Paternal obesity decreases infant MSC mitochondrial functional capacity.

Besides the well-recognized influence of maternal health on fetal in utero development, recent epidemiological studies appoint paternal preconception metabolic health as a significant factor in shaping fetal metabolic programming and subsequently offspring metabolic health; however, mechanisms behind these adaptations remain confined to animal models. To elucidate the effects of paternal obesity (P-OB) on infant metabolism in humans, we examined mesenchymal stem cells (MSCs), which give rise to infant tissue, remain involved in mature tissue maintenance, and resemble the phenotype of the offspring donor. Here, we assessed mitochondrial functional capacity, content, and insulin action in MSC from infants of fathers with overweight [body mass index (BMI: 25-30 kg/m2); paternal overweight (P-OW)] or obesity (BMI ≥ 30 kg/m2; P-OB) while controlling for maternal intrauterine environment. Compared with P-OW, infant MSCs in the P-OB group had lower intact cell respiration, OXPHOS, and electron transport system capacity, independent of any changes in mitochondrial content. Furthermore, glucose handling, insulin action, lipid content, and oxidation were similar between groups. Importantly, infants in the P-OB group had a greater weight-to-length ratio, which could be in part due to changes in MSC metabolic functioning, which precedes and, therefore, influences infant growth trajectories. These data suggest that P-OB negatively influences infant MSC mitochondria. ClinicalTrials.gov Identifier: NCT03838146.NEW & NOTEWORTHY Paternal obesity decreases infant mesenchymal stem cell (MSC) basal and maximal respiration. Lower OXPHOS and electron transport system capacity could be explained by lower complex I and IV respiratory capacity but not changes in OXPHOS expression in infant MSC from fathers with obesity. Paternal obesity and altered MSC mitochondrial functional capacity are associated with a greater infant weight-to-length ratio at birth.

Maternal exercise increases infant resting energy expenditure: preliminary results.

Maternal obesity is associated with lower infant resting energy expenditure (REE), predisposing them to more rapid weight and adiposity gain through early infancy. Maternal exercise (ME) decreases infant adiposity and risk for childhood obesity; however, it remains unknown if this is in part mediated by changes in infant energy expenditure. Thus, we measured REE in 1-month-old infants from pregnant individuals who performed moderate-intensity exercise during pregnancy and compared it to infants from non-exercising controls. We observed higher oxygen respiratory rates (p = 0.003 for VO2 and p = 0.007 for VCO2) and REE (p = 0.002) in infants exposed to exercise in utero, independent of any differences in infant body composition. Furthermore, maternal BMI was significantly and inversely associated with infant REE in the control (r = -0.86, R2 = 0.74, p = 0.029), but not the exercise group (r = 0.33, R2 = 0.11, p = 0.473). Together, these findings associate ME with increasing infant energy expenditure which could be protective of subsequent infant adiposity gain. Clinical Trial: ClinicalTrials.gov Identifier: NCT03838146 and NCT04805502.

Greater reliance on glycolysis is associated with lower mitochondrial substrate oxidation and insulin sensitivity in infant myogenic MSCs.

Individuals with insulin resistance and obesity display higher skeletal muscle production of nonoxidized glycolytic products (i.e., lactate), and lower complete mitochondrial substrate oxidation to CO2. These findings have also been observed in individuals without obesity and are associated with an increased risk for metabolic disease. The purpose of this study was to determine if substrate preference is evident at the earliest stage of life (birth) and to provide a clinical blood marker (lactate) that could be indicative of a predisposition for metabolic disease later. We used radiolabeled tracers to assess substrate oxidation and insulin sensitivity of myogenically differentiated mesenchymal stem cells (MSCs), a proxy of infant skeletal muscle tissue, derived from umbilical cords of full-term infants. We found that greater production of nonoxidized glycolytic products (lactate, pyruvate, alanine) is directly proportional to lower substrate oxidation and insulin sensitivity in MSCs. In addition, we found an inverse relationship between the ratio of complete glucose oxidation to CO2 and infant blood lactate at 1 mo of age. Collectively, considering that higher lactate was associated with lower MSC glucose oxidation and has been shown to be implicated with metabolic disease, it may be an early indicator of infant skeletal muscle phenotype.NEW & NOTEWORTHY In infant myogenically differentiated mesenchymal stem cells, greater production of nonoxidized glycolytic products was directly proportional to lower substrate oxidation and insulin resistance. Glucose oxidation was inversely correlated with infant blood lactate. This suggests that innate differences in infant substrate oxidation exist at birth and could be associated with the development of metabolic disease later in life. Clinical assessment of infant blood lactate could be used as an early indicator of skeletal muscle phenotype.

