Challenges in Pharmacokinetic Modelling of [18F]fluoro-PEG-folate PET/CT Imaging in Epithelial Ovarian Cancer Patients.

PURPOSE: To describe the pharmacokinetic properties of the [18F]fluoro-polyethylene glycol(PEG)-folate radiotracer in PET/CT imaging of patients with advanced stage epithelial ovarian cancer (EOC). PROCEDURES: In five patients with advanced EOC (FIGO stage IIIB/IIIC, Fédération Internationale de Gynécologie et d'Obstétrique), a 90-min dynamic PET acquisition of the pelvis was performed directly after i.v. administration of 185 MBq [18F]fluoro-PEG6-folate. Arterial blood samples collected at nineteen timepoints were used to determine the plasma input function. A static volume of interest (VOI) for included tumor lesions was drawn manually on the PET images. Modelling was performed using PMOD software. Three different models (a 1-tissue compartment model (1T2k) and two 2-tissue compartment models, irreversible (2T3k) and reversible (2T4k)) were compared in goodness of fit with the time activity curves by means of the Akaike information criterion. RESULTS: The pharmacokinetic analysis in the pelvic area has proven to be much more challenging than expected. Only four out of 22 tumor lesions in five patients were considered suitable to perform modelling on. The remaining tumor lesions were inapt due to either low tracer uptake, small size, proximity to other [18F]fluoro-PEG6-folate -avid structures and/or displacement by abdominal organ motion in the dynamic scan. Data from the four analyzed tumor lesions suggest that the irreversible 2T3k may best describe the pharmacokinetics. All 22 lesions were immunohistochemically stained positive for the folate receptor alpha (FRα) after resection. CONCLUSION: Performing pharmacokinetic analysis in the abdominal pelvic region is very challenging. This brief article describes the challenges and pitfalls in pharmacokinetic analysis of a tracer with high physiological accumulation in the intestines, in case of lesions of limited size in the abdominal pelvic area.

Effects of Commercial Probiotics on the Growth Performance, Intestinal Microbiota and Intestinal Histomorphology of Nile Tilapia (Oreochromis niloticus) Reared in Biofloc Technology (BFT).

Though different types of commercial probiotics are supplemented in biofloc technology (BFT), very little information is available on their effects on the farmed fish. Therefore, this study focused on evaluating the effects of three most commonly used commercial probiotics on the growth performance, intestinal histomorphology, and intestinal microbiota of Nile tilapia (Oreochromis niloticus) reared in BFT. Tilapia fry, with an average weight of 3.02 ± 0.50 g, were stocked at a density of 60 fry/0.2 m3, and cultured for 90 days. Three commercial probiotics were administered, with three replications for each: a single-genus multi-species probiotic (Bacillus spp.) (T1), a multi-genus multi-species probiotic (Bacillus sp., Lactobacillus sp., Nitrosomonas sp., Nitrobacter sp.) (T2), and a multi-species probiotic (Bacillus spp.) combined with enzymes including amylase, protease, cellulase, and xylanase (T3). The results showed significant variations in growth and feed utilization, with T3 outperforming other treatments in terms of weight gain, liver weight, and intestine weight. Adding Bacillus spp. with enzymes (T3) to water significantly increased the histomorphological parameters (villi length, villi depth, crypt depth, muscle thickness, intestinal thickness) as well as microbes (total viable count and total lactic acid bacteria) of intestine of fish compared to T1 and T2, leading to improved digestion and absorption responses. It is concluded that the supplementation of commercial probiotics has potential benefits on farmed fish species in BFT.

Virulence is associated with daily rhythms in the within-host replication of the malaria parasite Plasmodium chabaudi.

Most malaria (Plasmodium spp.) parasite species undergo asexual replication synchronously within the red blood cells of their vertebrate host. Rhythmicity in this intraerythrocytic developmental cycle (IDC) enables parasites to maximise exploitation of the host and align transmission activities with the time of day that mosquito vectors blood feed. The IDC is also responsible for the major pathologies associated with malaria, and plasticity in the parasite's rhythm can confer tolerance to antimalarial drugs. Both the severity of infection (virulence) and synchrony of the IDC vary across species and between genotypes of Plasmodium; however, this variation is poorly understood. The theory predicts that virulence and IDC synchrony are negatively correlated, and we tested this hypothesis using two closely related genotypes of the rodent malaria model Plasmodium chabaudi that differ markedly in virulence. We also test the predictions that, in response to perturbations to the timing (phase) of the IDC schedule relative to the phase of host rhythms (misalignment), the virulent parasite genotype recovers the correct phase relationship faster, incurs less fitness losses and so hosts benefit less from misalignment when infected with a virulent genotype. Our predictions are partially supported by results suggesting that the virulent parasite genotype is less synchronous in some circumstances and recovers faster from misalignment. While hosts were less anaemic when infected by misaligned parasites, the extent of this benefit did not depend on parasite virulence. Overall, our results suggest that interventions to perturb the alignment between the IDC schedule, and host rhythms and increase synchrony between parasites within each IDC, could alleviate disease symptoms. However, virulent parasites, which are better at withstanding conventional antimalarial treatment, would also be intrinsically better able to tolerate such interventions.

