Music therapy in tertiary neonatal intensive care: A matter of unlikely allies?

Over the past decades, music therapy in the neonatal intensive care unit (NICU) has been proven effective in physiological and psychological outcomes, including sucking, behaviour, stress reduction, neurodevelopment and promoting emotional bonding. However, not every NICU administers music therapy in their ward. Research on music therapy for neonates and their caregivers has lately accumulated, increasing the evidence of health benefits on brain development and across a variety of NICU-related pathologies, including neurological, cardiological, pulmonary and gastrointestinal problems. Conclusively, we will present the studied methods of music therapy for clinical benefits in neonatal intensive care.

Sens-ocular model: Cell-based assay to evaluate eye stinging potential of chemicals and baby cosmetic formulations.

The TRPV1 receptor, which is known to contribute significantly to pain perception, has recently been identified as a useful tool for predicting eye stinging potential in cosmetics. In this study, HEK-293 cells with high TRPV1 expression were utilized to evaluate calcium influx related to receptor activation triggered by chemicals and cosmetic formulations. The cells were exposed to increasing concentrations of substances to cause or not some aggression to the eye, and TRPV1 activity was assessed by measuring intracellular FURA-2 AM fluorescence signal. To confirm TRPV1 channel activation, capsazepine, a capsaicin antagonist, was employed in addition to using capsaicin as a positive control. The study's results indicate that this novel model can identify compounds known to cause some aggression to the eye, such as stinging, considering a cut-off value of 60% of Ca2+ influx exposed to the lowest evaluated concentration (0.00032%). When applied to the cosmetic baby formulation, although the presented model exhibited higher sensitivity by classifying as stinging formulations that had previously undergone clinical testing and were deemed non-stinging, the assay could serve as a valuable in vitro tool for predicting human eye stinging sensation and can be used as a tier 1 in an integrated testing strategy.

Concept and considerations of a medical device: the active noise cancelling incubator.

Background: An increasingly 24/7 connected and urbanised world has created a silent pandemic of noise-induced hearing loss. Ensuring survival to children born (extremely) preterm is crucial. The incubator is a closed medical device, modifying the internal climate, and thus providing an environment for the child, as safe, warm, and comfortable as possible. While sound outside the incubator is managed and has decreased over the years, managing the noise inside the incubator is still a challenge. Method: Using active noise cancelling in an incubator will eliminate unwanted sounds (i.e., from the respirator and heating) inside the incubator, and by adding sophisticated algorithms, normal human speech, neonatal intensive care unit music-based therapeutic interventions, and natural sounds will be sustained for the child in the pod. Applying different methods such as active noise cancelling, motion capture, sonological engineering. and sophisticated machine learning algorithms will be implemented in the development of the incubator. Projected Results: A controlled and active sound environment in and around the incubator can in turn promote the wellbeing, neural development, and speech development of the child and minimise distress caused by unwanted noises. While developing the hardware and software pose individual challenges, it is about the system design and aspects contributing to it. On the one hand, it is crucial to measure the auditory range and frequencies in the incubator, as well as the predictable sounds that will have to be played back into the environment. On the other, there are many technical issues that have to be addressed when it comes to algorithms, datasets, delay, microphone technology, transducers, convergence, tracking, impulse control and noise rejection, noise mitigation stability, detection, polarity, and performance. Conclusion: Solving a complex problem like this, however, requires a de-disciplinary approach, where each discipline will realise its own shortcomings and boundaries, and in turn will allow for innovations and new avenues. Technical developments used for building the active noise cancellation-incubator have the potential to contribute to improved care solutions for patients, both infants and adults.Code available at: 10.3389/fped.2023.1187815.

The Application of New Approach Methodologies in Respiratory Disease Research: Their Role in Improving Translational Medicine from Bench to Bedside.

