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Participation in complex listening situations such as group conversations in noisy environments sets high demands on the auditory system and on cognitive processing. Reports of hearing-impaired people indicate that strenuous listening situations occurring throughout the day lead to feelings of fatigue at the end of the day. The aim of the present study was to develop a suitable test sequence to evoke and measure listening effort (LE) and listening-related fatigue (LRF), and, to evaluate the influence of hearing aid use on both dimensions in mild to moderately hearing-impaired participants. The chosen approach aims to reconstruct a representative acoustic day (Time Compressed Acoustic Day [TCAD]) by means of an eight-part hearing-test sequence with a total duration of approximately 2½ h. For this purpose, the hearing test sequence combined four different listening tasks with five different acoustic scenarios and was presented to the 20 test subjects using virtual acoustics in an open field measurement in aided and unaided conditions. Besides subjective ratings of LE and LRF, behavioral measures (response accuracy, reaction times), and an attention test (d2-R) were performed prior to and after the TCAD. Furthermore, stress hormones were evaluated by taking salivary samples. Subjective ratings of LRF increased throughout the test sequence. This effect was observed to be higher when testing unaided. In three of the eight listening tests, the aided condition led to significantly faster reaction times/response accuracies than in the unaided condition. In the d2-R test, an interaction in processing speed between time (pre- vs. post-TCAD) and provision (unaided vs. aided) was found suggesting an influence of hearing aid provision on LRF. A comparison of the averaged subjective ratings at the beginning and end of the TCAD shows a significant increase in LRF for both conditions. At the end of the TCAD, subjective fatigue was significantly lower when wearing hearing aids. The analysis of stress hormones did not reveal significant effects.
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Estimulação Acústica , Auxiliares de Audição , Ruído , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Ruído/efeitos adversos , Correção de Deficiência Auditiva/instrumentação , Correção de Deficiência Auditiva/métodos , Atenção , Pessoas com Deficiência Auditiva/psicologia , Pessoas com Deficiência Auditiva/reabilitação , Adulto , Fadiga Auditiva , Fatores de Tempo , Tempo de Reação , Realidade Virtual , Percepção Auditiva/fisiologia , Fadiga , Perda Auditiva/psicologia , Perda Auditiva/reabilitação , Perda Auditiva/fisiopatologia , Perda Auditiva/diagnóstico , Percepção da Fala/fisiologia , Saliva/metabolismo , Saliva/química , Audição , Limiar AuditivoRESUMO
PURPOSE: The prevalence of germline pathogenic variants (PVs) in homologous recombination repair (HRR) and Lynch syndrome (LS) genes in ovarian cancer (OC) is uncertain. METHODS: An observational study reporting the detection rate of germline PVs in HRR and LS genes in all OC cases tested in the North West Genomic Laboratory Hub between September 1996 and May 2024. Effect sizes are reported using odds ratios (ORs) and 95% confidence intervals (95% CI) for unselected cases tested between April 2021 and May 2024 versus 50703 controls from the Breast Cancer Risk after Diagnostic Gene Sequencing study. RESULTS: 2934 women were tested for BRCA1/2 and 433 (14.8%) had a PV. In up to 1572 women tested for PVs in non-BRCA1/2 HRR genes, detection rates were PALB2=0.8%, BRIP1=1.1%, RAD51C=0.4% and RAD51D=0.4%. In 940 unselected cases, BRIP1 (OR=8.7, 95% CI 4.6-15.8) was the third commonest OC predisposition gene followed by RAD51C (OR=8.3, 95% CI 3.1-23.1), RAD51D (OR=6.5, 95% CI 2.1-19.7) and PALB2 (OR=3.9, 95% CI 1.5-10.3). No PVs in LS genes were detected in unselected cases. CONCLUSIONS: Panel testing in OC resulted in a detection rate of 2-3% for germline PVs in non-BRCA1/2 HRR genes, with the largest contributor being BRIP1. Screening for LS in unselected cases of OC is unnecessary.
