To address this gap, our study sought to first identify the factors that influenced fertility differentials in Morocco and Burundi during their fertility transition periods, and then to compare the effects of these factors between the two countries.using data from the 2003-4 Morocco and 2010 Burundi Demographic and Health Surveys, bivariable and multivariable Poisson regression analyses offset by the natural logarithm of the women´s age were performed to identify the socioeconomic and cultural factors that influenced fertility differentials in Morocco and Burundi during their fertility transition.our main findings showed that the total number of children ever born ranged from 0 to 17 with a mean of 2.71 ± 2.89 in Burundi and from 0 to 16 with a mean of 1.88 ± 2.80 in Morocco. In Burundi, both socioeconomic and cultural factors like rural residence adjusted incident rate ratio (AIRR) = 1.159, 95% CI: 1.103 - 1.217, P=0.020), women´s illiteracy  and agricultural profession , household poverty , infant mortality , early marriage , lack of knowledge of any contraceptives  and failure to use modern contraceptives  were associated with high number of children ever born. However, in Morocco socioeconomic factors like residence place, women´s agricultural profession and household poverty were not significant. In this country, women´s illiteracy , lack of access to mass media , infant mortality , early marriage , lack of knowledge of any contraceptives  and failure to use modern contraceptives  were associated with high fertility but with different effects than in Burundi.the evidence from this study suggests that interventions to accelerate the fertility transition processes in Burundi and many other countries with slow fertility transitions should be designed and implemented according to each country's local context. Fertility transition is characterized by enormous disparities between regions and within countries. While rapid fertility declines were observed in Asia, Latin America, Europe and Northern Africa, sub-Saharan African (SSA) countries are experiencing late and very slow fertility transitions ,2. MorocSeveral studies asserted that fertility differentials are influenced by socioeconomic -9, cultuHowever, many studies have focused on analyzing the factors that influenced fertility differentials in countries that have almost the same socioeconomic and cultural characteristics and therefore almost the same fertility transition paces ,9,26,27.Study design and setting: this is a retrospective, cross-sectional and comparative study using data from the Demographic and Health Surveys (DHS) conducted from October 15th, 2003 to February 2915th, 2004 in Morocco (2003-04 Morocco DHS) [th, 2010 to January 3015th, 2011 in Burundi (2010 Burundi DHS) [cco DHS)  and fromndi DHS) . The 200ndi DHS) ,18. We undi DHS)  periods Participants: participants in both surveys were women of reproductive age (women aged 15-49).Eligibility criteria: any woman aged 15-49 who usually resided in the selected households or a female visitor who spent the night before the day of the interview in the selected household [ousehold ,18, and Exclusion criteria: any woman under 15 or over 49 years old and woman´s refusal to participate in the survey.Sample size and sampling method: this study used two samples of 9,389 and 1,769 women aged 15-49 years for the 2010 Burundi and 2003-04 Morocco DHS surveys, respectively. A two-stage cluster sampling procedure was used to obtain the two samples [ samples .Bias control: to minimize bias, a pilot survey was conducted to adapt the data collection tools and data collection was carried out by specifically trained interviewers. In addition, in each team of interviewers, a supervisor was always in charge of controlling the quality of the data collected [ollected ,18.Outcome variable: this study used the total number of Children Ever Born (CEB) as the outcome variable. The total number of CEB is a measure of each woman's fertility level up to the time the 2003-4 Morocco and 2010 Burundi DHS survey data were collected. The total number of CEB was used as the dependent variable because the total number of CEB of women in the 15 to 49-year-old cohort captured both current and past fertility behavior [behavior . In addibehavior ,30, we cIndependent variables: using a preliminary literature review, socioeconomic and cultural variables were selected from the two databases to analyze their potential association with fertility differentials in the both countries. Selected variables include women´s age , place of residence , marital status , women and husband's education , women/husband´s profession (women/husband´s current activity), wealth quintile , mass media access , experience of infant mortality , age at first marriage (age at first marriage /cohabitation), knowledge of any contraceptive methods (whether a women has/not knowledge about any contraceptive methods) and use of modern contraceptives (current use of modern contraceptive methods).Statistical analysis: the statistical software STATA version 14.2 was used during statistical analyses. Since the 2003-4 Morocco and 2010 Burundi DHS data were obtained using a two-stage stratified cluster sampling process, the data were first weighted using the STATA svyset command to obtain unbiased parameter estimates and standard errors [d errors . Then, fd errors ,31. In aEthical considerations: the protocols, consent forms, and data collection instruments for the 2003-04 Moroccan and 2010 Burundi DHS surveys were reviewed and approved by International Coaching Federation (ICF's) Institutional Review Board (IRB) and those of Morocco and Burundi, respectively. While ICF's IRB ensured that these surveys complied with the U.S. Department of Health and Human Services regulations for the protection of human subjects, the Morocco and Burundi IRBs ensured that the surveys complied with the laws and standards of each respective country [ country . In addi country .Participants: in the first stage, 376 and 480 clusters were sampled in the 2010 Burundi and 2003-04 Morocco DHS surveys respectively using a systematic draw. Then, 9,024 (for Burundi) and 12,000 (for Morocco) households (24 and 25 households per cluster respectively) were sampled in the second stage using a systematic draw too. In these latter sampled households, respectively 9,737 and 17,443 women aged 15-49 were eligible, of whom 9,389 and 16,798 women consented to participate in the survey, representing participation rates of 96.4 and 96.3% respectively  and 29.62 (SD ± 9.99) for Burundi and Morocco respectively. The results showed that slightly more than three out of five women (61.7%) and slightly more than half of the women (52.9%) were less than 30 years of age for Burundi and Morocco respectively. For Burundi, most of the women (89.3%) lived in rural areas, while for Morocco most of the women (60.5%) lived in urban areas. Analysis of their marital status revealed that more than half of the women (57.7% in Burundi and 52.3% in Morocco) were married/living with a partner, while 33.2% and 42.1% in Burundi and Morocco respectively were still single. Regarding education level, 44.8% of the women were illiterate in Burundi compared to 50% in Morocco and only about 1% had a higher education level in Burundi compared to 5.3% in Morocco. Regarding their professional activity, our results showed that most of the women (77.6%) were working in an agricultural profession in Burundi while in Morocco most of the women (78.7%) were unemployed and only 2.7% were working in a modern profession in Burundi compared to 5.5% in Morocco. With respect to the household wealth index, the results indicate that 40.5% of women were from poor/very poor households in Burundi compared to 36.3% in Morocco  and 1.88 (SD ±2.80) in Burundi and Morocco respectively. In the bivariable analysis factors like place of residence, marital status, women and husband's education and profession, wealth index, mass media access, the experience of infant mortality, age at first marriage, knowledge of any contraceptive methods, and modern contraceptive use were analyzed. The result of this analysis showed that all of the latter variables met the required condition  to be considered in the multivariable Poisson regression analysis  when compared to those who had access to mass media in Morocco, while in Burundi access to mass media was not significant. Women who already lost at least one child had a higher fertility rate of 60.2%  in Burundi versus 22.2%  in Morocco in reference to those who have not yet lost any child. Also, women who married at age 15 or before and those who married at age 16 - 19 had respectively higher fertility rates of 31.3%  and15.5 %  in Burundi versus 48.1%  and 23 %  in Morocco when compared to those marrying at least at age 20. Women who did not have knowledge of any contraceptive method had a higher fertility rate of 26.3%  in Burundi versus 50.8%  in Morocco as compared to those who had knowledge of any contraceptive method. Similarly, women who were not using modern contraceptive methods had a higher fertility rate of 52%  in Burundi versus 74.5%  in Morocco when compared to those who were using modern contraceptive methods.This study was conducted to first examine the factors that influenced fertility differentials in Morocco and Burundi during their fertility transition periods and then to compare the effects of these factors between the two countries. The total number of CEB varied from 0 to 17 and 0 to 16 per woman with an average of 2.71 (SD ±2.89) and 1.88 (SD ±2.80) in Burundi and Morocco respectively. Factors like rural residence, illiteracy or low level of education of women and their partners, the experience of infant mortality, early marriage, women and husband/partner´s agricultural profession, household poverty, lack of access to mass media, lack of knowledge of any contraceptive methods and failure to use modern contraceptive methods were found to be associated with high fertility (high number of CEB) in at least one of the two countries.Indeed, our results revealed that rural residence was associated with high fertility in Burundi while its effect was no longer significant in Morocco. This finding could be attributed to the fact that Burundi remained the least urbanized country in the world with an urbanization rate of 10.6% in 2010 unlike Morocco whose urbanization rate was already 54.6% in 2004 . Moreoveet al. [Women and husbands/partners´ agricultural activity was found to be associated with a high number of CEB in Burundi. Our results are consistent with those found in SSA  and in tet al.  who statet al. .Similarly, access to mass media was significantly associated with low fertility in Morocco, while its effect was not significant in Burundi. This could be due to a lack of involvement of the Burundian mass media in spreading FP messages . Access While there was a substantial increase in the age at first marriage in Burundi  and MoroNote that this study would be among the first to examine the heterogeneity of the effects of socioeconomic and cultural factors on fertility differentials during fertility transitions in countries with different socioeconomic and cultural backgrounds and with different fertility transition patterns. Moreover, the findings of this study can be generalized since the analysis is based on good quality and nationally representative data ,18. In tThe results of this study revealed that both socioeconomic and cultural factors like rural residence, women´s illiteracy and agricultural profession, household poverty, infant mortality, early marriage, lack of knowledge of any contraceptives, and failure to use modern contraceptives were associated with a high number of children ever born in Burundi. However, in Morocco, socioeconomic factors like residence place, women´s agricultural profession, and household poverty were not significant. In this country, women´s illiteracy, lack of access to mass media, infant mortality, early marriage, lack of knowledge of any contraceptives, and failure to use modern contraceptives were associated with high fertility but with different effects than in Burundi. Intervention programs aimed at accelerating the fertility transition in Burundi and many other countries with slow fertility transitions should be designed and implemented according to the local context of each country.Many studies have focused on analyzing the factors that influenced fertility differentials in countries that have almost the same socioeconomic and cultural contexts;Many studies have focused on analyzing the factors that influenced fertility differentials in countries that have almost the same fertility transition pace;Few studies have examined the factors influencing fertility differentials and the variation in their effects in countries with different socioeconomic and cultural backgrounds and different fertility transition paces.This study is one of the few studies that focus on the comparative analysis of socioeconomic and cultural factors that influenced fertility differentials during the fertility transition periods between two countries with very different socioeconomic and cultural backgrounds;This study may also be among the first ones to focus on the comparative analysis of variations in the effects of socioeconomic and cultural factors on fertility differentials during the fertility transition periods between two countries that have experienced a very different pace of fertility transition;The results of this study contribute to a better understanding of the extent to which Burundi and many other countries with very slow fertility transitions could accelerate them using or not the same interventions as those used by other countries, like Morocco, that succeeded in accelerating their fertility transitions.


