Assessing the medical reasoning skills of GPT-4 in complex ophthalmology cases.

BACKGROUND/AIMS: This study assesses the proficiency of Generative Pre-trained Transformer (GPT)-4 in answering questions about complex clinical ophthalmology cases. METHODS: We tested GPT-4 on 422 Journal of the American Medical Association Ophthalmology Clinical Challenges, and prompted the model to determine the diagnosis (open-ended question) and identify the next-step (multiple-choice question). We generated responses using two zero-shot prompting strategies, including zero-shot plan-and-solve+ (PS+), to improve the reasoning of the model. We compared the best-performing model to human graders in a benchmarking effort. RESULTS: Using PS+ prompting, GPT-4 achieved mean accuracies of 48.0% (95% CI (43.1% to 52.9%)) and 63.0% (95% CI (58.2% to 67.6%)) in diagnosis and next step, respectively. Next-step accuracy did not significantly differ by subspecialty (p=0.44). However, diagnostic accuracy in pathology and tumours was significantly higher than in uveitis (p=0.027). When the diagnosis was accurate, 75.2% (95% CI (68.6% to 80.9%)) of the next steps were correct. Conversely, when the diagnosis was incorrect, 50.2% (95% CI (43.8% to 56.6%)) of the next steps were accurate. The next step was three times more likely to be accurate when the initial diagnosis was correct (p<0.001). No significant differences were observed in diagnostic accuracy and decision-making between board-certified ophthalmologists and GPT-4. Among trainees, senior residents outperformed GPT-4 in diagnostic accuracy (p≤0.001 and 0.049) and in accuracy of next step (p=0.002 and 0.020). CONCLUSION: Improved prompting enhances GPT-4's performance in complex clinical situations, although it does not surpass ophthalmology trainees in our context. Specialised large language models hold promise for future assistance in medical decision-making and diagnosis.

GPR15 in colon cancer development and anti-tumor immune responses.

Introduction: The chemoattractant receptor, G protein-coupled receptor 15 (GPR15), promotes colon homing of T cells in health and colitis. GPR15 function in colon cancer is largely unexplored, motivating our current studies. Methods: In human study, immune cells were isolated from tumor tissues and healthy surgical tumor margins (STM), and their proportions as well as expression of GPR15 was analyzed by flow cytometry. In mouse studies, colon cancer was induced in GPR15-deficient (KO) and GPR15-suficient (Het) mice using azoxymethane (AOM) and dextran sulfate sodium (DSS) solution in drinking water. Serial endoscopy was performed in mice to monitor and visualize the distal region of colon. Mice were euthanized 10 weeks after the initial DSS administration, and the colon length and the number of polyps were recorded. Next, we identified the effects of GPR15L on established tumors in the MC38-colorectal cancer (CRC) mouse model. Immune cells were isolated from the mice colons or tumors and assessed by flow cytometry. Results: Our analysis of human CRC tissue revealed a significant reduction in GPR15+ immune cell frequencies in tumors compared to 'tumor-free' surgical margins. Similarly, our data analysis using The Cancer Genome Atlas (TCGA) indicated that lower GPR15 expression is associated with poor survival in human colon cancer. In the AOM/DSS colitis-associated colon cancer model, we observed increased colonic polyps and lower survival in Gpr15 +-KO compared to Gpr15-Het mice. Analysis of immune cell infiltrates in the colonic polyps showed significantly decreased CD8+ T cells and increased IL-17+ CD4+ and IL-17+ CD8+ T cells in Gpr15-KO than in Het mice. Consistent with a protective role of GPR15, administration of GPR15L to established tumors in the MC38-CRC model increased CD45+ cell infiltration, enhanced TNFa expression on CD4+ and CD8+ T cells at the tumor site and dramatically reduced tumor burden. Discussion: Our findings highlight an important, unidentified role of the GPR15-GPR15L axis in promoting a tumor-suppressive immune microenvironment and unveils a novel, colon-specific therapeutic target for CRC.

Point-of-Care Ultrasound (POCUS) for Sideline Youth Sports Coverage.

