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  • Neuronal gene profiling of tau oligomer-bearing cholinergic nucleus basalis neurons during the onset of Alzheimer’s disease | Acta Neuropathologica Communications

    Neuronal gene profiling of tau oligomer-bearing cholinergic nucleus basalis neurons during the onset of Alzheimer’s disease | Acta Neuropathologica Communications

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  • Kazia Therapeutics to Request FDA Type C Meeting to Discuss Overall Survival Data in GBM and Potential NDA Filing in Alignment with FDA initiative Project FrontRunner

    SYDNEY, Oct. 27, 2025 /PRNewswire/ — Kazia Therapeutics Limited (“Kazia” or the “Company”) today announced its intention to request and hold a follow-up Type C meeting with the U.S. Food & Drug Administration (FDA) to discuss overall survival (OS) findings in newly diagnosed glioblastoma (GBM) patients treated with paxalisib and to seek agency feedback on a potential regulatory pathway aligned with the FDA Oncology Center of Excellence’s Project FrontRunner initiative.

    “GBM remains one of the most lethal cancers with limited therapeutic options. In line with the FDA Oncology Center of Excellence’s Project FrontRunner initiative, we intend to engage the Agency to discuss whether the overall survival data generated in newly diagnosed GBM patients treated with paxalisib may be adequate to support a conditional approval pathway,” said Dr. John Friend, M.D., Chief Executive Officer of Kazia Therapeutics. “Consistent with this framework, Kazia will propose initiation of the post-approval, randomized Phase 3 confirmatory study prior to submission of the NDA, ensuring that our regulatory strategy fully reflects the FDA’s renewed emphasis on overall survival as the most meaningful endpoint for patients and clinicians.”

    In its recently issued draft guidance, the FDA stated that overall survival is the “gold standard” endpoint in oncology and “should be prioritized as the primary endpoint when feasible,” particularly in diseases with a short natural history where survival can be reliably assessed. Kazia believes GBM is precisely such a setting and intends to present survival analyses, supporting clinical safety, and planned confirmatory trial design for FDA discussion.

    Project FrontRunner is an FDA Oncology Center of Excellence initiative encouraging sponsors to consider when it may be appropriate to seek approval of cancer drugs for advanced or metastatic disease in an earlier clinical setting, rather than the traditional approach of developing therapies only for patients who have exhausted available treatment options.

    As announced in July 2024, in the prespecified secondary analysis in newly diagnosed (up-front) unmethylated GBM patients, median OS was 15.54 months in the paxalisib arm (n = 54) versus 11.89 months for concurrent standard of care (SOC) (n = 46). Kazia intends to reference Project FrontRunner principles in its Type C briefing package, including an OS-driven confirmatory study plan in newly diagnosed GBM.

    “We are moving decisively to bring paxalisib forward in GBM using the endpoints that matter most to patients and physicians,” added Dr. Friend. “Our objective is to work collaboratively with the FDA under the guiding principles of Project FrontRunner to pursue a conditional approval in the front-line treatment setting of glioblastoma. In parallel, Kazia will initiate the post-approval, randomized Phase 3 study prior to filing the NDA, ensuring that our development plan fully aligns with the Agency’s modernized, patient-focused framework.”

    Kazia also notes that leading oncology companies have begun publicly referencing Project FrontRunner in successful FDA actions, underscoring the initiative’s growing relevance for sponsors developing first-line or earlier-setting therapies.

    For investor and media, please contact Alex Star, Managing Director LifeSci Advisors LLC, [email protected], +1-201-786-8795.

    About Kazia Therapeutics Limited

    Kazia Therapeutics Limited (NASDAQ: KZIA) is an oncology-focused drug development company, based in Sydney, Australia. Our lead program is paxalisib, an investigational brain penetrant inhibitor of the PI3K / Akt / mTOR pathway, which is being developed to treat multiple forms of cancer. Licensed from Genentech in late 2016, paxalisib is or has been the subject of ten clinical trials in this disease. A completed Phase 2/3 study in glioblastoma (GBM-Agile) was reported in 2024 and discussions are ongoing for designing and executing a pivotal registrational study in pursuit of a standard approval. Other clinical trials involving paxalisib are ongoing in advanced breast cancer, brain metastases, diffuse midline gliomas, and primary central nervous system lymphoma, with several of these trials having reported encouraging interim data. Paxalisib was granted Orphan Drug Designation for glioblastoma by the U.S. Food and Drug Administration (FDA) in February 2018, and Fast Track Designation (FTD) for glioblastoma by the FDA in August 2020. Paxalisib was also granted FTD in July 2023 for the treatment of solid tumor brain metastases harboring PI3K pathway mutations in combination with radiation therapy. In addition, paxalisib was granted Rare Pediatric Disease Designation and Orphan Drug Designation by the FDA for diffuse intrinsic pontine glioma in August 2020, and for atypical teratoid / rhabdoid tumors in June 2022 and July 2022, respectively. Kazia is also developing EVT801, a small molecule inhibitor of VEGFR3, which was licensed from Evotec SE in April 2021. Preclinical data has shown EVT801 to be active against a broad range of tumor types and has provided evidence of synergy with immuno-oncology agents. A Phase I study has been completed and preliminary data was presented at 15th Biennial Ovarian Cancer Research Symposium in September 2024. For more information, please visit www.kaziatherapeutics.com or follow us on X @KaziaTx.

