A Mega-Analysis of Anti-Müllerian Hormone Levels in Female Childhood Cancer Survivors Based on Treatment Risk, Time since Treatment, and Pubertal Status.

Purpose: Female childhood cancer survivors (CCSs) risk infertility due to gonadotoxic chemotherapy/radiation. Anti-Müllerian hormone (AMH) helps evaluate ovarian reserve, and the 2020 Oncofertility Pediatric Initiative Network (O-PIN) risk stratification is utilized to counsel risk of gonadal dysfunction/infertility. This study analyzed how AMH levels after cancer treatment differ with age and correlate AMH with O-PIN risk level and clinical outcomes. Methods: A literature review and mega-analysis of individual patient data were performed. Females ages 0-20 years at the time of cancer diagnosis with AMH values post-treatment were included. AMH outcomes were compared by O-PIN risk stratification, age at diagnosis, cyclophosphamide equivalent dose (CED), and hematopoietic stem cell transplant (HSCT). Multivariable random effects mixed models correlated AMH with diminished ovarian reserve (DOR), premature ovarian insufficiency (POI), and pregnancy. Results: In 13 studies with 608 CCSs, the median age (years) at diagnosis was 12.0 (interquartile range [IQR] 5.2-16.2) and 21.1 (IQR 17.1-30.0) at AMH measurement. AMH values were higher with time since treatment and correlated with the O-PIN risk level. Patients with HSCT had very low/undetectable AMH levels regardless of CED; when stratified by CED, AMH levels were lower if treated peripubertally or older. AMH was detectable in 54% (34/63) of patients with POI on hormone replacement. Pregnancy did not correspond to the gonadotoxicity risk level (p = 0.70). Conclusion: This study supports utilizing the O-PIN risk stratification system in estimating risk of DOR in CCSs and its categorization by pubertal status. AMH levels may return over time even after receiving the highest risk therapy. These findings may help counsel cancer patients pre- and post-therapy.

Neighborhood Food Access in Early Life and Trajectories of Child Body Mass Index and Obesity.

Importance: Limited access to healthy foods, resulting from residence in neighborhoods with low food access, is a public health concern. The contribution of this exposure in early life to child obesity remains uncertain. Objective: To examine associations of neighborhood food access during pregnancy or early childhood with child body mass index (BMI) and obesity risk. Design, Setting, and Participants: Data from cohorts participating in the US nationwide Environmental Influences on Child Health Outcomes consortium between January 1, 1994, and March 31, 2023, were used. Participant inclusion required a geocoded residential address in pregnancy (mean 32.4 gestational weeks) or early childhood (mean 4.3 years) and information on child BMI. Exposures: Residence in low-income, low-food access neighborhoods, defined as low-income neighborhoods where the nearest supermarket is more than 0.5 miles for urban areas or more than 10 miles for rural areas. Main Outcomes and Measures: BMI z score, obesity (age- and sex-specific BMI ≥95th percentile), and severe obesity (age- and sex-specific BMI ≥120% of the 95th percentile) from age 0 to 15 years. Results: Of 28 359 children (55 cohorts; 14 657 [51.7%] male and 13 702 [48.3%] female; 590 [2.2%] American Indian, Alaska Native, Native Hawaiian, or Other Pacific Islander; 1430 [5.4%] Asian; 4034 [15.3%] Black; 17 730 [67.2%] White; and 2592 [9.8%] other [unspecified] or more than 1 race; 5754 [20.9%] Hispanic and 21 838 [79.1%] non-Hispanic) with neighborhood food access data, 23.2% resided in low-income, low-food access neighborhoods in pregnancy and 24.4% in early childhood. After adjusting for individual sociodemographic characteristics, residence in low-income, low-food access (vs non-low-income, low-food access) neighborhoods in pregnancy was associated with higher BMI z scores at ages 5 years (ß, 0.07; 95% CI, 0.03-0.11), 10 years (ß, 0.11; 95% CI, 0.06-0.17), and 15 years (ß, 0.16; 95% CI, 0.07-0.24); higher obesity risk at 5 years (risk ratio [RR], 1.37; 95% CI, 1.21-1.55), 10 years (RR, 1.71; 95% CI, 1.37-2.12), and 15 years (RR, 2.08; 95% CI, 1.53-2.83); and higher severe obesity risk at 5 years (RR, 1.21; 95% CI, 0.95-1.53), 10 years (RR, 1.54; 95% CI, 1.20-1.99), and 15 years (RR, 1.92; 95% CI, 1.32-2.80). Findings were similar for residence in low-income, low-food access neighborhoods in early childhood. These associations were robust to alternative definitions of low income and low food access and additional adjustment for prenatal characteristics associated with child obesity. Conclusions: Residence in low-income, low-food access neighborhoods in early life was associated with higher subsequent child BMI and higher risk of obesity and severe obesity. We encourage future studies to examine whether investments in neighborhood resources to improve food access in early life would prevent child obesity.