Climacteric women often experience unfavorable metabolic changes. Consequently, identifying markers that may contribute to such undesirable changes is imperative. This study aimed to evaluate serum uric acid (UA) concentration and its association with metabolic and clinical parameters in climacteric women. We selected 672 women between 40 and 65 years and performed interviews, biochemical analyses, blood pressure, and anthropometric measurements. UA levels were determined using the enzymatic-colorimetric method. We compared variables according to the quartiles of UA using the Kruskal–Wallis test. The mean UA level was 4.9 ± 1.5 mg/dl, ranging from 2.0 to 11.6 mg/dl. We found that UA levels greater than 4.8 mg/dl were associated with adverse metabolic parameters in climacteric women. For all anthropometric and biochemical variables, we observed significantly better results in women who had lower UA levels (p < 0.05). Similarly, we observed a significant increase in blood pressure, frequency of metabolic syndrome, and cardiovascular risk as UA levels increased (p < 0.05). Our findings showed that climacteric women with high levels of UA were more likely to have adverse metabolic and clinical parameters than those with lower UA levels. Further studies may determine the causal relationship between UA and metabolic changes in climacteric women. Studies have shown that women experience an increase in weight, body fat percentage, and waist circumference during the menopausal transition and postmenopause2. The lipid profile of postmenopausal women becomes more atherogenic, with elevated levels of total cholesterol, LDL cholesterol, and apolipoprotein B, irrespective of age, ethnicity, or weight3.The aging process in women is characterized by a decline in serum estrogen concentrations, which significantly increases the risk of cardiovascular and metabolic diseases6. UA is a metabolite derived from purine oxidation, which occurs when nucleotides break down7. The serum concentration of UA remain relatively constant due to a balance between its production and excretion. However, conditions that increase UA production or decrease UA excretion can lead to hyperuricemia, which is generally defined as a UA blood concentration greater than 7.0 in men and 6.0 mg/dl in women8.Several studies have established a link between uric acid (UA) and an increased risk of metabolic disorders associated with menopause10.Hyperuricemia can be caused by many factors, including changes in purine metabolism, high protein intake, enzyme dysfunction, exposure to xenobiotics, and kidney or liver disease. Certain life stages, such as the third trimester of pregnancy and menopause, are also related to increased UA levels11.Elevated levels of UA in the blood are known to cause the deposition of urate crystals in the joints and kidneys, increasing the risk of gout, renal disease, and hypertension. In recent decades, evidence has emerged demonstrating the clinical significance of UA beyond rheumatology. Numerous studies have linked UA to various metabolic disorders, including cardiovascular disease, metabolic syndrome, dyslipidemia, non-alcoholic fatty liver disease, and obesityAlthough many studies have shown an association between hyperuricemia and metabolic diseases, few have examined the role of UA in menopausal changes. It is therefore important to investigate UA as a biological marker that may contribute to the development of metabolic diseases, leading to increased morbidity and mortality among middle-aged women. This study aimed to evaluate serum UA concentrations in climacteric women and assess their association with clinical and metabolic parameters.This cross-sectional study evaluated women between 40 and 65 years. Participants were recruited through active search in the Basic Health Units of Ouro Preto, Minas Gerais, Brazil, using a non-probabilistic convenience sampling method. The exclusion criteria were gout diagnosis and the use of urate-lowering therapy.Volunteers were invited to participate in the study by doctors, nurses, health agents, or researchers. All participants attended on predetermined days for an interview, blood collection, and anthropometric measurements. The study adhered to relevant guidelines and regulations, and all methods were carried out in accordance with them. The Research Ethics Committee of the Universidade Federal de Ouro Preto approved this study (Number: 56312916.8.0000.5150), and all eligible participants gave informed consent.During the interviews, the women provided information on several aspects, including their age, level of education, marital status, number of children, income, personal and family history of diseases, tobacco and alcohol use, physical activity levels, medication use, age at menarche, sexual activity, date of their last menstrual period, any changes in their menstrual cycle, surgeries they may have had, years since menopause, and age at menopause.We considered any medication used by the participants and classified them into the following categories: antihypertensive, antidepressant/anxiolytic, thyroid agents, lipid-lowering agents, vitamins/supplements, antidiabetic, hormones, analgesic/anti-inflammatory, and others.12.Participants were classified into the late reproductive phase, menopausal transition, and postmenopause using the STRAW + 10 criteria. The primary criterion used was the menstrual pattern, while FSH levels and age served as supportive criteria2) and waist-to-height ratio (WHtR = waist circumference (cm)/height (cm)).We evaluated weight, height, body fat percentage (BF), and waist circumference (WC). We measured height using a simple portable stadiometer with an accuracy of 0.1 cm. Participants were instructed to stand with their arms along the body, feet together, and pointed forward. We assessed weight and body fat percentage using a Tanita® bioimpedance scale (Model 2204), with a graduation of 100 g. Participants stood upright, barefoot, and looked straight ahead during the measurements. We measured WC using a measuring tape at the midpoint between the last rib and the iliac crest. Using the anthropometric measurements, we calculated the body mass index ((BMI = weight (kg)/height (m)We used a Bioland®—3005 digital wrist device to measure blood pressure. Participants were seated, with their feet on the floor and their left arm at heart level, following the manufacturer's recommended technique.After 12 to 14 h of fasting, we collected blood samples from the participants. They were instructed to avoid intense physical exercise 24 h before blood collection and alcohol consumption for 72 h. We determined uric acid (UA), fasting blood glucose (FBG), insulin, lipid profile , urea, and creatinine levels using the enzymatic-colorimetric method. HDL and LDL were analyzed using the direct homogeneous method, and hs-CRP was measured using the immunoturbidimetric method. We performed all biochemical analyses using the Cobas Integra® 400 Plus (Roche). We used the Access 2 Immunoassay System® (Beckman & Coulter) and chemiluminescence to determine insulin levels. All these determinations were performed in the Clinical Analysis Laboratory of the Federal University of Ouro Preto (LAPAC/UFOP).13; non-HDL (TC [mg/dl] – HDL [mg/dl]); visceral adiposity index (VAI = [WC/(36.58 + (1.89 × BMI))] × [TG/0.81] × [1.52 /HDL])14; lipid accumulation product (LAP = [WC − 58] × TG [mmol/l])15; and atherogenic index of plasma (AIP = log TG [mmol/l]/HDL [mmol/l])16. We then classified women according to their AIP levels into groups of low cardiovascular risk (AIP < 0.11) and moderate/high risk (AIP ≥ 0.11)17.We calculated the following indices: homeostasis model assessment of insulin resistance  harmonized criteriaEpiData software (version 3.2) was used to double enter and check the data. The statistical analyses were performed using the Solution for Statistical Products and Services software (IBM SPSS 20.0). We used Pearson's chi-square test to compare categorical variables. We tested the distribution of quantitative variables using the Kolmogorov–Smirnov test and the Kruskal–Wallis test, followed by the Bonferroni correction, to compare the quantitative variables. For all statistical analyses, we considered a significance level of 5% (p < 0.05).We initially selected 691 women aged between 40 and 65 years. However, we excluded 19 participants who reported a gout diagnosis or urate-lowering therapies, such as allopurinol and probenecid. Therefore, our study analyzed 672 participants.UA levels of the participants ranged from 2.0 to 11.6 mg/dl, with a mean value of 4.9 ± 1.5 mg/dl  included women with UA levels up to 4.0 mg/dl, the second quartile (Q2) included women with UA levels between 4.1 and 4.8 mg/dl, the third quartile (Q3) included women with UA levels between 4.9 and 5.6 mg/dl; and the fourth quartile (Q4) women with UA levels greater than 5.6 mg/dl.The median age of participants was between 50 and 53 years old (p = 0.002). In all quartiles of UA, most participants studied for more than 8 years, lived with a partner, used the public health system, did not smoke, did not have regular use of alcohol, and were sexually active and postmenopausal. In this study, we also included women after hysterectomy  since we found no significant differences between them