The Global Impact of Multisystemic Vulnerabilities on Criminal Variety: A Cross-Continental Study in Young Adults.

Previous research has shown a robust association between different childhood and adolescent vulnerabilities and youth offending. However, these investigations have primarily focused on youths from high-income Western countries. Consequently, the generalizability of these findings to better inform global justice policies remains uncertain. This study aimed to address this gap by examining the relationship between individual, familial, and contextual vulnerabilities and criminal versatility during young adulthood, accounting for sociodemographic factors and cross-national differences. Data were derived from a diverse sample of 4,182 young adults (67% female; mean age = 18.96; SD = 0.81) residing in 10 countries across 5 continents who participated in the International Study of Pro/Antisocial Behavior in Young Adults. The Psychosocial and Family Vulnerability Questionnaire and the Adverse Childhood Experiences questionnaire were used to assess social and family adversity, and past-year criminal diversity was measured with the Criminal Variety Index. Results indicate that child maltreatment, substance abuse, and delinquent peers are global risk factors for criminal variety. Moreover, they are independent across males and females and among youths living in countries that are ranked differently on the Human Development Index (HDI). In addition, some childhood vulnerabilities showed different predictive ability across sexes (e.g., school failure), and across countries ranked differently on the HDI (e.g., family dysfunction). These findings suggest that certain childhood factors contribute to criminal behavior through transcultural mechanisms. Moreover, they highlight the importance of developing evidence-based policies that focus on transcultural risk factors to globally prevent criminal behavior.

Early B-cell transcription factor-2 defect as a novel cause of lipodystrophy: disruption of the adipose tissue character and integrity.

We report a novel cause of partial lipodystrophy associated with early B cell factor 2 (EBF2) nonsense variant (EBF2 8:26033143 C>A, c.493G>T, p.E165X) in a patient with an atypical form of partial lipodystrophy. The patient presented with progressive adipose tissue loss and metabolic deterioration at pre-pubertal age. In vitro and in vivo disease modeling demonstrates that the EBF2 variant impairs adipogenesis, causing excess accumulation of undifferentiated CD34+ cells, extracellular matrix proteins, and inflammatory myeloid cells in subcutaneous adipose tissues. Thus, this EBF2 p.E165X variant disrupts adipose tissue structure and function, leading to the development of partial lipodystrophy syndrome.

Hospitalizations for mental and behavioral disorders due to alcohol and other psychoactive substance use among adolescents in Brazil, 2017-2022.

OBJECTIVE: To assess the epidemiological profile and trend in hospitalizations for mental and behavioral disorders due to alcohol and other psychoactive substance use among Brazilian adolescents, between 2017 and 2022. METHODS: This was a time-series study using data from the Hospital Information System of the Brazilian National Health System; the trend analysis was performed by estimating the annual percentage change (APC) of hospitalization rates per 100,000 inhabitants and respective confidence intervals (95%CI), using the Prais-Winsten method. RESULTS: A total of 29,991 hospitalizations were recorded in the study period, with a decreasing trend observed, from 16.18/100,000 inhabitants in 2017 to 13.72/100,000 inhab. in 2022 (percent change of -2.65%; 95%CI -4.47;-0.80), a greater decline was found in males (-3.48%; 95%CI -5.20;-1.72), in the age group of 15 to 19 years (-2.79%; 95%CI -4.49;-1.06), in the South (-3.29%; 95%CI -5.37;-1.16) and Midwest (-3.64%; 95%CI -5.75;-1.49) regions of the country. CONCLUSION: Hospitalizations showed a decreasing trend in the study period, with sociodemographic disparities.

Report of intraosseous intravascular papillary endothelial hyperplasia associated with an odontogenic cyst in the maxilla and literature review.

