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Inflammation primes the murine kidney for recovery by activating AZIN1 adenosine-to-inosine editing.The Journal of Clinical Investigation Jul 2024The progression of kidney disease varies among individuals, but a general methodology to quantify disease timelines is lacking. Particularly challenging is the task of...
The progression of kidney disease varies among individuals, but a general methodology to quantify disease timelines is lacking. Particularly challenging is the task of determining the potential for recovery from acute kidney injury following various insults. Here, we report that quantitation of post-transcriptional adenosine-to-inosine (A-to-I) RNA editing offers a distinct genome-wide signature, enabling the delineation of disease trajectories in the kidney. A well-defined murine model of endotoxemia permitted the identification of the origin and extent of A-to-I editing, along with temporally discrete signatures of double-stranded RNA stress and Adenosine Deaminase isoform switching. We found that A-to-I editing of Antizyme Inhibitor 1 (AZIN1), a positive regulator of polyamine biosynthesis, serves as a particularly useful temporal landmark during endotoxemia. Our data indicate that AZIN1 A-to-I editing, triggered by preceding inflammation, primes the kidney and activates endogenous recovery mechanisms. By comparing genetically modified human cell lines and mice locked in either A-to-I edited or uneditable states, we uncovered that AZIN1 A-to-I editing not only enhances polyamine biosynthesis but also engages glycolysis and nicotinamide biosynthesis to drive the recovery phenotype. Our findings implicate that quantifying AZIN1 A-to-I editing could potentially identify individuals who have transitioned to an endogenous recovery phase. This phase would reflect their past inflammation and indicate their potential for future recovery.
PubMed: 38954486
DOI: 10.1172/JCI180117 -
Journal of Osteopathic Medicine Jul 2024Orthopaedic surgery has become increasingly competitive over the years, with the COVID-19 pandemic creating additional challenges for applicants and programs. To promote...
CONTEXT
Orthopaedic surgery has become increasingly competitive over the years, with the COVID-19 pandemic creating additional challenges for applicants and programs. To promote an equitable match experience, the American Orthopaedic Association (AOA) introduced a formal preference signaling (PS) system into the 2022-2023 application cycle. PS allows applicants to indicate their heightened interest in specific programs, which improves the likelihood of receiving an interview and ultimately matching at their desired residency program.
OBJECTIVES
The objective of this anonymous survey is to assess applicants' opinions and perspectives toward PS in orthopaedic surgery prior to the 2022-2023 match results. Additionally, we sought to evaluate the signaling strategies being utilized by applicants.
METHODS
An anonymous 22-question survey was distributed to applicants of an orthopaedic surgery residency program (34.2 % response rate). Responses were collected after the application submission deadline but before the match lists and results were available. This survey included questions germane to demographics, signal utilization, signaling reasons and strategies, and opinions toward PS. Descriptive statistics were calculated utilizing R (version 4.2.1) and RStudio.
RESULTS
Most respondents (96.1 %) participated in PS, and 96.7 % utilized all 30 signals. Signaling encouraged 24.2 % of applicants to apply to fewer programs. In accordance with guidelines, 83.2 % of respondents signaled each away rotation program; however, only 53 % signaled their home program. Applicants commonly signaled 1-10 "reach" and "safety" programs each. and were the most important reasons for signaling, whereas was the least. A program's social presence and virtual interview option did not influence many applicants' decisions for signaling. Most applicants believe that the COVID-19 pandemic and pass/fail licensure examinations influenced PS adoption. Sixty-seven of 149 respondents (45 %) claimed that applicants and programs benefit equally from PS, while 41 % believe programs benefit more. Nearly half (40.94 %) knew or about PS.
CONCLUSIONS
During the inaugural introduction of PS in orthopaedic surgery, nearly every applicant utilized all 30 signals, prioritizing factors like family proximity and perceived operative experience over program prestige. This shift reflects the importance of geographic location and presumed training quality. Despite unfamiliarity toward PS, personalized signaling strategies were implemented, accompanied by a slight decrease in application volumes. The 30 allotted signals in orthopaedic surgery may serve as an informal application cap due to the necessity of signaling a program for an interview invite. However, improved educational efforts are needed to enhance the understanding and maximize the benefits of PS for both applicants and programs.
