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1.
J Biomech Eng ; 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32006012

RESUMO

Magnetic resonance elastography (MRE) has emerged as a sensitive imaging technique capable of providing a quantitative understanding of neural microstructural integrity. However, a reliable method for the quantification of the anisotropic mechanical properties of human white matter is currently lacking, despite the potential to illuminate the pathophysiology behind neurological disorders and traumatic brain injury. In this study, we examine the use of multiple excitations in MRE to generate wave displacement data sufficient for anisotropic inversion in white matter. We show the presence of multiple unique waves from each excitation which we combine to solve for parameters of an incompressible, transversely isotropic material: shear modulus, µ, shear anisotropy, φ, and tensile anisotropy, ζ. We calculate these anisotropic parameters in the corpus callosum body and find the mean values as µ = 3.78 kPa, φ = 0.151, and ζ = 0.099 (at 50 Hz vibration frequency). This study demonstrates that multi-excitation MRE provides displacement data sufficient for the evaluation of the anisotropic properties of white matter.

2.
Mol Psychiatry ; 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31969693

RESUMO

Depression is more frequent among individuals exposed to traumatic events. Both trauma exposure and depression are heritable. However, the relationship between these traits, including the role of genetic risk factors, is complex and poorly understood. When modelling trauma exposure as an environmental influence on depression, both gene-environment correlations and gene-environment interactions have been observed. The UK Biobank concurrently assessed Major Depressive Disorder (MDD) and self-reported lifetime exposure to traumatic events in 126,522 genotyped individuals of European ancestry. We contrasted genetic influences on MDD stratified by reported trauma exposure (final sample size range: 24,094-92,957). The SNP-based heritability of MDD with reported trauma exposure (24%) was greater than MDD without reported trauma exposure (12%). Simulations showed that this is not confounded by the strong, positive genetic correlation observed between MDD and reported trauma exposure. We also observed that the genetic correlation between MDD and waist circumference was only significant in individuals reporting trauma exposure (rg = 0.24, p = 1.8 × 10-7 versus rg = -0.05, p = 0.39 in individuals not reporting trauma exposure, difference p = 2.3 × 10-4). Our results suggest that the genetic contribution to MDD is greater when reported trauma is present, and that a complex relationship exists between reported trauma exposure, body composition, and MDD.

3.
AAPS PharmSciTech ; 21(3): 86, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31997096

RESUMO

The main goal of the presented work was to understand changes in the microstructure of tablets, as well as the properties of its main component viz. polyethylene oxide (PEO) as a function of sintering. Key polymer variables and sintering conditions were investigated, and sintering-induced increase in tablet tensile strength was evaluated. For the current study, binary-component placebo tablets comprised of varying ratios of PEO and anhydrous dibasic calcium phosphate (DCP) were prepared at two levels of tablet solid fraction. The prepared tablets were sintered in an oven at 80°C at different time points ranging from 10 to 900 min and were evaluated for pore size, tablet expansion (%), and PEO crystallinity. The results showed that for efficient sintering and a significant increase in the tablet tensile strength, a minimum of 50% w/w PEO was required. Moreover, all microstructural changes in tablets were found to occur within 60 min of sintering, with no significant changes occurring thereafter. Sintering also resulted in a decrease in PEO crystallinity, causing changes in polymer ductility. These changes in PEO ductility resulted in tablets with higher tensile strength. Formulation variables such as PEO level and PEO particle size distribution were found to be important influencers of the sintering process. Additionally, tablets with high initial solid fraction and sintering duration of 60 min were found to be optimal conditions for efficient sintering of PEO-based compacts. Finally, prolonged sintering times were not found to provide any additional benefits in terms of abuse-deterrent properties.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31942703

