When Is Higher Neuroticism Protective Against Death? Findings From UK Biobank

We examined the association between neuroticism and mortality in a sample of 321,456 people from UK Biobank and explored the influence of self-rated health on this relationship. After adjustment for age and sex, a 1- SD increment in neuroticism was associated with a 6% increase in all-cause mortality (hazard ratio = 1.06, 95% confidence interval = [1.03, 1.09]). After adjustment for other covariates, and, in particular, self-rated health, higher neuroticism was associated with an 8% reduction in all-cause mortality (hazard ratio = 0.92, 95% confidence interval = [0.89, 0.95]), as well as with reductions in mortality from cancer, cardiovascular disease, and respiratory disease, but not external causes. Further analyses revealed that higher neuroticism was associated with lower mortality only in those people with fair or poor self-rated health, and that higher scores on a facet of neuroticism related to worry and vulnerability were associated with lower mortality. Research into associations between personality facets and mortality may elucidate mechanisms underlying neuroticism's covert protection against death

Durable rust resistance in wheat is effective against multiple pathogens

Tese de doutoramento em Ciências da Saúde, no ramo de Medicina Dentária, apresentada à Faculdade de Medicina da Universidade de CoimbraA osteonecrose maxilar associada aos bifosfonatos, que se apresenta como uma lesão pós-cirúrgica associada a incapacidade de cicatrização, é um dos efeitos secundários mais frequentemente observados nos doentes submetidos a terapêutica com bifosfonatos nitrogenados. Assim, esta patologia é diagnosticada maioritariamente em doentes com metastização óssea, sob terapêutica com bifosfonatos nitrogenados intra-venosos. A fisiopatologia da osteonecrose maxilar associada aos bifosfonatos tem sido relacionada com a supressão da remodelação óssea, com a infeção local e com a toxicidade dos bifosfonatos nos tecidos envolventes, que mantém e perpetua a exposição óssea. Os fatores de risco da osteonecrose maxilar associada aos bifosfonatos foram categorizados em fatores relacionados com a terapêutica, que incluem a administração intravenosa em doenças oncológicas e a utilização do bifosfonato mais potente, o zoledronato; e factores locais, que incluem as exodontias, a colocação de implantes, a cirurgia periapical e a cirurgia periodontal que envolva os tecidos ósseos. No entanto, no caso da cirurgia periapical, não foram encontrados estudos que relacionem este procedimento com a osteonecrose maxilar. No contexto da toxicidade do zoledronato, uma vez que os compostos de fosfato de cálcio têm a capacidade de o adsorver, nomeadamente quando utilizados como sistemas transportadores de bifosfonatos, e são passíveis de aplicação nas locas cirúrgicas, constituindo substitutos ósseos adequados, colocou-se a hipótese de estes compostos poderem, potencialmente, ter um efeito protetor nos tecidos que envolvem as locas cirúrgicas. Assim, constituíram objetivos deste trabalho a avaliação da cirurgia periapical como desencadeadora de osteonecrose maxilar na presença de zoledronato e, paralelamente, a avaliação do potencial protetor da aplicação de compostos de fosfato de cálcio na loca cirúrgica. Para cumprir os objetivos propostos neste trabalho, realizaram-se estudos de química, estudos in vitro e estudos in vivo. No que respeita aos estudos de química, avaliou-se a reação entre o zoledronato e os compostos de fosfato de cálcio. Através de espetroscopia do visível e de análise elementar, verificou-se que o zoledronato é adsorvido, em solução aquosa, pelos compostos bifásicos de fosfato de cálcio. A etiologia da osteonecrose maxilar descreve um efeito deletério dos bifosfonatos nos tecidos moles, especialmente nos fibroblastos, que apresentam uma função insubstituível na cicatrização das lesões cirúrgicas orais. No contexto dos estudos in vitro, estabeleceram-se culturas primárias de fibroblastos gengivais humanos, que constituíram um modelo para avaliar a citotoxicidade na presença de zoledronato e na presença da associação zoledronato/compostos bifásicos de fosfato de cálcio. Avaliou-se a atividade metabólica dos fibroblastos gengivais humanos através do ensaio de MTT (brometo de 3-(4,5-dimetiltiazol-2-il)-2,5-difeniltetrazol), a sua viabilidade através do ensaio de SRB (ensaio da sulforrodamina B), os tipos de morte e o ciclo celular dos fibroblastos gengivais humanos através de citometria de fluxo e a capacidade de migração através do scratch assay. Verificou-se que o zoledronato apresentou um efeito citotóxico significativo nos fibroblastos gengivais humanos, com diminuição da atividade metabólica e da viabilidade, com aumento das populações celulares em morte por apoptose e por necrose e pela diminuição da capacidade de migração. Com a associação zoledronato/compostos bifásicos de fosfato de cálcio, foi possível diminuir, ou mesmo anular, a toxicidade do zoledronato, que se manifestou pela ausência de diferenças em relação aos grupos controlo. Nos estudos in vivo, foi utilizado um modelo experimental reprodutível já estudado, que relaciona diretamente a administração crónica de bifosfonatos com o desenvolvimento de osteonecrose maxilar após exodontia. Este modelo animal serviu como base ao desenvolvimento de um modelo de cirurgia apical com administração crónica de bifosfonatos. Os grupos de animais tratados foram submetidos a administração intra-peritoneal de zoledronato nas quatro semanas antecedentes à intervenção cirúrgica e nas duas ou três semanas seguintes. As mandíbulas foram avaliadas macroscopicamente, através da medicina nuclear, radiologia e histologia. No contexto da medicina nuclear, foi utilizado o radiofármaco 99mTc-zoledronato, que foi obtido após o desenvolvimento e a optimização de um procedimento de marcação radioquímica do zoledronato, e respetivo controlo de qualidade. Verificou-se que, nos animais submetidos à terapêutica com zoledronato, em que se desenvolveu a exodontia, existiu maior captação de 99mTc-zoledronato, menor densidade radiográfica e alterações histológicas compatíveis com cicatrização diminuída. Com a aplicação dos compostos bifásicos de fosfato de cálcio, não se observaram diferenças em relação aos animais controlo. No caso dos animais submetidos à cirurgia apical, não se verificaram alterações significativas em relação aos animais controlo, nos animais submetidos à terapêutica com zoledronato, tanto na presença como na ausência da aplicação de compostos bifásicos de fosfato de cálcio. Este