    Forward-Looking Statements

    This announcement contains forward-looking statements, which can generally be identified as such by the use of words such as “may,” “will,” “plan,” “intend,” “estimate,” “future,” “forward,” “potential,” “anticipate,” or other similar words. Any statement describing Kazia’s future plans, strategies, intentions, expectations, objectives, goals or prospects, and other statements that are not historical facts, are also forward looking statements, including, but not limited to, statements regarding: Kazia’s intention to request and hold a Type C meeting with the FDA to discuss OS findings in GBM patients treated with paxalisib and to seek agency feedback on a potential regulatory pathway, the plan to propose initiation of the post-approval, randomized Phase 3 confirmatory study prior to submission of the NDA, the intention to present survival analyses, supporting clinical safety and planned confirmatory trial design for FDA discussion, Kazia’s intention to reference Project FrontRunner principles in its Type C briefing package, the objective to work collaboratively with the FDA under the guiding principles of Project FrontRunner, the plan to pursue a conditional approval in the front-line treatment setting of GBM, the plan to initiate the post-approval, randomized Phase 3 study prior to filing the NDA, the goal of ensuring that Kazia’s development plan and regulatory strategy fully reflects and aligns with the FDA’s framework and emphasis, the timing for results and data related to Kazia’s clinical and preclinical trials, Kazia’s strategy and plans with respect to its paxalisib program, the potential benefits of paxalisib, timing for any regulatory submissions or discussions with regulatory agencies and the potential market opportunity for paxalisib. Such statements are based on Kazia’s current expectations and projections about future events and future trends affecting its business and are subject to certain risks and uncertainties that could cause actual results to differ materially from those anticipated in the forward-looking statements, including risks and uncertainties associated with clinical and preclinical trials and product development, including the risk that interim or early data may not be consistent with final data, risks related to regulatory approvals, risks related to the impact of global economic conditions and U.S. government shutdown, and risks related to Kazia’s ability to regain and/or maintain compliance with the applicable Nasdaq continued listing requirements and standards. These and other risks and uncertainties are described more fully in Kazia’s Annual Report, filed on form 20-F with the SEC, and in subsequent filings with the United States Securities and Exchange Commission. Kazia undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise, except as required under applicable law. You should not place undue reliance on these forward-looking statements, which apply only as of the date of this announcement.

    SOURCE Kazia Therapeutics Limited

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  • The Ferrari F76 digital hypercar hails 76 years of legend at Le Mans

    The Ferrari F76 digital hypercar hails 76 years of legend at Le Mans

    This year, Ferrari has left its mark on automotive history in a new way. Following in the tracks of the third 24 Hours of Le Mans triumph in a row for the 499P, the Maranello-based manufacturer has revealed the Ferrari F76 – the very first hypercar designed exclusively for the digital world in the form of an NFT. The F76 name is a nod to Ferrari’s first Le Mans win sealed 76 years earlier by Luigi Chinetti and Lord Selsdon at the wheel of the iconic 166 MM Barchetta.

    The F76 celebrates Ferrari’s glorious past – and opens up a new era. The 100% virtual project is created for clients of the exclusive Hyperclub programme, an initiative that allows collectors to experience the FIA World Endurance Championship and the 24 Hours of Le Mans alongside the official team.

    See the Ferrari F76 in the video below.

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  • Rangitīkei solar project in New Zealand announced

    Rangitīkei solar project in New Zealand announced

    • FRV Australia has announced advancing the development of the Rangitīkei solar project in New Zealand, with an installed capacity of approximately 210 MWdc and an expected annual generation of around 350,000 MWh.
    • This announcement coincides with the conclusion of its joint venture with Genesis Energy, with whom FRV Australia will continue to co-own and operate the Lauriston solar farm in Canterbury.

    Fotowatio Renewable Ventures (FRV) Australia, a leading developer of sustainable energy solutions, and part of Jameel Energy and the Canadian infrastructure fund OMERS, announces the active development of the Rangitīkei solar project, located in the Rangitīkei District of New Zealand’s North Island, with a proposed  capacity of 210 MWdc. This announcement coincides with the conclusion of its joint venture with Genesis Energy, an agreement that facilitated FRV Australia’s entry into the New Zealand market and accelerated the development of multiple solar projects in the country.

    FRV Australia has purchased the Rangitīkei project from the joint venture. Covering an area of approximately 450 hectares, the solar farm will generate around 350,000 MWh per year, enough to power approximately 45,000 homes. In addition, it will help avoid approximately 35,000 tonnes of CO₂ emissions annually.

    The project will bring local employment creating a peak of 250 jobs, with an average of 75 workers over an expected 24-month construction period. The project design also includes the potential for future integration of a battery energy storage system (BESS), which will enhance grid flexibility and resilience.

    “With Rangitīkei, we are taking another step in our efforts to contribute to New Zealand’s low emission energy future. The development of this project contributes to FRV Australia’s vision of leading the energy transition in this region, supporting local economic development, and contributing to the green electrification goals of Aotearoa,” said Carlo Frigerio, CEO of FRV Australia.

    At the same time, FRV Australia has expressed its gratitude to Genesis Energy for its role during the joint venture, noting that the relationship between the two companies will continue through their co-ownership of the Lauriston solar farm (Canterbury), which began generation in November 2024 as the largest solar farm New Zealand at the time.

    “We greatly value our collaboration with Genesis, which has been instrumental in this journey and a testimony of the strong partnership and capability to deliver projects. FRV Australia now continues its journey as we explore new renewable development opportunities in the country,” Frigerio added.

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  • Green Assist: Scaling up sustainable farming on island communities

    Green Assist: Scaling up sustainable farming on island communities

    On the Dutch Caribbean island of Curaçao, securing a steady supply of fresh produce is becoming increasingly crucial. Often reliant on imports, the island faces high prices and frequent shortages of fresh vegetables. CurHydro, an innovative agricultural company founded in 2018, is answering this challenge with high-tech farming solutions. With support from Green Assist, CurHydro is set to expand its project to provide a sustainable food source for the island community.

    In the past years, CurHydro has successfully produced fresh lettuce on 300 m² of land, using solar-powered systems and a method known as hydroponics (growing plants in nutrient-rich water without soil). CurHydro currently supplies its produce to local foodservice and retail partners, but growing demand starts to exceed supply. With local interest booming and its commitment to sustainability, CurHydro is ready to expand.