RESUMO

It has been proposed that covert visual search can be fast, efficient, and stimulus driven, particularly when the target is defined by a salient single feature, or slow, inefficient, and effortful when the target is defined by a nonsalient conjunction of features. This distinction between fast, stimulus-driven orienting and slow, effortful orienting can be related to the distinction between exogenous spatial attention and endogenous spatial attention. Several studies have shown that exogenous, covert orienting is limited to the range of saccadic eye movements, whereas covert endogenous orienting is independent of the range of saccadic eye movements. The current study examined whether covert visual search is affected in a similar way. Experiment 1 showed that covert visual search for feature singletons was impaired when stimuli were presented beyond the range of saccadic eye movements, whereas conjunction search was unaffected by array position. Experiment 2 replicated and extended this effect by measuring search times at 6 eccentricities. The impairment in covert feature search emerged only when stimuli crossed the effective oculomotor range and remained stable for locations further into the periphery, ruling out the possibility that the results of Experiment 1 were due to a failure to fully compensate for the effects of cortical magnification. The findings are interpreted in terms of biased competition and oculomotor theories of spatial attention. It is concluded that, as with covert exogenous orienting, biological constraints on overt orienting in the oculomotor system constrain covert, preattentive search.

5.
BMC Med Educ ; 20(1): 4, 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31900151

RESUMO

BACKGROUND: Gateway courses are increasingly popular widening participation routes into medicine. These six year courses provide a more accessible entry route into medical school and aim to support under-represented students' progress and graduation as doctors. There is little evidence on the performance of gateway students and this study compares attainment and aptitude on entry, and outcomes at graduation of students on the UK's three longest running gateway courses with students studying on a standard entry medical degree (SEMED) course at the same institutions. METHODS: Data were obtained from the UK Medical Education Database for students starting between 2007 and 2012 at three UK institutions. These data included A-levels and Universities Clinical Aptitude Test scores on entry to medical school and the Educational Performance Measure (EPM) decile, Situational Judgement Test (SJT) and Prescribing Safety Assessment (PSA) scores as outcomes measures. Multiple regression models were used to test for difference in outcomes between the two types of course, controlling for attainment and aptitude on entry. RESULTS: Four thounsand three hundred forty students were included in the analysis, 560 on gateway courses and 3785 on SEMED courses. Students on SEMED courses had higher attainment (Cohen's d = 1.338) and aptitude (Cohen's d = 1.078) on entry. On exit SEMED students had higher EPM scores (Cohen's d = 0.616) and PSA scores (Cohen's d = 0.653). When accounting for attainment and aptitude on entry course type is still a significant predictor of EPM and PSA, but the proportion of the variation in outcome explained by course type drops from 6.4 to 1.6% for EPM Decile and from 5.3% to less than 1% for the PSA score. There is a smaller significant difference in SJT scores, with SEMED having higher scores (Cohen's d = 0.114). However, when measures of performance on entry are accounted for, course type is no longer a significant predictor of SJT scores. CONCLUSIONS: This study shows the differences of the available measures between gateway students and SEMED students on entry to their medical degrees are greater than the differences on exit. This provides modest evidence that gateway courses allow students from under-represented groups to achieve greater academic potential.

6.
Psychol Med ; : 1-9, 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31973782

RESUMO

BACKGROUND: Recent work suggests that antihypertensive medications may be useful as repurposed treatments for mood disorders. Using large-scale linked healthcare data we investigated whether certain classes of antihypertensive, such as angiotensin antagonists (AAs) and calcium channel blockers, were associated with reduced risk of new-onset major depressive disorder (MDD) or bipolar disorder (BD). METHOD: Two cohorts of patients treated with antihypertensives were identified from Scottish prescribing (2009-2016) and hospital admission (1981-2016) records. Eligibility for cohort membership was determined by a receipt of a minimum of four prescriptions for antihypertensives within a 12-month window. One treatment cohort (n = 538 730) included patients with no previous history of mood disorder, whereas the other (n = 262 278) included those who did. Both cohorts were matched by age, sex and area deprivation to untreated comparators. Associations between antihypertensive treatment and new-onset MDD or bipolar episodes were investigated using Cox regression. RESULTS: For patients without a history of mood disorder, antihypertensives were associated with increased risk of new-onset MDD. For AA monotherapy, the hazard ratio (HR) for new-onset MDD was 1.17 (95% CI 1.04-1.31). Beta blockers' association was stronger (HR 2.68; 95% CI 2.45-2.92), possibly indicating pre-existing anxiety. Some classes of antihypertensive were associated with protection against BD, particularly AAs (HR 0.46; 95% CI 0.30-0.70). For patients with a past history of mood disorders, all classes of antihypertensives were associated with increased risk of future episodes of MDD. CONCLUSIONS: There was no evidence that antihypertensive medications prevented new episodes of MDD but AAs may represent a novel treatment avenue for BD.

