Recent publications
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Background: The literature on burden of disease studies of hepatocellular carcinoma is scarce. The aim of this analysis was to quantify the economic burden of disease recurrence in very early or early-stage HCC patients who underwent liver resection, ablation or transplantation in Spain. Methods: A decision-tree model was developed to estimate the cost of a recurrence after curative treatment with an initial complete response of very early or early-stage primary HCC tumor over a 5-year time horizon. Clinical parameters were collected by a multidisciplinary group of experts who also validated the assumptions and results of the analysis. According to the Barcelona Clinic Liver Cancer (BCLC) recommendations, patients with recurrent HCC were classified into five HCC stages (0, A, B, C, and D) and allocated to different treatment options. A payer perspective was adopted, so only direct costs (€2024) were considered (local/locoregional treatments costs, drug acquisition and administration costs, adverse events management costs, diagnostic and follow-up costs and end-of-life costs). Sensitivity analyses were performed to assess uncertainty. Results: A total of 1,250 HCC recurrences were estimated in Spain, resulting in a total cost of €32,817,142 in the first year of recurrence management. After 5-years follow-up, an additional €10,1M was estimated, mainly due to patient surveillance (€2,8M) and 228 new recurrences (€5,7M). The average cost of a relapse was €26,253 euros in the first year of recurrence management, rising to €34,342 euros for 5-years follow-up. A hypothetical patient experiencing a second relapse 5 years after their first relapse would incur costs of €58,758. Conclusions: This study is the first in Spain to explore the economic burden of hepatocellular carcinoma. Estimating the cost of recurrence after curative treatment and complete response of a primary HCC tumor is complex and depends on multiple factors, so further studies exploring both efficacy and costs in hepatocellular carcinoma are needed.
The rapid and economical synthesis of novel bioactive compounds remains a significant hurdle in drug discovery efforts. This study demonstrates an integrated medicinal chemistry workflow that effectively diversifies hit and lead structures, enabling an efficient acceleration of the critical hit-to-lead optimization phase. Employing high-throughput experimentation (HTE), we generated a comprehensive data set encompassing 13,490 novel Minisci-type C-H alkylation reactions. This data set served as the foundation for training deep graph neural networks to accurately predict reaction outcomes. Scaffold-based enumeration of potential Minisci reaction products, starting from moderate inhibitors of monoacylglycerol lipase (MAGL), yielded a virtual library containing 26,375 molecules. This virtual chemical library was evaluated using reaction prediction, physicochemical property assessment, and structure-based scoring, identifying 212 potential MAGL inhibitor candidates. Of these, 14 ligands were synthesized and exhibited subnanomolar activity, representing a potency improvement of up to 4500 times over the original hit compound. These compounds also displayed favorable pharmacological profiles. Co-crystallization of three computationally designed ligands with the MAGL protein provided valuable structural insights into their preferred binding poses. This study demonstrates the potential of combining miniaturized HTE with deep learning and molecular property optimization to reduce cycle times in drug discovery.
Background
The presented study identified the appropriate ocrelizumab dosing regimen for patients with pediatric-onset multiple sclerosis (POMS).
Methods
Patients with POMS aged 10–17 years were enrolled into cohort 1 (body weight [BW] < 40 kg, ocrelizumab 300 mg) and cohort 2 (BW ≥ 40 kg, ocrelizumab 600 mg) during a 24-week dose-exploration period (DEP), followed by an optional ocrelizumab (given every 24 weeks) extension period. Primary endpoints: pharmacokinetics, pharmacodynamics (CD19⁺ B-cell count); secondary endpoint: safety; exploratory endpoints: MRI activity, protocol-defined relapses, Expanded Disability Status Scale (EDSS) score change.
Results
A total of 23 patients (cohort 1: n = 6, age 10–12 years, BW 27.0–39.0 kg; cohort 2: n = 17, age 11–17 years, BW 42.1–108.4 kg) were enrolled. Median treatment duration was 120 (range, 24–193) weeks at the primary analysis cutoff (October 5, 2023). Overall, the pharmacokinetic data were within the range observed at 600 mg in adult patients with MS; however, the exposure at 300 mg in patients < 40 kg was lower than with 600 mg in patients ≥ 40 kg. Shifting the cutoff to 35 kg would provide better exposure to patients with 35–40 kg body weight. Sustained, near-complete B-cell depletion was observed. The safety profile was consistent with that in adults. EDSS scores remained stable; no clinical relapses were observed.