Prospective de novo drug design with deep interactome learning.

De novo drug design aims to generate molecules from scratch that possess specific chemical and pharmacological properties. We present a computational approach utilizing interactome-based deep learning for ligand- and structure-based generation of drug-like molecules. This method capitalizes on the unique strengths of both graph neural networks and chemical language models, offering an alternative to the need for application-specific reinforcement, transfer, or few-shot learning. It enables the "zero-shot" construction of compound libraries tailored to possess specific bioactivity, synthesizability, and structural novelty. In order to proactively evaluate the deep interactome learning framework for protein structure-based drug design, potential new ligands targeting the binding site of the human peroxisome proliferator-activated receptor (PPAR) subtype gamma are generated. The top-ranking designs are chemically synthesized and computationally, biophysically, and biochemically characterized. Potent PPAR partial agonists are identified, demonstrating favorable activity and the desired selectivity profiles for both nuclear receptors and off-target interactions. Crystal structure determination of the ligand-receptor complex confirms the anticipated binding mode. This successful outcome positively advocates interactome-based de novo design for application in bioorganic and medicinal chemistry, enabling the creation of innovative bioactive molecules.

Baricitinib and tofacitinib off-target profile, with a focus on Alzheimer's disease.

INTRODUCTION: Janus kinase (JAK) inhibitors were recently identified as promising drug candidates for repurposing in Alzheimer's disease (AD) due to their capacity to suppress inflammation via modulation of JAK/STAT signaling pathways. Besides interaction with primary therapeutic targets, JAK inhibitor drugs frequently interact with unintended, often unknown, biological off-targets, leading to associated effects. Nevertheless, the relevance of JAK inhibitors' off-target interactions in the context of AD remains unclear. METHODS: Putative off-targets of baricitinib and tofacitinib were predicted using a machine learning (ML) approach. After screening scientific literature, off-targets were filtered based on their relevance to AD. Targets that had not been previously identified as off-targets of baricitinib or tofacitinib were subsequently tested using biochemical or cell-based assays. From those, active concentrations were compared to bioavailable concentrations in the brain predicted by physiologically based pharmacokinetic (PBPK) modeling. RESULTS: With the aid of ML and in vitro activity assays, we identified two enzymes previously unknown to be inhibited by baricitinib, namely casein kinase 2 subunit alpha 2 (CK2-α2) and dual leucine zipper kinase (MAP3K12), both with binding constant (K d) values of 5.8 µM. Predicted maximum concentrations of baricitinib in brain tissue using PBPK modeling range from 1.3 to 23 nM, which is two to three orders of magnitude below the corresponding binding constant. CONCLUSION: In this study, we extended the list of baricitinib off-targets that are potentially relevant for AD progression and predicted drug distribution in the brain. The results suggest a low likelihood of successful repurposing in AD due to low brain permeability, even at the maximum recommended daily dose. While additional research is needed to evaluate the potential impact of the off-target interaction on AD, the combined approach of ML-based target prediction, in vitro confirmation, and PBPK modeling may help prioritize drugs with a high likelihood of being effectively repurposed for AD. Highlights: This study explored JAK inhibitors' off-targets in AD using a multidisciplinary approach.We combined machine learning, in vitro tests, and PBPK modelling to predict and validate new off-target interactions of tofacitinib and baricitinib in AD.Previously unknown inhibition of two enzymes (CK2-a2 and MAP3K12) by baricitinib were confirmed using in vitro experiments.Our PBPK model indicates that baricitinib low brain permeability limits AD repurposing.The proposed multidisciplinary approach optimizes drug repurposing efforts in AD research.

Adjuvant holmium-166 radioembolization after radiofrequency ablation in early-stage hepatocellular carcinoma patients: a dose-finding study (HORA EST HCC trial).