SERUM CALCIUM WAS NEGATIVELY ASSOCIATED WITH SERUM IRON AMONG GENERAL POPULATION: FINDINGS FROM A CROSS-SECTION STUDY.

INTRODUCTION: The progression of ferroptosis has been found to be associated with the onset and progression of many diseases. Disruption of iron homeostasis can lead to ferroptosis. We had previously hypothesized that vitamin D may affect serum calcium levels, which in turn regulates ferroptosis by regulating serum iron levels. However, the relationship between serum calcium level and serum iron level is unclear. The purpose of our study was to explore the relationship between serum calcium level and serum iron level among general population in Taizhou, China. METHODS: In this study, a cross-sectional study was conducted. Serum calcium levels and serum iron levels were determined in our work. Pearson's correlation analysis was used to determine the association between serum calcium level and serum iron level. RESULTS: The results showed that serum iron level was negatively correlated with serum calcium level and age. After controlling for age, sex and marital status, serum iron level was still negatively correlated with serum calcium level. CONCLUSIONS: The results suggest that improving serum calcium levels may be a potential strategy for regulating iron metabolism homeostasis. Whether calcium supplementation can reduce serum iron levels in people with low serum calcium levels needs further investigation.

Engineering Nicotiana benthamiana as a platform for natural product biosynthesis.

Nicotiana benthamiana is a model plant, widely used for research. The susceptibility of young plants to Agrobacterium tumefaciens has been utilised for transient gene expression, enabling the production of recombinant proteins at laboratory and commercial scales. More recently, this technique has been used for the rapid prototyping of synthetic genetic circuits and for the elucidation and reconstruction of metabolic pathways. In the last few years, many complex metabolic pathways have been successfully reconstructed in this species. In addition, the availability of improved genomic resources and efficient gene editing tools have enabled the application of sophisticated metabolic engineering approaches to increase the purity and yield of target compounds. In this review, we discuss recent advances in the use of N. benthamiana for understanding and engineering plant metabolism, as well as efforts to improve the utility of this species as a production chassis for natural products.

[Spatial and temporal distribution characteristics research of esophageal cancer in China].

Objectives: To explore the spatial distribution characteristics, trend changes, and spatial clustering of esophageal cancer among residents in China at the county (city, district) scale, a spatial epidemiological approach was used, with the aim of providing localized evidence for the prevention and treatment of esophageal cancer in China. Methods: The data source was the incidence (crude rate) and mortality (crude rate) of esophageal cancer from 2005 to 2016 in the 2008-2019 edition of China Cancer Registration Annual Report published by the National Cancer Center. The Joinpoint model was used for time trend analysis. The tumor registration area in 2016 was selected as the study area for spatial feature analysis, with a total of 487 counties (cities and districts), covering 27.6% of the national population. Spatial autocorrelation analysis was performed to reveal spatial distribution characteristics by using Arcgis 10.6 software, and spatial scanning statistics was used to analyze spatial clustering characteristics by using SaTScan 9.5 software. The log-likelihood ratio (LLR) and relative risk (RR) were calculated in different windows, and the region with the largest LLR value represented the most likely cluster. Results: From 2005 to 2016, the incidence and mortality rate of esophageal cancer in China showed a trend of increasing at first and then decreasing. The incidence and mortality rate of esophageal cancer in 2016 were characterized by spatial positive correlation. High incidence and high mortality were mainly concentrated in the areas through which the Huaihe River flowed. The primary clusters (taking high incidence rate as an example LLR=6 374.41, RR=2.37, P＜0.001) were mainly distributed in Jiangsu, Anhui and Shandong in eastern China and eastern Henan and southern Hebei in central China, and secondary clusters (taking high incidence rate as an example LLR=1 971.19, RR=1.91, P＜0.001) in Gansu, Ningxia Hui Autonomous Region, Shaanxi, Sichuan and other central and western regions. Conclusions: The incidence and mortality of esophageal cancer in China have decreased since 2010. The disease burden of esophageal cancer has obvious spatial differences, and measures should be taken according to local conditions in high-risk cluster areas such as the Huaihe River basin.

