiella spp. Ninety-five strains of klebsiellae were selected from clinical isolates at the London Hospital Medical College (LHMC). These included strains with a diversity of susceptibility profiles to amoxycillin/clavulanate, piperacillin, ceftazidime, cefuroxime, ciprofloxacin, gentamicin and trimethoprim. The strains were sent to 13 participating laboratories in Europe and the USA and laboratories were asked to test the susceptibility of these strains to these antibiotics by their usual methods. They were also asked to provide details of the method used to test susceptibility. Several different standard recommended testing methods were used. Reporting of susceptibilities was generally accurate, but a number of anomalies were noted. Discrepancies of reporting between the LHMC and the participating laboratories was more marked for resistant strains, particularly in the detection of resistance to cefuroxime and ciprofloxacin, as well as the assignment of susceptibility and resistance to piperacillin and amoxycillin/clavulanate. Some discrepancies could be attributed to the use of different breakpoints, leading to differing assignment of susceptibility. Methodological variations including disc content, inoculum and failure to measure and interpret zone sizes consistently also led to anomalies. This quality assessment programme has helped to identify problems in susceptibility testing which should be investigated further. [ABSTRACT FROM PUBLISHER]

In order to compare the prevalence of antibiotic resistance in different geographical areas, it is necessary to ensure agreement between laboratories on the assignment of strains to 'susceptible' and 'resistant' categories. An international quality assessment was performed to investigate the performance of susceptibility testing of Klebsiella spp. Ninety-five strains of klebsiellae were selected from clinical isolates at the London Hospital Medical College (LHMC). These included strains with a diversity of susceptibility profiles to amoxycillin/clavulanate, piperacillin, ceftazidime, cefuroxime, ciprofloxacin, gentamicin and trimethoprim. The strains were sent to 13 participating laboratories in Europe and the USA and laboratories were asked to test the susceptibility of these strains to these antibiotics by their usual methods. They were also asked to provide details of the method used to test susceptibility. Several different standard recommended testing methods were used. Reporting of susceptibilities was generally accurate, but a number of anomalies were noted. Discrepancies of reporting between the LHMC and the participating laboratories was more marked for resistant strains, particularly in the detection of resistance to cefuroxime and ciprofloxacin, as well as the assignment of susceptibility and resistance to piperacillin and amoxycillin/clavulanate. Some discrepancies could be attributed to the use of different breakpoints, leading to differing assignment of susceptibility. Methodological variations including disc content, inoculum and failure to measure and interpret zone sizes consistently also led to anomalies. This quality assessment programme has helped to identify problems in susceptibility testing which should be investigated further. [ABSTRACT FROM AUTHOR]

In order to compare the prevalence of antibiotic resistance in different geographical areas, it is necessary to ensure that agreement is achieved between laboratories on the assignment of strains to ‘susceptible’ and ‘resistant’ categories. An international quality assessment study, involving 15 laboratories in eight countries, was performed to investigate the standard of performance of the susceptibility testing of Haemophilus influenzae. One hundred and fifty strains of H. influenzae were distributed from the London Hospital Medical College (LHMC) to all laboratories who were asked to test the susceptibility of the strains to ampicillin, chloramphenicol, tetracycline, trimethoprim, cephalosporins and ciprofloxacin. Laboratories were also asked to provide the details of methodology to test the susceptibility. Significant discrepancy between the LHMC and the participating laboratories appeared in the detection of resistance to ampicillin (especially β-lactamase-negative strains resistant to ampicillin) as well as the assignment of susceptibility and resistance to chloramphenicol, tetracycline and trimethoprim. Often these reflected the use of inappropriate breakpoints which led to erroneous assignment of susceptibility. Other variations including disc content, medium and supplement, inoculum as well as failure to measure zone sizes properly also led to some repeating anomalies. [ABSTRACT FROM PUBLISHER]

Droopy shoulder syndrome (DSS) is characterized by a depression of the shoulders that stretches the brachial plexus, thus causing pain without any signs of neurological impairment. We describe ten patients with DSS; all had been treated for different diagnoses before. Contrary to previous reports, three patients had unilateral involvement, and five had accompanying disease of the cervical-shoulder region. All patients responded well to conservative treatment in 2-10 weeks. DSS must be kept in mind in the differential diagnosis of pain in the cervical-shoulder region, to prevent unnecessary medication. [ABSTRACT FROM AUTHOR]

A hydrodistilled essential oil from fruits of Cachrys alpina was analyzed by GC/MS. Twenty-nine compounds representing 98% of the oil were identified with α--humulene (33.1%), p-cymene (9.3%), α-phellandrene (9.1%), germacrene D (8.2%) and α-pinene (6.3%) as main constituents. [ABSTRACT FROM AUTHOR]

Abstract: High resolution Raman spectra of GeSe2 glass were measured and fitted using individual Gaussian components. The structural origin of the components were interpreted using the results of ab initio density functional theory calculations performed on GenSem nanoclusters (n=2–6, 12; m=6–9, 12, 14–16, 30) which represent the local structure of GeSe2 glass and on some “defect” GenSem clusters that are thought to be related to the inhomogeneity of the structure at the nanoscale. The calculated vibrational properties of GenSem nanoclusters and their couplings with the short- and medium-range order structure formations in GeSe2 glass are analyzed and discussed. [Copyright &y& Elsevier]