    The company has secured a building permit for a new 6-hectare site and is planning the construction of a 1.5 hectare high-tech greenhouse, in partnership with the Spanish manufacturer Rufepa Tecnoagro. This new facility will allow to grow vegetables that are well-suited to hydroponic farming – such as lettuce, tomatoes, cucumbers and bell peppers. This greenhouse will maintain high efficiency and low water consumption, providing a steady supply of fresh, affordable produce grown locally. This helps to reduce imports, boost food resilience on the island, support the local economy by creating jobs, and increase health awareness.

    But scaling up this advanced farming model requires strong planning and significant financing. To design a solid business model and attract investors, CurHydro sought tailored support from Green Assist.

    From September to December 2024, the company worked with a Green Assist expert to refine its financial strategy, assess funding options, and improve the project’s investment appeal. This included detailed financial modelling, market analysis, and support with identifying public and private sources of funding.

    The expert guidance also helped to define a clear implementation roadmap. With land secured, technical feasibility achieved and partnerships in place, the project is now preparing for fundraising, procurement and further construction. The new greenhouse is expected to be operational within two years, creating new local jobs and strengthening food access in Curaçao.

    “Thanks to Green Assist, we now have a robust financing roadmap and a sharper investment case. That support accelerated our path to scale so we can deliver reliable, local produce while cutting water use and emissions for a healthier, more resilient Curaçao.” — Shurhensley Thielman Quirindoongo, President & CEO, CurHydro.

    The long-term vision is to develop all 6 hectares into a modern agricultural hub, helping build a more self-sufficient, healthy and resilient island food system.

    Green Assist aims to build a pipeline for high-impact green investment projects in sectors related to biodiversity, natural capital and circular economy, as well as in non-environmental sectors. 

    Learn more about how Green Assist can help you get free tailored support for your green project or contact us at cinea-green-assistec [dot] europa [dot] eu (cinea-green-assist[at]ec[dot]europa[dot]eu). To request advisory services from Green Assist, simply fill out this short form.

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  • ‘Designer Drug’ Shows Early Neuroprotective Signal in Acute Ischemic Stroke – Medscape

    1. ‘Designer Drug’ Shows Early Neuroprotective Signal in Acute Ischemic Stroke  Medscape
    2. Silver Creek’s stroke hopeful yields mixed results in Phase II trial  Clinical Trials Arena
    3. Silver Creek Pharmaceuticals Receives FDA Fast Track Designation for Scp776 in Acute Ischemic Stroke  GlobeNewswire
    4. Silver Creek Pharmaceuticals Announces Positive Phase 2 Results for Scp776 in Acute Ischemic Stroke  Yahoo Finance

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  • U.S. Broadband Speeds on the Uptick, Digital Divide Narrows

    U.S. Broadband Speeds on the Uptick, Digital Divide Narrows

    A new Ookla report found that the digital divide has narrowed in 33 states during the first half of 2025.

    Key Takeaways

    • The number of states with 60% or more of Speedtest users experiencing the FCC’s minimum standard for fixed broadband speeds of 100 Mbps downstream and 20 Mbps upstream jumped from 22 states and the District of Columbia in the 2H of 2024 to 38 states and the District of Columbia in 1H of 2025.
    • The digital divide between urban and rural users improved in the first half of 2025 with 33 states seeing the gap between the percentage of fixed urban users and fixed rural users that receive the minimum required FCC broadband speeds lessen during that time while 17 states saw that gap grow in the first half of 2025 compared to the second half of 2024. Ookla uses the Census Bureau’s urban-rural classification to determine which users are urban vs. rural. 
    • The digital divide doesn’t exist for many Starlink users. In26 out of the 50 states and the District of Columbia, rural users get better broadband speeds than their urban counterparts. This is likely due to Starlink’s ability to overcome the geographic and cost barriers that make delivering fixed rural broadband so difficult. 

    U.S. broadband speeds are on the uptick, and more users are getting better performance than ever from their broadband connectivity. However, there are still some states (particularly those with lower population density and vast terrain) that are struggling to deliver broadband services to their residents. 

    Ookla Speedtest Intelligence® data found that the number of states that are able to deliver fixed broadband services (fiber, cable and DSL) to the minimum standard of broadband speeds (100 Mbps download and 20 Mbps upload) to 60% or more of Speedtest users in their state grew dramatically from 22 states and the District of Columbia in the second half of 2024 to 38 states and the District of Columbia in the first half of 2025. 

    In addition, there are now five states—Connecticut, Delaware, New Jersey, North Dakota and Rhode Island —delivering speeds of 100/20 Mbps to more than 70% of their users.

    Not only are broadband speeds improving, Speedtest data from the first half of 2025 also revealed that 33 states narrowed the gap between how many rural users vs. urban users were able to achieve the FCC’s minimum broadband speeds of 100/20 Mbps.

    This is a fairly dramatic turnaround from the second half of 2024 when Speedtest data showed that 32 states had increased their digital divide instead of decreasing it. Ookla uses the Census Bureau’s urban-rural classification to determine which users are urban vs. rural. 

    South Dakota No. 1 in Starlink-delivered broadband speeds

    As a result of NTIA’s June decision to allow other technologies such as LEO satellites to compete for BEAD funding, at least 32 states and territories have decided to include LEO satellite systems in their final proposals (not all final BEAD proposals have been submitted as some states received extensions). While many states are still prioritizing fiber, LEO services such as SpaceX’s Starlink and Amazon’s Kuiper are appearing in many of the revised proposals. 

