Early Development Research Articles

The projected global burden of modifiable risk factors on cardiovascular disease from 2025 to 2100

Abstract Background Cardiovascular diseases (CVDs) are the primary cause of global mortality and morbidity. Controlling modifiable risk factors driving the CVD epidemic is a vital focus of primary prevention efforts worldwide. Understanding the epidemiological trends in these risk factors is therefore essential in designing effective countermeasures against CVDs for the years to come. Purpose This study aims to forecast the disability-adjusted life years (DALYs) associated with CVDs attributable to high systolic blood pressure (SBP), high body-mass index (BMI), high fasting plasma glucose (FPG), high low-density lipoprotein (LDL) and tobacco use from 2025 to 2100, stratified by GBD super-regions, sex, sociodemographic index (SDI), and age-groups. Methods Historical data on DALYs from 1990 to 2019 from the Global Burden of Disease (GBD) study was used to project DALYs associated with modifiable risk factors of CVDs from 2025 to 2100. Trends across GBD super-regions, sex, SDI, and age-groups were also examined. Results Between 2025 and 2100, age-standardised DALY rates (ASDR) per 100,000 population are forecasted to fall across all modifiable risk factors, with the greatest decline seen in tobacco use (-76.0%) and high LDL (-66.9%). Globally, high SBP and high BMI expect the greatest ASDR in 2100 (both 891 per 100,000 population), while tobacco use expects the least (213 per 100,000 population). High BMI is expected to rise 623.0% in South Asia and 221.5% in South-east Asia, East Asia and Oceania from 2025 to 2100, while high FPG is expected to rise 114.2% in North Africa and the Middle-east and 110.6% in South Asia. Females are expected to have lower overall and greater reductions in ASDR across all modifiable risk factors when compared to males from 2025 to 2100. Notably, males expect a 11.0% rise in high BMI worldwide across this period. The age-prevalence of modifiable risk factors is expected to be bimodal in 2100, highest in those aged 50-59 as well as 75-84 years old, possibly suggesting improvements in global screening efforts or the earlier development of metabolic dysfunction. All modifiable risk factors are predicted to fall in high and high-middle SDI regions from 2025 to 2100. In contrast, low, low-middle, and middle SDI regions expect a rise in high FPG and high BMI across this same time frame. The burden of modifiable CVD risk factors is expected to be highest in low-middle SDI regions in 2100, as compared to high-middle SDI regions in 2025. Conclusion While the global decline in ASDR of modifiable risk factors suggests overall improvements in the primary prevention of CVDs, regional spikes in high BMI and FPG calls for the implementation of timely, targeted interventions accounting for local trends in CVD. Moreover, the disproportionate metabolic burden expected in lower SDI regions in the coming decades requires concerted, international support to alleviate the global burden of CVDs.

Affinity hierarchies and amphiphilic proteins underlie the co-assembly of nucleolar and heterochromatin condensates.

Nucleoli are surrounded by Pericentromeric Heterochromatin (PCH), reflecting a close spatial association between the two largest biomolecular condensates in eukaryotic nuclei. Nucleoli are the sites of ribosome synthesis, while the repeat-rich PCH is essential for chromosome segregation, genome stability, and transcriptional silencing. How and why these two distinct condensates co-assemble is unclear. Here, using high-resolution live imaging of Drosophila embryogenesis, we find that de novo establishment of PCH around the nucleolus is highly dynamic, transitioning from the nuclear edge to surrounding the nucleolus. Eliminating the nucleolus by removing the ribosomal RNA genes (rDNA) resulted in increased PCH compaction and subsequent reorganization into a toroidal structure. In addition, in embryos lacking rDNA, some nucleolar proteins were redistributed into new bodies or 'neocondensates', including enrichment in the PCH toroidal hole. Combining these observations with physical modeling revealed that nucleolar-PCH associations can be mediated by a hierarchy of interaction strengths between PCH, nucleoli, and 'amphiphilic' protein(s) that have affinities for both nucleolar and PCH components. We validated this model by identifying a candidate amphiphile, a DEAD-Box RNA Helicase called Pitchoune, whose depletion or mutation of its PCH interaction motif disrupted PCH-nucleolar associations. Together, this study unveils a dynamic program for establishing nucleolar-PCH associations during animal development, demonstrates that nucleoli are required for normal PCH organization, and identifies Pitchoune as an amphiphilic molecular link required for PCH-nucleolar associations.

