Human T cell generation is restored in CD3δ severe combined immunodeficiency through adenine base editing.

CD3δ SCID is a devastating inborn error of immunity caused by mutations in CD3D, encoding the invariant CD3δ chain of the CD3/TCR complex necessary for normal thymopoiesis. We demonstrate an adenine base editing (ABE) strategy to restore CD3δ in autologous hematopoietic stem and progenitor cells (HSPCs). Delivery of mRNA encoding a laboratory-evolved ABE and guide RNA into a CD3δ SCID patient's HSPCs resulted in a 71.2% ± 7.85% (n = 3) correction of the pathogenic mutation. Edited HSPCs differentiated in artificial thymic organoids produced mature T cells exhibiting diverse TCR repertoires and TCR-dependent functions. Edited human HSPCs transplanted into immunodeficient mice showed 88% reversion of the CD3D defect in human CD34+ cells isolated from mouse bone marrow after 16 weeks, indicating correction of long-term repopulating HSCs. These findings demonstrate the preclinical efficacy of ABE in HSPCs for the treatment of CD3δ SCID, providing a foundation for the development of a one-time treatment for CD3δ SCID patients.

Anti-TIGIT antibody improves PD-L1 blockade through myeloid and Treg cells.

Tiragolumab, an anti-TIGIT antibody with an active IgG1κ Fc, demonstrated improved outcomes in the phase 2 CITYSCAPE trial (ClinicalTrials.gov: NCT03563716 ) when combined with atezolizumab (anti-PD-L1) versus atezolizumab alone1. However, there remains little consensus on the mechanism(s) of response with this combination2. Here we find that a high baseline of intratumoural macrophages and regulatory T cells is associated with better outcomes in patients treated with atezolizumab plus tiragolumab but not with atezolizumab alone. Serum sample analysis revealed that macrophage activation is associated with a clinical benefit in patients who received the combination treatment. In mouse tumour models, tiragolumab surrogate antibodies inflamed tumour-associated macrophages, monocytes and dendritic cells through Fcγ receptors (FcγR), in turn driving anti-tumour CD8+ T cells from an exhausted effector-like state to a more memory-like state. These results reveal a mechanism of action through which TIGIT checkpoint inhibitors can remodel immunosuppressive tumour microenvironments, and suggest that FcγR engagement is an important consideration in anti-TIGIT antibody development.

ChatGPT4 Outperforms Endoscopists for Determination of Postcolonoscopy Rescreening and Surveillance Recommendations.

BACKGROUND & AIMS: Large language models including Chat Generative Pretrained Transformers version 4 (ChatGPT4) improve access to artificial intelligence, but their impact on the clinical practice of gastroenterology is undefined. This study compared the accuracy, concordance, and reliability of ChatGPT4 colonoscopy recommendations for colorectal cancer rescreening and surveillance with contemporary guidelines and real-world gastroenterology practice. METHODS: History of present illness, colonoscopy data, and pathology reports from patients undergoing procedures at 2 large academic centers were entered into ChatGPT4 and it was queried for the next recommended colonoscopy follow-up interval. Using the McNemar test and inter-rater reliability, we compared the recommendations made by ChatGPT4 with the actual surveillance interval provided in the endoscopist's procedure report (gastroenterology practice) and the appropriate US Multisociety Task Force (USMSTF) guidance. The latter was generated for each case by an expert panel using the clinical information and guideline documents as reference. RESULTS: Text input of de-identified data into ChatGPT4 from 505 consecutive patients undergoing colonoscopy between January 1 and April 30, 2023, elicited a successful follow-up recommendation in 99.2% of the queries. ChatGPT4 recommendations were in closer agreement with the USMSTF Panel (85.7%) than gastroenterology practice recommendations with the USMSTF Panel (75.4%) (P < .001). Of the 14.3% discordant recommendations between ChatGPT4 and the USMSTF Panel, recommendations were for later screening in 26 (5.1%) and for earlier screening in 44 (8.7%) cases. The inter-rater reliability was good for ChatGPT4 vs USMSTF Panel (Fleiss κ, 0.786; 95% CI, 0.734-0.838; P < .001). CONCLUSIONS: Initial real-world results suggest that ChatGPT4 can define routine colonoscopy screening intervals accurately based on verbatim input of clinical data. Large language models have potential for clinical applications, but further training is needed for broad use.