The SARS-CoV-2 outbreak focused global attention on the shortcomings of the drug discovery process. It led to its acceleration in several areas, particularly in the processes associated with the development and approval of COVID-19 vaccines. This situation contrasts with the low approval rates of new drugs for respiratory system diseases (e.g. asthma, chronic obstructive pulmonary disease, cancer, tuberculosis), which are leading causes of morbidity and mortality worldwide. In this context, innovation in respiratory system drug discovery is surely needed, and it is most likely to succeed through the use of preclinical models that are cost-effective, high-throughput and generate predictive human-relevant outcomes. Here, we highlight several non-animal new approach methodologies (NAMs) and their applications in respiratory research. We describe their potential uses for efficacy and toxicity assessments, to optimise the drug development process and reduce the high failure rates in clinical trials.

Paclitaxel-Loaded Lipid-Coated Magnetic Nanoparticles for Dual Chemo-Magnetic Hyperthermia Therapy of Melanoma.

Melanoma is the most aggressive and metastasis-prone form of skin cancer. Conventional therapies include chemotherapeutic agents, either as small molecules or carried by FDA-approved nanostructures. However, systemic toxicity and side effects still remain as major drawbacks. With the advancement of nanomedicine, new delivery strategies emerge at a regular pace, aiming to overcome these challenges. Stimulus-responsive drug delivery systems might considerably reduce systemic toxicity and side-effects by limiting drug release to the affected area. Herein, we report the development of paclitaxel-loaded lipid-coated manganese ferrite magnetic nanoparticles (PTX-LMNP) as magnetosomes synthetic analogs, envisaging the combined chemo-magnetic hyperthermia treatment of melanoma. PTX-LMNP physicochemical properties were verified, including their shape, size, crystallinity, FTIR spectrum, magnetization profile, and temperature profile under magnetic hyperthermia (MHT). Their diffusion in porcine ear skin (a model for human skin) was investigated after intradermal administration via fluorescence microscopy. Cumulative PTX release kinetics under different temperatures, either preceded or not by MHT, were assessed. Intrinsic cytotoxicity against B16F10 cells was determined via neutral red uptake assay after 48 h of incubation (long-term assay), as well as B16F10 cells viability after 1 h of incubation (short-term assay), followed by MHT. PTX-LMNP-mediated MHT triggers PTX release, allowing its thermal-modulated local delivery to diseased sites, within short timeframes. Moreover, half-maximal PTX inhibitory concentration (IC50) could be significantly reduced relatively to free PTX (142,500×) and Taxol® (340×). Therefore, the dual chemo-MHT therapy mediated by intratumorally injected PTX-LMNP stands out as a promising alternative to efficiently deliver PTX to melanoma cells, consequently reducing systemic side effects commonly associated with conventional chemotherapies.

Methyl benzoate and nerolidol attract the cyclocephaline beetle Cyclocephala paraguayensis to trumpet flowers.

Cyclocephaline beetles are flower visitors attracted primarily by major floral volatiles. Addressing the identity of these volatile compounds is pivotal for understanding the evolution of plant-beetle interactions. We report the identification and field testing of the attractant volatiles from trumpet flowers, Brugmansia suaveolens (Willd.) Sweet (Solanaceae), for the beetle Cyclocephala paraguayensis Arrow (Melolonthidae: Dynastinae). Analysis of headspace floral volatiles revealed 19 compounds, from which eucalyptol (57%), methyl benzoate (16%), and ß-myrcene (6%) were present in the largest amounts, whereas E-nerolidol in much lesser amounts (1.8%). During a first-field assay, traps baited with Mebe alone or blended with the other two major compounds attracted more beetles than myrcene and eucalyptol alone, which did not differ from the negative controls. In a second assay, Mebe and nerolidol attracted more beetles as a blend than individually. Nerolidol was more attractive than Mebe, and all treatments attracted more beetles than negative controls. The number of attracted beetles in the Mebe-nerolidol blend was greater than the combined sum of beetles attracted to these compounds alone, suggesting a synergistic interaction. The attraction of C. paraguayensis by trumpet-flower volatiles supports the beetle's extended preference for sphingophilous plants, especially when cantharophilous (beetle-pollinated) flowers are lacking. This phenomenon, thus, might have contributed to the widespread occurrence of this beetle throughout the Brazilian biomes.