trabalho de investigação permitiu elucidar acerca dos desígnios que deram origem a esta tese. No modelo animal de cirurgia periapical desenvolvido, não foi observado um atraso significativo da cicatrização nem sinais da osteonecrose maxilar, nos tempos avaliados, concluindo-se que a terapêutica com zoledronato poderá não constituir um fator de risco nesta intervenção cirúrgica. Pelo contrário, no modelo animal de exodontia confirmou-se que, efetivamente, o zoledronato constitui um fator de risco, e que os compostos bifásicos de fosfato de cálcio, apresentam potencial efeito protetor da toxicidade inerente aos bifosfonatos. Esta conclusão foi sustentada pelos estudos de química, em que se verificou a adsorção do zoledronato, corroborada por supressão da toxicidade nos estudos in vitro e cicatrização favorecida no modelo animal de exodontia com administração crónica de zoledronato.Bisphosphonate-associated osteonecrosis of the jaw, a post-surgical non-healing wound condition, is one of the most often seen side effects in patients treated with nitrogencontaining bisphosphonates. Therefore, this pathology is primarily diagnosed in patients with metastatic bone disease, receiving intravenous administration of nitrogen-containing bisphosphonates. Bisphosphonate-associated osteonecrosis of the jaw physiopathology has been related with suppression of bone turnover, local infections or soft tissue toxicity. Recent studies associate the physiopathological mechanisms of the osteonecrosis of the jaw with toxic effects of bisphosphonates on different cell types, besides osteoclast, being the most important cause of soft tissues toxicity that contributes for the maintenance of bone exposure. Bisphosphonate-associated osteonecrosis of the jaw risk factors were categorized as drug-related factors, including intravenous administration in oncological diseases and the use of the most potent bisphosphonate, zoledronate; and local factors including, dental extractions, dental implant placement, periapical surgery and periodontal surgery involving osseous injury. However, there are no studies that relate periapical surgery with osteonecrosis of the jaw. Considering zoledronate toxicity, since calcium phosphate compounds are able to adsorb it, namely when used as drug delivery vehicle, and are also used in surgical wounds, as a bone substitute, it was hypothesised this compounds had a potential protective effect to the soft tissues surrounding surgical osseous wounds. Thus, the aim of this study was to assess periapical surgery as a trigger of osteonecrosis of the jaw in the presence of zoledronate and also the potential protective effect of calcium phosphate compounds when applied in the surgical wound. To fulfil the proposed objectives of this work were carried out studies of chemistry, in vitro and in vivo studies. Regarding chemical studies, it was evaluated the chemical reaction between zoledronate and calcium phosphate compounds. Through ultraviolet-visible spectroscopy and elemental analysis it has been found that zoledronate, in aqueous solution, was adsorbed by biphasic calcium phosphate compounds. Bisphosphonate-associated osteonecrosis of the jaw aetiology describes a deleterious effect of bisphosphonates on soft tissues, especially on fibroblasts, which play an important role in oral wound healing. Considering in vitro studies it was established a primary culture of human gingival fibroblasts that constituted a model to evaluate the cytotoxicity in the presence of zoledronate and of zoledronate/biphasic calcium phosphate compounds association. It was investigated the metabolic activity of human gingival fibroblasts through MTT (3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, cell viability through SRB (sulforhodamine B) assay, types of cell death and cell cycle through flow cytometry and migration ability of human gingival fibroblasts through scratch assay. It was verified that zoledronate had a strong cytotoxic effect in the human gingival fibroblasts, by the reduction of metabolic activity, cell viability, increase of cells in apoptosis and reduction of migration. With the association zoledronate/biphasic calcium phosphate compounds it was possible to reduce or abolish zoledronate toxicity, as it was demonstrated by the absence of differences related to control. In the in vivo study it was used a reproducible experimental model that directly relates chronic bisphosphonate administration with the development of osteonecrosis of the jaw with tooth extraction. This animal model also served as basis to the development of a osteotomy in periapical surgery model with chronic bisphosphonate administration. The animals were treated with zoledronate intraperitoneally, during the four weeks that preceded the surgeries and in the following two and three weeks. The mandibles were macroscopic evaluated, examined by nuclear medicine, radiology and histologically analysed. Concerning nuclear medicine it was used the radiopharmaceutical 99mTc-zoledronate, which was obtained after the development and optimization of a procedure for zoledronate radiochemical labelling, and respective quality control. It has been found that the animals with zoledronate, submitted to tooth extraction, had a higher 99mTc-zoledronate uptake, lower radiological density and histologic images compatible with a decreased healing. With biphasic calcium phosphate compounds application, there were no differences related to controls. In the animals submitted to osteotomy in periapical surgery there were no significant differences related to the controls, in both animals with zoledronate, with and without biphasic calcium phosphate compounds application. This research work allowed the clarification of the goals that led to this thesis. In the created animal model of osteotomy in periapical surgery, it was not observed a significant delay in the wound healing, neither osteonecrosis of the jaw, in the evaluated periods, therefore it was conclude that zoledronate therapeutic may not constitute a risk factor in this surgical approach. Contrarily, in the tooth extraction animal model, it was confirmed that zoledronate therapeutic constitute a risk factor, and it was found that biphasic calcium phosphate compounds presents a potential protector effect from bisphosphonates toxicity. This conclusion was supported by the chemical studies, in which it was observed adsorption of zoledronate, corroborated by the lower toxicity in the in vitro studies and by the improved cicatrisation in the tooth extraction animal model with chronic bisphosphonates administration