Developmental trends in corpus callosum thickness among preschool children

BackgroundThe corpus callosum plays a crucial role in integrated brain functions, and its development in childhood is strongly associated with subsequent cognitive, emotional, and behavioral development. However, there is still a lack of clear understanding regarding the developmental trends of the corpus callosum in preschool children. This study aims to comprehensively investigate age and sex differences in the thickness of the corpus callosum in typical developing children between 1 and 6 years old. MethodsT1-weighted structural MRI data were collected from a sample of 295 neurologically normal children aged 1–6 years. Utilizing the specialized corpus callosum segmentation software Yuki, thickness measurements of the mid-sagittal plane of the corpus callosum were obtained. ResultsThe anterior part exhibited faster growth compared to the middle and posterior sections, while growth at the extremities was not statistically significant. Furthermore, gender differences were identified, with males showing earlier development of the corpus callosum, particularly between ages 1 and 3. Conversely, females exhibited the most notable increase in thickness between ages 3 and 5. ConclusionThis study provides significant insights into the developmental trends of the mid-sagittal plane of the corpus callosum in preschool children. It reveals distinct non-linear developmental patterns in different sections of the corpus callosum and highlights the influence of sex on these developmental patterns.

Governance structure, organizational form, and business performance: A study of the Shanxi piaohao (banks), 1820s–1930s

This paper studies Shanxi piaohao, China’s first and largest private remittance banking group, established by a group of merchants from Shanxi province. Drawing on extensive primary sources, our study offers the first empirical analysis of the piaohao’s business organisation and performance. We show that piaohao thrived but were also constrained by their own private rules. In their earlier development, they successfully overcame the commitment problem by implementing a townsmen-guarantor-based recruitment system, a centralised M-form structure, and a multilateral punishment mechanism. To align the interests of shareholders and employees, they created employment shareholders and offered a competitive compensation scheme. However, piaohao’s governance structure became obsolete as shareholders increasingly failed to monitor head managers in the later period. A drastic increase in business volume and a changing business climate also exposed the defects of a centralised structure. As modern Chinese banks rose to prominence, the piaohao were gradually outcompeted and declined.

OVO positively regulates essential maternal pathways by binding near the transcriptional start sites in the Drosophila female germline.

Differentiation of female germline stem cells into a mature oocyte includes the expression of RNAs and proteins that drive early embryonic development in Drosophila. We have little insight into what activates the expression of these maternal factors. One candidate is the zinc-finger protein OVO. OVO is required for female germline viability and has been shown to positively regulate its own expression, as well as a downstream target, ovarian tumor, by binding to the transcriptional start site (TSS). To find additional OVO targets in the female germline and further elucidate OVO's role in oocyte development, we performed ChIP-seq to determine genome-wide OVO occupancy, as well as RNA-seq comparing hypomorphic and wild type rescue ovo alleles. OVO preferentially binds in close proximity to target TSSs genome-wide, is associated with open chromatin, transcriptionally active histone marks, and OVO-dependent expression. Motif enrichment analysis on OVO ChIP peaks identified a 5'-TAACNGT-3' OVO DNA binding motif spatially enriched near TSSs. However, the OVO DNA binding motif does not exhibit precise motif spacing relative to the TSS characteristic of RNA polymerase II complex binding core promoter elements. Integrated genomics analysis showed that 525 genes that are bound and increase in expression downstream of OVO are known to be essential maternally expressed genes. These include genes involved in anterior/posterior/germ plasm specification (bcd, exu, swa, osk, nos, aub, pgc, gcl), egg activation (png, plu, gnu, wisp, C(3)g, mtrm), translational regulation (cup, orb, bru1, me31B), and vitelline membrane formation (fs(1)N, fs(1)M3, clos). This suggests that OVO is a master transcriptional regulator of oocyte development and is responsible for the expression of structural components of the egg as well as maternally provided RNAs that are required for early embryonic development.

