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1.
Water Res ; 168: 115136, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31622910

RESUMO

The mixed layer, or epilimnion, is a physical concept referring to an isothermal layer at the surface of a water body. This concept is ubiquitous within limnology, is fundamental to our understanding of chemical and ecological processes, and is an important metric for water body monitoring, assessment and management. Despite its importance as a metric, many different approaches to approximating mixed depth currently exist. Using data from field campaigns in a small meso-eutrophic lake in the UK in 2016 and 2017 we tested whether different definitions of mixed depth resulted in comparable estimates and whether variables other than temperature could be assumed to be mixed within the layer. Different methods resulted in very different estimates for the mixed depth and ecologically important variables were not necessarily homogenously spread through the epilimnion. Furthermore, calculation of simple ecologically relevant metrics based on mixed depth showed that these metrics were highly dependent on the definition of mixed depth used. The results demonstrate that an idealised concept of a well-defined fully mixed layer is not necessarily appropriate. The widespread use of multiple definitions for mixed depth impairs the comparability of different studies while associated uncertainty over the most appropriate definition limits the confirmability of studies utilising the mixed depths.


Assuntos
Lagos , Limnologia , Monitoramento Ambiental , Fitoplâncton , Estações do Ano , Temperatura Ambiente
2.
Clin Nephrol ; 93(1): 9-16, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31661063

RESUMO

PURPOSE: Ultrasound is considered a preferred first-line imaging technique for the assessment of kidney function. The potential relationship between tobacco smoke exposure and ultrasound-measured renal characteristics has yet to be explored. We hypothesized that exposure to tobacco smoke would be associated with reduced kidney dimensions. MATERIALS AND METHODS: This was a cross-sectional study that included all individuals over age 18 at a single site in Mojokerto, Indonesia. A questionnaire was used to assess prior history and environmental exposure, and blinded evaluators performed ultrasound assessments. Six kidney parameters (length, width, and parenchymal thickness of each kidney) were considered as dependent variables, and statistical relationships were assessed using multivariate analysis. Echogenicity was evaluated using a 5-point grading scale described previously. RESULTS: Of the 445 participants assessed, a total of 138 male and 269 female subjects were included in the final analysis. There was a statistically significant association between kidney measures and the following independent variables: pack years smoking (p < 0.001), height (p < 0.001), weight (p < 0.001), and beginning to smoke at the age of 25 or younger (p < 0.001). There was not a statistically significant association between kidney measures and hypertension (p > 0.05) or diabetes (p > 0.05). Echogenicity was similar among all smoking groups. CONCLUSION: Kidney dimensions were decreased in individuals with increased smoking history. This association is notable, particularly given that statistically significant associations were not observed between renal dimensions and hypertension or diabetes. The null findings using echogenicity are consistent with previous studies.

3.
Arthroscopy ; 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31784364

RESUMO

PURPOSE: To determine if the tendon-specific crosslinking gelatin (Col-Tgel) impregnated with growth factors promotes tendon healing at the bone interface and in a tendon window model. METHODS: Two different Col-Tgel formulations were first tested in vitro by evaluating cell morphology and tendogenic differentiation. After the optimum formulation was determined, the gel was mixed with either transforming growth factor-ß3 (TGF-ß3) or growth differentiation factor-7 (GDF-7) growth factor and prepared for injections. Window defects were induced in 12 animals, which were randomized into the following treatments: (1) sham, (2) empty Col-Tgel, (3) Col-Tgel containing TGF-ß3, or (4) Col-Tgel containing GDF-7. Based on these results, the sham, empty Col-Tgel, and Col-Tgel containing TGF-ß3 were applied to the supraspinatus repair interface. Tendons were analyzed biomechanically and histologically using hematoxylin and eosin and Masson's trichrome staining. RESULTS: In the window defect model, histologic scores were the best in rats treated with TGF-ß3 containing Col-Tgel, followed by the empty Col-Tgel scaffold, and finally the sham control. The GDF-7 Col-Tgel was not further tested because occasional ectopic cartilage and bone formation was found in the prior window defect model. In the supraspinatus repair model, there was no statistical difference (P > .05) in the biomechanical strength among the 3 treatment groups, but load-to-failure ratio improved when TGF-ß3 was added to the scaffold, suggesting improved tendon healing. CONCLUSIONS: This pilot study evaluated the performance of an injectable gel tendon graft in a population of retired breeder rats. The results suggest that Col-Tgel containing TGF-ß3 may be a useful adjunctive treatment for surgical repair of full-thickness rotator cuff tears. Histologic and biomechanical scores suggest that Col-Tgel containing TGF-ß3 promotes tendon healing. CLINICAL RELEVANCE: The results of this study suggest that shoulders injected with Col-Tgel may be a useful adjunctive treatment for repair of rotator cuff tears.

