Gene-based drug therapy for children and youth treated with psychoactive medications.

Psychoactive medications are increasingly used to treat children and youth with mental health conditions, but individual variations in response highlight the need for precision medicine. Pharmacogenetic (PGx) testing is a key component of precision medicine. The number of commercial pharmacogenetic testing companies promoting PGx, with the promise of achieving individualized and effective treatment of mental health conditions, has grown exponentially in recent years. Scientific evidence supporting the use of PGx to manage mental health conditions is limited, especially for paediatric populations. This practice point outlines steps guiding the use and interpretation of PGx testing for psychoactive medications in clinical settings, along with key supportive resources. Practice guidelines have been developed for variants in pharmacogenes encoding cytochrome P450 drug-metabolizing enzymes (e.g., CYP2C19, CYP2D6, CYP2C9) as one determinant of drug concentrations in blood, which can support both drug choice and dosing strategy for certain anti-psychotics, anti-depressants, and anti-epileptics. Adverse drug reactions to some anti-epileptic drugs (e.g., carbamazepine and phenytoin) have been associated with certain human leukocyte antigen types and variants in DNA polymerase gamma (POLG; valproic acid). Evidence remains limited for genetic variants of drug target proteins, making it challenging to identify patients with altered treatment responses at a therapeutic blood concentration.

La pharmacothérapie en fonction des gènes chez les enfants et les adolescents qui prennent des médicaments psychoactifs.

Les médicaments psychoactifs sont de plus en plus utilisés pour traiter les enfants et les adolescents ayant des troubles de santé mentale, mais la variabilité des réponses individuelles fait ressortir l'importance d'une médecine personnalisée. Les tests pharmacogénétiques sont un volet important d'un tel type de médecine. Le nombre d'entreprises de tests pharmacogénétiques commerciaux qui font la promotion de tests de ce genre et promettent un traitement efficace et individualisé des troubles de santé mentale se multiplie depuis quelques années. Les preuves scientifiques en appui à l'utilisation de la pharmacogénétique sont limitées, particulièrement dans les populations pédiatriques. Le présent point de pratique souligne les étapes qui orientent le recours à ces tests pour la prise de médicaments psychoactifs en milieu clinique et présente des ressources de soutien importantes. Il existe des directives cliniques sur les variants des pharmacogènes qui encodent les enzymes de métabolisation du cytochrome P450 (p. ex., CYP2C19, CYP2D6, CYP2C9), lesquels sont l'un des déterminants des concentrations pharmacologiques dans le sang et peuvent appuyer à la fois le choix du médicament et la stratégie posologique de certains antipsychotiques, antidépresseurs et antiépileptiques. Les effets indésirables de certains médicaments antiépileptiques (p. ex., la carbamazépine et la phénytoïne) sont associés à certains types d'antigènes d'histocompatibilité humaine et à des variants de l'ADN polymérase gamma (POLG; acide valproïque). Les données probantes sont limitées à l'égard des variants génétiques des protéines qui ciblent les médicaments, et c'est pourquoi il est difficile de déterminer quels patients présenteraient une réponse altérée au traitement à une concentration sanguine thérapeutique.

Coordinated changes in a cortical circuit sculpt effects of novelty on neural dynamics.

Recent studies have found dramatic cell-type-specific responses to stimulus novelty, highlighting the importance of analyzing the cortical circuitry at this granularity to understand brain function. Although initial work characterized activity by cell type, the alterations in cortical circuitry due to interacting novelty effects remain unclear. We investigated circuit mechanisms underlying the observed neural dynamics in response to novel stimuli using a large-scale public dataset of electrophysiological recordings in behaving mice and a population network model. The model was constrained by multi-patch synaptic physiology and electron microscopy data. We found generally weaker connections under novel stimuli, with shifts in the balance between somatostatin (SST) and vasoactive intestinal polypeptide (VIP) populations and increased excitatory influences on parvalbumin (PV) and SST populations. These findings systematically characterize how cortical circuits adapt to stimulus novelty.

Vitamin K Antagonists for Pregnant Women With Antiphospholipid Antibodies: A Scoping Review.