PURPOSE OF REVIEW: The purpose of this review is to discuss the use of point-of-care ultrasound for sideline youth sports coverage. RECENT FINDINGS: Participation in youth sports has been increasing, with trends that athletes are specializing earlier and competing at higher levels at younger ages (NSCH 2019, Fabricant 2013). Point-of-care ultrasound (POCUS) utilizes non-invasive imaging to diagnose and manage various musculoskeletal conditions ranging from traumatic injuries, such as fractures and intramuscular hematomas, to early screening for conditions such as asymptomatic knee lesions. Since it is well-tolerated by children and adolescents and allows for easy accessibility for sideline care, POCUS could provide a strong alternative to other imaging modalities such as x-ray and magnetic resonance imaging (MRI) as both have their limitations. Youth sideline sports coverage could be enhanced with immediate medical attention from ultrasound-trained medical professionals. On the sidelines of a traumatic injury, POCUS expedites patient care with immediate examination of acute injuries. In low resource and hard-to-reach locations such as a rural youth sporting event, it can be key in the triaging of injuries. As a supplement to a physical exam, the risk of a misdiagnosis is reduced, and a long, expensive trip to the hospital for unnecessary imaging studies may be avoided. Ultrasound is a versatile, non-invasive, radiation-free imaging modality that serves as an accessible option for sideline coverage at youth sporting events. Ultrasound is well-tolerated by children and adolescents. It can be used to evaluate, diagnose, and manage a range of musculoskeletal conditions at the sidelines of youth sports.

Methodology and design of platform trials: a meta-epidemiological study.

OBJECTIVES: Adaptive platforms allow for the evaluation of multiple interventions at a lower cost and have been growing in popularity, especially during the COVID-19 pandemic. The objective of this review is to summarize published platform trials, examine specific methodological design features among these studies, and hopefully aid readers in the evaluation and interpretation of platform trial results. METHODS: We performed a systematic review of EMBASE, MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and clinicaltrials.gov from January 2015 to January 2022 for protocols or results of platform trials. Pairs of reviewers, working independently and in duplicate, collected data on trial characteristics of trial registrations, protocols, and publications of platform trials. We reported our results using total numbers and percentages, as well as medians with interquartile range (IQR) when appropriate. RESULTS: We identified 15,277 unique search records and screened 14,403 titles and abstracts after duplicates were removed. We identified 98 unique randomized platform trials. Sixteen platform trials were sourced from a systematic review completed in 2019, which included platform trials reported prior to 2015. Most platform trials (n = 67, 68.3%) were registered between 2020 and 2022, coinciding with the COVID-19 pandemic. The included platform trials primarily recruited or plan to recruit patients from North America or Europe, with most subjects being recruited from the United States (n = 39, 39.7%) and the United Kingdom (n = 31, 31.6%). Bayesian methods were used in 28.6% (n = 28) of platform RCTs and frequentist methods in 66.3% (n = 65) of trials, including 1 (1%) that used methods from both paradigms. Out of the twenty-five trials with peer-reviewed publication of results, seven trials used Bayesian methods (28%), and of those, two (8%) used a predefined sample size calculation while the remainder used pre-specified probabilities of futility, harm, or benefit calculated at (pre-specified) intervals to inform decisions about stopping interventions or the entire trial. Seventeen (68%) peer-reviewed publications used frequentist methods. Out of the seven published Bayesian trials, seven (100%) reported thresholds for benefit. The threshold for benefit ranged from 80% to >99%. CONCLUSION: We identified and summarized key components of platform trials, including the basics of the methodological and statistical considerations. Ultimately, improving standardization and reporting in platform trials require an understanding of the current landscape. We provide the most updated and rigorous review of platform trials to date.

The Surgical Learning Curve: Does Robotic Technical Skill Explain Differences in Operative Performance?