4.
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.

5.
World J Pediatr Congenit Heart Surg ; 10(6): 669-677, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31701827

RESUMO

INTRODUCTION: Interpretation of risk by parents of children undergoing congenital cardiac surgery is poorly documented. The available evidence highlights a dichotomy where clinicians suggest parents may not grasp the complexity and risk associated with procedures, while some parents suggest risk is unnecessarily overemphasized. AIM: To quantify how risk is perceived by parents. METHODS: One hundred six parents of children undergoing cardiac surgery were recruited and completed a Likert-type scale from 1 (perceived low risk) to 6 (perceived high risk), at 5 points: arrival at preadmission, post discussion with anethetist/surgeon, day of surgery, discharge from intensive care, and at outpatient follow-up. The surgical sample was stratified according to Risk Adjustment in Congenital Heart Surgery level. ANALYSIS: Data were analyzed using Wilcoxon rank tests for differences in distributions of scores and Krippendorff α to examine the level of agreement. RESULTS: Median parental risk scores varied over time, with no consistent risk scores observed. Maternal scores were consistently higher than paternal scores at every time point (P < .001). Postoperative complications resulted in a persistent rise in risk perception at follow-up (P < .001). Analysis of parental risk scores and objective measures of surgical risk highlighted poor agreement that was particularly marked at the extremes of risk. CONCLUSIONS: Parents perceived higher risk scores than those reported by the clinical team. Mothers reported statistically significantly higher scores than their partners, highlighting potential tensions. In addition, the changing perception of risk over time emphasizes the need for flexible levels of support and information as parents navigate uncertainty.

