Immune modulation in untreated, contralateral hepatic metastases after Y90-radioembolization of microsatellite stable (MSS) colorectal cancer.

PURPOSE: To assess immunogenic effects in unembolized contralateral tumor after single lobar Y90-radioembolization (SIRT) of colorectal liver metastases(CRLM). MATERIAL AND METHODS: The analysis comprised 10 patients with microsatellite stable (MSS) CRLM scheduled for staged treatment in the prospective BLINDED trial. Eligibility criteria included bilobar metastatic disease with >5 lesions without any treatment within 3 weeks. Baseline biopsy was followed by initial SIRT treatment of one liver lobe, followed by a second biopsy of yet untreated tumors in the other liver lobe at a median of 13 (4-49) days immediately prior to second treatment. Tumor biopsies and peripheral blood mononuclear cells (PBMC) were collected before treatments for immune cell analysis. Patients were stratified into "responders" and "non-responders" based on tumor control or progression during follow up. RESULTS: At baseline, responders (n=4) displayed lower concentrations of FoxP3+ cells and co-location of CD4+FoxP3+ cells than non-responders (both p=0.02) in tumor tissues. At second biopsy, non-responders showed a higher CD68+ macrophage density (p=0.0014) than responders. Responders displayed fewer CD4+FoxP3+ T cells than CD8+ T cells at all timepoints (p=0.02 and p=0.0428). Non-responders demonstrated a trending increase of CD68+ macrophages (p=0.062), as well as a higher CD8+PD1+/CD8+ ratio (p=0.062). PBMC of non-responders displayed lower CD8+PD1+ T cells and CD8+PD1+/CD8+ ratio at both timepoints. CONCLUSION: SIRT induces local immunogenic effects in non-exposed MCC CRLM, as well as systemic exhaustion of immune cells in non-responders. Clinical implications such as a prognostic role or synergism of SIRT and checkpoint inhibition in MSS CRLM warrant further investigation.

Quantitative assessment of cardiac 123iodo-metaiodobenzylguanidine SPECT/CT in patients with arrhythmogenic right ventricular cardiomyopathy: Novel insight in disease monitoring.

BACKGROUND: The heart-to-mediastinum ratio (H/M-Ratio) of 123iodo-metaiodobenzylguanidine (123I-MIBG) represents state-of-the-art assessment for sympathetic dysfunction in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). This study aims to evaluate quantitative reconstruction of 123I-MIBG uptake and to demonstrate its correlation with echocardiographic parameters. METHODS: Cardiac innervation was assessed in 23 patients diagnosed with definite ARVC or borderline ARVC and 12 patients with other cardiac disease presenting arrhythmia, using quantitative 123I-MIBG Single Photon Emission Computed Tomography/Computed Tomography (SPECT/CT) imaging. Tracer uptake was evaluated in the left (LV) and right ventricle (RV) based on a CT scan after quantitative image reconstruction. The relationship between tracer uptake and echocardiographic parameter data was examined. RESULTS: Absolute quantification of 123I-MIBG uptake in the LV and RV is feasible and correlates accurately with the gold standard H/M Ratio. When comparing sensitivity and specificity, the area under the curve (AUC) favors standardized uptake value (SUV) of the RV over the right-ventricle-to-mediastinum-ratio (RV/M-Ratio) for diagnosing ARVC. A reduced RV-SUV in patients with definite ARVC is associated with reduced RV function. RV polar maps revealed globally reduced 123I-MIBG uptake without segment-specific reduction in the RV. CONCLUSIONS: Quantitative 123I-MIBG SPECT in ARCV patients offers robust potential for clinical reporting and demonstrates a significant correlation with RV function. Segmental RV analysis needs to be evaluated in larger samples. In summary, cardiac 123I-MIBG imaging using SUV could facilitate image-guided therapy in patients diagnosed with ARVC.

Molecular Basis of MC1R Activation: Mutation-Induced Alterations in Structural Dynamics.