Background: Prior studies on technical skills use small collections of videos for assessment. However, there is likely heterogeneity of performance among surgeons and likely improvement after training. If technical skill explains these differences, then it should vary among practicing surgeons and improve over time. Materials and Methods: Sleeve gastrectomy cases (n = 162) between July 2018 and January 2021 at one health system were included. Global evaluative assessment of robotic skills (GEARS) scores were assigned by crowdsourced evaluators. Videos were manually annotated. Analysis of variance was used to compare continuous variables between surgeons. Tamhane's post hoc test was used to define differences between surgeons with the eta-squared value for effect size. Linear regression was used for temporal changes. A P value <.05 was considered significant. Results: Variations in operative time discriminated between individuals (e.g., between 2 surgeons, means were 91 and 112 minutes, Tamhane's = 0.001). Overall, GEARS scores did not vary significantly (e.g., between those 2 surgeons, means were 20.32 and 20.6, Tamhane's = 0.151). Operative time and total GEARS score did not change over time (R2 = 0.0001-0.096). Subcomponent scores showed idiosyncratic temporal changes, although force sensitivity increased among all (R2 = 0.172-0.243). For a novice surgeon, phase-adjusted operative time (R2 = 0.24), but not overall GEARS scores (R2 = 0.04), improved over time. Conclusions: GEARS scores showed less variability and did not improve with time for a novice surgeon. Improved technical skill does not explain the learning curve of a novice surgeon or variation among surgeons. More work could define valid surrogate metrics for performance analysis.

Outcome prediction in bariatric surgery through video-based assessment.

INTRODUCTION: The relationship between intraoperative surgical performance scores and patient outcomes has not been demonstrated at a single-case level. The GEARS score is a Likert-based scale that quantifies robotic surgical proficiency in 5 domains. Given that even highly skilled surgeons can have variability in their skill among their cases, we hypothesized that at a patient level, higher surgical skill as determined by the GEARS score will predict individual patient outcomes. METHODS: Patients undergoing robotic sleeve gastrectomy between July 2018 and January 2021 at a single-health care system were captured in a prospective database. Bivariate Pearson's correlation was used to compare continuous variables, one-way ANOVA for categorical variables compared with a continuous variable, and chi-square for two categorical variables. Significant variables in the univariable screen were included in a multivariable linear regression model. Two-tailed p-value < 0.05 was considered significant. RESULTS: Of 162 patients included, 9 patients (5.5%) experienced a serious morbidity within 30 days. The average excess weight loss (EWL) was 72 ± 12% at 6 months and 74 ± 15% at 12 months. GEARS score was not significantly correlated with EWL at 6 months (p = 0.349), 12 months (p = 0.468), or serious morbidity (p = 0.848) on unadjusted analysis. After adjusting, total GEARS score was not correlated with serious morbidity (p = 0.914); however, GEARS score did predict EWL at 6 (p < 0.001) and 12 months (p < 0.001). All GEARS subcomponent scores, bimanual dexterity, depth perception, efficiency, force sensitivity, and robotic control were predictive of EWL at 6 months (p < 0.001) and 12 months (p < 0.001) on multivariable analysis. CONCLUSION: For patients undergoing sleeve gastrectomy, surgical skill as assessed by the GEARS score was correlated with EWL, suggesting that better performance of a sleeve gastrectomy can result in improved postoperative weight loss.

Medications for the treatment of pulmonary arterial hypertension: a systematic review and network meta-analysis.

BACKGROUND: There is no consensus on the most effective treatments of pulmonary arterial hypertension (PAH). Our objective was to compare effects of medications for PAH. METHODS: We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and Clinicaltrials.gov from inception to December 2021. We performed a frequentist random-effects network meta-analysis on all included trials. We rated the certainty of the evidence using the Grades of Recommendation, Assessment, Development, and Evaluation approach. RESULTS: We included 53 randomised controlled trials with 10 670 patients. Combination therapy with endothelin receptor antagonist (ERA) plus phosphodiesterase-5 inhibitors (PDE5i) reduced clinical worsening (120.7 fewer events per 1000, 95% CI 136.8-93.4 fewer; high certainty) and was superior to either ERA or PDE5i alone, both of which reduced clinical worsening, as did riociguat monotherapy (all high certainty). PDE5i (24.9 fewer deaths per 1000, 95% CI 35.2 fewer to 2.1 more); intravenous/subcutaneous prostanoids (18.3 fewer deaths per 1000, 95% CI 28.6 fewer deaths to 0) and riociguat (29.1 fewer deaths per 1000, 95% CI 38.6 fewer to 8.7 more) probably reduce mortality as compared to placebo (all moderate certainty). Combination therapy with ERA+PDE5i (49.9 m, 95% CI 25.9-73.8 m) and riociguat (49.5 m, 95% CI 17.3-81.7 m) probably increase 6-min walk distance as compared to placebo (moderate certainty). CONCLUSION: Current PAH treatments improve clinically important outcomes, although the degree and certainty of benefit vary between treatments.