OBJECTIVE: To describe characteristics of published research on the safety and efficacy of vitamin K antagonists (VKA) for pregnant patients with antiphospholipid antibodies (aPL), including their methodological characteristics and knowledge gaps. METHODS: This study followed the Joanna Briggs Institute methodology for scoping reviews and used the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews protocol system. Studies were primarily identified through searching electronic databases including MEDLINE, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials. Study characteristics and outcomes were reported and described using customized charting tables. RESULTS: Of 1528 publications, 17 remained in the final analysis. These reported up to 190 VKA-treated aPL-positive pregnancies diagnosed as antiphospholipid syndrome (APS); pregnancy cases were likely overlapping in some publications. In the 17 reports, there were 723 individuals in comparison groups, including healthy pretreatment pregnancies and women with APS treated with standard therapies without VKA. However, only 4 (23.5%) of the 17 publications stated a study objective focusing on VKA use, of which only one was a full-length article. In addition, information on VKA doses, disease diagnostic criteria, and the long-term outcomes of offspring were largely absent. CONCLUSION: The current evidence is insufficient to assess VKA efficacy and safety profiles in aPL-positive pregnant patients. Studies with a defined focus on VKA use in this population are lacking, and reporting of key information is not consistent. The relative lack of knowledge of VKA use in pregnant women with APS is concerning, and efficacy and safety questions remain.

Spontaneous hemopneumothorax causing life-threatening hemorrhage: a case report.

BACKGROUND: Spontaneous hemopneumothorax is a rare condition that can be life-threatening if not promptly diagnosed and treated. We report a case of early treatment with transcatheter arterial embolization and video-assisted thoracoscopic surgery. CASE PRESENTATION: A 19-year-old Japanese male was diagnosed with left pneumothorax and underwent chest tube drainage. A total of 10 hours after admission, the patient developed dyspnea, chest pain, and sudden massive bloody effusion. Contrast-enhanced computed tomography revealed contrast extravasation near the left lung apex, and spontaneous hemopneumothorax was diagnosed. Angiography revealed bleeding from a branch of the subscapular artery and transcatheter arterial embolization was performed. The patient underwent video-assisted thoracoscopic surgery and recovered uneventfully. CONCLUSIONS: Anesthesiologists involved in urgent surgeries must be aware that a patient with spontaneous pneumothorax can develop a hemopneumothorax, even when full lung expansion has been obtained following chest tube drainage, owing to latent aberrant artery disruption. Interprofessional team engagement is essential for spontaneous hemopneumothorax management.

Psychometric Analysis of the Heart Failure Somatic Perception Scale in Japanese Patients With Heart Failure.

BACKGROUND: Patients with heart failure (HF) experience a wide variety of symptoms. Appropriate recognition of symptoms is important in HF care. The Heart Failure Somatic Perception Scale (HFSPS) measures the presence of HF symptoms and the degree to which physical symptoms are bothersome. OBJECTIVE: The aim of this study was to assess the validity and reliability of the Japanese version of the HFSPS. METHODS: Confirmatory factor analysis was used to assess structural validity. Construct validity was assessed using Spearman's rank correlation coefficient to evaluate the association between HFSPS total and subscale scores and global physical health on the Patient-Reported Outcomes Measurement Information System. Internal consistency was assessed using the model-based internal consistency for the HFSPS as a whole and Cronbach α for the subscales. RESULTS: Participants were 315 Japanese outpatients (72.1% male), with a mean age of 72.9 ± 12.9 years. The result of confirmatory factor analysis was an adequate model fit by adding error correlations. Construct validity was significant for the correlation with global physical health of the Patient-Reported Outcomes Measurement Information System. The model-based internal consistency was 0.95. Cronbach αs for each subscale were 0.88 for dyspnea, 0.60 for chest discomfort, 0.77 for early and subtle symptoms, and 0.77 for edema. CONCLUSIONS: The findings support the use of the HFSPS in a more diverse population, suggesting that it is a reliable and valid instrument in Japanese patients with HF. The HFSPS may provide an accurate assessment of the symptoms experienced by patients with HF in daily life in future educational intervention studies to improve symptom perception and coping behaviors.

Validity and Reliability of the Child and Adolescent Version of the Iron Intake Scale (CIIS) as an Educational Tool.

