Category: 3. Business

In an analysis of 7-year follow-up data from the REASSURE study, Bertrand Tombal, MD, emphasized that the findings remain true to the study’s name—reassuring. The results show no significant increase in hematologic toxicity with Radium-223 in patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases, while highlighting the critical importance of timing and bone health management.

In an interview with Pharmacy Times, Tombal discussed key takeaways for clinicians and pharmacists, including the need to paid Radium-223 with agents such as denosumab or zoledronic acid and to initiate treatment earlier in the disease course rather than in a palliative setting.

Q: Can you walk us through the key safety findings over this seven-year follow-up and kind of what you found?

Bertrand Tombal, MD: So first I’ll explain why REASSURE was set up. OK, so REASSURE was set up shortly after the ALINA trial because when the data came, there was always that worry that when you use a radioactive compound that goes in the bone marrow of the patient, because that’s where bone metastases are, you could actually increase the rate of hematological malignancies. So that’s why initially REASSURE was done.

So, the first conclusion is that REASSURE is reassuring. We don’t see a significant increase in the toxicity in the hematological toxicity of [Radium-223], so that was very important.

And now it’s close to 1500 patients, so we’ve learned a lot about radium, and basically, we have learned 3 things. The first one is that, yes, the toxicity is hematological, but we rarely have dramatic toxicity like grade 4 or grade 5. Most of the toxicity is limited to grade 1 and grade 3, and it’s really reversible. The second one is linked to the first one to some extent, in that Radium-223 is not a drug that you should use too late as a kind of palliative care setting. If you do that, then you get the toxicity because this patient has bone marrow exhaustion, and you don’t get any therapeutic effect. So that’s something we learned, which is very important. Radium-223 is a drug that has to be given early to metastatic CRPC patients with bone metastasis. If you give it too late, that’s where you’ve got the toxicity, and you don’t have the effect.

And then the third and very important observation is that indeed there is a toxicity, which is not necessarily to the molecule itself but to the fact that you’re tackling bone metastasis. So, if you tackle bone metastasis and you don’t protect your bones, you’re going to get a lot of fractures. There was confusion in the minds of the doctors because drugs like zoledronic acid and denosumab were developed to delay what we call skeletal-related events, which are basically complications of the cancer. When ALINA was published, it showed that it significantly delays [skeletal-related events], so the doctor would say, “No hurry. You don’t need to start this treatment soon.” What happens even with radiotherapy is that we have a lot of frailty and osteoporotic fractures, and you need to protect your patient with this. And so that’s the central message: if you’re using a drug that is heavily targeting the bone, the price to pay for the efficacy is an increased risk of bone fracture, and you absolutely need to combine Radium-223 with a bone-protecting agent.

Is it disruptive? Is it new information? No, it’s been in the guidelines for 15 years. And actually, you could really summarize and say if you give Radium-223, please follow the guidelines. What do the guidelines say? Radium-223 is indicated in patients with metastatic castration-resistant prostate cancer and bone metastasis. The guidelines say zoledronic acid and denosumab should be given to anybody with metastatic CRPC and bone metastasis. So, no surprise, just comply with the guidelines.

What is very interesting is all these messages from REASSURE actually resonate perfectly in the PEACE-3 trial, which is enzalutamide versus enzalutamide plus Radium-223, where we made absolutely the same observation. We haven’t seen any increase in hematological toxicity, and this is a randomized controlled trial.
The toxicity is acceptable. We haven’t seen one single side effect increased by more than 5%, except we see a lot of fractures if we don’t give bone-protecting agents.

So that’s what we learned from this REASSURE trial, the main message being if you believe in Radium-223, it’s not a treatment you give in a palliative care setting. You have to give it quite early. What we see also in REASSURE, not necessarily in the poster represented here, but in other publications, is that the earliest you give it, the higher the chance you’re going to give all 6 cycles. So that, in a nutshell, is the summary of the poster.

Q: From the pharmacist’s perspective, what monitoring do you recommend when a patient is receiving this, especially given the data that you now have?

Tombal: Clearly, 2 things. Any drug that could increase the hematological toxicity—that’s very important. And second, most importantly, because I realize in my hospital [pharmacists] play a critical role in ensuring that the patient is receiving both targeted agents. You know, it’s not listed as a typical drug-drug interaction, so pharmacy software will not pop up because basically if you look at drug-drug interactions, there are no interactions with Radium-223. But the pharmacist is central to making sure that at the time of the prescription of the Radium-223, there is a prescription for 1 bone-targeted agent. We know that in places where the pharmacist has involvement in that quality control monitoring, the rate of incorporation of bone-protecting agents was higher, so that’s very important.

Q: Can you elaborate on how strong the association was between bone-protecting agents and reduced fracture risk, and what recommendations you would make about integrating these agents?

