Search

Abstract Various animal and plant species exhibit allometric relationships among their respective traits, wherein one trait undergoes expansion as a power-law function of another due to constraints acting on growth processes. For instance, the acknowledged consensus posits that tree height scales with the two-thirds power of stem diameter. In the context of human development, it is posited that body weight scales with the second power of height. This prevalent allometric relationship derives its nomenclature from fitting two variables linearly within a logarithmic framework, thus giving rise to the term “power-law relationship.” Here, we challenge the conventional assumption that a singular power-law equation adequately encapsulates the allometric relationship between any two traits. We strategically leverage quantile regression analysis to demonstrate that the scaling exponent characterizing this power-law relationship is contingent upon the centile within these traits’ distributions. This observation fundamentally underscores the proposition that individuals occupying disparate segments of the distribution may employ distinct growth strategies, as indicated by distinct power-law exponents. We introduce the innovative concept of “multi-scale allometry” to encapsulate this newfound insight. Through a comprehensive reevaluation of (i) the height-weight relationship within a cohort comprising 7, 863, 520 Japanese children aged 5–17 years for which the age, sex, height, and weight were recorded as part of a national study, (ii) the stem-diameter-height and crown-radius-height relationships within an expansive sample of 498, 838 georeferenced and taxonomically standardized records of individual trees spanning diverse geographical locations, and (iii) the brain-size-body-size relationship within an extensive dataset encompassing 1, 552 mammalian species, we resolutely substantiate the viability of multi-scale allometric analysis. This empirical substantiation advocates a paradigm shift from uni-scaling to multi-scaling allometric modeling, thereby affording greater prominence to the inherent growth processes that underlie the morphological diversity evident throughout the living world.

AbstractAccruals are regarded as investments in working capital and are an integral component in the growth process of firms. By assuming asymmetry of information among investors when predicting the returns on such investments, investors are exposed to adverse selection problems. Consequently, in market equilibrium, investors are believed to require compensation for the systematic risk associated with adverse selection exposure. By constructing the accruals factor as a variable to proxy for such risks, this study demonstrates that the accruals factor is priced and can enhance existing asset pricing models. Moreover, categorizing accruals into discretionary and non-discretionary components and constructing accruals factors from these components yields similar results. When the discretion of managers or market environment increases the degree of asymmetric information, adverse selection problems become more pronounced. Therefore, the accruals factor, serving as a proxy for the systematic risk associated with adverse selection, is an essential risk factor in asset pricing models.

ABSTRACT OBJECTIVE To confirm the diagram of the program’s impact pathways and Estratégia Amamenta e Alimenta Brasil (EAAB - Brazilian Breastfeeding and Complementary Feeding Strategy) core functions, and to determine indicators for evaluating EAAB. METHODS This is a qualitative study within the field of implementation research. Data collection included two focus groups with EAAB implementers, document analysis, and literature review. The analysis included a review of the participants’ suggestions and two stages of reviewing the diagram and the names of the impact pathways and core functions. Questions for evaluating the EAAB were then constructed based on the confirmed diagram. The indicators of the RE-AIM framework (reach, effectiveness, adoption, implementation, maintenance) were adapted to the EAAB context. The evaluation questions were revised according to the RE-AIM domains and, finally, indicators were determined for each evaluation question. RESULTS This study advanced the analysis of EAAB implementation, defining 22 indicators for its monitoring and evaluation. Most of the indicators are already used in implementation, however, the analysis with the RE-AIM framework allowed the indicators to be updated to be more specific, measurable, and relevant to the desired objectives. CONCLUSION The results of the study support the pragmatic application of RE-AIM evaluation in health programs and encourage the planning of evaluation indicators for other child health and development programs in primary care.