7.
Cortex ; 122: 115-122, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30103907

RESUMO

The neural and cognitive mechanisms of spatial working memory are tightly coupled with the systems that control eye-movements but the precise nature of this coupling is not well understood. In particular, there are very few neuropsychological studies that explicitly examine how deficits of oculomotor control affect visuospatial working memory. Here, we examined the link between spatial working memory and the oculomotor system in a sample of patients with Progressive Supranuclear Palsy, a degenerative neurological disease characterised by defective vertical eye-movements but relatively preserved horizontal eye-movements. Consistent with the idea that the oculomotor system plays a critical role in spatial working memory performance, people with PSP had significantly shorter spatial spans when stimuli were presented along the vertical axis compared to the horizontal axis. This effect was not observed in age matched controls. We hypothesise that PSP disrupts a colliculo-parietal feedback loop that contributes to the maintenance of activation in a parietal priority map during the delay period. This result is the first direct neuropsychological evidence for an association between oculomotor function and spatial working memory and is broadly consistent with idea that rehearsal in visuospatial working memory is mediated by an 'oculomotor loop', as proposed by Baddeley (1986). We conclude that optimal spatial working memory performance depends on an intact oculomotor system.

8.
Arterioscler Thromb Vasc Biol ; 40(2): 446-461, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31801372

RESUMO

OBJECTIVE: Atherosclerosis is the underlying cause of most cardiovascular disease, but mechanisms underlying atherosclerosis are incompletely understood. Ultrasound measurement of the carotid intima-media thickness (cIMT) can be used to measure vascular remodeling, which is indicative of atherosclerosis. Genome-wide association studies have identified many genetic loci associated with cIMT, but heterogeneity of measurements collected by many small cohorts have been a major limitation in these efforts. Here, we conducted genome-wide association analyses in UKB (UK Biobank; N=22 179), the largest single study with consistent cIMT measurements. Approach and Results: We used BOLT-LMM software to run linear regression of cIMT in UKB, adjusted for age, sex, and genotyping chip. In white British participants, we identified 5 novel loci associated with cIMT and replicated most previously reported loci. In the first sex-specific analyses of cIMT, we identified a locus on chromosome 5, associated with cIMT in women only and highlight VCAN as a good candidate gene at this locus. Genetic correlations with body mass index and glucometabolic traits were also observed. Two loci influenced risk of ischemic heart disease. CONCLUSIONS: These findings replicate previously reported associations, highlight novel biology, and provide new directions for investigating the sex differences observed in cardiovascular disease presentation and progression.

9.
Water Environ Res ; 92(2): 236-244, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31386767

RESUMO

A year-long bioretention container study in Maryland, USA, measured the relationship between three plant species (Eutrochium dubium, Iris versicolor, and Juncus effusus) and N ( NO 3 - , NO 2 - , NH 4 + , total nitrogen [TN], total dissolved nitrogen [TDN], dissolved organic nitrogen, particulate organic nitrogen [PON]) and total phosphorus (TP) removal from synthetic stormwater. Statistically significant removal was only found for NO 3 - and TP. Plant-independent NO 3 - removal occurred 9 months after planting, and then changed to removal only by the least-densely planted Juncus treatment. Removal in higher-density Juncus plantings was suspected to be limited by preferential pathways created by high root density. Juncus' low-density NO 3 - removal success correlates with its high growth rate, root mass and length, and large biomass, matching previous literature. TP removal was plant-independent. Shoot harvesting of one plant of each species after 1 year would remove 0.61 g N. Of the plant species in this study, Juncus effusus is most highly recommended for bioretention for its nutrient removal dynamics and year-round green aesthetics. PRACTITIONER POINTS: Only the one-Juncus density treatment had significant NO 3 - removal. All Juncus treatments as well as non-Juncus treatments prevented the PON, TN, or TDN export seen in the No-plants control. TP removal was plant-independent. Juncus had the greatest biomass increase and biomass N. Shoots contain the majority of biomass N for each plant species. Juncus and Iris had high survivorship. Joe Pye had low survivorship. These, and all other study results, need field-scale verification.