Differential growth trajectories of behavioral self-regulation from early childhood to adolescence: Implication for youth domain-general and school-specific outcomes

The current study examined the developmental trajectories of behavioral self-regulation from early childhood to adolescence and linked them to adolescent domain-general (i.e., positive functioning and delinquent behavior) and school-specific (i.e., school connectedness and peer victimization) outcomes. Using data from the Future of Families and Child Wellbeing Study (N = 4009), Growth Mixture Models identified four behavioral self-regulation trajectory classes: early developer (n = 2096, 52.3%), moderate stable (n = 1500, 37.4%), lagged developer (n = 212, 5.2%), and regressor (n = 201, 5%). Child and family characteristics were used to distinguish these four trajectories. The early developer trajectory had the strongest protective effect on adolescent outcomes, showing the highest levels of positive functioning and school connectedness and the lowest levels of delinquent behavior and peer victimization. Conversely, the regressor trajectory was linked with highest risky adolescent outcomes. The findings underscore the importance of implementing targeted intervention programs that promote behavioral self-regulation during middle childhood.

The Impact of Light-Dark Cycle Alteration on the Acceleration of Type 1 Diabetes in NOD Mice Model.

We aimed to evaluate the effect of light-dark cycle alteration and soft drink consumption on the acceleration of type 1 diabetes mellitus (T1DM) development among non-obese diabetic (NOD) mice model. We exposed female NOD and C57BL/6 mice from the age of 5 weeks to either adlib soft drink consumption and/or T20 light-dark cycle alteration until the development of diabetes, or the mice reached the age of 30 weeks. Each group consisted of 7-15 mice. We monitored weight, length, blood glucose level, and insulin autoantibody (IAA) levels weekly. Out of 75 NOD and 22 C57BL/6 mice, 41 NOD mice developed diabetes, and 6 mice died between 7 and 8 weeks of age. The mean time to development of T1DM among NOD control mice was 20 weeks. The time to development of T1DM was accelerated by two weeks in the NOD mice exposed to light-dark cycle alteration, hazard ratio of 2.65,95th CI (0.70, 10.04) p = 0.15). The other groups developed T1DM, similar to the control group. There was a trend toward earlier development of T1DM among NOD mice exposed to light-dark cycle alteration, but this difference was not statistically significant. Further studies are needed to confirm our findings using larger sample sizes and different animal species.

The influence of physiological and functional characteristics of the body of girls aged 17-18 years on playing sports

Achieving competitive results in women’s sports for athletes aged 17-18 requires structuring training processes around their physiological characteristics. This article analyzes recent scientific data on the impact of sexual dimorphism in girls aged 17-18 on sports participation and training. Relevant scientific works from the past five years were collected and analyzed. At this age, girls undergo the final stage of sexual maturation. The effectiveness of sports activities varies individually, influenced by the ovarian-menstrual cycle, hormonal background, and symptoms in each cycle phase. Physical activity declines during the menstrual, ovulatory, and premenstrual phases, while postmenstrual and postovulatory phases are more favorable for sports participation. Performance indicators depend on sexual dimorphism: female athletes show unique features in central nervous system activity, high psycho-emotional excitability, and earlier development of somatic and physical qualities compared to males. The skeletal structure in 17-18-year-old female athletes is smaller and shorter, with a wider pelvis and more developed shoulder girdle. These findings can be used by sports schools, rehabilitation specialists, coaches, and sports physicians to adapt and structure training processes, taking into account the physiological characteristics of 17-18-year-old female athletes, aiming for highly competitive results. Keywords: Sexual Dimorphism, Hormonal Changes, Women’s Sports, Physical Culture, Sports Performance.