PURPOSE: The aim of this study was to investigate the biodistribution of (super-)selective trans-arterial radioembolization (TARE) with holmium-166 microspheres (166Ho-MS), when administered as adjuvant therapy after RFA of HCC 2-5 cm. The objective was to establish a treatment volume absorbed dose that results in an absorbed dose of ≥ 120 Gy on the hyperemic zone around the ablation necrosis (i.e., target volume). METHODS: In this multicenter, prospective dose-escalation study in BCLC early stage HCC patients with lesions 2-5 cm, RFA was followed by (super-)selective infusion of 166Ho-MS on day 5-10 after RFA. Dose distribution within the treatment volume was based on SPECT-CT. Cohorts of up to 10 patients were treated with an incremental dose (60 Gy, 90 Gy, 120 Gy) of 166Ho-MS to the treatment volume. The primary endpoint was to obtain a target volume dose of ≥ 120 Gy in 9/10 patients within a cohort. RESULTS: Twelve patients were treated (male 10; median age, 66.5 years (IQR, [64.3-71.7])) with a median tumor diameter of 2.7 cm (IQR, [2.1-4.0]). At a treatment volume absorbed dose of 90 Gy, the primary endpoint was met with a median absorbed target volume dose of 138 Gy (IQR, [127-145]). No local recurrences were found within 1-year follow-up. CONCLUSION: Adjuvant (super-)selective infusion of 166Ho-MS after RFA for the treatment of HCC can be administered safely at a dose of 90 Gy to the treatment volume while reaching a dose of ≥ 120 Gy to the target volume and may be a favorable adjuvant therapy for HCC lesions 2-5 cm. TRIAL REGISTRATION: Clinicaltrials.gov NCT03437382 . (registered: 19-02-2018).

Testing a non-destructive assay to track Plasmodium sporozoites in mosquitoes over time.

BACKGROUND: The extrinsic incubation period (EIP), defined as the time it takes for malaria parasites in a mosquito to become infectious to a vertebrate host, is one of the most influential parameters for malaria transmission but remains poorly understood. The EIP is usually estimated by quantifying salivary gland sporozoites in subsets of mosquitoes, which requires terminal sampling. However, assays that allow repeated sampling of individual mosquitoes over time could provide better resolution of the EIP. METHODS: We tested a non-destructive assay to quantify sporozoites of two rodent malaria species, Plasmodium chabaudi and Plasmodium berghei, expelled throughout 24-h windows, from sugar-soaked feeding substrates using quantitative-PCR. RESULTS: The assay is able to quantify sporozoites from sugar-soaked feeding substrates, but the prevalence of parasite-positive substrates was low. Various methods were attempted to increase the detection of expelled parasites (e.g. running additional technical replicates; using groups rather than individual mosquitoes), but these did not increase the detection rate, suggesting that expulsion of sporozoites is variable and infrequent. CONCLUSIONS: We reveal successful detection of expelled sporozoites from sugar-soaked feeding substrates. However, investigations of the biological causes underlying the low detection rate of sporozoites (e.g. mosquito feeding behaviour, frequency of sporozoite expulsion or sporozoite clumping) are needed to maximise the utility of using non-destructive assays to quantify sporozoite dynamics. Increasing detection rates will facilitate the detailed investigation on infection dynamics within mosquitoes, which is necessary to explain the highly variable EIP of Plasmodium and to improve understanding of malaria transmission dynamics.

Impact of Pb Toxicity on the Freshwater Pearl Mussel, Lamellidens marginalis: Growth Metrics, Hemocyto-Immunology, and Histological Alterations in Gill, Kidney, and Muscle Tissue.

Pb is one of the most extensively used harmful heavy metals in Bangladesh, and its occurrence in waters affects aquatic organisms significantly. The tropical pearl mussel, Lamellidens marginalis, was exposed to different concentrations (T1 21.93 mgL-1, T2 43.86 mgL-1, and T3 87.72 mgL-1) of Pb(NO3)2 and was evaluated against a control C 0 mgL-1 of Pb(NO3)2, followed by a 96 h acute toxicity test. The LC50 value was recorded as 219.32 mgL-1. The physicochemical parameters were documented regularly for each treatment unit. The values of % SGR, shell weight, soft tissue wet weight, and weight gain remained statistically higher for the control group in comparison with the treatment. No mortality was noted for control units, while a gradually decreased survival rate was recorded for the different treatment groups. Fulton's condition factor was recorded as highest in the control and lowest in the T3 unit, while the condition indices did not vary between the control and treatment groups. The hemocyte was accounted as maximum in the control and T1, while minimum in T2 and T3. The serum lysosomal parameters also followed a similar pattern, and a significantly low level of lysosomal membrane stability, and serum lysosome activity was noted for T3 and T2 units in comparison to the control group. The histology of the gill, kidney, and muscle was well structured in the control group, while distinct pathologies were observed in the gill, kidney, and muscle tissue of different treatment groups. The quantitative comparison revealed that the intensity of pathological alteration increased as the dosage of Pb increased. The current study, therefore, indicated that intrusion of Pb(NO3)2 in the living medium significantly alters growth performance and hemocyte counts, and chronic toxicity induces histomorphological abnormalities in vital organs.