Abstract Background Phosphoinositide 3-kinases (PI3Ks) are critical regulators of diverse cellular functions and have emerged as promising targets in cancer therapy. Despite significant progress, existing PI3K inhibitors encounter various challenges such as suboptimal bioavailability, potential off-target effects, restricted therapeutic indices, and cancer-acquired resistance. Hence, novel inhibitors that overcome some of these challenges are needed. Here, we describe the characterization of KTC1101, a novel pan-PI3K inhibitor that simultaneously targets tumor cell proliferation and the tumor microenvironment. Our studies demonstrate that KTC1101 significantly increases the anti-PD-1 efficacy in multiple pre-clinical mouse models. Methods KTC1101 was synthesized and characterized employing chemical synthesis, molecular modeling, Nuclear Magnetic Resonance (NMR), and mass spectrometry. Its target specificity was confirmed through the kinase assay, JFCR39 COMPARE analysis, and RNA-Seq analysis. Metabolic stability was verified via liver microsome and plasma assays, pharmacokinetics determined by LC–MS/MS, and safety profile established through acute toxicity assays to determine the LD50. The antiproliferative effects of KTC1101 were evaluated in a panel of cancer cell lines and further validated in diverse BALB/c nude mouse xenograft, NSG mouse xenograft and syngeneic mouse models. The KTC1101 treatment effect on the immune response was assessed through comprehensive RNA-Seq, flow cytometry, and immunohistochemistry, with molecular pathways investigated via Western blot, ELISA, and qRT-PCR. Results KTC1101 demonstrated strong inhibition of cancer cell growth in vitro and significantly impeded tumor progression in vivo. It effectively modulated the Tumor Microenvironment (TME), characterized by increased infiltration of CD8+ T cells and innate immune cells. An intermittent dosing regimen of KTC1101 enhanced these effects. Notably, KTC1101 synergized with anti-PD-1 therapy, significantly boosting antitumor immunity and extending survival in preclinical models. Conclusion KTC1101's dual mechanism of action—directly inhibiting tumor cell growth and dynamically enhancing the immune response— represents a significant advancement in cancer treatment strategies. These findings support incorporating KTC1101 into future oncologic regimens to improve the efficacy of immunotherapy combinations.

Introduction: The Breastfeeding Support Room is part of the Working Women's Breastfeeding Action and is an important strategy to increase breastfeeding rates. Objective: To identify the profile and breastfeeding practices of women employees who attended Breastfeeding Support Rooms. Methods: A cross-sectional research was conducted through convenience sampling of women working in companies with breastfeeding support rooms. A semi-structured questionnaire was applied through interviews and online self-completion. The association between the duration of breastfeeding and time of room use with socioeconomic variables and company characteristics was analyzed using Fisher's exact test. A significance level of 5% was considered. Results: 87% of the women breastfed exclusively for 6 months; 60.3% had an undergraduate or graduate degree; 66% breastfed throughout their child's second year of life; 41% used their company's Breastfeeding Support Room for 5 to 10 months and 100% of women had six months' maternity leave. Women who were married or in a civil union (96%) received the most support to continue breastfeeding after returning to work (p=0.03). Conclusion: This data can be used to propose improvements to this strategy or subsidize a large-scale expansion of Breastfeeding Support Rooms. It is imperative to reflect upon future actions so that these rooms reach a higher number of attendees.

Abstract Interference in cell cycle progression has been noted as one of the important properties of anticancer drugs. In this study, we developed the cell cycle prediction model using high‐content imaging data of recipient cells after drug exposure and DNA‐staining with a low‐toxic DNA dye, SiR‐DNA. For this purpose, we exploited HeLa and MCF7 cells introduced with a fluorescent ubiquitination‐based cell cycle indicator (Fucci). Fucci‐expressing cancer cells were subjected to high‐content imaging analysis using OperettaCLS after 36‐h exposure to anticancer drugs; the nuclei were segmented, and the morphological and intensity properties of each nucleus characterized by SiR‐DNA staining were calculated using imaging analysis software, Harmony. For the use of training, we classified cells into each phase of the cell cycle using the Fucci system. Training data (n = 7500) and validation data (n = 2500) were randomly sampled and the binary classification prediction models for G1, early S, and S/G2/M phases of the cell cycle were developed using four supervised machine learning algorithms. We selected random forest as the model with the best performance through 10‐fold cross‐validation; the accuracy rate was approximately 75%–87%. Regarding feature importance, variables expected to be biologically related to the cell cycle, for example, signal intensity and nuclear size, were highly ranked, suggesting the validity of the model. These results showed that the cell cycle can be predicted in cancer cells by simply exploiting the current prediction model using fluorescent images of DNA‐staining dye, and the model could be applied for the use of future ex vivo drug sensitivity diagnosis.

