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1.
Neuromodulation ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31710408

RESUMO

OBJECTIVES: Electric stimulation is used to treat a number of neurologic disorders such as epilepsy and depression. However, delivering the required current to far-field neural targets is often ineffective because of current spread through low-impedance pathways. Here, the specific aims are to develop an empirical measure for current passing through the human head and to optimize stimulation strategies for targeting deeper structures, including the auditory nerve, by utilizing the cochlear implant (CI). MATERIALS AND METHODS: Outward input/output (I/O) functions were obtained by CI stimulation and recording scalp potentials in five CI subjects. Conversely, inward I/O functions were obtained by noninvasive transcranial electric stimulation (tES) and recording intracochlear potentials using the onboard recording capability of the CI. RESULTS: I/O measures indicate substantial current spread, with a maximum of 2.2% gain recorded at the inner ear target during tES (mastoid-to-mastoid electrode configuration). Similarly, CI stimulation produced a maximum of 1.1% gain at the scalp electrode nearest the CI return electrode. Gain varied with electrode montage according to a point source model that accounted for distances between the stimulating and recording electrodes. Within the same electrode montages, current gain patterns varied across subjects suggesting the importance of tissue properties, geometry, and electrode positioning. CONCLUSION: These results provide a novel objective measure of electric stimulation in the human head, which can help to optimize stimulation parameters that improve neural excitation of deep structures by reducing the influence of current spread.