    We looked at Speedtest data on SpaceX’s Starlink service in every state and the District of Columbia to see what percentage of Starlink users received the FCC’s minimum standard for broadband of 100/20 Mbps. South Dakota is the No. 1 state with 37.1% of Starlink users getting access to 100/20 Mbps speeds followed by Maine with 35.3% of users and Wyoming with 34.5% of users.

    Download the full report

    To find your state’s standing and how it compares to the rest of the country in broadband connectivity, download this free report here.

    Ookla retains ownership of this article including all of the intellectual property rights, data, content graphs and analysis. This article may not be quoted, reproduced, distributed or published for any commercial purpose without prior consent. Members of the press and others using the findings in this article for non-commercial purposes are welcome to publicly share and link to report information with attribution to Ookla.

    About the Author

    Sue Marek

    Sue Marek is Ookla’s editorial director and part of the company’s analyst team. She oversees the company’s thought leadership and editorial content. Sue is a journalist with more than 30 years of experience covering the telecom industry and her work has appeared in Fierce Network, Light Reading, and SDxCentral. She is a frequent speaker at industry events and has moderated panels at Mobile World Las Vegas, Connect(x), the Consumer Electronics Show, the Competitive Carriers’ Show and 5G North America. Sue has a B.S. in journalism from the University of Colorado.

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  • Big Tech to report earnings under specter of AI bubble – Reuters

    1. Big Tech to report earnings under specter of AI bubble  Reuters
    2. What to Expect in Markets This Week: Fed Interest-Rate Decision; Earnings From Apple, Microsoft, Meta, Amazon, Alphabet  Investopedia
    3. Big Tech earnings, a crucial Fed meeting, and a Trump-Xi sit-down: What to watch this week  Yahoo Finance
    4. Huge week and risks face stocks this week  TheStreet
    5. View From the Circle: A Big Tech Test  Barron’s

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  • The association between triglyceride glucose–body mass index and all–cause mortality in critically ill patients undergoing cardiac surgery: a retrospective analysis from the MIMIC–IV database | BMC Cardiovascular Disorders

    The association between triglyceride glucose–body mass index and all–cause mortality in critically ill patients undergoing cardiac surgery: a retrospective analysis from the MIMIC–IV database | BMC Cardiovascular Disorders

    This retrospective study is the first to investigate the relationship between TyG-BMI and all-cause mortality in individuals undergoing cardiac surgery. The analysis demonstrated a U-shaped pattern between TyG-BMI values and mortality during the 30- to 365-day follow-up periods. Postoperative mortality risk rose with both decreased and elevated TyG-BMI levels, pointing to a non-linear pattern between this marker and patient survival. The statistical significance of this nonlinear trend was further confirmed through spline-based regression modeling, highlighting the need to pay more attention to the dual-end risks of TyG-BMI in preoperative assessments.

    Insulin resistance (IR) is frequently observed in association with both metabolic syndrome and obesity [16]. The presence of insulin resistance has been linked to an increased risk of cardiovascular complications and unfavorable prognoses after cardiac surgery [17]. This relationship is attributed to disorders of glucose and lipid metabolism, as well as oxidative stress, inflammatory responses, endothelial dysfunction, and ectopic lipid storage [7]. The TyG index, based on fasting plasma glucose and triglyceride concentrations, has been recognized as a useful surrogate for assessing insulin resistance [18]. The TyG-BMI index, along with BMI, offers a more thorough evaluation of metabolic disorders and obesity levels [18, 19]. Recent studies have shown that the TyG-BMI index is associated with poor outcomes in patients undergoing percutaneous coronary intervention (PCI) [20,21,22]. Chen et al. and Zhang et al. have also found that the TyG index may be a valuable predictor of adverse outcomes in diabetic patients who have undergone coronary artery bypass grafting (CABG) [23]. Previous research has predominantly concentrated on the effects of elevated TyG or TyG-BMI on the risks associated with cardiovascular disease, metabolic syndrome, and all-cause mortality [24].

    Our study identified a U-shaped association between the TyG-BMI index and all-cause mortality within 30 to 365 days following cardiac surgery. We propose the following interpretations for this finding. First, as the TyG index is calculated using fasting triglyceride and glucose levels, a low TyG value may reflect either hypolipidemia or hypoglycemia. It is plausible that low fasting glucose contributes to the increased mortality observed at lower TyG levels. Previous studies have shown that hypoglycemia (≤ 4.0 mmol/L) is significantly associated with higher risks of atrial fibrillation, diabetes, stroke, and major adverse cardiovascular events [25]. Moreover, patients experiencing more than five hypoglycemic episodes per year have a 61% higher risk of cardiovascular events, including arrhythmia (65%), cerebrovascular accident (38%), and myocardial infarction (43%) [26]. Second, the cardiovascular impact of low lipid levels remains controversial. One prospective cohort study found that low LDL-C (< 70 mg/dL) and low triglyceride levels were associated with an increased risk of hemorrhagic stroke in women [27]. However, other studies suggest that cardiovascular benefits may continue to accrue with further reductions in LDL-C [28]. Interestingly, although obesity is a well-established risk factor for cardiovascular disease, numerous studies have reported a U- or J-shaped relationship between BMI and mortality [29]. In some contexts, individuals with lower BMI may face higher short-term mortality compared to those who are overweight [30]. This paradox may be partly explained by the limitations of BMI, which is calculated solely from height and weight and does not reflect fat distribution or body composition. As a result, individuals with low TyG-BMI may be misclassified as having low metabolic risk, while in fact they may suffer from malnutrition, sarcopenia, or frailty—conditions that independently increase the risk of mortality. Furthermore, we observed that the increase in mortality risk at higher TyG-BMI values was less pronounced than at lower values, consistent with the “obesity paradox”. This phenomenon has been documented in various cardiovascular populations but remains underexplored in ICU patients following cardiac surgery [31]. We propose that the inflection point of the TyG-BMI index (approximately 235–238) may represent a “metabolic intermediate zone”. This threshold warrants further investigation as a potential tool for risk stratification in future studies, but more clinical evidence is needed to validate our conclusions in the future.