BackgroundPrecision in evaluating underweight and overweight status among children and adolescents is paramount for averting health and developmental issues. Existing standards for these assessments have faced scrutiny regarding their validity. This study investigates the age and height dependencies within the international standards set by the International Obesity Task Force (IOTF), relying on body mass index (BMI), and contrasts them with Japanese standards utilizing the percentage of overweight (POW).MethodWe scrutinized a comprehensive database comprising 7,863,520 children aged 5–17 years, sourced from the School Health Statistics Research initiative conducted by Japan's Ministry of Education, Culture, Sports, Science, and Technology. Employing the quantile regression method, we dissected the structure of weight-for-height distributions across different ages and sexes, quantifying the potentially biased assessments of underweight and overweight status by conventional criteria.ResultsApplying IOFT criteria for underweight assessment revealed pronounced height dependence in males aged 11–13 and females aged 10–11. Notably, a discernible bias emerged, wherein children in the lower 25th percentile were classified as underweight five times more frequently than those in the upper 25th percentile. Similarly, the overweight assessment displayed robust height dependence in males aged 8–11 and females aged 7–10, with children in the lower 25th percentile for height deemed obese four or five times more frequently than their counterparts in the upper 25th percentile. Furthermore, using the Japanese POW criteria for assessment revealed significant age dependence in addition to considerably underestimating the percentage of underweight and overweight cases under the age of seven. However, the height dependence for the POW criterion was smaller than the BMI criterion, and the difference between height classes was less than 3-fold.ConclusionOur findings underscore the intricacies of age-dependent changes in body composition during the growth process in children, emphasizing the absence of gold standards for assessing underweight and overweight. Careful judgment is crucial in cases of short or tall stature at the same age, surpassing sole reliance on conventional criteria results.

The body mass index (BMI), defined as weight in kilograms divided by height in meters squared, has been widely used to assess thinness and obesity in all age groups, including children and adolescents. However, the validity and utility of BMI as a reliable measure of nutritional health have been questioned. This study discusses the mathematical conditions that support the validity of BMI based on population statistics. Here, we propose a condition defined as allometric uni-scaling to ensure the validity of BMI as an objective height-adjusted measure. Any given centile curve, including the median curve, in a weight-for-height distribution should be approximated using power-law functions with the same scaling exponent. In contrast, when the scaling exponent varies depending on the position of the centile curve, it is called allometric multi-scaling. By introducing a method for testing these scaling properties using quantile regression, we analyzed a large-scale Japanese database that included 7,863,520 children aged 5-17 years. We demonstrated the remarkable multi-scaling properties at ages 5-13 years for males and 5-11 years for females, and the convergence to uni-scaling with a scaling exponent close to 2 as they approached 17 years of age for both sexes. We confirmed that conventional BMI is appropriate as an objective height-adjusted mass measure at least 17 years of age, close to adulthood, for both males and females. However, the validity of BMI could not be confirmed in younger age groups. Our findings indicate that the growth of children's weight-for-height relation is much more complex than previously assumed. Therefore, a single BMI-type formula cannot be used to assess thinness and obesity in children and adolescents.

Resumo Objetivo Mapear sistematicamente as pesquisas de implementação com foco em intervenções voltadas ao desenvolvimento na primeira infância, suas principais características e estratégias de implementação. Métodos Uma revisão de escopo da literatura global foi planejada e executada conforme as recomendações do Instituto Joanna Briggs. A busca foi realizada em nove bases eletrônicas (PubMed, Scopus, Embase, Health System Evidence, Social Systems Evidence, Cochrane, ERIC e CINHAL e BVS), do início da indexação até agosto de 2021. Resultados As buscas mapearam 4.105 referências, sendo 2.805 únicas. Após triagem, 211 estudos foram lidos na íntegra e 82 incluídos. O setor saúde foi o mais frequente nas intervenções, seguido da educação e serviço social. Programas voltados ao desenvolvimento infantil e estratégias focadas na parentalidade, família, nutrição, foram principais intervenções. No total, 89,0% apresentaram as crianças como beneficiárias diretas das estratégias. A duração média das intervenções foi de 14,5 meses e 25,6% dos estudos fundamentaram sua metodologia em frameworks para analisar a implementação das intervenções. A metade analisou adaptações das intervenções ou programas, enquanto 29,3% citaram aspectos de equidade da implementação. Conclusão Esta revisão de escopo permitiu a análise de um conjunto de intervenções voltadas à primeira infância, demonstrando o potencial das pesquisas de implementação de programas de desenvolvimento da primeira infância, identificando estratégias mais adequadas aos contextos e o alcance dos objetivos pretendidos, a partir da incorporação dos desfechos de implementação.