Baseline and early digital [ 18 F]FDG PET/CT and multiparametric MRI contain promising features to predict response to neoadjuvant therapy in locally advanced rectal cancer patients: a pilot study.

OBJECTIVE: In this pilot study, we investigated the feasibility of response prediction using digital [ 18 F]FDG PET/computed tomography (CT) and multiparametric MRI before, during, and after neoadjuvant chemoradiation therapy in locally advanced rectal cancer (LARC) patients and aimed to select the most promising imaging modalities and timepoints for further investigation in a larger trial. METHODS: Rectal cancer patients scheduled to undergo neoadjuvant chemoradiation therapy were prospectively included in this trial, and underwent multiparametric MRI and [ 18 F]FDG PET/CT before, 2 weeks into, and 6-8 weeks after chemoradiation therapy. Two groups were created based on pathological tumor regression grade, that is, good responders (TRG1-2) and poor responders (TRG3-5). Using binary logistic regression analysis with a cutoff value of P  ≤ 0.2, promising predictive features for response were selected. RESULTS: Nineteen patients were included. Of these, 5 were good responders, and 14 were poor responders. Patient characteristics of these groups were similar at baseline. Fifty-seven features were extracted, of which 13 were found to be promising predictors of response. Baseline [T2: volume, diffusion-weighted imaging (DWI): apparent diffusion coefficient (ADC) mean, DWI: difference entropy], early response (T2: volume change, DWI: ADC mean change) and end-of-treatment presurgical evaluation MRI (T2: gray level nonuniformity, DWI: inverse difference normalized, DWI: gray level nonuniformity normalized), as well as baseline (metabolic tumor volume, total lesion glycolysis) and early response PET/CT (Δ maximum standardized uptake value, Δ peak standardized uptake value corrected for lean body mass), were promising features. CONCLUSION: Both multiparametric MRI and [ 18 F]FDG PET/CT contain promising imaging features to predict response to neoadjuvant chemoradiotherapy in LARC patients. A future larger trial should investigate baseline, early response, and end-of-treatment presurgical evaluation MRI and baseline and early response PET/CT.

Life Cycle Assessment of River Sand and Aggregates Alternatives in Concrete.

Urbanization processes in Asia are still ongoing; thus, aggregate demand is expected to increase in following years. Even though construction and demolition waste is a source for secondary building materials in industrialized countries, it is not yet an alternative construction material source in Vietnam as the urbanization process is still ongoing. Thus, there is a need for river sand and aggregates alternatives in concrete, namely manufactured sand (m-sand) from primary solid rock materials and secondary waste materials. The focus in the present study for Vietnam was on m-sand sand as alternative for river sand, and different ashes as alternatives for cement in concrete. The investigations comprised concrete lab tests according to the formulations of concrete strength class C 25/30 in accordance with DIN EN 206, followed by a lifecycle assessment study in order to identify the environmental impact of the alternatives. In total 84 samples were investigated, consisting of 3 reference samples, 18 samples with primary substitutes, 18 samples with secondary substitutes, and 45 samples with cement substitutes. This kind of holistic investigation approach comprising material alternatives and accompanying LCA was the first study for Vietnam, and even for Asia, and represents a substantial added value for future policy development in order to cope with resource scarcity. The results show that with the exception of metamorphic rocks, all m-sands meet the requirements for quality concrete. In terms of cement replacement, the mixes showed that a higher percentage of ash reduces the compressive strength. The compressive strength values of the mixes with up to 10% coal filter ash or rice husk ash were equivalent to the C25/30 standard concrete formulation. Higher ash contents up to 30% lead to the reduction of the concrete quality. The LCA study's results highlighted the better environmental footprints across environmental impact categories in the 10% substitution material in comparison to the use of primary materials. The LCA analysis results showed that cement as a component in concrete holds the highest footprint. The use of secondary waste as alternative for cement provides significant environmental advantage.