Background: Prognostic models are becoming increasingly relevant in clinical trials as potential surrogate endpoints, and for patient management as clinical decision support tools. However, the impact of competing risks on model performance remains poorly investigated. We aimed to carefully assess the performance of competing risk and noncompeting risk models in the context of kidney transplantation, where allograft failure and death with a functioning graft are two competing outcomes., Methods: We included 11,046 kidney transplant recipients enrolled in 10 countries. We developed prediction models for long-term kidney graft failure prediction, without accounting (i.e., censoring) and accounting for the competing risk of death with a functioning graft, using Cox, Fine-Gray, and cause-specific Cox regression models. To this aim, we followed a detailed and transparent analytical framework for competing and noncompeting risk modelling, and carefully assessed the models' development, stability, discrimination, calibration, overall fit, clinical utility, and generalizability in external validation cohorts and subpopulations. More than 15 metrics were used to provide an exhaustive assessment of model performance., Results: Among 11,046 recipients in the derivation and validation cohorts, 1,497 (14%) lost their graft and 1,003 (9%) died with a functioning graft after a median follow-up post-risk evaluation of 4.7 years (IQR 2.7-7.0). The cumulative incidence of graft loss was similarly estimated by Kaplan-Meier and Aalen-Johansen methods (17% versus 16% in the derivation cohort). Cox and competing risk models showed similar and stable risk estimates for predicting long-term graft failure (average mean absolute prediction error of 0.0140, 0.0138 and 0.0135 for Cox, Fine-Gray, and cause-specific Cox models, respectively). Discrimination and overall fit were comparable in the validation cohorts, with concordance index ranging from 0.76 to 0.87. Across various subpopulations and clinical scenarios, the models performed well and similarly, although in some high-risk groups (such as donors over 65 years old), the findings suggest a trend towards moderately improved calibration when using a competing risk approach., Conclusions: Competing and noncompeting risk models performed similarly in predicting long-term kidney graft failure., (Copyright © 2024 by the American Society of Nephrology.)

Purpose: Evaluate the safety/efficacy of novel potassium binders (patiromer, sodium zirconium cyclosilicate [SZ-9]) for early postoperative hyperkalemia following kidney transplantation., Methods: Retrospective, single-center, cohort study of deceased-donor kidney recipients transplanted between 1/2018 and 12/2020. Potassium-binder use was evaluated from immediately posttransplant until discharge. Potassium binders were administered ≥2 hours before/after medications., Results: A total of 179 patients were included, 24 (13%) of whom received potassium binders (16 [67%] patiromer, 7 [29%] SZ-9, 1 [4%] both) for a mean of 2.5 (±3.18) doses. Peak potassium levels were higher in the potassium-binder group (6.05 vs 5.35 mEq/L; P < .001). More patients on potassium binders transitioned to atovaquone than those on no binders (n = 21 [100%] vs n = 112 [75%], respectively; P = .005). Delayed graft function (DGF) was observed in 100 (56%) patients, with a higher proportion receiving potassium binders (18 [75%] vs 82 [53%], respectively; P = .042). There was no difference between groups in number of posttransplant dialysis sessions required in the general study population (P = .2), nor in the DGF group (P = .12). No difference was noted in the incidence of ileus (P = .2), or gastrointestinal symptoms (diarrhea, nausea, vomiting; P = .6). Of the 24 patients who received inpatient binders, 9 (37.5%) were discharged and remained on them for a mean of 46 (±49) days., Conclusion: Patiromer and SZ-9 appear safe in the early posttransplant period, but larger prospective trials are needed. Potassium-binder use does not appear to be associated with fewer dialysis sessions in DGF patients, however, they may be used as additional tools for lowering potassium in these patients., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Maria Ajaimy reports statistical analysis was provided by Montefiore Medical Center. Maria Ajaimy reports a relationship with Montefiore Medical Center that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Most kidney transplant patients who undergo biopsies are classified as having no rejection based on consensus thresholds. However, we hypothesized that because these patients have normal adaptive immune systems, T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) may exist as subthreshold activity in some transplants currently classified as no rejection. To examine this question, we studied genome-wide microarray results from 5086 kidney transplant biopsies (from 4170 patients). An updated molecular archetypal analysis designated 56% of biopsies as no rejection. Subthreshold molecular TCMR and/or ABMR activity molecular activity was detectable as elevated classifier scores in many biopsies classified as no rejection, with ABMR activity in many TCMR biopsies and TCMR activity in many ABMR biopsies. In biopsies classified as no rejection histologically and molecularly, molecular TCMR classifier scores correlated with increases in histologic TCMR features and molecular injury, lower estimated glomerular filtration rate, and higher risk of graft loss, and molecular ABMR activity correlated with increased glomerulitis and donor-specific antibody. No rejection biopsies with high subthreshold TCMR or ABMR activity had a higher probability of having TCMR or ABMR, respectively, diagnosed in a future biopsy. We conclude that many kidney transplant recipients have unrecognized subthreshold TCMR or ABMR activity, with significant implications for future problems., Competing Interests: Declaration of competing interest The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. P.F. Halloran holds shares in Transcriptome Sciences Inc., a University of Alberta research company dedicated to developing molecular diagnostics, supported in part by a licensing agreement between Transcriptome Sciences Inc. and Thermo Fisher Scientific, and by a research grant from Natera, Inc. P.F. Halloran is a consultant to Natera, Inc. and Argenx BV. The other authors have declared no conflict of interest exists., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Kidney transplant is not only the best treatment for patients with advanced kidney disease but it also reduces health care expenditure. The management of transplant patients is complex as they require special care by transplant nephrologists who have expertise in assessing transplant candidates, understand immunology and organ rejection, have familiarity with perioperative complications, and have the ability to manage the long-term effects of chronic immunosuppression. This skill set at the intersection of multiple disciplines necessitates additional training in Transplant Nephrology. Currently, there are more than 250,000 patients with a functioning kidney allograft and over 100,000 waitlisted patients awaiting kidney transplant, with a burgeoning number added to the kidney transplant wait list every year. In 2022, more than 40,000 patients were added to the kidney wait list and more than 25,000 received a kidney transplant. The Advancing American Kidney Health Initiative, passed in 2019, is aiming to double the number of kidney transplants by 2030 creating a need for additional transplant nephrologists to help care for them. Over the past decade, there has been a decline in the Nephrology-as well Transplant Nephrology-workforce due to a multitude of reasons. The American Society of Transplantation Kidney Pancreas Community of Practice created a workgroup to discuss the Transplant Nephrology workforce shortage. In this article, we discuss the scope of the problem and how the Accreditation Council for Graduate Medical Education recognition of Transplant Nephrology Fellowship could at least partly mitigate the Transplant Nephrology work force crisis., (Copyright © 2024 by the American Society of Nephrology.)