INTRODUCTION/OBJECTIVE: In Asia, 42% of young children suffer from iron deficiency anemia. Children have an increased requirement for iron intake because of growth and physical activity. Education plays an important role in anemia prevention and in ensuring children are aware of appropriate iron intake and the iron content of different foods. As a tool for this purpose, we adapted the adult version of the Revised Iron Intake Scale (RIIS) to create the Child and Adolescent Version of the Iron Intake Scale (CIIS), using illustrations to help children recognize the foods listed in the CIIS. We aimed to evaluate the validity and reliability of this new scale. METHODS: We conducted a cross-sectional study using a self-administered questionnaire to examine the criterion-related validity of the CIIS. We used Spearman's rank correlation coefficient to compare iron intake estimated by the CIIS with that calculated by the Brief-type Diet History Questionnaire (BDHQ-15y), which assesses respondents' dietary habits over the past month and is standardized among Japanese children. The survey was repeated twice to examine reliability. RESULTS: We found a moderate positive correlation for iron intake between the CIIS and BDHQ-15y, with a correlation coefficient of .52 (n = 258, P < .001). Cronbach's alpha coefficient was .718. The CIIS reproducibility test yielded a correlation coefficient of .67. CONCLUSION: Our results indicated that the CIIS was valid, reliable, and reproducible. We therefore believe that the scale can be used to improve education about iron deficiency anemia and thereby reduce anemia rates among children and adolescents.

Comparative study of eating behavior between patients with mental illness and healthy controls using the Japanese version of the Dutch Eating Behavior Questionnaire.

BACKGROUND AND OBJECTIVES: To examine the reliability and validity of the Japanese version of the Dutch Eating Behavior Questionnaire (DEBQ-J) for patients with mental illness, and to determine the characteristics of eating behavior among these patients when compared with healthy controls. METHODS AND STUDY DESIGN: In May 2018, 120 outpatients with mental illness and 132 healthy controls were surveyed. First, exploratory factor analysis was conducted on the DEBQ-J statement responses for both patients and healthy controls. Next, reliability coefficients were calculated for the eating behavior scale scores (emotional, restrained, and external eating) extracted from the factor analysis. The association between BMI and eating behavior was examined using Student's t-test and Pearson's correlation coefficient. RESULTS: The DEBQ-J had a similar factor structure to that of the original DEBQ for healthy controls, with a cumulative contribution of 52.4% for the three factors, and alpha coefficients ranging from 0.87 to 0.91. For patients, factor analysis showed that four statements classified as emotional eating items in the original DEBQ were recategorized as external eating items, and the percentage of patients with obesity (BMI≥25) was 57.5%, compared with only 25.4% among the healthy controls. The patients with obesity tended to score higher on the external eating scale than did those with BMI<25. CONCLUSIONS: Patients tended to blur the distinction between emotional feelings of mental irritability or anxiety and feelings in response to external stimuli. Monitoring of the DEBQ-J external eating score and appropriate intervention among patients living with mental illness may help to prevent obesity.

Maternal Ezetimibe Concentrations Measured in Breast Milk and Its Use in Breastfeeding Infant Exposure Predictions.

BACKGROUND: Lactating mothers taking ezetimibe, an antihyperlipidemic agent, may be hesitant to breastfeed despite the known benefit of breastfeeding to both mother and infant. Currently, no data exist on the presence or concentration of ezetimibe and its main active metabolite, ezetimibe-glucuronide (EZE-glucuronide), in human breast milk. METHODS: Voluntary breast milk samples containing ezetimibe and EZE-glucuronide were attained from lactating mothers taking ezetimibe as part of their treatment. An assay was developed and validated to measure ezetimibe and EZE-glucuronide concentrations in breast milk. A workflow that utilized a developed and evaluated pediatric physiologically based pharmacokinetic (PBPK) model, the measured concentrations in milk, and weight-normalized breast milk intake volumes was applied to predict infant exposures and determine the upper area under the curve ratio (UAR). RESULTS: Fifteen breast milk samples from two maternal-infant pairs were collected. The developed liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay showed an analytical range of 0.039-5.0 ng/mL and 0.39-50.0 ng/mL for ezetimibe and EZE-glucuronide, respectively. The measured concentrations in the breast milk samples were 0.17-1.02 ng/mL and 0.42-2.65 ng/mL of ezetimibe and EZE-glucuronide, respectively. The evaluated pediatric PBPK model demonstrated minimal exposure overlap in adult therapeutic dose and breastfed infant simulated area under the concentration-time curve from time zero to 24 h (AUC24). Calculated UAR across infant age groups ranged from 0.0015 to 0.0026. CONCLUSIONS: PBPK model-predicted ezetimibe and EZE-glucuronide exposures and UAR suggest that breastfeeding infants would receive non-therapeutic exposures. Future work should involve a 'mother-infant pair study' to ascertain breastfed infant plasma ezetimibe and EZE-glucuronide concentrations to confirm the findings of this work.