Prostate-Specific Membrane Antigen Targeted Pet/CT Imaging in Patients with Colon, Gastric and Pancreatic Cancer.

Current imaging modalities frequently misjudge disease stage in colorectal, gastric and pancreatic cancer. As treatment decisions are dependent on disease stage, incorrect staging has serious consequences. Previous preclinical research and case reports indicate that prostate-specific membrane antigen (PSMA)-targeted PET/CT imaging might provide a solution to some of these challenges. This prospective clinical study aims to assess the feasibility of [18F]DCFPyL PET/CT imaging to target and visualize primary colon, gastric and pancreatic cancer. In this prospective clinical trial, patients with colon, gastric and pancreatic cancer were included and underwent both [18F]DCFPyL and [18F]FDG PET/CT scans prior to surgical resection or (for gastric cancer) neoadjuvant therapy. Semiquantitative analysis of immunohistochemical PSMA staining was performed on the surgical resection specimens, and the results were correlated to imaging parameters. The results of this study demonstrate detection of the primary tumor by [18F]DCFPyL PET/CT in 7 out of 10 patients with colon, gastric and pancreatic cancer, with a mean tumor-to-blood pool ratio (TBR) of 3.3 and mean SUVmax of 3.6. However, due to the high surrounding uptake, visual distinction of these tumors was difficult, and the SUVmax and TBR on [18F]FDG PET/CT were significantly higher than on [18F]DCFPyL PET/CT. In addition, no correlation between PSMA expression in the resection specimen and SUVmax on [18F]DCFPyL PET/CT was found. In conclusion, the detection of several gastrointestinal cancers using [18F]DCFPyL PET/CT is feasible. However, low tumor expression and high uptake physiologically in organs/background hamper the clear distinction of the tumor. As a result, [18F]FDG PET/CT was superior in detecting colon, gastric and pancreatic cancers.

Reinducing Radioiodine-Sensitivity in Radioiodine-Refractory Thyroid Cancer Using Lenvatinib (RESET): Study Protocol for a Single-Center, Open Label Phase II Trial.

Background: Management of patients with radioiodine (RAI)-refractory differentiated thyroid cancer (DTC) is a challenge as I-131 therapy is deemed ineffective while standard-of-care systemic therapy with tyrosine kinase inhibitor (TKI) lenvatinib is associated with frequent toxicities leading to dose reductions and withdrawal. A potential new treatment approach is to use TKIs as redifferentiation agent to restore RAI uptake to an extent that I-131 therapy is warranted. Prior studies show that short-term treatment with other TKIs restores RAI uptake in 50-60% of radioiodine-refractory DTC patients, but this concept has not been investigated for lenvatinib. Furthermore, the optimal duration of treatment with TKIs for maximal redifferentiation has not been explored. Methods and Design: A total of 12 patients with RAI-refractory DTC with an indication for lenvatinib will undergo I-124 PET/CT to quantify RAI uptake. This process is repeated after 6 and 12 weeks post-initiating lenvatinib after which the prospective dose estimate to target lesions and organs at risk will be determined. Patients will subsequently stop lenvatinib and undergo I-131 treatment if it is deemed effective and safe by predefined norms. The I-124 PET/CT measurements after 6 and 12 weeks of the first six patients are compared and the optimal timepoint will be determined for the remaining patients. In all I-131 treated patients post-therapy SPECT/CT dosimetry verification will be performed. During follow-up, clinical response will be evaluated using serum thyroglobulin levels and F-18 FDG PET/CT imaging for 6 months. It is hypothesized that at least 40% of patients will show meaningful renewed RAI uptake after short-term lenvatinib treatment. Discussion: Shorter treatment duration of lenvatinib treatment is preferred because of frequent toxicity-related dose reductions and drug withdrawals in long-term lenvatinib treatment. Short-term treatment with lenvatinib with subsequent I-131 therapy poses a potential new management approach for these patients. Since treatment duration is reduced and I-131 therapy is more tolerable for most patients, this potentially leads to less toxicity and higher quality of life. Identifying RAI-refractory DTC patients who redifferentiate after lenvatinib therapy is therefore crucial. Trial Registration: ClinicalTrials.gov, NTC04858867.

Assessment of Lead (Pb) Toxicity in Juvenile Nile Tilapia, Oreochromis niloticus-Growth, Behaviour, Erythrocytes Abnormalities, and Histological Alterations in Vital Organs.