Assuntos
Fósforo , Poluentes Químicos da Água , Biomassa , Maryland , Nitrogênio
10.
AJR Am J Roentgenol ; 214(1): W11-W19, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31532253

RESUMO

OBJECTIVE. The purpose of this article is to provide for radiologists an overview of the radiologic, clinical, and pathologic features of hemophagocytic lymphohistiocytosis. CONCLUSION. Hemophagocytic lymphohistiocytosis is a rare, life-threatening syndrome characterized by abnormal, excessive activation of the immune system. Imaging plays an important role in determining the extent of involvement of hemophagocytic lymphohistiocytosis. Knowledge of this entity, including its imaging, clinical, and pathologic findings, is critical to facilitate timely diagnosis.

11.
Cortex ; 122: 170-186, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30528427

RESUMO

The relationship between covert shift of attention and the oculomotor system has been the subject of numerous studies. A widely held view, known as Premotor Theory, is that covert attention depends upon activation of the oculomotor system. However, recent work has argued that Premotor Theory is only true for covert, exogenous orienting of attention and that covert endogenous orienting is largely independent of the oculomotor system. To address this issue we examined how endogenous and exogenous covert orienting of attention was affected when stimuli were presented at a location outside the range of saccadic eye movements. Results from Experiment 1 showed that exogenous covert orienting was abolished when stimuli were presented beyond the range of saccadic eye movements, but preserved when stimuli were presented within this range. In contrast, in Experiment 2 endogenous covert orienting was preserved when stimuli appeared beyond the saccadic range. Finally, Experiment 3 confirmed the observations of Exp.1 and 2. Our results demonstrate that exogenous, covert orienting is limited to the range of overt saccadic eye movements, whereas covert endogenous orienting is not. These results are consistent with a weak, exogenous-only version of Premotor Theory.

12.
BMJ Open ; 9(11): e027389, 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31784428

RESUMO

OBJECTIVE: Smoking in people with serious mental illness is a major public health problem and contributes to significant levels of morbidity and mortality. The aim of the review was to systematically examine the efficacy of methods used to aid smoking cessation in people with serious mental illness. METHOD: A systematic review and meta-analysis of randomised controlled trials to compare the effectiveness and safety of pharmacological and behavioural programmes for smoking cessation in people with serious mental illness. Electronic databases were searched for trials to July 2018. We used the Cochrane Collaboration's tool for assessing the risk of bias. RESULTS: Twenty-eight randomised controlled trials were identified. Varenicline increased the likelihood of smoking cessation at both 3 months (risk ratio (RR) 3.56, 95% CI 1.82 to 6.96, p=0.0002) and at 6 months (RR 3.69, 95% CI 1.08 to 12.60, p=0.04). Bupropion was effective at 3 months (RR 3.96, 95% CI 1.86 to 8.40, p=0.0003), especially at a dose of 300 mg/day, but there was no evidence of effect at 6 months (RR 2.22, 95% CI 0.52 to 9.47, p=0.28). In one small study, nicotine therapy proved effective at increasing smoking cessation up to a period of 3 months. Bupropion used in conjunction with nicotine replacement therapy showed more effect than single use. Behavioural and bespoke interventions showed little overall benefit. Side effects were found to be low. CONCLUSION: The new information of this review was the effectiveness of varenicline for smoking cessation at both 3 and 6 months and the lack of evidence to support the use of both bupropion and nicotine products for sustained abstinence longer than 3 months. Overall, the review found relatively few studies in this population.