Tombal: Yes. At [the European Association of Urology Congress] last year we published a subset analysis of the first patients who received or did not [bone-protective agents]. And we see that actually, if you take, for instance, [progression-free survival], radiographic progression-free survival, administering a bone-protecting agent was increasing PFS by 15 or 17 months. So, the benefit is huge. And if we look at Radium-223, it was very simple. When we look at the initial part when we didn’t make use of bone protection agents compulsory, in the enzalutamide regimen arm, the rate of fracture was close to 20%. What was interesting is that in the enzalutamide arm alone it was 10%.

And when we administered the bone-protecting agent—in most cases it was denosumab, but zoledronic acid is good as well—we decreased that rate to 3% to 5%. So, my worry when we speak about Radium-223 and bone-protecting agents as a physician is that it’s not only when you give Radium-223; it’s every time your patient has bone metastasis and CRPC. So, my worry is that physicians say, “Oh, he doesn’t need radium, so he doesn’t need a bone-protecting agent.” No, the REASSURE data and the PEACE-3 data show this isn’t true.

Basically, there is a separate message beyond the radium. It’s the importance of bone-protecting agents, whatever drug you receive.

Patients

The study was approved by the Ethics Committee of the First Affiliated Hospital of Soochow University. A total of 880 patients diagnosed with pancreatic cancer between January 1, 2013, and December 31, 2023, were retrospectively collected from two hospitals, including 520 patients from the First Affiliated Hospital of Soochow University and 360 patients from the Second Affiliated Hospital of Soochow University. All patients received follow-up treatment in accordance with the CSCO guidelines for the diagnosis and treatment of pancreatic cancer [16]. The inclusion criteria were: (1) Histopathological diagnosis of pancreatic cancer; (2) Abdominal contrast-enhanced CT examinations performed at our hospital before definitive treatment. The exclusion criteria were: (1) Lack of complete baseline clinical data or follow-up data; (2) Combined with a history of other malignant tumors; (3) Poor quality of contrast-enhanced CT imaging, defined as scans with significant motion artifacts, insufficient contrast enhancement (i.e., poor visualization of pancreatic parenchyma and vessels during the portal venous phase), image blurring affecting tumor boundary visibility, or incomplete coverage of the pancreas within the scanning range. Patients were divided into a training set (n = 616) and a testing set (n = 264) in a 7:3 ratio. The specific selection process for the study cohort is shown in Fig. 1. Demographic characteristics such as gender and age were collected from electronic medical records. Tumor clinical staging was assessed according to the 8th edition of the AJCC (American Joint Committee on Cancer) staging system. Overall survival (OS) was followed up through telephone interviews and inpatient medical records, defined as the time from initial pathological diagnosis to death from any cause or the last known date of survival (Figure S 4). The follow-up was censored on June 1, 2024. OS was binarized as “survival” or “death” for machine learning classification. Death within 1-year, 2-year, and 3-year post-diagnosis was labeled as “death,” while survival at these time points was labeled as “survival.” Patients without follow-up information were already excluded according to the predefined exclusion criteria.

Imaging protocol and preprocessing

All patients underwent contrast-enhanced abdominal CT scans before initiating treatment. Imaging was performed using a 256-slice CT scanner, the GE Revolution CT from GE, USA, at the First Affiliated Hospital of Soochow University, and a 64-slice helical CT scanner, the GE Discovery CT 750 HD, at the Second Affiliated Hospital of Soochow University. Scan parameters were similar at both hospitals, with a tube voltage of 120 kV and a slice thickness and interslice gap of 5 mm. The Second Affiliated Hospital used automatic milliampere modulation, while the First Affiliated Hospital set the tube current between 200 and 450 mAs. Both hospitals used iodixanol 320 as the contrast agent, administered at a dose of approximately 1.4 mL per kilogram of body weight at an injection rate of 3 mL per second. Arterial phase images were acquired using an automatic triggering method, with a threshold of 100 Hounsfield units. Venous phase images were obtained after a 60-second delay.

Portal venous phase contrast-enhanced CT images in DICOM format were imported into 3D Slicer software (version 5.6.1). Guided by a senior radiotherapy oncologist (20 years of experience), a radiotherapy oncologist and a gastroenterologist (each with 3 years of experience) independently delineated tumor boundaries to create regions of interest (ROIs), carefully avoiding adjacent vessels, dilated bile ducts, and pancreatic ducts. Both physicians were blinded to the clinical outcomes prior to the ROI segmentation. If the two physicians produced significantly different ROIs for the same patient, a third radiologist (20 years of experience) reviewed the case and made the final decision in accordance with NCCN (National Comprehensive Cancer Network) guidelines. To assess the reliability and consistency of the ROI delineation, the intraclass correlation coefficient (ICC) was used for validation.

