Multicenter, Prospective, Randomized Controlled Trial of High-Sensitivity Cardiac Troponin I-Guided Combination Angiotensin Receptor Blockade and Beta-Blocker Therapy to Prevent Anthracycline Cardiotoxicity: The Cardiac CARE Trial.

BACKGROUND: Anthracycline-induced cardiotoxicity has a variable incidence, and the development of left ventricular dysfunction is preceded by elevations in cardiac troponin concentrations. Beta-adrenergic receptor blocker and renin-angiotensin system inhibitor therapies have been associated with modest cardioprotective effects in unselected patients receiving anthracycline chemotherapy. METHODS: In a multicenter, prospective, randomized, open-label, blinded end-point trial, patients with breast cancer and non-Hodgkin lymphoma receiving anthracycline chemotherapy underwent serial high-sensitivity cardiac troponin testing and cardiac magnetic resonance imaging before and 6 months after anthracycline treatment. Patients at high risk of cardiotoxicity (cardiac troponin I concentrations in the upper tertile during chemotherapy) were randomized to standard care plus cardioprotection (combination carvedilol and candesartan therapy) or standard care alone. The primary outcome was adjusted change in left ventricular ejection fraction at 6 months. In low-risk nonrandomized patients with cardiac troponin I concentrations in the lower 2 tertiles, we hypothesized the absence of a 6-month change in left ventricular ejection fraction and tested for equivalence of ±2%. RESULTS: Between October 2017 and June 2021, 175 patients (mean age, 53 years; 87% female; 71% with breast cancer) were recruited. Patients randomized to cardioprotection (n=29) or standard care (n=28) had left ventricular ejection fractions of 69.4±7.4% and 69.1±6.1% at baseline and 65.7±6.6% and 64.9±5.9% 6 months after completion of chemotherapy, respectively. After adjustment for age, pretreatment left ventricular ejection fraction, and planned anthracycline dose, the estimated mean difference in 6-month left ventricular ejection fraction between the cardioprotection and standard care groups was -0.37% (95% CI, -3.59% to 2.85%; P=0.82). In low-risk nonrandomized patients, baseline and 6-month left ventricular ejection fractions were 69.3±5.7% and 66.4±6.3%, respectively: estimated mean difference, 2.87% (95% CI, 1.63%-4.10%; P=0.92, not equivalent). CONCLUSIONS: Combination candesartan and carvedilol therapy had no demonstrable cardioprotective effect in patients receiving anthracycline-based chemotherapy with high-risk on-treatment cardiac troponin I concentrations. Low-risk nonrandomized patients had similar declines in left ventricular ejection fraction, bringing into question the utility of routine cardiac troponin monitoring. Furthermore, the modest declines in left ventricular ejection fraction suggest that the value and clinical impact of early cardioprotection therapy need to be better defined in patients receiving high-dose anthracycline. REGISTRATION: URL: https://doi.org; Unique identifier: 10.1186/ISRCTN24439460. URL: https://www.clinicaltrialsregister.eu/ctr-search/search; Unique identifier: 2017-000896-99.

One-year outcomes in a multicentre cohort study of incident rare diffuse parenchymal lung disease in children (ChILD).

We performed a prospective, observational, cohort study of children newly diagnosed with children's interstitial lung disease (ChILD), with structured follow-up at 4, 8, 12 weeks and 6 and 12 months. 127 children, median age 0.9 (IQR 0.3-7.9) years had dyspnoea (68%, 69/102), tachypnoea (75%, 77/103) and low oxygen saturation (SpO2) median 92% (IQR 88-96). Death (n=20, 16%) was the most common in those <6 months of age with SpO2<94% and developmental/surfactant disorders. We report for the first time that ChILD survivors improved multiple clinical parameters within 8-12 weeks of diagnosis. These data can inform family discussions and support clinical trial measurements.

International management platform for children's interstitial lung disease (chILD-EU).

