MRI in addition to CT in patients scheduled for local therapy of colorectal liver metastases (CAMINO): an international, multicentre, prospective, diagnostic accuracy trial.

BACKGROUND: Guidelines are inconclusive on whether contrast-enhanced MRI using gadoxetic acid and diffusion-weighted imaging should be added routinely to CT in the investigation of patients with colorectal liver metastases who are scheduled for curative liver resection or thermal ablation, or both. Although contrast-enhanced MRI is reportedly superior than contrast-enhanced CT in the detection and characterisation of colorectal liver metastases, its effect on clinical patient management is unknown. We aimed to assess the clinical effect of an additional liver contrast-enhanced MRI on local treatment plan in patients with colorectal liver metastases amenable to local treatment, based on contrast-enhanced CT. METHODS: We did an international, multicentre, prospective, incremental diagnostic accuracy trial in 14 liver surgery centres in the Netherlands, Belgium, Norway, and Italy. Participants were aged 18 years or older with histological proof of colorectal cancer, a WHO performance status score of 0-4, and primary or recurrent colorectal liver metastases, who were scheduled for local therapy based on contrast-enhanced CT. All patients had contrast-enhanced CT and liver contrast-enhanced MRI including diffusion-weighted imaging and gadoxetic acid as a contrast agent before undergoing local therapy. The primary outcome was change in the local clinical treatment plan (decided by the individual clinics) on the basis of liver contrast-enhanced MRI findings, analysed in the intention-to-image population. The minimal clinically important difference in the proportion of patients who would have change in their local treatment plan due to an additional liver contrast-enhanced MRI was 10%. This study is closed and registered in the Netherlands Trial Register, NL8039. FINDINGS: Between Dec 17, 2019, and July 31, 2021, 325 patients with colorectal liver metastases were assessed for eligibility. 298 patients were enrolled and included in the intention-to-treat population, including 177 males (59%) and 121 females (41%) with planned local therapy based on contrast-enhanced CT. A change in the local treatment plan based on liver contrast-enhanced MRI findings was observed in 92 (31%; 95% CI 26-36) of 298 patients. Changes were made for 40 patients (13%) requiring more extensive local therapy, 11 patients (4%) requiring less extensive local therapy, and 34 patients (11%) in whom the indication for curative-intent local therapy was revoked, including 26 patients (9%) with too extensive disease and eight patients (3%) with benign lesions on liver contrast-enhanced MRI (confirmed by a median follow-up of 21·0 months [IQR 17·5-24·0]). INTERPRETATION: Liver contrast-enhanced MRI should be considered in all patients scheduled for local treatment for colorectal liver metastases on the basis of contrast-enhanced CT imaging. FUNDING: The Dutch Cancer Society and Bayer AG - Pharmaceuticals.

Body mass index and cervical cancer screening among women aged 15-69 years in Eswatini: evidence from a population-based survey.

BACKGROUND: Cervical cancer stands as one of the most prevalent cancer types among women, despite its preventable nature through early screening and vaccination strategies. The link between being overweight or obese and various adverse health outcomes, including an elevated cancer risk, is well established. Within this study, our central objective was to explore the correlation between body mass index (BMI) and cervical cancer screening (CCS) rates. Moreover, we sought to investigate whether socioeconomic status potentially modulates this relationship. METHODS: Our analysis encompassed 1791 respondents who participated in the World Health Organization's STEPwise approach to noncommunicable disease risk factor surveillance carried out in Eswatini in 2014. We assessed the connection between BMI, along with other determinants, and CCS through both unadjusted and adjusted logistic regression models. RESULTS: The uptake of CCS was 14.4% and the prevalence of overweight and obesity was estimated at 28.1 and 34.9% respectively. After accounting for other pertinent variables, the likelihood of obtaining CCS was amplified for individuals classified as obese (adjusted odds ratio [aOR] = 1.99, 95% confidence interval [CI] = 1.26-3.12) or overweight (aOR = 1.98, 95% CI = 1.05-3.74). Furthermore, factors such as being separated or divorced (aOR = 2.03, 95% CI = 1.11-3.72) and engaging in regular physical exercise (aOR = 3.02, 95% CI = 1.21-6.02) were associated with increased odds of undergoing CCS. CONCLUSIONS: This study underscores the noteworthy role played by both overweight and obesity, in conjunction with various socioeconomic factors, in shaping CCS patterns among the surveyed women. For Eswatini, targeted interventions aimed at enhancing CCS participation should take into account the multifaceted factors highlighted within this investigation.

