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Fibronectin glomerulopathy (FG) is caused by fibronectin 1 ( FN1 ) gene mutations. A renal biopsy was performed on a 4-year-old girl with incidentally discovered proteinuria (150 mg/dL); her family history of renal disease was negative. Markedly enlarged glomeruli (mean glomerular diameter: 196 μm; age-matched controls: 140 μm), α-SMA-positive and Ki-67-positive mesangial cell proliferation (glomerular proliferation index 1.76), the mild expansion of mesangial areas, no immune or electron-dense deposits, normal glomerular basement membrane, and diffusely effaced foot processes were observed. Genetic testing identified a de novo heterozygous mutation (Gly417Val) in the collagen-binding site of the FN II-2 domain, prompting fibronectin immunostaining. Strong mesangial positivity was noted, hence FG was diagnosed. The follow-up period of 29 months revealed nephrotic range proteinuria, intermittent microhematuria, glomerular hyperfiltration, and preserved renal function. The biopsy features of early childhood-onset FG were compared to a case of FG with a lobular pattern diagnosed in a 44-year-old patient with undulating proteinuria, microhematuria, hypertension known for a year, and a positive family history. Early childhood-onset FG was characterized by glomerular enlargement, mesangial proliferation, and no changes that suggested fibronectin deposition disease. In summary, the novel aspects of the case were that the mutation was located at the collagen-binding site of the FN1 gene, not identified earlier, and the histologic spectrum of FG was expanded by the observed mesangial proliferative pattern and striking glomerulomegaly. Now, FG should also be considered among the monogenic causes of proteinuric kidney diseases in pediatric nephrology practice.

Fermentation is critical for producing high-quality cocoa, yet its kinetics and resulting chemical and sensory outcomes are poorly understood and thus difficult to manage. Cocoa sweatings (CS), the liquid runoff produced early during fermentation and typically drained off, may beneficially affect fermentation outcome when added back into the fermenting mass. Here, we report how back-addition of CS affects composition and sensory perception of roasted cocoa liquor after 5, 6, and 7 days of fermentation. Cocoa liquor (= 100% chocolate) made from beans fermented for 5 days with the addition of CS were similar in sensory perception to those fermented for 7 days without added CS. Twenty-one flavor compounds showed similar patterns to the sensory results: In the beans fermented with CS, these compounds remained at similar levels after 5, 6, and 7 days of fermentation, while the same compounds significantly changed in the samples fermented conventionally, without CS addition. These results suggest a link between changes in flavor composition and sensory differences in roasted cocoa. Future work is needed to reveal the mechanism of flavor stabilization throughout fermentation resulting from the back-addition of CS. PRACTICAL APPLICATION: Roasted cocoa liquor fermented with cocoa sweating (CS) is sensorily similar when fermented for 5 or 7 days and produces cocoa that is sensorily similar to traditionally fermented cocoa in shorter time (5 days vs. 7 days). The addition of CS seems to stabilize 21 flavor compounds throughout fermentation mimicking changes in sensory perception. The back-addition of CS could help standardize cocoa fermentation as indicated by more consistent temperature evolution., (© 2024 The Author(s). Journal of Food Science published by Wiley Periodicals LLC on behalf of Institute of Food Technologists.)

Several molecular mismatch assessment approaches exist, but data on their combined use are limited. In this study, we aimed to define distinct risk groups for rejection based on the combination of three molecular mismatch assessment approaches (i.e., eplet mismatch count, the number of highly immunogenic eplets and PIRCHE-II score) in 439 consecutive immunological standard risk transplantations. For each molecular mismatch assessment approach, ROC analyses were used to define cut-offs for prediction of (sub) clinical rejection according to Banff 2019 classification within the first year post-transplant as a reference. If all three scores were below the cut-off, the patient was assigned to the low-risk group (19% of patients); if all three scores were above the cut-off, the patient was assigned to the high-risk group (21% of patients). The one-year incidence of (sub) clinical rejection was 12% in the low-risk group and 33% in the high-risk group (p = 0.003). Internal validation of the assigned risk groups for prediction of other outcomes revealed a high consistency: clinical rejection (6% vs. 24%; p = 0.004), ATG-treated rejection (1% vs. 16%; p < 0.001) and development of de novo HLA-DSA at 5 years post-transplant (6% vs. 25%; p = 0.003). The molecular mismatch risk group was an independent predictor for (sub) clinical rejection (high-risk vs. low-risk: hazard ratio 3.11 [95%-CI 1.50-6.45]; p = 0.002). We conclude that combining molecular mismatch approaches allows us to distinguish low- and high-risk groups among standard renal allograft recipients. Independent validation in other patient populations and different ethnicities is required., (© 2024 The Author(s). HLA: Immune Response Genetics published by John Wiley & Sons Ltd.)