Intravascular papillary endothelial hyperplasia (IPEH) represents an uncommon reactive endothelial hyperplastic proliferation. A 46-year-old man experienced increased volume in the right maxilla, elevation of the nasal ala, and swelling of the hard palate with a reddish hue for 3 months. Computed tomography revealed an expansive hypodense region and cortical bone destruction associated with an impacted supernumerary tooth and an endodontically treated tooth. Under the differential diagnoses of a radicular cyst, dentigerous cyst, and ameloblastoma, an exploratory aspiration and incisional biopsy were performed. This revealed the formation of blood vessels of various diameters lined by endothelium, forming intravascular papillae positive for CD-34. The definitive diagnosis was IPEH, and the patient was treated by embolization and surgery. Histological analysis confirmed the presence of IPEH associated with an odontogenic cyst. After 12 months of follow-up, no recurrence was observed. Also, we reviewed case reports of IPEH affecting the maxilla and mandible. Fourteen intraosseous cases were reported in the maxilla and mandible, with a preference for males and affecting a wide age range. Complete surgical excision was the treatment of choice, and recurrences were not reported. The pathogenesis of IPEH is controversial and may originate from trauma or inflammatory processes. To the best of our knowledge, this is the first report of an association of IPEH with an odontogenic cyst. The importance of IPEH in the differential diagnosis of intraosseous lesions in the jaws is emphasized, and preoperative semiotic maneuvers are needed to prevent surgical complications.

A novel arylpiperazine derivative (LQFM181) protects against neurotoxicity induced by 3- nitropropionic acid in in vitro and in vivo models.

In the pursuit of novel antioxidant therapies for the prevention and treatment of neurodegenerative diseases, three new arylpiperazine derivatives (LQFM181, LQFM276, and LQFM277) were synthesized through a molecular hybridization approach involving piribedil and butylated hydroxytoluene lead compounds. To evaluate the antioxidant and neuroprotective activities of the arylpiperazine derivatives, we employed an integrated approach using both in vitro (SH-SY5Y cells) and in vivo (neurotoxicity induced by 3-nitropropionic acid in Swiss mice) models. In the in vitro tests, LQFM181 showed the most promising antioxidant activity at the neuronal membrane and cytoplasmic levels, and significant neuroprotective activity against the neurotoxicity induced by 3-nitropropionic acid. Hence, this compound was further subjected to in vivo evaluation, which demonstrated remarkable antioxidant capacity such as reduction of MDA and carbonyl protein levels, increased activities of succinate dehydrogenase, catalase, and superoxide dismutase. Interestingly, using the same in vivo model, LQFM181 also reduced locomotor behavior and memory dysfunction through its ability to decrease cholinesterase activity. Consequently, LQFM181 emerges as a promising candidate for further investigation into its neuroprotective potential, positioning it as a new therapeutic agent for neuroprotection.

Bipolar Patient-Specific In Vitro Diagnostic Test Reveals Underlying Cardiac Arrhythmia Phenotype Caused by Calcium Channel Genetic Risk Factor.

A common genetic risk factor for bipolar disorder is CACNA1C, a gene that is also critical for cardiac rhythm. The impact of CACNA1C mutations on bipolar patient cardiac rhythm is unknown. Here, we report the cardiac electrophysiological implications of a bipolar disorder-associated genetic risk factor in CACNA1C using patient induced pluripotent stem cell-derived cardiomyocytes. Results indicate that the CACNA1C bipolar disorder-related mutation causes cardiac electrical impulse conduction slowing mediated by impaired intercellular coupling via connexin 43 gap junctions. In vitro gene therapy to restore connexin 43 expression increased cardiac electrical impulse conduction velocity and protected against thioridazine-induced QT prolongation. Patients positive for bipolar disorder CACNA1C genetic risk factors may have elevated proarrhythmic risk for adverse events in response to psychiatric medications that slow conduction or prolong the QT interval. This in vitro diagnostic tool enables cardiac testing specific to patients with psychiatric disorders to determine their sensitivity to off-target effects of psychiatric medications.

