Background: Smoking is the leading cause of preventable morbidity worldwide and therefore developing effective smoking cessation strategies is a public health priority. However, what brain networks support maintenance of smoking cessation in the long term remains unexplored. Methods: We analyzed the baseline resting-state fMRI data acquired in 23 smokers (Mage = 61.52 ± 3.7) who were followed longitudinally in a cohort of cognitively normal older adults. Self-reported smoking status and amount were recorded at baseline and repeated after 4 years. We investigated the effect of smoking behaviour change on functional brain connectivity using seed-to-voxel approach. We examined a-priori regions of interest (ROIs) including the reward network (ventromedial prefrontal cortex (vMPFC) and ventral striatum) and the right insula. These ROIs are promising target mechanisms given prior behavioural research linking it to smoking cessation. Results: Our results revealed that reduced smoking was associated with reduced connectivity between ventral striatum and middle frontal gyrus and enhanced connectivity between right insula and middle temporal gyrus (voxel p <0.001, cluster p<0.05 FDR corrected). However, change in smoking did not reveal any significant effects in the vMPFC. Conclusions: Our findings suggest that successful smoking behaviour change is associated with altered reward network and insular functional connectivity in the long term.

Background: Early recognition of neonatal seizures secondary to pathogenic variants in potassium or sodium channel coding genes is crucial, as these seizures are often resistant to commonly used anti-seizure medications, but respond well to sodium-channel blockers. We report a unique aEEG pattern in neonatal seizures caused by SCN2A and KCNQ3 pathogenic variants, as well as adding regular EEG description. Methods: International multicentre descriptive study, reporting clinical characteristics, aEEG and conventional EEG findings of 10 newborns with seizures due to pathogenic SCN2A and KCNQ3 gene variants. Results: Seizures started in the first postnatal week. Seizure semiology typically included tonic posturing with apnea and desaturation. The aEEG showed a characteristic sequence of brief onset with a decrease, followed by a quick rise, and then postictal amplitude attenuation. This pattern correlated with bilateral attenuation in the EEG at onset, followed by rhythmic discharges ending in several seconds of post-ictal amplitude suppression. The majority of patients became seizure free upon initiation of a sodium-channel blocker. Conclusions: Neonatal seizures caused by SCN2A and KCNQ3 mutations can be recognized by a characteristic ictal aEEG pattern and clinical semiology. Awareness of this pattern facilitates the prompt initiation of precision treatment with sodium-channel blockers even before genetic test results are available.

Background: Effort mobilization is important in older adults to stay healthy, notably for decision-making. The process of decreasing subjective value of a reward as required effort increases is called effort discounting. By identifying underlying neural correlates related to effort discounting, we can better understand factors affecting normal cognitive aging. Methods: We acquired resting-state functional magnetic resonance images from 19 cognitively normal older adults (10 males; 66±6 years). Participants completed a computerized cognitive task—called Effort Expenditure for Rewards Task—capturing the willingness to expend effort for rewards through binary choices between high-reward-high-effort or low-reward-low-effort option to obtain varying monetary rewards. We modelled subjective value to assess the k parameter, effort discounting. A functional connectivity analysis examined the involvement of regions associated to the salience network. Results: The seed-to-voxel analysis revealed increased connectivity within the precuneus cortex and to clusters in the right temporal and posterior cingulate gyri, with increased k-value or decreased willingness to expend effort. There was also decreased connectivity between the anterior cingulate and right lateral occipital cortex, and between the left anterior insula to the cerebellum and precuneus cortex. Conclusions: The process of effort discounting is correlated to functional connectivity changes involving the precuneus, anterior cingulate, and left anterior insula in healthy older adults.

Diabetic ketoacidosis is one of the most serious and common complications of diabetes, with between 15 and 70% of new-onset type 1 diabetes mellitus worldwide presented with diabetic ketoacidosis. Supraventricular tachycardia, however, is an infrequent complication of diabetic ketoacidosis. We present the case of a child with a new-onset type 1 diabetes mellitus with supraventricular tachycardia as a complication of paediatric diabetic ketoacidosis. The patient received intravenous fluid resuscitation, insulin, and potassium supplementation and subsequently developed stable supraventricular tachycardia initially, confirmed on a 12-lead electrocardiogram despite a structurally normal heart and normal electrolytes. Vagal manoeuvers failed to achieve sinus rhythm. The patient went into respiratory distress and was intubated, for mechanical ventilation. She received one dose of adenosine with successful conversion to sinus rhythm and a heart rate decreased from 200 to 140 beats per minutes. We conclude that supraventricular tachycardia can occur as a complication of diabetic ketoacidosis, including in new-onset type 1 diabetes mellitus. Furthermore, a combination of acidosis, potassium derangement, falling magnesium, and phosphate levels may have precipitated the event. Here, we report a case of supraventricular tachycardia as a complication of paediatric diabetic ketoacidosis.