Even as record numbers of deceased donors are undergoing organ recovery, the global transplant community continues to struggle with a shortage of donor organs and a high organ discard rate. Acute kidney injury (AKI) occurs in many hospitalized patients, including up to 25% of patients in critical condition. Registry studies have shown a significant increase in nonrecovery or organ discard rates in AKI donors, despite most studies reporting similar clinical outcomes compared with non-AKI donors. This review aims to capture the salient information learned from these studies and to summarize the efforts that have been made to gain a more granular understanding of how kidneys from donors with AKI behave posttransplant. In particular, we reviewed the studies that analyzed the clinical outcomes in different stages of AKI and AKI in marginal donors, such as kidney donor profile index of >85%, older donors, and donation after circulatory death donors. We summarized studies investigating molecular biomarkers, transcriptomics, and possible future therapeutic targets for postdonation AKI., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Membranous nephropathy (MN) is a leading cause of kidney failure worldwide and frequently recurs after transplant. Available data originated from small retrospective cohort studies or registry analyses; therefore, uncertainties remain on risk factors for MN recurrence and response to therapy. Within the Post-Transplant Glomerular Disease Consortium, we conducted a retrospective multicenter cohort study examining the MN recurrence rate, risk factors, and response to treatment. This study screened 22,921 patients across 3 continents and included 194 patients who underwent a kidney transplant due to biopsy-proven MN. The cumulative incidence of MN recurrence was 31% at 10 years posttransplant. Patients with a faster progression toward end-stage kidney disease were at higher risk of developing recurrent MN (hazard ratio [HR], 0.55 per decade; 95% confidence interval [CI], 0.35-0.88). Moreover, elevated pretransplant levels of anti-phospholipase A2 receptor (PLA2R) antibodies were strongly associated with recurrence (HR, 18.58; 95% CI, 5.37-64.27). Patients receiving rituximab for MN recurrence had a higher likelihood of achieving remission than patients receiving renin-angiotensin-aldosterone system inhibition alone. In sum, MN recurs in one-third of patients posttransplant, and measurement of serum anti-PLA2R antibody levels shortly before transplant could aid in risk-stratifying patients for MN recurrence. Moreover, patients receiving rituximab had a higher rate of treatment response., Competing Interests: Declaration of competing interest The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. Helio Tedesco Silva is supported by research grants from Novartis, Natera, and Merck & Co. through his institution. He received honoraria for lectures from Takeda, EMS, CardeDx and Natera. Additionally, he received monetary support from Takeda to attend meetings. A. Bernard Collins receives royalties from Elsevier. He also reports receiving honoraria from Euroimmun. Nikhil Agrawal has employment stocks and options from CareDx Inc. He is also currently employed by CareDx Inc. Ayman Al Jurdi is supported by AstraZeneca through grant funding for an investigator-initiated study related to another project. Roberto C. Manfro served on the data safety monitoring board of Instituto Butanatan in São Paulo, Brazil, for which he did not receive any payments. Giorgia Comai received honoraria from Novartis, Hansa Biopharma, and Alexion. Additionally, she is a part of the Biotest Advisory Board, for which she receives payments. Paolo Cravedi is supported by the NIH award R01 DK123234 and has received research funding from Chinook Therapeutics. Leonardo V. Riella is supported by the NIH award R01 AI143887 and has received research funding for unrelated projects from Visterra, Caredx, AstraZeneca, Natera, and Bristol-Meyers-Squibb. All remaining authors have nothing to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The kidney solid organ response test (kSORT) has been investigated for the prediction of acute rejection in kidney transplant recipients with conflicting results. We aimed to investigate if the kSORT assay score is associated with rejection or immune quiescence., Methods: The blinded association between rejection and kSORT > 9 were investigated. Optimization of kSORT prediction was evaluated after unblinding to determine the optimal prediction cutoff value of kSORT score. Additionally, the predictive capability of the kSORT gene set was assessed using blinded normalized gene expression data from microarray (Affymetrix) and qPCR assays., Results: Of the 95 blood samples analyzed, 18 patients had blood samples before transplant, 77 patients after transplant and 71 had clinically indicated biopsies of which 15 biopsies showed acute rejection and 16 showed chronic active antibody-mediated rejection. When 31 patients with rejection were compared to the remaining 64 patients, positive predictive value (PPV) was 54.29% and negative predictive value (NPV) was 75% when stratified using a kSORT score > 9, and PPV was 57.89% and NPV was 78.95% when stratified using a kSORT score > 5. Using the kSORT assay for detection of rejection showed an area under the curve value of 0.71. Microarray data improved prediction accuracy with PPV of 53% and NPV of 84% compared to qPCR results (PPV and NPV were 36% and 66%), respectively., Conclusions: The kSORT assay has the potential to be used as a predictive tool for active rejection and/or immune quiescence, but additional studies will be useful in improving and refining the kSORT assay, in particular the prediction algorithm., Competing Interests: J.L., T.K.B., and R.W. are employees of Immucor Inc., which owns the rights to kSORT. The other authors declare no conflicts of interest. E.A. received research grants from Immucor and CareDx and served on the advisory boards of Immucor, CareDx, and Transplant Genomics., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Machine learning (ML) models have recently shown potential for predicting kidney allograft outcomes. However, their ability to outperform traditional approaches remains poorly investigated. Therefore, using large cohorts of kidney transplant recipients from 14 centers worldwide, we developed ML-based prediction models for kidney allograft survival and compared their prediction performances to those achieved by a validated Cox-Based Prognostication System (CBPS). In a French derivation cohort of 4000 patients, candidate determinants of allograft failure including donor, recipient and transplant-related parameters were used as predictors to develop tree-based models (RSF, RSF-ERT, CIF), Support Vector Machine models (LK-SVM, AK-SVM) and a gradient boosting model (XGBoost). Models were externally validated with cohorts of 2214 patients from Europe, 1537 from North America, and 671 from South America. Among these 8422 kidney transplant recipients, 1081 (12.84%) lost their grafts after a median post-transplant follow-up time of 6.25 years (Inter Quartile Range 4.33-8.73). At seven years post-risk evaluation, the ML models achieved a C-index of 0.788 (95% bootstrap percentile confidence interval 0.736-0.833), 0.779 (0.724-0.825), 0.786 (0.735-0.832), 0.527 (0.456-0.602), 0.704 (0.648-0.759) and 0.767 (0.711-0.815) for RSF, RSF-ERT, CIF, LK-SVM, AK-SVM and XGBoost respectively, compared with 0.808 (0.792-0.829) for the CBPS. In validation cohorts, ML models' discrimination performances were in a similar range of those of the CBPS. Calibrations of the ML models were similar or less accurate than those of the CBPS. Thus, when using a transparent methodological pipeline in validated international cohorts, ML models, despite overall good performances, do not outperform a traditional CBPS in predicting kidney allograft failure. Hence, our current study supports the continued use of traditional statistical approaches for kidney graft prognostication., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Brucellosis is significantly influenced by the interactions between the causative Brucella bacteria and host immunity. Recently identified cytokines have been described for their immunomodulatory effects in numerous inflammatory, autoimmune and infectious diseases. Some of them are new members of cytokine superfamilies, including several members of the IL-12 superfamily (IL-35, IL-39). The major purpose of the present study was to investigate the role of these new immunomodulatory cytokines in Brucella infections. The levels of IL-35 and IL-39 in the serum of 40 acute and 40 chronic brucellosis patients and 40 healthy controls were measured by ELISA. The mRNA levels of IL-35 and IL-39 in PBMCs were detected by RT-qPCR. Both IL-35 and IL-39 serum concentrations were significantly higher in healthy control subjects than in brucellosis patients, and IL-35 and IL-39 serum levels of chronic brucellosis patients were higher than those of acute cases. It was also found that the expression of Ebi3/IL-12A (IL-35 genes) and Ebi3/IL-23A (IL-39 genes) was upregulated in chronic brucellosis patients compared to healthy controls. Moreover, the expression of the Ebi3/IL-12A and Ebi3/IL-23A genes was lower in patients with acute brucellosis than in patients with chronic brucellosis. Overall, this study showed that IL-35 and IL-39 are positively correlated in brucellosis and significantly decreased during the disease. Significantly lower levels of IL-35 and IL-39 in acute brucellosis than in chronic brucellosis and healthy controls suggest that these cytokines may play a key role in suppressing the immune response to brucellosis and its progression to chronicity.