An immunofluorescence-guided segmentation model in H&E images is enabled by tissue artifact correction by CycleGAN.

Despite recent advances, the adoption of computer vision methods into clinical and commercial applications has been hampered by the limited availability of accurate ground truth tissue annotations required to train robust supervised models. Generating such ground truth can be accelerated by annotating tissue molecularly using immunofluorescence staining (IF) and mapping these annotations to a post-IF H&E (terminal H&E). Mapping the annotations between the IF and the terminal H&E increases both the scale and accuracy by which ground truth could be generated. However, discrepancies between terminal H&E and conventional H&E caused by IF tissue processing have limited this implementation. We sought to overcome this challenge and achieve compatibility between these parallel modalities using synthetic image generation, in which a cycle-consistent generative adversarial network (CycleGAN) was applied to transfer the appearance of conventional H&E such that it emulates the terminal H&E. These synthetic emulations allowed us to train a deep learning (DL) model for the segmentation of epithelium in the terminal H&E that could be validated against the IF staining of epithelial-based cytokeratins. The combination of this segmentation model with the CycleGAN stain transfer model enabled performative epithelium segmentation in conventional H&E images. The approach demonstrates that the training of accurate segmentation models for the breadth of conventional H&E data can be executed free of human-expert annotations by leveraging molecular annotation strategies such as IF, so long as the tissue impacts of the molecular annotation protocol are captured by generative models that can be deployed prior to the segmentation process.

Comparative Outcomes of Endoscopic Mucosal Resection for Laterally Spreading Lesions in Inflammatory Bowel Disease.

BACKGROUND: The role of endoscopic mucosal resection (EMR) for laterally spreading lesions (LSLs) in inflammatory bowel disease (IBD) remains controversial despite its effectiveness in the general population. We aim to characterize outcomes of EMR for IBD-associated LSLs compared to controls without IBD. METHODS: We performed a retrospective observational cohort study of patients with IBD who underwent EMR and endoscopic follow-up for LSLs, compared to a control group without IBD. The primary outcome was histologic recurrence; secondary outcomes included en bloc resection and adverse events. Factors associated with recurrence were identified using multivariate mixed effects logistic regression. RESULTS: A total of 210 pre-malignant lesions in 155 patients were included. By histology, 91% were adenoma/low-grade dysplasia or sessile serrated lesions. Average lesion size was 22.9 mm (SD 11.3 mm) in the IBD group, and 21.5 mm (SD 12.4 mm) in the control group. Recurrence occurred in 30.4% of IBD-associated lesions (7/23) compared to 20.9% of controls (39/187; OR=2.51, CI .59-10.71). En bloc resection was less common in the IBD group (2/23, 8.7%, 95% CI 1.1-28.0) versus controls (106/187, 57.9%, 95% CI 50.4-65.2). After adjusting for lesion size and histology, recurrence appeared more common in patients with IBD compared to controls (OR=3.08, 95% CI 1.04-9.13). CONCLUSIONS: Recurrence of LSLs after EMR appears more frequent in patients with IBD. Given the added complexity, EMR in patients with IBD should be performed in expert centers with close endoscopic surveillance.

Increasing Antibiotic-Resistant Infections With Inpatient Endoscopic Retrograde Cholangioscopies (ERCP) Is Associated With Higher Mortality in the United States: A Cross-sectional Cohort Study.

