Added sugar intake during adolescence has been associated with weight gain and cardiometabolic risk factors. Moreover, dietary habits may persist into adulthood, increasing chronic disease risk in later life. This systematic review investigated changes in intake of added sugars between the ages of 13 and 30 years.Literature databases were searched for longitudinal studies of diet during adolescence or early adulthood. Retrieved articles were screened for studies including multiple measures of intake of sugars or sugary foods from cohort participants between the ages of 13 and 30. Data were analysed using random‐effects meta‐analysis, by the three main nutrient and food group categories identified (PROSPERO: CRD42015030126).n = 6), sugar‐sweetened beverages (SSBs) (n = 20) and/or confectionery (n = 9). Meta‐analysis showed a non‐significant per year of age decrease in added sugar or sucrose intake ), a decrease in confectionery consumption ) and a non‐significant decrease in SSB consumption ). Taken together, the overall decrease in added sugar intake observed from adolescence to early adulthood may suggest opportunities for intervention to further improve dietary choices within this age range.Twenty‐four papers reported longitudinal data on intake of added sugar or sucrose ( Sugar intake in childhood and adolescence, specifically intake of sugar‐sweetened beverages (SSBs) has been associated with weight gain in prospective cohort studies and randomized controlled trials Intake of added sugars is of particular concern for health The period of late adolescence to early adulthood has been suggested as an important, but overlooked age for establishment of long‐term health behaviour patterns Our literature search was conducted as part of a broader literature search of longitudinal observational studies that provided data on diet and physical activity in adolescence and early adulthood, reported in a scoping review of this topic We searched seven electronic databases  from 1980 until January 2016. Search terms combined diet and physical activity outcomes, longitudinal methods and indicators of adolescent or young adult age range. We only searched for papers published after 1980 since data collection post‐1980 was one of our inclusion criteria to maximize relevance of findings for current and future populations. The full search strategy as applied to Medline is shown in the supporting information Table . We alson = 98) were re‐assessed against the inclusion and exclusion criteria for the current review  and checked by a second researcher (TP). Any discrepancies were resolved by discussion between the two researchers. Data extracted from each paper included study (cohort) name, country of cohort, ethnicity, sex and socio‐economic status of participants, and the year at which participants would have been age 13, where reported. Further details were extracted for each wave of data collection within the age range of interest: sample size, mean age of the cohort, mean and standard deviation (SD) (or median and interquartile range where mean and SD were not available) of intake of sugar or sugary food or drinks (with units), and method of diet data collection. Depending on the outcomes reported, we also extracted any additional detail on the types of foods or drinks that were included in the reported data. Where studies addressed the determinants of changes in added sugar intake, we extracted information on reported associations between determinants and change in intake.Data on sugar and sugary food or drink outcomes were reported according to three distinct outcomes, which we chose to analyse separately: (i) added sugar or sucrose intake; (ii) SSB intake and (iii) confectionery intake. Data on added sugar and sucrose were reported together as these provided nutrient level measures of dietary sugar intake. SSBs and confectionery were the two main food groups on which data were reported in the studies reviewed. We defined SSBs as any sweetened beverages not presented as diet or non‐caloric beverages. For each outcome, where papers reported data across the same age range, one paper representing each study was selected for use in further quantitative analysis. Papers selected were those with the highest number of waves of data reported, those in which we were able to convert the reported data to the common metric for each diet outcome and the largest sample size. Data extracted from the selected papers were converted to a common metric for each diet outcome, to enable comparison between studies. The metrics chosen were percentage of total energy intake for sucrose and added sugar intake, and servings per week for food and drink intakes; these were the most common metrics reported. Data were converted to the appropriate units, and manipulated where necessary to give an overall mean and SD for the whole cohort for each food group at each wave. Further details on the calculations performed on data from each study are documented in the Supporting Information . In ordeIncluded papers were assessed for methodological quality using a 10‐item quality assessment scale see , based o2 statistic. Where heterogeneity was high (I2 > 50%) and the analysis included more than 10 studies post‐hoc treating added sugar and sucrose as two separate outcomes, rather than together in a combined meta‐analysis, to explore differences between these two measures.Data on added sugar intake were analysed across the three main outcome categories: sucrose or added sugar, SSBs and confectionery. Quantitative data analysis was conducted using STATA (version 14). For each study, we regressed mean intake on average age of the cohort, weighted by number of participants at each data collection, to give change in intake per year across each study. From these initial analyses, the regression coefficient became the effect size estimate to be used in meta‐analysis, with the standard error (SE) of the beta coefficient used for weighting the meta‐analysis. For those studies with only two data points, where SEs were not available from the regression, SEs were calculated from the sample SDs. Random effects meta‐analysis was used, to account for differences between studies, using the method of DerSimonian and Laird, with the estimate of heterogeneity being taken from the inverse‐variance fixed‐effect model. The heterogeneity of associations was expressed using the ITo identify publication bias and small‐study effects we used funnel plot asymmetry for each outcome, as assessed visually and using Egger's test of bias For studies that could not be included in the meta‐analysis, due to inability to convert data into standardized metrics or lack of detail on population variance, we present a brief narrative summary of study findings. Data on determinants of changes in added sugar intake are presented as a narrative synthesis across all added sugar outcomes.Results are reported in accordance with the PRISMA statement Our initial searches identified a total of 21,402 records following the removal of duplicates. After initial screening of titles and abstracts, we considered 319 references for full text review for the published scoping review, which included 98 papers n = 3; 13%) scored positively on ‘Adjustment for misreporting’. The majority of papers scored positively on ‘Adequate description of sampling frame, recruitment methods, period of recruitment and place of recruitment’  and ‘Provision of exact information on follow‐up duration’ . Table Table ent’ n = 3; 96% anSix papers reported on intake of added sugar or sucrose intake from five different studies, as shown in Table p < 0.05 level; see Table Post‐hoc analyses of added sugars and sucrose as separate outcomes found a stronger decrease in sucrose consumption (−0.26% [95%CI −0.43 to −0.10]) compared with added sugar consumption (−0.12% [95%CI −0.86 to 0.62]). An overall decrease of −0.26% energy from sucrose per year suggests that over a period of five years adolescents would see a reduction of 1.3% of their total energy intake derived from sucrose.Meta‐analysis of the change in intake per year from each study suggests an overall decrease in added sugar and sucrose intake over this period; however, this effect was not significant at the Twenty papers reported on SSB intake, reporting on 17 independent studies. Of these, we were able to extract comparable data from 13 studies; the remaining four studies did not report data in a way that could be converted to the standard metric of servings per week, for example reporting proportion of participants above or below a given level of intake rather than average levels of intake. The mean data from the 13 included studies is illustrated in Fig. p < 0.05 level (Table p = 0.52).Of these 13 studies, one could not be included in the meta‐analysis Data on SSBs included both studies that used terms such as ‘soft drinks’ and ‘fruit drinks’ and did not specify whether drinks were sugar‐sweetened or artificially sweetened, as well as studies that used a more precise definition of SSBs. As a sensitivity analysis, we included only those studies that precisely defined SSBs (as containing added sugar) or where data on SSBs (precisely defined) were available separately from other categories of soft drinks that were less clearly defined As shown in Table p = 0.05 level.Using all SSBs as the outcome, a sub‐group analysis by gender looked at studies where changes were reported separately for boys and girls. We saw a slightly larger decrease in weekly servings of SSBs per year for girls  than for boys . However, changes for both genders remained non‐significant at the Meta‐regression to further test for causes of study heterogeneity showed no significant moderation of the effect estimates by study quality or method of diet data collection. Inclusion of the year of study mid‐point in a meta‐regression  showed a small but significant association of calendar year with change in consumption seen with age, suggesting that with each calendar year the change in consumption per year of age becomes more negative by 0.04 servings/week .Meta‐regression further assessed whether the effect was moderated by the age range covered by the cohort, using the age that fell at the mid‐point of each cohort age range. However, no significant effect was seen for inclusion of mid‐point age in the meta‐regression. We tested whether a stronger effect was seen if we looked at data only from adolescence age 13 to 18) or from early adulthood (age 18 to 30). While changes in intake were non‐significant across both age ranges when the data were split in this way  investigated the association of personal, social (family and friends) and environmental (school) factors with change in sugary food and drink consumption, reporting no significant associations of these factors with intake at follow‐up, controlling for baseline intake et