Effect of Glycocalyx-targeted Therapy on Vascular Function in Older Adults: A Randomized Controlled Trial.

Advancing age increases cardiovascular disease risk, in part, because of impaired glycocalyx thickness and endothelial dysfunction. Glycocalyx-targeted therapies, such as Endocalyx Pro{trade mark, serif}, could improve both glycocalyx thickness and endothelial function in older adults, however, this has yet to be tested. We hypothesized that Endocalyx Pro{trade mark, serif} supplementation would increase glycocalyx thickness and endothelial function in older adults. Twenty-three older adults aged 66±7 years (52% female) were enrolled in a randomized, double-blind, placebo-controlled, parallel-arms study to investigate the effect of 12-week Endocalyx Pro{trade mark, serif} supplementation (3,712 mg/day) on glycocalyx thickness and endothelial function. Glycocalyx thickness was assessed using the GlycoCheck and endothelial function was determined via brachial artery flow-mediated dilation (FMD). Between-group comparisons revealed Endocalyx Pro{trade mark, serif} did not increase glycocalyx thickness in microvessels 4-25µm (P=0.33), 4-7µm (P=0.07), or 10-25µm (P=0.47) in diameter when compared with placebo. Additionally, Endocalyx Pro did not significantly improve FMD [mean ratio (95% CI) for between-group comparisons, 1.16 (0.77-1.74); P=0.48]. However, Endocalyx Pro{trade mark, serif} improved FMD normalized to shear rate area under the curve [mean ratio (95% CI) for between-group comparisons, 2.41 (1.14,4.13); P=0.001]. Moreover, Endocalyx Pro{trade mark, serif} increased capillary glycocalyx thickness more than placebo in individuals not taking anti-hypertensive medication [mean difference (95% CI) for between-group comparison, -0.08 (-0.15,-0.01); P=0.02]. Our pilot study suggests that Endocalyx Pro{trade mark, serif} supplementation is feasible in older adults but had no measurable effect on overall glycocalyx thickness and FMD. However, Endocalyx Pro{trade mark, serif} may have select effects on capillary glycocalyx thickness and FMD normalized to shear rate among older adults, but further investigation is warranted.

Pancreatic body and tail adenocarcinoma: upfront resection versus neoadjuvant therapy, a contemporary analysis.

OBJECTIVES: There is a paucity of data regarding the use of neoadjuvant therapy in pancreatic body or tail ductal adenocarcinomas. Given the differing tumour biology and aggressive nature of pancreatic body or tail adenocarcinomas, patients presenting with these tumours may benefit from upfront resection. METHODS: A retrospective cohort study was performed analysing patients who underwent distal pancreatectomy for pancreatic ductal adenocarcinoma between January 2013 and June 2022. Patients who underwent upfront resection were compared to those who underwent neoadjuvant therapy. RESULTS: Forty-one patients underwent upfront distal pancreatectomy, while 40 patients underwent neoadjuvant therapy before curative intent resection. Neoadjuvant therapy did not improve overall survival (37 vs. 34 months, p = 0.962) or disease-free survival (13 vs. 15 months, p = 0.414), as compared with upfront resection. There was no significant difference in the rate or R0 resection or post-operative outcomes. CONCLUSION: No significant improvement in survival was demonstrated for patients undergoing neoadjuvant therapy for pancreatic ductal adenocarcinoma of the pancreatic body or tail when compared to upfront resection. Considering the potential for disease progression given the more aggressive tumour biology of pancreatic body and tail adenocarcinomas, appropriate surgical candidates should be offered upfront resection to provide the best chance of survival and cure.

Modelling Fatigue Crack Growth in High-Density Polyethylene and Acrylonitrile Butadiene Styrene Polymers.

Prior studies into fatigue crack growth (FCG) in fibre-reinforced polymer composites have shown that the two methodologies of Simple-Scaling and the Hartman-Schijve crack growth equation, which is based on relating the FCG rate to the Schwalbe crack driving force, Δκ, were able to account for differences observed in the measured delamination growth curves. The present paper reveals that these two approaches are also able to account for differences seen in plots of the rate of crack growth, da/dt, versus the range of the imposed stress intensity factor, ΔK, associated with fatigue tests on different grades of high-density polyethylene (HDPE) polymers, before and after electron-beam irradiation, and for tests conducted at different R ratios. Also, these studies are successfully extended to consider FCG in an acrylonitrile butadiene styrene (ABS) polymer that is processed using both conventional injection moulding and additive-manufactured (AM) 3D printing.