GOALS: This study aims to investigate associated mortality with inpatient endoscopic retrograde cholangiopancreatography (ERCP) with and without resistant infections. The co-primary objective compares frequencies of inpatient ERCP with resistant infections to overall hospitalizations with resistant infections. BACKGROUND: The risks of inpatient antibiotic-resistant organisms are known, but the associated mortality for inpatient ERCP is unknown. We aim to use a national database of hospitalizations and procedures to understand trends and mortality for patients with antibiotic-resistant infections during inpatient ERCP. STUDY: The largest publicly available all-payer inpatient database in the United States (National Inpatient Sample) was used to identify hospitalizations associated with ERCPs and antibiotic-resistant infections for MRSA, VRE, ESBL, and MDRO. National estimates were generated, frequencies were compared across years, and multivariate regression for mortality was performed. RESULTS: From 2017 to 2020, national weighted estimates of 835,540 inpatient ERCPs were generated, and 11,440 ERCPs had coincident resistant infections. Overall resistant infection, MRSA, VRE, and MDRO identified at the same hospitalization of inpatient ERCPs were associated with higher mortality (OR CI(95%): Overall: 2.2(1.77-2.88), MRSA: 1.90 (1.34-2.69), VRE: 3.53 (2.16-5.76), and MDRO: 2.52 (1.39-4.55)). While overall hospitalizations with resistant infections have been decreasing annually, there has been a yearly increase in admissions requiring ERCPs with simultaneous resistant infections ( P =0.001-0.013), as well as infections with VRE, ESBL, and MDRO ( P =0.001-0.016). Required Research Practices for Studies Using the NIS scoring was 0, or the most optimal. CONCLUSIONS: Inpatient ERCPs have increasing coincident resistant infections and are associated with higher mortality. These rising infections during ERCP highlight the importance of endoscopy suite protocols and endoscopic infection control devices.

Association of Standardized Radiology Reporting and Management of Abdominal CT and MRI With Diagnosis of Pancreatic Cancer.

BACKGROUND & AIMS: Follow-up of abdominal computed tomography (CT) and magnetic resonance imaging (MRI) findings suspicious for pancreatic cancer may be delayed if documentation is unclear. We evaluated whether standardized reporting and follow-up of imaging results reduced time to diagnosis of pancreatic cancer. METHODS: We used a quasi-experimental stepped-wedge cluster design to evaluate the effectiveness of newly implemented radiology reporting system. The system standardizes the reporting of CT and MRI reports using hashtags that classify pancreatic findings. The system also automates referral of patients with findings suspicious for pancreatic cancer to a multidisciplinary care team for rapid review and follow-up. The study examined 318,331 patients who underwent CT or MRI that included the abdomen from 2016 through 2019 who had not had an eligible CT or MRI in the preceding 24 months. We evaluated the association of the intervention with incidence of pancreatic cancer within 60 days and 120 days after imaging. RESULTS: Thirty-eight percent of patients received the intervention, and 1523 patients (0.48%) were diagnosed with pancreatic cancer. In multivariable analysis accounting for age, race/ethnicity, sex, Charlson comorbidity, history of cancer, diabetes, and 4-month calendar period, the intervention was associated with nearly 50% greater odds of diagnosing pancreatic cancer within 60 days (adjusted odds ratio, 1.47; 95% confidence interval, 1.05-2.06) and 120 days (adjusted odds ratio, 1.46; 95% confidence interval, 1.04-2.06). CONCLUSIONS: In this large quasi-experimental, community-based observational study, implementing standardized reporting of abdominal CT and MRI reports with clinical navigation was effective for increasing the detection and diagnosis of pancreatic cancer.

Equitable Implementation of Mailed Stool Test-Based Colorectal Cancer Screening and Patient Navigation in a Safety Net Health System.