and those who reported natural menopause for all parameters evaluated (data not shown). The frequency of postmenopausal women increased with higher UA quartiles (p = 0.007). In the first quartile, most of the participants were physically active , while in the fourth quartile, most of the women were sedentary  (p < 0.05). The use of drugs and hypertension frequency increased proportionally to UA levels. The statistical analysis showed that women in Q1 and Q2 used significantly lower medications than those in Q3 and Q4 (p < 0.001). Women in the fourth UA quartile had a significantly higher frequency of hypertension  than those in the first , second , and third quartiles  . Similarly, women classified in Q2 had significantly better anthropometric results than volunteers in Q3 and Q4. Additionally, significant differences were found between Q3 and Q4 for BMI and WHtR (p < 0.001)  had significantly higher median values in all the anthropometric parameters compared to participants in the first and second quartiles (≤ 4.8 mg/dl). In addition to changes in body composition typically seen during the climacteric period, studies have shown associations between UA and different adiposity markers, such as WC, weight, BMI, and BF29. UA induces oxidative stress in adipocytes and reduces adiponectin levels, which are related to insulin resistance26. Furthermore, UA can stimulate gluconeogenesis by blocking AMP-activated protein kinase31. Our findings are consistent with a study by Grygiel-Górniak and et al., which showed a strong association between increased UA concentrations and insulin resistance in postmenopausal women28. Additional studies have demonstrated an association between UA and type 2 diabetes mellitus33.Our results indicate that women with UA > 4.8 mg/dl had significantly higher levels of FBG, insulin, and HOMA-IR levels and used more hypoglycemic medications than those with lower urate levels. Adipose tissue, which is a central endocrine organ, plays critical metabolic functions in energy homeostasis and glucose regulation, with both visceral and subcutaneous fat being important contributors35. Some studies suggest that TG synthesis requires NADPH, which could lead to increased UA production26. Our findings are consistent with previous studies that showed the relationship between serum UA and dyslipidemia in adults36. Dobrzyńska and Przysławski showed that postmenopausal women with UA levels ≥ 5.0 mg/dl had significantly elevated values of serum TG, WHtR, and diastolic blood pressure than women with a UA concentration < 5 mg/dl37.Concerning the lipid profile, we observed a marked increase in serum concentrations of TG and non-HDL and a significant decrease in HDL levels across the four UA quartiles. Hyperuricemia (UA > 6.0 mg/dl) can induce oxidative stress and generate free radicals, which are associated with dyslipidemia and an increased risk of cardiovascular disease38. In the current study, we found that women classified in Q3 and Q4 (UA > 4.8 mg/dl) had higher serum concentrations of urea and creatinine than those classified in Q1 and Q2 (UA ≤ 4.8 mg/dl). These findings are consistent with a recent study that found higher UA quartiles were associated with elevated levels of urea and creatinine in adults aged between 20 and 93 years old39. In addition, another study showed that increased urea levels were associated with a 2.5 times greater likelihood of elevated UA levels40.As people age, the kidneys gradually filter solutes less effectively, resulting in the retention of substances like urea, creatinine, and UA42. Tao et al. reported that the UA/creatinine ratio is strongly associated with metabolic syndrome risk in postmenopausal Chinese women43. Other studies also showed a significant association between hyperuricemia and metabolic syndrome in climacteric women45.In this study, we found that climacteric women with UA levels greater than 4.8 mg/dl had a significantly higher frequency of metabolic syndrome and a higher risk of developing the syndrome. Previous research has indicated that high serum UA concentration can negatively influence all metabolic syndrome factors, including central obesity, insulin resistance, high blood pressure, hypertriglyceridemia, and reduced HDL. Upon entering cells via anion carriers, UA causes oxidative stress in vascular smooth muscle cells, endothelial cells, adipocytes, islet cells, renal tubular cells, and hepatocytes. This increases the risk of hepatic fat accumulation and metabolic syndromeAccording to our study, blood pressure increased progressively with increasing UA levels. We observed a significant difference between the first and fourth quartiles for both systolic and diastolic blood pressure. We also found a significantly increased cardiovascular risk in participants with higher serum concentrations of UA and a higher frequency of antihypertensive medications use among women with higher serum concentrations of UA.4. Intracellular urate increase is suggested to be a key factor in primary hypertension pathogenesis46. One relevant and widely accepted pathophysiological mechanism by which UA promotes cardiovascular disease is the reduction in levels of nitric oxide (NO). UA reacts with NO in a quick and irreversible reaction, leading to the production of 6-amino-uracil and consequent NO depletion4. NO depletion is a major cause of endothelial dysfunction related to hyperuricemia because it controls vascular tone, prevents platelet adhesion and aggregation, and reduces intima proliferation47. Additionally, UA has been shown to increase angiotensin II expression in vascular endothelial cells and activate the intrarenal renin-angiotensin system, exacerbating endothelial dysfunction42. A recent meta-analysis demonstrated an association between high serum urate and elevated blood pressure, which may contribute to cardiovascular disease48. Furthermore, other studies have reported UA as a risk factor for hypertension and cardiovascular disease in postmenopausal women50.Clinical, epidemiological, and experimental studies support an association between increased UA levels and hypertension and cardiovascular disease risk8. This range was established based on UA levels in individuals without clinical evidence of gout52. However, it is well established that UA is central to several metabolic processes beyond articular issues11. The worldwide increase in circulating UA highlights the need to re-evaluate this reference range51. In this study, we analyzed all data according to the UA quartiles. We found that Q1, Q2, and Q3 had lower UA levels than the hyperuricemia cut-off. Furthermore, our data suggested an association between serum UA concentrations greater than 4.8 mg/dl (Q3 and Q4) and impaired metabolic parameters in climacteric women. Malorbeti et al. reported a cut-off of 4.7 mg/dl for predicting total mortality, 5.6 mg/dl for cardiovascular mortality, and 5.7 mg/dl for myocardial infarction-related mortality in a sample of 23,475 subjects. These findings suggest that climacteric women should aim to manage their UA levels, and further studies should review the UA cut-off in this population.The normal reference range for serum UA in women is 1.5 to 6.0 mg/dlOur study has some limitations that should be acknowledged. Firstly, the cross-sectional design of the study precludes the establishment of a causal relationship between UA levels and metabolic changes. Secondly, although we did not find any significant differences between the volunteers who used diuretic agents and those who did not (data not shown), it is important to note that this medication can raise UA levels, which may have affected our results. Thirdly, we evaluated women in all three stages of reproductive aging. Although each stage tends to present specific changes, all the women included in our study were in the climacteric period and were experiencing the effects of reproductive aging to some extent. Fourthly, unmeasured confounding factors, such as age, smoking, and alcohol consumption, could have potentially biased our results.In this study, we chose to analyze the data using quartiles instead of using the reference value for hyperuricemia (UA > 6 mg/dl) in order to investigate the association between UA concentrations and metabolic disorders in climacteric women more comprehensively. Our findings suggest that the current cut-off point for hyperuricemia may not be appropriate for this population, as many women with UA levels below 6 mg/dl showed significant alterations. Women with UA levels greater than 4.8 mg/dl should be closely monitored, highlighting the importance of lifestyle changes, such as improvements in diet and physical activity and urate-lowering therapy in specific cases. We recommend conducting further longitudinal studies to confirm our findings, especially since UA is a modifiable risk factor that can be easily assessed during routine clinical visits.We have found that higher serum UA concentrations are associated with unfavorable metabolic and clinical parameters in climacteric women. These results suggest that UA may serve as an accurate marker of metabolic risk in the female population. Further studies are needed to establish an ideal cut-off point and clarify the causal relationship between UA levels and metabolic changes in climacteric women.