Evaluating the clinical and cost-effectiveness of a conservative approach to oxygen therapy for invasively ventilated adults in intensive care: Protocol for the UK-ROX trial.

Background: In the United Kingdom, around 184,000 adults are admitted to an intensive care unit (ICU) each year with over 30% receiving mechanical ventilation. Oxygen is the commonest therapeutic intervention provided to these patients but it is unclear how much oxygen should be administered for the best clinical outcomes. Methods: The UK-ROX trial will evaluate the clinical and cost-effectiveness of conservative oxygen therapy (the minimum oxygen concentration required to maintain an oxygen saturation of 90% ± 2%) versus usual oxygen therapy in critically ill adults receiving supplemental oxygen when invasively mechanically ventilated in ICUs in England, Wales and Northern Ireland. The trial will recruit 16,500 patients from approximately 100 UK adult ICUs. Using a deferred consent model, enrolled participants will be randomly allocated (1:1) to conservative or usual oxygen therapy until ICU discharge or 90 days after randomisation. Objectives: The primary clinical outcome is all cause mortality at 90 days following randomisation. Discussion: The UK-ROX trial has received ethical approval from the South Central - Oxford C Research Ethics Committee (Reference: 20/SC/0423) and the Confidentiality Advisory Group (Reference: 22/CAG/0154). The trial commenced in May 2021 and, at the time of publication, 95 sites had opened to recruitment.

"Blunt adrenal injury does not affect outcomes in adult patients with isolated abdominal injury - A National Trauma Data Bank review®".

INTRODUCTION: Traumatic blunt adrenal injury (BAI) has been an area of debate, with conflicting data on its impact. BAI from blunt abdominal injury is challenging to diagnose early due to retroperitoneal gland location and minimal clinical signs. The incidence of BAI ranges from 0.03 % to 4.95 %, with an increasing trend attributed to advanced CT imaging. Conflicting data exists regarding BAI's implications on patient outcomes, necessitating a comprehensive evaluation. METHODS: A retrospective review of the National Trauma Data Bank (NTDB®) for 2017-2021 included a total of 352,654 patients with 337,628 polytrauma patients and 15,026 isolated abdominal trauma patients. Patients were categorized into those with and without adrenal injury. Demographic data and outcomes were compared using statistical tests, focusing on Injury Severity Scores (ISS), mortality, length of stay, and ventilation days. RESULTS: Polytrauma patients with BAI had increased mortality, longer ICU and hospital stays, and ventilation requirements when compared to polytrauma patients without BAI. However, when evaluating isolated abdominal trauma patients with BAI showed no significant differences when compared to isolated abdominal trauma without BAI in mortality or ICU LOS and a slight decrease in ICU admissions, hospital LOS, and ventilation requirement. DISCUSSION: The study indicates a significant association between BAI and increased trauma severity among polytrauma patients. Mortality, however, did not exhibit a consistent rise across all patients with adrenal injury, emphasizing that BAI may not independently influence outcomes. These findings align with the notion that adrenal injury is linked to the overall trauma burden rather than being a primary determinant of mortality.

BUB1 regulates non-homologous end joining pathway to mediate radioresistance in triple-negative breast cancer.