Background: Recent evidence highlights the pivotal role of natural killer (NK) cells in allograft rejection., Methods: We explored associations of missing self and gene polymorphisms determining the phenotype and/or functionality of NK cells with microvascular inflammation (MVI) in a single-center cohort of 507 consecutive kidney transplant recipients. Patients were genotyped for killer cell Ig-like receptors and polymorphisms in 4 selected genes (FCGR3AV/F158 [rs396991], KLRC2wt/del, KLRK1HNK/LNK [rs1049174], and rs9916629-C/T)., Results: MVI was detected in 69 patients (13.6%). In a proportional odds model, the KLRC2del/del variant reduced MVI risk (odds ratio [OR] 0.26; 95% confidence interval [CI], 0.05-0.93; P = 0.037) independent of donor-specific antibodies, HLA class II eplet mismatch, and number of biopsies. Conversely, missing self (OR 1.40; 95% CI, 1.08-1.80; P = 0.011) and the rs9916629 T/T gene variant increased the risk (OR 1.70; 95% CI, 1.08-2.68; P = 0.021). Graft loss tended to be more frequent among patients with missing self ≥2 (hazard ratio 1.97; 95% CI, 0.89-4.37; P = 0.097), without influence on estimated glomerular filtration trajectories. FCGR3A variants were associated with MVI only in patients with preformed and/or de novo donor-specific antibodies (OR 4.14; 95% CI, 0.99-17.47; P = 0.052)., Conclusions: Missing self and NK-cell genetics may contribute to MVI, underscoring the important role of NK cells in transplant rejection., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Hepatitis E virus (HEV) infection, one of the most common forms of hepatitis worldwide, is often associated with extrahepatic, particularly renal, manifestations. However, the underlying mechanisms are incompletely understood. Here, we report the development of a de novo immune complex-mediated glomerulonephritis (GN) in a kidney transplant recipient with chronic hepatitis E. Applying immunostaining, electron microscopy, and mass spectrometry after laser-capture microdissection, we show that GN develops in parallel with increasing glomerular deposition of a non-infectious, genome-free and non-glycosylated HEV open reading frame 2 (ORF2) capsid protein. No productive HEV infection of kidney cells is detected. Patients with acute hepatitis E display similar but less pronounced deposits. Our results establish a link between the production of HEV ORF2 protein and the development of hepatitis E-associated GN in the immunocompromised state. The formation of glomerular IgG-HEV ORF2 immune complexes discovered here provides a potential mechanistic explanation of how the hepatotropic HEV can cause variable renal manifestations. These findings directly provide a tool for etiology-based diagnosis of hepatitis E-associated GN as a distinct entity and suggest therapeutic implications., (© 2024. The Author(s).)

Dark chocolate produced on equipment used to manufacture milk chocolate can contain milk due to cross-contact. This study evaluated the use of dry cleaning methods for removing milk chocolate residue from a butterfly or ball valve attached to a stainless steel pipe and from pilot-scale equipment used in chocolate manufacture. Milk-free dark chocolate (40 °C) was pumped through a milk chocolate-contaminated valve/pipe assembly after no cleaning, use of a pig purging treatment, or a 40 °C cocoa butter flush. Dark chocolate samples were collected at 7-sec intervals. Treatments investigated for the removal of residual milk chocolate from a conche and a ball mill included no cleaning, a 40 °C cocoa butter rinse, and wet cleaning. After cleaning, three batches of dark chocolate (40 °C) were processed in the ball mill and conche, and each batch was collected. Milk chocolate was processed on a 3-roll refiner, followed by push-through with dark chocolate (∼9 kg) with 0.3 kg samples collected at 5-min intervals. Dark chocolate samples were analyzed for milk concentrations by ELISA. Trials and analyses were completed in triplicate. Dark chocolate push-through alone resulted in milk concentrations ≥4,500 µg/g in samples obtained from the contaminated valve/pipe combinations within the first few seconds of collection, and ≥16.2 kg of dark chocolate was needed to obtain milk concentrations below the ELISA LOQ (2.5 µg/g). A pig purging treatment of the ball valve/pipe assembly resulted in milk concentrations below the ELISA LOQ. A cocoa butter flush of the butterfly valve/pipe decreased initial milk concentrations, but milk was detected until ≥18.7 kg dark chocolate purge. Milk concentrations in first batches of dark chocolate processed in a ball mill and conche without cleaning were ≥17,000 µg/g while the use of a cocoa butter rinse reduced milk levels in dark chocolate by ≥89%. Some dry cleaning treatments were effective at reducing levels of milk in dark chocolate due to cross-contact., (Published by Elsevier Inc.)