Radiomic feature extraction

Before feature extraction, the images were resampled using 3D Slicer software to a voxel size of 3 × 3 × 3 mm³ to ensure isotropy, thereby minimizing variability due to differences in scanning equipment and protocols. Radiomic features were then extracted using the Radiomics plugin within the 3D Slicer software. A total of 1,037 features were extracted, including 108 original features and 929 filtered features (LoG and wavelet), which were classified into seven categories: shape features, first-order (FO) features, features based on gray-level co-occurrence matrices (GLCM), gray-level dependence matrix (GLDM) features, features based on run-length matrices (RLM), features based on size-zone matrices (SZM), and features based on neighborhood gray-tone difference matrices (NGTDM).

The development and evaluation of models

Radiomics based model

To reduce the dimensionality of features and address the issue of multicollinearity, principal component analysis (PCA) was applied to the extracted radiomic features. We selected principal components that together explained 80% of the cumulative variance to minimize redundancy while retaining the most informative aspects of the original feature set. Subsequently, feature selection was further refined using the Least Absolute Shrinkage and Selection Operator (LASSO) regression, with the optimal λ value determined via 10-fold cross-validation. The final input features were determined by retaining principal components with non-zero coefficients.

The Random Survival Forest (RSF) algorithm, an ensemble tree-based method, is designed to analyze survival time data and predict individual survival probabilities or risks. RSF constructs models by integrating multiple survival trees, providing high stability and robustness while effectively reducing the risk of overfitting. Additionally, it captures complex non-linear relationships and automatically identifies key features closely associated with survival outcomes, thereby enhancing the interpretability of the model [17, 18]. In recent years, RSF has been widely applied to survival analysis problems [19]. In this study, the RSF algorithm was utilized to construct models in the training set for predicting 1-, 2-, and 3-year survival probabilities of patients. The RSF model was implemented using the randomForestSRC package in R. The number of trees (ntree) was set to 345, and the minimum terminal node size (nodesize) was optimized using the tune.nodesize() function, which selects the optimal value based on the out-of-bag (OOB) prediction error. The number of random splits (nsplit) was set to 11. The discriminatory ability of the models was evaluated using the receiver operating characteristic (ROC) curve and its area under the curve (AUC), while prediction consistency was assessed through accuracy measurements.

3D-Densenet based model

Given the importance of capturing three-dimensional structural information in medical imaging, we developed a deep learning model based on a three-dimensional densely connected convolutional network (3D-DenseNet) to predict 1-, 2-, and 3-year survival outcomes in pancreatic cancer patients. The 3D-DenseNet model was implemented using the MONAI (Medical Open Network for AI) framework, which is specifically designed for medical imaging analysis and provides robust deep learning tools optimized for healthcare applications.

The previously segmented tumor regions (ROI) were standardized to a fixed size of 96 × 96 × 96 voxels using linear interpolation to ensure uniform input dimensions and reduce computational complexity. To address the limitations of small sample datasets and enhance model robustness, image preprocessing was performed, including pixel intensity normalization, explicit channel dimension addition, and data type standardization. During the training phase, data augmentation techniques such as random 90-degree rotations, axis flipping, and Gaussian noise injection were applied to improve the model’s generalization capability.

The 3D-DenseNet architecture consisted of four densely connected blocks containing 6, 12, 24, and 16 convolutional layers, respectively. By leveraging dense connectivity, the model reused features from previous layers, improving feature learning efficiency and reducing the number of parameters. To extract both global and local features, a dual-input design (DualInputDenseNet) was adopted, integrating a whole-image branch and an ROI branch. The whole-image branch utilized 3D-DenseNet to extract global features, while the ROI branch employed two 3D convolutional layers, each followed by a ReLU activation function and max pooling operation, to progressively downsample and extract high-level ROI features. The outputs of both branches were concatenated along the channel dimension and passed through fully connected layers for feature fusion and final classification. The model was optimized using the Adam optimizer and trained for 100 epochs with a learning rate of 1 × 10⁻⁴. In each epoch, a batch loader was used to retrieve training data in batches. Cross-entropy loss was employed as the optimization objective, and model performance was monitored using test accuracy computed on the hold-out test set at each epoch. The model checkpoint that achieved the highest test set accuracy was saved for final evaluation. During the testing phase, data augmentation steps were disabled, and only normalization and resizing were applied to ensure stability and consistency in the evaluation process.

After training, the optimal 3D-DenseNet model was used to predict 1-, 2-, and 3-year survival probabilities for patients in both the training and test sets. AUC was calculated to assess the model’s discriminative ability. Additionally, accuracy was evaluated to measure classification consistency.