Bipolar disorder (BD) is associated with genetic risk factors that present as mutations in specific genes. One gene commonly associated with BD is the calcium channel gene CACNA1C, found in the brain and the heart. The impact of CACNA1C mutation on cardiac function in patients with BD is unclear. Here, we created a BD CACNA1C mutant patient "heart in a dish" using patient-specific stem cells. Gene editing was also used to correct the mutation to create an isogenic control cell line. We found that the BD calcium gene mutation caused slow electrical impulse propagation, reduced the function of the calcium channel, and was associated with low intercellular communication channels called connexin. Using connexin gene therapy in vitro, the the cardiac dysfunction could be corrected and cured. This new approach offers patient-specific hearts-in-a-dish that can be used to ensure that medications will not cause heart racing or arrhythmias.

Stromal Cell-SLIT3/Cardiomyocyte-ROBO1 Axis Regulates Pressure Overload-Induced Cardiac Hypertrophy.

BACKGROUND: Recently shown to regulate cardiac development, the secreted axon guidance molecule SLIT3 maintains its expression in the postnatal heart. Despite its known expression in the cardiovascular system after birth, SLIT3's relevance to cardiovascular function in the postnatal state remains unknown. As such, the objectives of this study were to determine the postnatal myocardial sources of SLIT3 and to evaluate its functional role in regulating the cardiac response to pressure overload stress. METHODS: We performed in vitro studies on cardiomyocytes and myocardial tissue samples from patients and performed in vivo investigation with SLIT3 and ROBO1 (roundabout homolog 1) mutant mice undergoing transverse aortic constriction to establish the role of SLIT3-ROBO1 in adverse cardiac remodeling. RESULTS: We first found that SLIT3 transcription was increased in myocardial tissue obtained from patients with congenital heart defects that caused ventricular pressure overload. Immunostaining of hearts from WT (wild-type) and reporter mice revealed that SLIT3 is secreted by cardiac stromal cells, namely fibroblasts and vascular mural cells, within the heart. Conditioned media from cardiac fibroblasts and vascular mural cells both stimulated cardiomyocyte hypertrophy in vitro, an effect that was partially inhibited by an anti-SLIT3 antibody. Also, the N-terminal, but not the C-terminal, fragment of SLIT3 and the forced overexpression of SLIT3 stimulated cardiomyocyte hypertrophy and the transcription of hypertrophy-related genes. We next determined that ROBO1 was the most highly expressed roundabout receptor in cardiomyocytes and that ROBO1 mediated SLIT3's hypertrophic effects in vitro. In vivo, Tcf21+ fibroblast and Tbx18+ vascular mural cell-specific knockout of SLIT3 in mice resulted in decreased left ventricular hypertrophy and cardiac fibrosis after transverse aortic constriction. Furthermore, α-MHC+ cardiomyocyte-specific deletion of ROBO1 also preserved left ventricular function and abrogated hypertrophy, but not fibrosis, after transverse aortic constriction. CONCLUSIONS: Collectively, these results indicate a novel role for the SLIT3-ROBO1-signaling axis in regulating postnatal cardiomyocyte hypertrophy induced by pressure overload.

Long-stay ICU patients with frailty: mortality and recovery outcomes at 6 months.

BACKGROUND: Prolonged intensive care unit (ICU) stay is associated with physical, cognitive, and psychological disabilities. The impact of baseline frailty on long-stay ICU patients remains uncertain. This study aims to investigate how baseline frailty influences mortality and post-ICU disability 6 months after critical illness in long-stay ICU patients. METHODS: In this retrospective cohort study, we assessed patients hospitalized for ≥ 7 days in the ICU between May 2018 and May 2021, following them for up to 6 months or until death. Based on the Clinical Frailty Scale (CFS) at ICU admissions, patients were categorized as frail (CFS ≥ 5), pre-frail (CFS 3-4) and non-frail (CFS 1-2). Kaplan-Meier curves and a multivariate Cox model were used to examine the association between frailty and mortality. At the 6 month follow-up, we assessed psychological, physical, cognitive outcomes, and health-related quality of life (QoL) using descriptive statistics and linear regressions. RESULTS: We enrolled 531 patients, of which 178 (33.6%) were frail, 200 (37.6%) pre-frail and 153 (28.8%) non-frail. Frail patients were older, had more comorbidities, and greater disease severity at ICU admission. At 6 months, frail patients presented higher mortality rates than pre-frail and non-frail patients (34.3% (61/178) vs. 21% (42/200) vs. 13.1% (20/153) respectively, p < 0.01). The rate of withdrawing or withholding of care did not differ significantly between the groups. Compared with CFS 1-2, the adjusted hazard ratios of death at 6 months were 1.7 (95% CI 0.9-2.9) for CFS 3-4 and 2.9 (95% CI 1.7-4.9) for CFS ≥ 5. At 6 months, 192 patients were seen at a follow-up consultation. In multivariate linear regressions, CFS ≥ 5 was associated with poorer physical health-related QoL, but not with poorer mental health-related QoL, compared with CFS 1-2. CONCLUSION: Frailty is associated with increased mortality and poorer physical health-related QoL in long-stay ICU patients at 6 months. The admission CFS can help inform patients and families about the complexities of survivorship during a prolonged ICU stay.

