The Paradox of Modern Technology in Standardizing Thermal Liver Ablation: Fostering Uniformity or Diversity?

PURPOSE: Currently, significant medical practice variation exists in thermal ablation (TA) of malignant liver tumors with associated differences in outcomes. The IMaging and Advanced Guidance for workflow optimization in Interventional Oncology (IMAGIO) consortium aims to integrate interventional oncology into the standard clinical pathway for cancer treatment in Europe by 2030, by development of a standardized low-complex-high-precision workflow for TA of malignant liver tumors. This study was conducted at the start of the IMAGIO project with the aim to explore the current state and future role of modern technology in TA of malignant liver tumors. MATERIALS AND METHODS: A cross-sectional questionnaire was conducted followed by an expert focus group discussion with core members and collaborating partners of the consortium. RESULTS: Of the 13 participants, 10 respondents filled in the questionnaire. During the focus group discussion, there was consensus on the need for international standardization in TA and several aspects of the procedure, such as planning based on cross-sectional images, the adoption of different techniques for needle placement and the importance of needle position- and post-ablative margin confirmation scans. Yet, also considerable heterogeneity was reported in the adoption of modern technology, particularly in navigational systems and computer-assisted margin assessment. CONCLUSION: This study mirrored the current diversity in workflow of thermal liver ablation. To obtain comparable outcomes worldwide, standardization is needed. While advancements in tools and software hold the potential to homogenize outcome measurement and minimize operator-dependent variability, the rapid increase in availability also contributes to enhanced workflow variation.

Shedding Light on the Origin of

Asymptotic giant branch stars are responsible for the production of most of the heavy isotopes beyond Sr observed in the solar system. Among them, isotopes shielded from the r-process contribution by their stable isobars are defined as s-only nuclei. For a long time the abundance of ^{204}Pb, the heaviest s-only isotope, has been a topic of debate because state-of-the-art stellar models appeared to systematically underestimate its solar abundance. Besides the impact of uncertainties from stellar models and galactic chemical evolution simulations, this discrepancy was further obscured by rather divergent theoretical estimates for the neutron capture cross section of its radioactive precursor in the neutron-capture flow, ^{204}Tl (t_{1/2}=3.78 yr), and by the lack of experimental data on this reaction. We present the first ever neutron capture measurement on ^{204}Tl, conducted at the CERN neutron time-of-flight facility n_TOF, employing a sample of only 9 mg of ^{204}Tl produced at the Institute Laue Langevin high flux reactor. By complementing our new results with semiempirical calculations we obtained, at the s-process temperatures of kT≈8 keV and kT≈30 keV, Maxwellian-averaged cross sections (MACS) of 580(168) mb and 260(90) mb, respectively. These figures are about 3% lower and 20% higher than the corresponding values widely used in astrophysical calculations, which were based only on theoretical calculations. By using the new ^{204}Tl MACS, the uncertainty arising from the ^{204}Tl(n,γ) cross section on the s-process abundance of ^{204}Pb has been reduced from ∼30% down to +8%/-6%, and the s-process calculations are in agreement with the latest solar system abundance of ^{204}Pb reported by K. Lodders in 2021.

Intravenous lidocaine for refractory pain in patients with pancreatic ductal adenocarcinoma and chronic pancreatitis (LIDOPAN): a multicenter prospective non-randomized pilot study.