Lead (Pb) is one of the toxins responsible for the deterioration of ecological health in aquatic environments. The present study investigated the effects of Pb(NO3)2 toxicity on growth, blood cell morphology, and the histopathology of gills, liver, and intestine of juvenile Nile tilapia, Oreochromis niloticus. A 30-day long aquarium trial was conducted by assigning three treatment groups T1 5.20 mg L-1, T2 10.40 mg L-1, and T3 20.80 mg L-1, and a control 0 mg L-1 following the 96 h LC50 of 51.96 mg L-1 from acute toxicity test. Overall growth performance significantly declined in all the Pb(NO3)2 treated groups and the highest mortality was recorded in T3. Behavioural abnormalities were intense in all the treatment groups compared to the control. Hepatosomatic index (HSI) values were reported as higher in treatment groups. Reduced nucleus diameter and nuclei size in erythrocytes were reported for T2 and T3 groups. Dose-dependent histological alterations were visible in the gills, liver, and intestine of all the Pb(NO3)2 treated groups. The width of the intestinal villi was highly extended in T3 showing signs of severe histological alterations. In conclusion, Pb toxicity causes a negative effect on growth performance, erythrocyte morphology, and affected the vital organs histomorphology of juvenile O. niloticus.

Circadian rhythmicity in murine blood: Electrical effects of malaria infection and anemia.

Circadian rhythms are biological adaptations to the day-night cycle, whereby cells adapt to changes in the external environment or internal physiology according to the time of day. Whilst many cellular clock mechanisms involve gene expression feedback mechanisms, clocks operate even where gene expression is absent. For example, red blood cells (RBCs) do not have capacity for gene expression, and instead possess an electrophysiological oscillator where cytosolic potassium plays a key role in timekeeping. We examined murine blood under normal conditions as well as in two perturbed states, malaria infection and induced anemia, to assess changes in baseline cellular electrophysiology and its implications for the electrophysiological oscillator. Blood samples were analyzed at 4-h intervals over 2 days by dielectrophoresis, and microscopic determination of parasitemia. We found that cytoplasmic conductivity (indicating the concentration of free ions in the cytoplasm and related to the membrane potential) exhibited circadian rhythmic behavior in all three cases (control, malaria and anemia). Compared to control samples, cytoplasm conductivity was decreased in the anemia group, whilst malaria-infected samples were in antiphase to control. Furthermore, we identified rhythmic behavior in membrane capacitance of malaria infected cells that was not replicated in the other samples. Finally, we reveal the historically famous rhythmicity of malaria parasite replication is in phase with cytoplasm conductivity. Our findings suggest the electrophysiological oscillator can impact on malaria parasite replication and/or is vulnerable to perturbation by rhythmic parasite activities.

Ventricular Arrhythmia Substrate Distribution and Its Relation to Sympathetic Innervation in Nonischemic Cardiomyopathy Patients.

BACKGROUND: Nonischemic cardiomyopathy patients referred for catheter ablation of ventricular arrhythmias (VAs) typically have either inferolateral (ILS) or anteroseptal (ASS) VA substrate locations, with poorer outcomes for ASS. Sympathetic denervation is an important determinant of arrhythmogenicity. Its relation to nonischemic fibrosis in general and to the different VA substrates is unknown. OBJECTIVES: This study sought to evaluate the association between VA substrates, myocardial fibrosis, and sympathetic denervation. METHODS: Thirty-five patients from the Leiden Nonischemic Cardiomyopathy Study, who underwent electroanatomic voltage mapping and iodine-123 metaiodobenzylguanidine imaging between 2011 and 2018 were included. Late gadolinium-enhanced cardiac magnetic resonance data were collected when available. The relation between global cardiac sympathetic innervation and area-weighted unipolar voltage (UV) as a surrogate for diffuse fibrosis was evaluated. For regional analysis, patients were categorized as ASS or ILS. The distribution of low UV, sympathetic denervation, and late gadolinium enhancement (LGE) scar were compared using the 17-segment model. RESULTS: Median area-weighted UV was 12.3 mV in patients with normal sympathetic innervation and 8.7 mV in patients with sympathetic denervation. Global sympathetic denervation correlated with diffuse myocardial fibrosis (R = 0.53; P = 0.02). ILS (n = 13) matched with low UV, sympathetic denervation, and LGE scar in all patients, whereas ASS (n = 11) matched with low UV in all patients, with LGE scar in 63% (P = 0.20), but with sympathetic denervation in only 27% of patients (P = 0.0002). CONCLUSIONS: Global cardiac sympathetic denervation is related to fibrosis in nonischemic cardiomyopathy patients with VA. The mismatch between regional fibrosis and preserved innervation for ASS may contribute to a VA substrate difficult to control by catheter ablation.