BACKGROUND: Mailed stool testing programs increase colorectal cancer (CRC) screening in diverse settings, but whether uptake differs by key demographic characteristics is not well-studied and has health equity implications. OBJECTIVE: To examine the uptake and equity of the first cycle of a mailed stool test program implemented over a 3-year period in a Central Texas Federally Qualified Health Center (FQHC) system. DESIGN: Retrospective cohort study within a single-arm intervention. PARTICIPANTS: Patients in an FQHC aged 50-75 at average CRC risk identified through electronic health records (EHR) as not being up to date with screening. INTERVENTIONS: Mailed outreach in English/Spanish included an introductory letter, free-of-charge fecal immunochemical test (FIT), and lab requisition with postage-paid mailer, simple instructions, and a medical records update postcard. Patients were asked to complete the FIT or postcard reporting recent screening. One text and one letter reminded non-responders. A bilingual patient navigator guided those with positive FIT toward colonoscopy. MAIN MEASURES: Proportions of patients completing mailed FIT in response to initial cycle of outreach and proportion of those with positive FIT completing colonoscopy; comparison of whether proportions varied by demographics and insurance status obtained from the EHR. KEY RESULTS: Over 3 years, 33,606 patients received an initial cycle of outreach. Overall, 19.9% (n = 6672) completed at least one mailed FIT, 5.6% (n = 374) tested positive during that initial cycle, and 72.5% (n = 271 of 374) of those with positive FIT completed a colonoscopy. Hispanic/Latinx, Spanish-speaking, and uninsured patients were more likely to complete mailed FIT compared with white, English-speaking, and commercially insured patients. Spanish-speaking patients were more likely to complete colonoscopy after positive FIT compared with English-speaking patients. CONCLUSIONS: Mailed FIT outreach with patient navigation implemented in an FQHC system was effective in equitably reaching patients not up to date for CRC screening.

A Preliminary Controlled Trial of Endoscopic Ultrasound-guided Fiducial Markers to Guide Pancreas Surgery.

OBJECTIVE: Endoscopic ultrasound (EUS) is routinely used for fiducial marker placement (FMP) to guide stereotactic radiation of pancreatic tumors, but EUS-FMP explicitly to guide surgery has not been studied in a prospective, controlled manner. Multipurpose EUS systems have been developed that facilitate simultaneous EUS-FMP at the time of biopsy. We aimed to evaluate the feasibility of EUS-FMP to guide pancreatic resection. METHODS: In this prospective trial, we enrolled patients with resectable pancreas masses undergoing tissue sampling and placed preloaded fiducials immediately after biopsy. Intraprocedure confirmation of carcinoma, neuroendocrine, and nonlymphomatous neoplasia by rapid on-site evaluation and lesion size <4 cm was required. The main outcomes were the feasibility and ease of preoperative placement and intraoperative detection of the markers using predefined Likert scales. RESULTS: In 20 patients, EUS-FMP was successful before planned surgery and placement was technically straightforward (Likert Scale: 9.1 ± 1.3; range: 1, most challenging to 10, most facile). Intraoperative detection was feasible and improved when compared with a pre-established comparator of 5 representing an equivalent lesion without a marker (Likert Scale: 7.8 ± 2.2; range: 1, most difficult to 10, most facile; P = 0.011). The mean tumor size on EUS was 1.7 ± 0.9 (range: 0.5 to 3.6) cm. CONCLUSION: EUS-FMP is feasible and safe for resectable pancreatic tumors before surgery and may assist in perioperative detection. Preloaded fiducials may be considered for placement at the time of initial referral for EUS-fine needle biopsy.

Delayed Diagnostic Paracentesis Is Associated with Increased Preventable Healthcare Utilization in Disadvantaged Patient Populations with Advanced Liver Disease and Elevated INR.