INTRODUCTION: Refractory pain is a major clinical problem in patients with pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP). New, effective therapies to reduce pain are urgently needed. Intravenous lidocaine is used in clinical practice in patients with PDAC and CP, but its efficacy has not been studied prospectively. METHODS: Multicentre prospective non-randomized pilot study including patients with moderate or severe pain (NRS ≥ 4) associated with PDAC or CP in 5 Dutch centers. An intravenous lidocaine bolus of 1.5mg/kg, was followed by continuous infusion at 1.5 mg/kg/hour. The dose was raised every 15 minutes until treatment response (up to a maximum 2mg/kg/hour) and consecutively administered for two hours. Primary outcome was the mean difference in pain severity, pre-infusion and the first day after (Brief Pain Inventory [BPI] scale 1-10). A BPI decrease ≥ 1.3 points was considered clinically relevant. RESULTS: Overall, 30 patients were included, 19 with PDAC (63%) and 11 with CP (37%). The mean difference in BPI at day one was 1.1 (SD±1.3) points for patients with PDAC and 0.5 (SD±1.7) for CP patients. A clinically relevant decrease in BPI on day one was reported in 9/29 patients (31%), this response lasted up to one month. No serious complications were reported, and only three minor complications (vertigo, nausea, tingling of mouth). Treatment with lidocaine did not impact quality of life. CONCLUSION: Intravenous lidocaine in patients with painful PDAC and CP did not show an overall clinically relevant reduction of pain. However, this pilot study shows that the treatment is feasible in this patient group, and had a positive effect in a third of patients which lasted up to a month with only minor side effects. To prove or exclude the efficacy of intravenous lidocaine, the study should be performed in a study with a greater sample size and less heterogeneous patient group.

Clinical implications of different methods to assess left atrial remodeling: A comparative study between echocardiography and cardiac magnetic resonance imaging for left atrial volume index quantification.

BACKGROUND: Left atrial volume index (LAVI) serves as a crucial marker for assessing left atrial (LA) remodeling, particularly in patients with mitral valve regurgitation (MR). Recent guidelines recommend a LAVI exceeding 60 mL/m2 as Class IIa recommendation for mitral valve repair surgery in asymptomatic MR patients with preserved left ventricular function. Traditionally, echocardiography is the standard for assessing LAVI in MR patients. However, cardiac magnetic resonance imaging (CMR) is increasingly recognized for its more precise measurements of cardiac dimensions and volumes. But still, literature remains scarce on comparing the efficacy of both modalities in assessing LAVI measurements. METHODS: This retrospective study included 168 MR patients undergoing both echocardiography and CMR assessments within a six-month period. LAVI measurements were compared using Pearson correlation and Bland-Altman plots. Patients were stratified based on MR grades, and clinical implications were assessed. RESULTS: Mean LAVI differed significantly between echocardiography and CMR (47.1 ± 20.8 mL/m2 versus 70 ± 20.3 mL/m2, p < 0.001, respectively). CMR consistently yielded higher LAVI measurements compared to echocardiography, with a mean difference of approximately 20 mL/m2. CMR measurements resulted in an increased incidence of patients meeting the class IIa LAVI criterion (LAVI >60 mL/m2) by 37%. Variations in LAVI did not differ across MR grades. CONCLUSION: Echocardiography systematically underestimates LAVI compared to CMR in MR patients. While current guidelines rely on echocardiography, CMR's precision suggests the need for CMR-specific LAVI cutoff values to guide clinical management effectively. Establishing such values could refine patient stratification and timing of surgery, potentially improving clinical outcomes for MR patients.

Contaminated Duodenoscopes in Endoscopic Retrograde Cholangiopancreatography: Sensitivity of detection and risk of underdetection.

BACKGROUND AND AIMS: Periodic duodenoscope cultures are essential to timely detect contamination, but their sensitivity remains unknown. This study aims to determine the sensitivity of duodenoscope cultures and to estimate the prevalence of contaminated duodenoscope use. METHODS: We combined duodenoscope microbiological surveillance data from March 2015 to June 2022 with usage data to evaluate patient exposure to duodenoscopes contaminated with microorganisms of gut or oral origin (MGO). We identified duodenoscopes with repeated species-level contamination within a year and used molecular typing to confirm genetic relatedness. Genetically related microorganisms over multiple duodenoscope cultures of a single duodenoscope indicated a period of sustained contamination and a cluster was defined as overlapping periods of sustained contamination between different duodenoscopes. If microorganisms were not available for molecular analysis, we marked the period as unconfirmed. A sample was defined as false-negative if it did not show the target microorganism(s) in a period of sustained contamination. We used three scenarios to hypothesize about contaminated use and culture sensitivity. RESULTS: We included 556 duodenoscope cultures with 185 (33.3%) contaminated with MGO. The total usage of duodenoscopes was 5226. We identified one period of sustained contamination, six unconfirmed periods, and two clusters. Depending on our scenario assumptions, the percentage of contaminated use varied from 12.3% to 23.7%, and culture sensitivity ranged from 82.2% to 98.9%. CONCLUSIONS: Limited sensitivity of duodenoscope cultures leads to improper clearance of duodenoscopes for clinical use, increasing risks of outbreaks. The applicability of a single culture to end a duodenoscope's quarantine should be reevaluated.