Conclusion
A dosing regimen of 300 mg ocrelizumab for patients < 35 kg, and 600 mg for patients ≥ 35 kg (every 24 weeks), was selected for the phase 3 OPERETTA II trial (NCT05123703).
Trial registration
ClinicalTrials.gov: NCT04075266.
Amyloid β (Aβ) has been confirmed as a therapeutic target in AD by recent findings in Phase 3 trials with anti‐Aβ antibodies. Modulators of γ‐secretase (GSMs) are an emerging complementary approach to target amyloid. GSMs “modulate” the interaction between γ‐secretase and amyloid precursor protein (APP), leading to a reduced production of long, amyloidogenic Aβ42 and Aβ40 and to concomitantly increased levels of the shorter, non amyloidogenic Aβ37 and Aβ38. This change in processivity of γ‐secretase results in a reduced formation of soluble and insoluble Aβ aggregates and plaque deposits. Unlike inhibitors of γ‐secretase or BACE1, GSMs do not inhibit the activity of γ‐secretase and thus do not block the processing of APP and of other substrates. In addition, non‐clinical studies showed that GSMs may have beneficial effects on synaptic integrity and Aβ‐associated neuro‐inflammation.
The clinical relevance of higher Aβ37 and Aβ38 ‐levels for a reduced risk of cognitive decline have been described in observational cohorts (vonKienlin et al. 2018; Cullen et al. 2022). Nevertheless, to date the effects of GSMs on brain function and course of disease in people living with AD have not been investigated. Our novel orally available GSM RG6289 has completed the Phase 1 study in healthy young and elderly volunteers. Safety, pharmacokinetic and pharmacodynamic data from this study support the further clinical development of the molecule. The Phase 2 study in individuals with AD is expected to start this year. Challenges of developing in clinic a new mechanism of action, as well as considerations regarding how to best position this molecule for AD will be discussed in this presentation.
Resting natural killer (NK) cells display immediate effector functions after recognizing transformed or infected cells. The environmental nutrients and metabolic requirements to sustain these functions are not fully understood. Here, we show that NK cells rely on the use of extracellular pyruvate to support effector functions, signal transduction and cell viability. Glucose-derived carbons do not generate endogenous pyruvate. Consequently, NK cells import extracellular pyruvate that is reduced to lactate to regenerate glycolytic NAD⁺ and is oxidized in the tricarboxylic acid (TCA) cycle to produce ATP. This supports serine production through phosphoglycerate dehydrogenase, a pathway required for optimal proliferation following cytokine stimulation but dispensable for effector functions. In addition, like mouse NK cells, human NK cells rely on a citrate–malate configuration of the TCA cycle that is not fed by glutamine. Moreover, supraphysiologic pyruvate concentrations dose-dependently increase the effector functions of NK cells. Overall, this study highlights the role of exogenous pyruvate in NK cell biology, providing knowledge that could be exploited to boost NK cell potential in therapeutic settings.
Delandistrogene moxeparvovec is an rAAVrh74 vector-based gene transfer therapy that delivers a transgene encoding delandistrogene moxeparvovec micro-dystrophin, an engineered, functional form of dystrophin shown to stabilize or slow disease progression in DMD. It is approved in the US and in other select countries. Two serious adverse event cases of immune-mediated myositis (IMM) were reported in the phase Ib ENDEAVOR trial (NCT04626674). We hypothesized that immune responses to the micro-dystrophin transgene product may have mediated these IMM events. An interferon-gamma ELISpot assay was used to detect T cell responses to delandistrogene moxeparvovec micro-dystrophin peptide pools. ELISpot analysis suggested that IMM resulted from T cell-mediated responses directed against specific micro-dystrophin peptides corresponding to exons 8 and 9 (Case 1) and exon 8 (Case 2) of the DMD gene. In silico epitope mapping based on the patients’ HLA-I alleles indicated greater probability for peptides derived from exons 8 and/or 9 to bind HLA-I, providing further evidence that peptides derived from corresponding micro-dystrophin regions may have higher immunogenic potential. Collectively, these data suggest that patients with DMD gene deletions involving exons 8 and/or 9 may be at increased risk of IMM following delandistrogene moxeparvovec micro-dystrophin gene therapy infusion.
