Effectiveness of tailored talks between a cancer screening specialist and general practitioners to improve the uptake of colorectal cancer screening in Ancona (Italy) during the pandemic period.

BACKGROUND: Colorectal cancer (CRC) screening uptake in many countries has been low and further impacted by the COVID-19 pandemic. General Practitioners (GPs) are key facilitators, however research on their impact on organised CRC screening is still limited. OBJECTIVES: To evaluate the effectiveness of tailored talks with GPs to increase population uptake of the long-established CRC screening programme in Ancona province, Italy. METHODS: In this prospective cohort study, one-to-one tailored talks were organised in January 2020 between the GPs of one county of the province (with GPs from other counties as controls) and the screening programme physician-in-chief to discuss the deployment and effectiveness of organised screening. Data was extracted from the National Healthcare System datasets and linear regression was used to assess the potential predictors of CRC screening uptake. RESULTS: The mean CRC screening uptake remained stable from 39.9% in 2018-19 to 40.8% in 2020-21 in the 22 GPs of the intervention county, whereas it statistically significantly decreased from 38.7% to 34.7% in the 232 control GPs. In multivariate analyses, belonging to the intervention county was associated with an improved uptake compared to the control counties (+5.1%; 95% Confidence Intervals - CI: 2.0%; 8.1%). CONCLUSION: Persons cared for by GPs who received a tailored talk with a cancer screening specialist avoided a drop in CRC screening adherence, which characterised all other Italian screening programmes during the COVID-19 emergency. If future randomised trials confirm the impact of tailored talks, they may be incorporated into existing strategies to improve population CRC screening uptake.

Tailored talks on CRC screening were conducted between one cancer screening specialist and GPs.Even during the pandemic, CRC screening uptake was stable among persons cared for by GPs targeted by tailored talks.If confirmed by randomised trials, tailored talks may be employed to improve CRC screening uptake.

The effects of non-diagnostic information on confidence and decision making.

Many decision-making tasks are characterized by a combination of diagnostic and non-diagnostic information, yet models of responding and confidence almost exclusively focus on the contribution of diagnostic information (e.g., evidence associated with stimulus discriminability), largely ignoring the contribution of non-diagnostic information. An exception is Baranski and Petrusic's Journal of Experimental Psychology: Human Perception and Performance, 24(3), 929-945, (1998) doubt-scaling model, which predicts a negative relationship between non-diagnostic information and confidence, and between non-diagnostic information and accuracy. In two perceptual-choice tasks, we tested the effects of manipulating non-diagnostic information on confidence, accuracy and response time (RT). In Experiment 1, participants viewed a dynamic grid consisting of flashing blue, orange and white pixels and indicated whether the stimulus was predominantly blue or orange (using a response scale ranging from low-confidence blue to high-confidence orange), with the white pixels constituting non-diagnostic information. Increasing non-diagnostic information reduced both confidence and accuracy, generally slowed RTs, and led to an increase in the speed of errors. Experiment 2 replicated these results for a decision-only task, providing further support for the doubt-scaling model of confidence.

L1 Cell Adhesion Molecule (L1CAM) Expression and Molecular Alterations Distinguish Low-Grade Oncocytic Tumor From Eosinophilic Chromophobe Renal Cell Carcinoma.