High expression of oleoyl-ACP hydrolase underpins life-threatening respiratory viral diseases.

Respiratory infections cause significant morbidity and mortality, yet it is unclear why some individuals succumb to severe disease. In patients hospitalized with avian A(H7N9) influenza, we investigated early drivers underpinning fatal disease. Transcriptomics strongly linked oleoyl-acyl-carrier-protein (ACP) hydrolase (OLAH), an enzyme mediating fatty acid production, with fatal A(H7N9) early after hospital admission, persisting until death. Recovered patients had low OLAH expression throughout hospitalization. High OLAH levels were also detected in patients hospitalized with life-threatening seasonal influenza, COVID-19, respiratory syncytial virus (RSV), and multisystem inflammatory syndrome in children (MIS-C) but not during mild disease. In olah-/- mice, lethal influenza infection led to survival and mild disease as well as reduced lung viral loads, tissue damage, infection-driven pulmonary cell infiltration, and inflammation. This was underpinned by differential lipid droplet dynamics as well as reduced viral replication and virus-induced inflammation in macrophages. Supplementation of oleic acid, the main product of OLAH, increased influenza replication in macrophages and their inflammatory potential. Our findings define how the expression of OLAH drives life-threatening viral disease.

Hoffa's fat pad resection during total knee arthroplasty does not affect functioning and gait: a double-blind randomized clinical trial.

INTRODUCTION: Hoffa's fat pad is considered a source of anterior knee pain and may limit prosthetic knee function. Resection of Hoffa's fat pad in total knee arthroplasty (TKA), however, is controversial, and little is known about the functional outcomes including gait quality. This double-blind randomized controlled trial (i) compared functional recovery between TKAs where Hoffa was resected or preserved, and (ii) compared recovery of self-reported function with objective (gait-related) outcomes. MATERIALS AND METHODS: Eighty-five patients (age 66.4 ± 8.0 years, 47% women) scheduled to undergo TKA for primary osteoarthritis were randomly assigned to either fat pad resection or preservation. Subjective measures of functioning were assessed at baseline, 6 weeks, 3 months, and 12 months postoperatively and included the Knee Injury and Osteoarthritis Outcome Score (KOOS), Kujala, and visual analog scale (VAS) for pain. Objective measures of functioning were assessed at baseline, 3 months, and 12 months postoperatively and included instrumented range-of-motion and gait analysis. Longitudinal analyses (generalized estimating equations) were used to compare recovery between groups, and chi-square tests compared attainment of minimal clinical important difference (MCID) and patient acceptable symptom state (PASS). Finally, correlation analyses explored associations between subjective and objective recovery in function. RESULTS: Resection patients showed poorer improvement in KOOS quality of life in the first 6 weeks (B=-10.02, 95% confidence interval (CI) [-18.91, -1.12], p = .027), but stronger improvement in knee extension after 3 months (B = 3.02, 95%CI [0.45, 5.60], p = .021) compared to preservation patients. Regarding MCID or PASS, no differences were noted between groups at 3 and 12 months (all p > .05). Subjective function substantially improved in the first 3 months, while objective outcomes improved only between 3 and 12 months. Moderate to strong correlations were identified between changes in knee flexion and gait with Kujala and KOOS in the resection but not in the preservation group. CONCLUSIONS: Similar functional outcomes were achieved after TKA with or without resection of Hoffa's fat pad. Hence, removing the fat pad to promote surgical exposure will not affect functional outcomes including gait quality. Functional recovery of objective outcomes was not always consistent with subjective recovery, suggesting that both self-reported as well as objective, gait-related outcomes may provide meaningful information on functional recovery following TKA. TRIAL REGISTRATION: This clinical trial was prospectively registered under the Netherlands Trial Registry (# NL3638). This registry has recently been replaced by the Dutch Trial Registry where this study can be accessed via https://onderzoekmetmensen.nl/en/trial/20994 .