BACKGROUND: Children's interstitial lung diseases (chILD) cover many rare entities, frequently not diagnosed or studied in detail. There is a great need for specialised advice and for internationally agreed subclassification of entities collected in a register.Our objective was to implement an international management platform with independent multidisciplinary review of cases at presentation for long-term follow-up and to test if this would allow for more accurate diagnosis. Also, quality and reproducibility of a diagnostic subclassification system were assessed using a collection of 25 complex chILD cases. METHODS: A web-based chILD management platform with a registry and biobank was successfully designed and implemented. RESULTS: Over a 3-year period, 575 patients were included for observation spanning a wide spectrum of chILD. In 346 patients, multidisciplinary reviews were completed by teams at five international sites (Munich 51%, London 12%, Hannover 31%, Ankara 1% and Paris 5%). In 13%, the diagnosis reached by the referring team was not confirmed by peer review. Among these, the diagnosis initially given was wrong (27%), imprecise (50%) or significant information was added (23%).The ability of nine expert clinicians to subcategorise the final diagnosis into the chILD-EU register classification had an overall exact inter-rater agreement of 59% on first assessment and after training, 64%. Only 10% of the 'wrong' answers resulted in allocation to an incorrect category. Subcategorisation proved useful but training is needed for optimal implementation. CONCLUSIONS: We have shown that chILD-EU has generated a platform to help the clinical assessment of chILD. TRIAL REGISTRATION NUMBER: Results, NCT02852928.

Oxygen saturation targets in infants with bronchiolitis (BIDS): a double-blind, randomised, equivalence trial.

BACKGROUND: The American Academy of Pediatrics recommends a permissive hypoxaemic target for an oxygen saturation of 90% for children with bronchiolitis, which is consistent with the WHO recommendations for targets in children with lower respiratory tract infections. No evidence exists to support this threshold. We aimed to assess whether the 90% or higher target for management of oxygen supplementation was equivalent to a normoxic 94% or higher target for infants admitted to hospital with viral bronchiolitis. METHODS: We did a parallel-group, randomised, controlled, equivalence trial of infants aged 6 weeks to 12 months of age with physician-diagnosed bronchiolitis newly admitted into eight paediatric hospital units in the UK (the Bronchiolitis of Infancy Discharge Study [BIDS]). A central computer randomly allocated (1:1) infants, in varying length blocks of four and six and without stratification, to be clipped to standard oximeters (patients treated with oxygen if pulse oxygen saturation [SpO2] <94%) or modified oximeters (displayed a measured value of 90% as 94%, therefore oxygen not given until SpO2 <90%). All parents, clinical staff, and outcome assessors were masked to allocation. The primary outcome was time to resolution of cough (prespecified equivalence limits of plus or minus 2 days) in the intention-to-treat population. This trial is registered with ISRCTN, number ISRCTN28405428. FINDINGS: Between Oct 3, and March 30, 2012, and Oct 1, and March 29, 2013, we randomly assigned 308 infants to standard oximeters and 307 infants to modified oximeters. Cough resolved by 15·0 days (median) in both groups (95% CI for difference -1 to 2) and so oxygen thresholds were equivalent. We recorded 35 serious adverse events in 32 infants in the standard care group and 25 serious adverse events in 24 infants in the modified care group. In the standard care group, eight infants transferred to a high-dependency unit, 23 were readmitted, and one had a prolonged hospital stay. In the modified care group, 12 infants were transferred to a high-dependency unit and 12 were readmitted to hospital. Recorded adverse events did not differ significantly. INTERPRETATION: Management of infants with bronchiolitis to an oxygen saturation target of 90% or higher is as safe and clinically effective as one of 94% or higher. Future research should assess the benefits and risks of different oxygen saturation targets in acute respiratory infection in older children, particularly in developing nations where resources are scarce. FUNDING: National Institute for Health Research, Health Technology Assessment programme.

Rationale and Design of the Cardiac CARE Trial: A Randomized Trial of Troponin-Guided Neurohormonal Blockade for the Prevention of Anthracycline Cardiotoxicity.