The Alzheimer's Disease Neuroimaging Initiative (ADNI) Private Partners Scientific Board (PPSB) Diversity, Equity, and Inclusion Working Group (DE&I WG) was established to work with the ADNI3 Diversity Task Force to provide an industry perspective on increasing the representation of diverse participants in ADNI3 and to build precompetitive cross‐industry knowledge in engagement and recruitment of under‐represented participants (URPs). In this article, we review and highlight the role and ongoing activities within the ADNI PPSB DE&I WG and provide a cross‐industry perspective on areas where precompetitive collaboration can improve the inclusiveness in clinical trials, drawing on examples from ADNI4.
Highlights
New collaboration crosses boundaries to allow PPSB DE&I WG members to work together in a preproprietary way.
When faced with the same challenges required by FDA combined with a growing prevalence of AD, the DE&I WG has drafted a range of initiatives that may benefit ADNI, AD patients, care partners, and respective companies involved in this work.
In order to address the multifactorial problem of successfully enrolling representative populations in clinical trials, it will “take a village” to bring about sustainable changes.
There is a growing interest in the implementation of platform trials, which provide the flexibility to incorporate new treatment arms during the trial and the ability to halt treatments early based on lack of benefit or observed superiority. In such trials, it can be important to ensure that error rates are controlled. This paper introduces a multi‐stage design that enables the addition of new treatment arms, at any point, in a preplanned manner within a platform trial, while still maintaining control over the family‐wise error rate. This paper focuses on finding the required sample size to achieve a desired level of statistical power when treatments are continued to be tested even after a superior treatment has already been found. This may be of interest if there are treatments from different sponsors which are also superior to the current control or multiple doses being tested. The calculations to determine the expected sample size is given. A motivating trial is presented in which the sample size of different configurations is studied. In addition, the approach is compared to running multiple separate trials and it is shown that in many scenarios if family‐wise error rate control is needed there may not be benefit in using a platform trial when comparing the sample size of the trial.
Anti-vascular endothelial growth factor (VEGF) therapies have transformed the treatment of retinal diseases. However, VEGF signaling is only one component of the complex, multifactorial pathophysiology of retinal diseases, and many patients have residual disease activity despite ongoing anti-VEGF treatment. The angiopoietin/tyrosine kinase with immunoglobulin and epidermal growth factor receptor-2 (Ang/Tie2) signaling pathway is critical to endothelial cell homeostasis, survival, integrity, and vascular stability. Ang-2 can interfere with Ang-1/Tie2 signaling and is increased in several retinal diseases. Lack of Tie2 signaling due to elevated Ang-2 levels drives vascular instability through pericyte dropout, neovascularization, vascular leakage, inflammation, and fibrosis. Although Ang-2 and VEGF can synergistically promote vascular instability and neovascularization, Ang-2 may also mediate vascular instability independently of VEGF. Faricimab is a bispecific antibody designed for intraocular use that inhibits two distinct pathways via Ang-2 and VEGF-A blockade. Clinical biomarkers of vascular instability are important for evaluating disease control and subsequent treatment decisions. These biomarkers include measurement/evaluation with optical coherence tomography (OCT) of intraretinal fluid, subretinal fluid, central subfield thickness, and pigment epithelial detachments (PEDs), and fluorescein angiography imaging of macular leakage and PEDs. Hyperreflective foci (HRF), thought to be representative of activated microglia, indicating an inflammatory microenvironment, and epiretinal membranes (ERMs), a marker for retinal fibrotic proliferation in diabetic macular edema (DME), are both also identified using OCT. Here we summarize data (secondary endpoint and prespecified exploratory analyses as well as post hoc analyses) from six Phase III trials suggest that dual therapy Ang-2/VEGF-A inhibition with faricimab (6 mg) has a greater effect on reducing/resolving biomarkers of vascular instability than aflibercept (2 mg), by both controlling neovascularization and vascular leakage (with resultant resolution of exudation associated with DME, neovascular age-related macular degeneration, and retinal vein occlusion), as well as by targeting inflammation (reduction of HRF in DME) and retinal fibrotic proliferation (reducing the risk of ERMs in eyes with DME). Modulation of both the Ang-2 and VEGF-A pathways with faricimab may therefore provide greater disease control than anti-VEGF monotherapy, potentially leading to extended treatment durability and improved long-term outcomes.