3.
Cochrane Database Syst Rev ; 10: CD008100, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31600820

RESUMO

BACKGROUND: Single-shot spinal anaesthesia (SSS) and combined spinal-epidural (CSE) anaesthesia are both commonly used for caesarean section anaesthesia. Spinals offer technical simplicity and rapid onset of nerve blockade which can be associated with hypotension. CSE anaesthesia allows for more gradual onset and also prolongation of the anaesthesia through use of a catheter. OBJECTIVES: To compare the effectiveness and adverse effects of CSE anaesthesia to single-shot spinal anaesthesia for caesarean section. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP), and reference lists of retrieved studies (search date: 8 August 2019). SELECTION CRITERIA: We considered all published randomised controlled trials (RCTs) involving a comparison of CSE anaesthesia with single-shot spinal anaesthesia for caesarean section. We further subgrouped spinal anaesthesia as either high-dose (10 or more mg bupivacaine), or low-dose (less than 10 mg bupivacaine). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risks of bias, extracted data and checked them for accuracy. We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We identified 18 trials including 1272 women, but almost all comparisons for individual outcomes involved relatively small numbers of women. Two trials did not report on this review's outcomes and therefore contribute no data towards this review. Trials were conducted in national or university hospitals in Australia (1), Croatia (1), India (1), Italy (1), Singapore (3), South Korea (4), Spain (1), Sweden (1), Turkey (2), UK (1), USA (2). The trials were at a moderate risk of bias overall.CSE versus high-dose spinal anaesthesiaThere may be little or no difference between the CSE and high-dose spinal groups for the number of women requiring a repeat regional block or general anaesthetic as a result of failure to establish adequate initial blockade (risk ratio (RR) 0.32, 95% confidence interval (CI) 0.05 to 1.97; 7 studies, 341 women; low-quality evidence). We are uncertain whether having CSE or spinal makes any difference in the number of women requiring supplemental intra-operative analgesia at any time after CSE or spinal anaesthetic insertion (average RR 1.25, 95% CI 0.19 to 8.43; 7 studies, 390 women; very low-quality evidence), or the number of women requiring intra-operative conversion to general anaesthesia (RR 1.00, 95% CI 0.07 to 14.95; 7 studies, 388 women; very low-quality evidence). We are also uncertain about the results for the number of women who were satisfied with anaesthesia, regardless of whether they received CSE or high-dose spinal (RR 0.93 95% CI 0.73 to 1.19; 2 studies, 72 women; very low-quality evidence). More women in the CSE group (13/21) experienced intra-operative nausea or vomiting requiring treatment than in the high-dose spinal group (6/21). There were 11 cases of post-dural puncture headache (5/56 with CSE versus 6/57 with SSS; 3 trials, 113 women) with no clear difference between groups. There was also no clear difference in intra-operative hypotension requiring treatment (46/86 with CSE versus 41/76 with SSS; 4 trials, 162 women). There were no babies with Apgar score less than seven at five minutes (4 trials, 182 babies).CSE versus low-dose spinal anaesthesiaThere may be little or no difference between the CSE and low-dose spinal groups for the number of women requiring a repeat regional block or general anaesthetic as a result of failure to establish adequate initial blockade (RR 4.81, 95% CI 0.24 to 97.90; 3 studies, 224 women; low-quality evidence). Similarly, there is probably little difference in the number of women requiring supplemental intra-operative analgesia at any time after CSE or low-dose spinal anaesthetic insertion (RR 1.75, 95% CI 0.78 to 3.92; 4 studies, 298 women; moderate-quality evidence). We are uncertain about the effect of CSE or low-dose spinal on the need for intra-operative conversion to general anaesthesia, because this was not required by any of the 222 women in the three trials (low-quality evidence). None of the studies examined whether women were satisfied with their anaesthesia.The mean time to effective anaesthesia was faster in women who received low-dose spinal compared to CSE, although it is unlikely that the magnitude of this difference is clinically meaningful (standardised mean difference (SMD) 0.85 minutes, 95% CI 0.52 to 1.18 minutes; 2 studies, 160 women).CSE appeared to reduce the incidence of intra-operative hypotension requiring treatment compared with low-dose spinal (average RR 0.59, 95% CI 0.38 to 0.93; 4 studies, 336 women). Similar numbers of women between the CSE and low-dose spinal groups experienced intra-operative nausea or vomiting requiring treatment (3/50 with CSE versus 6/50 with SSS; 1 study, 100 women), and there were no cases of post-dural puncture headache (1 study, 138 women). No infants in either group had an Apgar score of less than seven at five minutes (1 study; 60 babies). AUTHORS' CONCLUSIONS: In this review, the number of studies and participants for most of our analyses were small and some of the included trials had design limitations. There was some suggestion that, compared to spinal anaesthesia, CSE could be associated with a reduction in the number of women with intra-operative hypotension, but an increase in intra-operative nausea and vomiting requiring treatment. One small study found that low-dose spinal resulted in a faster time to effective anaesthesia compared to CSE. However, these results are based on limited data and the difference is unlikely to be clinically meaningful. Consequently, there is currently insufficient evidence in support of one technique over the other and more evidence is needed in order to further evaluate the relative effectiveness and safety of CSE and spinal anaesthesia for caesarean section.More high-quality, sufficiently-powered studies in this area are needed. Such studies could consider using the outcomes listed in this review and should also consider reporting economic aspects of the different methods under investigation.

4.
Sci Rep ; 9(1): 15247, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31649289

RESUMO

Noninvasive transcranial electric stimulation is increasingly being used as an advantageous therapy alternative that may activate deep tissues while avoiding drug side-effects. However, not only is there limited evidence for activation of deep tissues by transcranial electric stimulation, its evoked human sensation is understudied and often dismissed as a placebo or secondary effect. By systematically characterizing the human sensation evoked by transcranial alternating-current stimulation, we observed not only stimulus frequency and electrode position dependencies specific for auditory and visual sensation but also a broader presence of somatic sensation ranging from touch and vibration to pain and pressure. We found generally monotonic input-output functions at suprathreshold levels, and often multiple types of sensation occurring simultaneously in response to the same electric stimulation. We further used a recording circuit embedded in a cochlear implant to directly and objectively measure the amount of transcranial electric stimulation reaching the auditory nerve, a deep intercranial target located in the densest bone of the skull. We found an optimal configuration using an ear canal electrode and low-frequency (<300 Hz) sinusoids that delivered maximally ~1% of the transcranial current to the auditory nerve, which was sufficient to produce sound sensation even in deafened ears. Our results suggest that frequency resonance due to neuronal intrinsic electric properties need to be explored for targeted deep brain stimulation and novel brain-computer interfaces.