Fusion model

To further enhance the performance of the prognostic prediction model, this study built a fusion model by performing decision-level fusion of the radiomics model and the 3D-DenseNet model. The predictions from both models were combined with clinical features of patients (gender, age, T stage, N stage, and M stage) to predict the 1-, 2-, and 3-year survival outcomes. This approach aimed to fully leverage the different types of data to enhance the model’s predictive ability, thereby improving its generalizability and accuracy. To identify the optimal fusion model, four different machine learning algorithms were employed, including Logistic Regression, Random Forest, Support Vector Machine (SVM), and Decision Tree. The model performance was evaluated using accuracy and AUC.

After determining the optimal fusion model, patients were stratified based on mortality risk scores predicted by the model. Specifically, the optimal risk cutoff value was identified using X-tile software (version 3.6.1), and all patients were classified into low-risk and high-risk groups accordingly. Kaplan-Meier (KM) survival curves for the high-risk and low-risk groups were then plotted separately in both the training and test cohorts. A log-rank test was used to evaluate the statistical significance of survival differences between the two groups. Figure 2 provide an overview of the overall study workflow.

Statistical analysis

All statistical analyses were performed using SPSS 26.0, R software (version 4.3.2), and Python 2.7.5. The demographic and clinical characteristics between the training and test sets were compared using SPSS 26.0. For continuous variables, an independent sample t-test was applied if the data followed a normal distribution, while the Mann-Whitney U test was used for non-normally distributed variables. Categorical variables were compared using the chi-square test. All statistical tests were two-sided, and a p-value < 0.05 was considered statistically significant. Feature selection, model construction, and evaluation of radiomics-based predictive models were performed using R (version 4.3.2). The “glmnet” package was employed for LASSO regression to select significant radiomic features. The “randomForestSRC” and “survival” packages were used to develop survival prediction models, while the “ggplot2” package was utilized for data visualization. The 3D deep learning model was constructed and evaluated using Python 2.7.5. The remaining general statistical analyses were conducted using R software.

The outage affecting Amazon Web Services, a cloud service provider, points to an overreliance on a centralised system to power the internet.

Amazon’s cloud-computing division has infrastructure set up all around the world, which allows companies to make their products accessible to customers everywhere.

The AWS cloud spans 38 geographic regions, according to its website. But even with this decentralised set-up, there’s an inherent dependence on a small number of key locations. The outages affecting myriad apps and websites this morning were caused by “operational issues” at their datacentre in the US-EAST-1 Region centre in North Virginia, according to AWS. 

“This highlights how reliant we are on centralised services,” says Alp Tolker, founder and director of internet watchdog Netblocks. “The internet isn’t designed to be this way. 

“But what’s emerging is that even within their decentralised infrastructure… one weak link has the ability to take out these different services.”

Toker highlights how these major internet outages often serve as wake-up calls for companies to do things differently. In the case of the AWS outage, there has been a “build fast, fix later” approach. Firms that have been using Amazon’s cloud-computing services to host their data haven’t completed sufficient testing to see what their back-up options are if one datacentre goes down.

“We need to visualise these trees of dependencies, which hasn’t been done formally until now,” says Toker. 

This 8-year collaboration positions both companies at the forefront of the energy transition within the cruise and maritime sectors

MIAMI, Oct. 20, 2025 (GLOBE NEWSWIRE) — Norwegian Cruise Line Holdings Ltd. (NYSE: NCLH) and Repsol today announced a landmark 8-year agreement to supply renewable marine fuels at the Port of Barcelona, establishing an unprecedented long-term relationship within the cruise industry.

Beginning in the 2026 European season, Repsol will offer a portfolio of renewable fuels, including biofuels and, from 2029, renewable methanol, directly to NCLH’s vessels across its cruise brands—Norwegian Cruise Line, Oceania Cruises, and Regent Seven Seas Cruises—when calling at the Port of Barcelona.

“This partnership is an excellent example of how cross-industry collaboration can unlock meaningful progress,” said Harry Sommer, president and chief executive officer of Norwegian Cruise Line Holdings Ltd. “Securing long-term access to renewable marine fuels at a key European port aligns directly with our Sail & Sustain^® program and demonstrates our commitment to advancing towards a more sustainable future.”

“This milestone agreement highlights that renewable fuels are ready to play a key role in reducing the carbon footprint of the maritime sector. By partnering with NCLH, one of the world’s leading cruise companies, we show that renewable fuels are already deployable at scale to immediately start reducing emissions at sea,” said Juan Abascal, Repsol’s Executive Managing Director for Industrial Transformation and Circular Economy.

The agreement between NCLH and Repsol was established based on the changing international regulatory environment and both companies’ pursuit of Net Zero by 2050. All fuels provided under the agreement are certified under the ISCC EU framework and meet the standards necessary to support NCLH’s environmental compliance and decarbonization roadmap.

