Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk.

Normal platelet function is critical to blood hemostasis and maintenance of a closed circulatory system. Heightened platelet reactivity, however, is associated with cardiometabolic diseases and enhanced potential for thrombotic events. We now show gut microbes, through generation of trimethylamine N-oxide (TMAO), directly contribute to platelet hyperreactivity and enhanced thrombosis potential. Plasma TMAO levels in subjects (n > 4,000) independently predicted incident (3 years) thrombosis (heart attack, stroke) risk. Direct exposure of platelets to TMAO enhanced sub-maximal stimulus-dependent platelet activation from multiple agonists through augmented Ca(2+) release from intracellular stores. Animal model studies employing dietary choline or TMAO, germ-free mice, and microbial transplantation collectively confirm a role for gut microbiota and TMAO in modulating platelet hyperresponsiveness and thrombosis potential and identify microbial taxa associated with plasma TMAO and thrombosis potential. Collectively, the present results reveal a previously unrecognized mechanistic link between specific dietary nutrients, gut microbes, platelet function, and thrombosis risk.

Engagement of MHC class I by the inhibitory receptor LILRB1 suppresses macrophages and is a target of cancer immunotherapy.

Exciting progress in the field of cancer immunotherapy has renewed the urgency of the need for basic studies of immunoregulation in both adaptive cell lineages and innate cell lineages. Here we found a central role for major histocompatibility complex (MHC) class I in controlling the phagocytic function of macrophages. Our results demonstrated that expression of the common MHC class I component ß2-microglobulin (ß2M) by cancer cells directly protected them from phagocytosis. We further showed that this protection was mediated by the inhibitory receptor LILRB1, whose expression was upregulated on the surface of macrophages, including tumor-associated macrophages. Disruption of either MHC class I or LILRB1 potentiated phagocytosis of tumor cells both in vitro and in vivo, which defines the MHC class I-LILRB1 signaling axis as an important regulator of the effector function of innate immune cells, a potential biomarker for therapeutic response to agents directed against the signal-regulatory protein CD47 and a potential target of anti-cancer immunotherapy.

Even modest climate change may lead to major transitions in boreal forests.

The sensitivity of forests to near-term warming and associated precipitation shifts remains uncertain1-9. Herein, using a 5-year open-air experiment in southern boreal forest, we show divergent responses to modest climate alteration among juveniles of nine co-occurring North American tree species. Warming alone (+1.6 °C or +3.1 °C above ambient temperature) or combined with reduced rainfall increased the juvenile mortality of all species, especially boreal conifers. Species differed in growth responses to warming, ranging from enhanced growth in Acer rubrum and Acer saccharum to severe growth reductions in Abies balsamea, Picea glauca and Pinus strobus. Moreover, treatment-induced changes in both photosynthesis and growth help explain treatment-driven changes in survival. Treatments in which species experienced conditions warmer or drier than at their range margins resulted in the most adverse impacts on growth and survival. Species abundant in southern boreal forests had the largest reductions in growth and survival due to climate manipulations. By contrast, temperate species that experienced little mortality and substantial growth enhancement in response to warming are rare throughout southern boreal forest and unlikely to rapidly expand their density and distribution. Therefore, projected climate change will probably cause regeneration failure of currently dominant southern boreal species and, coupled with their slow replacement by temperate species, lead to tree regeneration shortfalls with potential adverse impacts on the health, diversity and ecosystem services of regional forests.

Synergistic HNO3-H2SO4-NH3 upper tropospheric particle formation.

New particle formation in the upper free troposphere is a major global source of cloud condensation nuclei (CCN)1-4. However, the precursor vapours that drive the process are not well understood. With experiments performed under upper tropospheric conditions in the CERN CLOUD chamber, we show that nitric acid, sulfuric acid and ammonia form particles synergistically, at rates that are orders of magnitude faster than those from any two of the three components. The importance of this mechanism depends on the availability of ammonia, which was previously thought to be efficiently scavenged by cloud droplets during convection. However, surprisingly high concentrations of ammonia and ammonium nitrate have recently been observed in the upper troposphere over the Asian monsoon region5,6. Once particles have formed, co-condensation of ammonia and abundant nitric acid alone is sufficient to drive rapid growth to CCN sizes with only trace sulfate. Moreover, our measurements show that these CCN are also highly efficient ice nucleating particles-comparable to desert dust. Our model simulations confirm that ammonia is efficiently convected aloft during the Asian monsoon, driving rapid, multi-acid HNO3-H2SO4-NH3 nucleation in the upper troposphere and producing ice nucleating particles that spread across the mid-latitude Northern Hemisphere.