From discovery to innovation in animal health: Maturing emerging technologies for industrial development

The Discovery to Innovation in Animal Health Conference (DIAH) was organised to bridge the gap between early developers, including academia, regulators, research organizations, and spin-offs/start-ups on one side, and medium-to large-sized companies on the other. The DIAH Conference confronted and aligned vision from academia, industry and regulators, emphasizing the need for early collaboration, careful IP management, and strategic planning for successful product development and partnerships. Recent breakthroughs in vaccinology have not only accelerated the vaccine production process but have also improved antigen quality significantly. These novel technologies are likely to transform vaccine development and play a crucial role in addressing both immediate health challenges (such as cancer vaccines) and ensuring preparedness for future pandemics. The potential and pitfalls of leveraging AI to drive forward R&I activities in the field of animal health were also discussed. Researchers and entrepreneurs looking for collaboration or investment presented a series of new technologies and start-ups, respectively. A market analysis showed that the animal health industry, while highly consolidated, also shows great diversity, ranging from big pharma to companies offering diagnostics, nutritional health services, wearables, feed additives, animal feed and genetic analyses. An analysis of the investment landscape, although subject to external factors, showed that the chances for success are high when good science, a well established regulatory pathways, with a clearly defined market need can be combined with experienced management and a strong investor consortium.

Exploring the Developmental Aspects of the Uncanny Valley Effect on Children’s Preferences for Robot Appearance

As robotic technology advances, robots are increasingly being designed and utilized for applications involving children across various fields. Since the acceptance of robots is profoundly affected by their appearance, understanding children’s preferences for the looks of robots becomes imperative. The uncanny valley effect (UVE) posits that the perceived likeability of robots increases as their appearance becomes more humanlike but then sharply drops when they approach near-perfect human similarity before rising once an extremely realistic likeness is achieved. Due to inconsistent results in the literature regarding when humans develop a sense of uncanniness toward humanlike robots, the present study aims to examine the emergence of the UVE in children. 67 1st-graders (aged six to seven years) and 95 4th-graders (aged nine to ten years) evaluated 12 robot faces on the scales of likeability, disgust, humanness, and intention to play with the robots (i.e., acceptance). The results demonstrated that the UVE was not observed in 1st-graders or 4th-grade boys. Nevertheless, a UVE-like pattern emerged among 4th-grade girls, particularly in their ratings of likeability and acceptance as a function of robots’ degree of humanness. A positive correlation between likeability and acceptance was consistently found across all age and gender groups. Additionally, negative correlations were found between likeability and disgust, as well as disgust and acceptance, specifically in the fourth graders but not in the first graders. These results suggest that the UVE may not be fully developed in 10-year-old children, with girls potentially exhibiting earlier development than boys. We conclude that age and gender differences should be considered when evaluating children’s preferences for robot appearance and their willingness to interact with robots.

Tolypella mongolica (Charophyceae, Characeae): A new dioecious charophyte species from the center of Eurasia and implications for charophyte taxonomy, including the validation of T. porteri and the new combination for T. jwalae

A new dioecious species of Tolypella, T. mongolica sp. nov. from the section Tolypella, was described using an integrative taxonomy. It was found in three distant localities – shallows of a brackish small lake and a channel in the midland steppe in Mongolia and the Altai Mountains, and a small brackish water body in the dry steppe in Southeast Europe. It differs from other species in rbcL and ITS sequences and in distinct complex ornamentation of the oospore surface, varying from sparsely coarsely tuberculate to having the appearance of an aerial view of mountain landscape with acute to mostly sharp edges of elements at probably the ripest stage. Wide intrapopulation variability of expression of this trait, only partly explainable by oospore ripening stage, was found and illustrated for two populations, indicating previous underestimation of this phenomenon in taxonomic research. T. mongolica is richly fertile and appears to be ephemeral as most species of this genus. Only female plants were found in all localities. The absence of male plants could be referred to either their earlier development during the growing season or, less likely, parthenogenesis in this species. The description of the new species suggests taxonomic changes for two dioecious species of charophytes. Tolypella porteri stat. et comb. nov. was validated here. T. jwalae was recognized as a species of Nitella, N. jwalae comb. nov.