Modelling of immune response in chronic myeloid leukemia patients suggests potential for treatment reduction prior to cessation.

Introduction: Discontinuation of tyrosine kinase inhibitor (TKI) treatment is emerging as the main therapy goal for Chronic Myeloid Leukemia (CML) patients. The DESTINY trial showed that TKI dose reduction prior to cessation can lead to an increased number of patients achieving sustained treatment free remission (TFR). However, there has been no systematic investigation to evaluate how dose reduction regimens can further improve the success of TKI stop trials. Methods: Here, we apply an established mathematical model of CML therapy to investigate different TKI dose reduction schemes prior to therapy cessation and evaluate them with respect to the total amount of drug used and the expected TFR success. Results: Our systematic analysis confirms clinical findings that the overall time of TKI treatment is a major determinant of TFR success, while highlighting that lower dose TKI treatment for the same duration is equally sufficient for many patients. Our results further suggest that a stepwise dose reduction prior to TKI cessation can increase the success rate of TFR, while substantially reducing the amount of administered TKI. Discussion: Our findings illustrate the potential of dose reduction schemes prior to treatment cessation and suggest corresponding and clinically testable strategies that are applicable to many CML patients.

The Institute of Physical Medicine and Rehabilitation, Hospital das Clínicas University of São Paulo School of Medicine comprehensive rehabilitation program for elderly people with knee osteoarthritis.

Background: Knee osteoarthritis (OA) is a leading cause of disability in the elderly population. Chronic disabling pain is associated with maladaptive neuroplastic changes in brain networks, commonly associated with central sensitization. The main clinical features of nociplastic pain conditions include combined peripheral and central sensitization, and it is crucial to recognize this type of pain, as it responds to different therapies than nociceptive and neuropathic pain. Objective: To report the effect of the Institute of Physical Medicine and Rehabilitation (IMREA) comprehensive rehabilitation program to reduce pain and to improve functioning in elderly people with knee OA, under the DEFINE cohort. Methods: This is a retrospective observational cohort of 96 patients with knee OA, recruited from October 2018 to December 2019. All patients were evaluated by a trained multidisciplinary team using the Kellgren Lawrence classification, bilateral knee ultrasonography, the visual analog scale (VAS), the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain, rigidity and difficulty scores, the Timed Up and Go Test (TUG), 10-m and 6-min walking test (10 and 6 MWT), Berg Balance Scale, isokinetic dynamometry for knee extension and flexion strength, and pain pressure thresholds. The rehabilitation program included paraspinous lidocaine blocks, focal extracorporeal shockwaves combined with radial pressure waves and functional electrical stimulation according to individual needs. The baseline was compred with the treatment results with a paired t-test. Results: The study sample is composed of 96 participants, mostly females (n = 81, 84.38%), with bilateral osteoarthritis (n = 91, 94.79%), and a mean age of 68.89 (SD 9.73) years. Functional improvement was observed in TUG (p = 0.019), 6-mwt (p = 0.033), right knee flexion strength (p < 0.0001), WOMAC rigidity and difficulty domains (p < 0.0001). Pain was reduced from baseline as measured by WOMAC pain domain (p < 0.0001), VAS for both knees (p < 0.0001), and SF-36 pain domain (p < 0.0001). Pressure pain threshold was modified above the patella (p = 0.005 and p = 0.002 for right and left knees, respectively), at the patellar tendons (p = 0.015 and p = 0.010 for right and left patellar tendons, respectively), left S2 dermatome (p = 0.017), and L1-L2 (p = 0.008). Conclusions: The IMREA comprehensive rehabilitation program improved functioning and reduced disabling pain in elderly people with knee OA. We highlight the relevance and discuss the implementation of our intervention protocol. Although this is an open cohort study, it is important to note the significant improvement with this clinical protocol.

Modeling Patient-Specific CAR-T Cell Dynamics: Multiphasic Kinetics via Phenotypic Differentiation.