The role of myocardial blood volume in the pathophysiology of angina with non-obstructed coronary arteries: The MICORDIS study.

BACKGROUND: Angina with Non-Obstructed Coronary Arteries (ANOCA) involves abnormal vasomotor responses. While reduced coronary flow is an established contributor to myocardial hypoxia, myocardial blood volume (MBV) independently regulates myocardial oxygen uptake but its role in ANOCA remains unclear. OBJECTIVES: We hypothesized that reduced MBV contributes to ANOCA, and associates with insulin resistance in ANOCA. METHODS: MBV in ANOCA patients was compared to age- and sex-matched healthy controls. ANOCA patients underwent coronary angiography with invasive coronary function testing (CFT) to identify vasospasm and coronary microvascular dysfunction. In all subjects MBV was quantified at baseline, during hyperinsulinemia and during dobutamine-induced stress using myocardial contrast echocardiography (MCE). The hyperinsulinemic-euglycemic clamp was used to assess insulin resistance. RESULTS: Twenty-eight ANOCA patients (21% men, 56.8 ± 8.6 years) and 28 healthy controls (21% men, 56.5 ± 7.0 years) were included. During CFT 11% of patients showed epicardial vasospasm, 39% microvascular vasospasm, 25% coronary microvascular dysfunction, and 11% of patients had a negative CFT. ANOCA patients had significant lower insulin-sensitivity (p < 0.01). During MCE, ANOCA patients showed a significantly lower MBV at baseline (0.388 vs 0.438 mL/mL, p = 0.04), during hyperinsulinemia (0.395 vs 0.447 mL/mL, p = 0.02), and during dobutamine-induced stress (0.401 vs 0.476 mL/mL, p = 0.030). CONCLUSIONS: In ANOCA patients MBV is diminished at baseline, during hyperinsulinemia and dobutamine-induced stress in the absence of differences in microvascular recruitment. These findings support the presence of capillary rarefaction in ANOCA patients. ANOCA patients showed metabolic insulin resistance, but insulin did not acutely alter myocardial perfusion.

A Structural Comparison of Oral SARS-CoV-2 Drug Candidate Ibuzatrelvir Complexed with the Main Protease (Mpro) of SARS-CoV-2 and MERS-CoV.

Ibuzatrelvir (1) was recently disclosed and patented by Pfizer for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has received fast-track status from the USA Food and Drug Administration (FDA) and has entered phase III clinical trials as a possible replacement for Paxlovid. Like nirmatrelvir (2) in Paxlovid, this orally active drug candidate is designed to target viral main proteases (Mpro) through reversible covalent interaction of its nitrile warhead with the active site thiol of the chymotrypsin-like cysteine protease (3CL protease). Inhibition of Mpro hinders the processing of the proteins essential for viral replication in vivo. However, ibuzatrelvir apparently does not require ritonavir (3), which is coadministered in Paxlovid to block human oxidative metabolism of nirmatrelvir. Here, we report the crystal structure of the complex of ibuzatrelvir with the active site of SARS-CoV-2 Mpro at 2.0 Šresolution. In addition, we show that ibuzatrelvir also potently inhibits the Mpro of Middle East respiratory syndrome-related coronavirus (MERS-CoV), which is fortunately not widespread but can be dangerously lethal (∼36% mortality). Co-crystal structures show that the binding mode of the drug to both active sites is similar and that the trifluoromethyl group of the inhibitor fits precisely into a critical S2 substrate binding pocket of the main proteases. However, our results also provide a rationale for the differences in potency of ibuzatrelvir for these two proteases due to minor differences in the substrate preferences leading to a weaker H-bond network in MERS-CoV Mpro. In addition, we examined the reversibility of compound binding to both proteases, which is an important parameter in reducing off-target effects as well as the potential immunogenicity. The crystal structures of the ibuzatrelvir complexes with Mpro of SARS-CoV-2 and of MERS-CoV will further assist drug design for coronaviral infections in humans and animals.