BACKGROUND: Anthracyclines are effective cytotoxic drugs used in the treatment of breast cancer and lymphoma but are associated with myocardial injury, left ventricular dysfunction, and heart failure. Anthracycline-induced cardiotoxicity is highly variable in severity and without a proven therapeutic intervention. ß-Adrenergic receptor blockers and renin-angiotensin-system inhibitor therapies have been associated with modest cardioprotective effects in unselected patients. METHODS: The Cardiac CARE trial is a multicentre prospective randomized open-label blinded end point trial of combination ß-adrenergic receptor blocker and renin-angiotensin-system inhibitor therapy in patients with breast cancer and non-Hodgkin lymphoma receiving anthracycline chemotherapy that is associated with myocardial injury. Patients at higher risk of cardiotoxicity with plasma high-sensitivity cTnI (cardiac troponin I) concentrations in the upper tertile at the end of chemotherapy are randomized to standard of care plus combination candesartan and carvedilol therapy or standard of care alone. All patients undergo cardiac magnetic resonance imaging before and 6 months after anthracycline treatment. The primary end point is the change in left ventricular ejection fraction at 6 months after chemotherapy. In low-risk nonrandomized patients, left ventricular ejection fraction before and 6 months after anthracycline will be compared with define the specificity of the high-sensitivity cTnI assay for identifying low-risk participants who do not develop left ventricular systolic dysfunction. DISCUSSION: Cardiac CARE will examine whether cardiac biomarker monitoring identifies patients at risk of left ventricular dysfunction following anthracycline chemotherapy and whether troponin-guided treatment with combination candesartan and carvedilol therapy prevents the development of left ventricular dysfunction in these high-risk patients.

The critical role of S-lactoylglutathione formation during methylglyoxal detoxification in Escherichia coli.

Survival of exposure to methylglyoxal (MG) in Gram-negative pathogens is largely dependent upon the operation of the glutathione-dependent glyoxalase system, consisting of two enzymes, GlxI (gloA) and GlxII (gloB). In addition, the activation of the KefGB potassium efflux system is maintained closed by glutathione (GSH) and is activated by S-lactoylGSH (SLG), the intermediate formed by GlxI and destroyed by GlxII. Escherichia coli mutants lacking GlxI are known to be extremely sensitive to MG. In this study we demonstrate that a ΔgloB mutant is as tolerant of MG as the parent, despite having the same degree of inhibition of MG detoxification as a ΔgloA strain. Increased expression of GlxII from a multicopy plasmid sensitizes E. coli to MG. Measurement of SLG pools, KefGB activity and cytoplasmic pH shows these parameters to be linked and to be very sensitive to changes in the activity of GlxI and GlxII. The SLG pool determines the activity of KefGB and the degree of acidification of the cytoplasm, which is a major determinant of the sensitivity to electrophiles. The data are discussed in terms of how cell fate is determined by the relative abundance of the enzymes and KefGB.

Accident frequency and unrealistic optimism: Children's assessment of risk.

Accidental injury is a major cause of mortality and morbidity among children, warranting research on their risk perceptions. Three hundred and seven children aged 10-11 years assessed the frequency, danger and personal risk likelihood of 8 accidents. Two social-cognitive biases were manifested. The frequency of rare accidents (e.g. drowning) was overestimated, and the frequency of common accidents (e.g. bike accidents) underestimated; and the majority of children showed unrealistic optimism tending to see themselves as less likely to suffer these accidents in comparison to their peers, offering superior skills or parental control of the environment as an explanation. In the case of pedestrian accidents, children recognised their seriousness, underestimated the frequency of this risk and regarded their own road crossing skill as protection. These findings highlight the challenging task facing safety educators who, when teaching conventional safety knowledge and routines, also need to alert children to the danger of over-confidence without disabling them though fear.

Preadaptation to efficient respiratory maintenance is essential both for maximal longevity and the retention of replicative potential in chronologically ageing yeast.