The MC1R protein is a receptor found in melanocytes that plays a role in melanin synthesis. Mutations in this protein can impact hair color, skin tone, tanning ability, and increase the risk of skin cancer. The MC1R protein is activated by the alpha-melanocyte-stimulating hormone (α-MSH). Previous studies have shown that mutations affect the interaction between MC1R and α-MSH; however, the mechanism behind this process is poorly understood. Our study aims to shed light on this mechanism using molecular dynamics (MD) simulations to analyze the Asp84Glu and Asp294His variants. We simulated both the wild-type (WT) protein and the mutants with and without ligand. Our results reveal that mutations induce unique conformations during state transitions, hindering the switch between active and inactive states and decreasing cellular levels of cAMP. Interestingly, Asp294His showed increased ligand affinity but decreased protein activity, highlighting that tighter binding does not always lead to increased activation. Our study provides insights into the molecular mechanisms underlying the impact of MC1R mutations on protein activity.

Impact of the Reference Multiple-Time-Point Dosimetry Protocol on the Validity of Single-Time-Point Dosimetry for [177Lu]Lu-PSMA-I&T Therapy.

Internal dosimetry supports safe and effective patient management during radionuclide therapy. Yet, it is associated with high clinical workload, costs, and patient burden, as patient scans at multiple time points (MTPs) must be acquired. Dosimetry based on imaging at a single time point (STP) has continuously gained popularity. However, MTP protocols, used as a reference to judge the validity of STP dosimetry, differ depending on local requirements and deviate from the unknown patient-specific ground truth pharmacokinetics. The aim of this study was to compare the error and optimum time point for different STP approaches using different reference MTP protocols. Methods: Whole-body SPECT/CT scans of 7 patients (7.4-8.9 GBq of [177Lu]Lu-PSMA-I&T) were scheduled at 24, 48, 72, and 168 h after injection. Sixty lesions, 14 kidneys, and 10 submandibular glands were delineated in the SPECT/CT data. Two curve models, that is, a mono- and a biexponential model, were fitted to the MTP data, in accordance with goodness-of-fit analysis (coefficients of variation, sum of squared errors). Three population-based STP approaches were compared: one method published by Hänscheid et al., one by Jackson et al., and one using population-based effective half-lives in the mono- or biexponential curve models. Percentage differences between STP and MTP dosimetry were evaluated. Results: Goodness-of-fit parameters show that a monoexponential function and a biexponential function with shared population-based parameters and physical tail are reasonable reference models. When comparing both reference models, we observed maximum differences of -44%, -19%, and -28% in the estimated absorbed doses for lesions, kidneys, and salivary glands, respectively. STP dosimetry with an average deviation of less than 10% from MTP dosimetry may be feasible; however, this deviation and the optimum imaging time point showed a dependence on the chosen reference protocol. Conclusion: STP dosimetry for [177Lu]Lu-PSMA therapy is promising to boost the integration of dosimetry into clinical routine. According to our patient cohort, 48 h after injection may be regarded as a compromise for STP dosimetry for lesions and at-risk organs. The results from this analysis show that a common gold standard for dosimetry is desirable to allow for reliable and comparable STP dosimetry.

Blood laboratory analyses preceding in-hospital cardiac arrest: A matched case-control study.

BACKGROUND: Whether blood laboratory analyses differ in patients who later suffer in-hospital cardiac arrest (IHCA) compared to other hospitalised patients remains unknown. The aim of this study was to describe pre-arrest sampling frequencies, results, and trends in blood laboratory analyses in patients with IHCA compared to controls. METHODS: This study was a matched case-control study using national registries in Denmark. Cases were defined as patients with IHCA from 2017 to 2021. Controls were defined as hospitalised patients and were matched on age, sex, and date and length of admission. Data on a total of 51 different blood laboratory analyses were obtained. The laboratory analyses of primary interest were lactate, sodium, potassium, and haemoglobin. The index time for cases was defined as the time of cardiac arrest, and a corresponding index time was defined for controls based on the time to cardiac arrest for their corresponding case. Blood sampling frequencies were reported for blood laboratory analyses obtained either within the last 24 h before the index time or between the time of hospital admission and the index time. Blood sampling results were reported for blood laboratory analyses obtained within the last 24 h before the index time. RESULTS: A total of 9268 cases and 92,395 controls were included in this study. Cases underwent more frequent sampling of all blood laboratory analyses compared to controls. This higher sampling frequency was more pronounced for lactate compared to sodium, potassium, or haemoglobin. The last measured lactate was higher in cases (median [IQR]: 2.3 [1.3, 4.9]) compared to controls (median [IQR]: 1.3 [0.9, 2.0]). Differences in sodium, potassium, and haemoglobin were negligible. The proportion of abnormally elevated levels of lactate and potassium increased as time to cardiac arrest decreased; no such effect was seen in controls. No temporal trend was evident for sodium or haemoglobin. CONCLUSIONS: Patients with IHCA undergo more frequent blood sampling prior to IHCA and have higher levels of lactate compared to matched controls.