6.
Am J Sports Med ; : 363546519881423, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31743037

RESUMO

BACKGROUND: Many clinical trials have investigated the use of platelet-rich plasma (PRP) to treat rotator cuff-related abnormalities. Several meta-analyses have been published, but none have focused exclusively on level 1 randomized controlled trials. PURPOSE: To assess the efficacy of PRP for rotator cuff-related abnormalities and evaluate how specific tendon involvement, the inclusion of leukocytes, and the use of gel/nongel formulations affect pain and functional outcomes. STUDY DESIGN: Systematic review and meta-analysis. METHODS: The literature was screened following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Baseline, short-term, and long-term data were extracted for the Constant score, University of California, Los Angeles (UCLA) score, visual analog scale (VAS) for pain, retear rate, Simple Shoulder Test (SST), and American Shoulder and Elbow Surgeons (ASES) score. The 100-point modified Coleman Methodology Score (CMS) was used to assess methodological quality. Funnel plots and the Egger test were used to screen for publication bias, and sensitivity analysis was performed to evaluate the effect of potential outliers. RESULTS: A total of 18 level 1 studies were included in this review, 17 (1116 patients) of which could be included in quantitative analysis. The mean modified CMS was 79.4 ± 10.39. The Constant scores of patients who received PRP were significantly better short term (weighted mean difference [WMD], 2.89 [95% CI, 0.89-4.90]; P < .01) and long term (WMD, 2.66 [95% CI, 1.13-4.19]; P < .01). The VAS scores were significantly improved short term (WMD, -0.45 [95% CI, -0.75 to -0.15]; P < .01). Sugaya grade IV and V retears in PRP-treated patients were significantly reduced long term (odds ratio [OR], 0.34 [95% CI, 0.20-0.57]; P < .01). In PRP-treated patients with multiple tendons torn, there were reduced odds of retears (OR, 0.28 [95% CI, 0.13-0.60]; P < .01). Patients who received leukocyte-rich PRP had significantly better Constant scores compared with the leukocyte-poor PRP group, but there was no difference in VAS scores. Patients receiving PRP gel reported higher Constant scores compared with the controls, whereas those receiving nongel PRP treatments did not, although there was no difference in VAS scores. Long-term odds of retears were decreased, regardless of leukocyte content (leukocyte-poor PRP: OR, 0.36 [95% CI, 0.16-0.82]; leukocyte-rich PRP: OR, 0.32 [95% CI, 0.16-0.65]; all P < .05) or usage of gel (nongel: OR, 0.42 [95% CI, 0.23-0.76]; gel: OR, 0.17 [95% CI, 0.05-0.51]; all P < .01). CONCLUSION: Long-term retear rates were significantly decreased in patients with rotator cuff-related abnormalities who received PRP. Significant improvements in PRP-treated patients were noted for multiple functional outcomes, but none reached their respective minimal clinically important differences. Overall, our results suggest that PRP may positively affect clinical outcomes, but limited data, study heterogeneity, and poor methodological quality hinder firm conclusions.

7.
J Affect Disord ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31744744

RESUMO

BACKGROUND: Women are particularly vulnerable to recurrence of bipolar disorder (BD) following childbirth. Risk of postpartum psychosis (PP) is especially high, but postpartum depression (PPD) is also common. Adverse childhood experiences (ACEs) have not been associated with PP, but have been associated with PPD in non-bipolar samples. The relationship between ACEs and PPD within BD remains to be investigated. Here, we examined this association in a large, well-defined sample of women with BD. METHODS: Participants were 575 parous women with DSM-IV BD. Lifetime psychopathology, including perinatal, was assessed via semi-structured interview and case-notes. ACEs, assessed via self-report and case-notes, were compared between women with lifetime PPD (n = 368) and those without a lifetime history of perinatal mood episodes (n = 207). RESULTS: In univariate analysis exposure to 3 or more ACEs, and to childhood abuse specifically, was significantly associated with PPD (p = 0.026 and 0.041 respectively), but this did not remain significant after adjusting for lifetime number of episodes of depression and parity. Post-hoc analysis revealed more frequent episodes of depression to be associated with both a history of 3 or more ACEs and of childhood abuse. LIMITATIONS: Limited range of ACEs assessed and potential recall bias. CONCLUSIONS: Increased frequency of ACEs and particularly childhood abuse was associated with more frequent lifetime episodes of depression, but not specifically episodes with postpartum onset. Understanding factors that mediate the pathway between ACEs and PPD in BD has implications for risk prediction of PPD.

8.
Behav Res Ther ; 123: 103503, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31715324

RESUMO

BACKGROUND: Anxiety and depression are common, debilitating and costly. These disorders are influenced by multiple risk factors, from genes to psychological vulnerabilities and environmental stressors, but research is hampered by a lack of sufficiently large comprehensive studies. We are recruiting 40,000 individuals with lifetime depression or anxiety and broad assessment of risks to facilitate future research. METHODS: The Genetic Links to Anxiety and Depression (GLAD) Study (www.gladstudy.org.uk) recruits individuals with depression or anxiety into the NIHR Mental Health BioResource. Participants invited to join the study (via media campaigns) provide demographic, environmental and genetic data, and consent for medical record linkage and recontact. RESULTS: Online recruitment was effective; 42,531 participants consented and 27,776 completed the questionnaire by end of July 2019. Participants' questionnaire data identified very high rates of recurrent depression, severe anxiety, and comorbidity. Participants reported high rates of treatment receipt. The age profile of the sample is biased toward young adults, with higher recruitment of females and the more educated, especially at younger ages. DISCUSSION: This paper describes the study methodology and descriptive data for GLAD, which represents a large, recontactable resource that will enable future research into risks, outcomes, and treatment for anxiety and depression.