Conditioning on a Collider May or May Not Explain the Relationship Between Lower Neuroticism and Premature Mortality in the Study by Gale et al. (2017): A Reply to Richardson, Davey Smith, and Munafò (2019)

We (Gale et al., 2017) analyzed data on 321,456 UK Biobank participants to address why higher neuroticism is sometimes related to lower mortality (e.g., Korten et al., 1999). We noted that the studies that revealed an inverse relationship between neuroticism and mortality included self-rated health as a predictor, perhaps because it is associated with mortality, even when multiple objective measures of health status are included in models (for reviews, see Benyamini & Idler, 1999; Idler & Benyamini, 1997). We therefore tested whether including self-rated health, which was modestly related to neuroticism, rS = .23 (Gale et al., p. 1348), in a model changed the sign of the neuroticism–mortality relationship. We found that it did so and then set out to test two possible explanations for this phenomenon

Conditioning on a Collider May or May Not Explain the Relationship Between Lower Neuroticism and Premature Mortality in the Study by Gale et al. (2017): A Reply to Richardson, Davey Smith, and Munafò (2019)

We (Gale et al., 2017) analyzed data on 321,456 UK Biobank participants to address why higher neuroticism is sometimes related to lower mortality (e.g., Korten et al., 1999). We noted that the studies that revealed an inverse relationship between neuroticism and mortality included self-rated health as a predictor, perhaps because it is associated with mortality, even when multiple objective measures of health status are included in models (for reviews, see Benyamini & Idler, 1999; Idler & Benyamini, 1997). We therefore tested whether including self-rated health, which was modestly related to neuroticism, rS = .23 (Gale et al., p. 1348), in a model changed the sign of the neuroticism–mortality relationship. We found that it did so and then set out to test two possible explanations for this phenomenon

Wheat rusts never sleep but neither do sequencers: will pathogenomics transform the way plant diseases are managed?

Field pathogenomics adds highly informative data to surveillance surveys by enabling rapid evaluation of pathogen variability, population structure and host genotype

Large-scale associations between the leukocyte transcriptome and BOLD responses to speech differ in autism early language outcome subtypes.