BK polyomavirus (BKPyV) remains a significant challenge after kidney transplantation. International experts reviewed current evidence and updated recommendations according to Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). Risk factors for BKPyV-DNAemia and biopsy-proven BKPyV-nephropathy include recipient older age, male sex, donor BKPyV-viruria, BKPyV-seropositive donor/-seronegative recipient, tacrolimus, acute rejection, and higher steroid exposure. To facilitate early intervention with limited allograft damage, all kidney transplant recipients should be screened monthly for plasma BKPyV-DNAemia loads until month 9, then every 3 mo until 2 y posttransplant (3 y for children). In resource-limited settings, urine cytology screening at similar time points can exclude BKPyV-nephropathy, and testing for plasma BKPyV-DNAemia when decoy cells are detectable. For patients with BKPyV-DNAemia loads persisting >1000 copies/mL, or exceeding 10 000 copies/mL (or equivalent), or with biopsy-proven BKPyV-nephropathy, immunosuppression should be reduced according to predefined steps targeting antiproliferative drugs, calcineurin inhibitors, or both. In adults without graft dysfunction, kidney allograft biopsy is not required unless the immunological risk is high. For children with persisting BKPyV-DNAemia, allograft biopsy may be considered even without graft dysfunction. Allograft biopsies should be interpreted in the context of all clinical and laboratory findings, including plasma BKPyV-DNAemia. Immunohistochemistry is preferred for diagnosing biopsy-proven BKPyV-nephropathy. Routine screening using the proposed strategies is cost-effective, improves clinical outcomes and quality of life. Kidney retransplantation subsequent to BKPyV-nephropathy is feasible in otherwise eligible recipients if BKPyV-DNAemia is undetectable; routine graft nephrectomy is not recommended. Current studies do not support the usage of leflunomide, cidofovir, quinolones, or IVIGs. Patients considered for experimental treatments (antivirals, vaccines, neutralizing antibodies, and adoptive T cells) should be enrolled in clinical trials., Competing Interests: C.N.K. received grants from Biohope and funding for serving on scientific advisory boards for Roche Diagnostics. N.K. received consulting fees, honoraria, and travel support from Astellas, AstraZeneca, Biotest, CSL Behring, Chiesi, Gilead, Hansa, Merck, Sharp and Dohme, Glasgow Smith Kline, Neovii, Novartis Pharma, Roche, Sanofi, Sandoz, and Takeda. P.R. received consulting fees from Allovir. M.S. received consulting fees from Merck, Sharp and Dohme, Moderna, and Biotest and honoraria from Biotest, Novartis, Merck, Sharp and Dohme, Takeda, and Qiagen. P.C. received honoraria from Atara Bio and Pierre Fabre Pharma. H.T.S. received grants from Biohope, Merck Sharp and Dohme, Natera, Novartis, and Takeda; honoraria from Alexion, CareDx, EMS Pharmaceuticals, Natera, and Takeda; and consulting fees and travel support from Takeda. D.C.B. received grants from CareDx and VeraTherapeutics and consulting fees from CareDx, Medeor Therapeutics, Natera, Sanofi, and Vera Therapeutics. L.P. received grants from Alexion, Chiesi, and Novartis; consulting fees from Alnylam and Chiesi; and travel support from Alexion. H.H.H. received consulting fees from AICuris, Allovir, Moderna, VeraTX, and Roche and honoraria from VeraTX, Takeda, Biotest, and Gilead. The other authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Nowadays, there is insufficient evidence for the recommendation of management patients with a primary membranoproliferative glomerulonephritis (MPGN). A better understanding of the pathogenesis has led to the reclassification of primary MPGN and distinction into the two main entities of either primary immune complex-MPGN or C3 glomerulopathy. Both entities share overlapping pathophysiological features with complement alternative pathway (AP) dysregulation. Iptacopan is an oral inhibitor of the complement factor B that effectively blocks the complement AP., Case Presentation: We report the first successful treatment of a 47-year-old man suffering from a primary immune complex-MPGN with iptacopan. So far established immunosuppressive therapies with prednisone and mycophenolate mofetil failed to control the current flare of the disease, mainly presenting with impaired kidney function and proteinuria within the nephrotic range. However, 3 months after starting the treatment with iptacopan urine protein-creatinine ratio decreased impressively to a level of 100-150 mg/mmol. Thereafter, low-level proteinuria and kidney function remained stable during follow-up. Do date, the treatment with iptacopan is continued as a monotherapy and is well tolerated., Conclusion: To the best of our knowledge, this is the first case report which suggests that iptacopan may be an interesting treatment option for primary immune complex-MPGN., Competing Interests: The authors of this manuscript declare no conflicts of interest as described by Karger Case Reports in Nephrology and Dialysis. This study received funding from Novartis Pharma AG, Basel, Switzerland as indicated within the funding section., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Scope: A study is conducted to determine the anti-inflammatory effects of cocoa and polyphenol-rich cocoa fractions in the dextran sulfate sodium (DSS)-induced mouse model of acute colonic inflammation., Methods and Results: Male C57BL/6J mice are treated with dietary cocoa powder, an extractable cocoa polyphenol fraction, or a non-extractable cocoa polyphenol fraction for 2 weeks prior to treatment with 2.5% DSS in the drinking water for 7 days to induce colonic inflammation. Cocoa treatment continues during the DSS period. Cocoa and/or cocoa fractions exacerbate DSS-induced weight loss and fail to mitigate DSS-induced colon shortening but do improve splenomegaly. Cocoa/cocoa fraction treatment fails to mitigate DSS-induced mRNA and protein markers of inflammation. Principal component analysis shows overlap between cocoa or cocoa fraction-treated mice and DSS-induced controls, but separation from mice not treated with DSS., Conclusion: The results suggest cocoa and cocoa polyphenols may not be useful in mitigating acute colonic inflammation., (© 2024 Wiley‐VCH GmbH.)