9.
JAMA Psychiatry ; 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31751445

RESUMO

Importance: Insomnia, hypersomnia, and an evening chronotype are common in individuals with bipolar disorder (BD), but whether this reflects shared genetic liability is unclear. Stratifying by BD subtypes could elucidate this association and inform sleep and BD research. Objective: To assess whether polygenic risk scores (PRSs) for sleep traits are associated with BD subtypes I and II. Design, Setting, and Participants: This case-control study was conducted in the United Kingdom and Sweden with participants with BD and control participants. Multinomial regression was used to assess whether PRSs for insomnia, daytime sleepiness, sleep duration, and chronotype are associated with BD subtypes compared with control participants. Affected individuals were recruited from the Bipolar Disorder Research Network. Control participants were recruited from the 1958 British Birth Cohort and the UK Blood Service. Analyses were repeated in an independent Swedish sample from August 2018 to July 2019. All participants were of European ancestry. Exposures: Standardized PRSs derived using alleles from genome-wide association studies of insomnia, sleep duration, daytime sleepiness, and chronotype. These were adjusted for the first 10 population principal components, genotyping platforms, and sex. Main Outcomes and Measures: Association of PRSs with BD subtypes, determined by semistructured psychiatric interview and case notes. Results: The main analysis included 4672 participants with BD (3132 female participants [67.0%]; 3404 with BD-I [72.9%]) and 5714 control participants (2812 female participants [49.2%]). Insomnia PRS was associated with increased risk of BD-II (relative risk [RR], 1.14 [95% CI, 1.07-1.21]; P = 8.26 × 10-5) but not BD-I (RR, 0.98 [95% CI, 0.94-1.03]; P = .409) relative to control participants. Sleep-duration PRS was associated with BD-I (RR, 1.10 [95% CI, 1.06-1.15]; P = 1.13 × 10-5) but not BD-II (RR, 0.99 [95% CI, 0.93-1.06]; P = .818). Associations between (1) insomnia PRS and BD-II and (2) sleep-duration PRS and BD-I were replicated in the Swedish sample of 4366 individuals with BD (2697 female participants [61.8%]; 2627 with BD-I [60.2%]) and 6091 control participants (3767 female participants [61.8%]). Chronotype and daytime-sleepiness PRS were not associated with BD subtypes. Conclusions and Relevance: Per this analysis, BD subtypes differ in genetic liability to insomnia and hypersomnia, providing further evidence that the distinction between BD-I and BD-II has genetic validity. This distinction will be crucial in selecting participants for future research on the role of sleep disturbance in BD.