Antiviral drug treatment for nonsevere COVID-19: a systematic review and network meta-analysis.

BACKGROUND: Randomized trial evidence suggests that some antiviral drugs are effective in patients with COVID-19. However, the comparative effectiveness of antiviral drugs in nonsevere COVID-19 is unclear. METHODS: We searched the Epistemonikos COVID-19 L·OVE (Living Overview of Evidence) database for randomized trials comparing antiviral treatments, standard care or placebo in adult patients with nonsevere COVID-19 up to Apr. 25, 2022. Reviewers extracted data and assessed risk of bias. We performed a frequentist network meta-analysis and assessed the certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. RESULTS: We identified 41 trials, which included 18 568 patients. Compared with standard care or placebo, molnupiravir and nirmatrelvir-ritonavir each reduced risk of death with moderate certainty (10.9 fewer deaths per 1000, 95% confidence interval [CI] 12.6 to 4.5 fewer for molnupiravir; 11.7 fewer deaths per 1000, 95% CI 13.1 fewer to 2.6 more). Compared with molnupiravir, nirmatrelvir-ritonavir probably reduced risk of hospital admission (27.8 fewer admissions per 1000, 95% CI 32.8 to 18.3 fewer; moderate certainty). Remdesivir probably has no effect on risk of death, but may reduce hospital admissions (39.1 fewer admissions per 1000, 95% CI 48.7 to 13.7 fewer; low certainty). INTERPRETATION: Molnupiravir and nirmatrelvir-ritonavir probably reduce risk of hospital admissions and death among patients with nonsevere COVID-19. Nirmatrelvir-ritonavir is probably more effective than molnupiravir for reducing risk of hospital admissions. Most trials were conducted with unvaccinated patients, before the emergence of the Omicron variant; the effectiveness of these drugs must thus be tested among vaccinated patients and against newer variants.

Systematic review of interventions that improve provider compliance to imaging guidelines for prostate cancer.

INTRODUCTION: Radiographic staging with bone scan or computed tomography is not indicated for men with low-risk prostate cancer. Physician compliance with these imaging recommendations has been widely variable, leading to inappropriate testing and increased costs. The purpose of this systematic review was to identify and learn from interventions associated with improved physician compliance to imaging guidelines for prostate cancer staging. METHODS: This systematic review followed Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. PubMed was searched through January 2022 for the following medical subject headings (MeSH) terms: ('practice patterns, physicians' or 'guideline adherence' or 'unnecessary procedures' or 'quality improvement') and ('prostatic neoplasms/diagnostic imaging'). Inclusion required discussion of an intervention for physician compliance to prostate cancer imaging guidelines and specific data describing associated outcomes. Publications focused on other malignancies or without this intervention, evaluation, or data were excluded. RESULTS: Of 82 papers screened, only five met inclusion criteria - representing 12 802 patients. Each focused on reducing unnecessary imaging and demonstrated statistically significant post-intervention improvement of physician compliance to imaging guidelines for staging prostate cancer. Four were multidimensional, with education, clinical champions, and performance feedback. One used the unidimensional intervention of an electronic medical record (EMR)-based clinical reminder order check (CROC). No studies used randomization or a control group. CONCLUSIONS: Post-intervention improvement in physician compliance to imaging guidelines for staging prostate cancer has been associated with EMR-based CROC and combination interventions using clinical champions, education, and feedback. This has been observed at individual institutions and larger organizations spanning a region or state.