In community settings, negative symptoms and cognitive deficits are the primary barriers to independent living, stable relationships, and employment for individuals suffering from schizophrenia-spectrum disorders. In contrast, however, positive psychotic symptoms (e.g., command hallucinations and persecutory delusions) often drive behavior which serves as the gateway to arrest and criminalization. Historically, the keystone of treatment for positive psychotic symptoms has been antagonism of dopamine D2 receptors in the mesolimbic tract. In this article, we review and explore the principles underlying dopamine antagonism for the treatment of psychosis; optimization of dopamine antagonists in treating positive psychotic symptoms; the advantages of depot dopamine antagonist antipsychotics in forensic settings; the concepts of pharmacokinetic and pharmacodynamic treatment failures; and the role of medication plasma concentrations in optimizing and managing treatment.

Background: Atrial fibrillation (AF) is associated with increased risk of ischemic stroke. In Canada, the contemporary burden of AF-related stroke is incompletely characterized. Our objective was to determine temporal trends in hospital admissions and in-hospital mortality for AF-related stroke in Canada from 2007 to 2015. Methods: We conducted a retrospective cohort study using Canadian national administrative data to identify admissions to hospital for stroke with comorbid AF between 2007 and 2015. We analyzed temporal trends in age- and sex-standardized proportion of admissions with comorbid AF and associated in-hospital mortality. Results: There were 222,100 admissions to hospital for ischemic (182,990) or hemorrhagic (39,110) stroke. The age-sex adjusted proportion of ischemic stroke admissions with comorbid AF increased from 16.2% to 20.5% (p for trend = 0.02) between 2007 and 2015, and was stable among hemorrhagic stroke. In-hospital mortality for ischemic stroke with comorbid AF decreased from 21.6% to 15.0% (p for trend = 0.001). Conclusions: Rates of hospital admission for ischemic stroke with comorbid AF have increased, while associated in-hospital mortality has decreased. These results identify AF as an important continued focus for stroke prevention. Our findings provide insight into current trends and highlight the need for continued focus on AF-related stroke.

Plasmodium knowlesi has risen in importance as a zoonotic parasite that has been causing regular episodes of malaria throughout South East Asia. The P. knowlesi genome sequence generated in 2008 highlighted and confirmed many similarities and differences in Plasmodium species, including a global view of several multigene families, such as the large SICAvar multigene family encoding the variant antigens known as the schizont-infected cell agglutination proteins. However, repetitive DNA sequences are the bane of any genome project, and this and other Plasmodium genome projects have not been immune to the gaps, rearrangements and other pitfalls created by these genomic features. Today, long-read PacBio and chromatin conformation technologies are overcoming such obstacles. Here, based on the use of these technologies, we present a highly refined de novo P. knowlesi genome sequence of the Pk1(A+) clone. This sequence and annotation, referred to as the ‘MaHPIC Pk genome sequence’, includes manual annotation of the SICAvar gene family with 136 full-length members categorized as type I or II. This sequence provides a framework that will permit a better understanding of the SICAvar repertoire, selective pressures acting on this gene family and mechanisms of antigenic variation in this species and other pathogens.

Antigenic variation in malaria was discovered in Plasmodium knowlesi studies involving longitudinal infections of rhesus macaques (M. mulatta). The variant proteins, known as the P. knowlesi Schizont Infected Cell Agglutination (SICA) antigens and the P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1) antigens, expressed by the SICAvar and var multigene families, respectively, have been studied for over 30 years. Expression of the SICA antigens in P. knowlesi requires a splenic component, and specific antibodies are necessary for variant antigen switch events in vivo. Outstanding questions revolve around the role of the spleen and the mechanisms by which the expression of these variant antigen families are regulated. Importantly, the longitudinal dynamics and molecular mechanisms that govern variant antigen expression can be studied with P. knowlesi infection of its mammalian and vector hosts. Synchronous infections can be initiated with established clones and studied at multi-omic levels, with the benefit of computational tools from systems biology that permit the integration of datasets and the design of explanatory, predictive mathematical models. Here we provide an historical account of this topic, while highlighting the potential for maximizing the use of P. knowlesi – macaque model systems and summarizing exciting new progress in this area of research.