Anemia-related subjective symptoms in the general adult population in Japan.

Objectives: Approximately 17% of Japanese women have hemoglobin concentrations less than 12 g/dL. Therefore, anemia prevention and early intervention are crucial public health issues in Japan. This study aimed to identify the symptoms and characteristics of anemic individuals in the general adult population by comparing survey responses of individuals with anemia and without anemia visiting blood donation centers. Materials and Methods: This cross-sectional study used self-administered questionnaires. Individuals who visited two Japanese Red Cross Society blood donation centers in Fukushima Prefecture, Japan were included. Hemoglobin levels were measured at blood donation, and the levels of 13 g/dL for men and 12 g/dL for women were defined as anemia. Results: Of the 857 individuals analyzed, 530 were men and 327 were women, of whom 19 (3.6%) and 12 (3.7%) had low hemoglobin levels, respectively. Logistic regression analysis was performed in men, and the results showed that "lightheadedness" (odds ratio [OR]=8.4) and "depressive symptoms" (OR=3.6) were significantly associated with hemoglobin levels. None of the evaluated items were significantly associated with hemoglobin levels in women. Conclusion: Among healthy Japanese men, those who exhibit lightheadedness and depressive symptoms have an increased risk of anemia. Lightheadedness and depressive symptoms may be indicative of undiagnosed anemia in men, which necessitates greater clinical attention.

An unusual concomitance of acute heart failure: prolactinoma in a patient with left ventricular dysfunction-a case report.

Background: Heart failure concomitant with prolactinoma is extremely rare. Case summary: We present the case of a 29-year-old man who had acute decompensated heart failure concomitant with visual loss in his right eye. Transthoracic echocardiography indicated severely decreased left ventricular (LV) function. A massive tumour on the sella turcica was detected by brain computed tomography. The findings of the laboratory tests showed hyperprolactinaemia with hypopituitarism, and the antigen test for coronavirus disease 2019 was positive as an incidental finding. Medication for heart failure and cabergoline therapy were started immediately. His LV function significantly improved, and he had no symptoms after a year. Discussion: Prolactinoma in men, which can cause visual loss and hypopituitarism, is frequently substantial when diagnosed. The cardiac manifestation of prolactinoma is uncommon. It is believed that a major contributing component to the pathogenesis of peripartum cardiomyopathy is hyperprolactinaemia. Hyperprolactinaemia may cause endothelial damage and cardiomyocyte dysfunction, eventually resulting in LV dysfunction. The success of LV reverse remodelling may be significantly impacted by heart failure and hormone treatments. Heart failure and endocrine therapy should be administered concurrently to patients who have prolactinoma and congestive heart failure.

Coordinated changes in a cortical circuit sculpt effects of novelty on neural dynamics.

Recent studies have found dramatic cell-type specific responses to stimulus novelty, highlighting the importance of analyzing the cortical circuitry at the cell-type specific level of granularity to understand brain function. Although initial work classified and characterized activity for each cell type, the specific alterations in cortical circuitry-particularly when multiple novelty effects interact-remain unclear. To address this gap, we employed a large-scale public dataset of electrophysiological recordings in the visual cortex of awake, behaving mice using Neuropixels probes and designed population network models to investigate the observed changes in neural dynamics in response to a combination of distinct forms of novelty. The model parameters were rigorously constrained by publicly available structural datasets, including multi-patch synaptic physiology and electron microscopy data. Our systematic optimization approach identified tens of thousands of model parameter sets that replicate the observed neural activity. Analysis of these solutions revealed generally weaker connections under novel stimuli, as well as a shift in the balance e between SST and VIP populations. Along with this, PV and SST populations experienced overall more excitatory influences compared to excitatory and VIP populations. Our results also highlight the role of VIP neurons in multiple aspects of visual stimulus processing and altering gain and saturation dynamics under novel conditions. In sum, our findings provide a systematic characterization of how the cortical circuit adapts to stimulus novelty by combining multiple rich public datasets.