The renewable methanol will be produced at Repsol’s Ecoplanta facility in Tarragona (Spain), a pioneering project in Europe to transform urban waste into renewable fuels and circular products, adding a solution for reducing CO₂ emissions in the transport sector, while at the same time promoting the circular economy. The new plant—set to begin operations in 2029— will have the capacity to process up to 400,000 tons of municipal solid waste per year and turn them into 240,000 tons of renewable fuels and circular products. NCLH is the first company to sign an offtake agreement for renewable methanol from the Ecoplanta facility.

This alliance underscores NCLH’s commitment to advancing low-carbon fuel solutions and supporting the circular economy, while maintaining operational flexibility and cost efficiency across its fleet. It also directly supports the company’s global program, Sail & Sustain^®, a company-wide initiative focused on reducing greenhouse gas intensity, investing in innovative fuel solutions, and fostering collaboration across the value chain. As part of its 2026 “Charting the Course” targets, the company is working to achieve a 10 percent reduction in GHG intensity by 2026 and 25 percent by 2030.¹

Renewable fuels are central to Repsol’s strategy to supply solutions to cut CO₂ emissions across all transport sectors. They are an already available alternative for decarbonizing current and future vehicles, without the need to change engines or modify existing distribution and refueling infrastructures. In Cartagena (Spain), the company operates the region’s first renewable diesel and SAF plant (250,000 t/year), and it is building a second plant in Puertollano (200,000 t/year), due in 2026. Next year, it will also start operations at its synthetic fuels demo plant in Bilbao. The company supplies renewable diesel at over 1,300 service stations in Spain and Portugal, aiming for 1,500 by year-end, making it one of the largest 100% renewable fuel networks in Europe. Repsol is also the Iberian Peninsula’s leading supplier of SAF, supporting aviation decarbonization and compliance with the EU’s 2% mandate.

About Norwegian Cruise Line Holdings Ltd.
Norwegian Cruise Line Holdings Ltd. (NYSE: NCLH) is a leading global cruise company which operates Norwegian Cruise Line, Oceania Cruises and Regent Seven Seas Cruises. With a combined fleet of 34 ships and more than 71,000 Berths, NCLH offers itineraries to approximately 700 destinations worldwide. NCLH expects to add 13 additional ships across its three brands through 2036, which will add over 38,400 Berths to its fleet. To learn more, visit www.nclhltd.com.

About Repsol
Repsol is a multi-energy company capable of meeting all its customers’ energy needs, both at home and on the move. The company currently employs 25,000 people in over 20 countries and serves 24 million customers. The company is transforming its industrial complexes on the Iberian Peninsula into multi-energy hubs capable of processing a wide variety of feedstocks and waste materials. These will be used to produce low-carbon products, such as 100% renewable fuels. To learn more, visit www.repsol.com/en.  

Cautionary Statement Concerning Forward-Looking Statements
Some of the statements, estimates or projections contained in this press release are “forward-looking statements” within the meaning of the U.S. federal securities laws intended to qualify for the safe harbor from liability established by the Private Securities Litigation Reform Act of 1995. All statements other than statements of historical facts contained in this press release, including statements regarding NCLH’s Sail & Sustain program, sustainability goals and initiatives, may be forward-looking statements. Many, but not all, of these statements can be found by looking for words like “expect,” “goal,” “project,” “plan,” “believe,” “will,” “may,” “estimate,” “intend,” “future” and similar words. Forward-looking statements do not guarantee future performance and may involve risks, uncertainties and other factors which could cause our actual results, performance or achievements to differ materially from the future results, performance or achievements expressed or implied in those forward-looking statements. For a discussion of these risks, uncertainties and other factors, please refer to the factors set forth under the sections entitled “Risk Factors” and “Cautionary Statement Concerning Forward-Looking Statements” in NCLH’s most recently filed Annual Report on Form 10-K, Quarterly Reports on Form 10-Q and subsequent filings with the United States Securities and Exchange Commission. These factors are not exhaustive and new risks emerge from time to time. There may be additional risks that we consider immaterial or which are unknown. Such forward-looking statements are based on our current beliefs, assumptions, expectations, estimates and projections regarding our present and future business strategies and the environment in which we expect to operate in the future. These forward-looking statements speak only as of the date made. We expressly disclaim any obligation or undertaking to release publicly any updates or revisions to any forward-looking statement to reflect any change in our expectations with regard thereto or any change of events, conditions or circumstances on which any such statement was based, except as required by law.

^{_____________________________________
1} GHG intensity is measured by MTCO2e on a per Capacity Day basis. The targets cover NCLH’s emissions from its fleet of ships, islands and facilities (Scopes 1 & 2) as well as upstream fuel- and energy-related activities, including well-to-tank emissions (portion of Scope 3). Capacity Days is defined as berths available for sale multiplied by the number of cruise days for the period for ships in service.

NCLH Media: nclhmedia@nclcorp.com

A photo accompanying this announcement is available at https://www.globenewswire.com/NewsRoom/AttachmentNg/b680c492-9f09-4145-b79e-cce1e55031cf

Source: Norwegian Cruise Line Holdings Ltd.