[An in vitro model study of the accuracy and operation time of oral surgery robot-assisted endodontic microsurgery].

Objective: To explore the operational accuracy and operative time of oral surgery robot-assisted endodontic microsurgery on a head-simulator for clinical reference. Methods: Three pairs of surgical simulation models were set up on head-simulator. Each model included 10 positions anteriorly and posteriorly, 20 teeth for each technique, for a total of 60 teeth. An attending physician with more than 3 years clinical experience in endodontic microsurgery completed fixed-point osteotomy and apicoectomy in three groups of endodontic microsurgery under freehand (FH), static navigation (SN), and surgery robot (SR). The duration of each operation was recorded. Cone-beam CT was taken before the operation and the surgical path was planned in the software; after surgery, a plug gauge (precision gauge for measuring hole dimensions) was inserted into the surgical path for intraoral scanning. Surgical accuracy (starting point, end point, and angular deviation) was assessed in all 3 groups, and surgery time was compared. Results: The deviation at the starting point and the end point, and angular deviation was (0.37±0.11), (0.37±0.10) mm, and 0.71°±0.17°in the SR group. The deviations in the SR group were significantly lower than those in the SN group [(0.59±0.14), (0.65±0.18) mm, and 2.64°±0.75°] (P<0.05), and both groups were significantly lower than the FH group [(1.37±0.31), (1.10±0.21) mm, and 9.84°±3.15°] (P<0.05). The operative time in the SN group [(1.20±0.03) min] was significantly less than that in the SR group [(2.18±0.03) min] (P<0.05), and both groups were significantly less than that in the FH group [(8.70±3.15) min] (P<0.05). Starting point deviation, end point deviation, and angular deviation [(1.09±0.10), (0.90±0.07) mm, 7.22°±1.13°] in anterior teeth using the FH was significantly lower than the starting deviation, endpoint deviation, and angular deviation [(1.65±0.14), (1.30±0.06) mm, 12.46°±2.10°] in the posterior teeth using FH (P<0.05), and the operative time in the anterior teeth using the FH [(5.75±0.57) min] was significantly less than that in the posterior teeth using [(11.65±1.14) min] (P<0.05). The difference in accuracy and operative time between using SN and SR on anterior and posterior teeth was not statistically significant (P>0.05). Conclusions: Oral surgery robot-assisted endodontic microsurgery helps improving the accuracy of clinicians' operations and shorten the operation time.

The metabolic role of vitamin D in children's neurodevelopment: a network study.

Neurodevelopmental disorders are rapidly increasing in prevalence and have been linked to various environmental risk factors. Mounting evidence suggests a potential role of vitamin D in child neurodevelopment, though the causal mechanisms remain largely unknown. Here, we investigate how vitamin D deficiency affects children's communication development, particularly in relation to Autism Spectrum Disorder (ASD). We do so by developing an integrative network approach that combines metabolomic profiles, clinical traits, and neurodevelopmental data from a pediatric cohort. Our results show that low levels of vitamin D are associated with changes in the metabolic networks of tryptophan, linoleic, and fatty acid metabolism. These changes correlate with distinct ASD-related phenotypes, including delayed communication skills and respiratory dysfunctions. Additionally, our analysis suggests the kynurenine and serotonin sub-pathways may mediate the effect of vitamin D on early life communication development. Altogether, our findings provide metabolome-wide insights into the potential of vitamin D as a therapeutic option for ASD and other communication disorders.

Network Analysis Reveals Protein Modules Associated with Childhood Respiratory Diseases.