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Peripheral nerve injuries are prevalent and their treatments present significant challenges. Among the various reconstructive options, nerve conduits and wraps are popular choices. Advances in bioengineering and regenerative medicine have led to the development of new biocompatible materials and implant designs that offer the potential for enhanced neural recovery. Cost, nerve injury type, and implant size must be considered when deciding on the ideal reconstructive option.
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Materiais Biocompatíveis , Regeneração Nervosa , Traumatismos dos Nervos Periféricos , Humanos , Traumatismos dos Nervos Periféricos/cirurgia , Alicerces Teciduais , Bioengenharia , Regeneração Tecidual Guiada , Engenharia Tecidual , Próteses e ImplantesRESUMO
SUMMARY: Non-inferiority trials, a distinct category within randomized controlled trials, are garnering increased attention in medical research. Their unique and evolving role comes to the forefront in scenarios where new treatments, despite not surpassing the efficacy of an existing standard, bring additional benefits like reduced side effects, enhanced compliance, or cost savings. As the field of surgery witnesses a growing number of published non-inferiority trials, it becomes imperative for surgeons to grasp the intricacies of this trial type to accurately decipher and interpret their outcomes.
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Heterozygous loss-of-function mutations in the GRN gene are a major cause of hereditary frontotemporal dementia. The mechanisms linking frontotemporal dementia pathogenesis to progranulin deficiency are not well understood, and there is currently no treatment. Our strategy to prevent the onset and progression of frontotemporal dementia in patients with GRN mutations is to utilize small molecule positive regulators of GRN expression to boost progranulin levels from the remaining functional GRN allele, thus restoring progranulin levels back to normal within the brain. This work describes a series of blood-brain-barrier-penetrant small molecules which significantly increase progranulin protein levels in human cellular models, correct progranulin protein deficiency in Grn+/- mouse brains, and reverse lysosomal proteome aberrations, a phenotypic hallmark of frontotemporal dementia, more efficiently than the previously described small molecule suberoylanilide hydroxamic acid. These molecules will allow further elucidation of the cellular functions of progranulin and its role in frontotemporal dementia and will also serve as lead structures for further drug development.
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Demência Frontotemporal , Haploinsuficiência , Lisossomos , Progranulinas , Proteoma , Progranulinas/metabolismo , Progranulinas/genética , Animais , Humanos , Demência Frontotemporal/genética , Demência Frontotemporal/metabolismo , Demência Frontotemporal/tratamento farmacológico , Proteoma/metabolismo , Camundongos , Lisossomos/metabolismo , Lisossomos/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Vorinostat/farmacologiaRESUMO
In 2021, the American Psychological Association (APA) passed a series of resolutions that initiated a process of atonement for its participation in promoting, perpetuating, and failing to challenge racism and discrimination toward communities of color (APA, 2021a, 2021b). The purpose of this special issue was to examine the ways in which the field of psychology has perpetuated racial hierarchy and harm toward communities of color. More importantly, the included articles offer guidance on the mechanisms and strategies that will aid in the dismantling of racism in the field of psychology and support efforts of reconciliation, repair, and healing. In this introduction, we present a brief history of racism in the field of psychology and highlight theories and methods that should be considered as efforts to combat systemic racial inequities. Articles in this special issue fall into four specific themes that include bias and scientific racism in research, intergroup collaboration, organizational and clinical implications, and changing the culture of psychology. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
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Psicologia , Racismo , Humanos , Racismo/psicologia , Psicologia/história , Sociedades CientíficasRESUMO
B355252 is a small molecular compound known for potentiating neural growth factor and protecting against neuronal cell death induced by glutamate in vitro and cerebral ischemia in vivo. However, its other biological functions remain unclear. This study aims to investigate whether B355252 suppresses neuroinflammatory responses and cell death in the brain. C57BL/6j mice were intraperitoneally injected with a single dosage of lipopolysaccharide (LPS, 1 mg/kg) to induce inflammation. B355252 (1 mg/kg) intervention was started two days prior to the LPS injection. The animal behavioral changes were assessed pre- and post-LPS injections. The animal brains were harvested at 4 and 24 h post-LPS injection, and histological, biochemical, and cytokine array outcomes were examined. Results showed that B355252 improved LPS-induced behavioral deterioration, mitigated brain tissue damage, and suppressed the activation of microglial and astrocytes. Furthermore, B355252 reduced the protein levels of key pyroptotic markers TLR4, NLRP3, and caspase-1 and inhibited the LPS-induced increases in IL-1ß, IL-18, and cytokines. In conclusion, B355252 demonstrates a potent anti-neuroinflammatory effect in vivo, suggesting that its potential therapeutic value warrants further investigation.