Chimeric Antigen Receptor (CAR)-T cell immunotherapy revolutionized cancer treatment and consists of the genetic modification of T lymphocytes with a CAR gene, aiming to increase their ability to recognize and kill antigen-specific tumor cells. The dynamics of CAR-T cell responses in patients present multiphasic kinetics with distribution, expansion, contraction, and persistence phases. The characteristics and duration of each phase depend on the tumor type, the infused product, and patient-specific characteristics. We present a mathematical model that describes the multiphasic CAR-T cell dynamics resulting from the interplay between CAR-T and tumor cells, considering patient and product heterogeneities. The CAR-T cell population is divided into functional (distributed and effector), memory, and exhausted CAR-T cell phenotypes. The model is able to describe the diversity of CAR-T cell dynamical behaviors in different patients and hematological cancers as well as their therapy outcomes. Our results indicate that the joint assessment of the area under the concentration-time curve in the first 28 days and the corresponding fraction of non-exhausted CAR-T cells may be considered a potential marker to classify therapy responses. Overall, the analysis of different CAR-T cell phenotypes can be a key aspect for a better understanding of the whole CAR-T cell dynamics.

Music appreciation phenotypes in patients with frontotemporal dementia: A pilot study.

OBJECTIVES: Frontotemporal dementia (FTD) can present with changes in music appreciation. Research has suggested a relationship of altered music appreciation phenotypes with typical socio-emotional changes. We aimed to determine the prevalence and severity of music appreciation phenotypes in FTD and study the relationship with emotion recognition capacities in order to examine whether they could serve as a proxy for changes in socio-emotional functioning. METHODS/DESIGN: Based on reported musical changes in the literature, we developed an informant-based questionnaire to assess musical changes and a music test to assess music emotion recognition. Social cognition was assessed with the Ekman 60 faces test in a subgroup of patients (n = 23). Relationships between measures were assessed with linear regressions. RESULTS: We included 47 patients (44.7% female, mean age 65.0 ± 8.4, 31 behavioral variant FTD (bvFTD), 10 semantic dementia (SD), and six progressive nonfluent aphasia (PNFA)). Thirty-six caregivers were included in the music emotion recognition test as controls. Altered music appreciation phenotypes were observed in 79% of the FTD patients. Musicophilia was present in a third of bvFTD patients, and only in up to 10% in language FTD variants. Changes in music appreciation were not associated with decreased music emotion recognition or visual emotion recognition. Compared to controls, bvFTD performed worse on the music emotion recognition task (p < 0.003), and no differences were found with SD (p = 0.06) and PNFA patients (p = 0.8). CONCLUSIONS: Music appreciation phenotypes are highly prevalent in FTD patients. Future studies should further investigate the potential diagnostic value of changes in music processing.

Circulating progesterone at insemination and accessory spermatozoa are associated with fertilization and embryo quality five or six days post insemination in dairy cattle.

This study aimed to evaluate animal and ovarian parameters that affected fertilization and embryo development up to the morula stage. The data were combined from four studies in which cows were inseminated between 46 and 60 days in milk, following a synchronization protocol, and flushed for embryo collection five or six days later. Parity and body condition score on the day of insemination were recorded. Cyclicity, ovarian structures, and circulating hormone concentrations before and on the day of insemination were also assessed. The recovered structures were graded on a 5-point scale (excellent-good quality, fair quality, poor quality, degenerated, and not fertilized). For recovered embryos, the total number of blastomeres, the number of nonviable blastomeres, and the number of accessory spermatozoa were assessed by epifluorescence microscopy. The risk factors for fertilization and embryo quality were identified using cumulative link mixed models. A total of 418 structures from 389 lactating Holstein cows (34% primiparous and 66% multiparous) were recovered. Thirty-five percent of the recovered structures were excellent-good quality embryos, 21% were fair quality embryos, 11% were poor quality embryos, 16% were degenerated embryos, and 17% were unfertilized oocytes. Structures from primiparous cows, from those with greater progesterone concentration at insemination, and from cows with seven or less accessory spermatozoa were less likely to be fertilized or of better quality than structures from multiparous cows, from those with lower progesterone concentration in plasma, and from those with more than seven accessory spermatozoa, respectively. Embryos with more blastomeres or without nonviable blastomeres were more likely to be of better quality than embryos with fewer blastomeres or with nonviable blastomeres. The results of this analysis highlight the importance of low circulating concentrations of progesterone near artificial insemination and potential positive association with number of accessory spermatozoa reaching the embryo and improvement of embryo development up to the morula stage.

