Secular Trends in Pubertal Growth Acceleration in Swedish Boys Born From 1947 to 1996.

IMPORTANCE: A secular trend for earlier menarcheal age has been established in girls but there are few studies of pubertal timing for boys. OBJECTIVE: To determine if there is a secular trend for earlier pubertal timing among boys. DESIGN, SETTING, AND PARTICIPANTS: For this population-based retrospective cohort study conducted in Gothenburg, Sweden, we collected heights and weights from school health records for boys born consecutively from January 1 and onwards in 1947 and every 5 years from 1951 to 1996 (n = 375 for each birth cohort from 1947-1991, n = 340 for the birth cohort in 1996, and n = 4090 for the total cohort). We estimated age at the peak height velocity (PHV), the maximum growth velocity during puberty, and childhood body mass index (BMI) at age 8 years for all study participants. The data were analyzed during 2018 and 2019. Boys were eligible if they had a complete personal identity number and data to calculate their age at PHV and childhood BMI. Approximately 2.4% of the original study population was excluded because they lacked a personal identity number, and in the remaining study population, 4090 (69%) had sufficient data to calculate childhood BMI and age at PHV. EXPOSURES: The exposure was birth year and a potential confounding factor was childhood BMI. MAIN OUTCOMES AND MEASURES: The outcome was age at PHV. RESULTS: Of the 4090 participants, most were white and the mean (SD) age at PHV was 13.9 (1.1) years. A linear regression model revealed a significant association between year of birth and age at PHV. Age at PHV was 1.5 months earlier for every decade increase in birth year (95% CI, -1.72 to -1.19; P < .001). After adjusting for childhood BMI, age at PHV was 1.2 months earlier per decade increase in birth year (95% CI, -1.41 to -0.89). All analyses were repeated in the subgroup of boys born in Sweden and with parents born in Sweden with similar results, indicating that the secular trend was not explained by demographic changes in the population between 1947 and 1996. CONCLUSIONS AND RELEVANCE: We provide evidence of a secular trend for earlier pubertal timing in boys that is partially explained by an increased childhood BMI, but other factors that are unknown contribute.

Folate pathway genes linked to mitochondrial biogenesis and respiration are associated with outcome of patients with stage III colorectal cancer.

5-fluorouracil in combination with the folate leucovorin is the cornerstone in treatment of colorectal cancer. Transport of leucovorin into cells, and subsequent metabolic action, require expression of several genes. The aim was to analyze if tumoral expression of genes putatively involved in leucovorin transport, polyglutamation, or metabolism was associated with outcome of patients with stage III colorectal cancer treated with adjuvant chemotherapy. A total of 363 stage III colorectal cancer patients who received adjuvant bolus 5-fluorouracil + leucovorin alone, or in combination with oxaliplatin according to Nordic bolus regimes were included. Expression of 11 folate pathway genes was determined in tumors using quantitative real-time polymerase chain reaction and related to disease-free survival. The median follow-up time was 5 years. During follow-up, 114 (31%) patients suffered from recurrent disease. A high tumoral expression of the genes SLC46A1/PCFT, SLC19A1/RFC-1, ABCC3/MRP3, GGH, and MTHFD1L, which are involved in folate transport, polyglutamation, or metabolism, was associated with longer disease-free survival of the patients. Each of these genes either encodes mitochondrial enzymes or is being regulated by mitochondrial transcription factors. Expression of the SLC46A1/PCFT gene was most strongly associated with disease-free survival, regardless of treatment regimen. In conclusion, the results show that expression of folate pathway genes are associated with outcome of colorectal cancer patients treated with adjuvant 5-fluorouracil in combination with leucovorin. A prospective study needs to be conducted to determine if expression of these genes can be used to predict response to leucovorin and other folates that are now being tested in clinical studies. Moreover, there seems to be a link between folate metabolism and mitochondrial biogenesis and respiration that deserves further exploration.

Secular trends of birthweight in boys from 1950 to 2010.

BACKGROUND: Birthweight is an indicator of fetal development and intrauterine conditions and is associated with future health outcomes. Secular birthweight trends prior to the 1970s are mostly unknown. Our aim was to explore secular birthweight trends in Swedish boys from 1950 to 2010. METHODS: We have collected detailed growth data including birthweight from archived School Health Care records for children born in Gothenburg from 1946 and onwards and established a unique population-based cohort, the Body Mass Index Epidemiology Study (BEST). The birthweight cohort spans six decades (1950-2010) and includes 46,548 boys. RESULTS: The mean birthweight of the complete study cohort was 3580 ± 562 g. Linear regression analysis of the entire period revealed a minimal negative secular trend for birthweight (BETA = -0.4 g/year; p < 0.01). However, three distinct trends appeared during sub-periods: a decrease 1950-80, an increase 1980-2000 and another decrease 2000-2010. CONCLUSION: We demonstrate that birthweight in boys has undergone periodic decreases and subsequent increases, but the overall trend from the 1950s to the present is stable.

BMI increase through puberty and adolescence is associated with risk of adult stroke.