Background: The first year of life is a period of rapid immune development that can impact health trajectories and the risk of developing respiratory-related diseases, such as asthma, recurrent infections, and eczema. However, the biology underlying subsequent disease development remains unknown. Methods: Using weighted gene correlation network analysis (WGCNA), we derived modules of highly correlated immune-related proteins in plasma samples from children at age 1 year (N=294) from the Vitamin D Antenatal Asthma Reduction Trial (VDAART). We applied regression analyses to assess relationships between protein modules and development of childhood respiratory diseases up to age 6 years. We then characterized genomic, environmental, and metabolomic factors associated with modules. Results: WGCNA identified four protein modules at age 1 year associated with incidence of childhood asthma and/or recurrent wheeze (Padj range: 0.02-0.03), respiratory infections (Padj range: 6.3×10-9-2.9×10-6), and eczema (Padj=0.01) by age 6 years; three modules were associated with at least one environmental exposure (Padj range: 2.8×10-10-0.03) and disrupted metabolomic pathway(s) (Padj range: 2.8×10-6-0.04). No genome-wide SNPs were identified as significant genetic risk factors for any protein module. Relationships between protein modules with clinical, environmental, and 'omic factors were temporally sensitive and could not be recapitulated in protein profiles at age 6 years. Conclusion: These findings suggested protein profiles as early as age 1 year predicted development of respiratory-related diseases through age 6 and were associated with changes in pathways related to amino acid and energy metabolism. These may inform new strategies to identify vulnerable individuals based on immune protein profiling.

[Preparation of interleukin-1ß-targeted nanobodies and their effects on apoptosis in hypoxic cardiomyocytes of mice].

Objective: To prepare interleukin-1ß-targeted nanoantibodies and observe their effects on apoptosis in hypoxic cardiomyocyte of mice. Methods: Using DNA recombination technology, the pET-16b and pHEN1 expression vectors were used to construct the prokaryotic expression plasmids of interleukin-1ß-targeted nanobodies (pET-16b-4G6M-VHH, pET-16b-5BVP-VHH, pET-16b-5MVZ-VHH, pHEN1-4G6M-VHH, pHEN1-5BVP-VHH and pHEN1-5MVZ-VHH, where VHH is a variable domain of heavy chain antibody, 4G6M-VHH, 5BVP-VHH, 5MVZ-VHH were three interleukin-1ß-targeted nanoantibodies respectively). The constructed plasmids were transferred into Escherichia coli Rosetta2 (DE3) for induction of expression and nickel column purification, respectively. The sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting were employed to identify the expression product and purified product, and the enzyme-linked immune sorbent assay (ELISA) was performed to determine their affinity. The cardiomyocyte hypoxia model was used with the highest affinity IL-1ß-targeted nanobody (pHEN1-5MVZ-VHH), and cell survival and apoptosis rates were detected (the experiment was divided into normal control group, hypoxia model group, blank plasmid group and 12.5, 25.0, 50.0 µg/ml pHEN1-5MVZ-VHH treatment groups). Results: SDS-PAGE and Western blotting results showed that the anti-interleukin-1ß (IL-1ß) nanobodies with a relative molecular mass of about 15 000 were successfully obtained. Likewise, ELISA results found that the nanobodies expressed in pHEN1 vector group had higher affinity for IL-1ß antigen compared with pET-16b vector group (4G6M-VHH group: 3.20±0.03 vs 1.20±0.03, P<0.001; 5BVP-VHH group: 3.18±0.06 vs 1.21±0.02, P<0.001; 5MVZ-VHH group: 3.38±0.05 vs 1.62±0.04, P<0.001). Additionally, the results of cell survival assay and apoptosis assay detected that compared with the hypoxia model group, HL-1 cell activity was significantly increased in the 25.0 µg/ml and 50.0 µg/ml pHEN1-5MVZ-VHH treatment groups [(75.55±2.23)% vs (46.90±2.51)%, P<0.001; (74.36±1.96)% vs (46.90±2.51)%, P<0.001], and apoptosis rate was significantly reduced [(6.83±0.27)% vs (10.24±0.76)%, P<0.001; (6.68±0.38)% vs (10.24±0.76)%, P<0.001]. Conclusions: 4G6M-VHH, 5BVP-VHH, and 5MVZ-VHH are expressed by both pET-16b and pHEN1 expression vectors and the nanobodies produced by the pHEN1 vector display enhanced antigen affinity. Furthermore, in hypoxic cardiomyocytes, pHEN1-5MVZ-VHH treatment reduces cell apoptosis.

Let's TOC Fertility: A stepped wedge cluster randomized controlled trial of the Telehealth Oncofertility Care (TOC) intervention in children, adolescent and young adult cancer survivors.