Validation of ferroptosis in canine cancer cells to enable comparative oncology and translational medicine.

Ferroptosis is a cell death mechanism that has attracted significant attention as a potential basis for the development of new cancer therapies. Validation of ferroptosis biology in species commonly used in translation and pre-clinical development is a necessary foundation for enabling the advancement of such ferroptosis modulating drugs. Here, we demonstrate that canine cancer cells exhibit sensitivity to a wide range of ferroptosis-inducing perturbations in a manner indistinguishable from human cancer cells, and recapitulate characteristic patterns of ferroptotic response across tumor types seen in the human setting. The foundation provided herein establishes the dog as a relevant efficacy and toxicology model for ferroptosis and creates new opportunities to leverage the canine comparative oncology paradigm to accelerate the development of ferroptosis-inducing drugs for human cancer patients.

Imputation of missing values in lipidomic datasets.

Lipidomic data often exhibit missing data points, which can be categorized as missing completely at random (MCAR), missing at random, or missing not at random (MNAR). In order to utilize statistical methods that require complete datasets or to improve the identification of potential effects in statistical comparisons, imputation techniques can be employed. In this study, we investigate commonly used methods such as zero, half-minimum, mean, and median imputation, as well as more advanced techniques such as k-nearest neighbor and random forest imputation. We employ a combination of simulation-based approaches and application to real datasets to assess the performance and effectiveness of these methods. Shotgun lipidomics datasets exhibit high correlations and missing values, often due to low analyte abundance, characterized as MNAR. In this context, k-nearest neighbor approaches based on correlation and truncated normal distributions demonstrate best performance. Importantly, both methods can effectively impute missing values independent of the type of missingness, the determination of which is nearly impossible in practice. The imputation methods still control the type I error rate.

Stakeholder opinions on perceived sub-standard emergency obstetric and newborn care in Ghana.

BACKGROUND: Sub-Saharan Africa is unlikely to achieve sustainable development goal (SDG) 3 on maternal and neonatal health due to perceived sub-standard maternal and newborn care in the region. This paper sought to explore the opinions of stakeholders on intricacies dictating sub-standard emergency obstetric and newborn care (EmONC) in health facilities in Northern Ghana. METHODS: Drawing from a qualitative study design, data were obtained from six focus group discussions (FGDs) among 42 health care providers and 27 in-depth interviews with management members, clients and care takers duly guided by the principle of data saturation. Participants were purposively selected from basic and comprehensive level facilities. Data analysis followed Braun and Clarke's qualitative thematic analysis procedure. RESULTS: Four themes and 13 sub-themes emerged as root drivers to sub-standard care. Specfically, the findings highlight centralisation of EmONC, inadequate funding, insufficient experiential training, delay in recruitment of newly trained essential staff and provider disinterest in profession. CONCLUSION: Setbacks in the training and recruitment systems in Ghana, inadequate investment in rural health coupled with extent of health provider inherent disposition to practice may be partly responsible for sub-standard obstetric care in the study area. Interventions targeting the afore-mentioned areas may reduce events of sub-standard care.

Multi-omics subgroups associated with glycaemic deterioration in type 2 diabetes: an IMI-RHAPSODY Study.