Value-assessment of computer-assisted navigation strategies during percutaneous needle placement.

PURPOSE: Navigational strategies create a scenario whereby percutaneous needle-based interventions of the liver can be guided using both pre-interventional 3D imaging datasets and dynamic interventional ultrasound (US). To score how such technologies impact the needle placement process, we performed kinematic analysis on different user groups. METHODS: Using a custom biopsy phantom, three consecutive exercises were performed by both novices and experts (n = 26). The exercise came in three options: (1) US-guidance, (2) US-guidance with pre-interventional image-registration (US + Reg) and (3) US-guidance with pre-interventional image-registration and needle-navigation (US + Reg + Nav). The traveled paths of the needle were digitized in 3D. Using custom software algorithms, kinematic metrics were extracted and related to dexterity, decision making indices to obtain overall performance scores (PS). RESULTS: Kinematic analysis helped quantifying the visual assessment of the needle trajectories. Compared to US-guidance, novices yielded most improvements using Reg (PSavg(US) = 0.43 vs. PSavg(US+Reg) = 0.57 vs. PSavg(US+Reg+Nav) = 0.51). Interestingly, the expert group yielded a reversed trend (PSavg(US) = 0.71 vs PSavg(US+Reg) = 0.58 vs PSavg(US+Reg+Nav) = 0.59). CONCLUSION: Digitizing the movement trajectory allowed us to objectively assess the impact of needle-navigation strategies on percutaneous procedures. In particular, our findings suggest that these advanced technologies have a positive impact on the kinematics derived performance of novices.

Identification of novel off targets of baricitinib and tofacitinib by machine learning with a focus on thrombosis and viral infection.

As there are no clear on-target mechanisms that explain the increased risk for thrombosis and viral infection or reactivation associated with JAK inhibitors, the observed elevated risk may be a result of an off-target effect. Computational approaches combined with in vitro studies can be used to predict and validate the potential for an approved drug to interact with additional (often unwanted) targets and identify potential safety-related concerns. Potential off-targets of the JAK inhibitors baricitinib and tofacitinib were identified using two established machine learning approaches based on ligand similarity. The identified targets related to thrombosis or viral infection/reactivation were subsequently validated using in vitro assays. Inhibitory activity was identified for four drug-target pairs (PDE10A [baricitinib], TRPM6 [tofacitinib], PKN2 [baricitinib, tofacitinib]). Previously unknown off-target interactions of the two JAK inhibitors were identified. As the proposed pharmacological effects of these interactions include attenuation of pulmonary vascular remodeling, modulation of HCV response, and hypomagnesemia, the newly identified off-target interactions cannot explain an increased risk of thrombosis or viral infection/reactivation. While further evidence is required to explain both the elevated thrombosis and viral infection/reactivation risk, our results add to the evidence that these JAK inhibitors are promiscuous binders and highlight the potential for repurposing.

Mutation in the CCAL1 locus accounts for bidirectional process of human subchondral bone turnover and cartilage mineralization.

OBJECTIVES: To study the mechanism by which the readthrough mutation in TNFRSF11B, encoding osteoprotegerin (OPG) with additional 19 amino acids at its C-terminus (OPG-XL), causes the characteristic bidirectional phenotype of subchondral bone turnover accompanied by cartilage mineralization in chondrocalcinosis patients. METHODS: OPG-XL was studied by human induced pluripotent stem cells expressing OPG-XL and two isogenic CRISPR/Cas9-corrected controls in cartilage and bone organoids. Osteoclastogenesis was studied with monocytes from OPG-XL carriers and matched healthy controls followed by gene expression characterization. Dual energy X-ray absorptiometry scans and MRI analyses were used to characterize the phenotype of carriers and non-carriers of the mutation. RESULTS: Human OPG-XL carriers relative to sex- and age-matched controls showed, after an initial delay, large active osteoclasts with high number of nuclei. By employing hiPSCs expressing OPG-XL and isogenic CRISPR/Cas9-corrected controls to established cartilage and bone organoids, we demonstrated that expression of OPG-XL resulted in excessive fibrosis in cartilage and high mineralization in bone accompanied by marked downregulation of MGP, encoding matrix Gla protein, and upregulation of DIO2, encoding type 2 deiodinase, gene expression, respectively. CONCLUSIONS: The readthrough mutation at CCAL1 locus in TNFRSF11B identifies an unknown role for OPG-XL in subchondral bone turnover and cartilage mineralization in humans via DIO2 and MGP functions. Previously, OPG-XL was shown to affect binding between RANKL and heparan sulphate (HS) resulting in loss of immobilized OPG-XL. Therefore, effects may be triggered by deficiency in the immobilization of OPG-XL Since the characteristic bidirectional pathophysiology of articular cartilage calcification accompanied by low subchondral bone mineralization is also a hallmark of OA pathophysiology, our results are likely extrapolated to common arthropathies.