Rapid growth of new atmospheric particles by nitric acid and ammonia condensation.

A list of authors and their affiliations appears at the end of the paper New-particle formation is a major contributor to urban smog1,2, but how it occurs in cities is often puzzling3. If the growth rates of urban particles are similar to those found in cleaner environments (1-10 nanometres per hour), then existing understanding suggests that new urban particles should be rapidly scavenged by the high concentration of pre-existing particles. Here we show, through experiments performed under atmospheric conditions in the CLOUD chamber at CERN, that below about +5 degrees Celsius, nitric acid and ammonia vapours can condense onto freshly nucleated particles as small as a few nanometres in diameter. Moreover, when it is cold enough (below -15 degrees Celsius), nitric acid and ammonia can nucleate directly through an acid-base stabilization mechanism to form ammonium nitrate particles. Given that these vapours are often one thousand times more abundant than sulfuric acid, the resulting particle growth rates can be extremely high, reaching well above 100 nanometres per hour. However, these high growth rates require the gas-particle ammonium nitrate system to be out of equilibrium in order to sustain gas-phase supersaturations. In view of the strong temperature dependence that we measure for the gas-phase supersaturations, we expect such transient conditions to occur in inhomogeneous urban settings, especially in wintertime, driven by vertical mixing and by strong local sources such as traffic. Even though rapid growth from nitric acid and ammonia condensation may last for only a few minutes, it is nonetheless fast enough to shepherd freshly nucleated particles through the smallest size range where they are most vulnerable to scavenging loss, thus greatly increasing their survival probability. We also expect nitric acid and ammonia nucleation and rapid growth to be important in the relatively clean and cold upper free troposphere, where ammonia can be convected from the continental boundary layer and nitric acid is abundant from electrical storms4,5.

Long-term follow-up study of necrotising pancreatitis: interventions, complications and quality of life.

OBJECTIVE: To describe the long-term consequences of necrotising pancreatitis, including complications, the need for interventions and the quality of life. DESIGN: Long-term follow-up of a prospective multicentre cohort of 373 necrotising pancreatitis patients (2005-2008) was performed. Patients were prospectively evaluated and received questionnaires. Readmissions (ie, for recurrent or chronic pancreatitis), interventions, pancreatic insufficiency and quality of life were compared between initial treatment groups: conservative, endoscopic/percutaneous drainage alone and necrosectomy. Associations of patient and disease characteristics during index admission with outcomes during follow-up were assessed. RESULTS: During a median follow-up of 13.5 years (range 12-15.5 years), 97/373 patients (26%) were readmitted for recurrent pancreatitis. Endoscopic or percutaneous drainage was performed in 47/373 patients (13%), of whom 21/47 patients (45%) were initially treated conservatively. Pancreatic necrosectomy or pancreatic surgery was performed in 31/373 patients (8%), without differences between treatment groups. Endocrine insufficiency (126/373 patients; 34%) and exocrine insufficiency (90/373 patients; 38%), developed less often following conservative treatment (p<0.001 and p=0.016, respectively). Quality of life scores did not differ between groups. Pancreatic gland necrosis >50% during initial admission was associated with percutaneous/endoscopic drainage (OR 4.3 (95% CI 1.5 to 12.2)), pancreatic surgery (OR 3.2 (95% CI 1.1 to 9.5) and development of endocrine insufficiency (OR13.1 (95% CI 5.3 to 32.0) and exocrine insufficiency (OR6.1 (95% CI 2.4 to 15.5) during follow-up. CONCLUSION: Acute necrotising pancreatitis carries a substantial disease burden during long-term follow-up in terms of recurrent disease, the necessity for interventions and development of pancreatic insufficiency, even when treated conservatively during the index admission. Extensive (>50%) pancreatic parenchymal necrosis seems to be an important predictor of interventions and complications during follow-up.