PubMed: 38954485
DOI: 10.1515/jom-2023-0127 -
JCI Insight Jul 2024Upon infection, naïve CD8+ T cells differentiate into cytotoxic effector cells to eliminate the pathogen-infected cells. Although many mechanisms underlying this...
Upon infection, naïve CD8+ T cells differentiate into cytotoxic effector cells to eliminate the pathogen-infected cells. Although many mechanisms underlying this process have been demonstrated, the regulatory role of chromatin remodel system in this process remains largely unknown. Here we showed that BRD7, a component of the polybromo-associated BRG1-associated factor complex (PBAF), was required for naïve CD8+ T cells to differentiate into functional short-lived effector cells (SLECs) in response to acute infections caused by influenza virus or lymphocytic choriomeningitis virus (LCMV). BRD7-deficiency in CD8+ T cells resulted in profound defects in effector population and functions, thereby impairing viral clearance and host recovery. Further mechanical studies indicated that the expression of BRD7 significantly turned to high from naïve CD8+ T cells to effector cells, bridged BRG1 and PBRM1 to the core module of PBAF complex, consequently facilitating the assembly of PBAF complex rather than BAF complex in the effector cells. The PBAF complex changed the chromatin accessibility at the loci of Tbx21 gene and up-regulated its expression, leading to the maturation of effector T cells. Our research confirms BRD7 and the PBAF complex are key in CD8+ T cell development and present a significant target for advancing immune therapies.
PubMed: 38954484
DOI: 10.1172/jci.insight.171605 -
JCI Insight Jul 2024Rheumatoid arthritis (RA) management lean toward achieving remission or low-disease activity. In this study, we conducted single-cell RNA sequencing (scRNAseq) of...
Rheumatoid arthritis (RA) management lean toward achieving remission or low-disease activity. In this study, we conducted single-cell RNA sequencing (scRNAseq) of peripheral blood mononuclear cells (PBMCs) from 36 individuals (18 RA patients and 18 matched controls, accounting for age, sex, race, and ethnicity), to identify disease-relevant cell subsets and cell type-specific signatures associated with disease activity. Our analysis revealed 18 distinct PBMC subsets, including an IFITM3 overexpressing Interferon-activated (IFN-activated) monocyte subset. We observed an increase in CD4+ T effector memory cells in patients with moderate to high disease activity (DAS28-CRP ≥ 3.2), and a decrease in non-classical monocytes in patients with low disease activity or remission (DAS28-CRP < 3.2). Pseudobulk analysis by cell type identified 168 differentially expressed genes between RA and matched controls, with a downregulation of pro-inflammatory genes in the gamma-delta T cells subset, alteration of genes associated with RA predisposition in the IFN-activated subset, and non-classical monocytes. Additionally, we identified a gene signature associated with moderate-high disease activity, characterized by upregulation of pro-inflammatory genes such as TNF, JUN, EGR1, IFIT2, MAFB, G0S2, and downregulation of genes including HLA-DQB1, HLA-DRB5, TNFSF13B. Notably, cell-cell communication analysis revealed an upregulation of signaling pathways, including VISTA, in both moderate-high and remission-low disease activity contexts. Our findings provide valuable insights into the systemic cellular and molecular mechanisms underlying RA disease activity.
PubMed: 38954480
DOI: 10.1172/jci.insight.178499 -
The Journal of Clinical Investigation Jul 2024Cystic fibrosis (CF) results from mutations in the CFTR anion channel, ultimately leading to diminished transepithelial anion secretion and mucociliary clearance. CFTR...
Cystic fibrosis (CF) results from mutations in the CFTR anion channel, ultimately leading to diminished transepithelial anion secretion and mucociliary clearance. CFTR correctors are therapeutics that restore the folding/trafficking of mutated CFTR to the plasma membrane. The BKCa potassium channel is also critical for maintaining lung ASL volume. Here, we show the CFTR corrector, VX-445 (Elexacaftor), a component of Trikafta, induces K+ secretion across WT and F508del CFTR primary human bronchial epithelial cells (HBEs), which was entirely inhibited by the BKCa antagonist paxilline. Similar results were observed with VX-121 - a corrector under clinical evaluation. Whole-cell patch-clamp recordings confirmed potentiated channel activity from CFTR correctors on the BKCa α-subunit, and excised patch-clamp recordings demonstrated a significant increase in open probability. In mesenteric artery, VX-445 induced a paxilline-sensitive vasorelaxation of preconstricted arteries. VX-445 also reduced action potential firing frequency in primary hippocampal and cortical neurons. VX-445 effects were observed at low micomolar concentrations (1-10 µM) - within the range reported in plasma and tissues from CF patients. We raise the possibilities that CFTR correctors gain additional clinical benefit by activation of BKCa in the lung, yet may lead to adverse events through BKCa activation, elsewhere.