Bone marrow-derived mitochondrial DNA has limited capacity for inter-tissue transfer in vivo.

Studies have shown that mitochondrial DNA (mtDNA) can be exchanged between tissues; however, the mechanism(s) behind this phenomenon remain unclear. Exosomes and other extracellular vesicles (EVs) including microvesicles (MV) have been shown to contain mtDNA. EVs can be derived from a number of tissues; however, the source and relative proportion of EVs containing mtDNA remains unknown. We sampled whole blood and the EV fractions (exosome-enriched, MV-enriched, and apoptotic body-enriched) as well as several tissues (epithelial-cheek and urine sediment), connective (fibroblasts), and skeletal muscle in two subjects who received allogenic bone marrow transplants. Next generation sequencing of the mtDNA confirmed that all EV fractions contained mtDNA and most was derived from the donor, confirming that most of the EV fractions in the serum are bone marrow/blood cell-derived. Even after exposure to the donor mtDNA in EV fractions (and potentially free in the plasma) for years, there was little to no transfer of the donor mtDNA to the host mtDNA fraction in epithelial, connective, or skeletal muscle tissues. These data call into question the potential therapeutic use of bone marrow transplant or EV-based delivery systems for mtDNA-based disorders and establish bone marrow as the primary source of most of the mtDNA enriched EVs in serum.

The influence of exercise during pregnancy on racial/ethnic health disparities and birth outcomes.

BACKGROUND: Non-Hispanic black (NHB) pregnant women disproportionately experience adverse birth outcomes compared to Non-Hispanic white (NHW) pregnant women. The positive effects of prenatal exercise on maternal and neonatal health may mitigate these disparities. This study evaluated the influence of prenatal exercise on racial/ethnic disparities in gestational age (GA), birthweight (BW), and risks of preterm birth (PTB), cesarean section (CS), and low-birthweight (LBW) neonates. METHODS: This study performed a secondary data analysis using data from a 24-week, two-arm exercise intervention trial (ENHANCED by Mom). Women with singleton pregnancies (< 16 weeks), aged 18-40 years, BMI between 18.5-34.99 kg/m2, and no preexisting health conditions were eligible. The aerobic exercisers (EX) participated in 150 min of moderate-intensity weekly exercise while non-exercising controls (CON) attended low-intensity stretching/breathing sessions. Data on GA, PTB (< 37 weeks), BW, LBW (< 2.5 kg), and delivery mode were collected. Poisson, median and linear regressions were performed. RESULTS: Participants with complete data (n = 125) were eligible for analyses (EX: n = 58, CON: n = 67). NHB pregnant women delivered lighter neonates (ß = - 0.43 kg, 95% CI: - 0.68, - 0.18, p = 0.001). After adjusting for prenatal exercise, racial/ethnic disparities in BW were reduced (ß = - 0.39 kg, 95% CI: - 0.65, - 0.13, p = 0.004). Prenatal exercise reduced borderline significant racial/ethnic disparities in PTB (p = 0.053) and GA (p = 0.07) with no effects found for CS and LBW. CONCLUSIONS: The findings of this study demonstrate that prenatal exercise may attenuate the racial/ethnic disparities observed in neonatal BW, and possibly GA and PTB. Larger, diverse samples and inclusion of maternal biomarkers (e.g., cytokines) are encouraged to further evaluate these relationships.

Screening for Opioid and Stimulant Exposure In Utero Through Targeted and Untargeted Metabolomics Analysis of Umbilical Cords.