HSP47 levels determine the degree of body adiposity.

Adiposity varies among individuals with the influence of diverse physiological, pathological, environmental, hormonal, and genetic factors, but a unified molecular basis remains elusive. Here, we identify HSP47, a collagen-specific chaperone, as a key determinant of body adiposity. HSP47 expression is abundant in adipose tissue; increased with feeding, overeating, and obesity; decreased with fasting, exercise, calorie restriction, bariatric surgery, and cachexia; and correlated with fat mass, BMI, waist, and hip circumferences. Insulin and glucocorticoids, respectively, up- and down-regulate HSP47 expression. In humans, the increase of HSP47 gene expression by its intron or synonymous variants is associated with higher body adiposity traits. In mice, the adipose-specific knockout or pharmacological inhibition of HSP47 leads to lower body adiposity compared to the control. Mechanistically, HSP47 promotes collagen dynamics in the folding, secretion, and interaction with integrin, which activates FAK signaling and preserves PPARγ protein from proteasomal degradation, partly related to MDM2. The study highlights the significance of HSP47 in determining the amount of body fat individually and under various circumstances.

Dramatic recovery of left ventricular dysfunction in a patient with pseudoaldosteronism, hypokalaemia, and rhabdomyolysis: a case report.

Background: Excessive liquorice ingestion sometimes causes pseudoaldosteronism. The association between liquorice-induced pseudoaldosteronism and acute heart failure has not been well described. Case summary: An 89-year-old woman was referred to the hospital due to muscle weakness with rhabdomyolysis and severe hypokalaemia. The electrocardiogram in the emergency department revealed pulseless ventricular tachycardia, thus, emergent defibrillation was delivered. Laboratory findings revealed severe hypokalaemia with metabolic alkalosis. Plasma renin activity and serum aldosterone were highly suppressed. Her medications included herbal medicines containing a great amount of liquorice. The patient was diagnosed with pseudoaldosteronism caused by liquorice over-ingestion. She developed acute pulmonary oedema with unexpected left ventricular (LV) dysfunction after the peak out of creatine kinase. She was managed with acute heart failure therapy, as well as optimal medical therapy. She accidentally developed an acute embolic stroke but fully recovered due to emergent thrombolytic therapy. Cardiac magnetic resonance imaging revealed banding late gadolinium enhancement in the basal-mid segments, which was inconsistent with takotsubo cardiomyopathy. As time passed, LV function unexpectedly improved, and congestive heart failure was completely compensated. Discussion: Liquorice contains glycyrrhetinic acid that inhibits 11ßHSD2. This invites the over-activation of mineralocorticoid receptors by cortisol in the kidneys and eventually causes hypokalaemia and hypertension. Acute heart failure caused by excessive liquorice ingestion is scarcely described. The triggering factors for LV dysfunction and acute congestive heart failure remain unclear. Rhabdomyolysis could affect massive catecholamine release and cause LV dysfunction.

Cannabidiol Exposure Through Maternal Marijuana Use: Predictions in Breastfed Infants.

BACKGROUND AND OBJECTIVE: Knowledge about exposure to cannabidiol (CBD) in breastfed infants can provide an improved understanding of potential risk. The aim was to predict CBD exposure in breastfed infants from mothers taking CBD and CBD-containing products. METHODS: Cannabidiol concentrations in milk previously attained from data collected through an existing human milk research biorepository were used to simulate infant doses and identify subgroups. A developed pediatric physiologically based pharmacokinetic model produced virtual breastfed infants administered the simulated CBD doses. Predicted breastfed infant exposures and upper area under the curve ratios were compared to the lowest therapeutic dose for approved indications in children. RESULTS: The existing human milk research biorepository contained 200 samples from 181 unique breastfeeding mothers for whom self-reported administration data and CBD concentrations had previously been measured. Samples that were above the lower limit of quantification with only one maternal administration type revealed that administration type, i.e., joint/blunt or edible versus oil or pipe, resulted in significantly different subgroups in terms of milk concentrations. Resulting simulated infant doses (ng/kg) were described by lognormal distributions with geometric means and geometric standard deviations: 0.61 ± 2.41 all concentrations, 0.10 ± 0.37 joint/blunt or edible, and 2.23 ± 8.15 oil or pipe. Doses administered to breastfed infants had exposures magnitudes lower than exposures in children aged 4-11 years administered the lowest therapeutic dose for approved indications, and low upper area under the curve ratios. CONCLUSIONS: Based on real-world use, breastfeeding infants are predicted to receive very small exposures of CBD through milk. Studies examining adverse reactions will provide further insight into potential risk.