13.
Adv Skin Wound Care ; 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31789623

RESUMO

OBJECTIVE: The purpose of this research was to build on previous work regarding predictive factors of acute skin failure (ASF) in the critically ill population. METHODS: Researchers conducted a retrospective case-control study with a main and validation analysis. Data were extracted from the New York Statewide Planning and Research Cooperative System. For the main analysis, there were 415 cases with a hospital-acquired pressure injury (HAPI) and 194,872 controls without. Researchers then randomly selected 100 cases with a HAPIs and 300 controls without for the validation analysis. A step-up logistic regression model was used. Researchers generated receiver operating characteristic curves for both the main and validation analyses, assessing the overall utility of the regression model. RESULTS: Eleven variables were significantly and independently related to ASF: renal failure (odds ratio [OR], 1.4, P = .003), respiratory failure (OR, 2.2; P = < .001), arterial disease (OR, 2.4; P = .001), impaired nutrition (OR, 2.3; P = < .001), sepsis (OR, 2.2; P = < .001), septic shock (OR, 2.3; P = < .001), mechanical ventilation (OR, 2.5; P = < .001), vascular surgery (OR, 2.2; P = .02), orthopedic surgery (OR, 3.4; P = < .001), peripheral necrosis (OR, 2.5; P = .003), and general surgery (OR, 3.8; P = < .001). The areas under the curve for the main and validation analyses were 0.864 and 0.861, respectively. CONCLUSIONS: The final model supports previous work and is consistent with the current definition of ASF in the setting of critical illness.

14.
Transl Psychiatry ; 9(1): 327, 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31797917

RESUMO

Anhedonia is a core symptom of several psychiatric disorders but its biological underpinnings are poorly understood. We performed a genome-wide association study of state anhedonia in 375,275 UK Biobank participants and assessed for genetic correlation between anhedonia and neuropsychiatric conditions (major depressive disorder, schizophrenia, bipolar disorder, obsessive compulsive disorder and Parkinson's Disease). We then used a polygenic risk score approach to test for association between genetic loading for anhedonia and both brain structure and brain function. This included: magnetic resonance imaging (MRI) assessments of total grey matter volume, white matter volume, cerebrospinal fluid volume, and 15 cortical/subcortical regions of interest; diffusion tensor imaging (DTI) measures of white matter tract integrity; and functional MRI activity during an emotion processing task. We identified 11 novel loci associated at genome-wide significance with anhedonia, with a SNP heritability estimate (h2SNP) of 5.6%. Strong positive genetic correlations were found between anhedonia and major depressive disorder, schizophrenia and bipolar disorder; but not with obsessive compulsive disorder or Parkinson's Disease. Polygenic risk for anhedonia was associated with poorer brain white matter integrity, smaller total grey matter volume, and smaller volumes of brain regions linked to reward and pleasure processing, including orbito-frontal cortex. In summary, the identification of novel anhedonia-associated loci substantially expands our current understanding of the biological basis of state anhedonia and genetic correlations with several psychiatric disorders confirm the utility of this phenotype as a transdiagnostic marker of vulnerability to mental illness. We also provide the first evidence that genetic risk for state anhedonia influences brain structure, including in regions associated with reward and pleasure processing.