The experiences of gender and sexually diverse parents using support and services for their young children: An integrative review.

To address: What are the experiences of 2SLGBTQQIA+ parents using parenting supports and services to meet their children's early childhood development needs (<5 years of age)? Whittemore and Knafl's (2005) integrative review methodology. Electronic databases were searched from 2000 to October 14, 2022 for empirical studies or reviews addressing the research question. The title and abstract of 12,158 articles were screened for inclusion in the review by two independent researchers; 175 of these articles underwent full-text review. Studies selected were critically appraised using a Joanna Briggs Institute Critical Appraisal tool. Relevant key findings were extracted from each study and entered into N-VIVO-12. Thematic content analysis was employed and PRISMA guidelines were adhered to. A total of 18 articles (15 qualitative and three multi-method studies) met the inclusion criteria and were selected for the review. Seven themes were revealed from analysis of the studies: (1) 2SLGBTQQIA+ Status kept a secret; (2) Forced to come out; (3) Heteronormative messaging; (4) Feeling excluded; (5) Stigmatised; (6) Parents act as educators; and (7) Positive experiences. This integrative review provides nurses with insight into the experiences of 2SLGBTQQIA+ parents using health care services for their young child. This article highlights what changes nurses need to make to their practice to ensure appropriate, inclusive care for clients of diverse sexual and gender identities and their families. Health care providers, especially nurses, have an opportunity to improve the experiences of these families and positively impact their health and well-being. Additionally, there is a need for research with the 2SLGBTQQIA+ parent community and the use of rigorous methodological techniques, including clearly linking participants' gender and sexual identities with study findings, to improve our understanding of 2SLGBTQQIA+ parent experiences. Although there was no direct patient contribution to the work since it was an integrative review of the literature, indirectly patient contributions are incorporated from the original research results of studies incorporated into this review.

Fit-for-purpose heterodivalent single-domain antibody for gastrointestinal targeting of toxin B from Clostridium difficile.

Single-domain antibodies (sdAbs), such as VHHs, are increasingly being developed for gastrointestinal (GI) applications against pathogens to strengthen gut health. However, what constitutes a suitable developability profile for applying these proteins in a gastrointestinal setting remains poorly explored. Here, we describe an in vitro methodology for the identification of sdAb derivatives, more specifically divalent VHH constructs, that displayextraordinary developability properties for oral delivery and functionality in the GI environment. We showcase this by developing a heterodivalent VHH construct that cross-inhibits the toxic activity of the glycosyltransferase domains (GTDs) from three different toxinotypes of cytotoxin B (TcdB) from lineages of Clostridium difficile. We show that the VHH construct possesseshigh stability and binding activity under gastric conditions, in the presence of bile salts, and at high temperatures. We suggest that the incorporation of early developability assessment could significantly aid in the efficient discovery of VHHs and related constructs fit for oral delivery and GI applications.

Depletion of DAND5 Hinders EMT in Mouse Embryonic Stem Cell Differentiation.

Dand5 encodes a protein that acts as an antagonist to Nodal/TGF-β and Wnt pathways. A mouse knockout (KO) model has shown that this molecule is associated with left-right asymmetry and cardiac development, with its depletion causing heterotaxia and cardiac hyperplasia. This study aimed to investigate the molecular mechanisms affected by the depletion of Dand5. DAND5-KO and wild-type embryoid bodies (EBs) were used to assess genetic expression with RNA sequencing. To complement the expression results that pointed towards differences in epithelial to mesenchymal transition (EMT), we evaluated migration and cell attachment. Lastly, in vivo valve development was investigated, as it was an established model of EMT. DAND5-KO EBs progress faster through differentiation. The differences in expression will lead to differences in the expression of genes involved with Notch and Wnt signalling pathways, as well as changes in the expression of genes encoding membrane proteins. Such changes were accompanied by lower migratory rates in DAND5-KO EBs, as well as higher concentrations of focal adhesions. Within valve development, Dand5 is expressed in the myocardium underlying future valve sites, and its depletion compromises correct valve structure. The DAND5 range of action goes beyond early development. Its absence leads to significantly different expression patterns in vitro and defects in EMT and migration. These results have an in vivo translation in mouse heart valve development. Knowledge regarding the influence of DAND5 in EMT and cell transformation allows further understanding of its role in development, or even in some disease contexts, such as congenital heart defects.