Modulation of sleep behavior in zebrafish larvae by pharmacological targeting of the orexin receptor.

New pharmacological approaches that target orexin receptors (OXRs) are being developed to treat sleep disorders such as insomnia and narcolepsy, with fewer side effects than existing treatments. Orexins are neuropeptides that exert excitatory effects on postsynaptic neurons via the OXRs, and are important in regulating sleep/wake states. To date, there are three FDA-approved dual orexin receptor antagonists for the treatment of insomnia, and several small molecule oral OX2R (OXR type 2) agonists are in the pipeline for addressing the orexin deficiency in narcolepsy. To find new hypnotics and psychostimulants, rodents have been the model of choice, but they are costly and have substantially different sleep patterns to humans. As an alternative model, zebrafish larvae that like humans are diurnal and show peak daytime activity and rest at night offer several potential advantages including the ability for high throughput screening. To pharmacologically validate the use of a zebrafish model in the discovery of new compounds, we aimed in this study to evaluate the functionality of a set of known small molecule OX2R agonists and antagonists on human and zebrafish OXRs and to probe their effects on the behavior of zebrafish larvae. To this end, we developed an in vitro IP-One Homogeneous Time Resolved Fluorescence (HTRF) immunoassay, and in vivo locomotor assays that record the locomotor activity of zebrafish larvae under physiological light conditions as well as under dark-light triggers. We demonstrate that the functional IP-One test is a good predictor of biological activity in vivo. Moreover, the behavioral data show that a high-throughput assay that records the locomotor activity of zebrafish throughout the evening, night and morning is able to distinguish between OXR agonists and antagonists active on the zebrafish OXR. Conversely, a locomotor assay with alternating 30 min dark-light transitions throughout the day is not able to distinguish between the two sets of compounds, indicating the importance of circadian rhythm to their pharmacological activity. Overall, the results show that a functional IP-one test in combination with a behavioral assay using zebrafish is well-suited as a discovery platform to find novel compounds that target OXRs for the treatment of sleep disorders.

Hyperactivation of mTORC1 in a double hit mutant zebrafish model of tuberous sclerosis complex causes increased seizure susceptibility and neurodevelopmental abnormalities.

Tuberous sclerosis complex (TSC) is a multisystem genetic disorder caused by pathogenic variants in TSC1 and TSC2 genes. TSC patients present with seizures and brain abnormalities such as tubers and subependymal giant cells astrocytoma (SEGA). Despite common molecular and clinical features, the severity of the disease varies greatly, even intrafamilially. The second hit hypothesis suggests that an additional, inactivating mutation in the remaining functional allele causes a more severe phenotype and therefore explains the phenotypic variability. Recently, second hit mutations have been detected frequently in mTORopathies. To investigate the pathophysiological effects of second hit mutations, several mouse models have been developed. Here, we opted for a double mutant zebrafish model that carries a LOF mutation both in the tsc2 and the depdc5 gene. To the best of our knowledge, this is the first time a second-hit model has been studied in zebrafish. Significantly, the DEP domain-containing protein 5 (DEPDC5) gene has an important role in the regulation of mTORC1, and the combination of a germline TSC2 and somatic DEPDC5 mutation has been described in a TSC patient with intractable epilepsy. Our depdc5 -/- x tsc2 -/- double mutant zebrafish line displayed greatly increased levels of mammalian target of rapamycin (mTORC1) activity, augmented seizure susceptibility, and early lethality which could be rescued by rapamycin. Histological analysis of the brain revealed ventricular dilatation in the tsc2 and double homozygotes. RNA-sequencing showed a linear relation between the number of differentially expressed genes (DEGs) and the degree of mTORC1 hyperactivity. Enrichment analysis of their transcriptomes revealed that many genes associated with neurological developmental processes were downregulated and mitochondrial genes were upregulated. In particular, the transcriptome of human SEGA lesions overlapped strongly with the double homozygous zebrafish larvae. The data highlight the clinical relevance of the depdc5 -/- x tsc2 -/- double mutant zebrafish larvae that showed a more severe phenotype compared to the single mutants. Finally, analysis of gene-drug interactions identified interesting pharmacological targets for SEGA, underscoring the value of our small zebrafish vertebrate model for future drug discovery efforts.