BACKGROUND: Neonatal abstinence syndrome is an array of signs and symptoms experienced by a newborn due to abrupt discontinuation of intrauterine exposure to certain drugs, primarily opioids. In the United States, the incidence of neonatal abstinence syndrome has tripled over the past decade. The current standard of care for drug testing includes the analysis of infant urine and meconium. Sample collection is associated with several limitations, including diaper media interferences, limited sample amount, sample heterogeneity, and the need for professional staff for collection. Umbilical cord tissue has emerged as a convenient sample matrix for testing owing to its universal availability. The purpose of this study was to examine umbilical cords using an untargeted metabolomics approach to determine the detected drugs and validate an analytical method to confirm and quantify the identified drugs. METHODS: A metabolomics analysis was performed with 21 umbilical cords to screen for drugs and drug metabolites by liquid chromatography-mass spectrometry. Drugs were identified using the National Institute of Standards and Technology database, and an analytical method was developed and validated using secondary liquid chromatography-mass spectrometry instrument for positive confirmation and quantitative analysis. RESULTS: Twenty-one random umbilical cords from women were tested: 4 were positive for cocaine and the primary and secondary metabolites; one was positive for methadone, the primary metabolite; 3 were positive for cotinine, the metabolite of nicotine; and 5 were positive for acetyl norfentanyl. CONCLUSIONS: Our research is a prospective method development study using untargeted and targeted approaches to characterize steady-state drug metabolite levels in the umbilical cord matrix at the time of delivery. By characterizing drug type and concentration, this methodology can be used to develop a reliable complementary testing method for meconium toxicology screens.

Influence of Prenatal Aerobic Exercise on Fetal Morphometry.

OBJECTIVE: The purpose of this study was to determine the effects of supervised prenatal aerobic exercise on fetal morphometrics at 36 weeks of gestation. METHODS: This study used data from a, 24-week, two-arm randomized controlled trial: aerobic exercise (EX) and stretching/breathing comparison group (CON). Singleton pregnancies (< 16 weeks pregnant) and women aged 18 to 40 years, BMI between 18.5 and 34.99 kg/m2, and no preexisting chronic health conditions were eligible. The EX group participated in 150 min of moderate-intensity weekly exercise while CON group participated in low-intensity stretching/breathing. Fetal morphometric outcomes included estimated fetal weight (EFW), ponderal index (PI), abdominal circumference (AC), anterior abdominal wall thickness (AAWT), fat mass, percent body fat, fat-free mass, assessed at 36 weeks gestation. Partial spearman rank correlations were performed, adjusting for 3rd trimester weight gain. RESULTS: Of the 128 pregnant women randomized, 83 (EX [n = 46] and CON [n = 37]) were eligible for analyses. Intention-to-treat analysis showed no differences in EFW (rhos = - 0.13; p = 0.28), PI (rhos = 0.03; p = 0.81), AC (rhos = - 0.22; p = 0.09), AAWT (rhos = - 0.11; p = 0.40), fat mass (rhos = - 0.16; p = 0.23), percent body fat (rhos = - 0.10; p = 0.43), and fat-free mass (rhos = - 0.22; p = 0.08), after adjusting for 3rd trimester weight gain. Similar results were observed in the per protocol analyses. CONCLUSIONS: For Practice Moderate-intensity aerobic exercise during pregnancy was not associated with select fetal morphometrics at 36 weeks gestation. Potential differences in offspring morphometrics may only appear in the postnatal period, as previously documented. Further research into offspring tissue composition after birth is encouraged, specifically studies investigating differences in cellular signaling pathways related to adipose and skeletal muscle tissue development.

Statin administration activates system xC- in skeletal muscle: a potential mechanism explaining statin-induced muscle pain.

