Citations

Objective Chronic kidney disease is a growing global health issue, contributing significantly to morbidity and mortality. The incidence of end-stage renal disease (ESRD) is approximately 100 per million population. Renal transplantation remains the cornerstone treatment for ESRD, with a projected 20-year survival rate of 60%. We aim to define the etiology of renal allograft dysfunction using the Banff 2019 classification by analyzing 200 renal allograft biopsies in correlation with creatinine levels across post-transplant time frames. Methodology 200 renal allograft biopsies are analyzed using the recent Banff 2019 classification with creatinine levels and post-transplant duration correlation. Results The study included 150 (75%) male patients and 50 (25%) female patients, with the majority 78 (39%) representing the age group of 16-30 years. 36 (18%) biopsies were within 3-month post-transplant, while 92 (46%) were 2-year post-transplant. According to the Banff 2019 classification, 92 (46.0%) transplant rejection biopsies were identified, with most 54 (27%) exhibiting antibody-mediated rejection (Category 2), including 40 (20%) active acute antibody-mediated rejection (ABMR) and 14 (7.0%) chronic active ABMR. T-cell-mediated rejection (TCMR; Category 4) represented 12 (6%) biopsies, including 10 (5%) acute TCMR and 2 (1%) chronic active TCMR. Category 5, the miscellaneous group, represented 100 (50%) biopsies, out of which 32 (16%) exhibited calcineurin inhibitor (CNI) toxicity, 38 (19%) acute tubular necrosis, and 8 (4%) thrombotic microangiopathy. A notable variation in the dysfunction distribution across different post-transplant time frames indicated a temporal evolution in the underlying causes of allograft dysfunction. Specific Banff categories showed a robust association with renal dysfunction, potentially contributing to the elevation of creatinine levels and renal function deterioration. Conclusion Our study highlights the intricate pathophysiology of renal allograft dysfunction. Most biopsies were attributed to ABMR whereas one-third of biopsies exhibited mixed lesions (ABMR and TCMR or ABMR and calcineurin inhibitor toxicity (CNIT)). Additionally, this study suggests that renal allograft rejection remains a significant contributor to graft dysfunction. A complex interplay between histological findings, Banff classification, and renal function is noted. A significant difference in the distribution of dysfunction across post-transplant time frames is noted suggesting a temporal evolution in the etiology of allograft dysfunction. Certain Banff categories demonstrate a stronger association with renal dysfunction that may influence creatinine level increase and renal function deterioration. In correspondence to the recent Banff 2019 guidelines for diagnosing ABMR, we emphasize the role of C4d staining on immunofluorescence or immunohistochemistry in allograft biopsies as imperative for timely diagnosis and immunosuppressant therapy adjustment, ultimately enhancing graft survival. Further research is needed to elucidate the underlying mechanisms driving renal dysfunction in different Banff categories, ultimately informing personalized management strategies for patients with renal allograft dysfunction. In line with the Banff 2019 guidelines for diagnosing ABMR, this study highlights the critical role of C4d staining through immunofluorescence or immunohistochemistry in allograft biopsies for early diagnosis and timely adjustment of immunosuppressive therapy, ultimately improving graft survival.

Sialadenoma papilliferum (SP) is a rare salivary gland tumor mostly reported in the oral cavity. Here we describe a bronchial SP in the left upper lobe bronchus of a 10-year-old boy. At bronchoscopy, a well-circumscribed polypoid lesion protruding into the bronchial lumen was identified. The tumor was excised, but eventually, the patient had to undergo a sleeve resection after 2 recurrences. Pathology revealed a papillocystic lesion with exophytic and endophytic components. The cells lining the exophytic surface and papillary structures were columnar and squamous, and the cells lining endophytic cystic and papillary structures were cuboidal to columnar, all of which were diffusely reactive with antibodies to SOX10 protein. The presence of basal cells was demonstrated by p63 immunoreactivity. The cells failed to immunohistochemically express BRAF V600E. Fluorescence in situ hybridization analysis revealed no MAML2 or RET gene rearrangement. The patient is alive 24 years after resection with no additional recurrences. Bronchial SP needs to be recognized and distinguished from other benign and malignant salivary gland and pulmonary neoplasms so that patients can receive appropriate treatment and follow-up.

Background/Objectives: The Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire is a widely employed self-report tool for assessing upper extremity function. The aim of this study was to assess the psychometric properties of the Serbian version of the DASH by determining its criterion and construct validity, as well as internal consistency. Methods: This cross-sectional study was conducted among patients with hand and wrist disabilities at the Institute for Orthopedics “Banjica”, Serbia. The psychometric properties of the Serbian version of the DASH were analyzed through an examination of its factorial structure and internal consistency. The DASH consists of 30 items, 24 of which assess function, 21 of which focus on physical function and three on social/role function. The remaining six items evaluate symptoms related to pain, tingling/numbness, weakness, and stiffness. Results: A total of 297 patients were included in the study. The mean age was 47.4 ± 16.8 years, with 50.5% males. Three models were assessed to determine the reliability and validity of the questionnaire across different domains. Model 1 examined a single-factor structure. In Model 2, the items were divided into two domains: Physical Function and Psychosocial/Symptoms. In Model 3, items were subdivided into three domains: Physical Function, Symptoms, and Psychosocial. All models demonstrated an excellent internal consistency with a Cronbach’s alpha > 0.9 for most domains. The values for the fit indices Tucker–Lewis index (TLI) and Comparative-Fit Index (CFI) were above their cut-off criteria of 0.9, while the Root Mean Square Error of Approximation (RMSEA) and Standardized Root Mean Square Residual (SRMR) were below the suggested value of 0.06, indicating an excellent level of models fit. Standardized factor loadings were statistically significant (p < 0.05). Conclusions: The present study provided the evidence for the appropriate metric properties of the Serbian version of the DASH. Results support both the unidimensional and multidimensional structures of the DASH.