Initial experience and cancer detection rates of office-based transperineal magnetic resonance imaging-ultrasound fusion prostate biopsy under local anesthesia.

INTRODUCTION: We aimed to demonstrate feasibility and cancer detection rates of office-based ultrasound-guided transperineal magnetic resonance imaging-ultrasound (MRI-US) fusion (TFB) prostate biopsy under local anesthesia. METHODS: With institutional review board approval, records of men undergoing TFB in the office setting under local anesthesia were reviewed. Baseline patient characteristics, MRI findings, cancer detection rates, and complications were recorded. The PrecisionPoint Transperineal Access System (Perineologic, Cumberland, MD, U.S.), along with UroNav 3.0 image-fusion system (Invivo International, Best, The Netherlands) were used for all procedures. Following biopsy, men were surveyed to assess patient experience. RESULTS: Between January 2019 and February 2020, 200 TFBs were performed, of which 141 (71%) were positive for prostate cancer, with 117 (83%) Gleason grade group 2 or higher. A total of 259 of 265 MRI lesions were biopsied, with 127 (49%) positive overall. Prostate Imaging-Reporting and Data System (PI-RADS) 4-5 lesions were positive for prostate cancer in 59% of cases. The mean procedural time was 20 minutes, with a patient enter-to-exit room time of 54 minutes. There were no septic complications, no patients required post-procedure hospital admission, and all procedures were successfully completed. Seventy-five percent of patients surveyed reported complete resolution of pain at three days following the procedure. CONCLUSIONS: Office-based TFB represents a viable approach to prostate cancer detection following prostate MRI. Larger-scale assessment is needed to categorize cancer detection rates more accurately by PI-RADs subset, patient selection factors, complication rate, and cost relative to TFB under anesthesia.

COVID-19 and the Rationale for Primary Selective Laser Trabeculoplasty and Diode Laser Transscleral Cyclophotocoagulation in Africa.

The recent COVID-19 pandemic has affected ophthalmologists' practices worldwide. Consequent global drug shortages and the limitations of medical glaucoma treatments in sub-Saharan Africa have highlighted the need for innovation in global ophthalmology to provide accessible, affordable, and effective glaucoma care. The role of lasers rather than medications for glaucoma patients in developing nations is emerging. Since lasers are easier to master than glaucoma surgery, it is pertinent to discuss the primary use of lasers in treating glaucoma in such nations. In particular, selective laser trabeculoplasty and diode laser transscleral cyclophotocoagulation seem to present a promising future for the treatment of glaucoma in Africa. In this report, we provide an evidence-based discussion exploring the emerging role of lasers in Africa.

Temporal and topographical changes in theta power between middle childhood and adolescence during sentence comprehension.

Time frequency analysis of the EEG is increasingly used to study the neural oscillations supporting language comprehension. Although this method holds promise for developmental research, most existing work focuses on adults. Theta power (4-8 Hz) in particular often corresponds to semantic processing of words in isolation and in ongoing text. Here we investigated how the timing and topography of theta engagement to individual words during written sentence processing changes between childhood and adolescence (8-15 years). Results show that topographically, the theta response is broadly distributed in children, occurring over left and right central-posterior and midline frontal areas, and localizes to left central-posterior areas by adolescence. There were two notable developmental shifts. First, in response to each word, early (150-300 msec) theta engagement over frontal areas significantly decreases between 8 and 9 years and 10-11 years. Second, throughout the sentence, theta engagement over the right parietal areas significantly decreases between 10 and 11 years and 12-13 years with younger children's theta response remaining significantly elevated between words compared to adolescents'. We found no significant differences between 12 and 13 years and 14-15 years. These findings indicate that children's engagement of the language network during sentence processing continues to change through middle childhood but stabilizes into adolescence.

National Implementation and Evaluation of a Virtual Subinternship in Urology.