Background
The prevalence of vision-threatening diseases, such as age-related macular degeneration (AMD) and diabetic macular edema (DME), is likely to increase in developed countries owing to an aging population, rising life expectancy, and unfavorable lifestyle changes. Increases in the burden of vision-threatening diseases pose a challenge to the healthcare system. After the emergence of intravitreal anti-VEGF inhibitors, treatment options for neovascular AMD (nAMD), DME, retinal vein occlusion (RVO) and myopic choroidal neovascularization (myopic CNV) have increased. As this change in treatment practices has occurred over the last two decades, it is important to demonstrate changes in patient numbers and administered treatments to provide solutions for handling the workload and productivity in ophthalmology departments. In addition, the registry data landscape has evolved in Finland in recent years. Thus, understanding the possibilities and limitations of ophthalmology registries and patient information systems is required.
Methods
This study involved the secondary use of retrospectively registered data from the data warehouse of the Hospital District of Southwest Finland. Our goal was to explore how the workload of ophthalmology departments caused by intravitreal injections has evolved from 2015 to 2022.
Results
The ophthalmology department workload increased significantly during our observation period as the total number of patients receiving intravitreal treatments for nAMD, DME, RVO, and myopic CNV increased 199.6% from 2015 to 2021. In addition, the total number of administered anti-VEGF injections increased during our observation period, but the increase rate began to subside (2019–2020: increase 23.7%, 2020–2021: increase 10.3%, 2021–2022: increase 6.7%).
Conclusion
Supporting the utilization of registry data is essential in evidence-based discussions evolving workload in healthcare. However, it is important to understand the limitations and the quality of the registries. Our study contributes to better understanding the Finnish registry perspective, and it demonstrates the increase in workload in ophthalmology departments caused by intravitreal injections.
Stride velocity 95th centile (SV95C) is a wearable-derived endpoint representing the 5% fastest strides taken during everyday living. In July 2023, SV95C received European Medicines Agency (EMA) qualification for use as a primary endpoint in trials of patients with Duchenne muscular dystrophy (DMD) aged ≥ 4 years—becoming the first digital endpoint to receive such qualification. We present the data supporting this qualification, providing insights into the evidentiary basis of qualification as a digital clinical outcome assessment. Clinical trials, natural history studies, and patient surveys (ages 5 − 14 years) showed that SV95C is accurate, valid, reliable, sensitive, and clinically meaningful. SV95C significantly correlated with traditional DMD assessments, increased rapidly after steroid initiation (0.090 m/s 3 months post-treatment), and declined steadily in patients on stable steroid regimens. Compared with traditional assessments, SV95C demonstrated earlier sensitivity to disease progression (3 vs 9 months) and greater sensitivity at 12 months. Distribution- and anchor-based approaches revealed a change of − 0.10 to − 0.20 m/s as clinically meaningful. The EMA qualification of SV95C illustrates the willingness of regulators to accept novel digital endpoints for drug approval, setting an important precedent for the evidentiary basis of regulatory digital endpoint qualification that could transform clinical development in disorders affecting movement.
Background
We evaluated the potential of circulating bone morphogenetic protein 10 (BMP10) as a biomarker for atrial stress and remodelling in patients with heart failure (HF), in comparison to N-terminal pro-B-type natriuretic peptide (NT-proBNP). We also assessed the predictive value of BMP10 for adverse clinical outcomes.
Methods
BMP10 levels were quantified in 2085 chronic HF patients from the European BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) cohort and in 1487 patients from the Scottish validation cohort. Multivariable linear regression identified independent associates of BMP10. Proteomic analysis of 6369 proteins with subsequent gene set enrichment analysis was used to explore biological pathways associated with elevated BMP10. Cox proportional hazards models adjusting for established risk factors were used to associate BMP10 levels with clinical outcomes, including all-cause mortality and HF hospitalisation.
Results
In a multivariable model including clinical and echocardiographic parameters, log-transformed and standardised BMP10 levels were significantly associated with a history of atrial fibrillation (Sβ=0.419; p<0.001), and with echocardiographic features reflecting atrial stress, such as increased left atrial diameter (Sβ=0.075; p=0.048). By contrast, these were not among the strongest associates of NT-proBNP levels. Gene set enrichment analysis showed significant overrepresentation in pathways of muscle contraction and extracellular matrix organisation. Higher log-transformed and standardised BMP10 levels predicted a combined outcome of 2-year all-cause mortality and HF rehospitalisation (HR=1.10, 95% CI=1.02–1.19), with the validation cohort yielding comparable results.