Faster eating rates are associated with increased energy intake, but little is known about the relationship between children’s eating rate, food intake and adiposity. We examined whether children who eat faster consume more energy and whether this is associated with higher weight status and adiposity. We hypothesised that eating rate mediates the relationship between child weight and ad libitum energy intake. Children (n 386) from the Growing Up in Singapore Towards Healthy Outcomes cohort participated in a video-recorded ad libitum lunch at 4·5 years to measure acute energy intake. Videos were coded for three eating-behaviours (bites, chews and swallows) to derive a measure of eating rate (g/min). BMI and anthropometric indices of adiposity were measured. A subset of children underwent MRI scanning (n 153) to measure abdominal subcutaneous and visceral adiposity. Children above/below the median eating rate were categorised as slower and faster eaters, and compared across body composition measures. There was a strong positive relationship between eating rate and energy intake (r 0·61, P<0·001) and a positive linear relationship between eating rate and children’s BMI status. Faster eaters consumed 75 % more energy content than slower eating children (Δ548 kJ (Δ131 kcal); 95 % CI 107·6, 154·4, P<0·001), and had higher whole-body (P<0·05) and subcutaneous abdominal adiposity (Δ118·3 cc; 95 % CI 24·0, 212·7, P=0·014). Mediation analysis showed that eating rate mediates the link between child weight and energy intake during a meal (b 13·59; 95 % CI 7·48, 21·83). Children who ate faster had higher energy intake, and this was associated with increased BMI z-score and adiposity.

Background: The pathophysiology of subarachnoid hemorrhage (SAH) is complex and includes disruption of the blood-brain barrier (BBB). We freshly isolated BBB endothelial cells (BECs) by 2 distinct methods after experimental SAH and then interrogated their gene expression profiles with the goal of uncovering new therapeutic targets. Methods: SAH was induced using the prechiasmatic blood injection mouse model. BBB permeability studies were performed by administering intraperitoneal cadaverine dye injections at 24h and 48h. BECs were isolated either by sequential magnetic-based sorting for CD45-CD31+ cells or by fluorescence-activated cell sorting (FACS) for Tie2+Pdgfrb- cells. Total RNA was extracted and analyzed using Affymetrix Mouse Gene 2.0 ST Arrays. Results: BBB impairment occurred at 24h and resolved by 48h after SAH. Analysis of gene expression patterns in BECs at 24h reveal clustering of SAH and sham samples. We identified 707 (2.8%) significant differentially-expressed genes (403 upregulated, 304 downregulated) out of 24,865 interrogated probe sets. Many significantly upregulated genes were involved in inflammatory pathways. These microarray results were validated with real-time polymerase chain reaction (RT-PCR). Conclusions: This study is the first to investigate in an unbiased manner, whole genome expression profiling of freshly-isolated BECs in an SAH animal model, yielding targets for novel therapeutic intervention.

Association mapping based on linkage disequilibrium (LD) is a promising tool to identify genes responsible for quantitative variations underlying complex traits. The present paper presents an association mapping panel consisting of 172 upland cotton (Gossypium hirsutum L.) accessions. The panel was phenotyped for five cotton plant architecture traits across multiple environments and genotyped using 386 simple sequence repeat (SSR) markers. Of these markers, 101 polymorphic SSR markers were used in the final analysis. There were abundant phenotypic variations within this germplasm panel and a total of 267 alleles ranging from two to seven per locus were identified in all collections. The threshold of LD decay was set to r2 = 0·1 and 0·2, and the genome-wide LD extended up to about 13–14 and 6–7 cM, respectively, providing the potential for association mapping of agronomically important traits in upland cotton. A total of 66 marker–trait associations were detected based on a mixed linear model, of which 35 were found in more than one environment. The favourable alleles from 35 marker loci can be used in marker-assisted selection of target traits. Both the synergistic alleles and the negative alleles for some traits, especially plant height and fruit branch angle, can be utilized in plant architecture breeding programmes according to specific breeding objectives.