Over the last half-century, variable responses to sweetness have repeatedly been shown to fall into a small number of hedonic responses, implying that looking only at group means may can obfuscate meaningfully different response patterns. Comparative data for sourness is quite sparse, especially in adults. While increased liking with higher acid concentration has been reported for some children, in adults, sourness is classically assumed to be aversive, with a monotonic drop in liking with increasing sourness. Here, we test this assumption using a simple model system or experimental beverage in convenience samples of adults from the United States (increasing citric acid in water) and Italy (increasing citric acid in pear juice). Participants rated intensity and liking of sampled stimuli. For both cohorts, we find clear evidence of three distinct patterns of responses: a strong negative group where liking dropped with increased sourness, an intermediate group who showed a more muted drop in liking with more sourness, and a strong positive group where liking increased with more sourness. Strikingly, both cohorts showed similar proportions of response patterns, with ~63-70% in the strong negative group, and 11-12% in the strong positive group, suggesting these proportions may be stable across cultures. Notably, the three groups did not differ by age or gender. These data support the existence of different hedonic response profiles to sour stimuli in adults, once again highlighting the importance of looking at individual differences and potential consumer segments, rather than merely averaging hedonic responses across all individuals within a group., Competing Interests: 9. Conflict of Interest The authors declare no conflict of interest. Several of the authors have received consulting or speaking fees from various industrial clients in the food industry, but these organizations have no involvement with the work described here and they were not involved in study conception, design or interpretation, or the decision to publish these data.

Despite its importance as an undesirable food texture, the phenomenon of chalkiness remains understudied. Chalky sensations presumably arise from fine particulates found in foods, but semantic overlap with other common descriptors of small particles, like gritty or sandy, is unclear. Here, we compare the usage of Chalky with related descriptors, and determine the effect of particle size, concentration, and xanthan content on Chalky ratings in a model beverage. A 2 3 factorial design with starch particle size (D 90 = 33.8 and 64.6 µm), starch concentrations (10 and 20% w / v ), and xanthan content (0.075 and 0.15% w / v ) was used. Participants' salivary flow rate was also assessed. A multi-sip taste test was performed where naïve consumers (n = 82; 39% men, 60% women; age range = 18-79 years) rated the intensity of Chalky , Powdery , Gritty , Sandy , Mouthdrying , and Residual mouthcoating at 0, 30, and 60 s after each of three consecutive sips. All attribute ratings were highly correlated, with Chalky , Powdery , and Residual Mouthcoating being more closely correlated with each other than Gritty or Sandy . Although Chalky was still reported 60 s after consumption, no evidence of build-up was found with repeated sips. A larger size and higher concentration increased Chalky ratings, with the low-salivary-flow group reporting greater ratings for Chalky relative to the high-flow group. Our results suggest consumer percepts of small particles are overlapping but not entirely redundant. This suggests researchers and product developers should carefully distinguish between these descriptors when trying to understand consumer perception of food products containing fine particles.