    In our study, the risks across all TyG-BMI quartiles were relatively close, with statistically significant associations observed only in certain subgroups. The reduced number of participants in some subgroups may have limited the statistical power, but other explanations may also exist. We found that the association between TyG-BMI and 30-day and 365-day all-cause mortality was more pronounced in male patients, non-White populations, patients with acute kidney injury, and those without type 2 diabetes mellitus, suggesting a certain degree of heterogeneity in the relationship between TyG-BMI and postoperative mortality risk. Clinically, insulin resistance (IR) is associated with several conditions, including obesity, T2DM, metabolic syndrome, cardiovascular disease, and cancer [32]. IR is a hallmark feature of patients with T2DM, who are already in a high-risk metabolic state. Therefore, the prognostic stratification value of the TyG-BMI index in diabetic patients may not be as evident as in non-diabetic individuals. In addition, our study did not perform subgroup analyses based on different BMI levels (e.g., normal weight vs. overweight/obese), as this was not planned in the initial study design. Given that BMI is an integral component of the TyG-BMI index, obesity status may modulate its predictive performance. Future studies are warranted to further explore the utility of this index across different BMI categories, which may help identify the optimal populations for its application.

    TyG-BMI is an index that can be calculated based on routine laboratory tests and physical measurements, with the advantages of being simple, cost-effective, and non-invasive [33]. This study highlights the potential of TyG-BMI as an informative metric for assessing preoperative risk [34]. Particularly for elderly cardiac surgery patients with multiple comorbidities, a TyG-BMI level within the appropriate range may represent a better metabolic state and balanced energy reserves, which can help improve postoperative survival rates [2]. Additionally, for patients with low TyG-BMI, nutritional support and overall health improvement can be enhanced preoperatively [35]; while for those with high TyG-BMI, metabolic control should be intensified and perioperative management optimized to achieve individualized interventions [12].

    This study has the following strengths: First, it employed a systematic and diverse set of statistical methods, including Kaplan-Meier survival curve analysis, Cox proportional hazards regression model, restricted cubic spline (RCS) regression, and subgroup analysis. The association between TyG-BMI and all-cause mortality in cardiac surgery patients was investigated using diverse analytical approaches, which enhanced the rigor and credibility of the findings. Second, the RCS model uncovered a nonlinear, U-shaped relationship between TyG-BMI and mortality across short-, medium-, and long-term periods, successfully identifying risk inflection points that traditional linear models failed to detect. Third, the study covered postoperative mortality outcomes at multiple time points, covering follow-up periods of 30 to 365 days, providing a more comprehensive assessment. Furthermore, utilizing a substantial real-world dataset of individuals who underwent cardiac surgery, this study has good clinical representativeness and generalizability.

    Nevertheless, this study has several limitations. Firstly, the study employs a retrospective observational approach. Although multiple factors have been adjusted for, it is still impossible to completely avoid the influence of confounding factors or to determine causality. Secondly, as an indirect metabolic indicator, TyG-BMI cannot distinguish between fat and muscle components through BMI alone, which may lead to some evaluation bias [36]. Thirdly, the MIMIC-IV database does not contain reliable data on cause-specific mortality. Therefore, only all-cause mortality was analyzed in this study. Future prospective research is warranted to investigate the association between TyG-BMI and specific causes of death, such as cardiovascular or infectious mortality, to further clarify its clinical implications. Additionally, direct comparison between TyG-BMI and existing risk scoring systems would help evaluate its additional predictive value. However, as this study is a retrospective analysis, and due to differences in the availability and calculation standards of each scoring system, we were unable to perform such comparisons. Future analyses using discrimination metrics (e.g., AUC), reclassification indices (e.g., NRI, IDI), or calibration curves would be beneficial in further assessing the incremental value of TyG-BMI in clinical decision-making. Meanwhile, as the TyG-BMI was calculated based on glucose and triglyceride values upon ICU admission, these parameters may have been influenced by surgical stress and acute-phase responses, potentially limiting its reflection of the patient’s baseline metabolic risk.

    In summary, TyG-BMI may serve as a useful and accessible biomarker for early risk stratification in critically ill patients after cardiac surgery. Future prospective studies are needed to validate its predictive performance in broader populations. Similar metabolic indices have shown prognostic utility in various cardiovascular populations. For instance, Yılmaz et al. reported that triglyceride-based indices predicted in-hospital mortality in coronary ICU patients [37], while Aslan et al. associated the atherosclerotic plasma index with cerebrovascular events in patients with carotid artery disease [38]. These findings support the broader applicability of TyG-like indices in risk stratification. In addition, with the growing role of artificial intelligence (AI) in clinical prediction and personalized risk assessment, the integration of artificial intelligence (AI)-based modeling techniques may further enhance the predictive accuracy and clinical utility of metabolic indices such as TyG-BMI. Recent advances have demonstrated the potential of AI to improve risk modeling in cardiovascular medicine, suggesting promising directions for future research in this field [39].

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  • Integrated Molecular Diagnostics Unmask Legionella pneumophila and Fun

    Integrated Molecular Diagnostics Unmask Legionella pneumophila and Fun

    Introduction

    Mortality related to severe pneumonia exceeds 30% among immunocompromised patients admitted to ICUs,1 largely attributable to delayed pathogen identification and inappropriate antimicrobial therapy.2 Legionella pneumophila (L. pneumophila), an elusive respiratory pathogen, exemplifies this diagnostic dilemma, accounting for 1%–10% of community-acquired pneumonia (CAP) with rapid progression to respiratory failure and multi-organ dysfunction.3 Approximately 44% of patients require intensive care, with mortality rates of 10%–15% that rise to 25%–50% in nosocomial settings.3 Misdiagnosis frequently leads to delayed or inappropriate therapy and unnecessary broad-spectrum antibiotic use, exacerbating both mortality risk and antimicrobial resistance.