Only recently have the studies of yeast ageing started to focus on the S288c-derived strains used extensively in genomics and on the longest lifespans. Chronological longevity (stationary (G(0)) survival) of such strains is greater when cells are pre-grown on a respiratory carbon source, as compared to when they are pre-grown on glucose (the latter a respiration-repressing sugar). Prior adaptation to efficient respiratory maintenance also ensures that such chronologically aged yeast cells still display a full replicative lifespan should they reenter the cell cycle. In contrast, cells that are pre-grown on glucose exhibit marked and progressive losses of replicative potential as they age chronologically in stationary phase. Increasing the respiratory activity in glucose-grown cultures by HAP4 gene overexpression increased survival and reversed the loss of replicative potential during a subsequent stationary phase. Adaptation to efficient respiratory maintenance is therefore important, not just for maximal longevity, but also for the maintenance of a full replicative lifespan by chronologically ageing cultures of yeast. In such respiration-adapted cultures, losses of the Sch9 protein kinase or Yca1 caspase both shortened lifespan. In contrast loss of Yap1, the major transcriptional regulator of the oxidative stress response, generated a small increase in chronological lifespan in certain strain backgrounds. It would appear, therefore, that any induction of oxidative stress response genes in chronologically ageing yeast is not operating to generate an increase in longevity, even though such protective effects might be expected from the increased proxidant status of these cells over time.

Contribution of lower order skills to the written composition of college students with and without dyslexia.

There has been a growth in students with dyslexia attending university. These students commonly rate writing as one of their greatest problem areas. Our research set out to describe the effects of dyslexia on the writing skills of students compared to age-matched peers and a spelling-skill-matched group. Generally, the texts of the students with dyslexia were poorer than age controls but not poorer than the spelling-skill controls. However, there were no major differences in "higher order" skills such as ideas and organization with the chronological age controls, only in "lower order" transcription skills such as spelling and handwriting fluency. The students with dyslexia made more spelling errors in their essays than one would predict given their dictated spelling skills.

The shortened replicative life span of prohibitin mutants of yeast appears to be due to defective mitochondrial segregation in old mother cells.

Prohibitin proteins have been implicated in cell proliferation, aging, respiratory chain assembly and the maintenance of mitochondrial integrity. The prohibitins of Saccharomyces cerevisiae, Phb1 and Phb2, have strong sequence similarity with their human counterparts prohibitin and BAP37, making yeast a good model organism in which to study prohibitin function. Both yeast and mammalian prohibitins form high-molecular-weight complexes (Phb1/2 or prohibitin/BAP37, respectively) in the inner mitochondrial membrane. Expression of prohibitins declines with senescence, both in mammalian fibroblasts and in yeast. With a total loss of prohibitins, the replicative (budding) life span of yeast is reduced, whilst the chronological life span (the survival of stationary cells over time) is relatively unaffected. This effect of prohibitin loss on the replicative life span is still apparent in the absence of an assembled respiratory chain. It also does not reflect the production of extrachromosomal ribosomal DNA circles (ERCs), a genetic instability thought to be a major cause of replicative senescence in yeast. Examination of cells containing a mitochondrially targeted green fluorescent protein indicates this shortened life span is a reflection of defective mitochondrial segregation from the mother to the daughter in the old mother cells of phb mutant strains. Old mother phb mutant cells display highly aberrant mitochondrial morphology and, frequently, a delayed segregation of mitochondria to the daughter. They often arrest growth with their last bud strongly attached and with the mitochondria adjacent to the septum between the mother and the daughter cell.

Base excision repair activities required for yeast to attain a full chronological life span.