The Teruel Orthorexia Scale (TOS) defines two related but distinct constructs: Orthorexia Nervosa (OrNe), a pathological fixation on a healthy diet, and Healthy Orthorexia (HeOr), an interest in a healthy diet independent of psychopathology. Here, we (a) assessed both types of Orthorexia in a large North American sample using the TOS and (b) explored if engaging in regular physical activity was associated with a greater risk of Orthorexia. A cohort of physically active adults ( n = 927; 41% men) completed the TOS, as well as the Rapid Assessment of Physical Activity (RAPA), to broadly assess aerobic physical activity level and participation in strength and/or flexibility training. As expected, scores for HeOr and OrNe differed between participants, with lower scores for Orthorexia Nervosa in our physically active non-clinical sample. Higher HeOr scores were associated with lower BMI, and this was true for both men and women. We also found that measures of Orthorexia were associated with self-reported physical activity: active adults reporting more aerobic physical activity had higher HeOr scores, with the most active men having the highest scores. Notably, adults who reported regular strength training had higher scores for both HeOr and OrNe, with men who strength trained showing higher OrNe scores than women. Here, those who participate in regular strength training are more likely to exhibit orthorexic behaviors, and this effect was more pronounced for men than women. Prior work has validated the TOS in young, primarily female samples of non-English speakers outside the United States: present data from an age-diverse, physically active, gender balanced sample support the use of TOS for measurement of Orthorexia Nervosa and Healthy Orthorexia in English speakers and suggest that more work is needed to assess potential gender differences in these constructs.

Background: Foods lower in saturated fat, sodium, and added sugars (ie, overconsumed dietary components) must have an acceptable flavor profile to promote intake., Objective: The aim of this research was to model the influence of using herbs/spices as flavor-enhancers when reducing overconsumed dietary components in commonly consumed foods and evaluate acceptance of these flavor-enhanced reformulations., Design: Ten leading sources of overconsumed dietary components were identified using the National Health and Nutrition Examination Survey 2015-2018 dietary data. These foods were reformulated to reduce overconsumed dietary components and herbs/spices were used to preserve acceptability. The influence of consumer adoption of the reformulated foods on intake of overconsumed dietary components was modeled using National Health and Nutrition Examination Survey data. Consumer acceptability of the reformulated recipes was assessed with blind taste testing., Participants/setting: Dietary data from adults aged 19 years and older (n = 9,812) included in the National Health and Nutrition Examination Survey 2015-2018 were used to identify foods for reformulation and model the potential influence of reformulation. The blind taste testing included 85 to 107 consumers per panel., Main Outcome Measures: Estimated daily change in total intake of saturated fat, sodium, added sugars, and energy with intake of the reformulated foods instead of the original foods. Consumer ratings of overall liking of the reformulated recipes vs the original recipes were assessed using standard 9-point hedonic scales., Statistical Analyses Performed: Descriptive statistics with use of survey procedures were used to model the influence of reformulated food adoption. Mixed effect models were used for analysis of the blind tasting data., Results: With intake of the reformulated foods, instead of the original versions, by 25% to 100% of current consumers, estimates suggest lowering of saturated fat (25% consumer adoption to 100% consumer adoption -2.9% to -11.4%, respectively), sodium (-3.2 to -11.5%, respectively), and added sugars (-0.5 to -2.7%, respectively) intake. The overall liking ratings for seven of the 10 reformulated foods were superior or at parity with the original foods., Conclusions: This proof-of-concept research suggests that using herbs/spices to create flavor-enhanced recipes lower in overconsumed dietary components has the potential to reduce intake and is acceptable to consumers., (Copyright © 2024 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.)

This study explores the use of food texture terms by adults in the northeastern United States. The purpose of the study was to compare the effect of food texture on food liking and texture term usage among age groups via two complementary online surveys that differed in the specific task given to participants. Survey 1 gathered common food items associated with 25 texture terms using open-ended questions from 345 participants (45% men, 55% women; age range = 20-79 years); it also collected liking scores for foods with these textures. Next, a new group of participants (n = 349, 46% men, 54% women; age range = 20-79 years) completed Survey 2, which asked them to match up to three texture terms to 32 different foods drawn from Survey 1, using a provided list of 35 texture terms. "Tough," "Chalky," and "Rubbery" had a negative impact on food liking scores while "Tender," "Juicy," and "Crispy" were associated with higher mean food liking scores. "Soft," "Crunchy," "Crispy," "Juicy," and "Greasy" were commonly used texture terms regardless of age. Within those aged 50-79 years, "Smooth," "Tender," "Crunchy," "Soft," "Moist," "Crispy," and "Creamy" were used more often while "Chalky," "Rough," "Mealy," "Foamy/Airy," "Gritty" were used less often. Our results identified commonly used texture terms and revealed differential usage in older and younger adults. These data deepen our understanding of the texture of foods in the modern food environment, highlighting how texture perception may vary with age., (© 2023 The Authors. Journal of Texture Studies published by Wiley Periodicals LLC.)