Introduction: Type 2 diabetes (T2D) onset, progression and outcomes differ substantially between individuals. Multi-omics analyses may allow a deeper understanding of these differences and ultimately facilitate personalised treatments. Here, in an unsupervised "bottom-up" approach, we attempt to group T2D patients based solely on -omics data generated from plasma. Methods: Circulating plasma lipidomic and proteomic data from two independent clinical cohorts, Hoorn Diabetes Care System (DCS) and Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS), were analysed using Similarity Network Fusion. The resulting patient network was analysed with Logistic and Cox regression modelling to explore relationships between plasma -omic profiles and clinical characteristics. Results: From a total of 1,134 subjects in the two cohorts, levels of 180 circulating plasma lipids and 1195 proteins were used to separate patients into two subgroups. These differed in terms of glycaemic deterioration (Hazard Ratio=0.56;0.73), insulin sensitivity and secretion (C-peptide, p=3.7e-11;2.5e-06, DCS and GoDARTS, respectively; Homeostatic model assessment 2 (HOMA2)-B; -IR; -S, p=0.0008;4.2e-11;1.1e-09, only in DCS). The main molecular signatures separating the two groups included triacylglycerols, sphingomyelin, testican-1 and interleukin 18 receptor. Conclusions: Using an unsupervised network-based fusion method on plasma lipidomics and proteomics data from two independent cohorts, we were able to identify two subgroups of T2D patients differing in terms of disease severity. The molecular signatures identified within these subgroups provide insights into disease mechanisms and possibly new prognostic markers for T2D.

Neurotensin accelerates atherosclerosis and increases circulating levels of short-chain and saturated triglycerides.

BACKGROUND AND AIMS: Obesity and type 2 diabetes are significant risk factors for atherosclerotic cardiovascular disease (CVD) worldwide, but the underlying pathophysiological links are poorly understood. Neurotensin (NT), a 13-amino-acid hormone peptide, facilitates intestinal fat absorption and contributes to obesity in mice fed a high-fat diet. Elevated levels of pro-NT (a stable NT precursor produced in equimolar amounts relative to NT) are associated with obesity, type 2 diabetes, and CVD in humans. Whether NT is a causative factor in CVD is unknown. METHODS: Nt+/+ and Nt-/- mice were either injected with adeno-associated virus encoding PCSK9 mutants or crossed with Ldlr-/- mice and fed a Western diet. Atherosclerotic plaques were analyzed by en face analysis, Oil Red O and CD68 staining. In humans, we evaluated the association between baseline pro-NT and growth of carotid bulb thickness after 16.4 years. Lipidomic profiles were analyzed. RESULTS: Atherosclerotic plaque formation is attenuated in Nt-deficient mice through mechanisms that are independent of reductions in circulating cholesterol and triglycerides but associated with remodeling of the plasma triglyceride pool. An increasing plasma concentration of pro-NT predicts atherosclerotic events in coronary and cerebral arteries independent of all major traditional risk factors, indicating a strong link between NT and atherosclerosis. This plasma lipid profile analysis confirms the association of pro-NT with remodeling of the plasma triglyceride pool in atherosclerotic events. CONCLUSIONS: Our findings are the first to directly link NT to increased atherosclerosis and indicate the potential role for NT in preventive and therapeutic strategies for CVD.

Comprehensive experimental and numerical validation of Lattice Boltzmann fluid flow and particle simulations in a child respiratory tract.

The numerical simulation of inhaled aerosols in medical research starts to play a crucial role in understanding local deposition within the respiratory tract, a feat often unattainable experimentally. Research on children is particularly challenging due to the limited availability of in vivo data and the inherent morphological intricacies. CFD solvers based on Finite Volume Methods (FVM) have been widely employed to solve the flow field in such studies. Recently, Lattice Boltzmann Methods (LBM), a mesoscopic approach, have gained prominence, especially for their scalability on High-Performance Computers. This study endeavours to compare the effectiveness of LBM and FVM in simulating particulate flows within a child's respiratory tract, supporting research related to particle deposition and medication delivery using LBM. Considering a 5-year-old child's airway model at a steady inspiratory flow, the results are compared with in vitro experiments. Notably, both LBM and FVM exhibit favourable agreement with experimental data for the mean velocity field and the turbulence intensity. For particle deposition, both numerical methods yield comparable results, aligning well with in vitro experiments across a particle size range of 0.1-20 µm. Discrepancies are identified in the upper airways and trachea, indicating a lower deposition fraction than in the experiment. Nonetheless, both LBM and FVM offer invaluable insights into particle behaviour for different sizes, which are not easily achievable experimentally. In terms of practical implications, the findings of this study hold significance for respiratory medicine and drug delivery systems - potential health impacts, targeted drug delivery strategies or optimisation of respiratory therapies.