Rise and decline of Holocene tufas across Europe: exploring east/west and north/south similarities and differences in their development

ABSTRACTAn extended inventory of 82 well‐dated European calcareous tufas is used to discuss the timing and amplitude of their onset, maximum and decline; in particular differences from east to west and between the Mediterranean area and the rest of Europe. Eastern deposits start to develop and reach their maximum slightly earlier than western tufas. Strong east–west differences in the timing and intensity of the climatic improvement during the first half of the Holocene explain the earlier development of eastern tufas compared with the west. The strongest differences are observed between Mediterranean deposits and other European tufas both in their development and decline, whether all or only fluvial deposits are considered, reflecting the important decoupling between Mediterranean and mid‐latitude climate records. During the Late Holocene, the earlier and more pronounced tufa decline observed in European mid‐latitudes is likely to result from more intense and rapid deforestation compared with the Mediterranean region.

Coding attitudes of fourth-grade latinx students during distance learning

ABSTRACT Background and Context Despite the growing initiatives in K-12 computer science (CS), there is a continued disparity in the participation of Latinx and multilingual students, a historically underrepresented group in computing. The inequitable participation may be understood by examining students’ early development of CS attitudes. Objective This study aims to explore shifts and elicitation in coding attitudes of fourth-grade, Latinx students (ages 9-10) who underwent a year-long remote coding curriculum, with consideration of gender and language designation. Method Using a mixed method approach, pre-post survey responses on coding attitudes were analyzed to understand shifts and portrayal of Interest, Confidence, Utility, Social Values, and Perception of Coders, with consideration of gender or designation as an English Language Learner. Findings Gender and language designation did not interact with overall attitude shifts. However, there is a significant difference in Social Values and Confidence over time. Student interviews revealed more nuance in social influences with siblings and cousins as key motivators for extended learning, underlying values of perseverance in confidence, mixed perception of what coders do, and the importance of creativity to develop interest. Implications The key role of social influence in driving higher identity among Latinx students points to the important role of extended family. Moreso, developing students’ confidence in domain-specific tasks should be a focus in curricula in order to have a longer-term impact on motivation. Finally, more research on the role that subjective task values pertaining to cultural values should be explored in early coding motivation in order to broaden participation. Keywords: Coding attitudes, elementary students, remote learning, expectancy-value theory, coding curriculum.

Climate change reduces elevational and latitudinal differences in spring phenology of pine caterpillar (Dendrolimus spectabilis Bulter)

The pine caterpillar (Dendrolimus spectabilis Bulter, Lepidoptera: Lasiocampidae), as an ectotherm, temperature plays a crucial role in its development. With climate change, earlier development of insect pests is expected to pose a more frequent threat to forest communities. Yet the quantitative research about the extent to which global warming affects pine caterpillar populations is rarely understood, particularly across various elevations and latitudes. Spring phenology of pine caterpillars showed an advancing trend with 0.8 d/10a, 2.2 d/10a, 2.2 d/10a, and 3.3 d/10a under the SSP1-2.6, SSP2-4.5, SSP3-7.0 and SSP5-8.5 scenario, respectively. There was a maximum advance of 20 d in spring phenology of pine caterpillars during the 2090s, from mid-March to early March, and even late February. This study highlighted the significant advance in spring phenology at elevations >1000 m and lower latitudes. Consequently, the differences in elevational and latitudinal gradients were relatively small as the increasing temperatures at the end of the 21st century. And the average temperature in February–March was effective in explaining theses variability. These findings are crucial for adapting and mitigating to climate change.