With the rapid advancement of cell-cultured meat processing technologies and regulations, commercialization of cell-cultured meat to market shelves requires the implementation of labeling that informs and protects consumers while ensuring economic competitiveness. In November 2022, the United States Food and Drug Administration (FDA) completed its first pre-market consultation of cell-cultured meat and did not question the safety of these products for human consumption. As of June 2023, commercialization of cell-cultured meat products has become a reality in the United States. To derive potential label terms and gain insight into how different stakeholders refer to these novel products, we analyzed 1,151 comments submitted to the 2021 U.S. Department of Agriculture's Food Safety and Inspection Services (USDA-FSIS) call on the labeling of cell-cultured meat and poultry. Our first aim was to systematically assess the nature of comments with regards to their length, cited references, and supplemental materials. In addition, we aimed to identify the most used terms to refer to these products through text analysis. We also asked how these analyses would vary by affiliation category and economic interest. Using the listed organizations for each comment, we first determined financial ties: 77 (7%) comments came from those with an economic interest, 12 (1%) of the comments did not have an identifiable economic interest, while for the remaining 1,062 (92%) comments economic interest could not be determined. We then grouped comments into affiliation categories. Cell-cultured meat companies and animal welfare non-profits had the highest median word count, whereas comments from the unknown affiliation category had the lowest. We found across all comments the predominantly mentioned potential label terms, in descending order, to be cultured meat, lab-grown meat, cultivated meat, cell-cultured meat, clean meat, and cell-based meat . While all label terms were discussed throughout overall submissions, percentages of comments mentioning each term differed between affiliation categories. Our findings suggest differences in how affiliation categories are discussing cell-cultured meat products for the US market. As a next step, the perception and acceptance of these terms must be evaluated to identify the optimal label term regarding the information and protection provided to consumers while ensuring economic competitiveness., 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., (Copyright © 2023 Failla, Hopfer and Wee.)

Significance Statement: This study is the first randomized controlled trial to investigate the clinical utility of a noninvasive monitoring biomarker in renal transplantation. Although urine CXCL10 monitoring could not demonstrate a beneficial effect on 1-year outcomes, the study is a rich source for future design of trials aiming to explore the clinical utility of noninvasive biomarkers. In addition, the study supports the use of urine CXCL10 to assess the inflammatory status of the renal allograft., Background: Urine CXCL10 is a promising noninvasive biomarker for detection of renal allograft rejection. The aim of this study was to investigate the clinical utility of renal allograft monitoring by urine CXCL10 in a randomized trial., Methods: We stratified 241 patients, 120 into an intervention and 121 into a control arm. In both arms, urine CXCL10 levels were monitored at three specific time points (1, 3, and 6 months post-transplant). In the intervention arm, elevated values triggered performance of an allograft biopsy with therapeutic adaptations according to the result. In the control arm, urine CXCL10 was measured, but the results concealed. The primary outcome was a combined end point at 1-year post-transplant (death-censored graft loss, clinical rejection between month 1 and 1-year, acute rejection in 1-year surveillance biopsy, chronic active T-cell-mediated rejection in 1-year surveillance biopsy, development of de novo donor-specific HLA antibodies, or eGFR <25 ml/min)., Results: The incidence of the primary outcome was not different between the intervention and the control arm (51% versus 49%; relative risk (RR), 1.04 [95% confidence interval, 0.81 to 1.34]; P = 0.80). When including 175 of 241 (73%) patients in a per-protocol analysis, the incidence of the primary outcome was also not different (55% versus 49%; RR, 1.11 [95% confidence interval, 0.84 to 1.47]; P = 0.54). The incidence of the individual end points was not different as well., Conclusions: This study could not demonstrate a beneficial effect of urine CXCL10 monitoring on 1-year outcomes (ClinicalTrials.gov&#95; NCT03140514 )., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology.)