BACKGROUND: Patients hospitalized with cirrhosis, ascites, and elevated INR often experience delays in timely diagnostic paracentesis. AIMS: Identify whether delays in diagnostic paracentesis were associated with adverse outcomes in a hospital system serving a large disadvantaged population. METHODS: Retrospective cohort analysis of patients admitted from January 2017 to October 2019 with cirrhosis, ascites, and INR ≥ 1.5 across a multi-hospital health system in central Texas. We examined demographic and clinical characteristics of patients with diagnostic paracentesis (1) ≤ 24 h; (2) > 24 h; (3) therapeutic only or no paracentesis. We used logistic regression to examine differences in clinical outcomes controlling for confounders. RESULTS: 479 patients met inclusion criteria. 30.0% (N = 143) were Latino, 6.7% (N = 32) African American, and 67.8% (N = 325) under or uninsured. 54.1% of patients received a diagnostic paracentesis ≤ 24 h of admission and 21.1% did not receive a diagnostic paracentesis during the hospitalization. Undergoing diagnostic paracentesis > 24 h of admission was associated with a 2.3 day increase in length of stay (95% CI 0.8-3.8), and OR 1.7 for an Emergency Room visit within 30 days of discharge (95% CI 1.1-2.7) compared to receiving a diagnostic paracentesis ≤ 24 h. Patients receiving diagnostic paracentesis in radiology were more likely to have a delay in procedure OR 5.8 (95% CI 2.8-8.6). CONCLUSION: Delayed diagnostic paracentesis is associated with increased preventable healthcare utilization compared with timely diagnostic paracentesis. Health systems should support efforts to ensure timely diagnostic paracentesis for patients with advanced liver disease, including performance at the bedside.

Optimal initial diet in mild acute pancreatitis: A comprehensive meta-analysis of randomized control trials.

OBJECTIVE: We performed a comprehensive systematic review and meta-analysis comparing initiation of full solid diet (FSD) versus stepwise diet to better define the management of patients with mild acute pancreatitis (AP). METHODS: Electronic databases were searched through August 2, 2021 for trials comparing initial FSD versus stepwise advancement in patients with mild AP on length of hospital stay (LOHS). We stratified by whether diet was initiated early (within 24 h or immediately upon presence of bowel sounds). RESULTS: We identified seven RCTs that compared LOHS in AP patients who received initial oral intake with solid diet versus stepwise diet. Across the studies a total of 305 patients were randomized to immediate FSD and 308 patients to sequential advancement. Patients who were initiated on a FSD had a significant reduction in total LOHS (Standardized Mean Difference (SMD) -0.52 [95% CI -0.69, -0.36]). There was no difference in post refeeding abdominal pain, tolerance of diet, or necessity to cease diet between the two groups. Sub-analysis of three studies that initiated FSD early reduced total LOHS (OR -0.95 [95% CI -1.26, -0.65]) compared to those who received graded diet advancement as well as higher likelihood of tolerating the assigned diet (OR 6.8 [95% CI 1.2, 39.2]). CONCLUSIONS: Our meta-analysis shows that initiation of FSD reduces total LOHS in patients with mild AP and does not increase post refeeding abdominal pain. Though additional high-quality studies are needed, these findings support initial solid diet for AP and consideration of feeding within the first 24 h.

PAMAM versus PEI complexation for siRNA delivery: interaction with model lipid membranes and cellular uptake.

PURPOSE: Cationic polymers have many advantages as vectors for mediated cellular entry and delivery of siRNA. However, toxicity related to their cationic charge has compromised clinical use. It is hypothesized that the siRNA-vector complex composition and properties can be controlled to optimize therapeutic performance. Here we investigate siRNA complexes with branched polyethylenimine (bPEI) versus generation 4 polyamidoamine dendrimers (PAMAM) on interactions with immobilized lipid membranes, and cellular uptake and toxicity. METHODS: A model siRNA was complexed with either PAMAM or bPEI, and their size and zeta-potential characterized. Interaction of the complexes and parent polymers with lipid bilayers was investigated using atomic force microscopy and correlated with the uptake and toxicity in HeLa cells. RESULTS: PAMAM and its siRNA complexes formed circular shaped micron-sized holes in lipid bilayers, while bPEI formed nanoscale holes. Flow cytometry and fluorescence microscopy demonstrated PAMAM-siRNA complexes to have a higher cellular uptake than bPEI-siRNA complexes. bPEI-siRNA complexes did not impact on viability, however PAMAM-siRNA complexes demonstrated increasing cell toxicity as N/P ratio increased. PAMAM-siRNA complexes accumulated around the cell nucleus, while PEI-siRNA complexes were located closer to the cell wall. CONCLUSION: Complexation of PAMAM dendrimer or bPEI with siRNA modified physicochemical properties of the parent polymer, however it did not impact on the mechanism of interaction with model lipid bilayers or how the polymer/siRNA complex interacted and was internalized by HeLa cells. Interaction of siRNA polymer complexes with cells is related to the action of the parent polymer.