DNA content and clinicopathological features aid in distinguishing ameloblastic carcinoma from ameloblastoma.

BACKGROUND: Ameloblastoma and ameloblastic carcinoma are epithelial odontogenic tumors that can be morphologically similar. In the present study, we evaluated the DNA content and Ki-67 index in the two tumors. METHODS: The paraffin blocks of the tumors were selected to obtain sections for the immunohistochemical reactions and preparation of the cell suspension for acquisition in a flow cytometer. The Random Forest package of the R software was used to verify the contribution of each variable to classify lesions into ameloblastoma or ameloblastic carcinoma. RESULTS: Thirty-two ameloblastoma and five ameloblastic carcinoma were included in the study. In our sample, we did not find statistically significant differences in Ki-67 labeling rates. A higher fraction of cells in 2c (G1) was correlated with the diagnosis of ameloblastoma, whereas higher rates of 5c-exceeding rate (5cER) were correlated with ameloblastic carcinoma. The Random Forest model highlighted histopathological findings and parameters of DNA ploidy study as important features for distinguishing ameloblastoma from ameloblastic carcinoma. CONCLUSION: Our findings suggest that the parameters of the DNA ploidy study can be ancillary tools in the classification of ameloblastoma and ameloblastic carcinoma.

Malignant tumors affecting the head and neck region in ancient times: Comprehensive study of the CRAB Database.

In the modern world, cancer is a growing cause of mortality, but archeological studies have shown that it is not exclusive to modern populations. The aim of this study is to examine the epidemiologic, social, and clinicopathologic features of head and neck cancers in ancient populations. To do this, we extracted all records that described malignant lesions in the head and neck region available in the Cancer Research in Ancient Bodies Database (CRAB). The estimated age, sex, physical condition of the remains (skeletonized, mummified), anatomic location of tumors, geographic location, chronology, tumor type, and methods of tumor diagnosis were collected. One hundred and sixty-seven cases were found, mostly originating from Europe (51.5%). Most records were of adults between 35 and 49 years of age (37.7%). The most involved site was the skullcap (60.4%), and the most common malignancies were metastases to the bone (65.3%) and multiple myeloma (17.4%). No primary soft tissue malignancies were registered. The results of our study indicate that head and neck cancers were present in ancient civilizations, at least since 500,000 BCE. The available data can help to improve the current understanding of the global distribution of head and neck cancer and its multidimensional impacts on populations in the contemporary world.

Convergent insights into intratumor heterogeneity.

Mathematics, conventional histology, and genomics converge to confirm that highly aggressive clear cell renal cell carcinomas (CCRCCs) display low levels of intratumor heterogeneity (ITH). We hypothesize that therapeutic strategies aimed at maintaining high ITH levels would be advisable to slow down cancer evolution and to improve survival.

Novel Proline Transporter Inhibitor (LQFM215) Presents Antipsychotic Effect in Ketamine Model of Schizophrenia.