al. (2014) reported that less frequent consumption of fast food at baseline predicted less frequent consumption of high‐energy beverages at follow‐up, controlling for baseline consumption et al. (2002) reported no effect of dieting on consumption of confectionery and SSBs at follow‐up, controlling for baseline consumption Six papers from five studies reported data on determinants of changes in added sugar consumption. Studies reported no effects of gender p = 0.05 level, the consistent direction of change across nutrients and food groups suggests an overall trend towards decreases in added sugar intake over this age range. The pooled estimates of change in intake per year are small , −0.26% energy from sucrose, −0.20 servings/week confectionery, −0.15 servings/week SSBs (n.s.)), but if maintained through the adolescence and early adulthood years these changes will make a positive contribution towards a more healthy diet. A very small number of papers reported on determinants of changes in added sugar intake, suggesting no association of time‐invariant sociodemographic factors with changes in consumption of sugary foods or drinks, but some association of other health behaviours with such changes.Meta‐analysis of available longitudinal data on intakes of total added sugar or sucrose, SSBs and confectionery together indicate a decrease in added sugar intake across adolescence and into early adulthood. While not all results from the meta‐analysis are significant at the To our knowledge this is the first study to systematically review and meta‐analyse data on changes in added sugar intake from adolescence to early adulthood. Our review found sufficient reported data to conduct meta‐analysis across three domains of dietary data: nutrient level data on added sugar or sucrose intake and data on two food groups high in added sugar (SSBs and confectionery). The pooled effects were all in a consistent direction, lending some confidence to our conclusion that added sugar intake decreases across this age range.Nevertheless, this review was limited by the data available in the reviewed papers and the quality of those papers. While in our review, we intended to look at change in intake across the period from ages 13 to 30, much of the data retrieved was from the adolescent years, with very few reports of studies including data collection in the late twenties. Thus, our findings reported in this review predominantly represent dietary change in adolescence alone. In addition, the majority of studies reviewed came from high income countries and the findings may not be generalizable to low and middle income countries. The limited evidence available on soft drink intake in the later part of the age range of interest suggested that the decrease in soft drink intake may be greater from age 18 to 30 than ages 13 to 18, which might suggest a stronger decrease in overall added sugar intake. However, these adult data came from only two studies, and the pooled effect was non‐significant.We found limited nutritional data on added sugar intake, with only three studies reporting on total dietary added sugar. Due to the low number of studies reporting on dietary sugar intake, we initially analysed together two different measures of dietary sugar: total added sugar, and total sucrose intake, both as a percentage of overall energy intake. These are partially overlapping but distinct categories of sugar; added sugar includes sucrose but also other sugars, for example high fructose corn syrup While more data were available on specific food items (SSBs and confectionery), our meta‐analysis of SSB and confectionery intakes shows a high degree of heterogeneity between studies, which could not be explained by the variables tested through meta‐regression. While this heterogeneity is to some extent accounted for by use of random effects meta‐analysis, such a high degree of heterogeneity suggests that pooled results should be interpreted with caution. Heterogeneity may be due to true differences between study populations, such as social and environmental factors, or may be due to methodological differences whereby studies suffer from different degrees of bias. Indeed, there was considerable variability of data on SSB and confectionery intakes, with differences in data collection, classification and grouping of foods, and units of reporting. Conversions were required in many cases between the reported data and the common units used for meta‐analysis. Some of the heterogeneity between studies may be due to differences in definitions of foods and drinks included in each food group. In several papers, the exact definition of the foods or drinks that were included in the data reported was unclear. However, this lack of precision is more likely to have weakened our findings than produced erroneous findings. In our meta‐analysis of SSB data, we found a larger decrease in intake when including only studies that clearly defined drinks as containing sugar. If some of the studies that were excluded using this stricter definition did indeed include some data on diet drinks, the difference in effect size may reflect a tendency for adolescents to switch from sugar‐sweetened to diet drinks as they get older, as suggested by cross‐sectional data One consistent limitation of dietary data is the potential for bias introduced through misreporting. However, when looking at change over time, the estimate of change may still be valid if the level of misreporting is constant over time. However, if misreporting changed over the course of the study, either as a result of increasing age of participants, or over time due to changes in public awareness of the health effects of particular food groups, this will have affected our measures of change. While this is difficult to assess, we are reassured that we did not see any of effects of data collection method on the overall effect estimate of change in SSB intake in meta‐regression.Our findings across several related outcomes suggest a small but significant reduction in consumption of added sugar through adolescence and into early adulthood. The overall decrease in added sugar intake over this age range corresponds well with experimental studies of taste preferences. These have shown that young adults have a higher sensitivity towards sucrose than adolescents and young adults have lower preferred optimal sucrose concentrations in foods than adolescents The reported levels of consumption from the studies included in our review are in line with nationally representative and cross‐national survey data −1 from 1988 to 1994 to 1999–2004 It is difficult using the longitudinal cohort data reviewed here to disentangle trends due to the increasing age of the cohorts and secular trends. Cross‐sectional data from the US suggest that between 2000 and 2010 there was a secular decrease in intake of added sugar among children and adolescents, including that from SSBs, of around 25% This review and meta‐analysis of longitudinal changes in added sugar consumption suggest a consistent trend across sugar categories for a decrease in consumption through adolescence and early adulthood. However, given the small size of the effects seen, this finding does not suggest that the high added sugar consumption in children will reduce to a healthy level by adulthood without further intervention. By contrast, the natural tendency to reduce added sugar intake over this age range may suggest an opportunity for intervention to direct this change in taste towards more healthy foods. School, university or workplace interventions may be helpful to restrict availability of sugary foods and drinks. Alternatively, sugar reduction may form one component of a broader weight control intervention such as those currently being tested by the EARLY consortium We identified a lack of data on trajectories of added sugar consumption into early adulthood, with few studies continuing beyond the early twenties. Further longitudinal data in this age range could provide a clearer picture of how changes in added sugar consumption continue into early adulthood. In addition, our analysis here is limited to a study of population means only, which while providing important information about the overall direction of population change, masks variation in trajectories within populations. Further primary data analysis would be useful to further explore variation in trajectories of added sugar intake within populations, as well as factors that contribute to such variation. While few studies included in this review focused on determinants of change in added sugar consumption, the available evidence suggested some association with other health behaviours. Further studies are needed that study in detail interactions between behaviours and explore the potential behavioural determinants of changes in added sugar intake within this age group.The work was undertaken by the Centre for Diet and Activity Research (CEDAR), a UKCRC Public Health Research Centre of Excellence. Funding from the British Heart Foundation, Cancer Research UK, Economic and Social Research Council, Medical Research Council, the National Institute for Health Research (NIHR) and the Wellcome Trust, under the auspices of the UK Clinical Research Collaboration, is gratefully acknowledged. This work was additionally supported by the Medical Research Council [Unit Programme number MC_UU_12015/7]. The views expressed in this paper are those of the authors and not necessarily those of the above named funders.www.icmje.org/coi_disclosure.pdf and declare: all authors had financial support from the above named funders for the submitted work, T.P. additionally declares support from a studentship from the Cambridge Commonwealth Trust; M.W. reports board membership of the MRC, employment by NIHR and grants from NIHR, MRC and the UK Department of Health, E.v.S. declares grants from the UK Department of Health, MRC, NIHR and ESRC; K.C. declares a grant from NIHR; K.C. declares that she is a Director of Ridgepoint Consulting Ltd.All authors have completed the ICMJE uniform disclosure form at Table S1: Medline search strategyTable S2: Data conversion and assumptions for each paper included in graphs and/or meta‐analysisTable S3: Quality assessment tool for longitudinal observational studies of dietFigure S1: Forest plot depicting % energy from added sugar or sucrose and study weighting for all studies reporting on change in intake of added sugar or sucrose, together with the combined estimate.Figure S2: Forest plot depicting servings/day and study weighting for all studies reporting on change in intake of SSBs, together with the combined estimate.Figure S3: Forest plot depicting servings/day and study weighting for all studies reporting on change in intake of confectionery, together with the combined estimate.Click here for additional data file.