These findings not only address the central questions of regenerative biology but also have potential implications for regenerative medicine. Whole-body regeneration is a multifaceted process that reinstates a body to its initial three-dimension size and structure after resection injury. It is well-known that signaling waves such as calcium and extracellular signal-related kinase (ERK) signaling waves can efficiently transmit information between tissues or cells. However, the mechanisms responsible for coordinating wound responses over long distances are largely unexplored. A recent study has reported that the propagation of ERK signaling waves  The comprehensive coordination of cellular dynamics at the tissue level that is necessary for appropriate morphogenesis and regeneration, encounters difficulties due to the substantial dimensions of regenerating body parts (Bertero and Murry 2+ waves and transmission of action potentials along neuronal pathways, other signaling waves such as Cdk1, Thrombin, and Notch waves have been shown to have significant impact on a variety of biological processes (Dashkevich et al. In order for spatiotemporal coordination to occur, regenerative signals need to propagate through both space and time. Ways in which signaling molecules can spread through space are well recognized as diffusion and active transport (Deneke and Di Talia Another elegant work presents the critical role of rhythmic travelling EKR waves in regulating the tempo-spatial growth of bone in regenerating zebrafish scales (De Simone et al. When examining the process of regeneration in vertebrates, our attention is typically directed towards a single organ, such as limb, brain and heart, etc. Regeneration of these organs usually takes weeks to months and requires the activation of a number of specific cell pools. And identifying remote responses and mapping communication networks between organs pose significant technical challenges. Planarian flatworms have the ability to regenerate into fully functioning organisms from small pieces of tissues in just a few days. Injury causes extensive alterations in gene expression across the entire organism. The ability to regenerate rapidly together with the rapid response of whole-body tissues at the molecular level makes planarians a valuable model for studying the response of distal tissues to injury and indicates the presence of injury signal that can move at a high speed. The ERK signaling waves are proposed to engage in long-distance communication, but their reported velocity, ranging from 10 to 100 μm/h, is insufficient to account for the initiation of distant wound reactions in planarians (De Simone et al. cebpd-linked enhancer is essential for activating cebpd at a distance and regulating fluid levels following cardiac injury (Sun et al. via ERK waves (De Simone et al. Together, these studies highlight the important phenomenon that local injury initiates and relays a complex signaling network that guides long-distance tissue regeneration, thus elucidating not only the mechanisms of transmission of damage signals over long distances, but also emphasizing the significance of distant tissue feedback to damage signals during regeneration Fig. . Both mT


Giardia duodenalis is a common gastrointestinal pathogen globally that has been associated with growth failure in children. Most of the studies have been done in school-age children, and there is a paucity of data in pre-school children. We determined the prevalence and factors associated with G. duodenalis infection in children aged 9–36 months presenting to Mulago Hospital with diarrhea or cough. Demographic and socio-economic characteristics, animal ownership, medical history, and physical examination findings were recorded. Stool was tested for G. duodenalis using real-time quantitative polymerase chain reaction (qPCR), and additional tests included stool microscopy and qPCR for Cryptosporidium. The overall prevalence of G. duodenalis infection was 6.7% . In children with diarrhea the prevalence was 6.9% , whereas it was 6.5%  in those with cough as the main symptom. Of 214 children with G. duodenalis infection, 19 (8.9%) were co-infected with Cryptosporidium. Older children (25–36 months) were more likely to have G. duodenalis infection . Use of an unimproved toilet  and the wet season  were associated with increased infection. Other factors associated with infection were recurrent diarrhea  and passing of mucoid stool . Having a ruminant at the homestead was also associated with infection . Giardia duodenalis infection occurred in 1 of 15 children aged 9–36 months with diarrhea or cough in Kampala, Uganda. Further studies are needed to clarify the zoonotic significance of G. duodenalis infection in this setting. Giardia duodenalis is a common gastrointestinal pathogen in humans and is present worldwide. The distribution tends to vary by geographical location, and it is more common in low-income countries.,Giardia duodenalis is also a common enteric parasite of animals, including livestock, companion animals, and wildlife, and therefore it is considered a potential zoonotic disease.–Giardia duodenalis  is transmitted by contaminated drinking water or food as well as by fomites or direct physical contact with infected hosts.,Giardia duodenalis is three times more common in children than adults.–G. duodenalis.G. duodenalis, ranging from 2.9% to 87%.–of G. duodenalis in pre–school-aged children. The objective of the current study was to describe the prevalence of G. duodenalis and associated factors in children aged 9–36 months presenting with diarrhea or cough as key symptoms at a tertiary hospital in Uganda.Studies from East African countries have shown a wide variation in prevalence and geographical distribution of Cryptosporidium, G. duodenalis, and other gastrointestinal pathogens. They were followed through household visits in the community to determine if household members also had Cryptosporidium by stool examination. This paper reports the outcomes of G. duodenalis testing in the hospital setting.This was a cross-sectional analytical study conducted between 2014 and 2017 among children presenting with diarrhea or cough as the main symptoms to the pediatric emergency care unit of Mulago National Referral and Teaching Hospital. This was a sub-study of a hospital and household study to describe the transmission of respiratory cryptosporidiosis in children with diarrhea or cough at Mulago Hospital. In the main study, children with diarrhea or cough were tested for Mulago National Referral and Teaching Hospital is situated in the capital city of Uganda and serves as a primary health care facility for people living within the surrounding areas; the majority of patients are referred from the lower heath facilities in Kampala and surrounding districts. More than half of the children admitted at the pediatric emergency unit (acute care unit [ACU]) come from the urban and peri-urban areas of Kampala. The ACU on average receives 80 patients per day, the majority of whom are aged < 5 years; the 9–36 months age group constitutes about 40% of the patient demographic. Children with diarrhea constitute 10%, whereas those with cough are approximately 25%.Children aged 9–36 months presenting with diarrhea or cough were screened for the study. Informed consent was obtained by the study doctor after explaining the details of the study and its significance to the parent or caregiver. Those who were not willing to wait for completion of the study procedures or those who could not produce a stool sample were excluded. Those who fulfilled the inclusion criteria were consecutively enrolled until the required sample size was accrued. Both inpatients and outpatients were enrolled.Socio-demographic information, such as the child’s age and sex and the caregivers’ age and education, were obtained using a structured questionnaire. Additional household information included source of water, type of toilet facility, and presence of domestic animals or poultry on the compound. Improved water source was defined as a household that used piped water or a borehole. Improved toilet was defined as a flush toilet, ventilated improved pit latrine, or pit latrine with a slab.Subsequently a detailed medical history and physical examination were performed on the child, which included weight, length and height, and mid-arm circumference as well as a detailed general and systemic examination. Consistency and color of the stool was determined based on inspecting the stool whenever the child passed stool or at the time of sample collection. Persistent diarrhea was defined as passing of watery or loose stool three or more times in 24 hours for a period of 14 days or more. Fever was assessed by history and confirmed by measuring the temperature. Any child who had an axillary temperature of ≥ 37.5°C was regarded as febrile. Hydration status was determined using the Integrated Management of Childhood Illness guidelines,Giardia duodenalis DNA from stool was extracted using the QIAamp Fast DNA Stool Mini Kit . The kit protocol was followed according to the manufacturer’s instructions except for the following modifications. After the second wash, buffer was added (AW2), and the collection tubes were centrifuged for 4 minutes to increase DNA yield. Real-time PCR was used to determine the presence of G. duodenalis as previously prescribed.Stool was collected from diapers or directly from the rectum using a tube connected to a syringe for those children who had diarrhea and placed into plastic containers. Samples were delivered to the laboratory within 4 hours of collection. G. duodenalis in the stool. This sample size resulted in an absolute precision of 0.5–1.7% .The sample size was dependent on the size of the parent study. Of the 3,180 participants enrolled in the parent study, 3,173 were examined for G. duodenalis. Multivariable binary logistic regression analyses was carried out to assess for the strength of association between selected exposures and G. duodenalis colonization. In our final model, we included variables whose P value was < 0.20 in bivariable analysis or where important sociodemographic characteristics or had biological plausibility. Strength of association was determined using adjusted odds ratios and 95% CIs.Data were analyzed using Stata version 14.2 . We summarized continuous variables using means with standard deviations or medians with interquartile ranges and categorical variables using their frequencies and percentages. The prevalence was defined as the proportion of participants enrolled in the study and who had a stool examined who tested positive for G. duodenalis infection was 6.7% . In children whose main symptom was diarrhea, the prevalence was 6.9% , whereas in children with cough as the key symptom it was 6.5%   were co-infected with Cryptosporidium spp. When plotted against months of the year, the frequency of G. duodenalis infection was higher during the wet season than during the dry season  . Of the y season .G. duodenalis a are shown in G. duodenalis, 112 (52.3%) were aged 13–24 months, 54 (25.2%) were 9–12 months, and 48 (22.4%) were 25–36 months old. The median age (interquartile range [IQR]) of the children who had G. duodenalis infection was 17 months (IQR: 12–23), compared with 14 months (IQR: 11–19) among those who were negative (P < 0.001). The age, level of education, and other socio-demographic characteristics of the caretakers were similar whether the child had G. duodenalis infection or not. The main source of water was a public tap or a stand pipe in 177/214 (82.7%) among those who had G. duodenalis compared with 2,223/2,959 (75.1%) without infection. Very few families had a privately connected piped water or a borehole. Most households used a toilet (improved or unimproved), commonly the pit latrine. Most of the households had animals in the compound; these were mainly domestic animals such as goats, sheep, cows, pigs, dogs, or cats.The socio-demographic and household characteristics of children with and without G. duodenalis in multivariable analysis were older age , using an unimproved toilet , and wet season . Among children with diarrhea as the key symptom, age and seasonality remained independently associated with G. duodenalis infection. Other factors were recurrent diarrhea , passing mucoid stool , and having a ruminant  in the compound .Results of univariable and multivariable regression exploring factors in the total study population and in the subset with diarrhea as the key symptom are shown in G. duodenalis infection in young children aged 9–36 months presenting with diarrhea or cough/difficult breathing at a tertiary hospital in Uganda. The overall prevalence of G. duodenalis in these pre-school children was 6.7%, with no significant difference in the prevalence between those who had diarrhea (6.9%) and those who had cough (6.5%) as key symptoms. This is lower than what was reported in a study of asymptomatic children aged 0–12 years living in Mulago village, which is adjacent to the current study site ,G. duodenalis in this study, similar to what was previously reported in a multi-country study of 2,089 children.G. duodenalis infection with age.G. duodenalis.G. duodenalis by other researchers,This study describes the prevalence of G. duodenalis infection is asymptomatic in high-transmission areas and may even be protective against pathogens that cause acute diarrhea.