Background: Biallelic mutations in LIG4 encoding DNA-ligase 4 cause a rare immunodeficiency syndrome manifesting as infant-onset life-threatening and/or opportunistic infections, skeletal malformations, radiosensitivity and neoplasia. LIG4 is pivotal during DNA repair and during V(D)J recombination as it performs the final DNA-break sealing step., Objectives: This study explored whether monoallelic LIG4 missense mutations may underlie immunodeficiency and autoimmunity with autosomal dominant inheritance., Methods: Extensive flow-cytometric immune-phenotyping was performed. Rare variants of immune system genes were analyzed by whole exome sequencing. DNA repair functionality and T-cell-intrinsic DNA damage tolerance was tested with an ensemble of in vitro and in silico tools. Antigen-receptor diversity and autoimmune features were characterized by high-throughput sequencing and autoantibody arrays. Reconstitution of wild-type versus mutant LIG4 were performed in LIG4 knockout Jurkat T cells, and DNA damage tolerance was subsequently assessed., Results: A novel heterozygous LIG4 loss-of-function mutation (p.R580Q), associated with a dominantly inherited familial immune-dysregulation consisting of autoimmune cytopenias, and in the index patient with lymphoproliferation, agammaglobulinemia, and adaptive immune cell infiltration into nonlymphoid organs. Immunophenotyping revealed reduced naive CD4 + T cells and low TCR-Vα7.2 + T cells, while T-/B-cell receptor repertoires showed only mild alterations. Cohort screening identified 2 other nonrelated patients with the monoallelic LIG4 mutation p.A842D recapitulating clinical and immune-phenotypic dysregulations observed in the index family and displaying T-cell-intrinsic DNA damage intolerance. Reconstitution experiments and molecular dynamics simulations categorize both missense mutations as loss-of-function and haploinsufficient., Conclusions: This study provides evidence that certain monoallelic LIG4 mutations may cause human immune dysregulation via haploinsufficiency., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Chocolate is a highly appreciated food that develops its characteristic flavors in large part during the roasting of cacao beans. Many functional classes have been noted for their importance to chocolate flavor, including volatile organic sulfur compounds (VSCs). Despite this, the effect of roasting on the concentration of VSCs has never been thoroughly assessed. Here, we studied the effects of roasting temperature, time, and cacao origin on the formation of VSCs. Twenty-seven 100% chocolate samples made from cacao from three different origins and roasted according to an I-optimal experimental design were analyzed by comprehensive gas chromatography with sulfur-selective detection (GCxGC-SCD). For two compounds, dimethyl disulfide and dimethyl trisulfide, the effects of roasting time, roasting temperature, and cacao origin were modelled using response surface methodology and semi-quantified relative concentration. Overall, roasting increased the number of sulfur-containing volatiles present in chocolate, with a total of 28 detected, far more than previously thought. Increased roasting time and especially roasting temperature were found to significantly increase the concentration of VSCs ( p < 0.05), while cacao origin effects were only seen for dimethyl disulfide ( p < 0.05). The identity of most VSCs remains tentative, and more research is needed to unravel the impact of these volatiles on flavor perception in chocolate.

Background: The use of small pediatric donors (age ≤ 5 years and body weight < 20kg) for adult transplant recipients is still regarded controversially in terms of early complications, long-term outcomes, and development of hyperfiltration injury due to body size mismatch., Objective: To investigate long-term outcomes of adult renal allograft recipients receiving a kidney from small pediatric donor (SPD) in terms of kidney function and early features of hyperfiltration injury such as histological changes and proteinuria., Design: Retrospective, single center study., Settings: Transplant center of the University Hospital of Basel, Switzerland., Patients: Adult renal allograft recipients receiving a kidney from a small pediatric donor at our center between 2005 and 2017., Methods: The outcome of 47 transplants from SPD were compared with 153 kidney transplants from deceased-standard criteria donors (SCD) occurring during the same time period. Incidence of clinical signs of hyperfiltration injury (eg, proteinuria) was investigated. According to our policy, surveillance biopsies were taken at 3 and 6 months post-transplant and were evaluated in terms of signs of hyperfiltration injury., Results: At a median follow-up of 2.3 years post-transplant, death-censored graft survival of SPD was comparable to transplants from SCD (94% vs 93%; P = .54). Furthermore, allograft function at last follow-up (estimated glomerular filtration rate-Modification of Diet in Renal Disease) was significantly higher in pediatric transplant (80 vs 55 ml/min/1.73 m 2 , P = .002). We found histological signs of early hyperfiltration injury in 55% of SPD. There was an equally low proteinuria in both groups during follow-up., Limitations: It is a single center and retrospective observational study with small sample size. The outcomes were investigated in a well-selected population of recipients with low body mass index, low immunological risk, and well-controlled hypertension and was not compared with equal selected group of recipients., Conclusions: Early histological and clinical signs of hyperfiltration injury in SPD is frequent. Despite the hyperfiltration injury, there is an equal allograft survival and even superior allograft function in SPD compared with SCD during follow-up. This observation supports the concept of high adaptive capacity of pediatric donor kidneys., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Membranous nephropathy (MN) is an antibody-mediated autoimmune disease characterized by glomerular immune complexes containing complement components. However, both the initiation pathways and the pathogenic significance of complement activation in MN are poorly understood. Here, we show that components from all three complement pathways (alternative, classical and lectin) are found in renal biopsies from patients with MN. Proximity ligation assays to directly visualize complement assembly in the tissue reveal dominant activation via the classical pathway, with a close correlation to the degree of glomerular C1q-binding IgG subclasses. In an antigen-specific autoimmune mouse model of MN, glomerular damage and proteinuria are reduced in complement-deficient mice compared with wild-type littermates. Severe disease with progressive ascites, accompanied by extensive loss of the integral podocyte slit diaphragm proteins, nephrin and neph1, only occur in wild-type animals. Finally, targeted silencing of C3 using RNA interference after the onset of proteinuria significantly attenuates disease. Our study shows that, in MN, complement is primarily activated via the classical pathway and targeting complement components such as C3 may represent a promising therapeutic strategy., (© 2023. The Author(s).)