Implication of asymptomatic and clinical Plasmodium falciparum infections on biomarkers of iron status among school-aged children in Malawi.

BACKGROUND: Iron status is considered as a continuum from an iron deficiency with anaemia, without anaemia, varying amounts of stored iron to iron overload. The burden of Plasmodium falciparum infections is typically high among school-aged children (SAC). Nonetheless, SAC are often less likely to be covered by malaria interventions, making them a group with an untreated reservoir of parasite transmission. This study aimed to assess the effects of asymptomatic and clinical malaria infections on biochemical markers of iron status among SAC in Malawi. METHODS: Data from the 2015-2016 Malawi Micronutrient Survey (MNS) was used and multivariable logistic regression models using a generalized estimating equation to account for the complex cluster survey design were constructed. Blood samples of 684 children aged 5 to 14 years old were evaluated for clinical and asymptomatic malaria infections. Furthermore, blood samples were used to estimate haemoglobin (Hb), serum ferritin (SF) and, soluble transferrin receptors (sTfR) concentrations. RESULTS: Of the 684 SAC analysed, approximately 42% had asymptomatic malaria, while 41.0% had clinical malaria. Anaemia (low Hb levels), iron deficiency (low SF concentration), and functional iron deficiency (high sTfR levels) were found in 20%, 5%, and 30% of the children, respectively. School-aged children with asymptomatic malaria had increased odds of being anaemic (adjusted odds ratio [aOR]: 3.71, 95% confidence interval [CI]: 2.29-5.99) and increased levels of sTfR (aOR: 3.00, 95% CI 2.01-4.47). Similarly, SAC with clinical malaria had increased odds of being anaemic (aOR: 3.54, 95% CI 2.19-5.72) and increased levels of sTfR (aOR: 3.02, 95% CI 2.02-4.52). CONCLUSIONS: Both asymptomatic and clinical malaria were independent risk factors for anaemia and functional iron deficiency (FID). The notion that asymptomatic and clinical malaria were associated with both anaemia and FID underscores the need for public health programmers to consider adding mass screening and treatment for malaria to existing school-based health programmes.

The effect of robot speed on comfortable passing distances.

Robots navigate ever more often in close proximity to people. In the current work, we focused on two distinctive navigational scenarios: passing and overtaking a person who is walking. In the first experiment, we compared nine different passing distances for a humanoid robot and found that human comfort increased with passing distance and that their relationship could be described by an inverted Gaussian. In the second experiment, we validated this relationship for an industrial autonomous robot and extended the study to also include overtaking distances and different robot moving speeds. The results showed that overtaking was considered to be less comfortable than passing but that the overtaking distance had a similar relationship with human comfort. Human comfort decreases with a higher robot movement speed. Results obtained through location trackers furthermore showed that people actively take a larger distance from the robot when it starts its trajectory closer to them. The current results can be used to quantify human comfort in environments where humans and robots co-exist and they can be used as input for human-aware navigational models for autonomous robots.

Connectivity Mapping Using a Novel sv2a Loss-of-Function Zebrafish Epilepsy Model as a Powerful Strategy for Anti-epileptic Drug Discovery.