–G. duodenalis infection have been associated with the different genotypes, with some causing diarrhea and others not.G. duodenalis infection was more likely to be associated with recurrent diarrhea and production of mucoid stool. Other studies have also reported recurrent or relapsing diarrhea in children with G. duodenalis infection.,G. duodenalis infection has been associated with growth failure in young children in a number of studies,–,The lack of difference in the prevalence between diarrhea and cough/pneumonia patients may indicate the background epidemiology of the disease in the general population of children aged 9–36 months and not necessarily symptoms of infection. Some authors have suggested that G. duodenalis. As mentioned, G. duodenalis is a common gastrointestinal pathogen that affects a broad range of hosts, including humans, livestock, and wildlife, and zoonotic transmission has been documented to occur because of similarities in assemblages in some species.G. duodenalis has been associated with seasonal peaks or temperature variation,In this study we found that children who came from households that had a ruminant on the compound were more likely to be infected with G. duodenalis in low-resource countries is based on the detection of cysts in stool samples by direct microscopy. The method we used in this study (quantitative PCR) is both highly specific and sensitiveThe traditional approach to diagnose G. duodenalis occurs in 1 of 15 children aged 9–36 months presenting to hospital with diarrhea or cough in Uganda. Overall, infection is associated with increasing age, use of and unimproved toilet facility, and wet season, whereas recurrent diarrhea, passing mucoid stool, and having a ruminant in the homestead are factors associated with G. duodenalis infection in children with diarrhea as a key symptom. Further studies are needed to clarify the zoonotic significance of G. duodenalis in this setting, with prevention strategies emphasizing personal protection measures in this age group especially during the wet season.Infection with


Strongyloides promotes ATL development, suggesting that the immunological status of infected individuals is a determinant of HTLV-1 pathogenicity. As CD4+ T cells play a central role in host immunity, the deregulation of their function and differentiation via HTLV-1 promotes the immune evasion of infected T cells. During ATL development, the accumulation of genetic and epigenetic alterations in key host immunity-related genes further disturbs the immunological balance. Various approaches are available for treating these abnormalities; however, hematopoietic stem cell transplantation is currently the only treatment with the potential to cure ATL. The patient’s immune state may contribute to the treatment outcome. Additionally, the activity of the anti-CC chemokine receptor 4 antibody, mogamulizumab, depends on immune function, including antibody-dependent cytotoxicity. In this comprehensive review, we summarize the immunopathogenesis of HTLV-1 infection in ATL and discuss the clinical findings that should be considered when developing treatment strategies for ATL.Human T-cell leukemia virus type-1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATL). HTLV-1 carriers have a lifelong asymptomatic balance between infected cells and host antiviral immunity; however, 5–10% of carriers lose this balance and develop ATL. Coinfection with  Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus that causes various diseases, including adult T-cell leukemia/lymphoma (ATL), HTLV-1–associated myelopathy/tropical spastic paraparesis (HAM/TSP), and HTLV-1 uveitis (HU). HTLV-1 mainly infects CD4+ T cells and can transform the infected cells to cause ATL, which has a poor prognosis . ATL is The genomic structures of HTLV-1 and the human immunodeficiency virus (HIV) are similar, with structural genes containing Gag, Pol, and Env; regulatory genes, such as HIV-1 transactivator of transcription (Tat) and Rev of HIV; Tax and Rex of HTLV-1; accessory genes such as Vif, Vpr, Vpx, Vpu, and Nef of HIV; p12, p13, p30, and the HTLV-1 bZIP factor (HBZ) of HTLV-1, which are flanked by 5′ and 3′ long terminal repeats (LTR) . PathogeHTLV-1 encodes the viral transcription transactivator, Tax, in the pX region of its genome, which promotes oncogenesis. Tax interacts with various host cell proteins, affects intracellular signaling pathways, regulates gene transcription, and contributes to HTLV-1-infected T-cell proliferation ,21. HowePneumocystis carinii, aspergillosis, and candidiasis, which are observed in patients with AIDS, and cytomegalovirus pneumonia and Strongyloides stercoralis infection [Clinically, patients with ATL develop profound immunodeficiency, similar to that seen in patients with AIDS . Furthernfection ,37. Opponfection ,39. Imponfection ,41. ThusApproximately 95% of HTLV-1 carriers remain asymptomatic throughout their lives, without any clinical symptoms associated with HTLV-1 infection. Therefore, unlike HIV, which continues to proliferate actively even during the asymptomatic period, HTLV-1 is a latent infection, which suggests that the HTLV-1 infection alone does not affect the infected host. However, several studies have shown that HTLV-1 can evade and disturb the host immune system. These processes are described below.Sense-strand transcription of HTLV-1 is generally silent; however, it is activated in ex vivo cultures under hypoxic stress or high-glucose conditions ,43. The HTLV-1 encodes a potent transcription factor, Tax, which strongly induces viral gene expression by enhancing the recruitment of enhancers such as p300 to the viral LTR ,46. Tax HBZ transgenic mice [HBZ has low immunogenicity and is persistently expressed during the viral incubation period and ATL onset and progression ,51. HBZ nic mice . Furthernic mice .Additionally, Rex, p30, p12, and p13 are transcribed from the sense strand of the pX region HTLV-1 via alternative RNA splicing. The CTLs recognize HLA class I presented with the Tax peptide, and p12 expression reduces the plasma membrane expression of HLA class I , likely A large-scale integrative genomic analysis of ATL revealed that approximately 90% of ATL cases were enriched with activating mutations in the T-cell receptor (TCR)–nuclear factor (NF)-κB pathway . FurtherIn addition, single-cell analysis revealed that HTLV-1-infected cells that acquired clonal proliferation ability exhibited the abnormal expression of various immune-related molecules . In addiTumor-associated macrophages (TAMs) are major constituents of tumor stromal cells and act as tumor promoters by promoting cancer cell proliferation, invasion, angiogenesis, and immunosuppression ,63,64. TPD-L1 is a transmembrane protein that suppresses immune responses by binding to two inhibitory receptors, PD-1 and B7-1 (CD80), and it is strongly expressed on the surface of tumor and non-transformed cells in the tumor microenvironment . PD-L1 eSingle-cell analyses have shown that ATL is accompanied by a decrease in B cells and an increase in myeloid cells . Among tStrongyloides stercoralis have a high risk of transmission [ATL occurs in less than 5% of HTLV-1 carriers after five to six decades of chronic infection. Moreover, HTLV-1 infection during childhood, specifically more than 6 months of breastfeeding  is a risk factor for ATL transformation . This tysmission .HIV and HTLV belong to the Retroviridae family and share genomic and epidemiological characteristics. Moreover, a recent meta-analysis showed that individuals with HIV and HTLV-I coinfection have accelerated HIV progression, worse survival, and a high incidence of HAM/TSP, peripheral neuropathy, encephalopathy, and opportunistic infections, such as scabies, candidiasis, and strongyloidiasis ,77. HTLVS. stercoralis is an opportunistic nematode that can cause severely disseminated infections in immunocompromised individuals. It is typically found in tropical regions, and its area of distribution overlaps with that of HTLV-1 [S. stercoralis infections may partially explain the clinical and genomic disparities in ATL cases between Japan and other regions. In countries other than Japan, S. stercoralis infections are associated with early-onset ATL [f HTLV-1 . HTLV-1 f HTLV-1 . Additiof HTLV-1 . Strongyf HTLV-1 . S. sternset ATL .Owing to the resistance to chemotherapy, high relapse rates, and opportunistic infections, ATL prognosis remains poor even with aggressive treatment, with a 3-year overall survival of less than 25%. Multiagent chemotherapy, interferon-α plus zidovudine, mogamulizumab, and allogeneic hematopoietic stem cell transplantation  remain the main treatment modalities. Mogamulizumab is a monoclonal antibody that targets CCR4 and is associated with a higher response rate in combination with chemotherapy. It may transiently improve the response before allo-HSCT, which is the only curative treatment available for patients with aggressive ATL. However, not all patients are candidates for allo-HSCT. In well-conducted clinical trials, only 7% of patients with aggressive ATL undergo allo-HSCT . The 5-ySeveral scoring methods have been developed worldwide using host-dependent and disease-burden factors. The ATL Prognostic Index was constructed retrospectively for patients with aggressive subtypes who did not undergo allo-HSCT . AdverseA nationwide survey in Japan evaluated patients with aggressive ATL undergoing intensive treatment with potential indications for allo-HSCT. The independent prognostic factors identified were clinical subtype , poor performance status (ECOG score > 1), corrected calcium levels (≥12 mg/dL), C-reactive protein level ≥ 2.5 mg/dL, and sIL-2R level > 5000 U/mL . The steTumor-specific CTL induction is associated with the prognosis of solid tumors . In pati114–125) sequence with HLA-DRB1*15:02 restriction is recognized by specific CD4+ T cells [The graft-versus-leukemia effect of allo-HSCT has been explained primarily by Tax-specific CTLs. Although Tax is expressed in only approximately 50% of patients with ATL, HBZ transcripts are present in all ATL cases. HBZ-specific CTLs have also been induced in vitro without showing limited cytotoxic activity against ATL cells . Additio T cells . FurtherMogamulizumab, an anti-CCR4 antibody, was the first molecular-targeted drug approved for ATL treatment in Japan. Its effects include antibody-dependent cellular cytotoxicity and the enhancement of antitumor immunity via regulatory T-cell suppression ,98. MogaThe anti-PD-1 antibody exerts an antitumor effect via binding to PD-1 on T cells and inhibits the transduction of inhibitory signals via inhibiting PD-1 binding to PD-L1/PD-L2, resulting in T-cell activation. It is effective in treating solid tumors such as malignant melanoma and lung cancer . AlthougLenalidomide, a thalidomide derivative, is an immunomodulatory agent used in the treatment of multiple myeloma. Lenalidomide has been reported to have immunopotentiating activity against multiple myeloma, including a direct tumor cell-killing effect and enhanced T and NK cell function . In ATL,Dendritic-cell vaccine therapy efficiently induces tumor antigen-specific CTLs and administering tumor antigen peptide-pulsed dendritic cells exerts an antitumor effect in patients with cancer . A dendrAntiviral therapy, multidrug chemotherapy, and allo-HSCT are the main forms of therapy for ATL. However, regardless of the treatment method used, controlling patient conditions is challenging, and further improvement is required. Among the therapeutic drugs for ATL, the effects of mogamulizumab, lenalidomide, and allo-HSCT are strongly dependent on the patient’s immune function . Recent