Rationale & Objective: Donor acute kidney injury (AKI) activates innate immunity, enhances HLA expression in the kidney allograft, and provokes recipient alloimmune responses. We hypothesized that injury and inflammation that manifested in deceased-donor urine biomarkers would be associated with higher rates of biopsy-proven acute rejection (BPAR) and allograft failure after transplantation., Study Design: Prospective cohort., Setting & Participants: 862 deceased donors for 1,137 kidney recipients at 13 centers., Exposures: We measured concentrations of interleukin 18 (IL-18), kidney injury molecule 1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) in deceased donor urine. We also used the Acute Kidney Injury Network (AKIN) criteria to assess donor clinical AKI., Outcomes: The primary outcome was a composite of BPAR and graft failure (not from death). A secondary outcome was the composite of BPAR, graft failure, and/or de novo donor-specific antibody (DSA). Outcomes were ascertained in the first posttransplant year., Analytical Approach: Multivariable Fine-Gray models with death as a competing risk., Results: Mean recipient age was 54 ± 13 (SD) years, and 82% received antithymocyte globulin. We found no significant associations between donor urinary IL-18, KIM-1, and NGAL and the primary outcome (subdistribution hazard ratio [HR] for highest vs lowest tertile of 0.76 [95% CI, 0.45-1.28], 1.20 [95% CI, 0.69-2.07], and 1.14 [95% CI, 0.71-1.84], respectively). In secondary analyses, we detected no significant associations between clinically defined AKI and the primary outcome or between donor biomarkers and the composite outcome of BPAR, graft failure, and/or de novo DSA., Limitations: BPAR was ascertained through for-cause biopsies, not surveillance biopsies., Conclusions: In a large cohort of kidney recipients who almost all received induction with thymoglobulin, donor injury biomarkers were associated with neither graft failure and rejection nor a secondary outcome that included de novo DSA. These findings provide some reassurance that centers can successfully manage immunological complications using deceased-donor kidneys with AKI., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Allograft biopsies with lesions of Antibody-Mediated Rejection (ABMR) with Microvascular Inflammation (MVI) have shown heterogeneous etiologies and outcomes., Methods: To examine factors associated with outcomes in biopsies that meet histologic ABMR criteria, we retrospectively evaluated for-cause biopsies at our center between 2011 and 2017. We included biopsies that met the diagnosis of ABMR by histology, along with simultaneous evaluation for anti-Human Leukocyte Antigen (HLA) donor-specific antibodies (DSA). We evaluated death-censored graft loss (DCGL) and used a principal component analysis (PCA) approach to identify key predictors of outcomes., Results: Out of the histologic ABMR cohort (n = 118), 70 were DSA-positive ABMR, while 48 had no DSA. DSA(+)ABMR were younger and more often female recipients. DSA(+)ABMR occurred significantly later post-transplant than DSA(-)ABMR suggesting time-dependence. DSA(+)ABMR had higher inflammatory scores (i,t), chronicity scores (ci, ct) and tended to have higher MVI scores. Immunodominance of DQ-DSA in DSA(+)ABMR was associated with higher i+t scores. Clinical/histologic factors significantly associated with DCGL after biopsy were inputted into the PCA. Principal component-1 (PC-1), which contributed 34.8% of the variance, significantly correlated with time from transplantation to biopsy, ci/ct scores and DCGL. In the PCA analyses, i, t scores, DQ-DSA, and creatinine at biopsy retained significant correlations with GL-associated PCs., Conclusions: Time from transplantation to biopsy plays a major role in the prognosis of biopsies with histologic ABMR and MVI, likely due to ongoing chronic allograft injury over time., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Among patients with COVID-19, kidney transplant recipients (KTRs) have poor outcomes compared with non-KTRs. To provide insight into management of immunosuppression during acute illness, we studied immune signatures from the peripheral blood during and after COVID-19 infection from a multicenter KTR cohort., Methods: We ascertained clinical data by chart review. A single sample of blood was collected for transcriptome analysis. Total RNA was poly-A selected and RNA was sequenced to evaluate transcriptome changes. We also measured cytokines and chemokines of serum samples collected during acute infection., Results: A total of 64 patients with COVID-19 in KTRs were enrolled, including 31 with acute COVID-19 (<4 weeks from diagnosis) and 33 with post-acute COVID-19 (>4 weeks postdiagnosis). In the blood transcriptome of acute cases, we identified genes in positive or negative association with COVID-19 severity scores. Functional enrichment analyses showed upregulation of neutrophil and innate immune pathways but downregulation of T cell and adaptive immune activation pathways. This finding was independent of lymphocyte count, despite reduced immunosuppressant use in most KTRs. Compared with acute cases, post-acute cases showed "normalization" of these enriched pathways after 4 weeks, suggesting recovery of adaptive immune system activation despite reinstitution of immunosuppression. Analysis of the non-KTR cohort with COVID-19 showed significant overlap with KTRs in these functions. Serum inflammatory cytokines followed an opposite trend ( i.e. , increased with disease severity), indicating that blood lymphocytes are not the primary source., Conclusions: The blood transcriptome of KTRs affected by COVID-19 shows decreases in T cell and adaptive immune activation pathways during acute disease that, despite reduced immunosuppressant use, associate with severity. These pathways show recovery after acute illness., (Copyright © 2022 by the American Society of Nephrology.)