PubMed: 38954478
DOI: 10.1172/JCI176328 -
JCI Insight Jul 2024Beside suppressing immune responses, regulatory T cells (Tregs) maintain tissue homeostasis and control systemic metabolism. Whether iron is involved in Treg-mediated...
Beside suppressing immune responses, regulatory T cells (Tregs) maintain tissue homeostasis and control systemic metabolism. Whether iron is involved in Treg-mediated tolerance is completely unknown. Here, we showed that the transferrin receptor CD71 was upregulated on activated Tregs infiltrating human liver cancer. Mice with a Treg-restricted CD71 deficiency spontaneously developed a scurfy-like disease, caused by impaired perinatal Treg expansion. CD71-null Tregs displayed decreased proliferation and tissue-Treg signature loss. In perinatal life, CD71 deficiency in Tregs triggered hepatic iron overload response, characterized by increased hepcidin transcription and iron accumulation in macrophages. Lower bacterial diversity, and reduction of beneficial species, were detected in the fecal microbiota of CD71 conditional knock-out neonates. Our findings indicate that CD71-mediated iron absorption is required for Treg perinatal expansion and related to systemic iron homeostasis and bacterial gut colonization. Therefore, we hypothesize that Tregs establish nutritional tolerance through competition for iron during bacterial colonization after birth.
PubMed: 38954474
DOI: 10.1172/jci.insight.167967 -
JCI Insight Jul 2024Solid organ transplantation remains the life-saving treatment for end-stage organ failure, but chronic rejection remains a major obstacle to long-term allograft outcomes...
Solid organ transplantation remains the life-saving treatment for end-stage organ failure, but chronic rejection remains a major obstacle to long-term allograft outcomes and has not improved substantially. Tertiary lymphoid organs (TLO) are ectopic lymphoid structures that form under conditions of chronic inflammation, and evidence from human transplantation suggests that TLO regularly form in allografts undergoing chronic rejection. In this study, we utilized a mouse renal transplantation model and manipulation of the lymphotoxin alpha (LTα) - lymphotoxin beta receptor (LTβR) pathway, which is essential for TLO formation, to define the role of TLO in transplantation. We showed that intragraft TLO are sufficient to activate the alloimmune response and mediate graft rejection in a model where the only lymphoid organs are TLO in the allograft. When transplanted to recipients with a normal set of secondary lymphoid organs, the presence of graft TLO or LTα overexpression accelerated rejection. If the LTβR pathway was disrupted in the donor graft, TLO formation was abrogated, and graft survival prolonged. Intravital microscopy of renal TLO demonstrated that local T and B cell activation in TLOs is similar to that observed in secondary lymphoid organs. In summary, we demonstrated that immune activation in TLO contributes to local immune responses, leading to earlier allograft failure. TLO and the LTαβ-LTβR pathway are therefore prime targets to limit local immune responses and prevent allograft rejection. These findings are applicable to other diseases such as autoimmunity or tumors, where either limiting or boosting local immune responses is beneficial and improves disease outcomes.
PubMed: 38954463
DOI: 10.1172/jci.insight.177555 -
Journal of Medical Internet Research Jul 2024In the era of the internet, individuals have increasingly accustomed themselves to gathering necessary information and expressing their opinions on public web-based...
BACKGROUND
In the era of the internet, individuals have increasingly accustomed themselves to gathering necessary information and expressing their opinions on public web-based platforms. The health care sector is no exception, as these comments, to a certain extent, influence people's health care decisions. During the onset of the COVID-19 pandemic, how the medical experience of Chinese patients and their evaluations of hospitals have changed remains to be studied. Therefore, we plan to collect patient medical visit data from the internet to reflect the current status of medical relationships under specific circumstances.