The glutamatergic hypothesis of schizophrenia suggests a correlation between NMDA receptor hypofunction and negative psychotic symptoms. It has been observed that the expression of the proline transporter (PROT) in the central nervous system (CNS) is associated with glutamatergic neurotransmission, as L-proline has the capacity to activate and modulate AMPA and NMDA receptors. In this study, we aimed to investigate whether inhibition of proline transporters could enhance glutamatergic neurotransmission and potentially exhibit antipsychotic effects in an experimental schizophrenia model. Using molecular dynamics analysis in silico, we validated an innovative PROT inhibitor, LQFM215. We quantified the cytotoxicity of LQFM215 in the Lund human mesencephalic cell line (LUHMES). Subsequently, we employed the ketamine-induced psychosis model to evaluate the antipsychotic potential of the inhibitor, employing behavioral tests including open-field, three-chamber interaction, and prepulse inhibition (PPI). Our results demonstrate that LQFM215, at pharmacologically active concentrations, exhibited negligible neurotoxicity when astrocytes were co-cultured with neurons. In the ketamine-induced psychosis model, LQFM215 effectively reduced hyperlocomotion and enhanced social interaction in a three-chamber social approach task across all administered doses. Moreover, the compound successfully prevented the ketamine-induced disruption of sensorimotor gating in the PPI test at all tested doses. Overall, these findings suggest that PROT inhibition could serve as a potential therapeutic target for managing symptoms of schizophrenia model.

Hospitalizations for mental and behavioral disorders due to alcohol and other psychoactive substance use among adolescents in Brazil, 2017-2022 / Hospitalizaciones por trastornos mentales y de conducta relacionados con el consumo de alcohol y otras sustancias psicoactivas en adolescentes en Brasil, 2017-2022 / Hospitalizações por transtornos mentais e comportamentais relacionados ao uso de álcool e outras substâncias psicoativas em adolescentes no Brasil, 2017-2022

Abstract Objective: To assess the epidemiological profile and trend in hospitalizations for mental and behavioral disorders due to alcohol and other psychoactive substance use among Brazilian adolescents, between 2017 and 2022. Methods: This was a time-series study using data from the Hospital Information System of the Brazilian National Health System; the trend analysis was performed by estimating the annual percentage change (APC) of hospitalization rates per 100,000 inhabitants and respective confidence intervals (95%CI), using the Prais-Winsten method. Results: A total of 29,991 hospitalizations were recorded in the study period, with a decreasing trend observed, from 16.18/100,000 inhabitants in 2017 to 13.72/100,000 inhab. in 2022 (percent change of -2.65%; 95%CI -4.47;-0.80), a greater decline was found in males (-3.48%; 95%CI -5.20;-1.72), in the age group of 15 to 19 years (-2.79%; 95%CI -4.49;-1.06), in the South (-3.29%; 95%CI -5.37;-1.16) and Midwest (-3.64%; 95%CI -5.75;-1.49) regions of the country. Conclusion: Hospitalizations showed a decreasing trend in the study period, with sociodemographic disparities.

Resumen Objetivo: Analizar el perfil epidemiológico y la tendencia de las hospitalizaciones por trastornos mentales y de comportamiento relacionados con el uso de alcohol y otras sustancias psicoactivas en adolescentes brasileños, desde 2017 hasta 2022. Métodos: Estudio de serie temporal utilizando el Sistema de Información Hospitalaria del Sistema Único de Salud; se evaluó la tendencia mediante la estimación del cambio porcentual anual (CPA) de las tasas de hospitalización por cada 100,000 habitantes y sus respectivos intervalos mediante el método de Prais-Winsten. Resultados: Se registraron 29.991 hospitalizaciones durante el período y se observó una tendencia decreciente en Brasil, desde 16,18 hospitalizaciones por cada 100.000 habitantes en 2017 hasta 13,72 en 2022 (variación de -2,65%; IC₉₅% -4,47;-0,80), con mayor declive en hombres (-3,48%; IC₉₅% -5,20;-1,72), en la edad de 15 a 19 años (-2,79%; IC₉₅% -4,49;-1,06), en las regiones del Sur (-3,29%; IC₉₅% -5,37; -1,16) y Centro-Oeste (-3,64%; IC₉₅% -5,75;-1,49). Conclusión: Las hospitalizaciones mostraron una tendencia decreciente en el período, con disparidades sociodemográficas.