ITPK1 Sensitizes Tumor Cells to IgA-dependent Neutrophil Killing In Vivo.

Neutrophils can efficiently trigger cytotoxicity toward tumor cells and other target cells upon engagement of the IgA receptor CD89. However, the cell-intrinsic factors that influence the induction of cell death upon exposure to neutrophil effector mechanisms in vivo remain largely unknown. To uncover genetic regulators that influence target cell sensitivity to IgA-induced neutrophil-mediated killing, we used a human CD89 (hCD89) transgenic mouse model in which IgA-mediated killing of Her2-positive CD47-deficient murine target cells is mediated by neutrophils. Using a genome-wide in vivo screening approach, we demonstrate that deletion of the gene encoding inositol-tetrakisphosphate 1 kinase (ITPK1) increases survival of target cells in anti-Her2 IgA-treated mice. Moreover, we show that this effect depends on neutrophil activity and on the ITPK1 kinase domain. Notably, ITPK1 deficiency did not measurably impact survival of IgA-opsonized target cells in in vitro systems, underscoring the importance of in vivo screening systems to uncover physiologically relevant regulators of neutrophil killing.

Comparison of clinical selection-based genetic testing with phenotype-agnostic extensive germline sequencing to diagnose genetic predisposition in children with cancer: a prospective diagnostic study.

BACKGROUND: Germline data have become widely available in paediatric oncology since the introduction of paired tumour-germline sequencing. To guide best practice in cancer predisposition syndrome (CPS) diagnostics, we aimed to assess the diagnostic yield of extensive germline analysis compared with clinical selection-based genetic testing among all children with cancer. METHODS: In this prospective diagnostic study, all children (aged 0-19 years) with newly diagnosed neoplasms treated in the Netherlands national centre, the Princess Máxima Center for Pediatric Oncology (Utrecht, Netherlands), between June 1, 2020, and July 31, 2022, were offered two approaches to identify CPSs. In a phenotype-driven approach, paediatric oncologists used the McGill Interactive Pediatric OncoGenetic Guidelines tool to select children for referral to a clinical geneticist, and for genetic testing. In a phenotype-agnostic approach, CPS gene panel sequencing (143 genes) was offered to all children. In children declining the research CPS gene panel, 49 CPS genes were still analysed as part of routine diagnostics by the pathologist. Children with a causative CPS identified before neoplasm diagnosis were excluded. The primary objective was to compare the number and type of patients diagnosed with a CPS between the two approaches. FINDINGS: 1052 children were eligible for this study, of whom 733 (70%) completed both the phenotype-driven approach and received phenotype-agnostic CPS gene panel sequencing (143 genes n=600; 49 genes n=133). In 53 children, a CPS was identified: 14 (26%) were diagnosed by the phenotype-driven approach only, 22 (42%) by CPS gene sequencing only, and 17 (32%) by both approaches. In 27 (51%) of the 53 children, the identified CPS was considered causative for the child's neoplasm. Only one (4%) of the 27 causative CPSs was missed by the phenotype-driven approach and was identified solely by phenotype-agnostic CPS gene sequencing. In 26 (49%) children, a CPS with uncertain causality was identified, including 14 adult-onset CPSs. The CPSs with uncertain causality were mainly detected by the phenotype-agnostic approach (21 [81%] of 26). INTERPRETATION: Phenotype-driven genetic testing and phenotype-agnostic CPS gene panel sequencing were complementary. The phenotype-driven approach identified the most causative CPSs. CPS gene panel sequencing identified additional CPSs, many of those with uncertain causality, but some with clinical utility. We advise clinical evaluation for CPSs in all children with neoplasms. Phenotype-agnostic testing of all CPS genes is preferably conducted only in research settings and should be paired with counseling. FUNDING: Stichting Kinderen Kankervrij.