Background: Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer subtype often treated with radiotherapy (RT). Due to its intrinsic heterogeneity and lack of effective targets, it is crucial to identify novel molecular targets that would increase RT efficacy. Here we demonstrate the role of BUB1 (cell cycle Ser/Thr kinase) in TNBC radioresistance and offer a novel strategy to improve TNBC treatment. Methods: Gene expression analysis was performed to look at genes upregulated in TNBC patient samples compared to other subtypes. Cell proliferation and clonogenic survivals assays determined the IC 50 of BUB1 inhibitor (BAY1816032) and radiation enhancement ratio (rER) with pharmacologic and genomic BUB1 inhibition. Mammary fat pad xenografts experiments were performed in CB17/SCID. The mechanism through which BUB1 inhibitor sensitizes TNBC cells to radiotherapy was delineated by γ-H2AX foci assays, BLRR, Immunoblotting, qPCR, CHX chase, and cell fractionation assays. Results: BUB1 is overexpressed in BC and its expression is considerably elevated in TNBC with poor survival outcomes. Pharmacological or genomic ablation of BUB1 sensitized multiple TNBC cell lines to cell killing by radiation, although breast epithelial cells showed no radiosensitization with BUB1 inhibition. Kinase function of BUB1 is mainly accountable for this radiosensitization phenotype. BUB1 ablation also led to radiosensitization in TNBC tumor xenografts with significantly increased tumor growth delay and overall survival. Mechanistically, BUB1 ablation inhibited the repair of radiation-induced DNA double strand breaks (DSBs). BUB1 ablation stabilized phospho-DNAPKcs (S2056) following RT such that half-lives could not be estimated. In contrast, RT alone caused BUB1 stabilization, but pre-treatment with BUB1 inhibitor prevented stabilization (t 1/2 , ∼8 h). Nuclear and chromatin-enriched fractionations illustrated an increase in recruitment of phospho- and total-DNAPK, and KAP1 to chromatin indicating that BUB1 is indispensable in the activation and recruitment of non-homologous end joining (NHEJ) proteins to DSBs. Additionally, BUB1 staining of TNBC tissue microarrays demonstrated significant correlation of BUB1 protein expression with tumor grade. Conclusions: BUB1 ablation sensitizes TNBC cell lines and xenografts to RT and BUB1 mediated radiosensitization may occur through NHEJ. Together, these results highlight BUB1 as a novel molecular target for radiosensitization in women with TNBC.

Living with your biome: how the bacterial microbiome impacts ocular surface health and disease.

Introduction: Microbiome research has grown exponentially but the ocular surface microbiome (OSM) remains an area in need of further study. This review aims to explore its complexity, disease-related microbial changes, and immune interactions, and highlights the potential for its manipulation as a therapeutic for ocular surface diseases. Areas Covered: We introduce the OSM by location and describe what constitutes a normal OSM. Second, we highlight aspects of the ocular immune system and discuss potential immune microbiome interactions in health and disease. Finally, we highlight how microbiome manipulation may have therapeutic potential for ocular surface diseases. Expert Opinion: The ocular surface microbiome varies across its different regions, with a core phyla identified, but with genus variability. A few studies have linked microbiome composition to diseases like dry eye but more research is needed, including examining microbiome interactions with the host. Studies have noted that manipulating the microbiome may impact disease presentation. As such, microbiome manipulation via diet, oral and topical pre and probiotics, and hygienic measures may provide new therapeutic algorithms in ocular surface diseases.

Cytomegalovirus drives Vδ1+ γδ T cell expansion and clonality in common variable immunodeficiency.

The function and phenotype of γδ T cells in the context of common variable immunodeficiency (CVID) has not been explored. CVID is a primary immunodeficiency disorder characterized by impaired antibody responses resulting in increased susceptibility to infections. γδ T cells are a subset of unconventional T cells that play crucial roles in host defence against infections. In this study, we aim to determine the roles and functions of γδ T cells in CVID. We observe a higher frequency of Vδ1+ γδ T cells compared to healthy controls, particularly in older patients. We also find a higher proportion of effector-memory Vδ1+ γδ T cells and a more clonal T cell receptor (TCR) repertoire in CVID. The most significant driver of the Vδ1+ γδ T cell expansion and phenotype in CVID patients is persistent cytomegalovirus (CMV) viremia. These findings provide valuable insights into γδ T cell biology and their contribution to immune defence in CVID.

TLR2 Supports γδ T cell IL-17A Response to ocular surface commensals by Metabolic Reprogramming.

The ocular surface is a mucosal barrier tissue colonized by commensal microbes, which tune local immunity by eliciting IL-17 from conjunctival γδ T cells to prevent pathogenic infection. The commensal Corynebacterium mastitidis (C. mast) elicits protective IL-17 responses from conjunctival Vγ4 T cells through a combination of γδ TCR ligation and IL-1 signaling. Here, we identify Vγ6 T cells as a major C. mast-responsive subset in the conjunctiva and uncover its unique activation requirements. We demonstrate that Vγ6 cells require not only extrinsic (via dendritic cells) but also intrinsic TLR2 stimulation for optimal IL-17A response. Mechanistically, intrinsic TLR2 signaling was associated with epigenetic changes and enhanced expression of genes responsible for metabolic shift to fatty acid oxidation to support Il17a transcription. We identify one key transcription factor, IκBζ, which is upregulated by TLR2 stimulation and is essential for this program. Our study highlights the importance of intrinsic TLR2 signaling in driving metabolic reprogramming and production of IL-17A in microbiome-specific mucosal γδ T cells.