SARS-CoV-2 viral load is associated with risk of transmission to household and community contacts.

BACKGROUND: Factors that lead to successful SARS-CoV-2 transmission are still not well described. We investigated the association between a case's viral load and the risk of transmission to contacts in the context of other exposure-related factors. METHODS: Data were generated through routine testing and contact tracing at a large university. Case viral loads were obtained from cycle threshold values associated with a positive polymerase chain reaction test result from October 1, 2020 to April 15, 2021. Cases were included if they had at least one contact who tested 3-14 days after the exposure. Case-contact pairs were formed by linking index cases with contacts. Chi-square tests were used to evaluate differences in proportions of contacts testing positive. Generalized estimating equation models with a log link were used to evaluate whether viral load and other exposure-related factors were associated with a contact testing positive. RESULTS: Median viral load among the 212 cases included in the study was 5.6 (1.8-10.4) log10 RNA copies per mL of saliva. Among 365 contacts, 70 (19%) tested positive following their exposure; 36 (51%) were exposed to a case that was asymptomatic or pre-symptomatic on the day of exposure. The proportion of contacts that tested positive increased monotonically with index case viral load (12%, 23% and 25% corresponding to < 5, 5-8 and > 8 log10 copies per mL, respectively; X2 = 7.18, df = 2, p = 0.03). Adjusting for cough, time between test and exposure, and physical contact, the risk of transmission to a close contact was significantly associated with viral load (RR = 1.27, 95% CI 1.22-1.32). CONCLUSIONS: Further research is needed to understand whether these relationships persist for newer variants. For those variants whose transmission advantage is mediated through a high viral load, public health measures could be scaled accordingly. Index cases with higher viral loads could be prioritized for contact tracing and recommendations to quarantine contacts could be made according to the likelihood of transmission based on risk factors such as viral load.

Effectiveness and Cost-effectiveness of Mailed FIT in a Safety Net Clinic Population.

BACKGROUND: Mailed fecal immunochemical testing (FIT) can increase colorectal cancer (CRC) screening rates, including for vulnerable patients, but its cost-effectiveness is unclear. OBJECTIVE: We sought to examine the effectiveness and cost-effectiveness of the initial cycle of our mailed FIT program from November 2017 to July 2019 in a federally qualified health center (FQHC) system in Central Texas. DESIGN: Single group intervention and economic analysis PARTICIPANTS: Eligible patients were those ages 50-75 who had been seen recently in a system practice and were not up to date with screening. INTERVENTION: The program mailing packet included an introductory letter in plain language, the FIT itself, easy to read instructions, and a postage-paid lab mailer, supplemented with written and text messaging reminders. MAIN MEASURES: We measured effectiveness based on completion of mailed FIT and cost-effectiveness in terms of cost per person screened. Costs were measured using detailed micro-costing techniques from the perspective of a third-party payer and expressed in 2019 US dollars. Direct costs were based on material supply costs and detailed observations of labor required, valued at the wage rate. KEY RESULTS: Of the 22,838 eligible patients who received program materials, mean age was 59.0, 51.5% were female, and 43.9% were Latino. FIT were successfully completed by 19.2% (4395/22,838) patients at an average direct cost of $5275.70 per 500-patient mailing. Assuming completed tests from the mailed intervention represent incremental screening, the direct cost per patient screened, compared with no intervention, was $54.83. Incorporating start-up and indirect costs increases total costs to $7014.45 and cost per patient screened to $72.90. Alternately, assuming 2.5% and 5% screening without the intervention increased the direct (total) cost per patient screened to $60.03 ($80.80) and $67.05 ($91.47), respectively. CONCLUSIONS: Mailed FIT is an effective and cost-effective population health strategy for CRC screening in vulnerable patients.