Conclusion
BMP10 emerges as a novel biomarker reflecting atrial stress and remodelling in chronic HF patients. Its additional predictive value for adverse outcomes underscores its potential utility in enhancing risk stratification and guiding therapeutic interventions in HF management.
Understanding spatial dynamics within tissue microenvironments is crucial for deciphering cellular interactions and molecular signaling in living systems. These spatial characteristics govern cell distribution, extracellular matrix components, and signaling molecules, influencing local biochemical and biophysical conditions. Despite significant progress in analyzing digital pathology images, current methods for capturing spatial relationships are limited. They often rely on specific spatial features that only partially describe the complex spatial distributions of cells and are frequently tied to particular outcomes within predefined model frameworks. Furthermore, these methods are typically limited to field of view analysis, which restricts their capacity to capture spatial patterns across whole-slide images, thereby limiting their ability to fully address the complexities of tissue architecture. To address these limitations, we present SpatialQPFs (Spatial Quantitative Pathology Features), an R package designed to extract interpretable spatial features from cell imaging data using spatial statistical methodologies. Leveraging segmented cell information, our package offers a comprehensive toolkit for applying a range of spatial statistical methods within a stochastic process framework, including analyses of point process data, areal data, and geostatistical data. By decoupling feature extraction from specific outcome models, SpatialQPFs enables thorough large-scale spatial analyses applicable across diverse clinical and biological contexts. This approach enhances the depth and accuracy of spatial insights derived from tissue data, empowering researchers to conduct comprehensive spatial analyses efficiently and reproducibly. By providing a flexible and robust framework for spatial feature extraction, SpatialQPFs facilitates advanced spatial analyses, paving the way for new discoveries in tissue biology and pathology. SpatialQPFs code and documentation are publicly available at https://github.com/Genentech/SpatialQPFs.
Purpose
Vascular endothelial growth factor (VEGF) inhibition is the current and high-volume standard-of-care for patients with neovascular age-related macular degeneration (nAMD) and diabetic retinopathy (DR) with diabetic macular edema (DME). This study assessed the impact of non-persistence in anti-VEGF treatment using claims data from two German states.
Methods
This study identified adults with nAMD or DR/DME and incident anti-VEGF treatment (= index) in January 2015-June 2019 using the German AOK PLUS claims database (January 2014-June 2021, ~ 3.5 million insured). Baseline characteristics were observed within 12 months before index. Patient follow-up lasted ≥ 24 months or until death. Non-persistence (gap of ≥ 180 days) was calculated using Kaplan–Meier estimation. Cox regression identified variables linked to non- persistence. The study analysed reimbursed anti-VEGF treatments, thus excluding off-label use of bevacizumab.
Results
5,498 patients diagnosed with nAMD (mean age, 80.09 years; male, 37.50%; mean Charlson Comorbidity Index [CCI] score, 3.07) and 484 patients with DR/DME (mean age, 67.14; male, 58.88%; mean CCI score, 4.54) were identified. Non-persistence to anti-VEGF treatment within 12 months after index occurred in 51.38% of nAMD patients and 62.60% of DR/DME patients, with mean times to first gap of 11.28 and 8.98 months, respectively. Cox regression revealed factors associated with non-persistence, including higher age, female gender, higher care needs, longer AMD history, and the use of ranibizumab.
Conclusion
Epidemiologic and ophthalmologic factors associated with anti-VEGF non-persistence were successfully identified in the first year of therapy. The analyzed dataset can potentially be enriched with additional health insurance database sets under the used criteria to gain more understanding of anti-VEGF non-persistence.
Background
Timothy syndrome (OMIM #601005) is a rare disease caused by variants in the gene CACNA1C . Initially, Timothy syndrome was characterized by a cardiac presentation of long QT syndrome and syndactyly of the fingers and/or toes, all associated with the CACNA1C variant, Gly406Arg. However, subsequent identification of diverse variants in CACNA1C has expanded the clinical spectrum, revealing various cardiac and extra-cardiac manifestations. It remains underexplored whether individuals with the canonical Gly406Arg variants in mutually exclusive exon 8A (Timothy syndrome 1) or exon 8 (Timothy syndrome 2) exhibit overlapping symptoms. Moreover, case reports have indicated that some CACNA1C variants may produce a cardiac-selective form of Timothy syndrome often referred to as non-syndromic long QT type 8 or cardiac-only Timothy syndrome, however few reports follow up on these patients to confirm the cardiac selectivity of the phenotype over time.