Polycomb Group Protein CBX7 Represses Cardiomyocyte Proliferation Through Modulation of the TARDBP/RBM38 Axis.

BACKGROUND: Shortly after birth, cardiomyocytes exit the cell cycle and cease proliferation. At present, the regulatory mechanisms for this loss of proliferative capacity are poorly understood. CBX7 (chromobox 7), a polycomb group (PcG) protein, regulates the cell cycle, but its role in cardiomyocyte proliferation is unknown. METHODS: We profiled CBX7 expression in the mouse hearts through quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemistry. We overexpressed CBX7 in neonatal mouse cardiomyocytes through adenoviral transduction. We knocked down CBX7 by using constitutive and inducible conditional knockout mice (Tnnt2-Cre;Cbx7fl/+ and Myh6-MCM;Cbx7fl/fl, respectively). We measured cardiomyocyte proliferation by immunostaining of proliferation markers such as Ki67, phospho-histone 3, and cyclin B1. To examine the role of CBX7 in cardiac regeneration, we used neonatal cardiac apical resection and adult myocardial infarction models. We examined the mechanism of CBX7-mediated repression of cardiomyocyte proliferation through coimmunoprecipitation, mass spectrometry, and other molecular techniques. RESULTS: We explored Cbx7 expression in the heart and found that mRNA expression abruptly increased after birth and was sustained throughout adulthood. Overexpression of CBX7 through adenoviral transduction reduced proliferation of neonatal cardiomyocytes and promoted their multinucleation. On the other hand, genetic inactivation of Cbx7 increased proliferation of cardiomyocytes and impeded cardiac maturation during postnatal heart growth. Genetic ablation of Cbx7 promoted regeneration of neonatal and adult injured hearts. Mechanistically, CBX7 interacted with TARDBP (TAR DNA-binding protein 43) and positively regulated its downstream target, RBM38 (RNA Binding Motif Protein 38), in a TARDBP-dependent manner. Overexpression of RBM38 inhibited the proliferation of CBX7-depleted neonatal cardiomyocytes. CONCLUSIONS: Our results demonstrate that CBX7 directs the cell cycle exit of cardiomyocytes during the postnatal period by regulating its downstream targets TARDBP and RBM38. This is the first study to demonstrate the role of CBX7 in regulation of cardiomyocyte proliferation, and CBX7 could be an important target for cardiac regeneration.

Safety and Efficacy of NVX-CoV2373 Covid-19 Vaccine.

BACKGROUND: Early clinical data from studies of the NVX-CoV2373 vaccine (Novavax), a recombinant nanoparticle vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that contains the full-length spike glycoprotein of the prototype strain plus Matrix-M adjuvant, showed that the vaccine was safe and associated with a robust immune response in healthy adult participants. Additional data were needed regarding the efficacy, immunogenicity, and safety of this vaccine in a larger population. METHODS: In this phase 3, randomized, observer-blinded, placebo-controlled trial conducted at 33 sites in the United Kingdom, we assigned adults between the ages of 18 and 84 years in a 1:1 ratio to receive two intramuscular 5-µg doses of NVX-CoV2373 or placebo administered 21 days apart. The primary efficacy end point was virologically confirmed mild, moderate, or severe SARS-CoV-2 infection with an onset at least 7 days after the second injection in participants who were serologically negative at baseline. RESULTS: A total of 15,187 participants underwent randomization, and 14,039 were included in the per-protocol efficacy population. Of the participants, 27.9% were 65 years of age or older, and 44.6% had coexisting illnesses. Infections were reported in 10 participants in the vaccine group and in 96 in the placebo group, with a symptom onset of at least 7 days after the second injection, for a vaccine efficacy of 89.7% (95% confidence interval [CI], 80.2 to 94.6). No hospitalizations or deaths were reported among the 10 cases in the vaccine group. Five cases of severe infection were reported, all of which were in the placebo group. A post hoc analysis showed an efficacy of 86.3% (95% CI, 71.3 to 93.5) against the B.1.1.7 (or alpha) variant and 96.4% (95% CI, 73.8 to 99.5) against non-B.1.1.7 variants. Reactogenicity was generally mild and transient. The incidence of serious adverse events was low and similar in the two groups. CONCLUSIONS: A two-dose regimen of the NVX-CoV2373 vaccine administered to adult participants conferred 89.7% protection against SARS-CoV-2 infection and showed high efficacy against the B.1.1.7 variant. (Funded by Novavax; EudraCT number, 2020-004123-16.).