Renal low-grade oncocytic tumor (LOT) is a recently recognized renal cell neoplasm designated within the "other oncocytic tumors" category in the 2022 World Health Organization classification system. Although the clinicopathologic, immunohistochemical, and molecular features reported for LOT have been largely consistent, the data are relatively limited. The morphologic overlap between LOT and other low-grade oncocytic neoplasms, particularly eosinophilic chromophobe renal cell carcinoma (E-chRCC), remains a controversial area in renal tumor classification. To address this uncertainty, we characterized and compared large cohorts of LOT (n = 67) and E-chRCC (n = 69) and revealed notable differences between the 2 entities. Clinically, LOT predominantly affected women, whereas E-chRCC showed a male predilection. Histologically, although almost all LOTs were dominated by a small-nested pattern, E-chRCC mainly showed solid and tubular architectures. Molecular analysis revealed that 87% of LOT cases harbored mutations in the tuberous sclerosis complex (TSC)-mTOR complex 1 (mTORC1) pathway, most frequently in MTOR and RHEB genes; a subset of LOT cases had chromosomal 7 and 19q gains. In contrast, E-chRCC lacked mTORC1 mutations, and 60% of cases displayed chromosomal losses characteristic of chRCC. We also explored the cell of origin for LOT and identified L1 cell adhesion molecule (L1CAM), a collecting duct and connecting tubule principal cell marker, as a highly sensitive and specific ancillary test for differentiating LOT from E-chRCC. This distinctive L1CAM immunohistochemical labeling suggests the principal cells as the cell of origin for LOT, unlike the intercalated cell origin of E-chRCC and oncocytoma. The ultrastructural analysis of LOT showed normal-appearing mitochondria and intracytoplasmic lumina with microvilli, different from what has been described for chRCC. Our study further supports LOT as a unique entity with a benign clinical course. Based on the likely cell of origin and its clinicopathologic characteristics, we propose that changing the nomenclature of LOT to "Oncocytic Principal Cell Adenoma of the Kidney" may be a better way to define and describe this entity.

The impact of alternate HPV vaccination and cervical screening strategies in Japan: a cost-effectiveness analysis.

Background: The Japanese 2020 cervical screening guidelines recommend conventional cervical cytology screening every 2-years for women aged 20-69 years. The nonavalent human papillomavirus (HPV) vaccine has also recently been approved in Japan. We therefore evaluated the cost-effectiveness of cervical cancer screening strategies alongside universal nonavalent HPV vaccination of girls (12-16 years). Methods: A cost-effectiveness analysis was performed using an age-specific Markov microsimulation model for Japan to evaluate total costs, quality adjusted life-years (QALYs) gained, incremental cost-effectiveness ratios (ICER), colposcopies, biopsies, precancer and cervical cancer treatments for 29 combined vaccination and screening strategies (conventional cytology, liquid-based cytology (LBC), HPV testing, and HPV self-collection). A cohort of 100,000 girls (12-16 years old) over a lifetime offered the nonavalent HPV vaccine was used (current vaccination coverage = 0.08%, current screening coverage = 43.7%). A discount rate of 3% was applied to costs and QALYs. Univariate and probabilistic sensitivity analysis was performed to assess robustness of the findings. Costs were reported in US dollars (2023). Findings: Compared with conventional cytology, evaluated strategies would incur an additional cost of US$839,280-738,182,669 and gain 62,755-247,347 quality-adjusted-life-years. HPV testing distinguishing HPV16/18 with reflex LBC (3-yearly) would be most cost-effective (ICER = US$7511 per QALY gained). At a willingness-to-pay (WTP) of 1-times gross domestic product (GDP) per capita, the probability of it being cost-effective was 70%. At historically high vaccination coverage (70%) ICERs decreased overall but did not affect the ranking of the most cost-effective strategy. While a 5-yearly interval became more cost-effective than a 3-yearly interval. Including HPV self-collection for under-screened women made all strategies more cost-effective. Interpretation: At current cervical screening participation (43.7%) and low vaccination coverage (<1.0%), HPV testing distinguishing HPV16/18 with reflex LBC (3-yearly) would be the most cost-effective screening strategy compared to conventional cytology (2-yearly). Funding: Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (17H03589) and Grants of the National Cancer Center Japan (Gan Kenkyu Kaihatsuhi 31-A-20 and 2023-A-23).

Clinicopathologic Features of Antibrush Border Antibody Disease.