Statins are a cholesterol-lowering drug class that significantly reduce cardiovascular disease risk. Despite their safety and effectiveness, musculoskeletal side-effects, particularly myalgia, are prominent and the most common reason for discontinuance. The cause of statin-induced myalgia is unknown, so defining the underlying mechanism(s) and potential therapeutic strategies is of clinical importance. Here we tested the hypothesis that statin administration activates skeletal muscle system xC-, a cystine/glutamate antiporter, to increase intracellular cysteine and therefore glutathione synthesis to attenuate statin-induced oxidative stress. Increased system xC- activity would increase interstitial glutamate; an amino acid associated with peripheral nociception. Consistent with our hypothesis, atorvastatin treatment significantly increased mitochondrial reactive oxygen species (ROS; 41%) and glutamate efflux (up to 122%) in C2C12 mouse skeletal muscle myotubes. Statin-induced glutamate efflux was confirmed to be the result of system xC- activation, as cotreatment with sulfasalazine (system xC- inhibitor) negated this rise in extracellular glutamate. These findings were reproduced in primary human myotubes but, consistent with being muscle-specific, were not observed in primary human dermal fibroblasts. To further demonstrate that statin-induced increases in ROS triggered glutamate efflux, C2C12 myotubes were cotreated with atorvastatin and various antioxidants. α-Tocopherol and cysteamine bitartrate reversed the increase in statin-induced glutamate efflux, bringing glutamate levels between 50 and 92% of control-treated levels. N-acetylcysteine (a system xC- substrate) increased glutamate efflux above statin treatment alone: up to 732% greater than control treatment. Taken together, we provide a mechanistic foundation for statin-induced myalgia and offer therapeutic insights to alleviate this particular statin-associated side-effect.

Influence of aerobic exercise on maternal lipid levels and offspring morphometrics.

BACKGROUND: Maternal BMI, lipid levels (cholesterol, triglyceride, LDL, HDL), and exercise amount are interrelated and each influence offspring body size. This study proposed to determine the influence of exercise on maternal lipid levels and infant body size. METHODS: We had 36 participants complete these measures. Participants in the aerobic exercise intervention (n = 14) completed three 50-min sessions weekly from 16 weeks gestation to delivery and were compared with a non-exercise control group (n = 22). Maternal lipid profiles were assessed at 16 and at 36 weeks gestation. Fetal body size was measured at 36 weeks gestational age using ultrasound assessment. Neonatal body size measures were acquired from birth records. Statistical analysis included two-sample t-tests, correlations, and regression models. RESULTS: Participants were similar in age, pre-pregnancy BMI, gravida, parity, education, and gestational weight gain (GWG). There were no differences in gestational age, Apgar scores at 1 and 5 min for infants of exercisers relative to controls. Exercisers had higher pre-training triglycerides (p = 0.004) and pregnancy change in triglycerides (p = 0.049) compared to controls. Head circumference was significantly larger in exercise exposed infants relative to infants of controls. Pregnancy METs had a positive relationship with birth length (r = .445, p = .006) and birth weight (r = .391, p = .02). GWG had a moderate, positive relationship with fetal abdominal circumference (r = .570, p = .004). Regression analysis indicated 5 predictors explained 61.7% of the variance in birth weight (Adj.R2 = 0.469, F(5,13) = 5,13, p = 0.02); it was found that pregnancy METs (ß = .724, p = .007), 36 week cholesterol (ß = 1.066, p = .02), and 36 week LDL (ß = -1.267, p = .006) significantly predict birth weight. Regression analysis indicated 4 predictors explained 43.8% of the variance in birth length (Adj.R2 = 0.306, F(4,17) = 3.32, p = 0.04); it was found that pregnancy METs (ß = .530, p = .03), and 36 week LDL (ß = -.891, p = .049) significantly predict birth length. CONCLUSION: The primary association and predictors of infant body size was related to pregnancy exercise and late pregnancy cholesterol and LDL levels. Considering these relationships, it is essential that women maintain aerobic exercise during pregnancy, but should also be cognizant of lipid levels during their pregnancy. Therefore intervention during pregnancy focused on infant body size should involve exercise and and quality nutritional intake foods during pregnancy.

Community deworming alleviates geohelminth-induced immune hyporesponsiveness.