10.
JAMA Oncol ; 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31621801

RESUMO

Importance: Adjuvant chemotherapy in patients with stage III colon cancer prevents recurrence by eradicating minimal residual disease. However, which patients remain at high risk of recurrence after completing standard adjuvant treatment cannot currently be determined. Postsurgical circulating tumor DNA (ctDNA) analysis can detect minimal residual disease and is associated with recurrence in colorectal cancers. Objective: To determine whether serial postsurgical and postchemotherapy ctDNA analysis could provide a real-time indication of adjuvant therapy efficacy in stage III colon cancer. Design, Setting, and Participants: This multicenter, Australian, population-based cohort biomarker study recruited 100 consecutive patients with newly diagnosed stage III colon cancer planned for 24 weeks of adjuvant chemotherapy from November 1, 2014, through May 31, 2017. Patients with another malignant neoplasm diagnosed within the last 3 years were excluded. Median duration of follow-up was 28.9 months (range, 11.6-46.4 months). Physicians were blinded to ctDNA results. Data were analyzed from December 10, 2018, through June 23, 2019. Exposures: Serial plasma samples were collected after surgery and after chemotherapy. Somatic mutations in individual patients' tumors were identified via massively parallel sequencing of 15 genes commonly mutated in colorectal cancer. Personalized assays were designed to quantify ctDNA. Main Outcomes and Measures: Detection of ctDNA and recurrence-free interval (RFI). Results: After 4 exclusions, 96 eligible patients were eligible; median patient age was 64 years (range, 26-82 years); 49 (51%) were men. At least 1 somatic mutation was identified in the tumor tissue of all 96 evaluable patients. Circulating tumor DNA was detectable in 20 of 96 (21%) postsurgical samples and was associated with inferior recurrence-free survival (hazard ratio [HR], 3.8; 95% CI, 2.4-21.0; P < .001). Circulating tumor DNA was detectable in 15 of 88 (17%) postchemotherapy samples. The estimated 3-year RFI was 30% when ctDNA was detectable after chemotherapy and 77% when ctDNA was undetectable (HR, 6.8; 95% CI, 11.0-157.0; P < .001). Postsurgical ctDNA status remained independently associated with RFI after adjusting for known clinicopathologic risk factors (HR, 7.5; 95% CI, 3.5-16.1; P < .001). Conclusions and Relevance: Results suggest that ctDNA analysis after surgery is a promising prognostic marker in stage III colon cancer. Postchemotherapy ctDNA analysis may define a patient subset that remains at high risk of recurrence despite completing standard adjuvant treatment. This high-risk population presents a unique opportunity to explore additional therapeutic approaches.

11.
Biol Psychiatry ; 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31570195

RESUMO

BACKGROUND: The prevalence of depression is higher in individuals with autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Shared genetic etiology is a plausible explanation for the overlap, and in this study we tested whether genetic variation in the major histocompatibility complex (MHC), which is associated with risk for autoimmune diseases, is also associated with risk for depression. METHODS: We fine-mapped the classical MHC (chr6: 29.6-33.1 Mb), imputing 216 human leukocyte antigen (HLA) alleles and 4 complement component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium Major Depressive Disorder Working Group and the UK Biobank. The total sample size was 45,149 depression cases and 86,698 controls. We tested for association between depression status and imputed MHC variants, applying both a region-wide significance threshold (3.9 × 10-6) and a candidate threshold (1.6 × 10-4). RESULTS: No HLA alleles or C4 haplotypes were associated with depression at the region-wide threshold. HLA-B*08:01 was associated with modest protection for depression at the candidate threshold for testing in HLA genes in the meta-analysis (odds ratio = 0.98, 95% confidence interval = 0.97-0.99). CONCLUSIONS: We found no evidence that an increased risk for depression was conferred by HLA alleles, which play a major role in the genetic susceptibility to autoimmune diseases, or C4 haplotypes, which are strongly associated with schizophrenia. These results suggest that any HLA or C4 variants associated with depression either are rare or have very modest effect sizes.

12.
Psychol Med ; : 1-9, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31530330

RESUMO

BACKGROUND: Childhood abuse is a risk factor for poorer illness course in bipolar disorder, but the reasons why are unclear. Trait-like features such as affective instability and impulsivity could be part of the explanation. We aimed to examine whether childhood abuse was associated with clinical features of bipolar disorder, and whether associations were mediated by affective instability or impulsivity. METHODS: We analysed data from 923 people with bipolar I disorder recruited by the Bipolar Disorder Research Network. Adjusted associations between childhood abuse, affective instability and impulsivity and eight clinical variables were analysed. A path analysis examined the direct and indirect links between childhood abuse and clinical features with affective instability and impulsivity as mediators. RESULTS: Affective instability significantly mediated the association between childhood abuse and earlier age of onset [effect estimate (θ)/standard error (SE): 2.49], number of depressive (θ/SE: 2.08) and manic episodes/illness year (θ/SE: 1.32), anxiety disorders (θ/SE: 1.98) and rapid cycling (θ/SE: 2.25). Impulsivity significantly mediated the association between childhood abuse and manic episodes/illness year (θ/SE: 1.79), anxiety disorders (θ/SE: 1.59), rapid cycling (θ/SE: 1.809), suicidal behaviour (θ/SE: 2.12) and substance misuse (θ/SE: 3.09). Measures of path analysis fit indicated an excellent fit to the data. CONCLUSIONS: Affective instability and impulsivity are likely part of the mechanism of why childhood abuse increases risk of poorer clinical course in bipolar disorder, with each showing some selectivity in pathways. They are potential novel targets for intervention to improve outcome in bipolar disorder.