Endoscopic ultrasound-guided choledochoduodenostomy using single-step lumen-apposing metal stents for primary drainage of malignant distal biliary obstruction (SCORPION-p): a prospective pilot study.

BACKGROUND: This study aimed to assess the safety and feasibility of endoscopic ultrasound-guided choledochoduodenostomy (EUS-CDS) using a lumen-apposing metal stent (LAMS) as a primary drainage strategy in patients with distal malignant biliary obstruction (MBO). METHODS: A prospective, single-center, pilot study was conducted in patients with pathology-confirmed MBO without gastric outlet obstruction. The primary outcome was technical success. Secondary outcomes included clinical success, adverse events (AEs), and reinterventions. The study was registered in the Netherlands Trial Registry (registry number NL9757). RESULTS: 22 patients were enrolled (median age 69.5 years [interquartile range 64-75.3]). Technical success was achieved in 20/22 patients (91 %). AEs occurred in one patient, namely perforation following inadequate stent deployment (5 %), which was treated in the same procedure. Clinical success was achieved in 19/22 patients (86 %). Stent dysfunction was observed in 11/20 patients (55 %) after technically successful EUS-CDS: two patients were treated conservatively and nine patients underwent reintervention(s). One patient died within ≤ 30 days due to fulminant disease progression. CONCLUSIONS: The results confirmed the safety and feasibility of EUS-CDS using LAMS as a primary drainage strategy. The high incidence of stent dysfunction should be improved before EUS-CDS with LAMS can be seen as a valid alternative to endoscopic retrograde cholangiopancreatography.

The predictive role of symptoms in COVID-19 diagnostic models: A longitudinal insight.

To investigate the symptoms of SARS-CoV-2 infection, their dynamics and their discriminatory power for the disease using longitudinally, prospectively collected information reported at the time of their occurrence. We have analysed data from a large phase 3 clinical UK COVID-19 vaccine trial. The alpha variant was the predominant strain. Participants were assessed for SARS-CoV-2 infection via nasal/throat PCR at recruitment, vaccination appointments, and when symptomatic. Statistical techniques were implemented to infer estimates representative of the UK population, accounting for multiple symptomatic episodes associated with one individual. An optimal diagnostic model for SARS-CoV-2 infection was derived. The 4-month prevalence of SARS-CoV-2 was 2.1%; increasing to 19.4% (16.0%-22.7%) in participants reporting loss of appetite and 31.9% (27.1%-36.8%) in those with anosmia/ageusia. The model identified anosmia and/or ageusia, fever, congestion, and cough to be significantly associated with SARS-CoV-2 infection. Symptoms' dynamics were vastly different in the two groups; after a slow start peaking later and lasting longer in PCR+ participants, whilst exhibiting a consistent decline in PCR- participants, with, on average, fewer than 3 days of symptoms reported. Anosmia/ageusia peaked late in confirmed SARS-CoV-2 infection (day 12), indicating a low discrimination power for early disease diagnosis.

Effects of climate warming on photosynthesis in boreal tree species depend on soil moisture.

Climate warming will influence photosynthesis via thermal effects and by altering soil moisture1-11. Both effects may be important for the vast areas of global forests that fluctuate between periods when cool temperatures limit photosynthesis and periods when soil moisture may be limiting to carbon gain4-6,9-11. Here we show that the effects of climate warming flip from positive to negative as southern boreal forests transition from rainy to modestly dry periods during the growing season. In a three-year open-air warming experiment with juveniles of 11 temperate and boreal tree species, an increase of 3.4 °C in temperature increased light-saturated net photosynthesis and leaf diffusive conductance on average on the one-third of days with the wettest soils. In all 11 species, leaf diffusive conductance and, as a result, light-saturated net photosynthesis decreased during dry spells, and did so more sharply in warmed plants than in plants at ambient temperatures. Consequently, across the 11 species, warming reduced light-saturated net photosynthesis on the two-thirds of days with driest soils. Thus, low soil moisture may reduce, or even reverse, the potential benefits of climate warming on photosynthesis in mesic, seasonally cold environments, both during drought and in regularly occurring, modestly dry periods during the growing season.