OBJECTIVE: To conduct a nationwide evaluation of student and program director (PD) perspectives of virtual subinternships that took place during the COVID-19 pandemic. MATERIALS AND METHODS: In December 2020, we distributed anonymous surveys to all 534 urology residency applicants and 161 urology PDs at academic medical centers across the United States to evaluate virtual subinternships. Surveys assessed curriculum composition, goals, satisfaction, barriers, and future reusability. The primary outcome was overall satisfaction with the subinternship, evaluated on a 5-point Likert scale. RESULTS: The survey was completed by 174 students (33%) and 82 PDs (51%), including 81 students (47%) and 32 PDs (41%) who participated in virtual subinternships at 29 institutions. Overall, 77% of students and 78% of PDs rated the electives "excellent" or "very good." On ordinal logistic regression, higher student ratings were associated with duration ≥3 weeks (odds ratio [OR] 4.64, P = .003) and class size ≤4 students (OR 3.33, P = .015). Higher PD ratings were associated with full-time electives (OR 11.18, P = .019), class size ≤4 students (OR 13.99, P = .042), and utilization of the standardized Guidebook from the Society of Academic Urologists (OR 11.89, P = .038). The most commonly reported challenge to the subinternship's efficacy was lack of hands-on learning (87% of students and 81% of PDs). Looking forward, 45% of students and 66% of PDs recommended incorporating virtual components into future electives. CONCLUSION: The virtual subinternship was a coordinated nationwide initiative to provide urologic education to medical students during a pandemic. The most successful courses were structured with longer duration, full-time commitment, and small class size.

Systematic review of robotic radical cystectomy functional and quality of life outcomes.

This systematic review summarizes the urinary continence, male sexual function, and female sexual function outcomes after robotic-assisted radical cystectomy (RARC). Greater intracorporeal diversion use, longer followup, and clearly stated urinary continence definitions have revealed RARC urinary continence rates for orthotopic ileal neobladders that are similar to those after open radical cystectomy (ORC) when using the strictest continence definitions. Nerve-sparing technique appears to be well-used in most studies, with short-term and long-term RARC potency rates similar those after ORC when using the strictest potency definitions. Level 1 evidence using validated questionnaires suggests that quality of life outcomes are also similar.

Laparoscopic Radical Nephrectomy.

In addition to its established advantages, laparoscopic radical nephrectomy (RN) poses a unique set of challenges over traditional open surgery. In this study, we discuss preoperative considerations and detailed steps for laparoscopic RN. We review the transabdominal approach in detail, including patient positioning, equipment, and port placement in addition to the surgical steps. Intraoperative decisions such as adrenal management, renal preservation, and tumor identification are reviewed. Common complications of laparoscopic renal surgery are also summarized.

Value of MRI to Improve Deep Learning Model That Identifies High-Grade Prostate Cancer. Comment on Gentile et al. Optimized Identification of High-Grade Prostate Cancer by Combining Different PSA Molecular Forms and PSA Density in a Deep Learning Model. Diagnostics 2021, 11, 335.

Prostate-specific antigen (PSA) has been criticized for its low specificity for prostate cancer, which has led to the increased adoption of additional biomarkers, PSA density (PSAD), and multiparametric magnetic resonance imaging (mpMRI) to increase the localization, risk stratification, and diagnosis of prostate cancer [...].

Feasibility and Utility of Mobile Applications for the Evaluation of Urology Residents' Surgical Competence.

OBJECTIVE: To provide real-time assessment and feedback on the competency of urology residents' surgical skill via mobile applications and examine their feasibility and utility. MATERIALS AND METHODS: Two mobile application-based systems (SIMPL and myTIPreport) were sequentially implemented for the case-by-case assessment of residents' performance of surgical skills at a single institution. Data was collected regarding residents' perception of their feedback pre- and post-implementation of the applications. Faculty were surveyed after their implementation to determine their feasibility and utility. RESULTS: 297 individual evaluations were completed with SIMPL and 822 with myTIPreport over four and eleven months respectively. Post-implementation, residents showed significantly improved perceptions regarding the quantity and personalization of surgical skill feedback (P = .043 and .005 respectively). A majority (75%) of the faculty found the mobile applications feasible to use, an improvement compared to prior methods of resident evaluation, and would recommend continued use. CONCLUSION: This study represents the first documented use of real-time surgical competency assessment in urology. The use of mobile applications to evaluate urology residents' surgical competency in clinical practice is both feasible and useful. Their use may allow for more individualized surgical skill teaching during training and for the verification of the surgical skills necessary to practice autonomously.