Summary: Background: In 2016, Brazil scaled up the Criança Feliz Program (PCF, from the acronym in Portuguese), making it one of the largest Early Childhood Development (ECD) programs worldwide. However, the PCF has not been able to achieve its intended impact. We aimed to identify barriers and facilitators to achieving the PCF implementation outcomes across the RE-AIM dimensions (Reach, Effectiveness or Efficacy, Adoption, Implementation and Maintenance) during the COVID-19 pandemic. Methods: This comparative case study analysis selected five contrasting municipalities based on population size, region of the country, implementation model, and length of time implementing the PCF. We conducted 244 interviews with PCF municipal team (municipal managers, supervisors, home visitors), families, and cross-sectoral professionals. A rapid qualitative analysis was used to identify themes across RE-AIM dimensions. Findings: Families’ limited knowledge and trust in PCF goals were a barrier to its reach. While the perceived benefit of PCF on parenting skills and ECD enabled reach, the lack of referral protocols to address social needs, such as connecting food-insecure families to food resources, undermined effectiveness. Questions about whether the social assistance sector should be in charge of PCF challenged its adoption. Implementation barriers exacerbated by the COVID-19 pandemic included low salaries, temporary contracts, high turnover, infrequent supervision, lack of an effective monitoring system, and nonexistence or non-functioning multisectoral committees. The absence of institutionalized funding was a challenge for sustainability. Interpretation: Complex intertwined system-level barriers may explain the unsuccessful implementation of PCF. These barriers must be addressed for Brazil to benefit from the enormous reach of the PCF and the evidence-based nurturing care principles it is based upon. Funding: NIH/NICHD.

Abstract Martensitic crystal structures are usually obtained by rapid thermal quenching of certain alloys, which induces stress and subsequent shear deformation. Here, we demonstrate that it is also possible to intentionally excite a suitable transverse acoustic phonon mode to induce a local shear deformation. We irradiate the surface of a partially stabilized zirconia plate with intense terahertz pulses and verify martensitic transformation from the tetragonal to the monoclinic phases by Raman spectroscopy and the observed destructive spallation of the zirconia microcrystals. We calculate the phonon modes in tetragonal zirconia and determine the decay channel that triggers the transformation. The phonon mode required for the martensitic transformation can be excited via the Klemens process. Since terahertz pulses can induce a specific local shear deformation beyond thermal equilibrium, they can be used to elucidate phase transformation mechanisms with approaches based on nonlinear phononics.

Abstract: Malnutrition in all its forms has risen on global agendas due to the recognition of its magnitude and consequences for a wide range of human, social, and economic outcomes. Implementing strategies and programs with the needed scale and quality is a major challenge. The Brazilian National Survey on Child Nutrition (ENANI-2019) pointed out several advances but numerous challenges. In this paper, we reflect on the implementation progress of breastfeeding, complementary feeding and young children malnutrition strategies and programs in Brazil and how existing challenges can be overcome through the lens of implementation science. First, we present a brief history of such programs. Second, we selected two breastfeeding initiatives to illustrate and reflect on common implementation challenges. In these case studies, we used the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework to analyze the implementation and scaling up barriers and facilitators. We found common barriers related to unclear goals about the reach of programs, challenges in assessing effectiveness and fidelity/quality during the real-world implementation, discontinuation or lack of funding, and lack of monitoring and evaluation impacting the sustainability of programs. We also discuss the use of implementation science to achieve adequate nutrition by 2030 and present critical elements for successful scale implementation of nutrition programs based on global evidence. Despite the investment to implement different actions aimed at facing infant feeding and malnutrition, high-quality implementation research must become a priority to catalyze progress in Brazil.

BACKGROUND: Maternal dietary exposures are considered to influence the development of infant allergies through changes in the composition of breast milk. Cohort studies have shown that ω3 polyunsaturated fatty acids (PUFAs) in breast milk may have a beneficial effect on the preventing of allergies in infants; however, the underlying mechanisms remain to be investigated. We investigated how the maternal intake of dietary ω3 PUFAs affects fatty acid profiles in the breast milk and their pups and reduced the incidence of allergic diseases in the pups. METHODS: Contact hypersensitivity (CHS) induced by 2,4-dinitrofluorobenzene (DNFB) and fluorescein isothiocyanate was applied to the skin in pups reared by mother maintained with diets mainly containing ω3 or ω6 PUFAs. Skin inflammation, immune cell populations, and expression levels of immunomodulatory molecules in pups and/or human cell line were investigated by using flow cytometric, immunohistologic, and quantitative RT-PCR analyses. ω3 PUFA metabolites in breast milk and infants serum were evaluated by lipidomics analysis using LC-MS/MS. RESULTS: We show that maternal intake of linseed oil, containing abundant ω3 α-linolenic acid, resulted in the increased levels of ω3 docosapentaenoic acid (DPA) and its 14-lipoxygenation products in the breast milk of mouse dams; these metabolites increased the expression of TNF-related apoptosis-inducing ligand (TRAIL) on plasmacytoid dendritic cells (pDCs) in their pups and thus inhibited infant CHS. Indeed, the administration of DPA-derived 14-lipoxygenation products to mouse pups ameliorated their DNFB CHS. CONCLUSION: These findings suggest that an inhibitory mechanism in infant skin allergy is induced through maternal metabolism of dietary ω3 PUFAs in mice.