Mouse models to investigate in situ cell fate decisions induced by p53.

Investigating how transcription factors control complex cellular processes requires tools that enable responses to be visualised at the single-cell level and their cell fate to be followed over time. For example, the tumour suppressor p53 (also called TP53 in humans and TRP53 in mice) can initiate diverse cellular responses by transcriptional activation of its target genes: Puma to induce apoptotic cell death and p21 to induce cell cycle arrest/cell senescence. However, it is not known how these processes are regulated and initiated in different cell types. Also, the context-dependent interaction partners and binding loci of p53 remain largely elusive. To be able to examine these questions, we here developed knock-in mice expressing triple-FLAG-tagged p53 to facilitate p53 pull-down and two p53 response reporter mice, knocking tdTomato and GFP into the Puma/Bbc3 and p21 gene loci, respectively. By crossing these reporter mice into a p53-deficient background, we show that the new reporters reliably inform on p53-dependent and p53-independent initiation of both apoptotic or cell cycle arrest/senescence programs, respectively, in vitro and in vivo.

Endoscopic ultrasound with tissue acquisition of lymph nodes in patients with potentially resectable intrahepatic cholangiocarcinoma.

Background and study aims Lymph node (LN) involvement is a poor prognostic factor for patients with intrahepatic cholangiocarcinoma (iCCA). The aim of this study was to evaluate the yield and impact on clinical decision making of endoscopic ultrasound with tissue acquisition (EUS-TA) of LNs in patients with potentially resectable iCCA. Patients and methods In this multicenter cohort study, patients with potentially resectable iCCA and preoperative EUS between 2010 and 2020 were retrospectively included. The impact of EUS-TA was defined as the percentage of patients who did not undergo surgical exploration due to pathologically confirmed positive LNs found with EUS-TA. Results A total of 56 patients underwent EUS, with 91% of patients to target suspicious LNs on imaging. EUS-TA of LNs confirmed malignancy in 21 LNs among 19 patients (34%). In 17 patients (30%), surgical exploration was withheld due to nodal involvement. Finally, 24 patients (43%) underwent surgical exploration among whom positive regional LNs were identified in six patients (25%). Conclusions In patients with potentially resectable iCCA and suspicious LNs on cross-sectional imaging, EUS-TA confirmed LN involvement in 30% of patients. Surgical exploration was withheld mostly because of extraregional LN involvement and regional LN involvement in patients with high surgical risk.

Risks of Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis After Liver Transplantation.

Biliary complications are common after liver transplantation (LT). Endoscopic retrograde cholangiopancreatography (ERCP) is the preferred method to treat biliary complications. Nevertheless, ERCP is not without complications and may have a greater complication rate in the LT population. Knowledge of the prevalence, severity, and possible risk factors for post-ERCP pancreatitis (PEP) in LT recipients is limited. Therefore, this study aims to determine the incidence and severity of PEP and identify potential risk factors in LT recipients. This retrospective cohort included patients ≥18 years who underwent ≥1 ERCP procedures after LT between January 2010 and October 2021. Two hundred thirty-two patients were included, who underwent 260 LTs and 1125 ERCPs. PEP occurred after 23 ERCP procedures (2%) with subsequent mortality in three (13%). Multivariate logistic regression identified wire cannulation of the pancreatic duct as a significant risk factor for PEP (OR, 3.21). The complication rate of PEP after LT in this study was shown to be low and is lower compared to patients without a history of LT. Nevertheless, the mortality rate of this group of patients was notably higher.

Dystrophin S3059 phosphorylation partially attenuates denervation atrophy in mouse tibialis anterior muscles.