Resumo Objetivo: Analisar o perfil epidemiológico e a tendência das internações hospitalares por transtornos mentais e comportamentais devido ao uso de álcool e de outras substâncias psicoativas em adolescentes brasileiros, de 2017 a 2022. Métodos: Estudo de série temporal com dados do Sistema de Informações Hospitalares do Sistema Único de Saúde. A tendência foi analisada estimando-se a variação percentual anual (VPA) das taxas de internação por 100 mil habitantes e respectivos Intervalos pelo método de Prais-Winsten. Resultados: Foram registradas 29.991 internações no período, sendo observada uma tendência decrescente das internações no Brasil, variando de 16,18 internações por 100 mil hab., em 2017, para 13,72 em 2022 (variação de -2,65%; IC₉₅% -4,47; -0,80), com maior declínio no sexo masculino (-3,48%; IC₉₅% -5,20;-1,72), na faixa etária de 15 a 19 anos (-2,79%; IC₉₅% -4,49;-1,06), nas regiões Sul (-3,29%; IC₉₅% -5,37;-1,16) e Centro-Oeste (-3,64%; IC₉₅% -5,75;-1,49). Conclusão: As internações apresentaram tendência decrescente no período, com disparidades sociodemográficas.

Malignant tumors affecting the head and neck region in ancient times: Comprehensive study of the CRAB Database

Abstract In the modern world, cancer is a growing cause of mortality, but archeological studies have shown that it is not exclusive to modern populations. The aim of this study is to examine the epidemiologic, social, and clinicopathologic features of head and neck cancers in ancient populations. To do this, we extracted all records that described malignant lesions in the head and neck region available in the Cancer Research in Ancient Bodies Database (CRAB). The estimated age, sex, physical condition of the remains (skeletonized, mummified), anatomic location of tumors, geographic location, chronology, tumor type, and methods of tumor diagnosis were collected. One hundred and sixty-seven cases were found, mostly originating from Europe (51.5%). Most records were of adults between 35 and 49 years of age (37.7%). The most involved site was the skullcap (60.4%), and the most common malignancies were metastases to the bone (65.3%) and multiple myeloma (17.4%). No primary soft tissue malignancies were registered. The results of our study indicate that head and neck cancers were present in ancient civilizations, at least since 500,000 BCE. The available data can help to improve the current understanding of the global distribution of head and neck cancer and its multidimensional impacts on populations in the contemporary world.

Georeferenced dataset of maritime piracy in the Gulf of Guinea from 2010 to 2021.

Piracy has been a global concern and a threat to the safety of people performing maritime trade around the globe. Since ancient times maritime piracy has been a common practice that, unfortunately, has not ended in the current days. A georeferenced dataset providing the position, meteorologic conditions, and a description of the occurrence can provide essential information for analyzing this global phenomenon. The dataset focuses on the Gulf of Guinea (GoG) as an area dominated by corruption and weak supervision capacity by the local authorities. The time interval considered in this paper is between 2010 and 2021. Using this simple dataset, it is possible to analyze attributes such as when the piracy occurred or if the illegal activity involved deaths or kidnapping. The accuracy of the data was guaranteed by cross-referencing data sources, so we have 595 pirate attacks accurately described. This dataset can easily be used for data mining, allowing further analysis of the patterns and trends of pirate attacks in the GoG over time.

Early Evolution in Cancer: A Mathematical Support for Pathological and Genomic Evidence in Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (CCRCC) is an aggressive form of cancer and a paradigmatic example of intratumor heterogeneity (ITH). The hawk-dove game is a mathematical tool designed to analyze competition in biological systems. Using this game, the study reported here analyzes the early phase of CCRCC development, comparing clonal fitness in homogeneous (linear evolutionary) and highly heterogeneous (branching evolutionary) models. Fitness in the analysis is a measure of tumor aggressiveness. The results show that the fittest clone in a heterogeneous environment is fitter than the clone in a homogeneous context in the early phases of tumor evolution. Early and late periods of tumor evolution in CCRCC are also compared. The study shows the convergence of mathematical, histological, and genomics studies with respect to clonal aggressiveness in different periods of the natural history of CCRCC. Such convergence highlights the importance of multidisciplinary approaches for obtaining a better understanding of the intricacies of cancer.