Synaptic vesicle glycoprotein 2A (SV2A) regulates action potential-dependent neurotransmitter release and is commonly known as the primary binding site of an approved anti-epileptic drug, levetiracetam. Although several rodent knockout models have demonstrated the importance of SV2A for functional neurotransmission, its precise physiological function and role in epilepsy pathophysiology remains to be elucidated. Here, we present a novel sv2a knockout model in zebrafish, a vertebrate with complementary advantages to rodents. We demonstrated that 6 days post fertilization homozygous sv2a-/- mutant zebrafish larvae, but not sv2a +/- and sv2a+/+ larvae, displayed locomotor hyperactivity and spontaneous epileptiform discharges, however, no major brain malformations could be observed. A partial rescue of this epileptiform brain activity could be observed after treatment with two commonly used anti-epileptic drugs, valproic acid and, surprisingly, levetiracetam. This observation indicated that additional targets, besides Sv2a, maybe are involved in the protective effects of levetiracetam against epileptic seizures. Furthermore, a transcriptome analysis provided insights into the neuropathological processes underlying the observed epileptic phenotype. While gene expression profiling revealed only one differentially expressed gene (DEG) between wildtype and sv2a +/- larvae, there were 4386 and 3535 DEGs between wildtype and sv2a-/- , and sv2a +/- and sv2a-/- larvae, respectively. Pathway and gene ontology (GO) enrichment analysis between wildtype and sv2a-/- larvae revealed several pathways and GO terms enriched amongst up- and down-regulated genes, including MAPK signaling, synaptic vesicle cycle, and extracellular matrix organization, all known to be involved in epileptogenesis and epilepsy. Importantly, we used the Connectivity map database to identify compounds with opposing gene signatures compared to the one observed in sv2a-/- larvae, to finally rescue the epileptic phenotype. Two out of three selected compounds rescued electrographic discharges in sv2a-/- larvae, while negative controls did not. Taken together, our results demonstrate that sv2a deficiency leads to increased seizure vulnerability and provide valuable insight into the functional importance of sv2a in the brain in general. Furthermore, we provided evidence that the concept of connectivity mapping represents an attractive and powerful approach in the discovery of novel compounds against epilepsy.

Knowledge of diabetes among Gambian adults: evidence from a nation-wide survey.

BACKGROUND: Diabetes is increasingly becoming a public health problem in developing countries like The Gambia. Prevention of diabetes and appropriate management of the disease largely depends on correct knowledge of the risk factors and signs and symptoms of the condition. However, studies that have assessed knowledge of diabetes at population level are limited. We examined the knowledge of diabetes risk factors, and signs and symptoms among Gambian adults. METHODS: The 2019-2020 Gambia demographic and health survey data was used to analyze 4, 436 men and 6, 186 women. Knowledge of diabetes was assessed two-fold: (1) diabetes risk factors and (2) diabetes signs and symptoms. Several sociodemographic factors were considered for analysis. A generalized estimating equation model was fitted to test the association between the selected sociodemographic factors and diabetes knowledge. RESULTS: Among the men, 7.6% and 3.1% had knowledge about diabetes risk factors, and signs and symptoms, respectively. Approximately 3.1% and 1.2% of the women included in the analysis had knowledge of diabetes risk factors, and signs and symptoms, respectively. Men who were aged ≥ 35 years were more likely to have knowledge regarding diabetes risk factors (adjusted odds ratio (AOR) = 1.90, 95% confidence interval (CI) = 1.12-3.22), and signs and symptoms (AOR = 2.59, 95% CI = 1.08-6.17). Having access to media was associated with increased odds of having knowledge regarding diabetes risk factors (AOR = 1.61, 95% CI = 1.09-2.37) and signs and symptoms (AOR = 2.04, 95% CI = 1.07-3.88) among men. Among other factors, educational level was positively associated with having diabetes knowledge among both men and women. Heterogeneities regarding diabetes knowledge were observed among different regions and areas of residence. CONCLUSION: There is a need to improve awareness regarding diabetes in The Gambia as low knowledge has been observed. Programs aimed to improve diabetes knowledge should consider regional and area of residence variations in their designs. The use of mass media and strengthening the education sector in The Gambia may be of importance in raising diabetes knowledge among Gambian adults.

Determinants of pentavalent and measles vaccination dropouts among children aged 12-23 months in The Gambia.