Introduction: Antibrush border antibody disease (ABBA) is an autoimmune tubulointerstitial kidney disease that primarily affects older individuals and results in progressive kidney failure. It is rare with only 20 reported cases. Here, we describe a case series to further define the clinicopathologic spectrum and natural history, and to inform management. Methods: We identified 67 patients with ABBA who underwent kidney biopsy, including 65 native and 2 transplants. Demographics, clinical findings, and laboratory data were obtained. Histopathologic data included light microscopy, immunofluorescence, electron microscopy and immunostaining for LRP2, CUBN, and AMN. Follow-up data, including treatment(s), laboratory values, and outcomes, were available from 51 patients. Results: Patients with ABBA were predominantly male with a median age of 72 years. Median serum creatinine was 2.7 mg/dl, proteinuria was 2.8 g/day, and hematuria was present in two-thirds of the patients. Tubular injury with LRP2-positive tubular basement membrane (TBM) deposits were seen in 94.2% of patients. Thirty-eight patients (56.7%) had a second kidney disease, commonly glomerular diseases with high-grade proteinuria. These diseases included podocytopathies, membranous nephropathy (MN), IgA nephropathy, diabetic glomerulopathy, lupus nephritis (LN), crescentic glomerulonephritis (GN), tubulointerstitial nephritis, and involvement by lymphoma. The majority of patients were treated with immunosuppression. Of those patients with follow-up, 29.4% achieved remission, 70.6% had no response, and 52.8% required dialysis or were deceased. Untreated patients were at the highest risk. Conclusion: ABBA is a rare autoimmune kidney disease that often occurs with other kidney diseases. Although the overall prognosis of ABBA is poor, there is potential benefit from immunosuppression.

Dancers Show More Accurate Trunk-Pelvic Joint Angle Reproduction While Wearing a Jacket Augmented With Elastic Bands.

Purpose: The Backalast® compression jacket is intended to improve posture and proprioception of the trunk and shoulder girdle for dancers and dance students during dance training by way of elastic bands in the rear of the garment (which include bands enclosing the inferior thorax). This study was intended to investigate whether there is evidence to support those objectives. Materials and Methods: Fifteen dance students participated (4 male, mean age 19.9 ± 1.4 years old). The dependent variables of trunk-pelvis angle and proximity of trunk axis to global vertical for each participant were measured using optical motion capture before and after the completion of a series of trunk movements. The Helen Hayes model, which we used to represent the trunk, includes the shoulder girdles as part of the trunk. We compared the effect of the type of garment (Backalast® or control compression shirt) worn upon the 2 dependent variables, within-subject with paired t-tests. The order of whether Backalast® or control compression shirt was worn first was alternated between participants. Results: The pre/posttest difference in trunk proprioception as represented by the construct of ability to reproduce trunk-pelvis angle wearing the Backalast® was 0.8° ± 0.8°, but for the control shirt, the difference was 1.8° ± 1.4°, P = .03. The difference between garments in vertical trunk alignment, measured after the series of trunk movements, was not significant. Conclusion: Our findings suggest that the Backalast® can help enhance trunk proprioception when compared to the control compression shirt, although it did not change the angle at which the participants' held their trunks while standing erect (proximity to global vertical).

Unraveling the epigenetic code: human kidney DNA methylation and chromatin dynamics in renal disease development.

Epigenetic changes may fill a critical gap in our understanding of kidney disease development, as they not only reflect metabolic changes but are also preserved and transmitted during cell division. We conducted a genome-wide cytosine methylation analysis of 399 human kidney samples, along with single-nuclear open chromatin analysis on over 60,000 cells from 14 subjects, including controls, and diabetes and hypertension attributed chronic kidney disease (CKD) patients. We identified and validated differentially methylated positions associated with disease states, and discovered that nearly 30% of these alterations were influenced by underlying genetic variations, including variants known to be associated with kidney disease in genome-wide association studies. We also identified regions showing both methylation and open chromatin changes. These changes in methylation and open chromatin significantly associated gene expression changes, most notably those playing role in metabolism and expressed in proximal tubules. Our study further demonstrated that methylation risk scores (MRS) can improve disease state annotation and prediction of kidney disease development. Collectively, our results suggest a causal relationship between epigenetic changes and kidney disease pathogenesis, thereby providing potential pathways for the development of novel risk stratification methods.

Greater target or lure variability? An exploration on the effects of stimulus types and memory paradigms.