The chronological life span of yeast, the survival of stationary (G0) cells over time, provides a model for investigating certain of the factors that may influence the aging of non-dividing cells and tissues in higher organisms. This study measured the effects of defined defects in the base excision repair (BER) system for DNA repair on this life span. Stationary yeast survives longer when it is pre-grown on respiratory, as compared to fermentative (glucose), media. It is also less susceptible to viability loss as the result of defects in DNA glycosylase/AP lyases (Ogg1p, Ntg1p, Ntg2p), apurinic/apyrimidinic (AP) endonucleases (Apn1p, Apn2p) and monofunctional DNA glycosylase (Mag1p). Whereas single BER glycosylase/AP lyase defects exerted little influence over such optimized G0 survival, this survival was severely shortened with the loss of two or more such enzymes. Equally, the apn1delta and apn2delta single gene deletes survived as well as the wild type, whereas a apn1delta apn2delta double mutant totally lacking in any AP endonuclease activity survived poorly. Both this shortened G0 survival and the enhanced mutagenicity of apn1delta apn2delta cells were however rescued by the over-expression of either Apn1p or Apn2p. The results highlight the vital importance of BER in the prevention of mutation accumulation and the attainment of the full yeast chronological life span. They also reveal an appreciable overlap in the G0 maintenance functions of the different BER DNA glycosylases and AP endonucleases.

Mnsod overexpression extends the yeast chronological (G(0)) life span but acts independently of Sir2p histone deacetylase to shorten the replicative life span of dividing cells.

Studies in Drosophila and Caenorhabditis elegans have shown increased longevity with the increased free radical scavenging that accompanies overexpression of oxidant-scavenging enzymes. This study used yeast, another model for aging research, to probe the effects of overexpressing the major activity protecting against superoxide generated by the mitochondrial respiratory chain. Manganese superoxide dismutase (MnSOD) overexpression increased chronological life span (optimized survival of stationary (G(0)) yeast over time), showing this is a survival ultimately limited by oxidative stress. In contrast, the same overexpression dramatically reduced the replicative life span of dividing cells (the number of daughter buds produced by each newly born mother cell). This reduction in the generational life span by MnSOD overexpression was greater than that generated by loss of the major redox-responsive regulator of the yeast replicative life span, NAD+-dependent Sir2p histone deacetylase. It was also independent of the latter activity. Expression of a mitochondrially targeted green fluorescent protein in the MnSOD overexpressor revealed that the old mother cells of this overexpressor, which had divided for a few generations, were defective in segregation of the mitochondrion from the mother to daughter. Mitochondrial defects are, therefore, the probable reason that MnSOD overexpression shortens replicative life span.

Cdc37 goes beyond Hsp90 and kinases.

Cdc37 is a relatively poorly conserved and yet essential molecular chaperone. It has long been thought to function primarily as an accessory factor for Hsp90, notably directing Hsp90 to kinases as substrates. More recent discoveries challenge this simplistic view. Cdc37 client proteins other than kinases have now been found, and Cdc37 displays a variety of Hsp90-independent activities both in vitro and in vivo. It can function as a molecular chaperone by itself, interact with other Hsp90 cochaperones in the absence of Hsp90, and even support yeast growth and protein folding without its Hsp90-binding domain. Thus, for many substrates, there may be many alternative chaperone pathways involving Cdc37, Hsp90, or both.

Working memory performance in children with and without intellectual disabilities.

Performance on working memory span tasks by children with intellectual disabilities ages 11 to 12 was compared to that of CA- and MA-matched controls. Limited evidence was available to support a "difference" position, whereby the intellectual disabilities group obtained lower scores than both the CA and MA groups. Some evidence was found for the "developmental" position, whereby the intellectual disabilities group performed at the same level as the MA group but more poorly than the CA-matched group. Finally, some evidence supported an unconventional "difference" account; children in the intellectual disabilities group performed better than the MA group, although still not as well as the CA-matched group. Results were interpreted with reference to the role of strategies in working memory performance.

Fungi and animals may share a common ancestor to nuclear receptors.