Released October 20, 2025

BSI episodes and baseline characteristics

During the study period, there were 554 episodes of Citrobacter spp. BSI in 525 patients. In total, eighteen patients each experienced two episodes of CBSI, four patients had three episodes of CBSI and one patient had four episodes of CBSI. The most common species was Citrobacter freundii complex (47%, n = 261), followed by Citrobacter koseri (42%, n = 233) and Citrobacter non-freundi complex, non-koseri (11%, n = 60). The median age of the included patients was 77 years (range 0-100), and 70% of the patients were men (n = 374). The median CCI was 6 (range 0–15) and 28% (n = 146) of patients were considered immunocompromised (Table 1). Out of all 534 episodes of CBSI, complete medical records were available for 537 episodes (97%).

The incidence of Citrobacter koseri increased during the study period

The age and sex-standardized incidence rate of Citrobacter spp. BSI increased from 3.4 episodes per 100 000 person-years in 2013 to 4.9 episodes per 100 000 person-years in 2023 (Fig. 1).

The increase was not statistically different from zero, with an APC of 3.2 (95% CI: -0.2% to 6.6%) for the entire study period. Separated into species, the crude rate of Citrobacter koseri and Citrobacter freundi complex increased from 0.9 to 1.9 in 2013, to 2.1 and 2.1 in 2023, respectively (Table A1). While the increase in crude incidence of Citrobacter freundi complex BSI was not statistically different from zero (APC of 2.74 95%CI: -2.3% to 8.1%), the crude incidence of increase of Citrobacter koseri during the study period was statistically significant (APC of 7.56 95%CI: 4.6% to 10.6%). Most BSI occurred in ages 75–84 years (Figure A1).

Microbiological findings and antimicrobial resistance

Resistance rates were statistically significantly higher for Citrobacter freundii compared to Citrobacter koseri for all antimicrobials compared, apart from gentamicin (Table A2). For Citrobacter freundii, resistance rates were 15% (n = 40) for ceftazidime, 7% (n = 18) for ciprofloxacin, 11% (n = 28) for piperacillin-tazobactam, 8% (n = 20) for trimethoprim/sulfamethoxazole and 1% (n = 6) and 2% (n = 9) were resistant against gentamicin and tobramycin, respectively. For Citrobacter koseri, 0.4% (n = 1) strains were resistant towards ciprofloxacin, 2% (n = 4) towards piperacillin-tazobactam and 1% (n = 2) towards trimethoprim/sulfamethoxazole. No strains were resistant towards ceftazidime, gentamicin or tobramycin. No carbapenem-resistant strains were found in the study.

In total, 38% (n = 208) of the BSI episodes were polymicrobial, with 306 pathogens other than Citrobacter detected. The most common microbiological findings in polymicrobial blood cultures other than Citrobacter spp. were Enterococcus spp. (32%, n = 66), Klebsiella spp. (25%, n = 51) and Escherichia coli (24%, n = 49) (Table 2).

Citrobacter bloodstream infection is most often associated with urinary tract infection

According to the medical records, the most common etiology of Citrobacter BSI was urinary tract infection 48% (n = 245). Urine cultures were obtained in 404 (73%) of BSI episodes, of which 373 (92%) were acquired prior to antimicrobials had been initiated. Out of all 404 urine cultures, 187 (46%) were positive for Citrobacter spp. Primary BSI constituted 24% (n = 134) of all Citrobacter BSI, after which intraabdominal source of infection was common 19% (n = 95) (Fig. 2).

Citrobacter bloodstream infection is associated with healthcare

In total, fever at blood culturing or within 48 h was present for 387 (70%) episodes and patients reported shivers in 252 (46%) episodes. The median NEWS score when blood cultures were obtained was 4 (range 0–18), the median CRP value was 108 mg/L (range < 4-563) and the median leukocyte count in blood was 12.9 10⁹/L (0.1–92) (Table 1). In nine episodes (2%) of Citrobacter BSI, patients were managed as outpatients, whereas hospitalization was required for all other BSI episodes. In total, 197 (36%) Citrobacter BSI were community acquired, 81 (15%) episodes were nosocomial and 255 (46%) were health care associated (Fig. 3). The median length of stay at hospital was 8 days (range 0-680).

Outcome

Out of all 554 Citrobacter BSI episodes, septic shock was seen in 25 (4%) episodes and in 38 (7%) episodes patients required intensive care. The 30-, 90-, 180- and 365-days mortality rates were 12%, 18%, 23% and 25%, respectively (Table 3). Although the 90-, 180- and 365-day mortality rates were significantly higher for C. freundii-complex BSI compared to C. koseri BSI, there was no statistically significant difference in mortality rates between C. freundii complex BSI compared to C. koseri BSI in the Kaplan-Meier estimator (Fig. 4). There was no statistical difference in all-cause mortality within 90 days between patients with one episode of Citrobacter spp. BSI (19%) and patients with two or more episodes (22%, p = 0.74).