In recognition memory, the variance of the target distribution is almost universally found to be greater than that of the lure distribution. However, these estimates commonly come from long-term memory paradigms where words are used as stimuli. Two exceptions to this rule have found evidence for greater lure variability: a short-term memory task (Yotsumoto et al., Memory & Cognition, 36, 282-294 2008) and in an eyewitness memory paradigm (Wixted et al., Cognitive Psychology, 105, 81-114 2018). In the present work, we conducted a series of recognition memory experiments using different stimulus (faces vs. words) along with different paradigms (long-term vs. short-term paradigms) to evaluate whether either of these conditions would result in greater variability in lure items. Greater target variability was observed across stimulus types and memory paradigms. This suggests that factors other than stimuli and retention interval might be responsible for cases where variability is less for targets than lures.

Strategic Operational Redesign Improves Prior Authorization Access: A Validation Study.

Purpose: Obtaining prior authorization (PA) before treatment is becoming increasingly burdensome in oncology, especially in radiation oncology. Here, we describe the impact of a strategic novel operational PA redesign to shorten authorization time and to improve patient access to cancer care at a large United States academic proton therapy center. We ask whether such a redesign may be replicable and adoptable across oncology centers. Materials and Methods: Our PA redesign strategy was based on a 3-tiered approach. Specifically, we (1) held payors accountable to legally backed timelines, (2) leveraged expertise on insurance policies and practices, and (3) updated the submission, appeal writing, and planning procedures for PA. Metrics were compared at the following 3 time points: 6 months before, at phase-in, and at 6 months after intervention. Results: In analyzing the impact of improving PA access to care, the percentage of approvals for commercial proton beam therapy improved by an absolute 30.6% postintervention (P < .001). The proportion of commercially insured patients treated with proton beam therapy also increased by 6.2%, and the number of new starts rose by 11.7 patients/mo. Overall patient census increased by 13 patients/d. Median authorization time was 1 week, and 90% of surveyed providers reported reduced PA burden and improved patient care. Conclusion: This is the first validated, comprehensive operational strategy to improve access to cancer therapy while reducing the burden of PA. This novel approach may be helpful for addressing barriers to PA in medical and surgical oncology because the redesign is predicated on laws that regulate PA across disciplines.

Cure Glomerulonephropathy Pathology Classification and Core Scoring Criteria, Reproducibility, and Clinicopathologic Correlations.

Introduction: Cure Glomerulonephropathy (CureGN) is an observational cohort study of patients with minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), or IgA nephropathy. We developed a conventional, consensus-based scoring system to document pathologic features for application across multiple pathologists and herein describe the protocol, reproducibility, and correlation with clinical parameters at biopsy. Methods: Definitions were established for glomerular, tubular, interstitial, and vascular lesions evaluated semiquantitatively using digitized light microscopy slides and electron micrographs, and reported immunofluorescence. Cases with curated pathology materials as of April 2019 were scored by a randomly assigned pathologist, with at least 10% of cases scored by a second pathologist. Scoring reproducibility was assessed using Gwet's agreement coefficient (AC)1 statistic and correlations with clinical variables were performed. Results: Of 800 scored biopsies (134 MCD, 194 FSGS, 206 MN, 266 IgA), 94 were scored twice (11.8%). Of 60 pathology features, 46 (76.7%) demonstrated excellent (AC1>0.8), and 12 (20.0%) had good (AC1 0.6-0.8) reproducibility. Mesangial hypercellularity scored as absent, focal, or diffuse had moderate reproducibility (AC1 = 0.58), but good reproducibility (AC1 = 0.71) when scored as absent or focal versus diffuse. The percent glomeruli scored as no lesions had fair reproducibility (AC1 = 0.34). Strongest correlations between pathologic features and clinical characteristics at biopsy included interstitial inflammation, interstitial fibrosis, and tubular atrophy with estimated glomerular filtration rate, foot process effacement with urine protein/creatinine ratio, and active crescents with hematuria. Conclusions: Most scored pathology features showed excellent reproducibility, demonstrating consistency for these features across multiple pathologists. Correlations between certain pathologic features and expected clinical characteristics show the value of this approach for future studies on clinicopathologic correlations and biomarker discovery.