Purpose: The goal of this study was to develop a lot release assay for iPSC residuals following directed differentiation of iPSCs to retinal pigment epithelial (RPE) cells. Methods: RNA Sequencing (RNA Seq) of iPSCs and RPE derived from them was used to identify pluripotency markers downregulated in RPE cells. Quantitative real time PCR (qPCR) was then applied to assess iPSC residuals in iPSC-derived RPE. The limit of detection (LOD) of the assay was determined by performing spike-in assays with known quantities of iPSCs serially diluted into an RPE suspension. Results: ZSCAN10 and LIN28A were among 8 pluripotency markers identified by RNA Seq as downregulated in RPE. Based on copy number and expression of pseudogenes and lncRNAs ZSCAN10 and LIN28A were chosen for use in qPCR assays for residual iPSCs. Reverse transcription PCR indicated generally uniform expression of ZSCAN10 and LIN28A in 21 clones derived from 8 iPSC donors with no expression of either in RPE cells derived from 5 donor lines. Based on qPCR, ZSCAN10 , and LIN28A expression in iPSCs was generally uniform. The LOD for ZSCAN10 and LIN28A in qPCR assays was determined using spike in assays of RPE derived from 2 iPSC lines. Analysis of ΔΔC t found the limit of detection to be <0.01% of cells, equivalent to <1 iPSC/10,000 RPE cells in both iPSC lines. Conclusions: qPCR for ZSCAN10 and LIN28A detects <1 in 10,000 residual iPSCs in a population of iPSC-derived RPE providing an adequate LOD of iPSC residuals for lot release testing.

Some prominent contemporary acupuncture pundits have published assertions that when the Huangdi Neijing was written 2000+ years ago, acupuncture clinicians had no knowledge of anatomy and “limited” clinical knowledge. Historical records as well as medical literature published over the past hundred years evidence those claims are grossly inaccurate. Those erroneous reports have likely contributed to the negative views of acupuncture that continue to be promulgated in the Western (allopathic) medical literature by prominent academic physicians and researchers: specifically, that acupuncture lacks a proper scientific basis, and that its clinical benefits most likely result from a potent (“enhanced”) placebo effect. The purpose of this review is to provide an accurate description of the extensive anatomical, physiological, and clinical knowledge of the founders of the acupuncture tradition, as reflected in both historical records and peer-reviewed literature. These data evidence that acupuncture is scientifically based in human anatomy and physiology, and further provide clues to acupuncture’s mechanisms.

Abstract Background Hypomagnesemia has been correlated with inferior outcomes in patients with large B cell lymphoma (LBCL) undergoing stem cell transplants. As T-cell and myeloid cell dysfunction have been associated with low magnesium conditions, we investigated whether serum magnesium (Mg) levels could predict clinical outcomes in LBCL patients who received chimeric antigen receptor T-cell therapy. Methods Patients with LBCL who received axi-cel under the ZUMA-1 trial or as FDA approved therapy at Mayo Clinic were examined. Serum samples were obtained at specified time points and cytokine analysis was performed. Single cell RNA sequencing was performed on peripheral blood mononuclear cells. The Student T-test, Kruskal Wallis, or Fisher's Exact Tests were used to compare differences in demographics across Mg levels. Survival curves were plotted using the Kaplan-Meier methodology and compared using the Wilcoxon test. Results We found that hypomagnesemia before lymphodepletion chemotherapy predicted for inferior progression-free and overall survival in the pivotal study ZUMA-1 (NCT02348216). These results were validated in an independent cohort of LBCL patients receiving axicabtagene ciloleucel (axi-cel) at Mayo Clinic. Hypomagnesemia correlated with increased inflammatory serum markers and cytokine levels including ferritin, IL-6, IL1Ra, IL-8, and MIP1a. scRNAseq analysis unveiled altered immune interactions between monocytes and T cells with a concordant immune suppressive transcriptome. Conclusions Hypomagnesemia at the time of CAR-T infusion associates with an unfavorable inflammatory profile and decreased response and survival in LBCL patients receiving axi-cel. These findings suggest a potentially actionable prognostic factor for patients with large cell lymphoma undergoing CAR-T.

Abstract Objective Aging is a major risk factor for OA, but the specific mechanisms underlying this connection remain unclear. Although chondrocytes rarely divide in adult articular cartilage, they undergo replicative senescence in vitro which provides an opportunity to study changes related to aging under controlled laboratory conditions. Methods Cartilage was recovered from two knees with OA and one normal knee. Chondrocyte cultures were established and sub-cultured until their Hayflick limit. Bulk RNA sequencing on early- and late-passage human articular chondrocytes allowed identification of transcriptomic changes associated with cellular aging. Results One male (80 years old) and one female (72 years old) patient provided OA cartilage. The donor of normal chondrocytes was a 26-year old male. Early passage chondrocytes from the two OA samples already had the phenotype of senescing cells, unlike normal chondrocytes. Nevertheless, all three chondrocyte cultures underwent 30 population doublings before replicative exhaustion, by which point all cells displayed a senescent phenotype. During this process, the cells lost their ability to form cartilaginous pellets. Differentially expressed genes (DEGs) analysis confirmed distinct transcriptomic profiles between early- and late-passage chondrocytes, as well as between cells isolated from normal and OA cartilage. Various changes in expression of genes related to cartilage matrix synthesis, degradation, inflammation and the senescence-associated secretory phenotype (SASP) were noted. Conclusions Although only a small pilot study, its data suggest that a larger and deeper study of the molecular and metabolic events accompanying the senescence of chondrocytes could provide important insights into the pathobiology of OA.