Recent developments in polymerization reactions utilizing thiocarbonylthio compounds have highlighted the surprising versatility of these unique molecules. The increasing popularity of reversible addition–fragmentation chain transfer (RAFT) radical polymerization as a means of producing well‐defined, ‘controlled’ synthetic polymers is largely due to its simplicity of implementation and the availability of a wide range of compatible reagents. However, novel modes of thiocarbonylthio activation can expand the technique beyond the traditional system  pushing the applicability and use of thiocarbonylthio compounds even further than previously assumed. The primary advances seen in recent years are a revival in the direct photoactivation of thiocarbonylthio compounds, their activation via photoredox catalysis, and their use in cationic polymerizations. These synthetic approaches and their implications for the synthesis of controlled polymers represent a significant advance in polymer science, with potentially unforeseen benefits and possibilities for further developments still ahead. This Research News aims to highlight key works in this area while also clarifying the differences and similarities of each system. In a manner remarkably similar to the original investigations by Otsu, direct photoactivation of compounds containing a TCT moiety has been shown to produce polymers of low dispersity and high end‐group fidelity , provided that the combination of monomer, TCT compound, and light source (wavelength and intensity) is appropriately selected.2sole source of initiation, in addition to being a key mediating species.The photoactivity of thio‐containing compounds is well known,direct photoactivation of TCT species and the implications thereof.Direct photoactivation of TCT compounds using UV irradiation has also been the subject of much investigationÐ < 1.2) at relatively high monomer conversions.[[qv: 8b]] This report clearly demonstrated that the direct photoactivation of TCTs with UV irradiation could provide a truly robust photopolymerization pathway, and re‐invigorated investigations in this area. In this work, the rate of polymerization was found to be strongly dependent on both the targeted degree of polymerization (DPn) ), as well as the intensity of irradiation. It was also reported that irradiation of a low concentration of TCT (0.45 mm) in the absence of monomer can lead to irreversible degradation of this species, while higher TCT concentrations (13.5 mm) show no structural change even after extended irradiation.[[qv: 8b]] Importantly, fragmentation of the C–S bond in the latter case was still occurring as evidenced by radical trapping experiments, illustrating that the rate of reversible termination was sufficient so as to avoid an extended lifetime of the potentially unstable thiyl radical.N‐isopropylacrylamide in the presence of a bis‐functional TCT.[[qv: 8a]] The authors demonstrated the “on–off” nature of the photopolymerization, and showed the reaction can be effectively activated under solar radiation – a feature that may be promising for industrial applications where natural light sources are desired or beneficial. Subsequently, Kwark et al. described the UV‐activation of a xanthate (S‐2‐cyano‐2‐propyl‐O‐ethyl xanthate) for the controlled photopolymerization of vinyl acetate (VA).[[qv: 8b]] This system was shown to generate poly(VA) with good control (Ð ≈ 1.2–1.3). The rate of the reaction was found to be inversely proportional to the targeted DPn , which conflicts with the previous report by Bai et al..[[qv: 8b]]In 2013, Bai et al. demonstrated that S‐1‐Dodecyl‐S′‐ trithiocarbonate (DDMAT) was capable of controlling the polymerization of methyl acrylate (MA) under UV irradiation, producing narrowly dispersed linear poly(MA) .[[qv: 13b]] Recently, the group of Qiao has exploited this phenomenon by selectively exciting the n→π* absorption band with blue light (λmax ≈ 460 nm), allowing for the visible light photoactivation of a range of TCTs.[[qv: 8f]] Despite the weak molar absorptivity in this region the TCTs investigated were shown to polymerize a range of acrylates and acrylamides, resulting in well‐defined linear polymers (Ð < 1.1), with high end group fidelities even at near complete monomer conversions (conv. > 95%) as evidenced by matrix‐assisted laser desorption/ionization‐time of flight mass spectrometry (MALDI‐ToF MS) analysis and in situ chain extension experiments. The Boyer group independently investigated the direct photopolymerization of methacrylates under low intensity (≈0.7 mW cm–2) blue and green light irradiation while developing their photoredox catalyzed system (vide infra).[[qv: 8e]] The proposed mechanism for these two techniques was carefully compared. The polymerization kinetics for direct photoactivation is dependent on light wavelengths, intensities, monomers and specific TCT compounds. Visible light activation had been reported by the group of Kamigaito previously,[[qv: 8c]] where irradiation with a weak white light source (a household fluorescent bulb) was demonstrated to activate the polymerization of vinyl monomers in the presence of a xanthate compound (O‐ethyl‐S‐(1‐ethoxycarbonyl)ethyldithiocarbonate). The authors astutely observed that this may make the employed TCT suitable as a ‘photoiniferter’, however further investigation was not pursued. However, a similar system was recently reported in which various xanthates were used for the blue light mediated photopolymerization of the unconjugated monomer vinyl acetate.TCTs are typically strongly yellow, red, or orange in color, which has been ascribed to the Although there exist some benefits to using visible light rather than UV as the source of activation , the potential mechanistic and structural benefits  require further examination. Regardless, this approach employing solely TCT compounds as the photoactive species and control agent offers the potential for further modification, optimization, as well as a deeper understanding of the competing reaction pathways.3FigureThe Boyer group recently introduced the concept of TCT activation via a photoinduced electron transfer (PET) process by incorporating a suitable photoredox catalyst with/without an electron donor.[[qv: 9a]] The employed photoredox catalyst is proposed to reduce the TCT to generate a radical anion, along with the catalyst in an elevated oxidation state. The resulting TCT anion can fragment to give an initiating carbon‐centered radical, before back electron transfer (re)generates the dormant polymer chain and the photocatalyst in its ground state, thereby completing the catalytic cycle 3], Ir(III)),[[qv: 9a]] which has been extensively employed for a variety of organic transformations.λmax = 435 and 460 nm) for a variety of different monomers (both activated and less activated monomers). The high end group fidelity of the resulting polymers was confirmed by 1H NMR analysis, UV–vis spectroscopy, and successive chain extension experiments to form (multi)block copolymers. The PET‐RAFT system was subsequently transferred to aqueous conditions through use of a water‐soluble catalyst (Ru(bpy)3Cl2, Ru(II)).[[qv: 9b]] This allowed for the efficient preparation of protein‐polymer conjugates with a high enzymatic activity.Initial investigations into the photoredox activation of TCTs was performed using an iridium complex .] Given that radical polymerizations are typically inhibited by oxygen due to its excellent radical scavenging behavior, the ability to perform controlled radical polymerization without the need for thorough degassing of the reaction mixture would represent a major advancement in the applicability of these systems. The strong photoreducing nature of the employed catalysts is thought to allow for the single electron reduction of dissolved oxygen, consuming any inhibiting oxygen species prior to the polymerization taking place. Photopolymerizations performed in air  were demonstrated to occur with minimal difference in reaction rate between deoxygenated and non‐deoxygenated reaction mixtures.[[qv: 9a]] An increased induction period was observed in the non‐deoxygenated mixtures for both acrylate and methacrylate monomer types, which was ascribed to the time during which molecular oxygen was consumed. The length of inhibition period is proportional to the volume of air present in the reaction flask and the concentration of the catalyst.a which could be extracted directly from spinach leaves),[[qv: 9f]] and various porphyrin structures, which greatly enhanced the versatility and applicability of these systems.[[qv: 9g]] The Qiao group recently reported the use of organic amines under UV irradiation for the photopolymerization of methacrylates with both homogeneous[[qv: 9e]] and heterogeneousA potential drawback of the initially reported PET‐RAFT process was the expensive and potentially toxic transition‐metal complex used . This was subsequently addressed via the use of a range of abundant and non‐toxic photoactive organic compounds,] naturally derived metallo‐complexes (including chlorophyll a) Boyer et al. recently demonstrated a PET‐RAFT system that could be regulated by near infrared (NIR) and far‐red light.Given the diversity of photoredox catalysts demonstrated, focus was then placed on expanding the range of irradiating wavelengths able to activate the polymerization. This can have advantages including lower energy consumption and deeper photon penetration through films and/or gels when longer wavelengths are employed. Tunable photocatalysis based on a single molecule was achieved via the use of a zinc‐porphyrin photoredox catalyst, with the rate of the polymerization linked to the absorption profile of the catalyst and thus tunable over a range of visible wavelengths.[[qv: 9g]] Interestingly, the zinc‐porphyrin employed displayed high activity towards trithiocarbonates, while other TCT compounds  displayed much slower kinetics, inferring selective polymerization activation. This was believed to suggest some form of novel molecular recognition occurring between the metal‐porphyrin and the trithiocarbonate, and may be similar to the interactions between zinc and sulfur sites in biomolecules and enzymes, where specific interactions mediate certain redox processes, DNA recognition events, and transcriptional activation.[[qv: 9g]] Surprisingly, the photopolymerizations can proceed in the presence of air with a minimal induction period . By using a novel biocatalyst (bacteriochlorophyll 3 or Yb(OTf)3), along with an Ir(III) photoredox catalyst. The choice of solvent is crucial in these experiments as the complexation strength of the monomer‐mediator pair determines the extent of stereocontrol. In light of this, Boyer et al. discovered that by gradually adding DMSO—a Lewis base that can interfere with the Lewis acid mediator—the stereocontrol of the polymerization could be modulated in situ, allowing for the preparation of a multiblock copolymer with five blocks of differing stereoregularity.Further development of the PET‐RAFT system was illustrated by the synthesis of polymers with varying levels of stereocontrol.4The Kamigaito group observed that the activation of oxygen‐ester bonds via Lewis acids (LAs) commonly employed for the cationic polymerization of vinyl ethers may be replicable with TCT compounds, allowing for transformations between RAFT radical polymerization and a living cationic polymerization in a single reaction vessel. This hypothesis was confirmed with the reported synthesis of block copolymers consisting of (meth)acrylate and vinyl ether blocks by an in situ transformation from radical initiated RAFT polymerization to a cationic system via the addition of a LA activator.