Novel Circulating and Tissue Monocytes as Well as Macrophages in Pancreatitis and Recovery.

BACKGROUND AND AIMS: Acute pancreatitis (AP) is an inflammatory disease with mild to severe course that is associated with local and systemic complications and significant mortality. Uncovering inflammatory pathways that lead to progression and recovery will inform ways to monitor and/or develop effective therapies. METHODS: We performed single-cell mass Cytometry by Time Of Flight (CyTOF) analysis to identify pancreatic and systemic inflammatory signals during mild AP (referred to as AP), severe AP (SAP), and recovery using 2 independent experimental models and blood from patients with AP and recurrent AP. Flow cytometric validation of monocytes subsets identified using CyTOF analysis was performed independently. RESULTS: Ly6C+ inflammatory monocytes were the most altered cells in the pancreas during experimental AP, recovery, and SAP. Deep profiling uncovered heterogeneity among pancreatic and blood monocytes and identified 7 novel subsets during AP and recovery, and 6 monocyte subsets during SAP. Notably, a dynamic shift in pancreatic CD206+ macrophage population was observed during AP and recovery. Deeper profiling of the CD206+ macrophage identified 7 novel subsets during AP, recovery, and SAP. Differential expression analysis of these novel monocyte and CD206+ macrophage subsets revealed significantly altered surface (CD44, CD54, CD115, CD140a, CD196, podoplanin) and functional markers (interferon-γ, interleukin 4, interleukin 22, latency associated peptide-transforming growth factor-ß, tumor necrosis factor-α, T-bet, RoRγt) that were associated with recovery and SAP. Moreover, a targeted functional analysis further revealed distinct expression of pro- and anti-inflammatory cytokines by pancreatic CD206+ macrophage subsets as the disease either progressed or resolved. Similarly, we identified heterogeneity among circulating classical inflammatory monocytes (CD14+CD16-) and novel subsets in patients with AP and recurrent AP. CONCLUSIONS: We identified several novel monocyte/macrophage subsets with unique phenotype and functional characteristics that are associated with AP, recovery, and SAP. Our findings highlight differential innate immune responses during AP progression and recovery that can be leveraged for future disease monitoring and targeting.

Clinical Significance of Isolated V1 Arteritis in Renal Transplantation.

BACKGROUND: The presence of intimal arteritis (v) in renal allograft biopsy specimens establishes the presence of acute T-cell mediated rejection (TCMR), Grade IIa-III, according to the Banff classification of rejection. The clinical significance of isolated v1 lesions (v1), characterized by arteritis alone, compared with lesions of arteritis with tubulointerstitial inflammation (i-t-v) has been controversial. METHODS: We performed a retrospective review of 280 patients undergoing renal transplantation between 2005 and 2015 who received a "for cause" transplant biopsy using the Banff 2013 classification. Patients with TCMR grade IIa (n = 83) were subdivided into groups with isolated v1 arteritis and i-t-v. Pre- and postoperative renal function, graft survival, and overall survival were evaluated in all patients. RESULTS: Donor and recipient demographics were similar between groups. One month following treatment of rejection, patients with v1 disease had superior recovery of glomerular filtration rate vs patients with i-t-v (P < .002). At a median follow-up of 41 months from transplant, death-censored graft survival was 92% vs 79% (P = .04), and overall survival was 98% vs 79% (P < .004) in the isolated v1 and i-t-v groups, respectively. CONCLUSION: Despite having identical Banff classification of TCMR IIa, our results indicate that graft survival in patients with isolated v1 rejection is superior to those with i-t-v. Following corroboration with data from other centers, modification of the Banff classification scheme should be considered.