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OBJECTIVE: Cytotoxic chemotherapy for ovarian cancer can be augmented by co-administration of vascular endothelial growth factor inhibitors but these are contraindicated in patients with bowel obstruction due to the risk of gastrointestinal perforation. We evaluated the safety and feasibility of paclitaxel plus cediranib to treat patients with platinum-resistant ovarian cancer at risk of malignant bowel obstruction. METHODS: A phase II trial included eligible patients between March 2018 and February 2021, identified by clinical symptoms and radiographic risk factors for malignant bowel obstruction. Cediranib (20 mg/day) was added to paclitaxel (70 mg/m2/week) within 9 weeks of starting paclitaxel if pretreatment bowel symptoms had improved. The primary endpoint was the number of patients treated for ≥5 days with cediranib that were free of grade 3-5 gastrointestinal perforation or fistula. Secondary endpoints were hospitalization for bowel obstruction, grade ≥3 adverse events, treatment compliance assessed by relative dose intensity, objective response, progression-free survival, and overall survival. RESULTS: Thirty patients were recruited. Of these, 12 received paclitaxel alone and 17 received paclitaxel and cediranib in combination. One patient died before starting treatment. No patient developed a grade 3-5 gastrointestinal perforation or fistula (one sided 95% confidence interval (CI) upper limit 0.16). One patient required hospitalization for bowel obstruction but recovered with conservative management. The most common cediranib-related grade ≥3 adverse events were fatigue (3/17), diarrhorea (2/17), and hypomagnesemia (2/17). Relative dose intensity for paclitaxel was 90% (interquartile range (IQR) 85-100%; n=29) and for cediranib 88% (IQR 76-93%; n=17). The objective response in patients who received paclitaxel and cediranib was 65.0% (one complete and 10 partial responses). Median progression-free survival was 6.9 months (95% CI 4.4-11.5 months; n=17) and overall survival was 19.4 months (95% CI 10.1-20.4 months; n=17). Median follow-up was 12.4 months (8.9-not reached; n=17). CONCLUSIONS: The unexpectedly high withdrawal rate during paclitaxel alone, before introducing cediranib, meant we were unable to definitely conclude that paclitaxel plus cediranib did not cause gastrointestinal perforation or fistula. The regimen was however tolerated. TRIAL REGISTRATION NUMBER: EudraCT 2016-004618-93.
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Protocolos de Quimioterapia Combinada Antineoplásica , Obstrução Intestinal , Neoplasias Ovarianas , Paclitaxel , Quinazolinas , Humanos , Feminino , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/complicações , Idoso , Obstrução Intestinal/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quinazolinas/administração & dosagem , Quinazolinas/efeitos adversos , Resistencia a Medicamentos Antineoplásicos , Adulto , Esquema de Medicação , Carcinoma Epitelial do Ovário/tratamento farmacológico , IndóisRESUMO
Introduction: Addressing femoral neck fractures resulting from ground-level falls in older adults with Alzheimer's disease (AD) involves a personalized treatment plan. There is considerable ongoing debate concerning the relative advantages and disadvantages of surgical treatment (internal fixation or arthroplasty) vs nonoperative treatment for femoral neck fractures in older persons with AD. Methods: This retrospective cohort study compared the mortality, hazard ratio, and survival rate between operative and nonoperative treatments, controlling for patients' demographic information and baseline health status. The study population consisted of Optum beneficiaries diagnosed with AD who experienced an initial femoral neck fracture claim between January 1, 2012, and December 31, 2017. Kaplan-Meier survival curves were applied to compare the treatment groups' post-fracture survival rates and mortality. Cox regression was used to examine the survival period by controlling the covariates. Results: Out of the 4157 patients with AD with femoral neck fractures, 59.8% were women (n = 2487). The median age was 81 years. The 1-year survival rate for nonoperative treatment (70.19%) was lower than that for internal fixation (75.27%) and arthroplasty treatment (82.32%). Compared with the nonoperative group, arthroplasty surgical treatment had significant lower hazard risk of death (arthroplasty hazard ratio: 0.850, 95% CI: 0.728-0.991, P < 0.05). Discussion: The findings suggest that the operative treatment group experiences higher survival rates and lower mortality rates than the nonoperative group. This paper provides insights into treatment outcomes of older adults with AD receiving medical care for femoral neck fractures.