New-Onset Neurosarcoidosis Following Heart Transplant for Cardiac Sarcoidosis.

A 63-year-old woman who underwent heart transplantation for cardiac sarcoidosis developed new headache and vision changes. Extensive workup resulted in a diagnosis of neurosarcoidosis treated with pulse dose steroids and infliximab. Recurrence of sarcoidosis after transplantation for isolated cardiac sarcoidosis occurs, but optimal surveillance methods remain unknown.

LINE-1 retrotransposons contribute to mouse PV interneuron development.

Retrotransposons are mobile DNA sequences duplicated via transcription and reverse transcription of an RNA intermediate. Cis-regulatory elements encoded by retrotransposons can also promote the transcription of adjacent genes. Somatic LINE-1 (L1) retrotransposon insertions have been detected in mammalian neurons. It is, however, unclear whether L1 sequences are mobile in only some neuronal lineages or therein promote neurodevelopmental gene expression. Here we report programmed L1 activation by SOX6, a transcription factor critical for parvalbumin (PV) interneuron development. Mouse PV interneurons permit L1 mobilization in vitro and in vivo, harbor unmethylated L1 promoters and express full-length L1 mRNAs and proteins. Using nanopore long-read sequencing, we identify unmethylated L1s proximal to PV interneuron genes, including a novel L1 promoter-driven Caps2 transcript isoform that enhances neuron morphological complexity in vitro. These data highlight the contribution made by L1 cis-regulatory elements to PV interneuron development and transcriptome diversity, uncovered due to L1 mobility in this milieu.

Design and Biocompatibility of a Novel, Flexible Artificial Cornea.

Purpose: We sought to introduce the materials, design, and biocompatibility of a flexible and suturable artificial corneal device. Methods: Single-piece, fully synthetic, optic-skirt design devices were made from compact perfluoroalkoxy alkane. The skirt and the optic wall surfaces were lined with a porous tissue ingrowth material using expanded polytetrafluoroethylene. Full-thickness macroapertures around the skirt perimeter were placed to facilitate nutrition of the recipient cornea. Material properties including the skirt's modulus of elasticity and bending stiffness, optic light transmission, wetting behavior, topical drug penetrance, and degradation profile were evaluated. Results: The final prototype suitable for human use has a transparent optic with a diameter of 4.60 mm anteriorly, 4.28 mm posteriorly, and a skirt outer diameter of 6.8 mm. The biomechanical and optical properties of the device closely align with the native human cornea with an average normalized device skirt-bending stiffness of 4.7 kPa·mm4 and light transmission in the visible spectrum ranging between 92% and 96%. No optical damage was seen in the 36 devices tested in fouling experiments. No significant difference was observed in topical drug penetrance into the anterior chamber of the device implanted eye compared with the naïve rabbit eye. Conclusions: The flexibility and biocompatibility of our artificial cornea device may offer enhanced tissue integration and decreased inflammation, leading to improved retention compared with rigid keratoprosthesis designs. Translational Relevance: We have developed a fully synthetic, flexible, suturable, optic-skirt design prototype artificial cornea that is ready to be tested in early human feasibility studies.

Fertility decline in Aedes aegypti (Diptera: Culicidae) mosquitoes is associated with reduced maternal transcript deposition and does not depend on female age.

Female mosquitoes undergo multiple rounds of reproduction known as gonotrophic cycles (GC). A gonotrophic cycle spans the period from blood meal intake to egg laying. Nutrients from vertebrate host blood are necessary for completing egg development. During oogenesis, a female prepackages mRNA into her oocytes, and these maternal transcripts drive the first 2 h of embryonic development prior to zygotic genome activation. In this study, we profiled transcriptional changes in 1-2 h of Aedes aegypti (Diptera: Culicidae) embryos across 2 GC. We found that homeotic genes which are regulators of embryogenesis are downregulated in embryos from the second gonotrophic cycle. Interestingly, embryos produced by Ae. aegypti females progressively reduced their ability to hatch as the number of GC increased. We show that this fertility decline is due to increased reproductive output and not the mosquitoes' age. Moreover, we found a similar decline in fertility and fecundity across 3 GC in Aedes albopictus. Our results are useful for predicting mosquito population dynamics to inform vector control efforts.