BACKGROUND: Every year, vaccination averts about 3 million deaths from vaccine-preventable diseases (VPDs). However, despite that immunization coverage is increasing globally, many children in developing countries are still dropping out of vaccination. Thus, the present study aimed to identify determinants of vaccination dropouts among children aged 12-23 months in The Gambia. METHODS: The study utilized cross-sectional data obtained from the Gambia Demographic and Health Survey 2019-20 (GDHS). The percentage of children aged 12-23 months who dropped out from pentavalent and measles vaccination were calculated by (1) subtracting the third dose of pentavalent vaccine from the first dose of Pentavalent vaccine, and (2) subtracting the first dose of measles vaccine from the first dose Pentavalent vaccine. Generalized Estimating Equation models (GEE) were constructed to examine the risk factors of pentavalent and measles vaccinations dropout. RESULTS: Approximately 7.0% and 4.0% of the 1,302 children aged 12-23 months had dropped out of measles and pentavalent vaccination respectively. The multivariate analyses showed that when caregivers attended fewer than four antenatal care sessions, when children had no health card or whose card was lost, and resided in urban areas increased the odds of pentavalent dropout. On the other hand, when women gave birth in home and other places, when children had no health card, and being an urban areas dweller increased the odds of measles dropout. CONCLUSION: Tailored public health interventions towards urban residence and health education for all women during ANC are hereby recommended.

From the North Sea to Drug Repurposing, the Antiseizure Activity of Halimide and Plinabulin.

PharmaSea performed large-scale in vivo screening of marine natural product (MNP) extracts, using zebrafish embryos and larvae, to identify compounds with the potential to treat epilepsy. In this study, we report the discovery of two new antiseizure compounds, the 2,5-diketopiperazine halimide and its semi-synthetic analogue, plinabulin. Interestingly, these are both known microtubule destabilizing agents, and plinabulin could have the potential for drug repurposing, as it is already in clinical trials for the prevention of chemotherapy-induced neutropenia and treatment of non-small cell lung cancer. Both halimide and plinabulin were found to have antiseizure activity in the larval zebrafish pentylenetetrazole (PTZ) seizure model via automated locomotor analysis and non-invasive local field potential recordings. The efficacy of plinabulin was further characterized in animal models of drug-resistant seizures, i.e., the larval zebrafish ethyl ketopentenoate (EKP) seizure model and the mouse 6 Hz psychomotor seizure model. Plinabulin was observed to be highly effective against EKP-induced seizures, on the behavioral and electrophysiological level, and showed activity in the mouse model. These data suggest that plinabulin could be of interest for the treatment of drug-resistant seizures. Finally, the investigation of two functional analogues, colchicine and indibulin, which were observed to be inactive against EKP-induced seizures, suggests that microtubule depolymerization does not underpin plinabulin's antiseizure action.

Effects of deworming medication on anaemia among children aged 6-59 months in sub-Saharan Africa.

BACKGROUND: Despite the limited knowledge regarding the effects of deworming medication (DM) on nutritional indicators in sub-Saharan Africa (SSA), deworming programmes continue to be implemented in resource-limited countries. Therefore, the current study aimed to examine the effects of DM on anaemia among children aged 6-59 months in SSA. METHODS: The analysis was performed using data obtained from 17 demographic and health surveys (DHSs) conducted in SSA. Children were considered to be anaemic if their haemoglobin (Hb) concentration was less than 11.0 g/dl, adjusting for altitude. To account for both multiple measures at the cluster level and the clustering of children within the same country, generalized linear mixed models were used to analyse the anaemia outcomes in 50,075 children aged 6-59 months. RESULTS: Overall, anaemia was reported in 61.8% of the children, and their median Hb concentration was 10.5 g/dl (interquartile range 9.4-11.5). The prevalence of anaemia ranged from 34.5% in Rwanda to 81.1% in Mali. Multivariate analyses showed that children who did not receive DM had increased odds of being anaemic (adjusted odds ratio [aOR]: 1.11; 95% confidence interval [CI] 1.07-1.16). CONCLUSIONS: The current study revealed that DM can decrease the risk of anaemia among preschool-age children (pre-SAC) in SSA. Thus, tailored public health programmes aimed at reducing childhood anaemia need to consider deworming. However, longitudinal studies are needed to validate the association that has been reported in this cross-sectional study.

