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.

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.

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.

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.

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.

Microwaves reduce water refractive index.

Microwaves, long used as a convenient household appliance, have been increasingly used in industrial processes such as organic synthesis and oil processing. It has been proposed that microwaves can enhance these chemical processes via a non-thermal effect. Here we report the instantaneous effect of microwaves on the permittivity and phase velocity of light in water through the in-situ measurement of changes in refractive index. Microwave irradiation was found to reduce the water refractive index (RI) sharply. The reduction increased as a function of microwave power to a far greater extent than expected from the change in temperature. The phase velocity of light in water increases up to ~ 5% (RI of 1.27) during microwave irradiation. Upon stopping irradiation, the return to the equilibrium RI was delayed by up to 30 min. Our measurement shows that microwaves have a profound non-thermal and long-lasting effect on the properties of water. Further investigation is planned to verify if the observed RI reduction is restricted to the region near the surface or deep inside water bulk. The observation suggests a relationship between microwave-induced and the enhanced aqueous reactions.

High-Frequency Hearing Is Required to Compute a Topographic Map of Auditory Space in the Mouse Superior Colliculus.

A topographic map of auditory space is a feature found in the superior colliculus (SC) of many species, including CBA/CaJ mice. In this genetic background, high-frequency monaural spectral cues and interaural level differences (ILDs) are used to compute spatial receptive fields (RFs) that form a topographic map along the azimuth. Unfortunately, C57BL/6 mice, a strain widely used for transgenic manipulation, display age-related hearing loss (AHL) because of an inbred mutation in the Cadherin 23 gene (Cdh23) that affects hair cell mechanotransduction. To overcome this problem, researchers have used young C57BL/6 mice in their studies, as they have been shown to have normal hearing thresholds. However, important details of the auditory response characteristics of the SC such as spectral responses and spatial localization, have not been characterized in young C57BL/6 mice. Here, we show that two- to four-month C57BL/6 mice lack neurons with frontal auditory RFs and therefore lack a topographic representation of auditory space in the SC. Analysis of the spectrotemporal RFs (STRFs) of the SC auditory neurons shows that C57BL/6 mouse SC neurons lack the ability to detect the high-frequency (>40 kHz) spectral cues that are needed to compute frontal RFs. We also show that crossing C57BL/6 mice with CBA/CaJ mice or introducing one copy of the wild-type Cdh23 to C57BL/6 mice rescues the high-frequency hearing deficit and improves the topographic map of auditory space. Taken together, these results demonstrate the importance of high-frequency hearing in computing a topographic map of auditory space.

Local connectivity and synaptic dynamics in mouse and human neocortex.

We present a unique, extensive, and open synaptic physiology analysis platform and dataset. Through its application, we reveal principles that relate cell type to synaptic properties and intralaminar circuit organization in the mouse and human cortex. The dynamics of excitatory synapses align with the postsynaptic cell subclass, whereas inhibitory synapse dynamics partly align with presynaptic cell subclass but with considerable overlap. Synaptic properties are heterogeneous in most subclass-to-subclass connections. The two main axes of heterogeneity are strength and variability. Cell subclasses divide along the variability axis, whereas the strength axis accounts for substantial heterogeneity within the subclass. In the human cortex, excitatory-to-excitatory synaptic dynamics are distinct from those in the mouse cortex and vary with depth across layers 2 and 3.

A pharmacogenomic investigation of the cardiac safety profile of ondansetron in children and pregnant women.

BACKGROUND: Ondansetron is a highly effective antiemetic for the treatment of nausea and vomiting. However, this medication has also been associated with QT prolongation. Pharmacogenomic information on therapeutic response to ondansetron exists, but no investigation has been performed on genetic factors that influence the cardiac safety of this medication. METHODS: Three patient groups receiving ondansetron were recruited and followed prospectively (pediatric post-surgical patients n = 101; pediatric oncology patients n = 98; pregnant women n = 62). Electrocardiograms were conducted at baseline, and 5- and 30-min post-ondansetron administration, to determine the effect of ondansetron treatment on QT interval. Pharmacogenomic associations were assessed via analyses of comprehensive CYP2D6 genotyping and genome-wide association study data. RESULTS: In the entire cohort, 62 patients (24.1%) met the criteria for prolonged QT, with 1.2% of the cohort exhibiting unsafe QT prolongation. The most significant shift from baseline occurred at five minutes post-ondansetron administration (P = 9.8 × 10-4). CYP2D6 activity score was not associated with prolonged QT. Genome-wide analyses identified novel associations with a missense variant in TLR3 (rs3775291; P = 2.00 × 10-7) and a variant linked to the expression of SLC36A1 (rs34124313; P = 1.97 × 10-7). CONCLUSIONS: This study has provided insight into the genomic basis of ondansetron-induced cardiac changes and has emphasized the importance of genes that have been implicated in serotonin-related traits. These biologically-relevant findings represent the first step towards understanding this adverse event with the overall goal to improve the safety of this commonly used antiemetic medication.