CureGN-Diabetes Study: Rationale, Design, and Methods of a Prospective Observational Study of Glomerular Disease Patients with Diabetes.

Glomerular diseases (GDs) represent the third leading cause of end-stage kidney disease (ESKD) in the US Diabetes was excluded from the CureGN Study, an NIH/NIDDK-sponsored observational cohort study of four leading primary GDs: IgA nephropathy (IgAN), membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), and minimal change disease (MCD). CureGN-Diabetes, an ancillary study to CureGN, seeks to understand how diabetes influences the diagnosis, treatment, and outcomes of GD. It is a multicenter, prospective cohort study, targeting an enrollment of 300 adults with prevalent type 1 or type 2 diabetes and MCD, FSGS, MN, or IgAN, with first kidney biopsy obtained within 5 years of enrollment in 80% (20% allowed if biopsy after 2010). CureGN and Transformative Research in DiabEtic NephropaThy (TRIDENT) provide comparator cohorts. Retrospective and prospective clinical data and patient-reported outcomes are obtained. Blood and urine specimens are collected at study visits annually. Kidney biopsy reports and digital images are obtained, and standardized pathologic evaluations performed. Light microscopy images are uploaded to the NIH pathology repository. Outcomes include relapse and remission rates, changes in proteinuria and estimated glomerular filtration rate, infections, cardiovascular events, malignancy, ESKD, and death. Multiple analytical approaches will be used leveraging the baseline and longitudinal data to compare disease presentation and progression across subgroups of interest. With 300 patients and an average of 3 years of follow-up, the study has 80% power to detect a HR of 1.4-1.8 for time to complete remission of proteinuria, a rate ratio for hospitalizations of 1.18-1.56 and difference in eGFR slope of 6.0-8.6 mL/min/year between two groups of 300 participants each. CureGN-Diabetes will enhance our understanding of diabetes as a modifying factor of the pathology and outcomes of GDs and support studies to identify disease mechanisms and improve patient outcomes in this understudied patient population.

Dupilumab-Associated Sweet Syndrome.

Sweet syndrome (SS), also known as acute febrile neutrophilic dermatosis, is characterized by the abrupt appearance of edematous and erythematous papules, plaques, or nodules on the skin that have a distinct histopathologic appearance. Several subtypes of SS exist, including classic (also referred to as idiopathic) and drug induced. Although multiple medications have been implicated as causative agents, we present a rare case of SS caused by dupilumab, a monoclonal antibody therapy, used in the treatment of severe eosinophilic asthma and other conditions. Clinicians should be aware of this potential adverse reaction, as prompt recognition and treatment are essential.

Planting design influences green infrastructure performance: Plant species identity and complementarity in rain gardens.

Green infrastructure's capacity to mitigate urban environmental problems, like heat island effects and excessive stormwater runoff, is partially governed by its plant community. Traditionally, green infrastructure design has focused on engineered aspects, such as substrate and drainage, rather than on the properties of its living components. Since the functioning of these plant assemblages is controlled by ecophysiological processes that differ by species, the identity and relative abundance of the species used will influence green infrastructure performance. We used trait-based modeling to derive principles for the effective composition of green infrastructure plant assemblages, parameterizing our model using the vegetation and ecophysiological traits of the species within New York City rain gardens. Focusing on two plant traits that influence rain garden performance, leaf surface temperature and stomatal conductance, we simulated the cumulative temperature and transpiration for plant communities of differing species composition and diversity. The outcomes of the model demonstrate that plant species composition, species identity, selection effects, and interspecific complementarity increase green infrastructure performance in much the way biodiversity affects ecosystem functioning in natural systems. More diverse assemblages resulted in more consistent transpiration and surface temperatures, with the former showing a positive, saturating curve as diversity increased. While the dominant factors governing individual species leaf temperature were abiotic, transpiration was more influential at the community level, suggesting that plants within diverse communities may be cooler in aggregate than any individual species on its own. This implies green infrastructure should employ a variety of vegetation; particularly plants with different statures and physical attributes, such as low-growing ground covers, erect herbaceous perennials, and shrubs.