OBJECTIVE
This study aims to explore the differences in patient comments across various stages (during, before, and after) of the COVID-19 pandemic, as well as among different types of hospitals (children's hospitals, maternity hospitals, and tumor hospitals). Additionally, by leveraging ChatGPT (OpenAI), the study categorizes the elements of negative hospital evaluations. An analysis is conducted on the acquired data, and potential solutions that could improve patient satisfaction are proposed. This study is intended to assist hospital managers in providing a better experience for patients who are seeking care amid an emergent public health crisis.
METHODS
Selecting the top 50 comprehensive hospitals nationwide and the top specialized hospitals (children's hospitals, tumor hospitals, and maternity hospitals), we collected patient reviews from these hospitals on the Dianping website. Using ChatGPT, we classified the content of negative reviews. Additionally, we conducted statistical analysis using SPSS (IBM Corp) to examine the scoring and composition of negative evaluations.
RESULTS
A total of 30,317 pieces of effective comment information were collected from January 1, 2018, to August 15, 2023, including 7696 pieces of negative comment information. Manual inspection results indicated that ChatGPT had an accuracy rate of 92.05%. The F1-score was 0.914. The analysis of this data revealed a significant correlation between the comments and ratings received by hospitals during the pandemic. Overall, there was a significant increase in average comment scores during the outbreak (P<.001). Furthermore, there were notable differences in the composition of negative comments among different types of hospitals (P<.001). Children's hospitals received sensitive feedback regarding waiting times and treatment effectiveness, while patients at maternity hospitals showed a greater concern for the attitude of health care providers. Patients at tumor hospitals expressed a desire for timely examinations and treatments, especially during the pandemic period.
CONCLUSIONS
The COVID-19 pandemic had some association with patient comment scores. There were variations in the scores and content of comments among different types of specialized hospitals. Using ChatGPT to analyze patient comment content represents an innovative approach for statistically assessing factors contributing to patient dissatisfaction. The findings of this study could provide valuable insights for hospital administrators to foster more harmonious physician-patient relationships and enhance hospital performance during public health emergencies.
Topics: COVID-19; Humans; China; Internet; Pandemics; Hospitals; Patient Satisfaction; SARS-CoV-2; Empirical Research
PubMed: 38954461
DOI: 10.2196/52992 -
JMIR Research Protocols Jul 2024Obesity prevalence in youth with spina bifida is higher than in their typically developing peers. Obesity is associated with lifelong medical, psychological, and...
BACKGROUND
Obesity prevalence in youth with spina bifida is higher than in their typically developing peers. Obesity is associated with lifelong medical, psychological, and economic burdens. Successful prevention or treatment of obesity in individuals with spina bifida is compromised by (1) the lack of valid and reliable methods to identify body fat in a clinical setting and (2) limited data on energy expenditure that are necessary to provide daily caloric recommendations.
OBJECTIVE
The objectives of this study will be to develop 2 algorithms for use in youth with spina bifida in a clinical setting, one to model body fat and one to predict total daily energy expenditure. In addition, physical activity and dietary intake will be described for the sample.
METHODS
This multisite, prospective, national clinical study will enroll 232 youth with myelomeningocele aged 5 to 18 years (stratified by age and mobility). Participants will be enrolled for 1 week. Data obtained include 4 measures of body composition, up to 5 height measures, a ramped activity protocol, and a nutrition and physical activity screener. Participants will wear an accelerometer for the week. On the final study day, 2 samples of urine or saliva, which complete the doubly labeled water protocol, will be obtained. The analysis will include descriptive statistics, Bland-Altman plots, concordance correlation, and regression analysis.
RESULTS
The study received extramural federal funding in July 2019. Data collection was initiated in March 2020. As of April 2024, a total of 143 (female participants: n=76, 53.1%; male participants: n=67, 46.9%) out of 232 participants have been enrolled. Data collection is expected to continue throughout 2024. A no-cost extension until November 2025 will be requested for data analysis and dissemination of findings.