[qv: 10a]] It was demonstrated that although vinyl ether cannot homopolymerize in a radical system, it can copolymerize with (meth)acrylate units. However, after addition of the LA the vinyl ether is rapidly consumed while no further conversion of the (meth)acrylate units occurs. The observed molecular weights correspond to theoretical values if one TCT compound initiates one polymer chain, indicating that control over these polymerizations is exerted by these species. It is postulated that activation occurs via coordination of the LA to the thiocarbonyl (C = S) moiety, releasing the R‐group as an active carbocation monomers strongly affects the number of times the mechanism was ‘interconverted’ during a typical chain growth. This directly alters the segment length of each monomer‐type during the copolymerization, imparting different glass transition temperature behaviors.3SO3H or TfOH) as an initiator, and a suitable TCT compound as a mediating agent.cationic species, and to therefore undergo a RAFT mechanism, was demonstrated for the first time  using a strong Bronsted‐Lowry organic acid  TCTs and monomers in the future. These systems also open new routes to advanced materials and novel structures that may be of interest for a variety of polymer‐based technologies Figure3. For 6The versatility of organic sulphur compounds, and in particular TCTs, for chemical transformations and polymerization reactions is rapidly expanding. For polymerizations, the activation of these species through direct photoexcitation, photoredox catalysis, and acid activation have been shown to provide exemplary pathways towards well‐defined polymers with high chemical fidelity provided that the conditions and reagents are selected appropriately so as to optimize the desired reaction pathway. We believe that these TCT‐based techniques offer further unexplored potential for expansion and refinement, and may bring about access to new and high‐value polymer‐based technologies. During the preparation of this manuscript, two comprehensive reviews regarding photopolymerization systems were published by the groups of Johnson


We provide the first comprehensive analysis of the relationships between large‐scale patterns of Southern Hemisphere climate variability and the detailed structure of Antarctic precipitation. We examine linkages between the high spatial resolution precipitation from a regional atmospheric model and four patterns of large‐scale Southern Hemisphere climate variability: the southern baroclinic annular mode, the southern annular mode, and the two Pacific‐South American teleconnection patterns. Variations in all four patterns influence the spatial configuration of precipitation over Antarctica, consistent with their signatures in high‐latitude meridional moisture fluxes. They impact not only the mean but also the incidence of extreme precipitation events. Current coupled‐climate models are able to reproduce all four patterns of atmospheric variability but struggle to correctly replicate their regional impacts on Antarctic climate. Thus, linking these patterns directly to Antarctic precipitation variability may allow a better estimate of future changes in precipitation than using model output alone. The primary Southern Hemisphere extratropical circulation patterns all influence the spatial distribution of Antarctic precipitationThey impact not only the mean but also the incidence of extreme precipitation eventsLocally, extreme precipitation may be associated especially with one polarity of a circulation pattern However, occasionally, atmospheric blocking pushes weather systems inland onto the Plateau, where they cause rapid changes in weather and can contribute a significant proportion (~25%) of the annual accumulation over a few days  circulation variability influence the spatial distribution of Antarctic precipitation. The atmospheric patterns comprise the southern baroclinic annular mode (BAM), the southern annular mode (SAM), and the two Pacific‐South American (PSA) teleconnection patterns. Previously, Marshall and Thompson (22.1We use two primary sources: atmospheric data comes from (1) the European Centre for Medium Range Weather Forecasts (ECMWF) ERA‐Interim reanalysis data  in which additional upper air relaxation is employed  of Southern Hemisphere (SH) daily mean zonal mean eddy kinetic energy while the SAM, PSA1, and PSA2 are defined as the first, second, and third EOFs of SH monthly mean 500 hPa geopotential height, respectively. The spatial domain used for the EOF analysis was 20–70°S. Daily mean time series of the SAM and PSA patterns are obtained by projecting daily mean 500 hPa geopotential height anomalies onto the respective EOF patterns.The time series of all patterns are standardized so that their mean is zero and variance is one. We define days having a positive (negative) polarity of a particular index as those when the index is >1 (< −1): hereinafter, positive and negative polarities of a particular mode are indicated with a “+” or “−” subscript, respectively. By construction, the SAM and PSA patterns are not correlated with each other, and none are significantly correlated with the BAM (see MT16 for an explanation). Nevertheless, an individual day may be associated with the positive (and/or negative) polarity of more than one pattern at a time.The BAM is characterized by hemispheric‐scale variations in the amplitudes of midlatitude storms, and its positive polarity is defined as days with larger than normal wave amplitudes  are characterized by zonally asymmetric pressure anomalies that extend southeastward across the extratropical Pacific Ocean to the Southern Ocean off West Antarctica, and their positive polarities are indicated in Figure 3To provide physical context for the linkages between large‐scale climate variability and Antarctic precipitation, we first explore the differences in the 850 hPa meridional moisture flux and near‐surface winds between the positive and negative polarities of the four patterns of atmospheric variability. Note that negative values (blue shading) denote poleward fluxes, and vice versa Figure .+) are uniformly poleward and peak at midlatitudes . The moisture fluxes associated with the positive polarity of the BAM  is centered at 120°W (150°W). Strong meridional wind anomalies bring especially large moisture fluxes into (out of) the continent to the west (east) of the high‐pressure anomaly. We note that in some areas of West Antarctica, PSA1 is centeDifference plots of daily precipitation anomalies between positive and negative polarities of the four patterns of atmospheric circulation variability are shown in Figure + is associated with significant increases in precipitation across much of coastal East Antarctica, West Antarctica, and the Antarctic Peninsula (blue shading), coincident with the anomalously poleward moisture fluxes across most of the Southern Ocean  tend to be associated with the opposite polarity to those days with the highest precipitation.At Byrd, days with greater than average precipitation are more likely to be associated with BAM+ and SAM− while there is relatively little difference in precipitation between the two polarities of both PSA patterns, as also indicated by Figures − conditions while none of the top 20 highest occurred during SAM+. In contrast, days of both polarities of the other three circulation indices exist in the 5 days of greatest precipitation. During 12 July 2009, when the maximum daily RACMO precipitation of ~0.27 m water equivalent fell  leads to greater precipitation over coastal East Antarctica.+ also acts to reduce the relatively small amounts of precipitation over the Plateau.The positive polarity of the SAM results in enhanced precipitation across much of West Antarctica and the western Antarctic Peninsula. However, the enhanced westerly winds impinging on the steep orography cause a “precipitation shadow” on the lee side of the Peninsula. SAMThe principal impact of the PSA patterns on precipitation anomalies is observed in West Antarctica, where significant increases (decreases) are linked with strong meridional moisture fluxes into (out of) the continent. However, both PSA patterns, especially PSA2, are also linked with precipitation anomalies across other parts of Antarctica.We provide the first comprehensive analysis of the role that the four principal patterns of Southern Hemisphere high‐latitude circulation variability—the BAM, SAM, and two PSA patterns—have on the spatial distribution of precipitation across Antarctica. Using composite difference plots Figure , we demo+ and, to a lesser extent, SAM− and PSA2− conditions. In contrast, at Law Dome, days with higher precipitation are typically allied to BAM− and SAM+.We examined pdfs of the daily time series of precipitation at Byrd and Law Dome, two sites where well‐studied ice cores have been drilled, to understand whether the circulation patterns are responsible for the most significant precipitation anomalies Figure . At the + conditions lead to a reduction in precipitation on the lee side .By comparing our results Figure  with tho− conditions.The long‐term trends in the circulation over Antarctica have been toward a greater frequency of both the positive polarity of the SAM during austral summer  at p < 0.10 and in the SAM in summer (December‐January‐February) at p < 0.05. Plots of trends in daily precipitation in these two seasons and the fraction of the trends that are congruent with the circulation patterns are provided in the + days during summer is predominantly responsible for the opposing trends in precipitation on the two sides of the Antarctic Peninsula, a region where the trends in the SAM are also known to have had a significant impact on SAT in this season (Marshall et al., However, during the 35 year period studied here, there are no statistically significant trends in the four circulation patterns in the Climate model projections forecast an increase in Antarctic precipitation as global temperatures rise. Indeed, modeling studies suggest that a distinct pattern of austral summer drying and moistening observed in Southern Hemisphere midlatitudes and high latitudes, respectively, over the last few decades is likely to have a strong anthropogenic component (Fyfe et al., Supporting Information S1Click here for additional data file.