Metastatic solid tumors to the testis: a clinicopathologic evaluation of 157 cases from an international collaboration.

To elucidate the spectrum of metastatic solid tumors to the testis and their clinicopathologic features. The databases and files of 26 pathology departments from 9 countries on 3 continents were surveyed to identify metastatic solid tumors to the testis and to characterize their clinicopathologic features in detail. We compiled a series of 157 cases of metastatic solid tumors that secondarily involved the testis. The mean patient age at diagnosis was 64 years (range, 12-93 years). Most patients (127/144; 88%) had clinical manifestation of the disease, with testicular mass/nodule (89/127; 70%) being the most common finding. The main mechanism of testicular involvement was metastasis in 154/157 (98%) cases. Bilateral testicular involvement was present in 12/157 (8%) patients. Concurrent or prior extratesticular metastases were present in 78/101 (77%) patients. The diagnosis was made mainly in orchiectomy specimens (150/157; 95%). Different types of carcinomas (138/157; 87%), most commonly adenocarcinoma (72/157; 46%), were the most common malignancies. The most common primary carcinomas included prostatic (51/149; 34%), renal (29/149; 20%), and colorectal (13/149; 9%). Intratubular growth was identified in 13/124 (11%) cases and paratesticular involvement was found in 73/152 (48%) cases. In patients with available follow-up (110/157; 70%), more than half (58/110; 53%) died of disease. In this largest series compiled to date, we found that most secondary tumors of the testis represent metastases from the genitourinary and gastrointestinal tract carcinomas and typically occur in the setting of disseminated disease.

Evaluation of Technical Performance of Ultrasound-Guided Procedures through Hand Motion Analysis: An Exploration of Motion Metrics.

PURPOSE: To evaluate the ability of hand motion analysis using conventional and new motion metrics to differentiate between operators of varying levels of experience for central venous access (CVA) and liver biopsy (LB). MATERIALS AND METHODS: In the CVA task, 7 interventional radiologists (experts), 10 senior trainees, and 5 junior trainees performed ultrasound-guided CVA on a standardized manikin; 5 trainees were retested after 1 year. In the LB task, 4 radiologists (experts) and 7 trainees biopsied a lesion on a manikin. Conventional motion metrics (path length and task time), a refined metric (translational movements), and new metrics (rotational sum and rotational movements) were calculated. RESULTS: In the CVA task, experts outperformed trainees on all metrics (P < .02). Senior trainees required fewer rotational movements (P = .02), translational movements (P = .045), and time (P = .001) than junior trainees. Similarly, on 1-year follow-up, trainees had fewer translational (P = .02) and rotational (P = .003) movements with less task time (P = .003). The path length and rotational sum were not different between junior and senior trainees or for trainees on follow-up. Rotational and translational movements had greater area under the curve values (0.91 and 0.86, respectively) than the rotational sum (0.73) and path length (0.61). In the LB task, experts performed the task with a shorter path length (P = .04), fewer translational (P = .04) and rotational (P = .02) movements, and less time (P < .001) relative to the trainees. CONCLUSIONS: Hand motion analysis using translational and rotational movements was better at differentiating levels of experience and improvement with training than the conventional metric of path length.

In science we trust? Public trust in Intergovernmental Panel on Climate Change projections and accepting anthropogenic climate change.

One barrier to action on climate change is public trust in climate science, and projections made by climate scientists. However, climate science projections are rarely measured in public surveys. We designed survey questions based on two Intergovernmental Panel on Climate Change projections regarding global warming and coral reef decline. We gauge Australians' trust in Intergovernmental Panel on Climate Change projections, and explore how trust in climate science is associated with accepting anthropogenic climate change. A slim majority of Australian adults trust Intergovernmental Panel on Climate Change projections, with trust correlated positively with accepting anthropogenic climate change. While partisan divisions are extant in accepting anthropogenic climate change, partisan influences are attenuated substantially after controlling for trust in Intergovernmental Panel on Climate Change projections, as trust in climate science mediates the influence of partisanship on the acceptance of anthropogenic climate change. A minority of those who accept anthropogenic climate change have low trust in Intergovernmental Panel on Climate Change projections, viewing scientists' computer models as unreliable, or believing climate scientists benefit from overstating the impact of climate change.