Behavioral traits and sexual recognition: multiple signaling in the reproductive behavior of Cyclocephala distincta (Melolonthidae, Cyclocephalini).

Night-foraging cyclocephaline scarab beetles rely on floral structures of specific plant hosts for food and shelter, as well as mating sites. Although the role of floral fragrances as long-range attractants in these interactions has been elucidated, the mechanisms that mediate close-range mate discrimination in aggregations are still unclear. We recorded the mating-oriented behavior of male Cyclocephala distincta, focusing on the influence of contact signaling and movement over mate selection in a series of controlled bioassays. Roughly half of the males chose a conspecific female over another male, readily engaging in copulation upon initial contact. The remainder males required more experience, acquired through successive mounts on both females and males. Eventually, all focal males invested in copulation with females. When faced with the choice for a live or an inert conspecific female, male C. distincta preferred the former in 76% of cases, although we also recorded sexual investment on inert females (10% of cases). In paired experiments with an inert female or a male, nonetheless, focal males significantly opted for the opposite sex, and that included mating with the inert females. Innate characteristics of the females of C. distincta are evaluated by males synergistically, and not separately, in discriminating potential sexual partners.

Folate-Targeted PEGylated Magnetoliposomes for Hyperthermia-Mediated Controlled Release of Doxorubicin.

Doxorubicin (DOX) is a chemotherapeutic agent commonly used for the treatment of solid tumors. However, the cardiotoxicity associated with its prolonged use prevents further adherence and therapeutic efficacy. By encapsulating DOX within a PEGylated liposome, Doxil® considerably decreased DOX cardiotoxicity. By using thermally sensitive lysolipids in its bilayer composition, ThermoDox® implemented a heat-induced controlled release of DOX. However, both ThermoDox® and Doxil® rely on their passive retention in tumors, depending on their half-lives in blood. Moreover, ThermoDox® ordinarily depend on invasive radiofrequency-generating metallic probes for local heating. In this study, we prepare, characterize, and evaluate the antitumoral capabilities of DOX-loaded folate-targeted PEGylated magnetoliposomes (DFPML). Unlike ThermoDox®, DOX delivery via DFPML is mediated by the heat released through dynamic hysteresis losses from magnetothermal converting systems composed by MnFe2O4 nanoparticles (NPs) under AC magnetic field excitation-a non-invasive technique designated magnetic hyperthermia (MHT). Moreover, DFPML dismisses the use of thermally sensitive lysolipids, allowing the use of simpler and cheaper alternative lipids. MnFe2O4 NPs and DFPML are fully characterized in terms of their size, morphology, polydispersion, magnetic, and magnetothermal properties. About 50% of the DOX load is released from DFPML after 30 min under MHT conditions. Being folate-targeted, in vitro DFPML antitumoral activity is higher (IC50 ≈ 1 µg/ml) for folate receptor-overexpressing B16F10 murine melanoma cells, compared to MCF7 human breast adenocarcinoma cells (IC50 ≈ 4 µg/ml). Taken together, our results indicate that DFPML are strong candidates for folate-targeted anticancer therapies based on DOX controlled release.

Correlation of hair cortisol and interleukin 6 with structural change in the active progression of keratoconus.