With the development of novel prognostic tools derived from omics technologies, transplant medicine is entering the era of precision medicine. Currently, there are no established predictive biomarkers for posttransplant kidney function. A total of 270 deceased donor pretransplant kidney biopsies were collected and posttransplant function was prospectively monitored. This study first assessed the utility of pretransplant gene expression profiles in predicting 24-month outcomes in a training set (n = 174). Nearly 600 differentially expressed genes were associated with 24-month graft function. Grafts that progressed to low function at 24 months exhibited upregulated immune responses and downregulated metabolic processes at pretransplantation. Using penalized logistic regression modeling, a 55 gene model area under the receiver operating curve (AUROC) for 24-month graft function was 0.994. Gene expression for a subset of candidate genes was then measured in an independent set of pretransplant biopsies (n = 96) using quantitative polymerase chain reaction. The AUROC when using 13 genes with three donor characteristics (age, race, body mass index) was 0.821. Subsequently, a risk score was calculated using this combination for each patient in the validation cohort, demonstrating the translational feasibility of using gene markers as prognostic tools. These findings support the potential of pretransplant transcriptomic biomarkers as novel instruments for improving posttransplant outcome predictions and associated management., (© 2022 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Characterization of anti-HLA versus anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) immune globulin isotypes in organ transplant recipients after coronavirus disease 2019 (COVID-19) infection has not been reported. We aimed to determine changes in anti-HLA antibodies in renal transplant patients with COVID-19 and compare the immunoglobulin and epitope-binding pattern versus anti-SARS-CoV-2 antibodies., Methods: This is a cross-sectional study of 46 kidney transplant recipients including 21 with longitudinal sampling. Using a semi-quantitative multiplex assay, we determined immunoglobulin (Ig) M, IgA, IgG, and IgG1-2-3-4 antibodies against Class I and Class II HLA, and 5 SARS-CoV-2 epitopes including the nucleocapsid protein and multiple regions of the spike protein., Results: Fourteen of 46 (30%) patients had donor-specific anti-HLA antibodies (donor-specific antibody [DSA]), 12 (26%) had non-DSA anti-HLA antibodies and 45 (98%) had anti-SARS-CoV-2 antibodies. Most DSAs targeted HLA-DQ (71%), with a dominant IgG isotype and IgG1 subtype prevalence (93%), and/or IgG3 (64%), followed by IgG2 (36%). Comparatively, there was a higher prevalence of IgA (85% versus 14%, P = 0.0001) and IgM (87%, versus 36%, P = 0.001) in the anti-SARS-CoV-2 antibody profile, when compared to DSAs, respectively. Anti-SARS-CoV-2 antibody profile was characterized by increased prevalence of IgM and IgA, when compared to DSAs. The median calculated panel reactive antibody before COVID-19 diagnosis (24%) tended to decrease after COVID-19 diagnosis (10%) but it was not statistically significant ( P = 0.1)., Conclusions: Anti-HLA antibody strength and calculated panel reactive antibody in kidney transplant recipients after COVID-19 do not significantly increase after infection. Although the IgG isotype was the dominant form in both HLA and SARS-CoV-2 antigens, the alloimmune response had a low IgA pattern, whereas anti-SARS-CoV-2 antibodies were high IgA/IgM., Competing Interests: J.S.M. has received honoraria from One Lambda, Inc./ThermoFisher, serves on the Qihan Biotech SAB, and has a family member who is employed by and has an equity interest in Genentech/Roche. E.A. has received research grant support from the National Institutes of Health (NIH), CareDx, Immucor and Advisory Board at CareDx, Immucor, Exosome, and Takeda. M.C.M. and P.C. have received research grant support from NIH National Institute of Allergy and Infectious Diseases (NIAID), ancillary mechanistic grant associated with Grant 3U01AI063594-17S1. P.A. has received research grant support from NIH NIAID, R25 AI147369. The other authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: In recent years there has been an increasing implementation of robotic technology in arthroplasty. Due to the unclear data situation the aim of this study was to analyze the learning curve for robotic technology in residency training., Methods: After its introduction, the first 351 consecutive robotic knee replacements were prospectively included in the study. Surgical times, preoperative and postoperative radiographs, intraoperatively recorded alignment data and complications were analyzed. Satisfaction, revision, and referral rates were determined in a 90-day follow-up survey. Data from the last 350 navigated total knee arthroplasties were analyzed as a historical control group., Results: A learning curve of between 3 and 53 procedures was identified, depending on the surgeon, with further reductions in time measured even after 1 year of use. The operative times of the navigated technique were achieved by all surgeons. With respect to precision (alignment outliers) and patient satisfaction rate, no learning curve was evident. Comparison between tutorial and non-tutorial surgery showed a 16-min increase in operating time, but no significant differences in precision, complications, and patient satisfaction rate., Conclusion: The study showed that there was a learning curve in terms of duration of surgery but not in terms of precision, complications, and patient satisfaction. Robotic tutorial surgery requires more time but provides the same outcome compared to experienced surgeons. Thus, the robotic surgical technique appears to be an excellent training tool in knee arthroplasty., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background and Objectives: There are no standardized benchmarks to measure productivity and compensation of transplant nephrologists in the United States, and consequently, criteria set for general nephrologists are often used., Design, Setting, Participants, & Measurements: A web-based survey was sent to 809 nephrologists who were members of the American Society of Transplantation to gather data on measures of productivity, compensation, and job satisfaction. Factors associated with higher total compensation and job satisfaction were examined., Results: Of 365 respondents, 260 were actively practicing in the United States and provided data on compensation. Clinical productivity was assessed variably, and although 194 (76%) had their work relative value units (wRVUs) reported to them, only 107 (44%) had an established RVU target. Two hundred thirty-four respondents (90%) had fixed base compensation, and 172 (66%) received a bonus on the basis of clinical workload (68%), academic productivity (31%), service (32%), and/or teaching responsibility (31%). Only 127 respondents (49%) filled out time studies, and 92 (35%) received some compensation for nonbillable transplant activity. Mean total compensation (base salary and bonus) was $274,460±$91,509. The unadjusted mean total compensation was higher with older age and was higher for men; Hispanic and White respondents; adult care transplant nephrologists; residents of the western United States; US medical school graduates; nonuniversity hospital employees; and those with an administrative title, higher academic rank, and a higher number of years in practice. Two hundred and nine respondents (80%) thought their compensation was unfair, and 180 (70%) lacked a clear understanding of how they were compensated. One hundred forty-five respondents (55%) reported being satisfied or highly satisfied with their job. Job satisfaction was greater among those with higher amounts of compensation and US medical school graduates., Conclusions: We report significant heterogeneity in the assessment of productivity and compensation for transplant nephrologists and the association of compensation with job satisfaction., (Copyright © 2022 by the American Society of Nephrology.)