    This fastidious gram-negative bacterium evades routine culture4 and presents nonspecifically.5 Hyponatremia and extrapulmonary symptoms may provide clues, but definitive diagnosis traditionally relies on urinary antigen testing (limited to serogroup 1) or retrospective serology (delayed antibody response).6 Although these methods retain useful in stable, community-acquired pneumonia or epidemiological surveillance due to their rapidity and cost-effectiveness, they are suboptimal for guiding initial therapy in critically ill immunocompromised hosts, in whom a broad range of pathogens must be rapidly ruled out. This diagnostic delay is particularly consequential in high-risk populations, such as patients with renal failure, diabetes, or immunosuppression, where mortality can reach 80% without targeted treatment.2

    Molecular diagnostics have emerged as promising tools to address these gaps. Pathogen-targeted PCR assays deliver results within hours but cover limited pathogen panels.7 Metagenomic next-generation sequencing (mNGS) enables hypothesis-free detection of all nucleic acids in clinical samples, yet its quantitative accuracy may be compromised by host DNA dominance or low pathogen biomass.8 Digital PCR (dPCR) provides absolute quantification of pathogen load but suffers from low throughput.9 Isothermal amplification technology, as one of the best candidates for replacing with PCR method, is also gradually being applied in the field of rapid pathogen detection.10 While individual technologies demonstrate advantages, evidence supporting their synergistic application for diagnosing rare pathogens like Legionella remains scarce.

    The COVID-19 pandemic has further complicated pneumonia management. Immunosuppressive therapies used in severe cases (eg corticosteroids) increase susceptibility to opportunistic infections, including Legionella and fungi.2 This creates a critical need for rapid, comprehensive diagnostic strategies that differentiate viral, bacterial, and fungal co-infections to guide precision therapy.

    Here, we present a clinically instructive case of severe pneumonia in an immunocompromised host, where an integrated molecular approach incorporating isothermal amplification, dPCR, and mNGS enabled rapid confirmation of L. pneumophila with concurrent Candida glabrata coinfection. This case yields three pivotal insights: (1) Technical synergy: Initial isothermal amplification delivered pathogen-specific positivity within 12 hours; subsequent dPCR overcame false negativity via sample dilution, confirming nucleic acid inhibition; while mNGS independently validated Legionella and uncovered fungal co-infection. (2) Therapeutic precision: Molecular diagnostics facilitated prompt transition from empirical antibiotics to targeted anti-legionella (fluoroquinolone/macrolide) and antifungal therapy (amphotericin B), with serial PCT/CRP trends objectively tracking therapeutic response. (3) Clinical impact: The 72-hour diagnostic pathway outperformed conventional methods, potentially reducing mortality risk by 3-fold versus traditional culture-dependent approaches.

    This report underscores the viability of integrated molecular diagnostics as a new standard for critical pneumonia in immunocompromised hosts, directly informing antimicrobial stewardship and improving outcomes in complex co-infections.

    Case Presentation

    A 57-year-old female with a complex medical history presented to the emergency department on September 7, 2024, with acute dyspnea exacerbation over 2 hours. Her comorbidities included: Rheumatic heart disease (mechanical valve replacement, 2018), Chronic renal failure (CKD stage 4, eGFR 22 mL/min/1.73m²), Type 2 diabetes mellitus (HbA1c 8.6%), Chronic nephritic syndrome on immunosuppressive therapy (prednisone 10 mg/day). Vital signs upon admission included temperature 37.8°C, heart rate 110 bpm (atrial fibrillation), respiratory rate 28 breaths/min, SpO2 88% on room air. Physical examination revealed bilateral basal crackles and pedal edema.

    Initial Diagnostic Investigations

    Laboratory findings demonstrated leukocytosis (WBC 19.03 × 109/L, neutrophils 89%), hyponatremia (Na+ 127 mmol/L), elevated inflammatory markers (PCT 42.55 ng/mL, CRP 12.2 mg/L), and renal impairment (creatinine 265 μmol/L, BUN 31.2 mmol/L). High-resolution CT showed bilateral multifocal consolidations with ground-glass opacities and interlobular septal thickening on admission day (Figure 1A), which further progressed to diffuse patchy ground-glass opacities by day 5 (Figure 1B), collectively suggestive of severe pneumonia with interstitial involvement.

    Figure 1 Radiological images of high-resolution chest CT. (A) Chest CT at admission showing bilateral multifocal consolidations with ground-glass opacities and interlobular septal thickening; (B) Chest CT on day 5 demonstrating a diffuse progression of patchy ground-glass opacities; (C) Chest CT on day 20 showed >70% resolution of consolidations.

    Molecular Diagnostic Cascade

    On Day 1 (ICU admission), empirical Imipenem-cilastatin (0.5g q12h, renal-adjusted) was initiated. Sputum samples were immediately subjected to respiratory pathogen panel testing via isothermal amplification (Isothermal Amplification on Disk Chip, CapitalBio Technology (Chengdu) Co., Ltd)., screening for 9 common (Streptococcus pneumoniae, Staphylococcus aureus, Methicillin-Resistant Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, Stenotrophomonas maltophilia, Haemophilus influenzae and Escherichia coli) and 5 atypical (Mycobacterium tuberculosis complex, Mycoplasma pneumoniae, Chlamydophila pneumoniae and Legionella pneumophila) pathogens associated with respiratory infections (Respiratory Pathogens Nucleic Acid Detection Kit). Positive result of L. pneumophila was reported 4 hours after sample delivered to laboratory (Figure 2A). Bronchoalveolar lavage fluid (BALF) collected on Day 2 underwent comprehensive testing. dPCR (Digital PCR Assay Kit, Pilot Gene Technology, Hangzhou) of undiluted sample yielded negative results (Figure 2B); 10-fold dilution demonstrated 4,455 copies/mL of L. pneumophila (Figure 2C), indicating that high-concentration nucleic acids can inhibit amplification reactions. On Day 3, mNGS (IDseqTM Ultra, Vision Medicals, Guangzhou) revealed L. pneumophila dominance (384,661 reads, 92.7% relative abundance, Figure 2D) with concurrent Candida glabrata (C. glabrata) coinfection (3,473 reads, 80.6% relative abundance, Figure 2E). An evolution to Mixed Infection and therapeutic challenges were on Day 6 due to recurrent fever (39.2°C) with CRP rebound (↑153.4 mg/L from 96.8 mg/L), with BALF biomarkers β-D-glucan 674.8 pg/mL (normal <80). Sputum culture also confirmed fungal coinfection with Candida glabrata (>105 CFU/mL, Figure 2F).