Genetic interaction between domesticated escapees and wild conspecifics represents a persistent challenge to an environmentally sustainable Atlantic salmon aquaculture industry. We used a recently developed eco‐genetic model (IBSEM) to investigate potential changes in a wild salmon population subject to spawning intrusion from domesticated escapees. At low intrusion levels (5%–10% escapees), phenotypic and demographic characteristics of the recipient wild population only displayed weak changes over 50 years and only at high intrusion levels (30%–50% escapees) were clear changes visible in this period. Our modeling also revealed that genetic changes in phenotypic and demographic characteristics were greater in situations where strayers originating from a neighboring wild population were domestication‐admixed and changed in parallel with the focal wild population, as opposed to nonadmixed. While recovery in the phenotypic and demographic characteristics was observed in many instances after domesticated salmon intrusion was halted, in the most extreme intrusion scenario, the population went extinct. Based upon results from these simulations, together with existing knowledge, we suggest that a combination of reduced spawning success of domesticated escapees, natural selection purging maladapted phenotypes/genotypes from the wild population, and phenotypic plasticity, buffer the rate and magnitude of change in phenotypic and demographic characteristics of wild populations subject to spawning intrusion of domesticated escapees. The results of our simulations also suggest that under specific conditions, natural straying among wild populations may buffer genetic changes in phenotypic and demographic characteristics resulting from introgression of domesticated escapees and that variation in straying in time and space may contribute to observed differences in domestication‐driven introgression among native populations. Second, to investigate the potential for recovery in native populations following introgression of domesticated escapees. Third, to quantify the degree to which phenotypic and demographic changes in wild populations due to the introgression of domesticated escapees can be influenced by straying among wild populations and the genetic admixture characteristics of strayers.22.1N equating to 50% intrusion in the first year and steadily increasing as the wild population declined), or varied in tandem with the focal wild population (domesticated intruders = Fixed 50%), (B) the number of strayers from a neighboring wild population was either held at a “Fixed N” or alternatively “Fixed % of the focal population”—thus declining if the focal population declined, and (C) the strayers from a neighboring wild population were either “not admixed” or “domestication‐admixed at the same degree as the focal population.”The study was divided into two parts. First, we conducted a sensitivity analysis to investigate how straying (and thereafter gene‐flow) from a neighboring wild population may potentially buffer domestication‐driven genetic changes in a focal wild population subject to spawning intrusion of farmed escapees. We used a factorial design with the following three fully crossed binary factors  and included a detailed examination of the outputs of IBSEM. These outputs included density of eggs deposited in the river, juvenile growth/size and density, smolt growth/size, age and density, number of returning adults, and their growth/size and age of maturation.Second, we conducted an in‐depth examination of the two most contrasting scenarios emerging from the sensitivity analysis . Both these scenarios were tested under three levels of domesticated salmon intrusion  is the sum of “1” alleles in a certain gene, weighted by loci‐specific degree of influence, and scaled such that the minimum (Sϕ = 0) and the maximum (Sϕ = 1) are obtained for, respectively, “00” and “11” homozygotes for all 20 loci of that gene. An individual could be anywhere on the scale between these two extremal values, depending on their genetic composition across these loci for each of the three independent sets of genes. The resultant genetic value, hereon referred to as the sum of the genetic effects, determines an individual's phenotypic value in terms of growth and survival for the three life stages in the model . The genotype–phenotype maps are linear . Each of these sets of genes consists of 21 diploid and unlinked biallelic loci , with the ability for gamete recombination and random inheritance during sexual reproduction. Therefore, the random evolutionary force of genetic drift may play a role, especially when r Figure .The phenotypic differences between domesticated and wild salmon are expressed through their genotypes. Specifically, wild salmon in their native river were initiated with the allele frequency equal to 0.9 in all non‐neutral loci, whereas the farmed salmon were initiated with frequency 0.1 in all non‐neutral loci. The genotype–phenotype maps were tuned such that the average phenotype in wild salmon resulted in a population with demographic and life‐history characteristics similar to Atlantic salmon from the river Os in Norway  as opposed to varying in tandem with the focal wild population . In order to achieve this, intrusion of escapees was set at either 50% of the number of adults returning to the focal population each year (Fixed % scenarios 1–4), or set to a constant value of 250 for each year regardless of N‐adults returning to the focal population which corresponds to 50% in the first year of intrusion (Fixed N scenarios 5–8)  Table , and bas8) Table , this leN) as opposed to varying in tandem with the focal wild population . In order to achieve this, strayers were set at 5% of the N‐adults returning to the focal population , or fixed to 25, corresponding to 5% of the N‐adults returning to the focal population in the first year of intrusion . This level of straying is within the variation displayed between Atlantic salmon populations , or alternatively, not admixed with domesticated escapees and thus set to a fixed value of 0.8 . Both of these sets of scenarios, that is, admixed vs. nonadmixed strayers, are realistic given that in the wild, populations displaying both different and similar admixture levels can be observed in the same region . These two scenarios reflect the contrasting situations where there is global introgression in a region and all rivers are simultaneously influenced by intrusion of domesticated escapees , as opposed to where there is only introgression in the focal wild population and the neighboring rivers are not influenced by intrusion of domesticated escapees . “Global” and “local” reflect the two extreme points and were thus chosen to illustrate the potential influence that straying elicits on changes in populations influenced by intrusion of domesticated escapees.Following the initial sensitivity analyses as described above, two contrasting scenarios were chosen for an in‐depth analysis of the potential genetic changes in a wild population subject to spawning intrusion from domesticated escapees. These were scenario 5 whereby the neighbor population providing the strayers is ecologically linked and admixed at the same degree as the focal wild population itself (thus straying at 5% and admixed at the same degree as the wild population), and scenario 8, whereby the neighbor population providing the strayers is not ecologically linked nor admixed at the same degree as the focal wild population itself , smolt density and size in May prior to migration from the river (split by age), number of adult salmon returning to the river to spawn, and their size (split by age). Domesticated salmon intrusion levels were set to 33.1In all scenarios investigated, intrusion of domesticated escapees led to changes in the sums of genetic effects  in the direction of the domesticated genotype, reflecting introgression in the focal wild population Figures , 3. ThesN = 250 which is equal to 50% the number of wild spawners returning to the focal population in the first year of the simulation , compared to when it was ecologically connected to the focal wild population and equally admixed .3.2Two contrasting scenarios emerging from the sensitivity analyses described above  were chosen for an in‐depth analysis of the phenotypic and demographic response of wild populations subject to spawning intrusion of domesticated escapees Figure , 5, 6. ILooking closer at the sums of the genetic effects Figure , it is pIn part due to demographic stochasticity, the effects of the escapees on population demography were hardly discernible when intrusion was set at 5% and 10% Figure . Concent4This is the first study to model a set of phenotypic and demographic characteristics in an Atlantic salmon population subject to spawning intrusion by maladapted domesticated escapees. The results of our simulations indicate that at domesticated salmon spawning intrusion levels of 5% and 10% (~1%–2% gene‐flow per year), most of the phenotypic and demographic traits measured in the recipient wild population only displayed weak changes on a relatively short time scale . Only when the frequency of domesticated escapees on the spawning grounds was increased to 30% or 50% (~5%–9% gene‐flow per year), were phenotypic and demographic changes clearly visible in the recipient wild population on this time scale. Based upon results from these simulations, together with existing knowledge, we suggest that a combination of reduced spawning success of domesticated escapees, natural selection purging maladapted phenotypes/genotypes from the wild population, and phenotypic plasticity buffer the rate and magnitude of change in phenotypic and demographic characteristics of wild populations subject to spawning intrusion of domesticated escapees. These suggestions are in line with empirical data demonstrating that domesticated escapees display reduced spawning success in comparison with wild salmon , as opposed to uninfluenced . This result is intuitive and suggests that unaffected  neighboring populations may provide a partial buffer against fitness changes in wild Atlantic salmon populations invaded by domesticated escapees. In turn, we suggest that variation in population connectivity in time and space, and regional differences in the degree to which introgression of domesticated salmon occurs globally or locally, may contribute to the overall picture of large interpopulation patterns of domestication‐driven introgression that has been reported among wild Atlantic salmon populations , the resulting changes in native populations are not expected to be very large, potentially making them difficult to detect (Figures 0 years, The ultimate approach to protect native populations from further genetic changes from interbreeding of farmed escaped salmon is a significant reduction in the number of domesticated escapees and/or sterilization of farmed fish (Glover et al., Each year, the Institute of Marine Research conducts an environmental risk assessment of Norwegian aquaculture (Taranger et al., There are no raw data associated with this work.None declared.