Alzheimer's disease (AD), recognized as the leading cause of dementia, occupies a prominent position on the list of significant neurodegenerative disorders, representing a significant global health concern with far‐reaching implications at both individual and societal levels. The primary symptom of Alzheimer's disease is a decrease in synaptic potency along with synaptic connection loss. Synapses, which act as important linkages between neuronal units within the cerebral region, are critical in signal transduction processes essential to orchestrating cognitive tasks. Synaptic connections act as critical interconnections between neuronal cells inside the cerebral environment, facilitating critical signal transduction processes required for cognitive functions. The confluence of axonal and dendritic filopodial extensions culminates in the creation of intercellular connections, coordinated by various signals and molecular mechanisms. The progression of synaptic maturation and plasticity is a critical determinant in maintaining mental well‐being, and abnormalities in these processes have been linked to the development of neurodegenerative diseases. Wnt signaling pathways are important to the orchestration of synapse development. This review examines the complicated interplay between Wnt signaling and dendritic filopodia, including an examination of the regulatory complexities and molecular machinations involved in synaptogenesis progression. Then, these findings are contextualized within the context of AD pathology, allowing for the consideration of prospective therapeutic approaches based on the findings and development of novel avenues for future scientific research. Alzheimer's disease (AD) is the leading etiological factor in the development of dementia. A prominent causative factor for its onset is the aggregation of amyloid β‐protein (Aβ). The presence of Aβ aggregates contributes to abnormal axonal and presynaptic terminal functioning, ultimately resulting in the formation of immature synapses connecting presynaptic terminals with a variety of dendritic spines. This process is potentially modulated by regulatory mechanisms orchestrated by the Wnt signaling pathway. The initial phase of the disorder is characterized by deficits in the ability to encode and store new memories. Later stages are then accompanied by progressive neuronal loss and cognitive impairment. Changes are caused by modifications in amyloid precursor protein (APP) breakdown, synthesis of the APP fragment amyloid β‐protein (Aβ), and hyperphosphorylated tau protein aggregation, all of which contribute to decreased synaptic strength and synapse loss.Synapses are asymmetric intercellular connections, mediated by cell adhesion molecules (CAMs), that allow neurons to communicate quickly and connect neurons to circuits.Wnt signaling is one of the most critical signaling systems that comprises evolutionarily conserved and entangled pathways. Cell adhesion and cell fate determination have been demonstrated to be critically and irreplaceably related to Wnt signaling.2Wingless and Int‐1.Wnt represents a combination and is an abbreviation of the words 2+) .2+ and DAG. Active kinase proteins are typically related to the activation of downstream transcription factors such as nuclear factor associated with T cells (NFAT) and nuclear factor‐kappa B (NFkB).2+ signaling has been linked to several biological processes, such as control of gene expression, cell motility, differentiation, and proliferation.One branch of the Wnt noncanonical pathway is the Wnt/PCP pathway Figure . It is e) Figure . Wnt lig3Wnt signaling is a highly conserved pathway that regulates several biological activities, including cell proliferation, differentiation, and cell fate determination. It has been linked to the onset of several diseases, including cancer and neurological disorders like AD.2+ pathways, have also been implicated. Wnt/PCP and Wnt β‐catenin are mutually repressive.2+; signaling pathway by regulating CaMKII, thus affecting neurite growth.Wnt signaling is important in controlling synaptic plasticity and neurogenesis in the brain, and changes in this system may contribute to the development of AD. Wnt signaling pathway activation has been found to have neuroprotective benefits by boosting neuron survival and differentiation and decreasing Aβ build‐up and tau hyperphosphorylation.4The regulation of synaptogenesis involves critical signaling systems, notably the Wnt pathways  spines characterized by elongated, slender necks and diminutive heads, termed “thin spines,” (2) spines possessing wider necks and prominent heads, referred to as “mushroom spines,” and (3) abbreviated spines lacking delineated necks, denoted as “stubby spines.”Nonetheless, the prevailing perspective posits that a filopodia‐like extension originating from the dendritic shaft may establish a connection with the axon, initiating the synaptogenesis process. This nascent connection is believed to develop into a slender spine, which undergoes maturation to transition into the mature morphology characteristic of a mushroom spine  receptors containing GluN2B subunits.AD is marked by several prevalent attributes, including synaptic abnormalities and dysfunctions, such as synaptic damage, synaptic loss, and structural modifications in the synapse  antagonist (reviewed in FarlowA prominent cause of morbidity among the elderly, age‐related diseases, notably AD, has been the focus of extensive research efforts dedicated to investigating potential therapeutic interventions and preventive strategies. However, finding a permanent cure requires a thorough understanding of the underlying molecular mechanisms governing the disease pathology. This knowledge can serve as the foundation for the development of targeted interventions to mitigate the symptomatic manifestations associated with the disorder. At present, the prevailing pharmacological approaches predominantly involve the administration of cholinesterase inhibitors and a NMDAR (N‐methyl‐Drosophila gut stem cells.The activation of the Wnt pathway, by repression of factors implicated in Toll pathway activation, has demonstrated the capacity to ameliorate the deleterious outcomes associated with amyloidogenesis and oligomerization, concurrently exerting inhibitory effects on inflammation within a designed optogenetic paradigm utilizing 7According to research, synaptogenesis requires the activation of a wide array of signaling pathways to promote the proliferation, directional guidance, and stabilization of interneuronal connections required for the normal processes of cognition, memory, and learning. The Wnt family, which is delivered to specific locations via signaling filopodia, also called cytoneme, is notable among these signaling molecules. The structural and functional molecular mechanisms governing cytonemes and synaptogenic dendritic filopodia show substantial similarities, implying that these protrusions are part of a common system whose efficiency varies depending on the signaling milieu.Changes in filopodia stability have a negative impact on synapse formation in neurodegenerative disorders such as AD, resulting in impaired cognitive capacities. Furthermore, the number and shape of dendritic filopodia increase in the context of Alzheimer's disease. Improving our understanding of the molecular mechanisms underlying or contributing to AD holds promise for improving treatment strategies and laying the groundwork for future research into novel pharmacological targets. However, the implementation of such approaches poses significant problems. This could include boosting Wnt factors that rely on β‐catenin or decreasing PCP‐dependent factors that maintain homeostasis. The precision of therapy application must be limited to neurons only, preventing misalignment of Wnt signaling in other somatic tissues, which could lead to the onset of carcinogenic processes. This is significant since abnormal levels of Wnt signaling, both increased and decreased, have been linked to the development of a variety of cancers. On the other hand, altering Wnt/β‐catenin signaling activity appears to be an attractive avenue for therapeutic intervention; the effort to develop pharmacological agents, either as activators or inhibitors, is hampered by difficulties in achieving optimal safety profiles and the desired selectivity.As a result, further research validating the relationship between Wnt and dendritic filopodia could lead to a new field of collaborative investigation and propel advancements in Alzheimer's research while broadening the scope of understanding neuronal regulation in general. Nonetheless, evidence of dissimilarity across these filopodia would highlight areas of divergence accessible to targeting cell‐specific processes, expanding the evolving wealth of knowledge about synaptogenesis and signal transit.Cheng‐Ting Zhang and Wen‐Yuan Wang conceptualized this review and wrote the manuscript. Joy Wang revised the manuscript.Cheng‐Ting Zhang is an editorial member of Ibrain and Wen‐Yuan Wang is the Associate editor of Ibrain; they are co‐authors of this article. They were excluded from editorial decision‐making related to the acceptance and publication of this article. The authors declare no conflicts of interest.Not applicable.


It is known to all that Wnt signaling pathway plays an important role in the early development of tooth. Our previous research found that Wnt signaling pathway played crucial roles in dental development, and mutations in antagonist of Wnt signaling pathway may lead to the formation of supernumerary teeth. However, the expression pattern of Wnt signaling molecules in early development of tooth, especially genes with stage specificity, remains unclear. Hence, we applied RNA-seq analysis to determine the expression levels of wnt signal molecules at five different stages of rat first molar tooth germ. In addition, after literature review we summarized the function of Wnt signaling molecules during tooth development and the relationship between Wnt signaling molecules variation and tooth agenesis. Our research may have implications for exploring the role of Wnt signaling molecules in different stages of tooth development. The Wnt signaling pathway plays an important role in many processes of biological development, including embryogenesis, tissue homeostasis and wound repair. Several biological behaviors such as cell proliferation, differentiation, polarization, and apoptosis were regulated by the Wnt signal pathway. The Wnt signaling pathway is a complex system that consist of extracellular secreted glycoproteins (19 Wnt ligands), wnt receptors , cytoplasmic proteins  and several Wnt-associated molecules  of rat tooth germ development. It is observed that when the embryo developed to E14.5, E16.5 and E18.5, the first molar tooth germ was in bud stage, cap stage and early bell stage respectively, while the tooth germs of 1-and 7-day-old mice were in late bell stage and eruption stage respectively. After sequencing, a total of 143 mRNA related to Wnt signal pathway were detected. Expression of Wnt signaling molecules were displayed in Since it is difficult to completely distinguish the molecules involved in canonical Wnt signaling pathway and the noncanonical Wnt signaling pathway, therefore we classified and integrated all genes together in We summarized the genes with special expression levels in  We investigated five time points  of rat tooth germ development. Considering the small size of rat tooth germs, it is difficult to separate dental papilla and dental sac, so we took the whole tooth germs for sequencing. The sequencing results include both epithelial genes and dental papilla genes. Totally 128 mRNA related to Wnt signal pathway of rat tooth germ samples from different stages of development were detected. We observed that the expression levels of these molecules showed significant time specificity, including Fzd10, Prkaca, Fzd7, Dkk2, Cer1, Ctnnbip1, Dkk1, Wnt10b, Wnt3a, Serpinf1, Dkk3, Wnt16. Wnt10b, Dkk1 and Serpinf1 have been found to be associated with tooth agenesis, but little research has been done on the relationship between the other genes mentioned above and tooth germ development. We obtained a relatively complete gene expression profile related to Wnt signaling pathway through RNA sequencing. Our study enriches the understanding of Wnt signal pathways and provides a lot of useful information for subsequent research.Gene mutation may disrupt specific signaling networks and cause a wide variety of selective tooth agenesis patterns. Tooth agenesis can either occur as an isolated condition (non-syndromic tooth agenesis) or can occur as part of a genetic syndrome (syndromic tooth agenesis). Some genes are responsible for syndromic tooth agenesis, including Robinow syndrome and Gardner syndrome. The mutations of APC may cause Gardner syndrome, besides gene mutations of Ror2, Dvl1, Dvl3 and Wnt5a are associated with Robinow syndrome. Genes responsible for tooth agenesis were displayed in 61 Mutations in Apc may cause familial adenomatous polyposis (FAP), an autosomal dominant pre-malignant disease that usually progresses to malignancy.62 Besides, other diseases such as Gardner syndrome, which is characterized by the presence of multiple intracolonic polyps and extracolonic tumors, can also be caused by Apc mutation. Our previous study found that patients with Gardner syndrome also had multiple impacted and supernumerary teeth.16 We found that Apc was expressed at E14.5-P7 and there are up to 2037 different mutation forms in Apc, suggesting that Apc played an important role in all stages of early tooth