In cross-sectional studies, chronic helminth infections have been associated with immunological hyporesponsiveness that can affect responses to unrelated antigens. To study the immunological effects of deworming, we conducted a cluster-randomized, double-blind, placebo-controlled trial in Indonesia and assigned 954 households to receive albendazole or placebo once every 3 mo for 2 y. Helminth-specific and nonspecific whole-blood cytokine responses were assessed in 1,059 subjects of all ages, whereas phenotyping of regulatory molecules was undertaken in 121 school-aged children. All measurements were performed before and at 9 and 21 mo after initiation of treatment. Anthelmintic treatment resulted in significant increases in proinflammatory cytokine responses to Plasmodium falciparum-infected red blood cells (PfRBCs) and mitogen, with the largest effect on TNF responses to PfRBCs at 9 mo-estimate [95% confidence interval], 0.37 [0.21-0.53], P value over time (Ptime) < 0.0001. Although the frequency of regulatory T cells did not change after treatment, there was a significant decline in the expression of the inhibitory molecule cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) on CD4+ T cells of albendazole-treated individuals, -0.060 [-0.107 to -0.013] and -0.057 [-0.105 to -0.008] at 9 and 21 mo, respectively; Ptime = 0.017. This trial shows the capacity of helminths to up-regulate inhibitory molecules and to suppress proinflammatory immune responses in humans. This could help to explain the inferior immunological responses to vaccines and lower prevalence of inflammatory diseases in low- compared with high-income countries.

Water for all: Towards an integrated approach to wetland conservation and flood risk reduction in a lowland catchment in Scotland.

Strategies for sustainable water resources management require integration of hydrological, ecological and socio-economic concerns. The "Water for all" project has sought to develop a multi-disciplinary science case for innovative management of water levels and flows in a lowland catchment in Scotland. Water demands of arable agriculture, protection from flood risk and conservation needs of lowland mesotrophic wetlands needed to be considered. Water management strategy focused on the outlet zone of Balgavies lake in Eastern Scotland, where the Lunan Water discharges into a partially confined common channel (lade). Water releases to a mill, to the downstream river, and to floodplain wetlands (Chapel Mires) are partially controlled by an existing weir. Based on observations of management of this weir, we postulated that upgrading hydraulic management in this zone could reduce upstream flood risk, help protect mesotrophic wetlands and facilitate downstream water supply at low flows. We considered potential for: (a) installing a remotely operated tilting weir, for improved management of release and routing of flows from the common lade; (b) dredging of the common lade in combination or instead of the tilting weir. Rapid ecological assessment and mixing analysis of the Lunan Water with waters in Chapel Mires showed a gradient of trophic status across the wetlands linked to impact of river-borne nutrients. Stage-discharge relationships, derived from steady-state approximations of the in-channel hydraulics, showed that the proposed tilting weir had potential to divert seasonal nutrient rich water from the upstream Lake away from Chapel Mires. Significant impact of the proposed weir on upstream flood risk was not demonstrated, but carrying out dredging of the channel reduced the current observed probability of upstream flooding. The proposed weir could help to maintain these dredging benefits. Survey and interviews with catchment stakeholders and residents showed constructive interest in the scheme, with half of the respondents willing to pay to support its implementation. The survey also revealed concerns about the proposed project, especially its long-term governance. The lessons learned have wider relevance to development of an integrated approach to water ecosystem services provision, especially where benefits are uncertain and thinly spread across a range of users.

Influence of exercise mode on pregnancy outcomes: ENHANCED by Mom project.

BACKGROUND: The extent of the benefits of exercise training during pregnancy on maternal, fetal, and neonatal health outcomes has not been sufficiently addressed. While aerobic exercise training has been determined as safe and efficacious throughout pregnancy, the effects of other training modes on fetal health and development as well as any continued benefits for the neonate, especially with regards to cardiovascular development and function, is largely unknown. In the ENHANCED by Mom study we aim to determine the effects of different modes of exercise training (aerobic, circuit, and resistance) throughout pregnancy on childhood health by controlling individual exercise programs and assessing the effects of each on fetal and neonatal health adaptations. METHODS/DESIGN: ENHANCED by mom is a cross sectional comparison study utilizing 3 intervention groups in comparison to a control group. Participants will complete three 5 min warmup + 45 min sessions weekly from 16 weeks to 36 weeks gestation of aerobic, resistance, or circuit training, in comparison to non-exercising controls. Maternal physical measurements will occur every 4 weeks throughout the intervention period. Fetal morphometric and heart measurements will occur at 34 weeks gestation. Neonatal measurements will be acquired at birth and at 1 month, 6 months, and 12 months. DISCUSSION: A better understanding on the effects of exercise training during pregnancy on fetal and neonatal health could have a profound impact on the prevention and development of chronic diseases such as obesity, hypertension, and diabetes.