THE) and transthoracic esophagectomies (TTE). Some studies report that the learning curve is approximately 20 cases. Following the initial series, operative results of robotic TTE have shown a tendency to improve, and oncological long‐term results are reported to be effective and acceptable: R0 resection approaches 95%, and locoregional recurrence is rare. Several recent studies have demonstrated advantages of robotic esophagectomy in lymphadenectomy compared with the thoracoscopic approach. Such technical innovations as three‐dimensional view, articulated instruments with seven degrees of movement, tremor filter etc. have the potential to outperform any conventional procedures. With the aim of preventing postoperative pulmonary complications without diminishing lymphadenectomy performance, a nontransthoracic radical esophagectomy procedure combining a video‐assisted cervical approach for the upper mediastinum and a robot‐assisted transhiatal approach for the middle and lower mediastinum, transmediastinal esophagectomy, was developed; its short‐term outcomes are promising.Since the introduction of robotic systems in esophageal surgery in 2000, the number of robotic esophagectomies has been gradually increasing worldwide, although robot‐assisted surgery is not yet regarded as standard treatment for esophageal cancer, because of its high cost and the paucity of high‐level evidence. In 2016, more than 1800 cases were operated with robot assistance. Early results with small series demonstrated feasibility and safety in both robotic transhiatal (Thus, the merits or demerits of robotic surgery in this field remain quite difficult to assess. However, in the near future, the merits will definitely outweigh the demerits because the esophagus is an ideal organ for a robotic approach. A total of three such papers have been published.3A total of nine published papers reported initial cases of transthoracic esophagectomy (TTE).4Some papers focused on the learning curve with robotic surgery. Robotic console time with this innovative procedure was reported to be significantly reduced after the initial six patients.5To the best of our knowledge, very few or no series of robotic THE have been published following the initial small series; more results of robotic TTE, albeit few, have been published.6More than 15 years have passed since robotic surgery began to be used in esophageal cancer treatment, and several papers have reported oncological long‐term results. The Utrecht group, one of the pioneers in this field, reported that, based on 108 cases, their radical resection (R0) rate was 95%, 5‐year overall survival (OS) was 42%, and locoregional recurrence was only 6%.7One experimental study showed that the robot‐assisted thoracic approach was associated with improved intraoperative cardiopulmonary function and less stress compared with the open thoracic approach.In comparisons of robotic to thoracoscopic approaches , the first such paper published failed to show any clear advantages.8Several published review articles have focused on robotic esophagectomy.9With the aim of averting postoperative pulmonary complications without diminishing lymphadenectomy , a nontransthoracic radical esophagectomy procedure has been developed which combines a video‐assisted cervical approach for the upper mediastinum Figure A and a r10No‐one denies the technical innovativeness and advantages of robotic surgery, and the anatomical features of the esophagus make it an ideal organ for robotic surgery. Robotic surgery therefore has merits for esophageal cancer, but it is still not regarded as a standard procedure, as a result of the paucity of definite high‐level evidence and its unacceptably high cost. We must wait for the results of ongoing randomized controlled trials to be reportedConflict of Interest: Authors declare no conflicts of interest for this article.


Implementation of noninvasive prenatal testing (NIPT) as a highly accurate aneuploidy screening test has raised questions around whether the high uptake may result in more terminations of pregnancies and fewer births of children with Down syndrome (DS).The aim of the study was to investigate the impact of NIPT on termination and live birth rates for DS.. Termination rates were calculated for women with a high‐risk NIPT result for DS. Two audits of pregnancy outcomes where NIPT indicated DS were conducted in the United Kingdom and Singapore.Literature reporting pregnancy outcomes following NIPT was reviewedFourteen studies from the United States, Asia, Europe, and the United Kingdom were included in the review. Live births of children with DS were reported in 8 studies. Termination rates following NIPT were unchanged or decreased when compared to termination rates prior to the introduction of NIPT. Audits found 15 of 43 women in the United Kingdom and 2 of 6 in Singapore continued pregnancies following a high‐risk NIPT result.Termination rates following the detection of DS by NIPT are unchanged or decreased compared to historical termination rates. Impact on live birth rates may be minimal in settings where termination rates fall. Population‐based studies are required to determine the true impact. WHAT IS ALREADY KNOWN ABOUT THIS TOPIC?Noninvasive prenatal testing (NIPT) has been shown to be a highly accurate prenatal screening test for DS and is being implemented widely throughout the world.Introduction of NIPT has increased the prenatal detection of DS with a significantly reduced invasive testing rate, but the impact on rates of termination of pregnancy and the number of children born with DS is not yet known.WHAT DOES THIS STUDY ADD?Introduction of NIPT has a variable effect on termination rates for DS, but rates have remained unchanged or decreased when compared to termination rates reported prior to the introduction of NIPT, with many parents using NIPT for information and continuing pregnancies when results show a high risk of DS.Practical and emotional support structures are needed for these families.Where termination rates fall NIPT may have a minimal impact on live birth rates for DS.Monitoring at population levels is required for a more accurate assessment of live birth rates. These figures vary between countries: in the United States there were 30% fewer individuals with DS 2007),07,20 48%While we await definitive population‐based studies, there are several lines of evidence available to us now that can help assess the impact the introduction of NIPT might ultimately have on the numbers of parents choosing to continue their pregnancy following a prenatal diagnosis of DS. Here we examine the literature to look at reports of pregnancy outcomes following NIPT. We also describe 2 new audits of NIPT services in clinical practice that were conducted in England and in Singapore.Noninvasive prenatal testing (NIPT) has been shown to be a highly accurate prenatal screening test for DS and is being implemented widely throughout the world.Introduction of NIPT has increased the prenatal detection of DS with a significantly reduced invasive testing rate, but the impact on rates of termination of pregnancy and the number of children born with DS is not yet known.Introduction of NIPT has a variable effect on termination rates for DS, but rates have remained unchanged or decreased when compared to termination rates reported prior to the introduction of NIPT, with many parents using NIPT for information and continuing pregnancies when results show a high risk of DS.Practical and emotional support structures are needed for these families.Where termination rates fall NIPT may have a minimal impact on live birth rates for DS.Monitoring at population levels is required for a more accurate assessment of live birth rates.22.1We reviewed the published literature reporting the number of live births of children with DS following screening with NIPT. A search of English‐language articles from the time NIPT entered clinical practice  was conducted. We searched the PubMed electronic database using the following search terms: “cell free fetal DNA,” “NIPT” or “Non‐invasive prenatal test*” or “noninvasive prenatal test*” or “NIPD” or “non‐invasive prenatal diagnosis” or “noninvasive prenatal diagnosis.” A manual search of the reference lists of included studies and relevant original and review articles was also performed. Publications were included if they described data on numbers of women having NIPT for DS and provided information on pregnancy outcomes, such as live births, pregnancy termination, fetal demise, or stillbirths. Studies that described modelled data were excluded. The search identified 1726 articles. Titles and abstracts were examined by 1 reviewer (M.H.), and full‐text articles were obtained for 87 potentially relevant articles. Sixteen articles describing 14 studies met the inclusion criteria.country name” AND “Down* syndrome” AND “termination” or “abortion” or “live‐birth rates.”A separate search was conducted to identify published termination of pregnancy rates prior to introduction of NIPT. Termination rates were sought for each of the countries where the studies included in the review were conducted. The PubMed electronic database was searched using the following terms: “2.2NIPT has been offered at the National University Hospital Singapore since April 2014. NIPT is offered to all patients as an out‐of‐pocket test, with no subsidies. Invasive testing is recommended for confirmation of a high‐risk NIPT result. Other criteria for offering invasive diagnostic testing include a previous affected pregnancy, a high‐risk combined screening test, advanced maternal age, and structural abnormalities. A retrospective audit of pregnancy outcomes for women who chose to have NIPT or went straight to invasive testing without prior NIPT from April 1, 2014, to January 31, 2017, was conducted (DSRB number 2016/00253). Termination rates were calculated as a proportion of all pregnancies that had a high‐risk NIPT result . Termination rates were also calculated for women going directly to invasive testing without NIPT.2.3Following the development and validation of a cfDNA sequencing protocol by our NHS service laboratory , NIPT was initially offered as part of a research trial in 8 UK maternity units, which demonstrated that NIPT could be successfully offered as a contingent test without increasing costs in the NHS.33.1Fourteen studies were included in the review, 8 were prospectivePregnancy outcome data from each of the studies are summarised in Table 3.2Between April 1, 2014, and January 31, 2017, there were 20 701 new bookings at National University Hospital Singapore; 700 women had NIPT (3.4%). For 6 women NIPT indicated that the baby had a high risk of being affected with DS. Five chose to confirm their results by amniocentesis, and the sixth declined further testing. There were no false positives. Of the 5 women with a confirmed pregnancy affected with DS, 4 opted for a termination (80%), and 1 continued the pregnancy. The woman who declined further testing following NIPT also continued the pregnancy. The termination rate for these women with high‐risk NIPT results for DS was 67%. Nine women were lost to follow‐up, and it was not possible to issue a result in 4 cases, because of high variance or low fetal fraction. Over the same period, 706 women (3.4%) opted for an invasive test without prior NIPT, and 39 had a positive result for DS. Twelve cases were lost for follow‐up; of the remaining, 27 women, 25 women chose to terminate their affected pregnancy (92.6%), including 1 woman who had a selective feticide for a single affected twin. There was 1 intrauterine death, and 1 continued pregnancy. Overall, from the 33 cases with confirmed DS following invasive testing or high risk NIPT where outcomes were known, 29 terminated (87.9%) and 4 (12.1%) continued with 1 being stillborn. A summary of the audit findings