13.
Viruses ; 11(9)2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31491938

RESUMO

Coronaviruses represent current and emerging threats for many species, including humans. Middle East respiratory syndrome-related coronavirus (MERS-CoV) is responsible for sporadic infections in mostly Middle Eastern countries, with occasional transfer elsewhere. A key step in the MERS-CoV replication cycle is the fusion of the virus and host cell membranes mediated by the virus spike protein, S. The location of the fusion peptide within the MERS S protein has not been precisely mapped. We used isolated peptides and giant unilamellar vesicles (GUV) to demonstrate membrane binding for a peptide located near the N-terminus of the S2 domain. Key residues required for activity were mapped by amino acid replacement and their relevance in vitro tested by their introduction into recombinant MERS S protein expressed in mammalian cells. Mutations preventing membrane binding in vitro also abolished S-mediated syncytium formation consistent with the identified peptide acting as the fusion peptide for the S protein of MERS-CoV.

14.
Am J Hypertens ; 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31560753

RESUMO

OBJECTIVES: Carotid artery diameter responses to sympathetic stimulation, i.e. carotid artery reactivity (CAR), represents a novel test of vascular health and relates to cardiovascular disease/risk. This study aims to understand the relationship between the increase in blood pressure and carotid artery diameter response during the CAR-test in healthy, middle-aged men. METHODS: Sample consisted of 40 normotensive men (aged 31-59) with no history of cardiovascular disease of currently taking medication. Non-invasive ultrasound was used to measure carotid artery diameter during the cold pressor test (CPT), with CAR% being calculated as the relative change from baseline (%). Mean arterial pressure (MAP) was measured with beat-to-beat blood pressure recording. RESULTS: CAR% was 4.4±5.4%, peaking at 92±43s. MAP increased from 88±9 mmHg to 110±15 mmHg, peaked at 112±38 seconds, which was significantly later than the diameter peak (P=0.04). The correlation between resting MAP and CAR% was weak (r=0.209 P=0.197). Tertiles based on resting MAP or MAP-increase revealed no significant differences between groups in subject characteristics including age, BMI or CAR% (all P>0.05). Subgroup analysis of individuals with carotid constriction (n=6) versus dilation (n=34), revealed no significant difference in resting MAP or increase in MAP (P=0.209 and 0.272, respectively). CONCLUSION: Our data suggests that the characteristic increase in MAP during the CPT does not mediates carotid artery vasomotion.