Common conditions of use elements. Atomic concepts for consistent and effective information governance.

Myriad policy, ethical and legal considerations underpin the sharing of biological resources, implying the need for standardised and yet flexible ways to digitally represent diverse 'use conditions'. We report a core lexicon of terms that are atomic, non-directional 'concepts of use', called Common Conditions of use Elements. This work engaged biobanks and registries relevant to the European Joint Programme for Rare Diseases and aimed to produce a lexicon that would have generalised utility. Seventy-six concepts were initially identified from diverse real-world settings, and via iterative rounds of deliberation and user-testing these were optimised and condensed down to 20 items. To validate utility, support software and training information was provided to biobanks and registries who were asked to create Sharing Policy Profiles. This succeeded and involved adding standardised directionality and scope annotations to the employed terms. The addition of free-text parameters was also explored. The approach is now being adopted by several real-world projects, enabling this standard to evolve progressively into a universal basis for representing and managing conditions of use.

Ni(I) and Ni(II) Bis(trimethylsilyl)amides Obtained in Pursuit of the Elusive Structure of Ni{N(SiMe3)2}2.

Salt metathesis routes to five new -N(SiMe3)2 nickel derivatives were studied to illuminate their mode of formation, structures, and spectroscopy. The reaction between NiI2 and K{N(SiMe3)2} afforded the Ni(II) and Ni(I) complexes [K][Ni{N(SiMe3)2}3] (1) and [K][Ni{N(SiMe3)2}2] (2). Dissolving 1 in tetrahydrofuran (THF) gave the Ni(II) species [K(THF)2][Ni{N(SiMe3)2}3] (3). The Ni(I) salt [K(DME)][Ni2{N(SiMe3)2}3] (4) was obtained by using NiCl2(DME) (DME = 1,2-dimethoxyethane) as the nickel source rather than NiI2. The isolation of the Ni(I) complexes 2 and 4 highlights the tendency for K{N(SiMe3)2} to function as a reducing agent. Introduction of adventitious O2 to solutions of [K][Ni{N(SiMe3)2}2] (2) gave the nickel inverse crown ether (ICE) species [K2][O(Ni{N(SiMe3)2}2)2] (5). Complex 5 is the first ICE complex of nickel and is one of four known ICE complexes for the 3d metals. The experimental results indicate that the reduced Ni(I) bis(trimethylsilyl)amides are relatively easily generated, whereas Ni(III) derivatives that might be expected from a disproportionation of a Ni(II) derivative are apparently not yet isolable by the above routes. Overall, the new species crystallize readily from the reaction mixtures, but under ambient conditions, they begin to decompose as solids within ca. 24 h, which hinders their characterization.

Validation of an ICD-Code-Based Case Definition for Psychotic Illness Across Three Health Systems.

BACKGROUND AND HYPOTHESIS: Psychosis-associated diagnostic codes are increasingly being utilized as case definitions for electronic health record (EHR)-based algorithms to predict and detect psychosis. However, data on the validity of psychosis-related diagnostic codes is limited. We evaluated the positive predictive value (PPV) of International Classification of Diseases (ICD) codes for psychosis. STUDY DESIGN: Using EHRs at 3 health systems, ICD codes comprising primary psychotic disorders and mood disorders with psychosis were grouped into 5 higher-order groups. 1133 records were sampled for chart review using the full EHR. PPVs (the probability of chart-confirmed psychosis given ICD psychosis codes) were calculated across multiple treatment settings. STUDY RESULTS: PPVs across all diagnostic groups and hospital systems exceeded 70%: Mass General Brigham 0.72 [95% CI 0.68-0.77], Boston Children's Hospital 0.80 [0.75-0.84], and Boston Medical Center 0.83 [0.79-0.86]. Schizoaffective disorder PPVs were consistently the highest across sites (0.80-0.92) and major depressive disorder with psychosis were the most variable (0.57-0.79). To determine if the first documented code captured first-episode psychosis (FEP), we excluded cases with prior chart evidence of a diagnosis of or treatment for a psychotic illness, yielding substantially lower PPVs (0.08-0.62). CONCLUSIONS: We found that the first documented psychosis diagnostic code accurately captured true episodes of psychosis but was a poor index of FEP. These data have important implications for the case definitions used in the development of risk prediction models designed to predict or detect undiagnosed psychosis.