Assessment of Kaistella jeonii esterase conformational dynamics in response to poly(ethylene terephthalate) binding.

The pervasive presence of plastic in the environment has reached a concerning scale, being identified in many ecosystems. Bioremediation is the cheapest and most eco-friendly alternative to remove this polymer from affected areas. Recent work described that a novel cold-active esterase enzyme extracted from the bacteria Kaistella jeonii could promiscuously degrade PET. Compared to the well-known PETase from Ideonella sakaiensis, this novel esterase presents a low sequence identity yet has a remarkably similar folding. However, enzymatic assays demonstrated a lower catalytic efficiency. In this work, we employed a strict computational approach to investigate the binding mechanism between the esterase and PET. Understanding the underlying mechanism of binding can shed light on the evolutive mechanism of how enzymes have been evolving to degrade these artificial molecules and help develop rational engineering approaches to improve PETase-like enzymes. Our results indicate that this esterase misses a disulfide bridge, keeping the catalytic residues closer and possibly influencing its catalytic efficiency. Moreover, we describe the structural response to the interaction between enzyme and PET, indicating local and global effects. Our results aid in deepening the knowledge behind the mechanism of biological catalysis of PET degradation and as a base for the engineering of novel PETases.

Lower cerebral blood flow predicts cognitive decline in patients with vascular cognitive impairment.

INTRODUCTION: Chronic cerebral hypoperfusion is one of the assumed pathophysiological mechanisms underlying vascular cognitive impairment (VCI). We investigated the association between baseline cerebral blood flow (CBF) and cognitive decline after 2 years in patients with VCI and reference participants. METHODS: One hundred eighty-one participants (mean age 66.3 ± 7.4 years, 43.6% women) underwent arterial spin labeling (ASL) magnetic resonance imaging (MRI) and neuropsychological assessment at baseline and at 2-year follow-up. We determined the association between baseline global and lobar CBF and cognitive decline with multivariable regression analysis. RESULTS: Lower global CBF at baseline was associated with more global cognitive decline in VCI and reference participants. This association was most profound in the domain of attention/psychomotor speed. Lower temporal and frontal CBF at baseline were associated with more cognitive decline in memory. DISCUSSION: Our study supports the role of hypoperfusion in the pathophysiological and clinical progression of VCI. HIGHLIGHTS: Impaired cerebral blood flow (CBF) at baseline is associated with faster cognitive decline in VCI and normal aging. Our results suggest that low CBF precedes and contributes to the development of vascular cognitive impairment. CBF determined by ASL might be used as a biomarker to monitor disease progression or treatment responses in VCI.

Health-Related Quality of Life in Multiple Myeloma Patients Treated with High- or Low-Dose Lenalidomide Maintenance Therapy after Autologous Stem Cell Transplantation-Results from the LenaMain Trial (NCT00891384).

INTRODUCTION: The LenaMain trial (NCT00891384) reported increased progression-free survival with 25 mg of lenalidomide maintenance compared to 5 mg. Here, we report the patient-reported outcomes. MATERIALS AND METHODS: Scores obtained from the EORTC Quality of Life Questionnaire C30 were analyzed for longitudinal changes from baseline within the groups as well as cross-sectional scores. RESULTS: Compliance rates were high, with 95.7% at baseline and 70% during maintenance. At study entry, scores were high for functioning and low for symptoms. During maintenance, the median global health status/quality of life (GHS/QoL) was constant, without significant differences over time (median GHS/QoL: 68 at baseline and 58 for Len high and 68 for Len low at 2 years) and between treatment arms (mean change < 2). Similarly, most functional scale domains were constant. Notably, diarrhea increased consistently for both treatment arms (baseline: -1.905 (range: -5.78-1.97); end of year 2: 16.071 (range: 5.72-26.42); p < 0.05). The subgroup analysis showed that neither disease activity, duration of treatment, nor adverse events affected the health-related quality of life (HR-QoL) or utility. CONCLUSION: High baseline scores were maintained throughout the trial without significant differences between the Len dosages, which supports continuous treatment with a dose tailored to patients' HR-QoL.