Methods
A survey was administered to the parents of patients with Timothy syndrome, querying a broad range of symptoms and clinical features. Study participants were organized into 5 separate categories based on genotype and initial diagnosis, enabling comparison between groups of patients which have been described differentially in the literature.
Results
Our findings reveal that Timothy syndrome patients commonly exhibit both cardiac and extra-cardiac features, with long QT syndrome, neurodevelopmental impairments, hypoglycemia, and respiratory issues being frequently reported. Notably, the incidence of these features was similar across all patient categories, including those diagnosed with non-syndromic long QT type 8, suggesting that the ‘non-syndromic’ classification may be incomplete.
Conclusions
This study represents the first Natural History Study of Timothy syndrome, offering a comprehensive overview of the disease’s clinical manifestations. We demonstrate that both cardiac and extra-cardiac features are prevalent across all patient groups, underscoring the syndromic nature of CACNA1C variants. While the critical role of long QT syndrome and cardiac arrhythmias in Timothy syndrome has been well recognized, our findings indicate that hypoglycemia and respiratory dysfunction also pose significant life-threatening risks, emphasizing the need for comprehensive therapeutic management of affected individuals.
Hepatocellular carcinoma (HCC) is often detected at advanced stages among patients with hepatitis B virus (HBV), underscoring the urgency for more precise surveillance tests. Here, we compare the clinical performance of the novel - GAAD (gender [biological sex], age, alpha-fetoprotein [AFP], protein-induced by vitamin K absence-II [PIVKA-II]) and GALAD (gender [biological sex], age, AFP, Lens-culinaris AFP [AFP-L3]), PIVKA-II) algorithms to assess the utility of AFP-L3 for distinguishing HCC from benign chronic liver disease (CLD) in Chinese patients with predominantly chronic HBV infection. Eligible adults were enrolled, and biomarkers were measured using Elecsys (Cobas) or µTASWAKO assays. In total, 411 participants provided serum samples (HCC, n = 176 [early-stage, n = 110]; CLD, n = 136; specificity n = 101). HBV was the underlying disease etiology for most participants (HCC, 95%; benign CLD, 72%). For GAAD (Cobas), GALAD (Cobas), and GALAD (µTASWAKO), AUCs were 93.1% (95% CI: 90.0–96.2), 93.2% (90.0–96.3), and 92.7% (88.4–96.9) for early-stage, and 95.6% (93.6–97.6), 95.6% (93.6–97.7), and 95.8% (93.2–98.3) for all-stage HCC, versus CLD, respectively. Interestingly, both GAAD and GALAD algorithms demonstrated comparable diagnostic performance regardless of disease etiology (HBV vs. non-HBV), presence of cirrhosis, geographic region, and within pan-tumor specificity panels (p < 0.001), indicating AFP-L3 may have a negligible role in HCC surveillance.
Supplementary Information
The online version contains supplementary material available at 10.1038/s41598-024-80257-w.
Cancer is a heterogeneous disease requiring costly genetic profiling for better understanding and management. Recent advances in deep learning have enabled cost-effective predictions of genetic alterations from whole slide images (WSIs). While transformers have driven significant progress in non-medical domains, their application to WSIs lags behind due to high model complexity and limited dataset sizes. Here, we introduce SEQUOIA, a linearized transformer model that predicts cancer transcriptomic profiles from WSIs. SEQUOIA is developed using 7584 tumor samples across 16 cancer types, with its generalization capacity validated on two independent cohorts comprising 1368 tumors. Accurately predicted genes are associated with key cancer processes, including inflammatory response, cell cycles and metabolism. Further, we demonstrate the value of SEQUOIA in stratifying the risk of breast cancer recurrence and in resolving spatial gene expression at loco-regional levels. SEQUOIA hence deciphers clinically relevant information from WSIs, opening avenues for personalized cancer management.