Tracking immunization coverage, dropout and equity gaps among children ages 12-23 months in Malawi - bottleneck analysis of the Malawi Demographic and Health Survey.

BACKGROUND: Between 2010 and 2016, the proportion of children 12-23 months of age who received full immunization in Malawi decreased from 81% to 76%. Most studies on immunization have mainly focused on the risk factors of vaccination coverage while data on dropouts and equity gaps is very scanty. Thus the aim of the present study was to describe the trend in immunization coverage, dropout rates and effective immunization coverage (EIC) among children ages 12-23 months in Malawi. METHODS: Secondary analyses of the cross-sectional data obtained from the three waves of the Demographic and Health Surveys (2004, 2010 and 2015-16) were conducted. Using bottleneck analysis, outputs were generated based on service coverage, demand/equity (service utilization) and quality (full immunization). The World Health Organization benchmarks were used to assess gaps in the immunization coverage indicators. RESULTS: The coverage was >90.0% in most of the antigens while full immunization status was estimated at 65%, 84% and 73% in 2004, 2010 and 2015, respectively. The highest coverage was observed in Bacillus Calmette-Guérin (BCG) and lowest in oral polio vaccine 1 (OPV1). OPV1 coverage was <90% in the 2004 cohort year, while pentavalent 3 (Penta3) and measles-containing vaccine 1 (MCV1) coverages were <90% in 2004. Dropout rates of Penta3 and MCV1 were significantly >10% in 2004. The logistic regression analyses showed that children were significantly less likely to be immunized with Penta3 and MCV1 in all cohort years compared with Penta1. CONCLUSIONS: Although immunization coverage was in line with the national and district targets for various antigens, full vaccination coverage (FVC) is still lagging behind. Furthermore, the dropout rates for Penta3 and MCV1 showed upside U-shaped patterns. Thus health education, supervision and orientation of service providers are urgently needed to address disparities that are existing in FVC.

Pericardial Injection of Kainic Acid Induces a Chronic Epileptic State in Larval Zebrafish.

Epilepsy is a common disorder of the brain characterized by spontaneous recurrent seizures, which develop gradually during a process called epileptogenesis. The mechanistic processes underlying the changes of brain tissue and networks toward increased seizure susceptibility are not fully understood. In rodents, injection of kainic acid (KA) ultimately leads to the development of spontaneous epileptic seizures, reflecting similar neuropathological characteristics as seen in patients with temporal lobe epilepsy (TLE). Although this model has significantly contributed to increased knowledge of epileptogenesis, it is technically demanding, costly to operate and hence not suitable for high-throughput screening of anti-epileptic drugs (AEDs). Zebrafish, a vertebrate with complementary advantages to rodents, is an established animal model for epilepsy research. Here, we generated a novel KA-induced epilepsy model in zebrafish larvae that we functionally and pharmacologically validated. KA was administered by pericardial injection at an early zebrafish larval stage. The epileptic phenotype induced was examined by quantification of seizure-like behavior using automated video recording, and of epileptiform brain activity measured via local field potential (LFP) recordings. We also assessed GFP-labeled GABAergic and RFP-labeled glutamatergic neurons in double transgenic KA-injected zebrafish larvae, and examined the GABA and glutamate levels in the larval heads by liquid chromatography with tandem mass spectrometry detection (LC-MS/MS). Finally, KA-injected larvae were exposed to five commonly used AEDs by immersion for pharmacological characterization of the model. Shortly after injection, KA induced a massive damage and inflammation in the zebrafish brain and seizure-like locomotor behavior. An abnormal reorganization of brain circuits was observed, a decrease in both GABAergic and glutamatergic neuronal population and their associated neurotransmitters. Importantly, these changes were accompanied by spontaneous and continuous epileptiform brain discharges starting after a short latency period, as seen in KA rodent models and reminiscent of human pathology. Three out of five AEDs tested rescued LFP abnormalities but did not affect the seizure-like behavior. Taken together, for the first time we describe a chemically-induced larval zebrafish epilepsy model offering unique insights into studying epileptogenic processes in vivo and suitable for high-throughput AED screening purposes and rapid genetic investigations.