Heterogeneity in early language development in autism spectrum disorder (ASD) is clinically important and may reflect neurobiologically distinct subtypes. Here, we identified a large-scale association between multiple coordinated blood leukocyte gene coexpression modules and the multivariate functional neuroimaging (fMRI) response to speech. Gene coexpression modules associated with the multivariate fMRI response to speech were different for all pairwise comparisons between typically developing toddlers and toddlers with ASD and poor versus good early language outcome. Associated coexpression modules were enriched in genes that are broadly expressed in the brain and many other tissues. These coexpression modules were also enriched in ASD-associated, prenatal, human-specific, and language-relevant genes. This work highlights distinctive neurobiology in ASD subtypes with different early language outcomes that is present well before such outcomes are known. Associations between neuroimaging measures and gene expression levels in blood leukocytes may offer a unique in vivo window into identifying brain-relevant molecular mechanisms in ASD

Age-related changes in global motion coherence: conflicting haemodynamic and perceptual responses

Our aim was to use both behavioural and neuroimaging data to identify indicators of perceptual decline in motion processing. We employed a global motion coherence task and functional Near Infrared Spectroscopy (fNIRS). Healthy adults (n = 72, 18-85) were recruited into the following groups: young (n = 28, mean age = 28), middle-aged (n = 22, mean age = 50), and older adults (n = 23, mean age = 70). Participants were assessed on their motion coherence thresholds at 3 different speeds using a psychophysical design. As expected, we report age group differences in motion processing as demonstrated by higher motion coherence thresholds in older adults. Crucially, we add correlational data showing that global motion perception declines linearly as a function of age. The associated fNIRS recordings provide a clear physiological correlate of global motion perception. The crux of this study lies in the robust linear correlation between age and haemodynamic response for both measures of oxygenation. We hypothesise that there is an increase in neural recruitment, necessitating an increase in metabolic need and blood flow, which presents as a higher oxygenated haemoglobin response. We report age-related changes in motion perception with poorer behavioural performance (high motion coherence thresholds) associated with an increased haemodynamic response

Comparison of symptom-based versus self-reported diagnostic measures of anxiety and depression disorders in the GLAD and COPING cohorts

Background: Understanding and improving outcomes for people with anxiety or depression often requires large sample sizes. To increase participation and reduce costs, such research is typically unable to utilise “gold-standard” methods to ascertain diagnoses, instead relying on remote, self-report measures. Aims: Assess the comparability of remote diagnostic methods for anxiety and depression disorders commonly used in research. Method: Participants from the UK-based GLAD and COPING NBR cohorts (N = 58,400) completed an online questionnaire between 2018 and 2020. Responses to detailed symptom reports were compared to DSM-5 criteria to generate symptom-based diagnoses of major depressive disorder (MDD), generalised anxiety disorder (GAD), specific phobia, social anxiety disorder, panic disorder, and agoraphobia. Participants also self-reported any prior diagnoses from health professionals, termed self-reported diagnoses. “Any anxiety” included participants with at least one anxiety disorder. Agreement was assessed by calculating accuracy, Cohen’s kappa, McNemar’s chi-squared, sensitivity, and specificity. Results: Agreement between diagnoses was moderate for MDD, any anxiety, and GAD, but varied by cohort. Agreement was slight to fair for the phobic disorders. Many participants with self-reported GAD did not receive a symptom-based diagnosis. In contrast, symptom-based diagnoses of the phobic disorders were more common than self-reported diagnoses. Conclusions: Agreement for MDD, any anxiety, and GAD was higher for cases in the case-enriched GLAD cohort and for controls in the general population COPING NBR cohort. For anxiety disorders, self-reported diagnoses classified most participants as having GAD, whereas symptom-based diagnoses distributed participants more evenly across the anxiety disorders. Further validation against gold standard measures is required

cDNA Immunization of Mice with Human Thyroglobulin Generates Both Humoral and T Cell Responses: A Novel Model of Thyroid Autoimmunity

Thyroglobulin (Tg) represents one of the largest known self-antigens involved in autoimmunity. Numerous studies have implicated it in triggering and perpetuating the autoimmune response in autoimmune thyroid diseases (AITD). Indeed, traditional models of autoimmune thyroid disease, experimental autoimmune thyroiditis (EAT), are generated by immunizing mice with thyroglobulin protein in conjunction with an adjuvant, or by high repeated doses of Tg alone, without adjuvant. These extant models are limited in their experimental flexibility, i.e. the ability to make modifications to the Tg used in immunizations. In this study, we have immunized mice with a plasmid cDNA encoding the full-length human Tg (hTG) protein, in order to generate a model of Hashimoto's thyroiditis which is closer to the human disease and does not require adjuvants to breakdown tolerance. Human thyroglobulin cDNA was injected and subsequently electroporated into skeletal muscle using a square wave generator. Following hTg cDNA immunizations, the mice developed both B and T cell responses to Tg, albeit with no evidence of lymphocytic infiltration of the thyroid. This novel model will afford investigators the means to test various hypotheses which were unavailable with the previous EAT models, specifically the effects of hTg sequence variations on the induction of thyroiditis