PURPOSE: To evaluate interleukin (IL) and hair cortisol concentrations (HCCs) in progressive keratoconus (KC) and compare them with KC-stable eyes and healthy control, and to determine the correlation of these inflammatory mediators and HCCs and their relationship with structural damage represented by increased corneal curvature. SETTING: University of Sao Paulo, Brazil. DESIGN: Prospective observational comparative study. METHODS: 133 eyes of 74 patients were included. The concentrations of tear cytokines: IL1B, IL6, IL8, IL10, IL12p70, and tumor necrosis factor α were obtained by capillary flow and measured using a flow cytometer. HCCs were determined from the most proximal hair segment as an index of cumulative secretion and measured by liquid chromatography mass spectrometry. RESULTS: 133 eyes of 74 patients. Only IL6 was increased in progressive KC tears compared with stable KC (6.59 ± 3.25 pg/mL vs 4.72 ± 1.91 pg/mL; P < .0001) with a positive correlation between IL6 and maximum keratometry (Kmax) (P < .0001). Progressive KC exhibited significantly higher HCC than stable KC (0.624 ± 0.160 ng/mg vs 0.368 ± 0.0647 ng/mg; P < .0001) and healthy controls (0.624 ± 0.160 ng/mg vs 0.351 ± 0.0896 ng/mg; P < .0001). There was a significant correlation between HCC and Kmax (P < .0001). CONCLUSIONS: KC eyes that are progressing have a higher concentration of IL6 and long-term cortisol than patients with stable forms of KC; second, there is a significant correlation between this increase in IL6 and cortisol with corneal structural damage. Finally, there is a meaningful relationship between this interleukin and the previous few months' cortisol levels.

Milk lymphocyte profile and macrophage functions: new insights into the immunity of the mammary gland in quarters infected with Corynebacterium bovis.

BACKGROUNDS: The present study explored the viability of bovine milk macrophages, their intracellular production of reactive oxygen and nitrogen species (RONS), and their phagocytosis of Staphylococcus aureus, as well as the profile of lymphocytes, from healthy udder quarters and udder quarters infected by Corynebacterium bovis. The study included 28 healthy udder quarters from 12 dairy cows and 20 udder quarters infected by C. bovis from 10 dairy cows. The percentages of macrophages and lymphocytes were identified by flow cytometry using monoclonal antibodies. Macrophage viability, RONS production, and S. aureus phagocytosis were evaluated by flow cytometry. RESULTS: Milk samples from quarters infected with C. bovis showed a lower percentage of macrophages but an increased number of milk macrophages per mL and a higher percentage of macrophages that produced intracellular RONS and phagocytosed S. aureus. No effect of C. bovis infection on macrophage viability was found. Udder quarters infected by C. bovis showed a higher percentage of T cells and CD4+ T lymphocytes, but no effect was found on the percentage of CD8+ CD4- T, CD8- CD4- T, or B lymphocytes. CONCLUSIONS: Thus, our results corroborate, at least in part, the finding that intramammary infections by C. bovis may offer protection against intramammary infections by major pathogens.

Maternal Anxiety, Infant Stress, and the Role of Live-Performed Music Therapy during NICU Stay in The Netherlands.

Having an infant in the neonatal intensive care unit (NICU) elicits maternal anxiety, which may hamper parent-child bonding. We performed a prospective cohort study to describe anxiety in mothers of infants born before 30 weeks of gestation during NICU stay in The Netherlands, and investigated the influence of infant stress and gestational age. Second, we performed a randomized-controlled live-performed music therapy trial (LPMT trial) to investigate whether music therapy applied to the infant alleviated maternal anxiety. The relation between infant stress, gestational age, and maternal anxiety was measured in 45 mother-infant dyads, using the Neonatal Infant Stressor Scale and the State-Trait Anxiety Inventory (STAI). The effect of LPMT on anxiety was assessed in 21 mothers whose infants were assigned to either LPMT (n = 12) or waitlist (n = 9). Mothers completed the STAI before and after this period. Maternal anxiety decreased over time in all mothers, and was strongly related with infant stress (r = 0.706, p < 0.001), but not with gestational age. Anxiety scores decreased by 12% after LMPT, and increased by 1% after a waitlist period (p = 0.30). Our results indicate that LPMT in the weeks after birth may accelerate the reduction of maternal anxiety. Further research should focus on the effects on mother-child bonding.

Combining Kangaroo Care and Live-Performed Music Therapy: Effects on Physiological Stability and Neurological Functioning in Extremely and Very Preterm Infants.