Endorsement of scientific inquiry promotes better evaluation of climate policy evidence.

Public and scientific consensus about climate change do not align. Problematically, higher scientific knowledge has been associated with lower acceptance of climate information among those with more conservative socio-political ideologies. Positive attitudes towards science can attenuate this effect. We investigated the association between endorsement of scientific inquiry (ESI) and decision-making with scientific evidence about climate policies. Participants rated support for 16 climate policies accompanied by weaker or stronger evidence. In study 1 (N = 503), higher ESI was associated with greater discernment between strongly and weakly evidenced climate policies, irrespective of worldview. In studies 2 (N = 402) and 3 (N = 600), an ESI intervention improved discrimination, and, in study 3, increased ESI specifically for hierarchical/individualistic participants. Unlike ESI, the link between scientific knowledge and evaluation of evidence was influenced by worldview. Increasing ESI might improve the evaluation of scientific evidence and increase public support for evidence-based climate policies. Supplementary Information: The online version contains supplementary material available at 10.1007/s10584-023-03535-y.

Unbiased Human Kidney Tissue Proteomics Identifies Matrix Metalloproteinase 7 as a Kidney Disease Biomarker.

SIGNIFICANCE STATEMENT: Although gene expression changes have been characterized in human diabetic kidney disease (DKD), unbiased tissue proteomics information for this condition is lacking. The authors conducted an unbiased aptamer-based proteomic analysis of samples from patients with DKD and healthy controls, identifying proteins with levels that associate with kidney function (eGFR) or fibrosis, after adjusting for key covariates. Overall, tissue gene expression only modestly correlated with tissue protein levels. Kidney protein and RNA levels of matrix metalloproteinase 7 (MMP7) strongly correlated with fibrosis and with eGFR. Single-cell RNA sequencing indicated that kidney tubule cells are an important source of MMP7. Furthermore, plasma MMP7 levels predicted future kidney function decline. These findings identify kidney tissue MMP7 as a biomarker of fibrosis and blood MMP7 as a biomarker for future kidney function decline. BACKGROUND: Diabetic kidney disease (DKD) is responsible for close to half of all ESKD cases. Although unbiased gene expression changes have been extensively characterized in human kidney tissue samples, unbiased protein-level information is not available. METHODS: We collected human kidney samples from 23 individuals with DKD and ten healthy controls, gathered associated clinical and demographics information, and implemented histologic analysis. We performed unbiased proteomics using the SomaScan platform and quantified the level of 1305 proteins and analyzed gene expression levels by bulk RNA and single-cell RNA sequencing (scRNA-seq). We validated protein levels in a separate cohort of kidney tissue samples as well as in 11,030 blood samples. RESULTS: Globally, human kidney transcript and protein levels showed only modest correlation. Our analysis identified 14 proteins with kidney tissue levels that correlated with eGFR and found that the levels of 152 proteins correlated with interstitial fibrosis. Of the identified proteins, matrix metalloprotease 7 (MMP7) showed the strongest association with both fibrosis and eGFR. The correlation between tissue MMP7 protein expression and kidney function was validated in external datasets. The levels of MMP7 RNA correlated with fibrosis in the primary and validation datasets. Findings from scRNA-seq pointed to proximal tubules, connecting tubules, and principal cells as likely cellular sources of increased tissue MMP7 expression. Furthermore, plasma MMP7 levels correlated not only with kidney function but also associated with prospective kidney function decline. CONCLUSIONS: Our findings, which underscore the value of human kidney tissue proteomics analysis, identify kidney tissue MMP7 as a diagnostic marker of kidney fibrosis and blood MMP7 as a biomarker for future kidney function decline.