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Plants commonly produce families of structurally related metabolites with similar defensive functions. This apparent redundancy raises the question of underlying molecular mechanisms and adaptive benefits of such chemical variation. Cardenolides, a class defensive compounds found in the wallflower genus Erysimum (L., Brassicaceae) and scattered across other plant families, show substantial structural variation, with glycosylation and hydroxylation being common modifications of a steroid core, which itself may vary in terms of stereochemistry and saturation. Through a combination of chemical mutagenesis and analysis of gene coexpression networks, we identified four enzymes involved in cardenolide biosynthesis in Erysimum that work together to determine stereochemistry at carbon 5 of the steroid core: Ec3ßHSD, a 3ß-hydroxysteroid dehydrogenase, Ec3KSI, a ketosteroid isomerase, EcP5ßR2, a progesterone 5ß-reductase, and EcDET2, a steroid 5α-reductase. We biochemically characterized the activity of these enzymes in vitro and generated CRISPR/Cas9 knockout lines to confirm activity in vivo. Cardenolide biosynthesis was not eliminated in any of the knockouts. Instead, mutant plants accumulated cardenolides with altered saturation and stereochemistry of the steroid core. Furthermore, we found variation in carbon 5 configuration among the cardenolides of 44 species of Erysimum, where the occurrence of some 5ß-cardenolides is associated with the expression and sequence of P5ßR2. This may have allowed Erysimum species to fine-tune their defensive profiles to target specific herbivore populations over the course of evolution. SIGNIFICANCE STATEMENT: Plants use an array of toxic compounds to defend themselves from attack against insects and other herbivores. One mechanism through which plants may evolve more toxic compounds is through modifications to the structure of compounds they already produce. In this study, we show how plants in the wallflower genus Erysimum use four enzymes to fine-tune the structure of toxic metabolites called cardenolides. Natural variation in the sequence and expression of a single enzyme called progesterone 5ß-reductase 2 partly explains the variation in cardenolides observed across the Erysimum genus. These alterations to cardenolide structure over the course of evolution suggests that there may be context-dependent benefits to Erysimum to invest in one cardenolide variant over another.
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Frontotemporal dementia (FTD) is a debilitating neurodegenerative disorder with currently no disease-modifying treatment options available. Mutations in GRN are one of the most common genetic causes of FTD, near ubiquitously resulting in progranulin (PGRN) haploinsufficiency. Small molecules that can restore PGRN protein to healthy levels in individuals bearing a heterozygous GRN mutation may thus have therapeutic value. Here, we show that epigenetic modulation through bromodomain and extra-terminal domain (BET) inhibitors (BETi) potently enhance PGRN protein levels, both intracellularly and secreted forms, in human central nervous system (CNS)-relevant cell types, including in microglia-like cells. In terms of potential for disease modification, we show BETi treatment effectively restores PGRN levels in neural cells with a GRN mutation known to cause PGRN haploinsufficiency and FTD. We demonstrate that BETi can rapidly and durably enhance PGRN in neural progenitor cells (NPCs) in a manner dependent upon BET protein expression, suggesting a gain-of-function mechanism. We further describe a CNS-optimized BETi chemotype that potently engages endogenous BRD4 and enhances PGRN expression in neuronal cells. Our results reveal a new epigenetic target for treating PGRN-deficient forms of FTD and provide mechanistic insight to aid in translating this discovery into therapeutics.