Exercise during pregnancy Dose: Influence on preterm birth outcomes.

BACKGROUND: Preterm delivery typically increases health risk for neonates and is associated with longer infant hospital stay and financial burden. Prenatal exercise dose (frequency, intensity, type, time, volume) have been shown to influence birth outcomes. Increased prenatal exercise dose could therefore provide a critical reduction in health risk and financial burden in preterm neonates. OBJECTIVE: It was our aim to explore the effects of prenatal exercise dose from a supervised exercise intervention in pregnant women on the occurrence of preterm (<37 weeks gestation) births, and the impact on health outcomes in preterm neonates. STUDY DESIGN: This study is a retrospective, secondary analysis of pooled data from three blinded, prospective, randomized controlled trials. Prenatal exercise dose were assessed in supervised aerobic, resistance, and combination sessions throughout pregnancy. In addition to gestational age, birth weight, resting heart rate, neonatal morphometrics (body circumferences, ponderal index), and health status (Apgar-1 and -5) metrics were obtained for 21 women at birth. One-way analysis of variance tests were used to assess the differences between dose grouped as tertiles, while Pearson correlations determined the association between dose and birth outcomes. RESULTS: Women exercised for an average of 19.6 wks (range: 6 - 21 wks) during pregnancy. Exercise during pregnancy tended to result in later preterm deliveries (p = 0.08). Greater prenatal exercise volume and duration were associated with reduced infant hospital stay post-delivery (p = 0.02). Weekly exercise volume was associated with increased Apgar scores (p = 0.01). CONCLUSION: Increased prenatal exercise volume and duration is associated with improved birth outcomes in preterm neonates.

Exercise FITT-V during pregnancy: Association with birth outcomes.

BACKGROUND: Prenatal exercise improves birth outcomes, but research into exercise dose-response effects is limited. METHODS: This study is a retrospective, secondary analysis of pooled data from three blinded, prospective, randomized controlled trials. Prenatal exercise frequency, intensity, type, time, and volume (FITT-V) were assessed in supervised sessions throughout pregnancy. Gestational age (GA), neonatal resting heart rate (rHR), morphometrics (body circumferences, weight-to-length and ponderal index) Apgar and reflex scores, and placental measures were obtained at birth. Stepwise regressions and Pearson correlations determined associations between FITT-V and birth outcomes. RESULTS: Prenatal exercise frequency reduces ponderal index (R2 = 0.15, F = 2.76, p = .05) and increased total number of reflexes present at birth (R2 = 0.24, F = 7.89, p < .001), while exercise intensity was related to greater gestational age and birth length (R2 = 0.08, F = 3.14; R2 = 0.12, F = 3.86, respectively; both p = .04); exercise weekly volume was associated with shorter hospital stay (R2 = 0.24, F = 4.73, p = .01). Furthermore, exercise type was associated with placenta size (R2 = 0.47, F = 3.51, p = .01). CONCLUSIONS: Prenatal exercise is positively related to birth and placental outcomes in a dose-dependent manner.

Effects of maternal exercise on infant mesenchymal stem cell mitochondrial function, insulin action, and body composition in infancy.

Maternal exercise (ME) has been established as a useful non-pharmacological intervention to improve infant metabolic health; however, mechanistic insight behind these adaptations remains mostly confined to animal models. Infant mesenchymal stem cells (MSCs) give rise to infant tissues (e.g., skeletal muscle), and remain involved in mature tissue maintenance. Importantly, these cells maintain metabolic characteristics of an offspring donor and provide a model for the investigation of mechanisms behind infant metabolic health improvements. We used undifferentiated MSC to investigate if ME affects infant MSC mitochondrial function and insulin action, and if these adaptations are associated with lower infant adiposity. We found that infants from exercising mothers have improvements in MSC insulin signaling related to higher MSC respiration and fat oxidation, and expression and activation of energy-sensing and redox-sensitive proteins. Further, we found that infants exposed to exercise in utero were leaner at 1 month of age, with a significant inverse correlation between infant MSC respiration and infant adiposity at 6 months of age. These data suggest that infants from exercising mothers are relatively leaner, and this is associated with higher infant MSC mitochondrial respiration, fat use, and insulin action.