    Figure 2 Multi-Platform Pathogen Diagnostic Results. (A) Isothermal amplification curves of BALF; Results of dPCR from undiluted (B) and 10-fold diluted (C) BALF; BALF mNGS gene sequence coverage depth map for Legionella pneumophila (D) and Candida glabrata (E); (F) Candida glabrata colonies from sputum culture.

    Therapeutic Interventions

    Antimicrobial therapy was dynamically adjusted (Table 1). (1) Legionella-targeted therapy [(Moxifloxacin (400mg IV q24h) + azithromycin (500mg IV q24h)] initiated on Day 1. (2) Immunomodulation: Methylprednisolone (40mg IV q24h) started on Day 2, ends on Day 7. (3) Antifungal therapy: Fluconazole (800mg loading, then 400mg q24h) on Day 6; switched to amphotericin B lipid complex (5mg/kg/day) on Day 11 due to persistent fever and rising β-D-glucan (↑832 pg/mL). (4) Broad-spectrum coverage: Imipenem-cilastatin (1000mg q12h) maintained until Day 10; sulbactam/cefoperazone added on Day 11 for suspected gram-negative coinfection. (5) Biomarker-guided response assessment: PCT declined from 42.55 → 9.23 ng/mL by Day 7 (bacterial control). CRP spiked to 256.2 mg/mL on Day 7 (fungal breakthrough), declining to 58.8 mg/mL after amphotericin B (Figure 3). (6) Supportive care: Hemodialysis (3×/week) for fluid/electrolyte management. Non-invasive ventilation (FiO2 50%, PEEP 8 cmH2O).

    Table 1 Key Diagnostic and Therapeutic Timeline

    Outcome and Follow-up

    Day 20: CT showed >70% resolution of consolidations (Figure 1C).

    Day 23: Discharged with oral levofloxacin (750mg q24h) and posaconazole (300mg q24h).

    1-month follow-up: PCT 0.3 ng/mL, CRP 6 mg/L. Renal function stabilized (creatinine 201 μmol/L).

    Diagnostic Validation and Quality Control

    Pre-analytical: Respiratory tract samples processed within 1 hour (cold chain maintained).

    Analytical: dPCR inhibition resolved by protocolized dilution (validated with spike-in controls). mNGS human DNA depletion efficiency: 98.7%.

    Post-analytical: Legionella results communicated to clinicians within 4 hours of validation. Multidisciplinary review of discordant results (microbiologist, intensivist, pharmacist).

    Discussion

    Multi-Platform Molecular Diagnostics

    The “stealth” nature of L. pneumophila – characterized by fastidious growth, nonspecific symptoms, and high mortality in immunocompromised hosts (up to 80% if untreated) – demands rapid diagnostic innovation.11 This case demonstrates a tripartite molecular strategy that overcomes traditional barriers: Isothermal amplification provided critical first-line detection within 12h (vs 3–7 days for culture), triggering life-saving macrolide/fluoroquinolone therapy.12 The initial positivity (Figure 2A) was pivotal given the patient’s rapid respiratory deterioration. dPCR’s dilution-reflex protocol resolved false negatives caused by nucleic acid inhibition (undiluted: negative; 10× dilution: 4,455 copies/mL). This phenomenon, attributed to polymerase competition at high DNA concentrations,13 underscores the necessity of standardized validation workflows for quantitative molecular tools. mNGS independently confirmed Legionella dominance (384,661 reads) while revealing clinically significant C. glabrata coinfection (3,473 reads + elevated β-D-glucan), enabling comprehensive antimicrobial coverage.14 This represents the first validated “Screen-Quantify-Expand” algorithm for respiratory pathogens, reducing diagnostic time by >72h versus culture-dependent pathways.

    A multi-center epidemiological study of severe community-acquired pneumonia (SCAP) has demonstrated that molecular diagnostics (including PCR and mNGS) demonstrate superior performance in rapidly detecting atypical pathogens. While culture and antigen tests are more accessible, the combined pathogen testing upon hospital admission for SCAP patients is recommended, as the clinical benefit and potential mortality reduction from appropriate targeted therapy outweigh the initial cost.15 Although nucleic acid amplification techniques have been widely applied in pathogen detection with the advancement of molecular methods, promoting the adoption of such integrated molecular diagnostic approaches requires practical considerations at three levels at least, beyond cost: 1) Defined diagnostic stewardship: Establishing clear clinical criteria for test deployment (eg, in severe pneumonia or immunocompromised hosts unresponsive to initial therapy) is essential to ensure appropriate use and resource allocation. 2) Integrated interpretation frameworks: Implementing multidisciplinary team reviews (involving intensivists, clinical microbiologists, and pharmacists) is critical for accurately interpreting complex, multi-platform results and translating them into timely, targeted therapeutic actions. 3) Standardized operational pathways: Developing standardized protocols encompassing pre-analytics (sample processing), analytics (eg, inhibition checks via dilution), and post-analytics (structured reporting) is fundamental to ensuring reliability and reproducibility across different institutions.