Abstract Background One cause of the increase in cervical cancer rates in Japan is the long-term stagnation in the cervical cancer screening consultation rate. Therefore, improving the screening consultation rate is of urgent concern to reduce cervical cancer incidence. Self-collected human papilloma virus (HPV) tests have been successfully adopted in several countries, such as the Netherlands and Australia, as a measure of individuals who have not undergone cervical cancer screening in national programs. This study aimed to verify whether self-collected HPV tests presented an effective countermeasure for individuals who had not undergone the recommended cervical cancer screenings. Methods This study was conducted from December 2020 to September 2022 in Muroran City, Japan. The primary evaluated endpoint was the percentage of citizens who underwent cervical cancer screening at a hospital with positive self-collected HPV test results. The secondary endpoint was the percentage of included participants who were diagnosed with cervical intraepithelial neoplasia (CIN) or higher among those who visited a hospital and underwent cervical cancer screening. Results The included study participants were 7,653 individuals aged 20–50 years with no record of previous cervical cancer examination in the past 5 years. We mailed these participants information on self-administered HPV tests as an alternative screening procedure and sent the kit to 1,674 women who requested the test. Among them, 953 returned the kit. Among the 89 HPV-positive individuals (positive rate, 9.3%), 71 (79.8%) visited the designated hospital for an examination. A closer examination revealed that 13 women (18.3% of hospital visits) had a CIN finding of CIN2 or higher, among whom one each had cervical cancer and vulvar cancer, eight presented with CIN3, and three presented with CIN2; two cases of invasive gynecologic cancer were also identified. Conclusions We conclude that the self-collected HPV tests showed a certain efficacy as a measure of individuals who had not undergone the recommended cervical cancer screening. We devised ways to have the unexamined patients undergo HPV testing and ensure that HPV-positive individuals visited the hospital. Despite a few limitations, our findings suggest the effectiveness of this public health intervention.

Abstract Translocation-related sarcomas (TRSs) harbor an oncogenic fusion gene generated by chromosome translocation and account for approximately one-third of all sarcomas; however, effective targeted therapies have yet to be established. We previously reported that a pan-phosphatidylinositol 3-kinase (PI3K) inhibitor, ZSTK474, was effective for the treatment of sarcomas in a phase I clinical trial. We also demonstrated the efficacy of ZSTK474 in a preclinical model, particularly in cell lines from synovial sarcoma (SS), Ewing’s sarcoma (ES) and alveolar rhabdomyosarcoma (ARMS), all of which harbor chromosomal translocations. ZSTK474 selectively induced apoptosis in all these sarcoma cell lines, although the precise mechanism underlying the induction of apoptosis remained unclear. In the present study, we aimed to determine the antitumor effect of PI3K inhibitors, particularly with regards to the induction of apoptosis, against various TRS subtypes using cell lines and patient-derived cells (PDCs). All of the cell lines derived from SS (six), ES (two) and ARMS (one) underwent apoptosis accompanied by the cleavage of poly-(ADP-ribose) polymerase (PARP) and the loss of mitochondrial membrane potential. We also observed apoptotic progression in PDCs from SS, ES and clear cell sarcoma (CCS). Transcriptional analyses revealed that PI3K inhibitors triggered the induction of PUMA and BIM and the knockdown of these genes by RNA interference efficiently suppressed apoptosis, suggesting their functional involvement in the progression of apoptosis. In contrast, TRS-derived cell lines/PDCs from alveolar soft part sarcoma (ASPS), CIC-DUX4 sarcoma and dermatofibrosarcoma protuberans failed to undergo apoptosis nor induce PUMA and BIM expression, as well as cell lines derived from non-TRSs and carcinomas. Thus, we conclude that PI3K inhibitors induce apoptosis in selective TRSs such as ES and SS via the induction of PUMA and BIM and the subsequent loss of mitochondrial membrane potential. This represents proof of concept for PI3K-targeted therapy, particularly such TRS patients.