Quantized Majorana conductance.

Majorana zero-modes-a type of localized quasiparticle-hold great promise for topological quantum computing. Tunnelling spectroscopy in electrical transport is the primary tool for identifying the presence of Majorana zero-modes, for instance as a zero-bias peak in differential conductance. The height of the Majorana zero-bias peak is predicted to be quantized at the universal conductance value of 2e2/h at zero temperature (where e is the charge of an electron and h is the Planck constant), as a direct consequence of the famous Majorana symmetry in which a particle is its own antiparticle. The Majorana symmetry protects the quantization against disorder, interactions and variations in the tunnel coupling. Previous experiments, however, have mostly shown zero-bias peaks much smaller than 2e2/h, with a recent observation of a peak height close to 2e2/h. Here we report a quantized conductance plateau at 2e2/h in the zero-bias conductance measured in indium antimonide semiconductor nanowires covered with an aluminium superconducting shell. The height of our zero-bias peak remains constant despite changing parameters such as the magnetic field and tunnel coupling, indicating that it is a quantized conductance plateau. We distinguish this quantized Majorana peak from possible non-Majorana origins by investigating its robustness to electric and magnetic fields as well as its temperature dependence. The observation of a quantized conductance plateau strongly supports the existence of Majorana zero-modes in the system, consequently paving the way for future braiding experiments that could lead to topological quantum computing.

Guideline summary: assessment, diagnosis, care and support for people with dementia and their carers [Scottish Intercollegiate Guidelines Network SIGN Guideline 168].

The Scottish Intercollegiate Guidelines Network (SIGN) have recently published their guideline SIGN168 on 'Assessment, Diagnosis, Care, and Support for People with Dementia and their Carers'. The guideline makes evidence-based recommendations for best practice in the assessment, care and support of adults living with dementia. Topics featured in this guideline are limited to those prioritised by stakeholders, especially people with lived and living experience, and those not well covered under pre-existing guidance. We summarise the guideline recommendations related to identification and diagnosis of dementia, investigative procedures, postdiagnostic support living with dementia, including non-pharmacological approaches for distressed behaviours, using technology to support people with dementia, grief and dementia and changing needs of people with dementia. The guideline content is summarised as officially published, with additional commentary in the final section.

Virus Infections in Older People.

Older people are more prone to viral infections, and often have worse outcomes. This was well demonstrated during the COVID-19 pandemic, where a disproportionate number of deaths occurred in the oldest and frailest people. The assessment of the older person with a viral infection is complicated by the high prevalence of multiple comorbidities and sensory or cognitive impairment. They often present with common geriatric syndromes such as falls or delirium, rather than the more typical features of a viral illness in younger people. Comprehensive geriatric assessment by a specialist multidisciplinary team is the gold standard of management, as viral illness is unlikely to present in isolation of other healthcare needs. We discuss the presentation, diagnosis, prevention, and management of common viral infections-respiratory syncytial virus, coronavirus, norovirus, influenza, hepatitis, herpes, and dengue viruses-with special consideration of infections in the older patient.

Direct field evidence of autocatalytic iodine release from atmospheric aerosol.