Coronavirus disease 2019 (COVID-19) has clinical manifestations ranging from mild symptoms to respiratory failure, septic shock, and multi-organ failure. Lymphocytes are divided into different subtypes based on their cytokine production pattern. In this study, we investigated the role of cytokine expressions of CD4 + T (T helper [Th]1, Th2, Th17, Th22) and CD8 + T cell subtypes (T cytotoxic [Tc]1, Tc2, Tc17, Tc22) in the pathogenesis of COVID-19. Peripheral blood mononuclear cells (PBMCs) were extracted with Ficoll by density gradient centrifugation from blood samples of 180 COVID-19 patients (children and adults) and 30 healthy controls. PBMCs were stimulated with PMA and Ionomycin and treated with Brefeldin A in the fourth hour, and a 10-colored monoclonal antibody panel was evaluated at the end of the sixth hour using flow cytometry. According to our findings, the numbers of Th22 (CD3 + , CD4 + , and interleukin [IL]-22 + ) and Tc22 (CD3 + , CD8 + , IL-22 + ) cells increased in adult patients regardless of the level of pneumonia (mild, severe, or symptom-free) as compared with healthy controls ( p  < 0.05). In addition, the number of Tc17 (CD3 + , CD8 + , and IL-17A + ) cells increased in low pneumonia and severe pneumonia groups compared with the healthy controls ( p  < 0.05). Both IL-22 and IL-17A production decreased during a follow-up within 6 weeks of discharge. Our findings suggest that the increase in only IL-22 expressed Tc22 cells in the 0-12 age group with a general symptom-free course and higher levels of Th22 and Tc22 in uncomplicated adult cases may indicate the protective effect of IL-22. On the contrary, the association between the severity of pneumonia and the elevation of Tc17 cells in adults may reveal the damaging effect of IL-22 when it is co-expressed with IL-17.