is presented in Figure 3.3Nine hundred and sixty seven women with a high‐risk DS screening result in the North Thames Region had NIPT and 46 were found to be highly likely to have DS. There were no false positive DS results; however, 3 women in this group were lost to follow‐up. Of the 46 women found to be highly likely to have DS by NIPT, outcomes were available for 43. There were 27 (62.7%) women who chose to terminate the pregnancy, 1 had a still birth (2.3%), and 15 (34.9%) continued the pregnancy. Out of 15 parents who chose to continue the pregnancy, 12 did not have their NIPT result confirmed by invasive testing, 2 had invasive testing, and 1 decision was unknown. Twenty one of the 27 parents who chose to have a termination of pregnancy had invasive testing to confirm the NIPT result, 1 declined and the decision was not reported for 5. A summary of the audit findings is presented in Figure 4Our literature review and audits show that many women opting for NIPT who had a result indicating they were highly likely to have a baby with DS chose to continue their pregnancy. Although numbers are relatively small, when we look at the data as a whole our findings suggest that the high uptake of NIPT worldwide includes many women who would like additional information about their baby that will not necessarily be used for decision making about termination of pregnancy. In addition, several studies in the review reported that some women declined an invasive test to confirm the NIPT result and continued their pregnancy, further emphasising that many women choosing to have NIPT want information about the health of their baby, but would not risk miscarriage with an invasive test. Differences in the number of live births were seen between countries as women chose to continue pregnancies highly likely to be affected with DS in the United States, the United Kingdom, the Netherlands, and Singapore, but there were no confirmed live births reported in the studies from China, Hong Kong, Taiwan, France, and Spain.Termination rates for DS prior to the introduction of NIPT vary quite markedly throughout the world. In the United States, a systematic review of termination rates in studies published between 1995 and 2011 found that 67% of women opted for termination of pregnancy following prenatal diagnosis of DS.It is important to be cautious when interpreting comparisons between the studies discussed here and historical controls, as numbers are small in the included studies and there may be differences between the populations used for determining the historical termination rates and those of the included studies, for example, in the systematic review of termination rates from the United States, Natoli et alAs one of the common reasons women have declined screening in the past is the miscarriage risk associated with invasive testing,We know from the literature that the uptake of NIPT is high,Ultimately, however, the research included here describes relatively small numbers of women and can only give insights into pregnancy outcomes following prenatal testing and we do not know how many children with DS were born to parents who chose not to have prenatal testing. Population‐based studies of live birth rates are therefore essential to allow us to see the overall impact of NIPT. The importance of the population‐based studies is highlighted by reports from countries such as the Netherlands where the termination rate following a prenatal diagnosis of DS is high, but the overall live birth rate has increased over time as many women opt not to have DS screening.Research looking at women's hypothetical choices regarding how they would respond to an NIPT result that suggests DS is highly likely support our findings that many women will choose to continue their pregnancies.Decision making about next steps following a diagnosis of DS is complex. Every woman must have access to the support they need to make informed decisions that take into consideration their own circumstances, experiences, the needs of their family and are in keeping with their personal beliefs and values.5Parents value having the option of NIPT so that they can obtain information about DS early in pregnancy without putting their pregnancy at risk of miscarriage. The data presented here suggest that parents choose NIPT for different reasons, and a significant number of parents will use the results for information so that they can prepare for the birth of a child with DS. Comparison of termination rates reported in the studies reviewed here with termination rates reported prior to the introduction of NIPT suggest that in many settings the implementation of NIPT may not alter the overall numbers of children born with DS. Long‐term population‐based studies are needed to accurately determine the impact of NIPT on the number of children born with DS. Future research should also consider the implications for cost‐effectiveness and service provision of NIPT being used for information and planning as well as to direct decisions about termination of pregnancy.J.F. is used by the charity Antenatal Results and Choices (ARC), which in the past has received small amounts of funding from some commercial companies marketing NIPT. All other authors declare no conflict of interest.


Despite therapeutic innovations, the prognosis for lung cancer patients has not significantly changed in the last years. Therefore, a proper understanding of cell signaling pathways involved in cancer pathogenesis seems to be essential for improvement in cancer therapy field. The knowledge of crosstalk between epidermal growth factor receptor (EGFR) and Notch pathway can lead to enhanced screening for the expression of these genes allowing patients to optimize treatment options and predict potential treatment resistance. This review focuses on recent advances related to the mechanisms of EGFR and Notch signaling in non‐small‐cell lung cancer and the effectiveness of current Notch‐ and EGFR‐targeted therapies.Lung cancer is the most common reason of cancer deaths and about 85% of these are non‐small‐cell lung cancer. Currently, lung cancer therapy is mainly based on the  Epidermal growth factor receptor (EGFR) has tyrosine kinase activity and is a transmembrane glycoprotein. The EGFR and members of its family play a significant role in carcinogenesis through contribution into cell proliferation, apoptosis, cell motility, and angiogenesis. EGFR alterations are involved in the pathogenesis and progression of many malignancies including lung cancer One of the most common alteration in non‐small‐cell lung cancer (NSCLC) patients and cells is overexpression of EGFR, which is demonstrated in more than half cases of NSCLC and is associated with a poor prognosis and chemoresistance Epidermal growth factor receptor mutations are significant predictors of treatment response to tyrosine kinase inhibitors (TKISs) in patients with non‐small‐cell lung cancer. However, according to researchers, diverse response to the treatment is common. Therefore, there are group of patients with mutations who do not show any response and some patients without mutations who can respond to the treatment. Moreover, other investigators γ‐secretase complex, releasing the Notch intracellular domain (NICD). The intracellular domain is later moved into the nucleus where it cooperates with CBF‐1 (transcription factor recombining binding protein suppressor of hairless). The noncanonical way can take place without γ‐secretase cleavage and CBF‐1 α). Therefore, according to some authors, hypoxia stabilizes NICD which can interact with hypoxia‐inducible factor 1 alpha (HIF‐1α)  and five ligands  There are some studies indicating Notch is highly activated in NSCLC On the other hand, altered Notch genes may influence the stabilization of Notch in NSCLC. Hence, two types of alterations were detected in NSCLC: heterozygous mutations of the Notch‐1 locus in 10% of the cases, and loss of Numb expression in 30% of the cases of NSCLC Although, the role of Notch in non‐small‐cell lung cancer remains unclear, the observations reveal that Notch signaling in NSCLC depends on the specific tissue context, microenvironment, and crosstalk with other signaling pathways. Consequently, it might be important in development of tumor or can act as a tumor suppressor Many research groups try to explain crosstalk between Notch and EGFR in order to understand the mechanism of this cooperation and to know how cancer cells use the Notch pathway to compensate for EGFR‐targeted inhibition. Notch and epidermal growth factor receptor (EGFR) signaling are essential in cell proliferation, differentiation, and apoptosis, and thereby may contribute to the development of lung cancer.It has been described that those pathways can cooperate in different mechanisms, either antagonistic or synergistic Fig. , dependiAlthough recent studies have shown that Notch and EGFR signaling are associated with drug resistance, antiangiogenic agent and EGFR tyrosine kinase inhibitors have been accepted for NSCLC treatment Moreover, current clinical trials examine the efficacy and safety of antiangiogenic and anti‐EGFR agents combinations, as well as additional agents such as multitargeted antiangiogenic tyrosine kinase inhibitors The researchers revealed that the expression of Notch‐1 was upregulated in EGFR‐TKISs developed resistant lung cancer cells. Additional, Notch‐1 contributed to the achievement of the epithelial–mesenchymal transition (EMT) phenotype, which was correlated with developed resistance to EGFR‐TKISs γ ‐secretase inhibitors could reverse this phenotype. Furthermore, the scientists noticed that phosphorylation of Notch3 can be linked to EGFR receptor, but no exact mechanism is known yet Another study showed that while inhibition of EGFR leads to reduction in tumor cell number, it also leads to a potent activation of the Notch pathway. Combined inhibition of EGFR and Notch3 receptors significantly reduced the growth of stem‐like cells. Taking together, investigators concluded that treatment of EGFR‐mutated lung cancer cell lines with erlotinib enriched then stem‐like cells with stem‐like cell potential through EGFR‐dependent activation of Notch3. Moreover, γ‐secretase inhibitor DAPT ‐l‐alanyl]‐S‐phenylglycine t‐butyl ester) and related this to EGFR status. DAPT was effective in proliferation of cells expressing wt EGFR (wild type), whereas it did not affect HCC827 cells expressing mutated EGFR. In addition, alterations were observed among the cells with wild‐type EGFR The crosstalk between Notch and EGFR pathway was also conducted by Konishi et al. and Kolev et al. The investigators demonstrated that the interaction between both pathways results in the inhibition of apoptosis As researchers have developed knowledge about the alterations in lung cancer cells that help them grow, they have developed newer drugs that specifically target these changes. Despite of new drugs and therapeutic regiments, the prognosis for lung cancer patients has not significantly transformed in the last years. There is now overwhelming data on the prognostic and predictive value of each EGFR signaling in NSCLC. Although the role of EGFR signaling in the pathogenesis and progression of NSCLC is well recognized, the importance of Notch pathway and its correlation with EGFR in lung cancer is still under investigation. Notch may act as an oncogene or a tumor suppressor gene in lung cancer cells depending on tissue, developmental context, and microenvironment. However, recently agents targeting the fundamental molecular signaling pathways in lung cancer are already under clinical trials with more promising results. Thus, the mechanism(s) of crosstalk between EGFR and Notch in non‐small‐cell lung cancer need to be identified.The author declares that there is no conflict of interests regarding the publication of this study.