The dystrophin protein has well-characterized roles in force transmission and maintaining membrane integrity during muscle contraction. Studies have reported decreased expression of dystrophin in atrophying muscles during wasting conditions, and that restoration of dystrophin can attenuate atrophy, suggesting a role in maintaining muscle mass. Phosphorylation of S3059 within the cysteine-rich region of dystrophin enhances binding between dystrophin and ß-dystroglycan, and mimicking phosphorylation at this site by site-directed mutagenesis attenuates myotube atrophy in vitro. To determine whether dystrophin phosphorylation can attenuate muscle wasting in vivo, CRISPR-Cas9 was used to generate mice with whole body mutations of S3059 to either alanine (DmdS3059A) or glutamate (DmdS3059E), to mimic a loss of, or constitutive phosphorylation of S3059, on all endogenous dystrophin isoforms, respectively. Sciatic nerve transection was performed on these mice to determine whether phosphorylation of dystrophin S3059 could attenuate denervation atrophy. At 14 days post denervation, atrophy of tibialis anterior (TA) but not gastrocnemius or soleus muscles, was partially attenuated in DmdS3059E mice relative to WT mice. Attenuation of atrophy was associated with increased expression of ß-dystroglycan in TA muscles of DmdS3059E mice. Dystrophin S3059 phosphorylation can partially attenuate denervation-induced atrophy, but may have more significant impact in less severe modes of muscle wasting.

Late cholangitis after pancreatoduodenectomy: A common complication with or without anatomical biliary obstruction.

BACKGROUND: Postoperative cholangitis is a common complication after pancreatoduodenectomy that can occur with or without anatomical biliary obstruction. This study aimed to investigate the incidence, diagnosis, treatment, and risk factors of cholangitis after pancreatoduodenectomy. METHODS: We performed a retrospective cohort study of consecutive patients who underwent pancreatoduodenectomy in 2 Dutch tertiary pancreatic centers (2010-2019). Primary outcome was postoperative cholangitis, defined as systemic inflammation with abnormal liver tests without another focus of infection, at least 1 month after resection. Diagnostic and therapeutic strategies were evaluated. Two types of postoperative cholangitis were distinguished; obstructive cholangitis (benign stenosis of the hepaticojejunostomy) and nonobstructive cholangitis. Potential risk factors were identified using logistic regression analysis. RESULTS: Postoperative cholangitis occurred in 93 of 900 patients (10.3%). Median time to first episode of cholangitis was 8 months (interquartile range 4-16) after pancreatoduodenectomy. Multiple episodes of cholangitis occurred in 44 patients (47.3%) and readmission was necessary in 83 patients (89.2%). No cholangitis-related mortality was observed. Obstructive cholangitis was seen in 37 patients (39.8%) and nonobstructive cholangitis in 56 patients (60.2%). Surgery was performed for cholangitis in 7 patients (7.5%) and consisted of revision of the hepaticojejunostomy or elongation of the biliary limb. Postoperative biliary leakage (odds ratio 2.56; 95% confidence interval 1.42-4.62; P = .0018) was independently associated with postoperative cholangitis. CONCLUSION: Postoperative cholangitis unrelated to cancer recurrence was seen in 10% of patients after pancreatoduodenectomy. Nonobstructive cholangitis was more common than obstructive cholangitis. Postoperative biliary leakage was an independent risk factor.

Clinical use of [18F]fluoro-ethyl-L-tyrosine PET co-registered with MRI for localizing prolactinoma remnants.