Comprehensive meta-analysis of randomized controlled trials of Lactated Ringer's versus Normal Saline for acute pancreatitis.

INTRODUCTION: Fluid resuscitation is the keystone of treatment for acute pancreatitis. Though clinical guidelines and expert opinions agree on large volume resuscitation, debate remains on the optimal fluid type. The most commonly used fluids are Lactated Ringer's (LR) and Normal Saline (NS), but the studies published to date comparing LR vs NS yield conflicting results. We aimed to identify and quantitatively synthesize existing high quality data of the topic of fluid type or acute pancreatitis resuscitation. METHODS: In collaboration with the study team, an information specialist performed a comprehensive literature review to identify reports addressing type of fluid resuscitation. Studies were screened using the Covidence system by two independent reviewers in order to identify Randomized controlled trials comparing LR versus NS. The main outcome was the development of moderately severe or severe pancreatitis and additional outcomes included local complications, ICU admission, and length of stay. Pooled odds ratios were estimated using the random effects model and standardized mean difference to compare continuous variables. RESULTS: We reviewed 7964 abstracts and 57 full text documents. Four randomized controlled trials were identified and included in our meta-analyses. There were a total of 122 patients resuscitated with LR versus 126 with NS. Patients resuscitated with LR were less likely to develop moderately severe/severe pancreatitis (OR 0.49; 95 % CI 0.25-0.97). There was no difference in development of SIRS at 24 or 48 h or development of organ failure between the two groups. Patients resuscitated with LR were less likely to require ICU admission (OR 0.33; 95 % CI 0.13-0.81) and local complications (OR 0.42; 95 % CI 0.2-0.88). While there was a trend towards shorter hospitalizations for LR (SMD -0.18, 99 % CI -0.44-0.07), it was not statistically significant. CONCLUSION: Resuscitation with LR reduces the development of moderately severe-severe pancreatitis relative to NS. Nevertheless, no difference in SIRS development or organ failure underscores the need for further studies to verify this finding and define its mechanism.

Serum metabolomic profile of incident diabetes.

AIMS/HYPOTHESIS: Metabolomic profiling offers the potential to reveal metabolic pathways relevant to the pathophysiology of diabetes and improve diabetes risk prediction. METHODS: We prospectively analysed known metabolites using an untargeted approach in serum specimens from baseline (1987-1989) and incident diabetes through to 31 December 2015 in a subset of 2939 Atherosclerosis Risk in Communities (ARIC) study participants with metabolomics data and without prevalent diabetes. RESULTS: Among the 245 named compounds identified, seven metabolites were significantly associated with incident diabetes after Bonferroni correction and covariate adjustment; these included a food additive (erythritol) and compounds involved in amino acid metabolism [isoleucine, leucine, valine, asparagine, 3-(4-hydoxyphenyl)lactate] and glucose metabolism (trehalose). Higher levels of metabolites were associated with increased risk of incident diabetes (HR per 1 SD increase in isoleucine 2.96, 95% CI 2.02, 4.35, p = 3.18 × 10-8; HR per 1 SD increase in trehalose 1.16, 95% CI 1.09, 1.25, p = 1.87 × 10-5), with the exception of asparagine, which was associated with a lower risk of diabetes (HR per 1 SD increase in asparagine 0.78, 95% CI 0.71, 0.85, p = 4.19 × 10-8). The seven metabolites modestly improved prediction of incident diabetes beyond fasting glucose and established risk factors (C statistics 0.744 vs 0.735, p = 0.001 for the difference in C statistics). CONCLUSIONS/INTERPRETATION: Branched chain amino acids may play a role in diabetes development. Our study is the first to report asparagine as a protective biomarker of diabetes risk. The serum metabolome reflects known and novel metabolic disturbances that improve prediction of diabetes.