Safety of medicines during breastfeeding - from case report to modeling: a contribution from the ConcePTION project.

INTRODUCTION: Despite many research efforts, current data on the safety of medicines during breastfeeding are either fragmented or lacking, resulting in restrictive labeling of most medicines. In the absence of pharmacoepidemiologic safety studies, risk estimation for breastfed infants is mainly derived from pharmacokinetic (PK) information on medicine. This manuscript provides a description and a comparison of the different methodological approaches that can yield reliable information on medicine transfer into human milk and the resulting infant exposure. AREA COVERED: Currently, most information on medicine transfer in human milk relies on case reports or traditional PK studies, which generate data that can hardly be generalized to the population. Some methodological approaches, such as population PK (popPK) and physiologically based PK (PBPK) modeling, can be used to provide a more complete characterization of infant medicine exposure through human milk and simulate the most extreme situations while decreasing the burden of sampling in breastfeeding women. EXPERT OPINION: PBPK and popPK modeling are promising approaches to fill the gap in knowledge of medicine safety in breastfeeding, as illustrated with our escitalopram example.

Simulations of cortical networks using spatially extended conductance-based neuronal models.

The Hodgkin-Huxley model of action potential generation and propagation, published in the Journal of Physiology in 1952, initiated the field of biophysically detailed computational modelling in neuroscience, which has expanded to encompass a variety of species and components of the nervous system. Here we review the developments in this area with a focus on efforts in the community towards modelling the mammalian neocortex using spatially extended conductance-based neuronal models. The Hodgkin-Huxley formalism and related foundational contributions, such as Rall's cable theory, remain widely used in these efforts to the current day. We argue that at present the field is undergoing a qualitative change due to new very rich datasets describing the composition, connectivity and functional activity of cortical circuits, which are being integrated systematically into large-scale network models. This trend, combined with the accelerating development of convenient software tools supporting such complex modelling projects, is giving rise to highly detailed models of the cortex that are extensively constrained by the data, enabling computational investigation of a multitude of questions about cortical structure and function.

High-frequency ultrasound-guided intrathecal injections in a young mouse model: Targeting the central nervous system in drug delivery.

BACKGROUND: Intrathecal injections provide important access to the central nervous system for delivery of anesthetic, analgesic or chemotherapeutic drugs that do not otherwise cross the blood-brain barrier. The administration of drugs via this route in animal models is challenging due to an inability to visualize the small target space during injection. Successful drug delivery therefore requires expertise in indirectly assessing vertebral and spinal cord anatomy and gaining advanced procedural skills. These factors are especially compounded in small animals such as mice (the most common mammalian model) and in investigations modeling pediatric drug delivery, where the animal is even smaller. NEW METHOD: To address these issues, we have developed a method in which high-frequency ultrasound imaging is used to visualize and target the lumbar intrathecal space for injections. The technique is demonstrated in mice as young as postnatal day 16. To evaluate the method, a gadolinium-based magnetic resonance imaging (MRI) contrast agent was injected intrathecally, and subsequent brain delivery was verified post-injection by MRI. RESULTS: Successful intrathecal injections of the MRI contrast agent showed distribution to the brain. In this study, we achieved a targeting success rate of 80% in 20 animals. COMPARISON WITH EXISTING METHODS AND CONCLUSION: We expect that the new method will be convenient for drug delivery to the central nervous system in rodent research and provide higher reliability than unguided approaches, an essential contribution that will enable intrathecal delivery in pediatric mouse models.