Nuclear medicine imaging methods of radiation-induced cardiotoxicity.

Breast cancer survival is significantly improved over the past decades due to major improvements in anti-tumor therapies and the implementation of regular screening, which leads to early detection of breast cancer. Therefore, it is of utmost importance to prevent patients from long-term side effects, including radiotherapy-induced cardiotoxicity. Radiotherapy may contribute to damage of myocardial structures on the cellular level, which eventually could result in various types of cardiovascular problems, including coronary artery disease and (non-)ischemic cardiomyopathy, leading to heart failure. These cardiac complications of radiotherapy are preceded by alterations in myocardial perfusion and blood flow. Therefore, early detection of these alterations is important to prevent the progression of these pathophysiological processes. Several radionuclide imaging techniques may contribute to the early detection of these changes. Single-Photon Emission Computed Tomography (SPECT) cameras can be used to create Multigated Acquisition scans in order to assess the left ventricular systolic and diastolic function. Furthermore, SPECT cameras are used for myocardial perfusion imaging with radiopharmaceuticals such as 99mTc-sestamibi and 99mTc-tetrofosmin. Accurate quantitative measurement of myocardial blood flow (MBF), can be performed by Positron Emission Tomography (PET), as the uptake of some of the tracers used for PET-based MBF measurement almost creates a linear relationship with MBF, resulting in very accurate blood flow quantification. Furthermore, there are PET and SPECT tracers that can assess inflammation and denervation of the cardiac sympathetic nervous system. Research over the past decades has mainly focused on the long-term development of left ventricular impairment and perfusion defects. Considering laterality of the breast cancer, some early studies have shown that women irradiated for left-sided breast cancer are more prone to cardiotoxic side effects than women irradiated for right-sided breast cancer. The left-sided radiation field in these trials, which predominantly used older radiotherapy techniques without heart-sparing techniques, included a larger volume of the heart and left ventricle, leading to increased unavoidable radiation exposure to the heart due to the close proximity of the radiation treatment volume. Although radiotherapy for breast cancer exposes the heart to incidental radiation, several improvements and technical developments over the last decades resulted in continuous reduction of radiation dose and volume exposure to the heart. In addition, radiotherapy reduces loco-regional tumor recurrences and death from breast cancer and improves survival. Therefore, in the majority of patients, the benefits of radiotherapy outweigh the potential very low risk of cardiovascular adverse events after radiotherapy. This review addresses existing nuclear imaging techniques, which can be used to evaluate (long-term) effects of radiotherapy-induced mechanical cardiac dysfunction and discusses the potential use of more novel nuclear imaging techniques, which are promising in the assessment of early signs of cardiac dysfunction in selected irradiated breast cancer patients.

Does Fish Farming Improve Household Nutritional Status? Evidence from Bangladesh.

In the present study, nutritional status was assessed using dietary diversity of fish and non-fish farming households in Mymensingh district of Bangladesh. It has determined the incidence of poverty in fish and non-fish farm households through a comparative analysis of family profile, food consumption, calories, and protein intake. A total of 420 farms were selected for data collection using structured questionnaires with 210 fish and 210 non-fish farm families. The study using both descriptive and functional analysis revealed that the respondent age of both farms was 45.10 years, family size was 5.70, average education was 4.64 schooling years, and average farm size was 0.514 hectares. As a result, due to the increase in household income, fish farm families improved their food consumption, calories, and protein intake in comparison with non-fish farms. On a direct calorie intake (DCI) basis, the overall absolute and hardcore poverty levels of fish farm households were 32 percent and 18 percent, respectively, while those of non-fish farm households were 22 percent and 10 percent, respectively. Therefore, the incidence of poverty was higher in non-fish farming families than in fish farming families. In principle, provision of various forms of government assistance through the Department of Fisheries (DOF) will further intensify and strengthen fish farming, which will easily bring fallow and uncultivated lands of the area under fish farming. Moreover, it is possible to inspire the younger generation through this research that will help them to become a fish farm-based entrepreneur. The main conclusion of the present study is that fish farming is more positively related to household income, family food intake, and nutritional status than any other type of farming.