Interventions such as kangaroo care (KC) and live-performed music therapy (LPMT), are increasingly used to facilitate stress reduction in neonates. This study aims to investigate the effect of combining the two on physiological responses and neurological functioning in very preterm infants. Infants received six sessions of LPMT. KC was added to one LPMT session. Physiological responses included heart rate, respiratory rate and oxygen saturation. We videotaped infants for 30 min before and after two sessions to assess general movements (GMs). We included 17 infants, gestational age median 26.0 weeks (IQR 25.6-30.6 weeks), of whom six were males. Combined interventions showed a decrease in heart rate from mean 164 bpm before to 157 bpm during therapy, p = 0.001. Oxygen saturation levels increased during combination therapy from median 91.4% to 94.5%, p = 0.044. We found no effects of LPMT or combined interventions on GMs. Infants with a postnatal age (PNA) <7 days generally seem to display less optimal GMs after therapy compared with infants with a PNA >7 days. In conclusion, combining interventions is equally beneficial for physiological stability and neurological functioning as LPMT alone. Future studies should focus on the effects of this combination on parent-infant bonding.

CARTmath-A Mathematical Model of CAR-T Immunotherapy in Preclinical Studies of Hematological Cancers.

Immunotherapy has gained great momentum with chimeric antigen receptor T cell (CAR-T) therapy, in which patient's T lymphocytes are genetically manipulated to recognize tumor-specific antigens, increasing tumor elimination efficiency. In recent years, CAR-T cell immunotherapy for hematological malignancies achieved a great response rate in patients and is a very promising therapy for several other malignancies. Each new CAR design requires a preclinical proof-of-concept experiment using immunodeficient mouse models. The absence of a functional immune system in these mice makes them simple and suitable for use as mathematical models. In this work, we develop a three-population mathematical model to describe tumor response to CAR-T cell immunotherapy in immunodeficient mouse models, encompassing interactions between a non-solid tumor and CAR-T cells (effector and long-term memory). We account for several phenomena, such as tumor-induced immunosuppression, memory pool formation, and conversion of memory into effector CAR-T cells in the presence of new tumor cells. Individual donor and tumor specificities are considered uncertainties in the model parameters. Our model is able to reproduce several CAR-T cell immunotherapy scenarios, with different CAR receptors and tumor targets reported in the literature. We found that therapy effectiveness mostly depends on specific parameters such as the differentiation of effector to memory CAR-T cells, CAR-T cytotoxic capacity, tumor growth rate, and tumor-induced immunosuppression. In summary, our model can contribute to reducing and optimizing the number of in vivo experiments with in silico tests to select specific scenarios that could be tested in experimental research. Such an in silico laboratory is an easy-to-run open-source simulator, built on a Shiny R-based platform called CARTmath. It contains the results of this manuscript as examples and documentation. The developed model together with the CARTmath platform have potential use in assessing different CAR-T cell immunotherapy protocols and its associated efficacy, becoming an accessory for in silico trials.

Frontotemporal dementia, music perception and social cognition share neurobiological circuits: A meta-analysis.

Frontotemporal dementia (FTD) is a neurodegenerative disease that presents with profound changes in social cognition. Music might be a sensitive probe for social cognition abilities, but underlying neurobiological substrates are unclear. We performed a meta-analysis of voxel-based morphometry studies in FTD patients and functional MRI studies for music perception and social cognition tasks in cognitively normal controls to identify robust patterns of atrophy (FTD) or activation (music perception or social cognition). Conjunction analyses were performed to identify overlapping brain regions. In total 303 articles were included: 53 for FTD (n = 1153 patients, 42.5% female; 1337 controls, 53.8% female), 28 for music perception (n = 540, 51.8% female) and 222 for social cognition in controls (n = 5664, 50.2% female). We observed considerable overlap in atrophy patterns associated with FTD, and functional activation associated with music perception and social cognition, mostly encompassing the ventral language network. We further observed overlap across all three modalities in mesolimbic, basal forebrain and striatal regions. The results of our meta-analysis suggest that music perception and social cognition share neurobiological circuits that are affected in FTD. This supports the idea that music might be a sensitive probe for social cognition abilities with implications for diagnosis and monitoring.