    Biomarker-Driven Antimicrobial Stewardship

    Immunocompromised hosts with pneumonia exhibit 34–68% polymicrobial infection rates,2 yet differentiating colonization from invasion remains challenging. Our case illustrates how serial biomarker profiling optimizes stewardship: PCT- guided bacterial de-escalation: The rapid decline (42.55 → 8.2 ng/mL by Day 7) confirmed Legionella treatment efficacy (Figure 3), allowing cessation of empiric carbapenems. This aligns with PCT’s high negative predictive value (94%) for bacterial clearance.8 CRP biphasic response as a therapeutic compass: Initial decline was seen on Day 5, CRP dropped from 228.2 to 96.8 mg/L after initiating moxifloxacin/azithromycin, suggesting partial inflammatory control. Secondary surge was seen by Day 6, CRP rebounded to 256.2 mg/L despite antifungal escalation (fluconazole → amphotericin B) and imipenem doubling on Day 6. This paradoxical rise reflects two intertwined factors: (1) Legionella’s intrinsic slow response: Even appropriate therapy requires 48–72 hours for significant biomarker improvement due to intracellular persistence.16 (2) Antifungal lag phase: Amphotericin B’s maximal effect against C. glabrata manifests after 48–96 hours.17

    This biphasic CRP pattern underscores that in immunocompromised hosts, biomarker trends must be interpreted within pathogen-specific response timelines. Early immunomodulation with methylprednisolone may have mitigated systemic inflammation in this critically ill patient with multiorgan dysfunction. Premature regimen abandonment based on transient CRP rise could jeopardize outcomes. Dual-trending PCT (bacterial burden) and CRP (inflammatory activity) thus creates a nuanced “infection barometer” – a strategy critical for mixed-infection management.18

    Antifungal Management in Renal-Impaired Hosts: Balancing Efficacy and Toxicity

    The emergence of C. glabrata in this renal failure patient posed unique challenges: Fluconazole failure was anticipated (inherent resistance in 15–20% of C. glabrata19) yet initiated empirically due to renal safety concerns. Amphotericin B optimization: Lipid formulation dosing (5 mg/kg/day) required therapeutic drug monitoring (target trough 1–2 μg/mL) to mitigate nephrotoxicity, with parallel hemodialysis mitigating electrolyte disturbances.20 Biomarker-driven duration: β-D-glucan decline from 832 to normal guided 14-day amphotericin B course, avoiding prolonged exposure. Contrast with typical legionellosis: While pure Legionella pneumonia rarely requires >10–14 days therapy,21 coinfection extended treatment to 23 days, highlighting the impact of comorbidities on antimicrobial planning.

    Diagnostic Stewardship: Laboratory-Clinician Synergy

    This case exemplifies how proactive laboratory engagement optimizes clinical outcomes through integrated pre-analytical, analytical, and post-analytical interventions: Pre-analytical, BALF processing within 1 hour under validated cold-chain conditions (4°C) preserved nucleic acid integrity. During analysis, protocolized dilution resolved dPCR inhibition while 98.7% human mNGS human DNA depletion enhanced pathogen detection. Post-analytically, Legionella positivity was communicated to the ICU within 4 hours, and fungal reads from mNGS triggered consequent β-D-glucan monitoring.

    Limitations and Translational Perspectives

    Despite its success, this approach faces hurdles: Cost-effectiveness remains a concern: mNGS and dPCR add approximately $800 per test compared to $50 for conventional culture.22 However, the potential reduction in ICU stay may partially offset these expenses.23 Technical barriers also exist: dPCR availability is still limited, while isothermal amplification assays cover only a narrow spectrum of respiratory pathogens. Future directions should focus on: (1) Developing point-of-care platforms for rapid quantification. (2) Leveraging host-response transcriptomics to differentiate colonization from invasion,24 and (3) Integrating AI with biomarker trends to enable automated clinical alerts.25

    Conclusion

    This case redefines diagnostic paradigms for severe pneumonia in immunocompromised hosts. The synergistic use of isothermal amplification, dPCR, and mNGS enabled rapid, accurate identification of L. pneumophila and C. glabrata, overcoming limitations of single platforms. Dynamic PCT/CRP monitoring optimized antimicrobial stewardship, while laboratory-clinical communication ensured timely intervention. While this integrated model offers a promising template for managing complex infections, its broader adoption faces barriers including cost, technical complexity, and the need for standardized protocols and interdisciplinary collaboration. Future efforts should focus on developing cost-effective point-of-care platforms, establishing clear diagnostic pathways for high-risk patients, and validating their impact on patient outcomes through multi-center studies. As molecular diagnostics evolve, this approach underscores that precision medicine in critical care begins with precision diagnostics, though its implementation requires careful consideration of practical and economic factors alongside clinical benefit.

    Ethical Approval

    The study was approved by the Research Ethics Committee of Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University (KY2023-405-02). Institutional approval was also required and obtained for the publication of the case details. All procedures performed were in accordance with the ethical standards of the institutional research committee and with the principles outlined in the Declaration of Helsinki and its amendments. The strains involved in the study were residual clinical isolates, without animal experiments and animal ethical requirements.

    Consent Statement

    Written informed consent was obtained from the patient for academic publication, including any accompanying images and case details.

    Acknowledgments

    The study was supported by various colleagues from the hospital’s Department of Clinical Laboratory.

    Author Contributions

    All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

    Funding

    This research was supported by the National Natural Science Foundation of China (Grant No. 82302571); Basic and Applied Basic Research Foundation of Guangdong (2024A1515011037); Medical Science and Technology Research Foundation of Guangdong (B2025152).

    Disclosure

    The authors report no conflicts of interest in this work.

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