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Demência Frontotemporal , Humanos , Progranulinas/metabolismo , Demência Frontotemporal/tratamento farmacológico , Demência Frontotemporal/genética , Demência Frontotemporal/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas Nucleares/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Mutação , Epigênese Genética , Proteínas que Contêm Bromodomínio , Proteínas de Ciclo Celular/metabolismoRESUMO
Richard M. Suinn, an eminent psychologist known for his work in cognitive behavioral therapy (CBT), sports psychology, ethnic minority issues, and professional association leadership, passed away on January 5, 2024, in Fort Collins, Colorado, at the age of 90 years. Suinn was born on May 8, 1933, in Hawai'i. Suinn was an expert in anxiety management and developed the widely used Mathematics Anxiety Rating Scale. He was the first psychologist appointed team psychologist to a U.S. Olympic team, applying his CBT expertise to five Olympic teams. Suinn developed the Suinn-Lew Asian Self-Identity Acculturation Scale, the most widely used measure of Asian American acculturation. He served as a president of the American Psychological Association (APA) where he opened the door for APA presidents of color, and the Association of Behavioral and Cognitive Therapies (ABCT) and a member of the Board of Directors of APA, the American Psychological Foundation, American Board of Professional Psychology, Association for the Advancement of Psychology, ABCT, and the Asian American Psychological Association (AAPA). (PsycInfo Database Record (c) 2024 APA, all rights reserved).
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Psicologia , História do Século XX , Humanos , História do Século XXI , Psicologia/história , Estados Unidos , Terapia Cognitivo-Comportamental/história , Sociedades Científicas/históriaRESUMO
Plants in the genus Erysimum produce both glucosinolates and cardenolides as a defense mechanism against herbivory. Two natural isolates of Erysimum cheiranthoides (wormseed wallflower) differed in their glucosinolate content, cardenolide content, and their resistance to Myzus persicae (green peach aphid), a broad generalist herbivore. Both classes of defensive metabolites were produced constitutively and were not further induced by aphid feeding. To investigate the relative importance of glucosinolates and cardenolides in E. cheiranthoides defense, we generated an improved genome assembly, genetic map, and segregating F2 population. The genotypic and phenotypic analysis of the F2 plants identified quantitative trait loci, which affected glucosinolates and cardenolides, but not the aphid resistance. The abundance of most glucosinolates and cardenolides was positively correlated in the F2 population, indicating that similar processes regulate their biosynthesis and accumulation. Aphid reproduction was positively correlated with glucosinolate content. Although the overall cardenolide content had little effect on aphid growth and survival, there was a negative correlation between aphid reproduction and helveticoside abundance. However, this variation in defensive metabolites could not explain the differences in aphid growth on the two parental lines, suggesting that processes other than the abundance of glucosinolates and cardenolides have a predominant effect on aphid resistance in E. cheiranthoides.
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BACKGROUND: Although maternal hemoglobin levels during pregnancy are commonly associated with perinatal outcomes, their link to childhood neurodevelopment remains uncertain. OBJECTIVE: This study aimed to examine the associations between maternal hemoglobin in early and late pregnancy and the educational attainment of offspring mid-childhood in a high-resource obstetric setting. STUDY DESIGN: Pregnancy data from a prospective birth cohort (Pregnancy Outcome Prediction Study, Cambridge, United Kingdom, 2008-2012, N=3285) were linked to mid-childhood educational outcomes (Department for Education, United Kingdom). Regression models adjusted for maternal, child, and socioeconomic factors were used to determine associations between maternal hemoglobin, pregnancy complications, and offspring educational outcomes (aged 5-7 years). RESULTS: No association was observed between maternal hemoglobin at 12 weeks and the likelihood of either adverse pregnancy outcomes or children meeting expected educational standards between ages 5-7 years. Higher maternal hemoglobin at 28 weeks was associated with an increased risk of small-for-gestational-age infants (adjusted odds ratio, 1.26 [95% confidence interval, 1.11-1.59]; P=.002) and preterm birth (adjusted odds ratio, 1.38 [95% confidence interval, 1.11-1.81]; P=.005). There were no adverse birth outcomes associated with anemia. However, children of mothers who were anemic at 28 weeks had â¼40% increased risk of not attaining expected educational standards at age 5 (adjusted odds ratio, 1.42 [95% confidence interval, 1.03-1.95]; P=.03). There was no association between maternal anemia at 28 weeks and educational performance at ages 6-7. No associations were found between high maternal hemoglobin concentrations (top decile) or change in hemoglobin concentrations between 12 and 28 weeks and childhood educational attainment. CONCLUSION: Maternal anemia at 28 weeks of pregnancy is associated with reduced educational attainment at 5 years old but not at older ages (6-7 years old). A proactive approach to increasing maternal hemoglobin in high-resource settings is unlikely to impact long-term childhood educational attainment.