INTRODUCTION: Children, adolescent, and young adult cancer survivors experience overall increased risks of infertility that are preventable through effective fertility preservation services prior to starting cancer treatment. Oncofertility care is the evidence-based practice of informing newly diagnosed cancer patients about their reproductive risks and supporting shared decision-making on fertility preservation services. Despite longstanding clinical guidelines, oncofertility care delivery continues to be limited and highly variable across adult and pediatric oncology settings. MATERIALS AND METHODS: We describe the design of a stepped wedge cluster randomized clinical trial to evaluate the effectiveness of the multi-component Telehealth Oncofertility Care (TOC) intervention conducted in 20 adult and pediatric oncology clinics across three health systems in Southern California. Intervention components are: 1) electronic health record-based oncofertility needs screen and referral pathway to a virtual oncofertility hub; 2) telehealth oncofertility counseling through the hub; and 3) telehealth oncofertility financial navigation through the hub. We hypothesize the intervention condition will be associated with increased proportions of patients who engage in goal-concordant oncofertility care (i.e., engagement in reproductive risk counseling and fertility preservation services that meet the patient's fertility goals) and improved patient-reported outcomes, compared to the usual care control condition. We will also evaluate intervention implementation in a mixed-methods study guided by implementation science frameworks. DISCUSSION: Our overall goal is to speed implementation of a scalable oncofertility care intervention at cancer diagnosis for children, adolescent and young adult cancer patients to improve their future fertility and quality of life. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT05443737.

Metabolite signatures associated with microRNA miR-143-3p serve as drivers of poor lung function trajectories in childhood asthma.

BACKGROUND: Lung function trajectories (LFTs) have been shown to be an important measure of long-term health in asthma. While there is a growing body of metabolomic studies on asthma status and other phenotypes, there are no prospective studies of the relationship between metabolomics and LFTs or their genomic determinants. METHODS: We utilized ordinal logistic regression to identify plasma metabolite principal components associated with four previously-published LFTs in children from the Childhood Asthma Management Program (CAMP) (n = 660). The top significant metabolite principal component (PCLF) was evaluated in an independent cross-sectional child cohort, the Genetic Epidemiology of Asthma in Costa Rica Study (GACRS) (n = 1151) and evaluated for association with spirometric measures. Using meta-analysis of CAMP and GACRS, we identified associations between PCLF and microRNA, and SNPs in their target genes. Statistical significance was determined using an false discovery rate-adjusted Q-value. FINDINGS: The top metabolite principal component, PCLF, was significantly associated with better LFTs after multiple-testing correction (Q-value = 0.03). PCLF is composed of the urea cycle, caffeine, corticosteroid, carnitine, and potential microbial (secondary bile acid, tryptophan, linoleate, histidine metabolism) metabolites. Higher levels of PCLF were also associated with increases in lung function measures and decreased circulating neutrophil percentage in both CAMP and GACRS. PCLF was also significantly associated with microRNA miR-143-3p, and SNPs in three miR-143-3p target genes; CCZ1 (P-value = 2.6 × 10-5), SLC8A1 (P-value = 3.9 × 10-5); and TENM4 (P-value = 4.9 × 10-5). INTERPRETATION: This study reveals associations between metabolites, miR-143-3p and LFTs in children with asthma, offering insights into asthma physiology and possible interventions to enhance lung function and long-term health. FUNDING: Molecular data for CAMP and GACRS via the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI).

A Western Dietary Pattern during Pregnancy is Associated with Neurodevelopmental Disorders in Childhood and Adolescence.

Despite the high prevalence of neurodevelopmental disorders, there is a notable gap in clinical studies exploring the impact of maternal diet during pregnancy on child neurodevelopment. This observational clinical study examined the association between pregnancy dietary patterns and neurodevelopmental disorders, as well as their symptoms, in a prospective cohort of 10-year-old children (n=508). Data-driven dietary patterns were derived from self-reported food frequency questionnaires. A Western dietary pattern in pregnancy (per SD change) was significantly associated with attention-deficit / hyperactivity disorder (ADHD) (OR 1.66 [1.21 - 2.27], p=0.002) and autism diagnosis (OR 2.22 [1.33 - 3.74], p=0.002) and associated symptoms (p<0.001). Findings for ADHD were validated in three large (n=59725, n=656, n=348), independent mother-child cohorts. Objective blood metabolome modelling at 24 weeks gestation identified 15 causally mediating metabolites which significantly improved ADHD prediction in external validation. Temporal analyses across five blood metabolome timepoints in two independent mother-child cohorts revealed that the association of Western dietary pattern metabolite scores with neurodevelopmental outcomes was consistently significant in early to mid-pregnancy, independent of later child timepoints. These findings underscore the importance of early intervention and provide robust evidence for targeted prenatal dietary interventions to prevent neurodevelopmental disorders in children.