Differences in patient characteristics between BSI due to C. freundii complex and C. koseri

There were no differences in age, CCI-score, rate of immunosuppression or substance abuse between patients with BSI caused by C. freundii complex and C. koseri. However, a greater proportion of men suffered from C. koseri BSI compared to C. freundii-complex BSI (p = 0.01). The rate of polymicrobial BSI (p = 0.0001) as well as BSIs with abdominal source of infection (p = 0.03) were greater for C. freundii complex compared to BSIs due to C. koseri. Patients with C. koseri BSI had to a greater extent UTI symptoms (p = 0.005), positive nitrite dipsticks (p = 0.006), and analogous Citrobacter species cultured in the urine (p = < 0.0001) compared to patients with BSI due to C. freundii complex (Table 4).

Univariate and multivariate analysis of variables associated with mortality within 90 days

In the univariate model, female sex, higher CCI score, immunosuppression and longer duration of hospitalisation was associated with death within 90 days of Citrobacter BSI, as was lack of UTI symptoms and non-community acquired infection (Table 5).Similarly, primary BSI and abdominal focus was significantly more common in patients that died within 90 days. In the multivariate model, higher Charlson comorbidity index, immunosuppression, higher CRP, and a urinary tract focus, were independently associated with 90 days mortality, while age, sex, septic shock, polymicrobial culture and fever were not (Table 6).

The parent company behind Secret Cinema, the London-based immersive film and TV business, has been bought by the Hollywood power broker Ari Emanuel.

TodayTix, which is changing hands for an undisclosed sum, marks the latest acquisition by Emanuel’s new global events company, Mari, which bought the Frieze global art fair and publishing group in May for $200m (£148m).

Mari is backed by Apollo Global Management and RedBird Capital Partners, which has invested in the football clubs Liverpool FC and AC Milan and is trying to push through a deal to buy the Telegraph newspaper group.

Emanuel already runs the company behind World Wrestling Entertainment and the Ultimate Fighting Championship.

TodayTix will now join the fold, after being bought from Great Hill Partners, a private equity company which took a controlling stake in the business in 2019.

TodayTix had its start selling theatre tickets for Broadway and West End shows. It later branched out to New York-based events including a supper club in Times Square and concerts in Brooklyn, before buying Secret Cinema in a $100m (£88m) deal in 2022.

Secret Cinema is best known for its mystery screenings at undisclosed venues, involving sets and interactive performances. It also has deals with Disney and Netflix to create immersive experiences for shows including Guardians of the Galaxy and Stranger Things.

Brian Fenty, who founded TodayTix with fellow Broadway producer Merritt Baer in 2013, told the Guardian the takeover followed an “incredibly competitive” bidding process and said Mari’s ownership would create opportunities for the Secret Cinema producer and Emanuel’s other ventures.

Mari will benefit from access to 20 million TodayTix members and Fenty said his company could expand ticketing options to sports and art venues.

He said: “As a single venue, for example, you only market to people who have bought from you before, whether or not they want to see that type of programming again. And in our case … we’re able to look at how people are behaving across a wide array of events and types of shows.”

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Emanuel has acquired tennis assets including the Miami Open and Madrid Open tournaments from Endeavor this year. He stepped down from Endeavor after it was bought by the private equity company Silver Lake earlier this year but remains executive chair of its Hollywood talent agency.

Fenty will remain chief executive of TodayTix and will join Mari’s executive team.

TodayTix employs about 200 staff, with half based in London. “We are big believers that the UK and London can be sort of the pole market from which to build many of these brands and events,” said Fenty, who moved his family from New York to London during the pandemic.

When asked whether he had any concerns about tax changes in the budget next month that could hit consumer spending on live events, Fenty replied: “I’m an entrepreneur. So I hope that the UK continues to create a great home for entrepreneurs and the arts, and I hope that the budget does nothing to take away from that.”

AUSTIN, Texas — October 20, 2025 — Commerce, (Nasdaq: CMRC), an open, intelligent ecosystem of technology solutions and the parent company of BigCommerce, today announced a new embedded payment processing solution available exclusively to BigCommerce merchants. Powered by PayPal (Nasdaq: PYPL), BigCommerce Payments is slated for a U.S. launch in 2026, with international expansion planned in subsequent phases.

This strategic expansion builds on more than a decade of close partnership between Commerce and PayPal, marking a new chapter in their collaboration. Through this optional co-branded integration, merchants will gain access to advanced payment capabilities, simplified account management, and buy now, pay later (BNPL) via PayPal’s Pay Later offering, all seamlessly managed within the BigCommerce Control Panel.