CDKN2A homozygous deletion is associated with muscle invasion in FGFR3-mutated urothelial bladder carcinoma.

The gene cyclin-dependent kinase inhibitor 2A (CDKN2A) is frequently inactivated by deletion in bladder carcinoma. However, its role in bladder tumourigenesis remains unclear. We investigated the role of CDKN2A deletion in urothelial carcinogenesis, as a function of FGFR3 mutation status, a marker for one of the two pathways of bladder tumour progression, the Ta pathway. We studied 288 bladder carcinomas: 177 non-muscle-invasive (123 Ta, 54 T1) and 111 muscle-invasive (T2-4) tumours. CDKN2A copy number was determined by multiplex ligation-dependent probe amplification, and FGFR3 mutations by SNaPshot analysis. FGFR3 mutation was detected in 124 tumours (43.1%) and CDKN2A homozygous deletion in 56 tumours (19.4%). CDKN2A homozygous deletion was significantly more frequent in FGFR3-mutated tumours than in wild-type FGFR3 tumours (p = 0.0015). This event was associated with muscle-invasive tumours within the FGFR3-mutated subgroup (p < 0.0001) but not in wild-type FGFR3 tumours. Similar findings were obtained for an independent series of 101 bladder carcinomas. The impact of CDKN2A deletions on recurrence-free and progression-free survival was then analysed in 89 patients with non-muscle-invasive FGFR3-mutated tumours. Kaplan-Meier survival analysis showed that CDKN2A losses (hemizygous and homozygous) were associated with progression (p = 0.0002), but not with recurrence, in these tumours. Multivariate Cox regression analysis identified CDKN2A loss as a predictor of progression independent of stage and grade. These findings highlight the crucial role of CDKN2A loss in the progression of non-muscle-invasive FGFR3-mutated bladder carcinomas and provide a potentially useful clinical marker for adapting the treatment of such tumours, which account for about 50% of cases at initial clinical presentation.

Phosphorus legacy: overcoming the effects of past management practices to mitigate future water quality impairment.

The water quality response to implementation of conservation measures across watersheds has been slower and smaller than expected. This has led many to question the efficacy of these measures and to call for stricter land and nutrient management strategies. In many cases, this limited response has been due to the legacies of past management activities, where sinks and stores of P along the land-freshwater continuum mask the effects of reductions in edge-of-field losses of P. Accounting for legacy P along this continuum is important to correctly apportion sources and to develop successful watershed remediation. In this study, we examined the drivers of legacy P at the watershed scale, specifically in relation to the physical cascades and biogeochemical spirals of P along the continuum from soils to rivers and lakes and via surface and subsurface flow pathways. Terrestrial P legacies encompass prior nutrient and land management activities that have built up soil P to levels that exceed crop requirements and modified the connectivity between terrestrial P sources and fluvial transport. River and lake P legacies encompass a range of processes that control retention and remobilization of P, and these are linked to water and sediment residence times. We provide case studies that highlight the major processes and varying timescales across which legacy P continues to contribute P to receiving waters and undermine restoration efforts, and we discuss how these P legacies could be managed in future conservation programs.

Variation in chlorophyll a to total phosphorus ratio across 94 UK and Irish lakes: implications for lake management.