COVID-19 is a disease characterized by acute respiratory failure and is a major health problem worldwide. Here, we aimed to investigate the role of CD39 expression in Treg cell subsets in COVID-19 immunopathogenesis and its relationship to disease severity. One hundred and ninety COVID-19 patients (juveniles, adults) and 43 volunteers as healthy controls were enrolled in our study. Flow cytometric analysis was performed using a 10-color monoclonal antibody panel from peripheral blood samples. In adult patients, CD39 + Tregs increased with disease severity. In contrast, CD39 + Tregs were decreased in juvenile patients in an age-dependent manner. Overall, our study reveals an interesting profile of CD39-expressing Tregs in adult and juvenile cases of COVID-19. Our results provide a better understanding of the possible role of Tregs in the mechanism of immune response in COVID-19 cases., (© 2022 Wiley Periodicals LLC.)

Background: Acute kidney injury (AKI) in deceased donors is not associated with graft failure (GF). We hypothesize that hemodynamic AKI (hAKI) comprises the majority of donor AKI and may explain this lack of association., Methods: In this ancillary analysis of the Deceased Donor Study, 428 donors with available charts were selected to identify those with and without AKI. AKI cases were classified as hAKI, intrinsic (iAKI), or mixed (mAKI) based on majority adjudication by three nephrologists. We evaluated the associations between AKI phenotypes and delayed graft function (DGF), 1-year eGFR and GF. We also evaluated differences in urine biomarkers among AKI phenotypes., Results: Of the 291 (68%) donors with AKI, 106 (36%) were adjudicated as hAKI, 84 (29%) as iAKI and 101 (35%) as mAKI. Of the 856 potential kidneys, 669 were transplanted with 32% developing DGF and 5% experiencing GF. Median 1-year eGFR was 53 (IQR: 41-70) ml/min/1.73m2. Compared to non-AKI, donors with iAKI had higher odds DGF [aOR (95%CI); 4.83 (2.29, 10.22)] and had lower 1-year eGFR [adjusted B coefficient (95% CI): -11 (-19, -3) mL/min/1.73 m2]. hAKI and mAKI were not associated with DGF or 1-year eGFR. Rates of GF were not different among AKI phenotypes and non-AKI. Urine biomarkers such as NGAL, LFABP, MCP-1, YKL-40, cystatin-C and albumin were higher in iAKI., Conclusion: iAKI was associated with higher DGF and lower 1-year eGFR but not with GF. Clinically phenotyped donor AKI is biologically different based on biomarkers and may help inform decisions regarding organ utilization., Competing Interests: The authors have declared that no competing interests exist.