development.Adenomatous polyposis coli (APC) gene encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway. It is also involved in cell migration and adhesion, transcriptional activation, and apoptosis.11–13 Besides, mutations of Wnt10b are associated not only with oligodontia and tooth agenesis, but also with microdontia, short tooth roots, dental pulp stones, and taurodontism.11 The mutations of Wnt10b decreased Wnt signaling in dental pulp stem cells, affecting the development of permanent dentition, particularly the lateral incisors.13 Wnt10b mutation allele-transfected into stem cells from human exfoliated deciduous teeth resulted in decreased gene transcription, while Wnt10b protein increased with the increase of mutant alleles, indicating that Wnt10b variants have functional effects on gene regulation and reveal that these variants may affect tooth development leading to tooth agenesis.63 A. Nadiri et al. observed that the relative amount of Wnt10b was maximal at E14 stage during the development of rat molar tooth germs by western blotting.64 At the late bell stage, Wnt10b was mainly detected in the inner dental epithelium, indicating that Wnt10b may be involved in cell proliferation.64 Unlike other studies, our study found that Wnt10b was significantly expressed at E18.5 (early bell stage) and P1 (late bell stage) stages. Therefore, the expression of Wnt10b during the tooth germ development needs to be further verified and explored.Wingless-Type MMTVIntegration Site Family, Member 10B (Wnt10b) is a ligand of Wnt signaling pathway and has been implicated in regulation of embryogenesis. Multiple variants of Wnt10b were found by mutational analysis in patients with non-syndromic tooth agenesis.65 Tooth agenesis in SSPS patients can be characterized by conical primary teeth, agenesis of permanent teeth and hypodontia.24 Odonto-onycho-dermal dysplasia (OODD) is a rare autosomal recessive syndrome mainly characterized by dry hair, anodontia of permanent teeth, smooth tongue, keratoderma, and hyperhidrosis.26 Recently, Wnt10a mutations were found in patients with nonsyndromic tooth agenesis as well, mainly characterized by oligodontia and agenesis of the maxillary permanent canines. Upper and lower premolars were the most affected missing teeth.21 In our research, Wnt10a was significantly expressed in E18.5 (early bell stage) and P1 (late bell stage) stages and the expression level decreased in P7 phase. Our results implied that Wnt10a played an important role in the formation of tooth hard tissue.Wingless-Type MMTV Integration Site Family, Member 10A (Wnt10a) is another important ligand of Wnt signaling pathway, which appears to have specific relevance to skin, its appendages and teeth. Wnt10a is associated with both syndromic and non-syndromic tooth agenesis. Schöpf-Schulz-Passarge syndrome (SSPS) is an autosomal recessive form of ectodermal dysplasia resulting from mutations in Wnt10a.66 Researchers observed that strong expression of Dkk1 was localized in preodontoblasts on the labial side of the incisors.67 At postnatal day 2, Dkk1 is prominently expressed in the preodontoblasts and odontoblasts in mouse molar germs.68 In Dkk1 transgenic mice, overexpression of Dkk1 in pulp and odontoblast cells delayed the maturation of dentinogenesis during post-natal development.69 The dental crown begins to form in the late bell stage (P1). In this stage, peripheral cells of the dental papilla differentiate into odontoblasts that secrete dentin. Our results demonstrated that Dkk1 was significantly expressed in the P1 phase, which indicated that Dkk1 played an important role in the formation of dentin.Dickkopf-related protein 1(Dkk1) is a typical antagonist of Wnt/β-catenin signaling by competing for the Wnt receptor LRP5/6. The mutation of Dkk1 may cause oligodontia and short root anomaly.70  Mutations in Serpinf1 have been reported in Chinese individuals with OI.46  Our findingSerpinf1 mainly high expressed during postnatal stages, indicated that Serpinf1 played an important role in the formation and mineralization of tooth hard tissues.Serpin family F member 1 (Serpinf1) encodes the 50-kDa secreted glycoprotein pigment epithelium-derived factor (PEDF), which inhibits Wnt/β-catenin signaling pathway. Mutation of Serpinf1 may cause a unique autosomal recessive disease, Osteogenesis imperfecta (OI) type VI (MIM #610968). OI is characterized by recurrent fractures, progressive skeletal deformities, and growth deficiency, blue or gray discoloration of the sclera and dentinogenesis imperfecta.42 Fzd10regulates cell proliferation and mediates Wnt1-induced neurogenesis in the developing spinal cord.71 Investigations have demonstrated that mutations in the gene of Prkaca result in the development of adrenocortical adenomas associated with Cushing’s syndrome.72 Fzd7 plays a significant role in the regulation of multipotentiality of human pluripotent stem cells and its down-regulation accompanies differentiation and exit from the pluripotent stem cell state Dkk2 plays an important role in ovarian cancer.74 It has been well documented that Cer1 plays dual roles in neural induction and suppression of mesodermal or endodermal lineages.40 We observed that the mRNA expression levels of Fzd10 and Prkaca were mainly high during bud stage (E14.5), Fzd7 and Dkk2 were mainly highly expressed during cap stage (E16.5), and Cer1 was high during early bell stage (E18.5), indicating that they may play important roles in the early stage of tooth germ development. The expression level of Ctnnnbip1 was mainly high during P1 stage (late bell stage), enlightening that Ctnnbipmay be related to the formation and mineralization of enamel and dentin. Compared to the embryonic stages, the mRNA expression levels of Wnt3a and Dkk3 were highly expressed during postnatal stages, which implied that once significant high expression of Wnt3a and Dkk3 were found, it indicated that tooth germ has developed to the stage of hard tissue formation and mineralization. By contrary, Wnt16 was expressed only during E14.5 and E16.5, suggesting that Wnt16 was one of the important markers of early development of tooth germ.Fzd10 is one of the FZD family receptors which act through canonical Wnt signaling.In summary, we determined the expression levels of Wnt signaling molecules at each stage of rat first molar tooth germ development by RNA-seq analysis and after literature review we summarized the relationship between Wnt signaling molecules variants and tooth agenesis. Our data provided important information about novel genes in tooth germ development. Our findings may help to elucidate the molecular mechanisms of tooth germ development and provide a theoretical basis for further studies on the expression and function of genes involved in human tooth development and regeneration.Specific pathogen-free (SPF)-grade Sprague Dawley (SD) rats  were used in our study. The day when the vaginal plug was formed as a reference of embryonic day 0 (E0), embryos at E14.5, E16.5 and E18.5 stages were used. One-day-old (P1) and seven-day-old (P7) rats were used as well. We separated the embryos from the uterus of pregnant female rats. Each group has 8 mouse embryos, and the sex of the embryos was randomized to both males and females. The first mandibular molar tooth germs were isolated from these embryos and rats using a zoom stereo microscope  and prepared for subsequent experiments. All molars were dissected by one same researcher. The rats were euthanized with phenobarbital sodium  anesthesia. All animal experiments were approved by the Institutional Animal Care and Use Committee of Fudan University.Total RNA was obtained from the tooth germ cells in the embryonic  and postnatal (P1 and P7) phases using TRI reagent . More than eight tooth germs were used in each phase. An RNA-seq library was constructed following the manufacturer’s instructions. Then, next-generation sequencing was performed using an Illumina NovaSeq platform . mRNAs related to wnt signal pathway were selected and hierarchical clustering analysis was performed.®) (https://www.hgmd.cf.ac.uk/ac/index.php) for all variants of Wnt signaling genes. A comprehensive review of the PubMed database was undertaken for reports in the English language from 1January 2012 to 1 October 2022. The following search terms were used: (tooth [MeSHTerms]) AND (((Wnt Pathway [MeSH Terms]) OR Wnt Pathway, Canonical) OR Wntbeta-Catenin Signaling Pathway). Titles and abstracts were reviewed, and references and citations of relevant studies were also examined.We queried the Human Gene Mutation Database(HGMD


SnRK1 (sucrose non-fermenting-related kinase protein), two main components of the sugar-signaling pathways [SnRK1, these authors proposed that NSC remobilization in the stem may follow a “feast-or-famine”-like model, which fits perfectly well with the fluctuating source–sink relationship during the grain filling stage. In addition, this remobilization could be mainly driven by the sink strength of the panicle. These two works lay a solid foundation for further exploring the relationship between the stem sugar signaling network, the stem carbon metabolism and sink strength, and open up promising research prospects on the molecular regulatory network and the way sink organs remotely control carbon remobilization in the stem.Sucrose and its derivative hexoses are key metabolites of the plant metabolism, structural units of cell walls and stored reserves , and also crucial metabolic signals that interplay with other metabolic, hormonal and environmental cues to fine-tune plant growth and development ,2,3. TheDimocarpus longan), a subtropic fruit tree with high economic value and sensitivity to cold, ref. [cis-acting elements and tissue-expression patterns. They found that this transporter family is divided into four clades with conserved motifs and similar exon–intron organization. More notably, and based on the genetic approach, they found evidence that only DiSWEET1 was greatly induced by cold, supporting its contribution to the adaptive response of longan to low temperature. Similarly, ref. [CsSWEET2 in the cold tolerance of cucumber (Cucumis sativus). CsSWEET2 encodes an energy-independent hexose/H+ uniporter and is localized on the plasma membrane and endoplasmic reticulum. Interestingly, its overexpression in Arabidopsis plants resulted in the accumulation of soluble sugars (glucose and fructose) and resistance to cold stress. All these results point out the functional diversity of SWEET sugar transporters in plant physiology and open new avenues of research on the molecular network orchestrating SWEET upregulation by environmental factors.Sugar transport across the plant involves a variety of transporters gathered into three main families: monosaccharide transporter-like (MST) genes, sucrose transporters (SUTs/SUCs) and sugar-will-eventually-be-exported transporters (SWEETS) . In addild, ref.  carried ly, ref.  highlighVitis vinifira maturation, stress, abscisic-acid induced; VvMSA) transcriptionally regulates the hexose transporter gene Vitis vinifera Hexose Transporter 1 (VvHT1), and its expression is at the crosstalk of glucose and ABA signaling [VvMSA in glucose signaling, ref. [VvMSA gain- and loss-of-function embryogenic and non-embryogenic grapevine cells. The choice of these two models is crucial for discriminating between glucose-sensitive signaling and glucose-metabolism-dependent processes. These authors clearly highlighted that VvMSA acts as a transcriptional regulator of the glucose transporter gene VvHT1 in glycolysis-dependent glucose signaling and regulates the interplay between glucose metabolism, transport and signaling. These results shed new light on the regulatory network of the ASR family and fill a gap in our understanding of the regulation of this complex protein family.Sugar-signaling pathways interact with hormonal pathways in several biological contexts and throughout the life cycle of the plant ,9,10,11.ignaling . To gainng, ref.  used a cRosa sp. roots [Among the sugar-related signaling pathways, the oxidative pentose phosphate pathway (OPPP) remains the least investigated, even though it is involved in sugar-mediated nitrate and sulfate transporters in p. roots  and bud p. roots ,19. In tp. roots  focused Concluding remarks. This Special Issue “Sugar Transport, Metabolism and Signaling in Plants” is an excellent opportunity to gather a variety of scientific research works involving in-depth investigations. Each of them sheds new and interesting light on sugar-related topics, including the sink–source relationship, focusing on the role of the stem node, the role of SWEET in plant stress responses and the hitherto neglected sugar-signaling pathway within the OPPP. They open up promising avenues for uncovering the molecular regulatory network behind this physiological function and integrating this knowledge within the overall functioning of the plant.