Inflammatory markers in persons with clinically-significant depression, anxiety or PTSD: A systematic review and meta-analysis.

BACKGROUND: Depression, anxiety and PTSD appear to be risk factors for dementia, but it is unclear whether they are causal or prodromal. The inflammatory-mediated neurodegeneration hypothesis suggests a causal link, proposing that mental illness is associated with an inflammatory response which, in turn, triggers neurodegenerative changes that lead to dementia. Existing meta-analyses have yet to examine inflammatory markers in depression, anxiety or PTSD with the view to exploring the inflammatory-mediated neurodegeneration hypothesis. The current meta-analysis therefore examined whether: a) depression, anxiety and PTSD are individually associated with inflammation, independently of comorbid mental illnesses and physical health problems with known inflammatory responses, and b) there are any similarities in the inflammatory profiles of these disorders in order to provide a basis for exploring inflammation in people with dementia who have a history of clinically-significant anxiety, depression or PTSD. METHODS: PubMed, EMBASE, PsycINFO and CINAHL searches identified 64 eligible studies. RESULTS: Depression is associated with an inflammatory response, with tentative evidence to suggest anxiety and PTSD are also associated with inflammation. However, the specific response may differ across these disorders. LIMITATIONS: The data for anxiety, PTSD and multiple inflammatory markers were limited. CONCLUSIONS: Depression, anxiety, and PTSD each appear to be associated with an inflammatory response in persons who do not have comorbid mental or physical health problems that are known to be associated with inflammation. Whether this inflammatory response underlies the increased risk of dementia in persons with a history of depression and anxiety, and possibly PTSD, remains to be determined.

Genome-wide association analysis of plasma lipidome identifies 495 genetic associations.

The human plasma lipidome captures risk for cardiometabolic diseases. To discover new lipid-associated variants and understand the link between lipid species and cardiometabolic disorders, we perform univariate and multivariate genome-wide analyses of 179 lipid species in 7174 Finnish individuals. We fine-map the associated loci, prioritize genes, and examine their disease links in 377,277 FinnGen participants. We identify 495 genome-trait associations in 56 genetic loci including 8 novel loci, with a considerable boost provided by the multivariate analysis. For 26 loci, fine-mapping identifies variants with a high causal probability, including 14 coding variants indicating likely causal genes. A phenome-wide analysis across 953 disease endpoints reveals disease associations for 40 lipid loci. For 11 coronary artery disease risk variants, we detect strong associations with lipid species. Our study demonstrates the power of multivariate genetic analysis in correlated lipidomics data and reveals genetic links between diseases and lipid species beyond the standard lipids.

Bicarbonate, calcium, and magnesium for in-hospital cardiac arrest - An instrumental variable analysis.

INTRODUCTION: Bicarbonate, calcium, and magnesium are commonly used during in-hospital cardiac arrest. Whether these drugs are associated with survival in cardiac arrest patients is uncertain. METHODS: This was an observational study using data from the Get With The Guidelines registry. Adult patients with an in-hospital cardiac arrest between January 2008 and December 2021 were included. An instrumental variable approach was used based on hospital preferences for bicarbonate, calcium, and magnesium, respectively. The primary outcome was survival to hospital discharge. RESULTS: A total of 319,230 patients were included. The median age was 66 years, 59% patients were male, and 85% patients presented with a non-shockable rhythm. Bicarbonate was administered in 58% patients, calcium in 33% patients, and magnesium in 10% patients. When considering drug use in the previous cardiac arrest patient at a given hospital as an instrument, the absolute difference in survival to hospital discharge was estimated at -14.2% (95% CI, -19.9 to -8.6) for bicarbonate, -3.0% (95% CI, -8.6 to 2.6) for calcium, and 10.7% (95% CI, -0.8 to 22.2) for magnesium as compared to no drug. When considering the proportion of drug use within the past year at a given hospital as an instrument, the confidence intervals were very wide, making the results difficult to interpret. CONCLUSIONS: In this analysis, the results for bicarbonate, calcium, and magnesium were inconclusive due to wide confidence intervals and inconsistencies in estimates across instrumental variables. Randomized trials are needed to investigate the effect of these drugs on patient outcomes.