The abbot Alberto Fortis and the elephant bones from Romagnano: the early development of the concepts of biostratinomy and taphonomy sensu lato

The abbot Alberto Fortis and the elephant bones from Romagnano: the early development of the concepts of biostratinomy and taphonomy sensu lato

The clinical, molecular, and therapeutic implications of time from primary diagnosis to brain metastasis in lung and breast cancer patients

AbstractPurposeLung cancer (LC) and breast cancer (BC) are the most common causes of brain metastases (BMs). Time from primary diagnosis to BM (TPDBM) refers to the time interval between initial LC or BC diagnosis and development of BM. This research aims to identify clinical, molecular, and therapeutic risk factors associated with shorter TPDBM.MethodsWe retrospectively reviewed all diagnosed LC and BC patients with BM at Harbin Medical University Cancer Hospital from 2016 to 2020. A total of 570 patients with LC brain metastasis (LCBM) and 173 patients with breast cancer brain metastasis (BCBM) patients who met the inclusion criteria were enrolled for further analysis. BM free survival time curves were generated using Kaplan–Meier analyses. Univariate and multivariate Cox regression analyses were applied to identify risk factors associated with earlier development of BM in LC and BC, respectively.ResultsThe median TPDBM was 5.3 months in LC and 44.4 months in BC. In multivariate analysis, clinical stage IV and M1 stage were independent risk factors for early development of LCBM. LC patients who received chemotherapy, targeted therapy, pulmonary radiotherapy, and pulmonary surgery had longer TPDBM. For BC patients, age ≥ 50 years, Ki67 ≥ 0.3, HER2 positive or triple‐negative breast cancer subtype, advanced N stage, and no mastectomy were correlated with shorter TPDBM.ConclusionsThis single‐institutional study helps identify patients who have a high risk of developing BM early. For these patients, early detection and intervention could have clinical benefits.

BK polyomavirus DNAemia, allograft rejection, and de novo donor-specific antibodies after lowering target tacrolimus levels in pediatric kidney transplant recipients.

BK polyomavirus (BKV) DNAemia is a challenging infectious complication after kidney transplant (KT). Reduction of immunosuppression is the mainstay of management, and tacrolimus is often the first immunosuppressive medication adjusted upon the diagnosis of BKV DNAemia. This study aimed to evaluate the impact of a new institutional protocol with lower target tacrolimus levels on BKV DNAemia, allograft rejection, and de novo donor-specific antibodies (dnDSA) among pediatric KT recipients. We conducted a retrospective chart review of all KT episodes between January 2013 and December 2018. The new protocol with lower target tacrolimus levels was implemented in March 2015. One hundred twenty-seven patients were included in primary analysis. All patients received induction with basiliximab and methylprednisolone and were maintained on a steroid-based immunosuppressive regimen. In the post-intervention cohort, cumulative incidence of BKV DNAemia at 100 days (13.4% vs. 17.8%, p = .605) and 18 months post-KT (34.1% vs. 26.7%, p = .504) was not significantly different from the pre-intervention cohort. Biopsy-proven rejection rate did not change. However, we observed a trend toward earlier development of dnDSA in the post-intervention cohort using the Kaplan-Meier survival analysis (log-rank p = .06). Younger recipient age at the time of transplant was found to slightly increase the risk of BKV DNAemia (OR: 1.09, 95% CI [1.01, 1.16], p = .024). There was an association between BKV DNAemia and biopsy-proven rejection of any type (adjustedOR: 2.77, 95% CI [1.26, 6.23], p = .012), especially acute T-cell-mediated rejection grade 1A and above (adjustedOR: 2.95, 95% CI [1.06, 8.30], p = .037), after adjusted for recipient age at the time of transplant. Targeting lower tacrolimus levels did not decrease the incidence of BKV DNAemia within 100 days or 18 months post-KT, nor did it increase the risk of biopsy-proven rejection among pediatric KT recipients in our center. However, there was a trend toward earlier development of dnDSA, which may portend worse long-term graft outcome post-KT. Our findings highlight the need for individualized immunosuppressive regimens based on immunologic and infectious risk factors and the importance of implementing innovative biomarkers to guide therapy and improve outcomes.