The correlation between Helicobacter pylori infection and iron deficiency anemia in women.

OBJECTIVE: In recent years, Helicobacter pylori (H. pylori) has been increasingly associated with extra-digestive manifestations, including scleroderma, rheumatism, and blood system diseases. Iron deficiency anemia (IDA) is a common chronic disease worldwide, with an insidious onset, but as the disease progresses, it will eventually seriously affect the quality of life of patients. The aim of our study was to investigate the relationship between H. pylori infection, iron deficiency (ID), and IDA, and to identify potential serological markers. PATIENTS AND METHODS: We conducted a cross-sectional study of 998 individuals who had regular physical examinations at Beijing Shijitan Hospital from January 2021 to March 2022. We detected H. pylori infection by the 13C breath test, and recorded the patient's serum iron, ferritin, transferrin saturation, blood count, etc. We assessed the association between IDA and H. pylori infection and related serum markers using logistic regression and multiple linear regression. Afterward, we analyzed the correlation between sex and potential serum biomarkers. RESULTS: Among all study participants, 57.5% of patients had H. pylori and 42.5% did not have H. pylori. ID and IDA were significantly associated with H. pylori infection in women (p=0.031). This association persisted after further adjustment for sex, metabolic variables, liver function, and kidney function. Fasting blood glucose, triglycerides, and uric acid may be associated with IDA. CONCLUSIONS: In women, H. pylori infection is associated with ID and IDA. The relationship between H. pylori and IDA may be mediated by glycometabolism, lipid metabolism, and uric acid metabolism.

[Chlorogenic acid alleviates acute kidney injury in septic mice by inhibiting NLRP3 inflammasomes and the caspase-1 canonical pyroptosis pathway].

OBJECTIVE: To investigate the role of caspase-1-medicated canonical pyroptosis pathway in chlorogenic acid (CGA) treatment of acute kidney injury (AKI) in mice. METHOD: Twenty-four C57Bl/6J mice were randomized into sham-operated group, cecal ligation and puncture (CLP) group, CLP+dexamethasone group (CLP+DXM group), and CLP+CGA group (n=6) and subjected to either sham operation (laparotomy only) or CLP. After modeling the mice received intravenous infusion of 10 mg/kg normal saline (in sham and CLP groups), 1 µg/kg dexamethasone or 15 mg/kg of chlorogenic acid for 6 h delivered using an intravenous pump. Eight hours after the infusion, renal morphology and histology, renal cell apoptosis, and the renal function parameters such as urea nitrogen (BUN), creatinine (Scr), and kidney injury molecule 1 (KIM-1) were compared among the 4 groups; the 7-day survival rates of the mice were recorded, and the expressions of NLRP3 inflammasomes and key proteins of the caspase-1 pathway in the renal tissue were detected. RESULTS: CGA treatment significantly improved the 7-day survival rate, reduced renal pathologies of the septic mice (P < 0.05), and lowered the levels of BUN, Scr, KIM-1, NLRP3 inflammasome and expressions of key proteins of the caspase-1 pathway. CONCLUSION: CGA alleviates AKI in mice with CLP-induced sepsis by inhibiting NLRP3 inflammasomes and the caspase-1 signaling pathway.

Association of platinum-based chemotherapy with live birth and infertility in female survivors of adolescent and young adult cancer.

OBJECTIVE: To estimate the effect of platinum-based chemotherapy on live birth (LB) and infertility after cancer, in order to address a lack of treatment-specific fertility risks for female survivors of adolescent and young adult cancer, which limits counseling on fertility preservation decisions. DESIGN: Retrospective cohort study. SETTING: US administrative database. PATIENTS: We identified incident breast, colorectal, and ovarian cancer cases in females aged 15-39 years who received platinum-based chemotherapy or no chemotherapy and matched them to females without cancer. INTERVENTION: Platinum-based chemotherapy. MAIN OUTCOME MEASURES: We estimated the effect of chemotherapy on the incidence of LB and infertility after cancer, overall, and after accounting for competing events (recurrence, death, and sterilizing surgeries). RESULTS: There were 1,287 survivors in the chemotherapy group, 3,192 in the no chemotherapy group, and 34,147 women in the no cancer group, with a mean age of 33 years. Accounting for competing events, the overall 5-year LB incidence was lower in the chemotherapy group (3.9%) vs. the no chemotherapy group (6.4%). Adjusted relative risks vs. no chemotherapy and no cancer groups were 0.61 (95% confidence interval [CI] 0.42-0.82) and 0.70 (95% CI 0.51-0.93), respectively. The overall 5-year infertility incidence was similar in the chemotherapy group (21.8%) compared with the no chemotherapy group (20.7%). The adjusted relative risks vs. no chemotherapy and no cancer groups were 1.05 (95% CI 0.97-1.15) and 1.42 (95% CI 1.31-1.53), respectively. CONCLUSIONS: Cancer survivors treated with platinum-based chemotherapy experienced modestly increased adverse fertility outcomes. The estimated effects of platinum-based chemotherapy were affected by competing events, suggesting the importance of this analytic approach for interpretations that ultimately inform clinical fertility preservation decisions.