“Commerce is thrilled to extend our longstanding partnership with PayPal and work together on this new payments solution,” said Travis Hess, CEO at Commerce. “BigCommerce Payments represents a major step forward in creating a seamless and simplified intelligent commerce experience for Commerce merchants. By embedding PayPal’s trusted payment solutions directly into our platform, we will give merchants more control, visibility and flexibility to grow their businesses with confidence.”

“Together with Commerce, we’re not just addressing the needs of today’s merchants, we’re empowering them to seize the future with confidence and agility,” said Michelle Gill, Executive Vice President and General Manager, Small Business & Financial Services, PayPal. “By bringing together PayPal’s world-renowned reliability, security and global reach with Commerce’s merchant-focused platform, we’re helping merchants thrive in the next era of ecommerce.”

The BigCommerce Payments architecture is built to ensure transparency and merchant ownership. While BigCommerce Payments is co-branded and embedded into BigCommerce, the merchant’s payment relationship remains directly with PayPal. BigCommerce Payments will introduce a dedicated “Money” dashboard within the BigCommerce Control Panel, offering merchants direct access to manage and monitor their payments and balance activity. Features include:

• Real-time balance insights
• Top-ups and payouts
• Bank and card connections
• Currency management

This embedded experience will mirror key capabilities of the merchant’s PayPal dashboard, providing a streamlined experience where merchants can manage their payments along with the rest of their business through a single portal and reducing the need to toggle between multiple systems. For more advanced settings, the BigCommerce Payments settings page will provide direct access to the PayPal dashboard.

In coordination with PayPal, BigCommerce will enable the migration of existing merchants currently utilizing PayPal Complete Payments (PPCP). These merchants will receive personalized communications, offering them the option to seamlessly transition to BigCommerce Payments.

About Commerce

Commerce (Nasdaq: CMRC) empowers businesses to innovate, grow, and thrive by providing an open, AI-driven commerce ecosystem. As the parent company of BigCommerce, Feedonomics, and Makeswift, Commerce connects the tools and systems that power growth, enabling businesses to unlock the full potential of their data, deliver seamless and personalized experiences across every channel, and adapt swiftly to an ever-changing market. Trusted by leading businesses like Coldwater Creek, Cole Haan, Harvey Nichols, King Arthur Baking Co., Mizuno, Perry Ellis, Puma, SportsShoes, and Uplift Desk, Commerce delivers the storefront control, optimized data, and AI-ready tools businesses need to grow, serve diverse buyers, and operate with confidence in an increasingly intelligent, multi-surface world. For more information, visit commerce.com or follow us on X and LinkedIn.

About PayPal

PayPal has been revolutionizing commerce globally for more than 25 years. Creating innovative experiences that make moving money, selling, and shopping simple, personalized, and secure, PayPal empowers consumers and businesses in approximately 200 markets to join and thrive in the global economy. For more information, visit https://www.paypal.com, https://about.pypl.com/ and https://investor.pypl.com/.

BigCommerce®, the Commerce logo, and other brands are the trademarks or registered trademarks of BigCommerce Pty. Ltd. Third-party trademarks and service marks are the property of their respective owner.

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Media Contact:

PayPal: MediaRelations@paypal.com

 

Watson Farley & Williams (“WFW”) advised shipping company MPC Container Ships ASA (“MPCC”) on the order of two 1,600 TEU container ships and related eight-year charter agreements with a renowned shipping liner company.

The contracts for the two high-cube container-optimised newbuilds were signed with the Fujian Mawei Shipyard in China, with the total investment amounting to US$66m. Delivery of the two vessels is scheduled for the second half of 2027. MPCC also holds options for further units, enabling future scalability in line with market opportunities.

The new vessels feature a highly advanced, fuel-efficient design optimised for operations in Northern Europe and its narrow fairways, whilst offering further efficiency advantages, even compared to existing ECO designs in this market segment. The order is part of MPCC’s strategic fleet modernisation programme aimed at increasing energy efficiency and minimising regulatory and environmental risks.

Oslo-based MPCC is a leading container ship owner with a focus on small to medium-sized vessels. It primarily owns and operates a portfolio of container ships serving regional trade routes under long-term charter agreements.

The WFW Maritime team that advised MPCC was led by Hamburg Corporate Partner Dr Christian Finnern, supported by Associates Maximilian Hennig and Bjarne Ruthke. Hamburg partner Dr F. Maximilian Boemke advised on regulatory matters, whilst London Partners Joe McGladdery and Charles Buss in advised on English law.

Christian commented: “It was a pleasure to advise MPCC on this strategic step. The transaction is exemplary for fleet modernisation and market positioning – and at the same time reflects the dynamics of an industry that calls for strategic decisions and legal clarity more than ever. Our maritime transaction expertise enables us to advise on such complex projects in a targeted and forward-looking manner”.