Cellulitis is one of the most important troubling complications of breast cancer treatment. Therefore, elucidating the risk factors for cellulitis in patients that have undergone breast cancer treatment is crucial. This is a retrospective medical record study among 523 patients who had received breast cancer treatment and were referred to the Lymphedema Clinic. Data on age, height, weight, BMI (body mass index), education level, arm dominance, history of previous surgery, axillary lymph node dissection, radiotherapy, and chemotherapy were noted. The time between operation and onset of lymphedema, duration of lymphedema, history of cellulitis, and number of cellulitis attacks were recorded. Circumference measurements were taken at four points on the upper limb. Univariate analysis showed that longer duration of lymphedema, larger circumference of the unaffected arm and larger circumference of the arm with lymphedema were associated with higher risk of cellulitis (p=0.008, p=0.007, p< 0.001, respectively). The incidence of cellulitis was higher in patients with lymphedema than patients who had no lymphedema (p< 0.001). Moreover, the frequency of cellulitis was higher in patients with lower education level (p=0.015). It was deter-mined that patients with cellulitis needed more compression garments (p< 0.001) and multi-layered bandage therapy (p< 0.001) than those without. Regression analysis revealed that presence of lymphedema (p=0.036), duration of lymphedema (p=0.048), radiotherapy (p=0.01) and educational level (0.019) are significantly associated with developing upper extremity cellulitis. It is important to consider these risk factors for the prevention and management of cellulitis in patients who undergo treatment for breast cancer. Early detection and treatment of lymphedema also remains essential for these patients., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright by International Society of Lymphology.)

Cellular therapies are engineered using foreign and synthetic protein sequences, such as chimeric antigen receptors (CARs). The frequently observed humoral responses to CAR T cells result in rapid clearance, especially after re-infusions. There is an unmet need to protect engineered cells from host-versus-graft rejection, particularly for the advancement of allogeneic cell therapies. Here, utilizing the immunoglobulin G (IgG) protease "IdeS," we programmed CAR T cells to defeat humoral immune attacks. IdeS cleavage of host IgG averted Fc-dependent phagocytosis and lysis, and the residual F(ab') 2 fragments remained on the surface, providing cells with an inert shield from additional IgG deposition. "Shield" CAR T cells efficiently cleaved cytotoxic IgG, including anti-CAR antibodies, detected in patient samples and provided effective anti-tumor activity in the presence of anti-cell IgG in vivo. This technology may be useful for repeated human infusions of engineered cells, more complex engineered cells, and expanding widespread use of "off-the-shelf" allogeneic cellular therapies., Competing Interests: Declaration of interests MSKCC has filed for patent protection for D.A.S., M.M.D., and L.P. for work related to this paper. D.A.S. has an equity interest in, consults for, or is on the Board of Sellas Life Sciences, Pfizer, Oncopep, Actinium, Co-Immune, Eureka, Repertoire, Sapience, Iovance, and Arvinas. J.H.P. receives funding from the Conquer Cancer Foundation of ASCO, a Leukemia and Lymphoma Society Career Development Grant, the Geoffrey Beene Cancer Foundation, a National Comprehensive Cancer Center Young Investigator Award, and an American Society of Hematology Scholar Junior Faculty Award. J.H.P. has consulted and provided an advisory role for Amgen, Novartis, Kite Pharma, Incyte, Allogene, Autolus, Intellia, Artiva, AstraZeneca, Pfizer, Takeda, and Servier. E.L.S. received funding from NCI K08 CA241400-02. E.L.S. has licensed patents and royalties with BMS, as well as consulting and receiving research funding. E.L.S. has consulted for Fate Therapeutics and Chimeric Therapeutics., (Copyright © 2021 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Kidney allograft failure is a common cause of end-stage renal disease. We aimed to develop a dynamic artificial intelligence approach to enhance risk stratification for kidney transplant recipients by generating continuously refined predictions of survival using updates of clinical data., Methods: In this observational study, we used data from adult recipients of kidney transplants from 18 academic transplant centres in Europe, the USA, and South America, and a cohort of patients from six randomised controlled trials. The development cohort comprised patients from four centres in France, with all other patients included in external validation cohorts. To build deeply phenotyped cohorts of transplant recipients, the following data were collected in the development cohort: clinical, histological, immunological variables, and repeated measurements of estimated glomerular filtration rate (eGFR) and proteinuria (measured using the proteinuria to creatininuria ratio). To develop a dynamic prediction system based on these clinical assessments and repeated measurements, we used a Bayesian joint models-an artificial intelligence approach. The prediction performances of the model were assessed via discrimination, through calculation of the area under the receiver operator curve (AUC), and calibration. This study is registered with ClinicalTrials.gov, NCT04258891., Findings: 13 608 patients were included (3774 in the development cohort and 9834 in the external validation cohorts) and contributed 89 328 patient-years of data, and 416 510 eGFR and proteinuria measurements. Bayesian joint models showed that recipient immunological profile, allograft interstitial fibrosis and tubular atrophy, allograft inflammation, and repeated measurements of eGFR and proteinuria were independent risk factors for allograft survival. The final model showed accurate calibration and very high discrimination in the development cohort (overall dynamic AUC 0·857 [95% CI 0·847-0·866]) with a persistent improvement in AUCs for each new repeated measurement (from 0·780 [0·768-0·794] to 0·926 [0·917-0·932]; p<0·0001). The predictive performance was confirmed in the external validation cohorts from Europe (overall AUC 0·845 [0·837-0·854]), the USA (overall AUC 0·820 [0·808-0·831]), South America (overall AUC 0·868 [0·856-0·880]), and the cohort of patients from randomised controlled trials (overall AUC 0·857 [0·840-0·875])., Interpretation: Because of its dynamic design, this model can be continuously updated and holds value as a bedside tool that could refine the prognostic judgements of clinicians in everyday practice, hence enhancing precision medicine in the transplant setting., Funding: MSD Avenir, French National Institute for Health and Medical Research, and Bettencourt Schueller Foundation., Competing Interests: Declaration of interests AL holds shares in Cibiltech, a company that develops software and IT solutions. C-SC is affiliated with Deep Learning in Medicine and Genomics, DNAnexus. All other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)