Implementation of state health insurance benefit mandates for cancer-related fertility preservation: following policy through a complex system.

BACKGROUND: A myriad of federal, state, and organizational policies are designed to improve access to evidence-based healthcare, but the impact of these policies likely varies due to contextual determinants of, reinterpretations of, and poor compliance with policy requirements throughout implementation. Strategies enhancing implementation and compliance with policy intent can improve population health. Critically assessing the multi-level environments where health policies and their related health services are implemented is essential to designing effective policy-level implementation strategies. California passed a 2019 health insurance benefit mandate requiring coverage of fertility preservation services for individuals at risk of infertility due to medical treatments, in order to improve access to services that are otherwise cost prohibitive. Our objective was to document and understand the multi-level environment, relationships, and activities involved in using state benefit mandates to facilitate patient access to fertility preservation services. METHODS: We conducted a mixed-methods study and used the policy-optimized exploration, preparation, implementation, and sustainment (EPIS) framework to analyze the implementation of California's fertility preservation benefit mandate (SB 600) at and between the state insurance regulator, insurer, and clinic levels. RESULTS: Seventeen publicly available fertility preservation benefit mandate-relevant documents were reviewed. Interviews were conducted with four insurers; 25 financial, administrative, and provider participants from 16 oncology and fertility clinics; three fertility pharmaceutical representatives; and two patient advocates. The mandate and insurance regulator guidance represented two "Big P" (system level) policies that gave rise to a host of "little p" (organizational) policies by and between the regulator, insurers, clinics, and patients. Many little p policies were bridging factors to support implementation across levels and fertility preservation service access. Characterizing the mandate's functions (i.e., policy goals) and forms (i.e., ways that policies were enacted) led to identification of (1) intended and unintended implementation, service, and patient outcomes, (2) implementation processes by level and EPIS phase, (3) actor-delineated key processes and heterogeneity among them, and (4) inner and outer context determinants that drove adaptations. CONCLUSIONS: Following the midstream and downstream implementation of a state health insurance benefit mandate, data generated will enable development of policy-level implementation strategies, evaluation of determinants and important outcomes of effective implementation, and design of future mandates to improve fit and fidelity.

[The clinical significance of lateral pelvic sentinel lymph node biopsy using indocyanine green fluorescence navigation in laparoscopic lateral pelvic lymph node dissection].

Objectives: This study aims to explore the clinical significance of lateral pelvic sentinel lymph node biopsy (SLNB) using indocyanine green (ICG) fluorescence navigation in laparoscopic lateral pelvic lymph node dissection (LLND) and evaluate the accuracy and feasibility of this technique to predict the status of lateral pelvic lymph nodes (LPLNs). Methods: The clinical and pathological characteristics, surgical outcomes, lymph node findings and perioperative complications of 16 rectal cancer patients who underwent SLNB using ICG fluorescence navigation in laparoscopic LLND in the Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College during April 2017 and October 2022 were retrospectively collected and analyzed. The patients did not receive preoperative neoadjuvant radiotherapy and presented with LPLNs but without LPLN enlargement (MRI showed the maximum short axes of the LPLNs were ≥5 mm and <10 mm at first visit). Results: All 16 patients were successfully performed SLNB using ICG fluorescence navigation in laparoscopic LLND. Three patients underwent bilateral LLND and 13 patients underwent unilateral LLND. The lateral pelvic sentinel lymph nodes (SLNs) were clearly fluorescent before dissection in 14 patients and the detection rate of SLNs for these patients was 87.5%. Lateral pelvic SLN metastasis was diagnosed in 2 patients and negative results were found in 12 patients by frozen pathological examinations. Among the 14 patients in whom lateral pelvic SLNs were detected, the dissected lateral pelvic non-SLNs were all negative. All dissected LPLNs were negative in two patients without fluorescent lateral pelvic SLNs. The specificity, sensitivity, negative predictive value, and accuracy was 85.7%, 100%, 100%, and 100%, respectively. Conclusions: This study indicates that lateral pelvic SLNB using ICG fluorescence navigation shows promise as a safe and feasible procedure with good accuracy. This technique may replace preventive LLND for locally advanced lower rectal cancer.