Eutrophication is the most widespread pressure impacting on lakes worldwide and, in general, its control is underpinned by the premise that algal biomass is regulated by phosphorus availability. This paper aims to demonstrate that not all lakes will conform to the underlying principle of the Chl:TP relationships using variables collected widely in lake monitoring programmes across the world (i.e. total phosphorus (TP) and chlorophyll a (Chl) concentrations). The ratio of annual mean Chl and TP concentrations in 94 lakes (2007 and 2008) was used as a measure of the efficiency with which TP is transferred into algal biomass (i.e. as an indicator of P limitation) to investigate the validity of the phosphorus reduction approach. Chl:TP ratios ranged from 0.02 to 0.84 in 2007 and from 0.03 to 0.96 in 2008. Chl and TP values were positively correlated (p < 0.05) with alkalinity, and negatively correlated with depth and surface area, in both years. In general, mean annual Chl and TP concentrations increased as alkalinity increased and depth decreased. However, Chl:TP ratio was highest in high alkalinity lakes in 2007, and moderate alkalinity lakes in 2008. Our results indicate that the use of TP water quality targets alone is insufficient to accurately manage eutrophication pressures at the lake specific scale, and that a wider range of ecological and ecosystem service evaluation targets would provide a more comprehensive assessment of management needs. The wide range of Chl:TP ratio values reported in this study suggests that, although reducing TP concentrations in lakes is undoubtedly a sensible approach to eutrophication management in many cases, TP reductions alone may not result in the expected reductions in phytoplankton biomass in all lakes.

A narrative review of exercise dose during pregnancy.

The current recommendations for prenatal exercise dose align with those from the American College of Sports Medicine; 150 min of moderate intensity every week of pregnancy. However, recent works suggest there may be a dose-dependent beneficial effect for mother and offspring; maternal and offspring health outcomes respond differently to low, medium, and high doses of prenatal exercise. It is, therefore, our aim to summarize the published evidence (years 1950-2023) for five metrics of prenatal exercise training commonly reported, that is, "FITT-V": Frequency (number of sessions), Intensity (metabolic equivalents "METs"), Time (duration of sessions), Type (exercise mode), Volume (exercise MET*mins). The target audience includes clinicians and health care professionals, as well as exercise professionals and physiologists. Data suggest that moderate exercise frequency (3-4 times weekly) appears safe and efficacious for mother and offspring, while there is contradictory evidence for the safety and further benefit of increased frequency beyond 5 sessions per week. Moderate (3-6 METs) and vigorous (>6 METs) intensity prenatal exercise have been shown to promote maternal and offspring health, while little research has been performed on low-intensity (<3 METs) exercise. Exercise sessions lasting less than 1 hr are safe for mother and fetus, while longer-duration exercise should be carefully considered and monitored. Taken together, aerobic, resistance, or a combination of exercise types is well tolerated at medium-to-high volumes and offers a variety of type-specific benefits. Still, research is needed to define (1) the "minimum" effective dose of exercise for mother and offspring health, as well as (2) the maximum tolerable dose from which more benefits may be seen. Additionally, there is a lack of randomized controlled trials addressing exercise doses during the three trimesters of pregnancy. Further, the protocols adopted in research studies should be more standardized and tested for efficacy in different populations of gravid women.

Methods for analyzing infant heart rate variability: A preliminary study.

Heart rate (HR) and heart rate variability (HRV) reflect autonomic development in infants. To better understand the autonomic response in infants, reliable HRV recordings are vital, yet no protocol exists. The purpose of this paper is to present reliability of a common procedure for analysis from two different file types. In the procedure, continuous electrocardiograph recordings of 5-10 min are obtained at rest in infants at 1 month of age by using a Hexoskin Shirt-Junior's (Carre Technologies Inc., Montreal, QC, Canada). Electrocardiograph (ECG; .wav) and R-R interval (RRi; .csv) files are extracted. The RRi of the ECG signal is generated by VivoSense (Great Lakes NeuroTechnologies, Independence, OH). Two MATLAB (The MathWorks, Inc., Natick, MA) scripts converted files for analysis with Kubios HRV Premium (Kubios Oy, Kuopio, Finland). A comparison was made between RRi and ECG files for HR and HRV parameters, and then tested with t tests and correlations via SPSS. There are significant differences in root mean squared successive differences between recording types, with only HR and low-frequency measures significantly correlated together. Recording with Hexoskin and analysis with MATLAB and Kubios enable infant HRV analysis. Differences in outcomes exist between procedures, and standard methodology for infant HR analysis is needed.