15.
Mod Pathol ; 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31471586

RESUMO

TP53 mutations drive colorectal cancer development, with missense mutations frequently leading to accumulation of abnormal TP53 protein. TP53 alterations have been associated with poor prognosis and chemotherapy resistance, but data remain controversial. Here, we examined the predictive utility of TP53 overexpression in the context of current adjuvant treatment practice for patients with stage III colorectal cancer. A prospective cohort of 264 stage III patients was tested for association of TP53 expression with 5-year disease-free survival, grouped by adjuvant treatment. Findings were validated in an independent retrospective cohort of 274 stage III patients. Overexpression of TP53 protein (TP53+) was found in 53% and 52% of cases from the prospective and retrospective cohorts, respectively. Among patients receiving adjuvant chemotherapy, TP53+ status was associated with shorter disease-free survival (p ≤ 0.026 for both cohorts), while no difference in outcomes between TP53+ and TP53- cases was observed for patients treated with surgery alone. Considering patients with TP53- tumors, those receiving adjuvant treatment had better outcomes compared with those treated with surgery alone (p ≤ 0.018 for both cohorts), while no treatment benefit was apparent for patients with TP53+ tumors. Combined cohort-stratified analysis adjusted for clinicopathological variables and DNA mismatch repair status confirmed a significant interaction between TP53 expression and adjuvant treatment for disease-free survival (pinteraction = 0.030). For the combined cohort, the multivariate hazard ratio for TP53 overexpression among patients receiving adjuvant chemotherapy was 2.03 (95% confidence interval 1.41-2.95, p < 0.001), while the hazard ratio for adjuvant treatment among patients with TP53- tumors was 0.42 (95% confidence interval 0.24-0.71, p = 0.001). Findings were maintained irrespective of tumor location or when restricted to mismatch repair-proficient tumors. Our data suggest that adjuvant chemotherapy benefit in stage III colorectal cancer is restricted to cases with low-level TP53 protein expression. Identifying TP53+ tumors could highlight patients that may benefit from more aggressive treatment or follow-up.

16.
Cardiol Young ; 29(11): 1361-1367, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31514764

RESUMO

INTRODUCTION: The way risk is interpreted by parents of children undergoing congenital cardiac surgery is poorly documented. Literature suggests clinicians have concerns that parents may not understand the complexity of procedures. Conversely, some parents perceive an unnecessary over-emphasis of risks. AIM: To explore how risk is encountered by parents of children who are undergoing cardiac surgery, in order to deliver effective and compassionate care. METHODS: A qualitative approach was adopted. Interviews were undertaken with 18 parents (mothers n = 10; fathers n = 8). Recordings were transcribed verbatim and analysed using a constant comparative-based approach. FINDINGS: Three themes emerged from the data: the nature of risk, reflecting the complexity of parental perception of risk and the influence of the doctor-parent relationship; presenting risk, highlighting the way in which risk is presented to and interpreted by parents; and risk and responsibility, examining the way in which parents engaged with risk and the impact of this on their relationship. CONCLUSIONS: The way in which risk is perceived by parents is complex and multi-factorial. The doctor-parent relationship is key to parental engagement. However, parents manage risk and uncertainty through a number of mechanisms, including those perceived as being not rational. This can cause tension, particularly when required to engage in informed decision-making.

17.
Nat Genet ; 51(8): 1252-1262, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31367015

RESUMO

Mutations in gene regulatory elements have been associated with a wide range of complex neuropsychiatric disorders. However, due to their cell-type specificity and difficulties in characterizing their regulatory targets, the ability to identify causal genetic variants has remained limited. To address these constraints, we perform an integrative analysis of chromatin interactions, open chromatin regions and transcriptomes using promoter capture Hi-C, assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and RNA sequencing, respectively, in four functionally distinct neural cell types: induced pluripotent stem cell (iPSC)-induced excitatory neurons and lower motor neurons, iPSC-derived hippocampal dentate gyrus-like neurons and primary astrocytes. We identify hundreds of thousands of long-range cis-interactions between promoters and distal promoter-interacting regions, enabling us to link regulatory elements to their target genes and reveal putative processes that are dysregulated in disease. Finally, we validate several promoter-interacting regions by using clustered regularly interspaced short palindromic repeats (CRISPR) techniques in human excitatory neurons, demonstrating that CDK5RAP3, STRAP and DRD2 are transcriptionally regulated by physically linked enhancers.