15.
Front Microbiol ; 10: 2567, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31798545

RESUMO

S. mitis is an abundant member of the commensal microbiota of the oral cavity and pharynx, which has the potential to promote systemic infections. By analyzing a collection of S. mitis strains isolated from the oral cavity at commensal states or from systemic infections (blood strains), we established that S. mitis ubiquitously express the surface immunodominant protein, PcsB (also called GbpB), required for binding to sucrose-derived exopolysaccharides (EPS). Immuno dot blot assays with anti-PcsB antibodies and RT-qPCR transcription analyses revealed strain-specific profiles of PcsB production associated with diversity in pcsB transcriptional activities. Additionally, blood strains showed significantly higher levels of PcsB expression compared to commensal isolates. Because Streptococcus mutans co-colonizes S. mitis dental biofilms, and secretes glucosyltransferases (GtfB/C/D) for the synthesis of highly insoluble EPS from sucrose, profiles of S. mitis binding to EPS, biofilm formation and evasion of the complement system were assessed in sucrose-containing BHI medium supplemented or not with filter-sterilized S. mutans culture supernatants. These analyses showed significant S. mitis binding to EPS and biofilm formation in the presence of S. mutans supernatants supplemented with sucrose, compared to BHI or BHI-sucrose medium. In addition, these phenotypes were abolished if strains were grown in culture supernatants of a gtfBCD-defective S. mutans mutant. Importantly, GtfB/C/D-associated phenotypes were enhanced in high PcsB-expressing strains, compared to low PcsB producers. Increased PcsB expression was further correlated with increased resistance to deposition of C3b/iC3b of the complement system after exposure to human serum, when strains were previously grown in the presence of S. mutans supernatants. Finally, analyses of PcsB polymorphisms and bioinformatic prediction of epitopes with significant binding to MHC class II alleles revealed that blood isolates harbor PcsB polymorphisms in its functionally conserved CHAP-domain, suggesting antigenic variation. These findings reveal important roles of PcsB in S. mitis-host interactions under commensal and pathogenic states, highlighting the need for studies to elucidate mechanisms regulating PcsB expression in this species.

16.
Artigo em Inglês | MEDLINE | ID: mdl-31802253

RESUMO

Recent genome-wide association studies have demonstrated that the genetic burden associated with depression correlates with depression severity. Therefore, conducting genetic studies of patients at the most severe end of the depressive disorder spectrum, those with treatment-resistant depression and who are prescribed electroconvulsive therapy (ECT), could lead to a better understanding of the genetic underpinnings of depression. Despite ECT being one of the most effective forms of treatment for severe depressive disorders, it is usually placed at the end of treatment algorithms of current guidelines. This is perhaps because ECT has controlled risk and logistical demands including use of general anaesthesia and muscle relaxants and side-effects such as short-term memory impairment. Better understanding of the genetics and biology of ECT response and of cognitive side-effects could lead to more personalized treatment decisions. To enhance the understanding of the genomics of severe depression and ECT response, researchers and ECT providers from around the world and from various depression or ECT networks, but not limited to, such as the Psychiatric Genomics Consortium, the Clinical Alliance and Research in ECT, and the National Network of Depression Centers have formed the Genetics of ECT International Consortium (Gen-ECT-ic). Gen-ECT-ic will organize the largest clinical and genetic collection to date to study the genomics of severe depressive disorders and response to ECT, aiming for 30,000 patients worldwide using a GWAS approach. At this stage it will be the largest genomic study on treatment response in depression. Retrospective data abstraction and prospective data collection will be facilitated by a uniform data collection approach that is flexible and will incorporate data from many clinical practices. Gen-ECT-ic invites all ECT providers and researchers to join its efforts.

17.
Artigo em Inglês | MEDLINE | ID: mdl-31852584

RESUMO

We did a clinical service evaluation of patient-reported outcomes for pain and change in interincisal distance in patients treated with botulinum toxin A (BTX-A) for temporomandibular myofascial pain at nurse-led clinics. We retrospectively reviewed the clinical records of 100 patients and the prescribing patterns of two OMFS consultants. The mean starting pain score of 7.54 out of 10 was reduced by a mean (SD) of 2.48 (2.1) points after the intervention (p<0.001). The most common prescription was for 100 units (n=59 prescriptions). The change in the mean pain scores did not differ significantly whether 100 or 200 units were prescribed (p=0.19). Interincisal distance increased by a mean (SD) of 0.5 (5.24) mm after treatment with BTX-A, which was not significant (p=0.35). In most cases the treatment helped to manage and reduce the symptoms of temporomandibular myofascial pain. Considerable improvement in interincisal distance as a result of this treatment alone, however, is unlikely, but it may have a role in a multifaceted approach, particularly when other conservative methods have failed. The use of a pro forma may allow for more consistent record keeping and the detailed assessment of patient-reported pain scores in the weeks and months after treatment. Development of an electronic patient-reported outcome (ePRO) tool may facilitate this further.