Unveiling LoRa's Oceanic Reach: Assessing the Coverage of the Azores LoRaWAN Network from an Island.

In maritime settings, effective communication between vessels and land infrastructure is crucial, but existing technologies often prove impractical for energy-sensitive IoT applications, like deploying sensors at sea. In this study, we explore the viability of a low-power, cost-effective wireless communication solution for maritime sensing data. Specifically, we conduct an experimental assessment of the Azorean Long Range Wide Area Network (LoRaWAN) coverage. Our tests involve positioning the gateway at the island's highest point and installing end nodes on medium-sized fishing vessels. Through measurements of received signal strength indicator (RSSI), signal-to-noise ratio (SNR), and lines of sight (LOS), we showcase the potential of LoRaWAN transmissions to achieve communication distances exceeding 130 km in a LOS-free scenario over the ocean. These findings highlight the promising capabilities of LoRaWAN for reliable and long-range maritime communication of sensing data.

High-throughput longitudinal electrophysiology screening of mature chamber-specific hiPSC-CMs using optical mapping.

hiPSC-CMs are being considered by the Food and Drug Administration and other regulatory agencies for in vitro cardiotoxicity screening to provide human-relevant safety data. Widespread adoption of hiPSC-CMs in regulatory and academic science is limited by the immature, fetal-like phenotype of the cells. Here, to advance the maturation state of hiPSC-CMs, we developed and validated a human perinatal stem cell-derived extracellular matrix coating applied to high-throughput cell culture plates. We also present and validate a cardiac optical mapping device designed for high-throughput functional assessment of mature hiPSC-CM action potentials using voltage-sensitive dye and calcium transients using calcium-sensitive dyes or genetically encoded calcium indicators (GECI, GCaMP6). We utilize the optical mapping device to provide new biological insight into mature chamber-specific hiPSC-CMs, responsiveness to cardioactive drugs, the effect of GCaMP6 genetic variants on electrophysiological function, and the effect of daily ß-receptor stimulation on hiPSC-CM monolayer function and SERCA2a expression.

Validation of formulas calculating normalized protein catabolic rate in patients undergoing home hemodialysis.

Depner and Daugirdas developed a simplified formula to estimate the normalized protein catabolic rate in patients on twice- or thrice-weekly hemodialysis (JASN, 1996). The aim of our work was to establish formulas in more frequent schedules and validate them in home-based hemodialysis patients. We realized that the structure of Depner and Daugirdas' normalized protein catabolic rate formulas has a general meaning and can be expressed as PCRn = C0/[a + b*(Kt/V) + c/(Kt/V)] + d, where C0 is pre-dialysis blood urea nitrogen, Kt/V is dialysis dose, a, b, c, d are the specific coefficients for each combination of home-based hemodialysis schedules and the day of blood sampling. The same applies to the formula that adjusts C0 (C'0) for residual kidney clearance of blood water urea (Kru) and urea distribution volume (V): C'0 = C0*[1 + (a1 + b1/(Kt/V))*Kru/V]. On this basis, we computed the six coefficients (a, b, c, d, a1, b1) for each of the 50 possible combinations and simulated a total of 24,000 weekly dialysis cycles using the Daugirdas Solute Solver software recommended by the KDOQI 2015 guidelines. From the associated statistical analyses we obtained 50 sets of coefficient values, which were validated comparing the paired normalized protein catabolic rate values (i.e., those estimated with our formulas with those modeled with Solute Solver) in 210 datasets of 27 patients on home-based hemodialysis. The mean values ± SD were 1.06 ± 0.262 and 1.07 ± 0.283 g/kg/day, respectively, with a mean difference of 0.004 ± 0.034 g/kg/day (p = 0.11). The paired values were highly correlated (R2 = 0.99). In conclusion, even if the coefficient values were validated in a relatively small sample of patients, they allow an accurate estimation of normalized protein catabolic rate in home-based hemodialysis patients.