PURPOSE: To assess the utility of [18F]fluoroethyl-L-tyrosine PET co-registered with magnetic resonance imaging ([18F]FET-PET/MRICR) in patients with difficult-to-localize prolactinoma to inform clinical decision-making and (surgical) treatment planning. METHODS: Retrospective cohort study of 17 consecutive patients with prolactinoma undergoing [18F]FET-PET/MRICR between October 2020 and September 2022 for either (1) additional information in case of difficult-to-visualize remnants after prior transsphenoidal surgery (TSS), or pharmacological treatment, or (2) radiological diagnosis in absence of a (clear) adenoma on diagnostic/post-treatment conventional MRI. RESULTS: [18F]FET-PET/MRICR identified a lesion in 14/17 patients, yet failed to identify active lesions in 2 patients with negative conventional MRI despite prolactin > 7.5 times upper limit of normal. [18F]FET-PET/MRICR results were inconclusive in 1 patient due to diffuse tracer uptake 10 weeks post-surgery. [18F]FET-PET/MRICR was completely concordant with a suspected lesion on conventional MRI in 10/17 patients, and partially concordant in 3/17 patients. New foci were identified in 4/17 patients. The [18F]FET-PET/MRICR conclusions influenced clinical shared decision-making in 15/17 patients, of whom 7 patients underwent TSS and 8 refrained from TSS. One patient underwent TSS despite negative [18F]FET-PET/MRICR, and one patient underwent additional imaging. Intraoperative findings corresponded with [18F]FET-PET/MRICR in 5/8 patients, and immunohistochemistry was positive in 5/8 patients. The treatment goal was achieved in 7/8 patients, and remission was achieved in 5/7 patients in whom total resection was considered feasible. CONCLUSION: [18F]FET-PET/MRICR can be of added value in the preoperative decision-making process for selected patients with difficult-to-localize prolactinoma (remnants), or patients lacking a substrate on conventional MRI.

Candida tropicalis PMT2 Is a Dispensable Gene for Viability but Required for Proper Interaction with the Host.

Candidemia is an opportunistic mycosis with high morbidity and mortality rates. Even though Candida albicans is the main causative agent, other Candida species, such as Candida tropicalis, are relevant etiological agents of candidiasis and candidemia. Compared with C. albicans, there is currently limited information about C. tropicalis' biological aspects, including those related to the cell wall and the interaction with the host. Currently, it is known that its cell wall contains O-linked mannans, and the contribution of these structures to cell fitness has previously been addressed using cells subjected to chemical treatments or in mutants where O-linked mannans and other wall components are affected. Here, we generated a C. tropicalis pmt2∆ null mutant, which was affected in the first step of the O-linked mannosylation pathway. The null mutant was viable, contrasting with C. albicans where this gene is essential. The phenotypical characterization showed that O-linked mannans were required for filamentation; proper cell wall integrity and organization; biofilm formation; protein secretion; and adhesion to extracellular matrix components, in particular to fibronectin; and type I and type II collagen. When interacting with human innate immune cells, it was found that this cell wall structure is dispensable for cytokine production, but mutant cells were more phagocytosed by monocyte-derived macrophages. Furthermore, the null mutant cells showed virulence attenuation in Galleria mellonella larvae. Thus, O-linked mannans are minor components of the cell wall that are involved in different aspects of C. tropicalis' biology.

Trapping an Elusive Fe(IV)-Superoxo Intermediate Inside a Self-Assembled Nanocage in Water at Room Temperature.

Molecular cavities that mimic natural metalloenzymes have shown the potential to trap elusive reaction intermediates. Here, we demonstrate the formation of a rare yet stable Fe(IV)-superoxo intermediate at room temperature subsequent to dioxygen binding at the Fe(III) site of a (Et4N)2[FeIII(Cl)(bTAML)] complex confined inside the hydrophobic interior of a water-soluble Pd6L412+ nanocage. Using a combination of electron paramagnetic resonance, Mössbauer, Raman/IR vibrational, X-ray absorption, and emission spectroscopies, we demonstrate that the cage-encapsulated complex has a Fe(IV) oxidation state characterized by a stable S = 1/2 spin state and a short Fe-O bond distance of ∼1.70 Å. We find that the O2 reaction in confinement is reversible, while the formed Fe(IV)-superoxo complex readily reacts when presented with substrates having weak C-H bonds, highlighting the lability of the O-O bond. We envision that such optimally trapped high-valent superoxos can show new classes of reactivities catalyzing both oxygen atom transfer and C-H bond activation reactions.