Comparative Antiseizure Analysis of Diverse Natural Coumarin Derivatives in Zebrafish.

Coumarins are a well-known group of plant secondary metabolites with various pharmacological activities, including antiseizure activity. In the search for new antiseizure drugs (ASDs) to treat epilepsy, it is yet unclear which types of coumarins are particularly interesting as a systematic analysis has not been reported. The current study performed behavioral antiseizure activity screening of 18 different coumarin derivatives in the larval zebrafish pentylenetetrazole (PTZ) model using locomotor measurements. Activity was confirmed for seven compounds, which lowered seizure-like behavior as follows: oxypeucedanin 38%, oxypeucedanin hydrate 74%, notopterol 54%, nodakenetin 29%, hyuganin C 35%, daphnoretin 65%, and pimpinellin 60%. These coumarins, together with nodakenin, underwent further antiepileptiform analysis by local field potential recordings from the zebrafish opticum tectum (midbrain). All of them, except for nodakenetin, showed pronounced antiepileptiform activity, decreasing PTZ-induced elevation in power spectral density (PSD) by 83-89% for oxypeucedanin, oxypeucedanin hydrate, and notopterol, 77% for nodakenin, 26% for nodakenetin, 65% for hyuganin C, 88% for daphnoretin, and 81% for pimpinellin. These data demonstrate the potential of diverse coumarin scaffolds for ASD discovery. Finally, the structural differences between active and inactive coumarins were investigated in silico for oxypeucedanin hydrate and byacangelicin for their interaction with GABA-transaminase, a hypothetical target.

The Impact of Mindset on Self-Tracking Experience.

Self-tracking technologies aim to offer a better understanding of ourselves through data, create self-awareness, and facilitate healthy behavior change. Despite such promising objectives, very little is known about whether the implicit beliefs users may have about the changeability of their own behavior influence the way they experience self-tracking. These implicit beliefs about the permanence of the abilities are called mindsets; someone with a fixed mindset typically perceives human qualities (e.g., intelligence) as fixed, while someone with a growth mindset perceives them as amenable to change and improvement through learning. This paper investigates the concept of mindset in the context of self-tracking and uses online survey data from individuals wearing a self-tracking device (n = 290) to explore the ways in which users with different mindsets experience self-tracking. A combination of qualitative and quantitative approaches indicates that implicit beliefs about the changeability of behavior influence the extent to which users are self-determined toward self-tracking use. Moreover, differences were found in how users perceive and respond to failure, and how self-judgmental vs. self-compassionate they are toward their own mistakes. Overall, considering that how users respond to the self-tracking data is one of the core dimensions of self-tracking, our results suggest that mindset is one of the important determinants in shaping the self-tracking experience. This paper concludes by presenting design considerations and directions for future research.

An Emerging Role for Sigma-1 Receptors in the Treatment of Developmental and Epileptic Encephalopathies.

Developmental and epileptic encephalopathies (DEEs) are complex conditions characterized primarily by seizures associated with neurodevelopmental and motor deficits. Recent evidence supports sigma-1 receptor modulation in both neuroprotection and antiseizure activity, suggesting that sigma-1 receptors may play a role in the pathogenesis of DEEs, and that targeting this receptor has the potential to positively impact both seizures and non-seizure outcomes in these disorders. Recent studies have demonstrated that the antiseizure medication fenfluramine, a serotonin-releasing drug that also acts as a positive modulator of sigma-1 receptors, reduces seizures and improves everyday executive functions (behavior, emotions, cognition) in patients with Dravet syndrome and Lennox-Gastaut syndrome. Here, we review the evidence for sigma-1 activity in reducing seizure frequency and promoting neuroprotection in the context of DEE pathophysiology and clinical presentation, using fenfluramine as a case example. Challenges and opportunities for future research include developing appropriate models for evaluating sigma-1 receptors in these syndromic epileptic conditions with multisystem involvement and complex clinical presentation.