Objectives
To evaluate the tolerability of crovalimab versus eculizumab in C5 inhibitor (C5i)‐naive and ‐experienced patients with PNH from COMMODORE 2, 3 and 1 (NCT04434092, NCT04654468 and NCT04432584).
Methods
Pooled safety data were assessed in the total crovalimab and eculizumab populations and by C5i‐naive versus C5i‐switched status in patients receiving crovalimab. Analyses include 6.5 months of additional follow‐up from the COMMODORE 2 and 1 primary analyses.
Results
COMMODORE safety data (crovalimab, 393 patients [naive, 192 patients; switched, 201 patients]; eculizumab, 111 patients) were analysed. The total patient years (PY) were 503.9 and 51.1 in the total crovalimab and eculizumab populations, respectively, with 471 and 581 adverse events (AEs) per 100 PY. Serious infection rates were 8.9 and 13.7 AEs per 100 PY, respectively; no meningococcal infections were reported. Fatal AEs occurred in eight (2%) patients receiving crovalimab (naive, six patients; switched, two patients) and one (1%) receiving eculizumab, all treatment unrelated. In C5i‐switched patients, 39 (19%) had transient immune complex reactions (risk when switching between C5i and crovalimab); the majority were Grades 1–2 arthralgia and rash, and 16 (8%) had Grade 3 events.
Conclusions
Crovalimab's safety profile was consistent with eculizumab's and was generally comparable between C5i‐naive and C5i‐switched patients.
Posttraumatic stress disorder (PTSD) has a significant impact on quality of life and affects more than 13 million individuals in the United States, with limited treatments available. EXUVIA (NCT05401565) was a Phase 2, randomized, placebo-controlled, double-blind trial, conducted across eight sites in the United States. The study aimed to assess the efficacy, safety, and pharmacokinetics of balovaptan, a highly selective vasopressin 1a receptor antagonist, in adults with PTSD. Between August 2022 and October 2023, a total of 57 adult participants (aged 18–60 years) were screened, and 29 participants were randomly allocated (1:1) to receive either balovaptan (13/29 [44.8%]) or placebo (16/29 [55.2%]). No meaningful differences were observed for balovaptan (–17.2 [±10.7]) versus placebo (–15.6 [±10.7]) as measured by the primary endpoint of change from baseline at Week 12 in Clinician-Administered PTSD Scale for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition total symptom severity score. No meaningful differences for balovaptan versus placebo were observed at Week 12 for any secondary endpoints. Balovaptan was well tolerated with no new safety findings. The number of participants with at least one adverse event of any intensity was 9/13 (69.2%) in the balovaptan group and 7/16 (43.8%) in the placebo group.
Background
Klotho, encoded by the KLOTHO gene, is an anti-aging and neuroprotective protein. KLOTHO KL-VS heterozygosity (KL-VS HET ) is hypothesized to be protective against the accumulation of Alzheimer's disease (AD) neuropathological hallmarks (amyloid-β (Aβ) and tau).
Objective
We examine whether being positive for Aβ (A+) or tau (T+), or A/T joint status [positive for Aβ (A + T-), tau (A-T+), both (A + T+) or neither (A-T-)] vary by KL-VS and whether serum klotho protein levels vary based on A+, T+, or A/T status in a cohort enriched for AD risk.
Methods
The sample consisted of 704 cognitively unimpaired, late middle-aged, and older adults; Mean Age (SD) = 64.9(8.3). Serum klotho was available for a sub-sample of 396 participants; Mean Age (SD) = 66.8(7.4). Covariate-adjusted logistic regression examined whether A + or T+, and multinomial regression examined whether A/T status, vary by KL-VS genotype. Covariate-adjusted linear regression examined whether serum klotho levels differ based on A+, T+, or A/T status.
Results
A+ prevalence was lower in KL-VS HET ( p = 0.05), with no differences in T + prevalence ( p = 0.52). KL-VS HET also had marginally lower odds of being A + T- ( p = 0.07). Serum klotho levels did not differ based on A+, T+, or A/T status (all ps ≥ 0.40).
Conclusions
KL-VS HET is associated with lower odds of being positive for Aβ, regardless of whether one is also positive for tau. Conversely, the likelihood of being tau positive did not differ based on KL-VS genotype. Our findings add to the growing KLOTHO literature and suggests the need for further research focused on understanding the mechanisms underlying KL-VS-related putative resilience to AD.
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