NAD(P)H oxidase and could oxidize catecholamines. Administration of renalase lowers blood pressure and heart rate and also protects cells and organs against ischaemic and toxic injury. Although renalase's protective effect was initially ascribed to its oxidase properties, a paradigm shift in our understanding of the cellular actions of renalase is underway. We now understand that, independent of its enzymatic properties, renalase functions as a cytokine that provides protection to cells, tissues and organs by interacting with its receptor to activate protein kinase B, JAK/STAT, and the mitogen‐activated protein kinase pathways. In addition, recent studies suggest that dysregulated renalase signalling may promote survival of several tumour cells due to its capacity to augment expression of growth‐related genes. In this review, we focus on the cytoprotective actions of renalase and its capacity to sustain cancer cell growth and also the translational opportunities these findings represent for the development of novel therapeutic strategies for organ injury and cancer.Renalase was discovered as a protein synthesized by the kidney and secreted in blood where it circulates at a concentration of approximately 3–5 μg/ml. Initial reports suggested that it functioned as an  Renalase, first discovered in 2005, is a flavin/adenine/dinucleotide‐dependent amine oxidase that is secreted into the blood by the kidneys and is suggested to participate in catecholamine metabolism Renalase is secreted in blood, and its levels are regulated by at least three factors: renal function, renal perfusion and catecholamine levels. Plasma renalase levels measured by Western blot suggest a direct relationship with glomerular filtration rate and renal mass, resulting in renalase deficiency as renal function declines Remarkable progress has been achieved over the past 3 years in understanding the cellular actions of renalase, its pathophysiology and potential therapeutic utility. The protein exerts its cytoprotective effects by interacting with a plasma membrane receptor PMCA4b (and possibly another receptor) independent of its catalytic activity in vivo. Its expression and activity were down‐regulated by increased dietary phosphate in vivo administration of recombinant renalase to KO mice led to a significant decrease in plasma levels of EPI, DA and L‐DOPA as well as in urinary excretion of EPI, DA and DA/L‐DOPA ratios Initially, a number of studies showed that renalase expression had a major effect on catecholamine metabolism et al. 2O2 and superoxide anion generated as by‐products of NADH oxidation could oxidize EPI to adrenochrome. Aliverti and Moran et al. Renalase was first shown to metabolize NADH by Farzaneh‐Far et al. Fedchenko via MAPKs and fully mimicked the protective effect of renalase in cells exposed to cisplatin Renalase‐deficient mice subjected to renal ischaemia reperfusion (I/R) developed significantly worse renal tubular necrosis, inflammation and apoptosis, and administration of recombinant renalase ameliorated these changes in ischaemic acute kidney injury (AKI) in vivo by a rat model of renal I/R injury after remote preconditioning (IPC) also highlights renalase role. Remote preconditioning (RPC) refers to the process by which short periods of induced ischaemia of an organ or limb confers protective effects to other tissues 2O2, suggesting that renalase protected CIN in rats through antioxidation, anti‐apoptosis and anti‐inflammation mechanisms via activation of the TNF‐α/NF‐κB pathway An et al. et al. In addition to its effects on kidney injury, renalase protects against acute cardiac ischaemia and prevents the development of cardiac hypertrophy. The degree of myocardial necrosis caused by acute ischaemia was threefold more severe in the global renalase KO, compared to WT, and the phenotype could be rescued by the administration of recombinant renalase et al. et al. Renalase protects against the development of cardiac hypertrophy associated with CKD. Baraka 2+ signalling by binding to and activating PMCA4b, a key mechanism for Ca2+ efflux from the acinar cell Similar to its protective effect in kidney and heart, renalase ameliorates the course of acute pancreatitis. Genetic deletion of renalase is associated with more severe acute pancreatitis, and the administration of exogenous renalase  dramatically reduced the severity of acute pancreatitis There is strong evidence that renalase exerts a powerful cytoprotective function in acute tissue and organ injury states, including AKI, cardiac injury and acute pancreatitis. Whether renalase‐dependent cytoprotection is mediated exclusively by outside‐in signalling driven by extracellular renalase remains to be proven. And additional studies should be carried out to establish the relative contribution of extra‐ and intracellular renalase to organ protection against acute injury. Furthermore, although the mechanism of action of intracellular renalase has been assumed to rely on its putative enzymatic function, preliminary results suggest that intracellular renalase also displays transcription factor‐like properties such as nuclear translocation and a positive feedback loop with STAT3, and further studies on the function of intracellular renalase are warranted.As renalase functions as a survival factor by activating ERK, AKT and signal transducer and activator of transcription (STAT3) and appears to participate in a positive feedback loop with STAT3 In vitro studies indicate that recombinant renalase increased PDAC cells survival rate by twofold to fivefold. Inhibition of renalase signalling using siRNA or inhibitory antirenalase antibodies decreased the viability of cultured PDAC cells. Renalase also improved PDAC survival in an ERK‐ and STAT3‐dependent manner because pre‐treating with U0126, an inhibitor of the MAP kinase MEK1 and AG490, a compound inhibits JAK2, Erk2 and STAT3 activity, abrogated its protective effect. In two xenograft mouse models, either the renalase monoclonal antibody m28‐Renalase or shRNA knockdown of renalase inhibited PDAC growth. Inhibition of renalase caused tumour cell apoptosis and cell cycle arrest We first examined renalase expression in commercially available cDNA arrays at various tumours and found that renalase expression was significantly increased in cancers of the pancreas, bladder and breast and in melanoma. We focused on pancreatic cancer due to its particularly poor survival and limited therapeutic options. In a cohort of patients with pancreatic ductal adenocarcinoma (PDAC), we found that renalase levels significantly increased (>twofold) in PDAC tumours compared to the adjacent non‐tumour pancreatic tissue, and overall survival was inversely correlated with renalase expression in the tumour mass We next examined the role of renalase in promoting the growth of melanoma, a disorder in which the MAPK, PI3K and JAK/STAT pathways are regulated abnormally, and found that renalase expression was increased progressively from normal skin to benign nevi to primary malignant melanoma and finally to metastatic melanoma. Significant renalase expression was detected in CD163+ M2‐like) tumour‐associated macrophages (TAMs). In clinical specimens, renalase expression in the tumour correlated inversely with disease‐specific survival, suggesting a pathogenic role for renalase. Treatment with recombinant renalase in melanoma cells showed increased cell counts and increased percentage of live cells. Attenuation of renalase expression and signalling by RNAi, or the inhibitory renalase monoclonal antibody m28‐RNLS, decreased cell proliferation and increased apoptosis in tumour cells. m28‐RNLS blocked tumour growth in an immune competent murine xenograft model ‐like tumIt will be important to develop standardized validated methods to assess renalase activity and levels in various fluids, including urine, and to resolve the discrepancies in blood levels based on Western blots and ELISA in patients with kidney disease. We have discussed this issue in detail in a prior review article Another key goal will be to define the therapeutic utility of renalase‐based therapy for acute tissue and organ injury. The data in acute kidney and cardiac injury are compelling, as they are for acute pancreatitis. Conversely, the inhibition of renalase signalling may provide new therapeutic opportunities for cancer patients, and the developments of humanized and fully human antirenalase antibodies are currently underway. It will be interesting to test whether inhibition of extracellular renalase signalling by renalase antibodies affects intracellular renalase levels. We will also need to assess the potential side‐effects of antirenalase therapy and develop protocols that provide favourable risk benefit ratios.Our understanding of the physiology and pathophysiology of renalase has expanded dramatically over the past 3 years. The discovery that, independent of its intrinsic enzymatic properties, renalase functions as a cytokine with general cytoprotective actions, by interacting with plasma membrane receptor PMCA4b to activate cell survival pathways, is a major step forward. These findings could serve as the basis for further work aimed at elucidating key molecular mechanisms in injury states such as AKI, myocardial infarction and acute pancreatitis and for exploring the therapeutic utility of acute and short‐term administration of renalase to treat these disorders. Furthermore, dysregulated renalase signalling provides a survival advantage to cancer cells, and inhibition of renalase signalling using inhibitory antibodies not only has direct cytotoxic effect on tumour cells, but also modulates the immune response to tumour by shifting TAMs from a M2‐like tumour promoting phenotype to a M1‐like tumour inhibitory one. These findings suggest that renalase inhibition may provide novel therapeutic options for patients with pancreatic cancer and melanoma and perhaps other tumours.G Desir is a named inventor on several issued patents related to the discovery and therapeutic use of renalase. Renalase is licensed to Bessor Pharma, and G Desir holds an equity position in Bessor and its subsidiary Personal Therapeutics.