Using Zebrafish as a Disease Model to Study Fibrotic Disease.

In drug discovery, often animal models are used that mimic human diseases as closely as possible. These animal models can be used to address various scientific questions, such as testing and evaluation of new drugs, as well as understanding the pathogenesis of diseases. Currently, the most commonly used animal models in the field of fibrosis are rodents. Unfortunately, rodent models of fibrotic disease are costly and time-consuming to generate. In addition, present models are not very suitable for screening large compounds libraries. To overcome these limitations, there is a need for new in vivo models. Zebrafish has become an attractive animal model for preclinical studies. An expanding number of zebrafish models of human disease have been documented, for both acute and chronic diseases. A deeper understanding of the occurrence of fibrosis in zebrafish will contribute to the development of new and potentially improved animal models for drug discovery. These zebrafish models of fibrotic disease include, among others, cardiovascular disease models, liver disease models (categorized into Alcoholic Liver Diseases (ALD) and Non-Alcoholic Liver Disease (NALD)), and chronic pancreatitis models. In this review, we give a comprehensive overview of the usage of zebrafish models in fibrotic disease studies, highlighting their potential for high-throughput drug discovery and current technical challenges.

Pharmacokinetics in Zebrafish Embryos (ZFE) Following Immersion and Intrayolk Administration: A Fluorescence-Based Analysis.

Zebrafish embryos (ZFE) have increasingly gained in popularity as a model to perform safety screenings of compounds. Although immersion of ZFE is the main route of exposure used, evidence shows that not all small molecules are equally absorbed, possibly resulting in false-negative readouts and incorrect conclusions. In this study, we compared the pharmacokinetics of seven fluorescent compounds with known physicochemical properties that were administered to two-cell stage embryos by immersion or by IY microinjection. Absorption and distribution of the dyes were followed at various timepoints up to 120 hpf by spatiotemporal fluorescence imaging. The concentration (10 µM) and dose (2 mg/kg) used were selected as quantities typically applied in preclinical experiments and zebrafish studies. The data show that in the case of a lipophilic compound (log D: 1.73) the immersion procedure resulted in an intrabody exposure which is similar or higher than that seen after the IY microinjection. In contrast, zero to low intrabody exposure was reached after immersion of the embryos with less lipophilic compounds. In the latter case IY microinjection, a technical procedure that can be easily automated, is highly recommended.

Contextual factors associated with knowledge and attitudes of HIV/AIDS among Malawian women of reproductive age.

BACKGROUND: Increasing the knowledge and attitude toward human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) is a key in the management of the condition. However, in Malawi, there is limited information regarding individual- and community-level factors associated with HIV/AIDS knowledge and attitudes. This study examined the contextual factors associated with HIV/AIDS knowledge and attitudes among women of childbearing age (WOCBA) (aged 15-49 years) in Malawi. METHODS: The 2015-16 Malawi demographic and health survey was used to analyze 24 562 WOCBA who were nested in 850 communities. Mixed effects logistic regression models were fitted to estimate the fixed and random effects of individual- and community-level factors on HIV/AIDS knowledge and attitudes. RESULTS: Approximately 30.9% of the participants had good HIV/AIDS knowledge while 80.5% had good HIV/AIDS attitudes. Among others, at the individual-level, woman's age, educational level and household wealth were positively associated with both good HIV/AIDS knowledge and attitudes. At the community-level, those from communities with a high percentage of women complaining about the distance to health facility were less likely to have both good HIV/AIDS knowledge and attitudes. CONCLUSIONS: Individual- and community-level factors have been shown to be associated with HIV/AIDS knowledge and attitudes among WOCBA in Malawi. Additionally, residual heterogeneity in terms of HIV/AIDS knowledge and attitudes across communities was observed. Therefore, thorough profiling of communities when designing public health programs and strategies may prove beneficial.