18.
Langmuir ; 35(38): 12483-12491, 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31454251

RESUMO

Polymerization of synthetic phospholipid monomers has been widely used to enhance the stability of lipid membranes in applications such as membrane-based biosensing, where the inherent instability of fluid-phase lipid bilayers can be problematic. However, lipid polymerization typically decreases membrane fluidity, which may be required to maintain the activity of reconstituted integral proteins and peptides. Prior work has shown that a bilayer composed of binary mixtures of poly(lipid) and fluid lipid exhibits enhanced stability and supports the function of incorporated biomolecules. This work examines the structural basis of these findings using planar supported lipid bilayers (PSLBs) composed of binary mixtures of a polymerizable lipid, 1,2-bis[10-(2',4'-hexadienoloxy)decanoyl]-sn-glycero-3-phosphocholine (bis-SorbPC), and a nonpolymerizable lipid, 1,2-diphytanoyl-sn-glycero-3-phosphocholine (DPhPC). Fluorescence recovery after photobleaching (FRAP) measurements showed that long-range lateral diffusion was minimally affected when the poly(lipid) mole ratio was ≤0.7. Atomic force microscopy, used to examine phase segregation in these PSLBs, showed that DPhPC forms a continuous lipid matrix that is 0.2-0.4 nm thicker than the island-like poly(bis-SorbPC) domains, with lateral dimensions of ≤200 nm. The nanoscale phase segregation allows for long-range lateral diffusion of lipid probes in the DPhPC matrix. The combination of fluidity and stability in these materials should make them useful in membrane-based biosensing applications.

19.
J Knee Surg ; 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31434143

RESUMO

The aim of this study is to evaluate diurnal variation in knee cartilage 3 Tesla magnetic resonance imaging (MRI) T2 mapping relaxation times, as well as activity- and body mass index (BMI)-dependent variability, using quantitative analysis of T2 values from segmented regions of the weight-bearing articular surfaces of the medial and lateral femoral condyles and tibial plateaus. Ten healthy volunteers' daily activity (steps) were tracked with Fitbit pedometers. Sagittal MRI T2 maps were obtained in the morning and afternoon on days 2 and 3. Mean T2 values were analyzed for variation related to the number of steps taken (activity), time of day (diurnal variation), and BMI using mixed effect model. Significant (albeit small) differences in the medial femoral and medial tibial cartilage regions were identified between morning and afternoon scans (diurnal variation). Daily activity did not result in significant changes and increasing BMI only demonstrated a slight increase in T2 values for the lateral tibial plateau. These findings suggest that it may be necessary to control diurnal variation when using quantitative MRI T2 mapping to assess articular cartilage longitudinally in healthy participants. Further investigation is needed to confirm these findings and determine if they also apply to symptomatic patients.

20.
Psychoneuroendocrinology ; 108: 14-19, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31181440

RESUMO

OBJECTIVES: Seasonal changes in mood and behaviour are commonly reported in the general population but considerably less is known regarding seasonality and pregnancy. This study investigated the relationship between seasons and depression and anxiety symptoms, salivary cortisol concentrations, custom birthweight centiles (CBWC) and placenta weight for pregnant women living in South Wales. METHODS: This study utilised data from the longitudinal Grown in Wales (GiW) cohort. Women were recruited at the presurgical elective caesarean section (ELCS) appointment, when they provided saliva samples and completed the Edinburgh Postnatal Depression Scale (EPDS) and trait subscale of the State-Trait Anxiety Inventory (STAI). Data on birthweight and placental weight was extracted from medical notes. Seasonal data was available for 316 participants. RESULTS: No association was identified between seasons and EPDS (p = .178), STAI scores (p = .544), CBWC (p = .683) or placental weight (p = .857). Significance was identified between seasons and salivary cortisol concentration (p<.001), with highest levels in autumn and winter. Adjusted linear regression identified spring (B=-.05, p=.007, 95% CI -.09, -.01) and summer (B=-.06, p = .001, 95% CI -09, -.02) compared to autumn, and spring (B=-.05, p=.009, 95% CI -.09, -.01) and summer (B=-.06, p=.002, 95% CI -.10, -.02) compared to winter to be associated with decreased cortisol concentrations. CONCLUSION: This study found no association between season and maternally-reported mental health symptoms, birthweight by CBWC or placental weight but did between season and term salivary cortisol. This finding will have implications for studies that do not account for seasonality when using salivary cortisol as a biomarker.

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