CONCLUSIONS
This study furthers previous pilot work that confirmed the acceptability and feasibility of obtaining alternate height, body composition, and energy expenditure measures. The findings from this study will enhance screening, prevention, and treatment of abnormal weight status by facilitating the accurate identification of youths' weight status category and recommendations of daily caloric needs for this population that is at higher risk of obesity. Furthermore, the findings have the potential to impact outcomes for youth diagnosed with disabilities other than spina bifida who experience similar challenges related to alterations in body composition or fat distribution or measurement challenges secondary to mobility issues or musculoskeletal problems.
INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID)
DERR1-10.2196/52779.
Topics: Humans; Adolescent; Child; Spinal Dysraphism; Energy Metabolism; Cross-Sectional Studies; Body Composition; Female; Male; Child, Preschool; Prospective Studies; Exercise
PubMed: 38954458
DOI: 10.2196/52779 -
JMIR Research Protocols Jul 2024Starting in 2010, the epidermal growth factor receptor (EGFR) kinase inhibitors erlotinib and gefitinib were introduced into routine use in Aotearoa New Zealand (NZ) for...
Erlotinib or Gefitinib for Treating Advanced Epidermal Growth Factor Receptor Mutation-Positive Lung Cancer in Aotearoa New Zealand: Protocol for a National Whole-of-Patient-Population Retrospective Cohort Study and Results of a Validation Substudy.
BACKGROUND
Starting in 2010, the epidermal growth factor receptor (EGFR) kinase inhibitors erlotinib and gefitinib were introduced into routine use in Aotearoa New Zealand (NZ) for treating advanced lung cancer, but their impact in this setting is unknown.
OBJECTIVE
The study described in this protocol aims to understand the effectiveness and safety of these new personalized lung cancer treatments and the contributions made by concomitant medicines and other factors to adverse outcomes in the general NZ patient population. A substudy aimed to validate national electronic health databases as the data source and the methods for determining patient eligibility and identifying outcomes and variables.
METHODS
This study will include all NZ patients with advanced EGFR mutation-positive lung cancer who were first dispensed erlotinib or gefitinib before October 1, 2020, and followed until death or for at least 1 year. Routinely collected health administrative and clinical data will be collated from national electronic cancer registration, hospital discharge, mortality registration, and pharmaceutical dispensing databases by deterministic data linkage using National Health Index numbers. The primary effectiveness and safety outcomes will be time to treatment discontinuation and serious adverse events, respectively. The primary variable will be high-risk concomitant medicines use with erlotinib or gefitinib. For the validation substudy (n=100), data from clinical records were compared to those from national electronic health databases and analyzed by agreement analysis for categorical data and by paired 2-tailed t tests for numerical data.
RESULTS
In the validation substudy, national electronic health databases and clinical records agreed in determining patient eligibility and for identifying serious adverse events, high-risk concomitant medicines use, and other categorical data with overall agreement and κ statistic of >90% and >0.8000, respectively; for example, for the determination of patient eligibility, the comparison of proxy and standard eligibility criteria applied to national electronic health databases and clinical records, respectively, showed overall agreement and κ statistic of 96% and 0.8936, respectively. Dates for estimating time to treatment discontinuation and other numerical variables and outcomes showed small differences, mostly with nonsignificant P values and 95% CIs overlapping with zero difference; for example, for the dates of the first dispensing of erlotinib or gefitinib, national electronic health databases and clinical records differed on average by approximately 4 days with a nonsignificant P value of .33 and 95% CIs overlapping with zero difference. As of May 2024, the main study is ongoing.
CONCLUSIONS
A protocol is presented for a national whole-of-patient-population retrospective cohort study designed to describe the safety and effectiveness of erlotinib and gefitinib during their first decade of routine use in NZ for treating EGFR mutation-positive lung cancer. The validation substudy demonstrated the feasibility and validity of using national electronic health databases and the methods for determining patient eligibility and identifying the study outcomes and variables proposed in the study protocol.
TRIAL REGISTRATION
Australian New Zealand Clinical Trials Registry ACTRN12615000998549; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368928.
INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID)
DERR1-10.2196/51381.
Topics: Humans; Erlotinib Hydrochloride; Gefitinib; Lung Neoplasms; ErbB Receptors; Retrospective Studies; New Zealand; Mutation; Female; Male; Protein Kinase Inhibitors; Antineoplastic Agents; Cohort Studies; Middle Aged; Aged
PubMed: 38954434
DOI: 10.2196/51381