OBJECTIVE: To evaluate the contribution of prepubertal childhood body mass index (BMI) and BMI change through puberty and adolescence, 2 distinct developmental BMI parameters, for risk of adult stroke in men. METHODS: In this population-based study in Gothenburg, Sweden, men born in 1945-1961 with information on both childhood BMI at age 8 and BMI change through puberty and adolescence (BMI at age 20-BMI at age 8) were followed until December 2013 (n = 37,669). Information on stroke events was retrieved from high-quality national registers (918 first stroke events, 672 ischemic stroke events [IS], 207 intracerebral hemorrhage events [ICH]). RESULTS: BMI increase through puberty and adolescence (hazard ratio [HR] 1.21 per SD increase; 95% confidence interval [CI] 1.14-1.28), but not childhood BMI, was independently associated with risk of adult stroke. Subanalyses revealed that BMI increase through puberty and adolescence was associated with both IS (HR per SD increase 1.19; 95% CI 1.11-1.28) and ICH (HR per SD increase 1.29; 95% CI 1.15-1.46). High BMI increase during puberty was strongly associated with increased risk of adult hypertension (odds ratio per SD increase 1.35; 95% CI 1.32-1.39). CONCLUSIONS: BMI increase through puberty and adolescence is associated with risk of adult IS and ICH in men. We propose that greater BMI increases during puberty contribute to increased risk of adult stroke at least partly via increased blood pressure.

Association between excessive BMI increase during puberty and risk of cardiovascular mortality in adult men: a population-based cohort study.

BACKGROUND: Being overweight during childhood and adolescence is associated with increased risk of cardiovascular disease in adulthood, but the relative contribution of prepubertal childhood BMI and BMI change during puberty to adult mortality due to cardiovascular disease is unknown. We assessed the contribution of these two distinct developmental BMI parameters for cardiovascular mortality in adult men. METHODS: As a part of the ongoing population-based BMI Epidemiology Study (BEST) in Gothenburg, Sweden, men born between 1945 and 1961 with information on both their childhood BMI at age 8 years and BMI change during puberty were included in the study and followed up until December, 2013. Participants who died or emigrated before age 20 years were excluded from the analysis. BMI was collected from paediatric growth charts and mandatory military conscription tests. Childhood overweight (BMI of ≥17·9 kg/m2) was defined according to the Centers for Disease Control and Prevention's cutoff at 8 years of age, and BMI change during puberty was defined as the difference between young adult BMI and childhood BMI (BMI at age 20 years minus BMI at age 8 years). Information on mortality was retrieved from high quality national registers with the participants' ten-digit personal identity number. We used Cox proportional hazard regression to analyse the association between exposures and mortality. The ethics committee of the University of Gothenburg, Sweden, approved the study and waived the requirement for written informed consent. FINDINGS: We followed 37 672 Swedish men from age 20 years for a mean of 37·8 years (1 422 185 person-years follow-up). 3188 all-cause deaths and 710 cardiovascular deaths occurred during follow-up. The correlation between childhood BMI and BMI change during puberty was marginal (r=0·06). BMI change during puberty, but not childhood BMI, was independently associated with adult all-cause and cardiovascular mortality in men. Boys that became overweight during puberty (HR 2·39; 95% CI 1·86-3·09) and boys who were overweight consistently throughout childhood and puberty (1·85; 1·28-2·67), but not boys overweight in childhood that normalised during puberty (0·99, 0·65-1·50), had increased risk of cardiovascular mortality compared with participants who were not overweight in childhood or as young adults. The association between BMI change during puberty and cardiovascular mortality was non-linear with a substantial association above a threshold of 6·7 units increase in BMI. INTERPRETATION: Excessive BMI increase during puberty is a risk marker of adult cardiovascular mortality. These results indicate that BMI should be monitored during puberty to identify boys with increased risk of adult cardiovascular mortality. FUNDING: Swedish Research Council, the Swedish Government (under the Avtal om Läkarutbildning och Medicinsk Forskning [Agreement for Medical Education and Research]), the Lundberg Foundation, the Torsten Söderberg Foundation, the Novo Nordisk Foundation, the Knut and Alice Wallenberg Foundation, and the Anna Ahrenberg Foundation.

Expression of Folate Pathway Genes in Stage III Colorectal Cancer Correlates with Recurrence Status Following Adjuvant Bolus 5-FU-Based Chemotherapy.

Colorectal cancer is commonly treated with 5-fluorouracil and 5-formyltetrahydrofolate (leucovorin). Metabolic action of leucovorin requires several enzymatic steps that are dependent on expression of corresponding coding genes. To identify folate pathway genes with possible impact on leucovorin metabolism, a retrospective study was performed on 193 patients with stage III colorectal cancer. Relative expression of 22 genes putatively involved in leucovorin transport, polyglutamation and metabolism was determined in tumor and mucosa samples using quantitative real-time polymerase chain reaction. After surgery, patients received adjuvant 5-fluorouracil-based bolus chemotherapy with leucovorin during six months, and were followed for 3 to 5 years. Cox regression analysis showed that high tumoral expression of the genes SLC46A1/PCFT (proton-coupled folate transporter) and SLC19A1/RFC-1 (reduced folate carrier 1) correlated significantly (p < 0.001 and p < 0.01, respectively) with a decreased risk of recurrent disease, measured as disease-free survival (DFS). These two genes are involved in the transport of folates into the cells and each functions optimally at a different pH. We conclude that SLC46A1/PCFT and SLC19A1/RFC-1 are associated with DFS of patients with colorectal cancer and hypothesize that poor response to 5-fluorouracil plus leucovorin therapy in some patients may be linked to low expression of these genes. Such patients might need a more intensified therapeutic approach than those with high gene expression. Future prospective studies will determine if the expression of any of these genes can be used to predict response to leucovorin.