Reactive iodine plays a key role in determining the oxidation capacity, or cleansing capacity, of the atmosphere in addition to being implicated in the formation of new particles in the marine boundary layer. The postulation that heterogeneous cycling of reactive iodine on aerosols may significantly influence the lifetime of ozone in the troposphere not only remains poorly understood but also heretofore has never been observed or quantified in the field. Here, we report direct ambient observations of hypoiodous acid (HOI) and heterogeneous recycling of interhalogen product species (i.e., iodine monochloride [ICl] and iodine monobromide [IBr]) in a midlatitude coastal environment. Significant levels of ICl and IBr with mean daily maxima of 4.3 and 3.0 parts per trillion by volume (1-min average), respectively, have been observed throughout the campaign. We show that the heterogeneous reaction of HOI on marine aerosol and subsequent production of iodine interhalogens are much faster than previously thought. These results indicate that the fast formation of iodine interhalogens, together with their rapid photolysis, results in more efficient recycling of atomic iodine than currently considered in models. Photolysis of the observed ICl and IBr leads to a 32% increase in the daytime average of atomic iodine production rate, thereby enhancing the average daytime iodine-catalyzed ozone loss rate by 10 to 20%. Our findings provide direct field evidence that the autocatalytic mechanism of iodine release from marine aerosol is important in the atmosphere and can have significant impacts on atmospheric oxidation capacity.

Managing dysfunctions and reinterventions in endoscopic ultrasound-guided choledochoduodenostomy with lumen apposing metal stents: Illustrated technical review (with videos).

Endoscopic ultrasound-guided choledochoduodenostomy (EUS-CDS) with lumen apposing metal stent is emerging both as a rescue strategy and a primary treatment for distal malignant biliary obstruction. The large-scale diffusion of the procedure and improved overall survival of patients with pancreatobiliary neoplasms is resulting in a growing population of long-term EUS-CDS lumen apposing metal stent carriers. Recent studies have reported a need for reintervention during follow-up as high as 55%, and the Leuven-Amsterdam-Milan Study Group classification has been developed, identifying five mechanisms of stent dysfunction and 11 possible rescue strategies aimed at restoring biliary drainage. This illustrated technical review aims to further dissect the recent classification through a comprehensive analysis of nine illustrative cases, offering insights into the pathophysiology underlying dysfunction and clinical reasoning behind rescue interventions, as well as technical considerations and practical tips and tricks. By exploring mechanisms of dysfunction, this review also assists clinicians in selecting the ideal candidates for EUS-CDS while identifying patients deemed high risk for dysfunction or clinical failure.

Evaluating Natural Language Processing Packages for Predicting Hospital-Acquired Pressure Injuries From Clinical Notes.

Incidence of hospital-acquired pressure injury, a key indicator of nursing quality, is directly proportional to adverse outcomes, increased hospital stays, and economic burdens on patients, caregivers, and society. Thus, predicting hospital-acquired pressure injury is important. Prediction models use structured data more often than unstructured notes, although the latter often contain useful patient information. We hypothesize that unstructured notes, such as nursing notes, can predict hospital-acquired pressure injury. We evaluate the impact of using various natural language processing packages to identify salient patient information from unstructured text. We use named entity recognition to identify keywords, which comprise the feature space of our classifier for hospital-acquired pressure injury prediction. We compare scispaCy and Stanza, two different named entity recognition models, using unstructured notes in Medical Information Mart for Intensive Care III, a publicly available ICU data set. To assess the impact of vocabulary size reduction, we compare the use of all clinical notes with only nursing notes. Our results suggest that named entity recognition extraction using nursing notes can yield accurate models. Moreover, the extracted keywords play a significant role in the prediction of hospital-acquired pressure injury.

Towards a 'step-up approach' for the treatment of recurrent non-stenotic cholangitis after hepaticojejunostomy: systematic review.

BACKGROUND: Recurrent non-stenotic cholangitis (NSC) is a difficult-to-treat complication after hepaticojejunostomy (HJ) leading to multiple hospital admissions. The optimal treatment strategy is unclear as a systematic review is lacking. METHODS: A systematic review was performed including studies detailing treatment strategies and outcomes for recurrent NSC in patients with a surgical HJ in PubMed, Embase, and Cochrane Library (inception - September 2023). Primary outcome was resolution of NSC as defined by the included studies. RESULTS: Overall, 72 patients with recurrent NSC after HJ were included from seven retrospective studies. The rate of recurrent NSC (specified in five studies) was 4% (46/1143 HJs). Diagnosis of NSC was mostly made after excluding HJ stenosis and assessing bile reflux. Initial treatment consisted of short-course antibiotics for all patients. Second step treatment consisted of prolonged antibiotic therapy (n = 10, 13.8%). Third step treatment consisted of surgery (n = 9, n = 12.5%); mostly lengthening of the biliary loop. Together, the overall reported resolution-rate of recurrent NSC was 66.6% (n = 48). CONCLUSION: A 'step-up approach' may be effective in two-thirds of patients with recurrent NSC after HJ, starting with short-course antibiotics, and eventually adding prolonged antibiotic therapy and, ultimately, surgery aimed at preventing intestinal content and food reflux. Prospective studies are needed.