Infant drug exposure via breast milk.

More than half of women take medications during breastfeeding, predisposing their infants to medication exposure via breast milk. As a result, adverse drug reactions may emerge in the infant, although they are rarely reported. Disposition of maternal drugs in breast milk is described with several key parameters, which include relative infant dose (RID): infant drug intake via milk (weight- and time-adjusted) expressed as a percentage of the similarly adjusted mother's dose. Most drugs show RID values of <10%, indicating that drug concentrations in infant serum do not reach a level known to be therapeutic in adults unless drug clearance is markedly lower than the adult level on a weight basis. RID is a function of milk-to-(maternal) plasma drug concentration ratio (MP ratio) and maternal drug clearance. Therefore, MP ratio between drugs must be interpreted not by itself but with maternal drug clearance of each drug. This is why some drugs such as phenobarbital show an MP ratio of <1 but an RID as high as 50-70%, while morphine shows an MP ratio of 2 but an RID in the range of 5%. Using RID, we interpreted case reports of infant adverse outcomes, and we observed cases with relatively low infant serum concentrations of drug, consistent with low RID, as well as those with near- or above-adult therapeutic serum concentrations, with or without increased drug intake (i.e. high RID). It is important to consider both pharmacokinetic and pharmacodynamic factors in interpreting adverse outcomes in infants breastfed by a mother taking medications.

Imputing missing patient-level data and propensity score matching in cost-effectiveness analysis in Crohn's disease.

OBJECTIVES: The effect of imputing missing data followed by propensity score analysis on the incremental cost-effectiveness ratio (ICER) in a cost-effectiveness analysis is unknown. The objective was to compare alternative approaches in grouping data following imputation and prior to calculating propensity scores for use in economic evaluation. METHODS: Patient-level data from an observational study of 573 children with Crohn's disease were used in a microsimulation model to determine the incremental cost of early anti-tumor necrosis factor-α treatment compared to standard care per remission week gained. Multiple imputation of a missing covariate followed by propensity score matching to create comparator groups was approached in two ways. The Within approach calculated propensity scores on each imputed dataset separately, while the Across method averaged propensity scores to create one matched population resulting in multiple sets of health state transition probabilities. RESULTS: The incremental cost per remission week gained ranged from CAD$2,236 to CAD$12,464 (mean CAD$4,266) with Within datasets and was CAD$4,679 per remission week gained with the Across dataset. CONCLUSION: Imputation of missing patient-level data and propensity score analysis increases methodological uncertainty in cost-effectiveness analysis. The present study indicated that the Across approach may be less cumbersome, and slightly reduce bias and variance.

Nonlinear visuoauditory integration in the mouse superior colliculus.

Sensory information from different modalities is processed in parallel, and then integrated in associative brain areas to improve object identification and the interpretation of sensory experiences. The Superior Colliculus (SC) is a midbrain structure that plays a critical role in integrating visual, auditory, and somatosensory input to assess saliency and promote action. Although the response properties of the individual SC neurons to visuoauditory stimuli have been characterized, little is known about the spatial and temporal dynamics of the integration at the population level. Here we recorded the response properties of SC neurons to spatially restricted visual and auditory stimuli using large-scale electrophysiology. We then created a general, population-level model that explains the spatial, temporal, and intensity requirements of stimuli needed for sensory integration. We found that the mouse SC contains topographically organized visual and auditory neurons that exhibit nonlinear multisensory integration. We show that nonlinear integration depends on properties of auditory but not visual stimuli. We also find that a heuristically derived nonlinear modulation function reveals conditions required for sensory integration that are consistent with previously proposed models of sensory integration such as spatial matching and the principle of inverse effectiveness.

Implementation and Evaluation of Life-planning Lecture to Enhance Perspective-Taking among High School Students: A School-based Nonrandomized Waitlist Intervention Study in Japan.

INTRODUCTION: The Australian "empathy session," which is a parenting program aimed at alleviating postpartum depression by increasing empathy among expecting couples, was adapted to a life-planning education program for Japanese high school students. In this present study, we aimed to assess changes in high school students' empathy levels. METHODS: A nonrandomized, controlled, waitlist intervention was performed in 210 first-year students. They were divided into intervention and waitlist control groups. The life-planning lecture consisted of two parts: (1) reproductive health and (2) empathy and communication skills. The main outcome indicator was the Perspective-Taking subscale of an empathy index. Logistic regression was used to examine the association between the intervention and change in the Perspective-Taking scale score controlling for background factors. RESULTS: As per our findings, a significant difference was noted in the scale scores of Perspective-Taking before and after the program within the intervention group (3.76 ± 0.61 before the lecture and 3.86 ± 0.64 after the lecture; P = 0.01). In the between-group analysis, the likelihood of an increase in the scale score of Perspective-Taking was significantly higher in the intervention group (OR = 2.29, 95 % confidence interval = 1.23-4.26). CONCLUSIONS: Japanese high school students' Perspective-Taking improved through learning reproductive life-planning and communication skills.