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Escolaridade , Hemoglobinas , Humanos , Feminino , Gravidez , Hemoglobinas/análise , Hemoglobinas/metabolismo , Estudos Prospectivos , Criança , Pré-Escolar , Adulto , Reino Unido/epidemiologia , Masculino , Resultado da Gravidez/epidemiologia , Estudos de Coortes , Complicações na Gravidez/epidemiologia , Complicações na Gravidez/sangue , Complicações na Gravidez/diagnóstico , Anemia/epidemiologia , Anemia/sangue , Anemia/diagnóstico , Nascimento Prematuro/epidemiologiaRESUMO
BACKGROUND: This study examined perceptions of coercion, pressures and procedural injustice and how such perceptions influenced psychological well-being in those who experienced a UK COVID-19 lockdown, with a view to preparing for the possibility of future lockdowns. METHODS: 40 individuals categorised as perceiving the lockdown(s) as either highly or lowly coercive took part in one of six asynchronous virtual focus groups (AVFGs). RESULTS: Using thematic analysis, the following key themes were identified in participants' discussions: (1) Choice, control and freedom; (2) threats; (3) fairness; (4) circumstantial factors; and (5) psychological factors. CONCLUSIONS: As the first qualitative study to investigate the psychological construct of perceived coercion in relation to COVID-19 lockdowns, its findings suggest that the extent to which individuals perceived pandemic-related lockdowns as coercive may have been linked to their acceptance of restrictions. Preparing for future pandemics should include consideration of perceptions of coercion and efforts to combat this, particularly in relation to differences in equity, in addition to clarity of public health messaging and public engagement.
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COVID-19 , Coerção , Humanos , Pandemias/prevenção & controle , COVID-19/prevenção & controle , Controle de Doenças Transmissíveis , Justiça Social , Reino Unido/epidemiologiaRESUMO
Plants in the genus Erysimum produce both glucosinolates and cardiac glycosides as defense against herbivory. Two natural isolates of Erysimum cheiranthoides (wormseed wallflower) differed in their glucosinolate content, cardiac glycoside content, and resistance to Myzus persicae (green peach aphid), a broad generalist herbivore. Both classes of defensive metabolites were produced constitutively and were not induced further by aphid feeding. To investigate the relative importance of glucosinolates and cardiac glycosides in E. cheiranthoides defense, we generated an improved genome assembly, genetic map, and segregating F2 population. Genotypic and phenotypic analysis of the F2 plants identified quantitative trait loci affecting glucosinolates and cardiac glycosides, but not aphid resistance. The abundance of most glucosinolates and cardiac glycosides was positively correlated in the F2 population, indicating that similar processes regulate their biosynthesis and accumulation. Aphid reproduction was positively correlated with glucosinolate content. Although overall cardiac glycoside content had little effect on aphid growth and survival, there was a negative correlation between aphid reproduction and helveticoside abundance. However, this variation in defensive metabolites could not explain the differences in aphid growth on the two parental lines, suggesting that processes other than the abundance of glucosinolates and cardiac glycosides have a predominant effect on aphid resistance in E. cheiranthoides.