Numerous cases of glomerulonephritis manifesting shortly after SARS-CoV-2 vaccination have been reported, but causality remains unproven. Here, we studied the association between mRNA-based SARS-CoV-2 vaccination and new-onset glomerulonephritis using a nationwide retrospective cohort and a case-cohort design. Data from all Swiss pathology institutes processing native kidney biopsies served to calculate incidence of IgA nephropathy, pauci-immune necrotizing glomerulonephritis, minimal change disease, and membranous nephropathy in the adult Swiss population. The observed incidence during the vaccination campaign (January to August 2021) was not different from the expected incidence calculated using a Bayesian model based on the years 2015 to 2019 (incidence rate ratio 0.86, 95% credible interval 0.73-1.02) and did not cross the upper boundary of the 95% credible interval for any month. Among 111 patients 18 years and older with newly diagnosed glomerulonephritis between January and August 2021, 38.7% had received at least one vaccine dose before biopsy, compared to 39.5% of the general Swiss population matched for age and calendar-time. The estimated risk ratio for the development of new-onset biopsy-proven glomerulonephritis was not significant at 0.97 (95% confidence interval 0.66-1.42) in vaccinated vs. unvaccinated individuals. Patients with glomerulonephritis manifesting within four weeks after vaccination did not differ clinically from those manifesting temporally unrelated to vaccination. Thus, vaccination against SARS-CoV-2 was not associated with new-onset glomerulonephritis in these two complementary studies with most temporal associations between SARS-CoV-2 vaccination and glomerulonephritis likely coincidental., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Obesity causes inflammation which may lead to development of co-morbidities like cardiovascular diseases. Cocoa is a popular food ingredient that has been shown to mitigate obesity and inflammation in preclinical models. Cocoa typically undergoes fermentation and roasting prior to consumption, which can affect the polyphenol content in cocoa. The aim of this study was to compare the effect of fermentation and roasting protocols on the ability of cocoa to mitigate obesity, gut barrier dysfunction, and chronic inflammation in high fat (HF)-fed, obese C57BL/6J mice. We found that treatment of mice with 80 mg/g dietary cocoa powder for 8 weeks reduced rate of body weight gain in both male and female mice (46-57%), regardless of fermentation and roasting protocol. Colonic length was increased (11-24%) and gut permeability was reduced (48-79%) by cocoa supplementation. Analysis of the cecal microbiome showed that cocoa, regardless of fermentation and roasting protocol, reduced the ratio of Firmicutes to Bacteroidetes. Multivariate statistical analysis of markers of inflammation and body weight data showed sex differences in the effect of both the HF diet as well as cocoa supplementation. Based on this data there was strong protective efficacy from cocoa supplementation especially for the more processed cocoa samples. Overall, this study shows that anti-obesity and anti-inflammatory efficacy of cocoa is resilient to changes in polyphenol content and composition induced by fermentation or roasting. Further, this study shows that although cocoa has beneficial effects in both males and females, there are significant sex differences., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Starch-guest inclusion complexes (ICs) are a novel, clean-label flavor encapsulation system with the potential to improve stability of aroma volatiles. While amylase has been shown to modulate guest release in vitro, release by sensory perception has not been evaluated. Here, Temporal Check-All-That-Apply (TCATA) and CATA were used to compare flavor perception of starch-limonene ICs to uncomplexed limonene, and the differences in perception were explored as a function of participant salivary α-amylase activity (sAA) and salivary flow rate (sFR). High sFR levels decreased limonene perception while high sAA increased limonene perception, highlighting the potential influence of these physiological factors on flavor perception of foods. Temporal flavor perception of a chewing gum containing starch-limonene ICs and a second chewing gum containing uncomplexed limonene and corn starch (CTL) was evaluated by 99 untrained consumers who assessed taste, texture, and aroma attributes over 17 min by TCATA and CATA. In addition, participants were segmented into three clusters based on their sAA and sFR, and cluster TCATA curves for each sample and attribute were statistically compared. Overall, participants rated Citrus, Sour and Bitter (p < 0.05) significantly higher for the IC sample and rated Sweet higher for the CTL. For Citrus, Sour, and Bitter, significant differences were observed between the three clusters for the IC chewing gum, while the CTL gum showed no significant differences for these three attributes. We demonstrate that flavor perception of starch-guest ICs varies with participants' salivary α-amylase activity and flow rate. Additionally, TCATA and CATA were found to be well suited to characterize flavor release systems over a long period of time as multiple flavor percepts can be simultaneously tracked., (Copyright © 2022 Elsevier Ltd. All rights reserved.)