Recurrent cholangitis in patients with a non-stenotic hepaticojejunostomy: incidence and risk factors.

BACKGROUND: Cholangitis is a well-known complication after hepaticojejunostomy (HJ), which is mainly caused by a stenotic anastomosis. However, the rate of cholangitis in patients with a non-stenotic (i.e. patent) HJ is unknown. We aimed to evaluate the incidence and risk factors of recurrent cholangitis in patients with a non-stenotic HJ. METHODS: This single-center retrospective cohort study included all consecutive patients who had undergone hepatobiliary or pancreatic (HPB) surgery requiring HJ (2015-2022). Primary outcome was recurrent non-stenotic cholangitis, risk factors for recurrent non-stenotic cholangitis were identified using logistic regression. RESULTS: Overall, 835 patients with a HJ were included of whom 31/698 (4.4%) patients developed recurrent cholangitis with a non-stenotic HJ during a median follow-up of 34 months (IQR 22-50) and 98/796 (12.3%) patients developed a symptomatic HJ stenosis. These 31 patients experienced 205 cholangitis episodes, median 7.0 (IQR 3.8-8.8) per patient, and 71/205 (34.6%) cholangitis episodes required hospitalization. Male sex (aOR 3.17 (95% CI: 1.34-7.49)) and benign disease (aOR 2.97, 95% CI 1.40-6.33) were identified as risk factors for recurrent cholangitis in non-stenotic HJ in both univariate and multivariable analysis. CONCLUSION: This study shows that 4% of patients developed recurrent cholangitis without an underlying HJ stenosis.

Patient selection for urgent endoscopic retrograde cholangio-pancreatography by endoscopic ultrasound in predicted severe acute biliary pancreatitis (APEC-2): a multicentre prospective study.

OBJECTIVE: Routine urgent endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic biliary sphincterotomy (ES) does not improve outcome in patients with predicted severe acute biliary pancreatitis. Improved patient selection for ERCP by means of endoscopic ultrasonography (EUS) for stone/sludge detection may challenge these findings. DESIGN: A multicentre, prospective cohort study included patients with predicted severe acute biliary pancreatitis without cholangitis. Patients underwent urgent EUS, followed by ERCP with ES in case of common bile duct stones/sludge, within 24 hours after hospital presentation and within 72 hours after symptom onset. The primary endpoint was a composite of major complications or mortality within 6 months after inclusion. The historical control group was the conservative treatment arm (n=113) of the randomised APEC trial (Acute biliary Pancreatitis: urgent ERCP with sphincterotomy versus conservative treatment, patient inclusion 2013-2017) applying the same study design. RESULTS: Overall, 83 patients underwent urgent EUS at a median of 21 hours (IQR 17-23) after hospital presentation and at a median of 29 hours (IQR 23-41) after start of symptoms. Gallstones/sludge in the bile ducts were detected by EUS in 48/83 patients (58%), all of whom underwent immediate ERCP with ES. The primary endpoint occurred in 34/83 patients (41%) in the urgent EUS-guided ERCP group. This was not different from the 44% rate (50/113 patients) in the historical conservative treatment group (risk ratio (RR) 0.93, 95% CI 0.67 to 1.29; p=0.65). Sensitivity analysis to correct for baseline differences using a logistic regression model also showed no significant beneficial effect of the intervention on the primary outcome (adjusted OR 1.03, 95% CI 0.56 to 1.90, p=0.92). CONCLUSION: In patients with predicted severe acute biliary pancreatitis without cholangitis, urgent EUS-guided ERCP with ES did not reduce the composite endpoint of major complications or mortality, as compared with conservative treatment in a historical control group. TRIAL REGISTRATION NUMBER: ISRCTN15545919.