Survival rates for children and adolescents diagnosed with malignancy have been steadily increasing due to advances in oncology treatments. These treatments can have a toxic effect on the gonads. Currently, oocyte and sperm cryopreservation are recognized as well-established and successful strategies for fertility preservation for pubertal patients, while the use of gonadotropin-releasing hormone agonists for ovarian protection is controversial. For prepubertal girls, ovarian tissue cryopreservation is the sole option. However, the endocrinological and reproductive outcomes after ovarian tissue transplantation are highly heterogeneous. On the other hand, immature testicular tissue cryopreservation remains the only alternative for prepubertal boys, yet it is still experimental. Although there are several published guidelines for navigating fertility preservation for pediatric and adolescent patients as well as transgender populations, it is still restricted in clinical practice. This review aims to discuss the indications and clinical outcomes of fertility preservation. We also discuss the probably effective and efficient workflow to facilitate fertility preservation. Long-term survival for children and adolescents diagnosed with malignancy has steadily increased and exceeded 80% over the past decade –3. As thThe incidence of pediatric and adolescent cancers is estimated to range between 50 to 200 cases per million children per year , 15 and In females, these treatments substantially accelerate the activation and atresia of primordial follicles, leading to premature ovarian insufficiency (POI) and permanent amenorrhea , 21–24. Spermatogenesis is particularly sensitive to chemotherapy and radiotherapy . Long-teYounger patients affected by certain non-oncological medical conditions which require gonadotoxic treatments are potential candidates for fertility preservation as well , 32, 33.Potential risks for fertility impairment vary depending on patients’ age, gender, body mass index, medical condition, and subsequent treatment scheme. A comprehensive and individual assessment is essential to determine the appropriate timing and methods for fertility preservation . PreviouEmbryo cryopreservation, as a long-established fertility preservation method, can guarantee the best outcomes for fertility preservation. However, oocyte cryopreservation is preferred since most adolescents are unlikely to have a permanent partner and using donor sperm is less desired and poses ethical issues , 17. Sinin vitro maturated oocytes may be a feasible strategy when present with time constraints  during chemotherapy is controversial  and currOvarian tissue cryopreservation (OTC) is perhaps the sole option for fertility preservation in prepubertal children and post-pubertal adolescents who cannot delay the start of chemotherapy , 53, 81.in vitro embryo formation   . In someon (IVF) , 104. Maon (IVF) , 106 andon (IVF) . Heteroton (IVF) , abdomenon (IVF) , chest won (IVF) , breast on (IVF) , rectus on (IVF) , and subon (IVF) , where aon (IVF) , 108. Thon (IVF) . Heteroton (IVF)  and liveon (IVF)  followinon (IVF) , 112, inon (IVF) , 99, theSurvival of grafted tissue and ovarian follicles depends on several factors, including the timing and location of transplantation, surgical techniques, and most importantly, the levels of revascularization soon after the procedure . StudiesOne of the leading concerns over the autograft of cryopreserved ovarian tissue is the risk of reintroducing malignant cells among malignancy survivors , which iSperm cryopreservation with masturbation is the easiest and most reliable method for fertility preservation for pubertal boys , 128. PeCryopreservation of immature testicular tissue (ITT) is the only fertility preservation option for prepubertal boys as spermatogenesis is absent . Small pTesticular stem cells (TSC) can be stored in immature testicular tissue or a cell suspension. Detailed procedures of both strategies, including sample preparation, storage containers, cryoprotection, and cooling and warming process, have been elaborated elsewhere . Differein vitro maturation of TSCs  and technical factors   .Currently, most studies focus on adult subjects with little attention to ovarian tissue cryopreservation and transplantation from tissue taken from prepubertal children and post-pubertal adolescents. There are several large cohorts of young girls reporting ovarian tissue cryopreservation, but the return-to-use rates are extremely low , 190, leAnother subject of study is the relationship between follicular density/quantity and the longevity of restored ovarian function. Several studies observed an association between younger age at the time of ovarian tissue cryopreservation and preferable clinical outcomes including the longevity of graft survival  and liveNotably, some patients may undergo chemotherapy before ovarian tissue cryopreservation. The latest studies have demonstrated similar resumption in ovarian function and pregnancy rates per woman in patients who received low gonadotoxic risk chemotherapy compared to those who were chemo-naïve , 182. ImSperm cryopreservation is the most successful method for male fertility preservation. While some studies suggested reduced sperm viability and motility after thawing , 203, crThe documented clinical pregnancy rates using thawed sperm collected before cancer therapy ranges from 18% to 57% , 206–210Sperm can be stored for decades under ultra-low temperatures. The longest duration of sperm cryopreservation to date is 28 years, which successfully resulted in a healthy live birth with IUI . Unfortuin vitro maturation of TSCs  or transgender men  in the United States . In addiA variety of studies suggest transgender individuals have a strong desire for parenthood. 62% to 82% of transgender individuals want to have children, biological or adopted –256. ButSeveral scientific societies have issued guidelines navigating health care to the transgender population, recommending that all transgender individuals should receive a consultation about potential fertility risks of gender-affirming treatments and preservation options before transition , 262. HoOocyte cryopreservation, embryo preservation, and ovarian tissue cryopreservation are established methods for fertility preservation for transmen. While ovarian stimulation and the accompanying unpleasant experience of estradiol elevation, vaginal examination and oocyte retrieval are unavoidable for oocyte cryopreservation , 266, ovSome transmen may have already started testosterone treatment before ovarian stimulation. It was previously deemed that testosterone induced polycystic ovary syndrome (PCOS) . But recIn vitro maturation of immature oocytes from oophorectomy can be another source of oocytes  and 4 transferable blastocysts. Collectively, given the poor maturation rate (28% to 36%) and utilization efficacy after IVM  , 76. It A formal and separate discussion about fertility issues is advocated to ensure patients’ full comprehension of potential fertility risks and fertility preservation options , 294. ImThe establishment of a standardized intra-institutional or inter-institutional referral pathway between the clinical team and fertility preservation team is strongly suggested , 53. In Firstly, it facilitates fertility preservation consultation , 304. CoSecondly, it facilitates referral , 294. AnThirdly, it enables optimal decision-making . The ferFinally, it reduces repetitive work and improve efficiency. As described above, a fertility specialist can engage in both patient counseling and proposing a feasible fertility preservation plan with the clinical team, saving their time and energy. A fertility specialist can focus on other affairs concerning fertility preservation, such as logistics of the procedure, cryopreservation of relevant materials, and future use. Considering the highly time-sensitive nature of fertility preservation, any improvement in efficiency would benefit patients significantly.Based on previous literature, there are two identified key factors in establishing an effective and efficient fertility preservation program, namely sensitive faculties , 305 andin vitro development of follicles (Although different communities have made great achievements in fertility preservation, there are still some restrictions in clinical practice. For instance, unlike embryo or gamete cryopreservation, transplantation of cryopreserved ovarian tissue generally leads to variable outcomes between patients and institutions, warranting optimization and standardization of this technique. Currently, the greatest challenge is the massive follicle atresia after transplantation, with more than 70% of primordial follicles failing to survive . Future ollicles  are poteollicles , highligIn conclusion, fertility preservation is an increasingly important issue in pediatric and adolescent healthcare as most malignant diseases are curable with contemporary means. Mature gamete cryopreservation is the most reliable and successful strategy for fertility preservation when embryo freezing is not practicable. In addition, ovarian tissue cryopreservation is an effective option for female fertility preservation though there is room for improvement in its efficacy. Autograft of immature testicular tissue is currently the most promising method for prepubertal patients, but additional efforts are required to gather data on animal models and in clinical trials.LC, ZD and XC: Substantial contribution to the conception and design of the work. LC: Participation in the acquisition of literature. LC and XC: Manuscript drafting and revision. All authors contributed to the article and approved the submitted version.