Prevalence and impact of fertility concerns in young women with breast cancer.

Survey data from the Mayo Clinic Breast Disease Registry were used to assess fertility counseling and fertility preservation strategies in a modern cohort of young women with breast cancer. One hundred respondents were identified who were under age 50 at the time of breast cancer diagnosis and who expressed interest in future childbearing near the time of diagnosis and/or 1 year later. Ninety-three percent of the 81 respondents to the year one survey recalled fertility counseling prior to cancer treatment. Most who reported a high level of fertility concern declared that this concern had impacted their treatment decisions, often shortening their planned duration of endocrine therapy. Approximately half had taken steps to preserve future fertility, and a third had used a gonadotropin-releasing hormone agonist either alone or combined with another method (e.g., embryo or oocyte cryopreservation).

Metabolomic data presents challenges for epidemiological meta-analysis: a case study of childhood body mass index from the ECHO consortium.

INTRODUCTION: Meta-analyses across diverse independent studies provide improved confidence in results. However, within the context of metabolomic epidemiology, meta-analysis investigations are complicated by differences in study design, data acquisition, and other factors that may impact reproducibility. OBJECTIVE: The objective of this study was to identify maternal blood metabolites during pregnancy (> 24 gestational weeks) related to offspring body mass index (BMI) at age two years through a meta-analysis framework. METHODS: We used adjusted linear regression summary statistics from three cohorts (total N = 1012 mother-child pairs) participating in the NIH Environmental influences on Child Health Outcomes (ECHO) Program. We applied a random-effects meta-analysis framework to regression results and adjusted by false discovery rate (FDR) using the Benjamini-Hochberg procedure. RESULTS: Only 20 metabolites were detected in all three cohorts, with an additional 127 metabolites detected in two of three cohorts. Of these 147, 6 maternal metabolites were nominally associated (P < 0.05) with offspring BMI z-scores at age 2 years in a meta-analytic framework including at least two studies: arabinose (Coefmeta = 0.40 [95% CI 0.10,0.70], Pmeta = 9.7 × 10-3), guanidinoacetate (Coefmeta = - 0.28 [- 0.54, - 0.02], Pmeta = 0.033), 3-ureidopropionate (Coefmeta = 0.22 [0.017,0.41], Pmeta = 0.033), 1-methylhistidine (Coefmeta = - 0.18 [- 0.33, - 0.04], Pmeta = 0.011), serine (Coefmeta = - 0.18 [- 0.36, - 0.01], Pmeta = 0.034), and lysine (Coefmeta = - 0.16 [- 0.32, - 0.01], Pmeta = 0.044). No associations were robust to multiple testing correction. CONCLUSIONS: Despite including three cohorts with large sample sizes (N > 100), we failed to identify significant metabolite associations after FDR correction. Our investigation demonstrates difficulties in applying epidemiological meta-analysis to clinical metabolomics, emphasizes challenges to reproducibility, and highlights the need for standardized best practices in metabolomic epidemiology.

A temporal extracellular transcriptome atlas of human pre-implantation development.

Non-invasively evaluating gene expression products in human pre-implantation embryos remains a significant challenge. Here, we develop a non-invasive method for comprehensive characterization of the extracellular RNAs (exRNAs) in a single droplet of spent media that was used to culture human in vitro fertilization embryos. We generate the temporal extracellular transcriptome atlas (TETA) of human pre-implantation development. TETA consists of 245 exRNA sequencing datasets for five developmental stages. These data reveal approximately 4,000 exRNAs at each stage. The exRNAs of the developmentally arrested embryos are enriched with the genes involved in negative regulation of the cell cycle, revealing an exRNA signature of developmental arrest. Furthermore, a machine-learning model can approximate the morphology-based rating of embryo quality based on the exRNA levels. These data reveal the widespread presence of coding gene-derived exRNAs at every stage of human pre-implantation development, and these exRNAs provide rich information on the physiology of the embryo.