Nuclear receptors (NRs) are a large family of transcription factors. One hallmark of this family is the ligand-binding domain (LBD), for its primary sequence, structure, and regulatory function. To date, NRs have been found exclusively in animals and sponges, which has led to the generally accepted notion that they arose with them. We have overcome the limitations of primary sequence searches by combining sequence profile searches with structural predictions at a genomic scale, and have discovered that the heterodimeric transcription factors Oaf1/Pip2 of the budding yeast Saccharomyces cerevisiae contain putative LBDs resembling those of animal NRs. Although the Oaf1/Pip2 LBDs are embedded in an entirely different architecture, the regulation and function of these transcription factors are strikingly similar to those of the mammalian NR heterodimer peroxisome proliferator-activated receptor alpha/retinoid X receptor (PPAR alpha/RXR). We demonstrate that the induction of Oaf1/Pip2 activity by the fatty acid oleate depends on oleate's direct binding to the Oaf1 LBD. The alteration of two amino acids in the predicted ligand-binding pocket of Oaf1 abolishes both ligand binding and the transcriptional response. Hence, LBDs may have arisen as allosteric switches, for example, to respond to nutritional and metabolic ligands, before the animal and fungal lineages diverged.

A yeast-based assay reveals a functional defect of the Q488H polymorphism in human Hsp90alpha.

It has been argued that the molecular chaperone Hsp90 guards the organism against genetic variations by stabilizing variant Hsp90 substrate proteins. However, little is known about polymorphisms affecting its own functions. We have followed up on a recent study describing two polymorphisms that alter the amino acid sequences of the two Hsp90 isoforms Hsp90alpha and Hsp90beta. Hsp90 is essential for cell proliferation in the budding yeast Saccharomyces cerevisiae, but the human proteins can replace the endogenous ones. In this growth assay, the variant V656M of Hsp90beta was indistinguishable from wild-type. In contrast, the Hsp90alpha variant Q488H, which carries an alteration of a very highly conserved residue, was severely defective for growth compared to wild-type Hsp90alpha. Hence, the characteristics of this yeast-based system-simplicity, rapidity, low cost-make it ideal for phenotype screening of polymorphisms in HSP90 and possibly many other human genes.

Aprendendo a ler e a escrever: a narrativa das crianças sobre a alfabetizaçäo / Learning to read and write: children's oral stories about literacy

Esse estudo examina as narrativas orais feitas por crianças da primeira série escolar acerca da alfabetizaçäo. Foram entrevistadas 38 crianças vindas de famílias de baixa renda e que freqüentavam uma escola pública da cidade do Rio de Janeiro. A maioria das crianças que encontraram dificuldade durante o processo de alfabetizaçäo produziu narrativas que se referiam à descriçäo da rotina escolar ou de atividade relacionada à leitura e à escrita sem mençäo ao desempenho do protagonista da história. Por outro lado, as crianças que foram bem-sucedidas produziram um número significativo de histórias relatando o sucesso do protagonista durante o aprendizado inicial da leitura e da escrita. Poucas histórias foram produzidas, por ambos os grupos, narrando o insucesso do protagonista. Os resultados foram discutidos com relaçäo às representaçöes acerca da experiência de sucesso ou fracasso experimentado pela criança em seu aprendizado

Era uma vez...um viläo chamado matemática: um estudo intercultural da dificuldade atribuída à matemática / Once upon a time... a villain called mathematics: an intercultural study of the relative difficulty attributed to mathematics

Procurando investigar o grau de dificuldade atribuídoà Matemática em relaçäo a outras disciplinas que compöem o currículo escolar, foi pedido a estudantes de 5ª a 8ª séries residentes no Rio de Janeiro e a estudantes ingleses (de séries correlatas) da cidade de Oxford que assinalassem o grau de dificuldade que atribuíam a cinco disciplinas de seu currículo (Matemática, Ciências, Português/Inglês, Geografia e História), escolhendo uma dentre cinco posiçöes numa escala cujo intervalo variava entre muito fácil e muito difícil. A avaliaçäo dos alunos, tanto no que se refere à Matemática como a outras disciplinas de seu currículo, mostra-se influenciada pelas especificidades de cada área de conhecimento de acordo com a maneira pela qual as situaçöes didáticas säo organizadas ao longo de sua escolaridade e em cada cultura