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The chemical arms race between plants and insects is foundational to the generation and maintenance of biological diversity. We asked how the evolution of a novel defensive compound in an already well-defended plant lineage impacts interactions with diverse herbivores. Erysimum cheiranthoides (Brassicaceae), which produces both ancestral glucosinolates and novel cardiac glycosides, served as a model. We analyzed gene expression to identify cardiac glycoside biosynthetic enzymes in E. cheiranthoides and characterized these enzymes via heterologous expression and CRISPR/Cas9 knockout. Using E. cheiranthoides cardiac glycoside-deficient lines, we conducted insect experiments in both the laboratory and field. EcCYP87A126 initiates cardiac glycoside biosynthesis via sterol side-chain cleavage, and EcCYP716A418 has a role in cardiac glycoside hydroxylation. In EcCYP87A126 knockout lines, cardiac glycoside production was eliminated. Laboratory experiments with these lines revealed that cardiac glycosides were highly effective defenses against two species of glucosinolate-tolerant specialist herbivores, but did not protect against all crucifer-feeding specialist herbivores in the field. Cardiac glycosides had lesser to no effect on two broad generalist herbivores. These results begin elucidation of the E. cheiranthoides cardiac glycoside biosynthetic pathway and demonstrate in vivo that cardiac glycoside production allows Erysimum to escape from some, but not all, specialist herbivores.
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Glicosídeos Cardíacos , Erysimum , Glucosinolatos , Herbivoria , Glucosinolatos/metabolismo , Animais , Glicosídeos Cardíacos/farmacologia , Erysimum/metabolismo , Regulação da Expressão Gênica de Plantas , Técnicas de Inativação de Genes , Adaptação Fisiológica/genética , Adaptação Fisiológica/efeitos dos fármacosRESUMO
PREDICT Breast ( www.breast .predict.nhs.uk ) is a prognostication tool for early invasive breast cancer. The current version was based on cases diagnosed in 1999-2003 and did not incorporate the benefits of radiotherapy or the harms associated with therapy. Since then, there has been a substantial improvement in the outcomes for breast cancer cases. The aim of this study was to update PREDICT Breast to ensure that the underlying model is appropriate for contemporary patients. Data from the England National Cancer Registration and Advisory Service for invasive breast cancer cases diagnosed 2000-17 were used for model development and validation. Model development was based on 35,474 cases diagnosed and registered by the Eastern Cancer Registry. A Cox model was used to estimate the prognostic effects of the year of diagnosis, age at diagnosis, tumour size, tumour grade and number of positive nodes. Separate models were developed for ER-positive and ER-negative disease. Data on 32,408 cases from the West Midlands Cancer Registry and 100,551 cases from other cancer registries were used for validation. The new model was well-calibrated; predicted breast cancer deaths at 5-, 10- and 15-year were within 10 per cent of the observed validation data. Discrimination was also good: The AUC for 15-year breast cancer survival was 0.809 in the West Midlands data set and 0.846 in the data set for the other registries. The new PREDICT Breast model outperformed the current model and will be implemented in the online tool which should lead to more accurate absolute treatment benefit predictions for individual patients.
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Minority populations will continue to grow in the United States. Such pluralism necessitates iterative, geospatial measurements of cultural contexts. Our objective in this study was to create a measure of social determinants of health in geographic areas with varying ethnic, linguistic, and religious diversity in the United States. We extracted geographic information systems data based on community characteristics that have known associations with population health disparities from 2015 to 2019. We used principal component analysis to construct a Cultural Context Index (CCI). We created the CCI for 73,682 census tracts across 50 states and five inhabited territories. We identified hot and cold spots that are the highest and lowest CCI quintile, respectively. Hot spots census tracts were mostly located in metropolitan areas (84.8%), in the Southern census region (41.5%), and also had larger Black and Hispanic populations. The census tracts with the greatest need for culturally competent health care also had the sickest populations. Census tracts with a CCI rank of 5 ('greatest need') had higher prevalences of self-reported poor physical health (17.2%) and poor mental health (17.4%), compared to either the general population (13.9% and 14.5%) or to CCI rank of 1 ('lowest need') (11.9% and 10.8%). The CCI can pinpoint census tracts with a need for culturally competent health care and inform supply-side policy planning as healthcare and social service providers will inevitably come in contact with consumers from different backgrounds.