Systems metabolic engineering of Corynebacterium glutamicum to assimilate formic acid for biomass accumulation and succinic acid production.

Formate as an ideal mediator between the physicochemical and biological realms can be obtained from electrochemical reduction of CO2 and used to produce bio-chemicals. Yet, limitations arise when employing natural formate-utilizing microorganisms due to restricted product range and low biomass yield. This study presents a breakthrough: engineered Corynebacterium glutamicum strains (L2-L4) through modular engineering. L2 incorporates the formate-tetrahydrofolate cycle and reverse glycine cleavage pathway, L3 enhances NAD(P)H regeneration, and L4 reinforces metabolic flux. Metabolic modeling elucidates C1 assimilation, guiding strain optimization for co-fermentation of formate and glucose. Strain L4 achieves an OD600 of 0.5 and produces 0.6 g/L succinic acid. 13C-labeled formate confirms C1 assimilation, and further laboratory evolution yields 1.3 g/L succinic acid. This study showcases a successful model for biologically assimilating formate in C. glutamicum that could be applied in C1-based biotechnological production, ultimately forming a formate-based bioeconomy.

The role of truth and bias in parents' judgments of children's science interests.

Parents' judgments about their children's level of interest in different science topics may affect the science-learning opportunities they provide their children. However, little is known about how parents judge these interests. We used the truth and bias model of judgment of West and Kenny (Psychological Review [2011], Vol. 118, pp. 357-378) to examine factors that may affect parents' judgments of their children's science interests such as the truth (children's self-reported interest) and potential sources of parental bias. We also investigated whether several individual difference measures moderated the effect of truth or bias on judgments. Children (N = 139, ages 7-11 years) rated their level of interest in five science and five non-science topics. Separately, parents (N = 139) judged their children's interest in the same topics. Overall, parents accurately judged their children's science interests, but we also found evidence of some forms of bias, namely that parents generally under-estimated their children's science interests. In addition, parents' personal science attitudes were related to judgments of science interests, such that parents more favorable of science tended to rate their children's interest in science topics higher than parents with a less favorable view. We did not find evidence that individual differences among parents moderated the effect of truth or bias on judgments; however, parents were more accurate at judging the non-science interests of older children than younger children. Parents should be aware that they may be under-estimating their children's interest in science topics and that their personal attitudes about science may be influencing their judgments of their children's science interests.

Lipase-to-Amylase Ratio for the Prediction of Clinically Relevant Postoperative Pancreatic Fistula following Pancreaticoduodenectomy.

AIM: Postoperative pancreatic fistula(POPF) represents a leading cause of morbidity and mortality following major pancreatic resections. This study aimed to evaluate the use of post-operative drain fluid lipase-to-amylase ratio(LAR) for the prediction of clinically relevant fistulae(CR-POPF). METHODS: Consecutive patients undergoing pancreaticoduodenectomy between 2017-2021 at a tertiary centre were retrospectively reviewed. Univariable and multivariable analyses were performed to identify predictors for CR-POPF(ISGPS Grades B/C). Receiver operator characteristic(ROC) curve analyses were conducted to evaluate the performance of LAR and determine optimum prediction thresholds. RESULTS: Among 130 patients, 28(21.5%) developed CR-POPF. Variables positively associated with CR-POPF included soft gland texture, acinar cell density, diagnosis other than PDAC or chronic pancreatitis, resection without neoadjuvant therapy, and postoperative drain fluid lipase, amylase, and LAR(all p < 0.05). Multivariable regression analysis identified LAR as an independent predictor of CR-POPF(p < 0.05). ROC curve analysis showed that LAR had moderate ability to predict CR-POPF on POD1(AUC = 0.64,95%CI = 0.54-0.74) and excellent ability on POD3(AUC = 0.85,95%CI = 0.78-0.92) and POD5(AUC = 0.86,95%CI = 0.79-0.92). Optimum thresholds were consistent over POD1-5 (ratio > 2.6) and associated with 92% sensitivity and 46-71% specificity. CONCLUSION: Postoperative drain fluid LAR represents a reliable predictor for the development of CR-POPF. With early prognostication, the postoperative care of patients deemed at risk of developing high-grade fistulas may be optimised.