18.
Insights Imaging ; 10(1): 111, 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31781977

RESUMO

The introduction of high throughput sequence analysis in the past decade and the decrease in sequencing costs has made available an enormous amount of genomic data. These data have shaped the landscape of cancer genome, which encompasses mutations determining tumorigenesis, the signaling pathways involved in cancer growth, the tumor heterogeneity, and its role in development of metastases. Tumors develop acquiring a series of driver mutations over time. Of the many mutated genes present in cancer, only few specific mutations are responsible for invasiveness and metastatic potential, which, in many cases, have characteristic imaging appearance. Ten signaling pathways, each with targetable components, have been identified as responsible for cancer growth. Blockage of any of these pathways form the basis for molecular targeted therapies, which are associated with specific pattern of response and toxicities. Tumor heterogeneity, responsible for the different mutation pattern of metastases and primary tumor, has been classified in intratumoral, intermetastatic, intrametastatic, and interpatient heterogeneity, each with specific imaging correlates. The purpose of this article is to introduce the key components of the landscapes of cancer genome and their imaging counterparts, describing the types of mutations associated with tumorigenesis, the pathways of cancer growth, the genetic heterogeneity involved in metastatic disease, as well as the current challenges and opportunities for cancer genomics research.

19.
Transl Psychiatry ; 9(1): 310, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31748543

RESUMO

Chronic pain is a complex trait that is moderately heritable and genetically, as well as phenotypically, correlated with major depressive disorder (MDD). Use of the conditional false discovery rate (cFDR) approach, which leverages pleiotropy identified from existing GWAS outputs, has been successful in discovering novel associated variants in related phenotypes. Here, genome-wide association study outputs for both von Korff chronic pain grade and for MDD were used to identify variants meeting a cFDR threshold for each outcome phenotype separately, as well as a conjunctional cFDR (ccFDR) threshold for both phenotypes together. Using a moderately conservative threshold, we identified a total of 11 novel single nucleotide polymorphisms (SNPs), six of which were associated with chronic pain grade and nine of which were associated with MDD. Four SNPs on chromosome 14 were associated with both chronic pain grade and MDD. SNPs associated only with chronic pain grade were located within SLC16A7 on chromosome 12. SNPs associated only with MDD were located either in a gene-dense region on chromosome 1 harbouring LINC01360, LRRIQ3, FPGT and FPGT-TNNI3K, or within/close to LRFN5 on chromosome 14. The SNPs associated with both outcomes were also located within LRFN5. Several of the SNPs on chromosomes 1 and 14 were identified as being associated with expression levels of nearby genes in the brain and central nervous system. Overall, using the cFDR approach, we identified several novel genetic loci associated with chronic pain and we describe likely pleiotropic effects of a recently identified MDD locus on chronic pain.

20.
Br J Psychiatry ; : 1-8, 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31753047

RESUMO

BACKGROUND: Psychiatric disorders are associated with increased risk of ischaemic heart disease (IHD) and stroke, but it is not known whether the associations or the role of sociodemographic factors have changed over time. AIMS: To investigate the association between psychiatric disorders and IHD and stroke, by time period and sociodemographic factors. METHOD: We used Scottish population-based records from 1991 to 2015 to create retrospective cohorts with a hospital record for psychiatric disorders of interest (schizophrenia, bipolar disorder or depression) or no record of hospital admission for mental illness. We estimated incidence and relative risks of IHD and stroke in people with versus without psychiatric disorders by calendar year, age, gender and area-based deprivation level. RESULTS: In all cohorts, incidence of IHD (645 393 events) and stroke (276 073 events) decreased over time, but relative risks decreased for depression only. In 2015, at the mean age at event onset, relative risks were 2- to 2.5-fold higher in people with versus without a psychiatric disorder. Age at incidence of outcome differed by cohort, gender and socioeconomic status. Relative but not absolute risks were generally higher in women than men. Increasing deprivation conveys a greater absolute risk of IHD for people with bipolar disorder or depression. CONCLUSIONS: Despite declines in absolute rates of IHD and stroke, relative risks remain high in those with versus without psychiatric disorders. Cardiovascular disease monitoring and prevention approaches may need to be tailored by psychiatric disorder and cardiovascular outcome, and be targeted, for example, by age and deprivation level.

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