5.
Allergy ; 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31506971

RESUMO

BACKGROUND: Whether the clinical or pathophysiologic significance of the "treatable trait" high blood eosinophil count in COPD is the same as for asthma remains controversial. We sought to determine the relationship between the blood eosinophil count, clinical characteristics and gene expression from bronchial brushings in COPD and asthma. METHODS: Subjects were recruited into a COPD (emphysema versus airway disease [EvA]) or asthma cohort (Unbiased BIOmarkers in PREDiction of respiratory disease outcomes, U-BIOPRED). We determined gene expression using RNAseq in EvA (n = 283) and Affymetrix microarrays in U-BIOPRED (n = 85). We ran linear regression analysis of the bronchial brushings transcriptional signal versus blood eosinophil counts as well as differential expression using a blood eosinophil > 200 cells/µL as a cut-off. The false discovery rate was controlled at 1% (with continuous values) and 5% (with dichotomized values). RESULTS: There were no differences in age, gender, lung function, exercise capacity and quantitative computed tomography between eosinophilic versus noneosinophilic COPD cases. Total serum IgE was increased in eosinophilic asthma and COPD. In EvA, there were 12 genes with a statistically significant positive association with the linear blood eosinophil count, whereas in U-BIOPRED, 1197 genes showed significant associations (266 positive and 931 negative). The transcriptome showed little overlap between genes and pathways associated with blood eosinophil counts in asthma versus COPD. Only CST1 was common to eosinophilic asthma and COPD and was replicated in independent cohorts. CONCLUSION: Despite shared "treatable traits" between asthma and COPD, the molecular mechanisms underlying these clinical entities are predominately different.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31343485

RESUMO

Ectopic adrenocorticotropic hormone syndrome is a paraneoplastic phenomenon rarely seen in pediatrics and rarely described in Ewing sarcoma. We report a 15-year-old boy with abdominal Ewing sarcoma and clinical and laboratory findings of ectopic adrenocorticotropic hormone syndrome that promptly resolved with treatment of the tumor.

7.
Int J Chron Obstruct Pulmon Dis ; 14: 1177-1185, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31239655

RESUMO

We hypothesized whether the reduction in eosinophilic airway inflammation in patients with chronic obstructive pulmonary disease (COPD) following treatment with benralizumab, a humanized, afucosylated, monoclonal antibody that binds to interleukin-5 receptor α, increases the airway bacterial load. Analysis of sputum samples of COPD patients participating in a Phase II trial of benralizumab indicated that sputum 16S rDNA load and Streptococcus pneumoniae were reduced following treatment with benralizumab. However, in vitro, eosinophils did not affect the killing of the common airway pathogens S. pneumoniae or Haemophilus influenzae. Thus, benralizumab may have an indirect effect upon airway bacterial load.

8.
Am J Respir Crit Care Med ; 200(8): 982-991, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31106566

RESUMO

Rationale: Asthma is characterized by disease within the small airways. Several studies have suggested that forced oscillation technique-derived resistance at 5 Hz (R5) - resistance at 20 Hz (R20) is a measure of small airway disease; however, there has been limited validation of this measurement to date.Objectives: To validate the use of forced oscillation R5 - R20 as a measure of small airway narrowing in asthma, and to investigate the role that small airway narrowing plays in asthma.Methods: Patient-based complete conducting airway models were generated from computed tomography scans to simulate the impact of different degrees of airway narrowing at different levels of the airway tree on forced oscillation R5 - R20 (n = 31). The computational models were coupled with regression models in an asthmatic cohort (n = 177) to simulate the impact of small airway narrowing on asthma control and quality of life. The computational models were used to predict the impact on small airway narrowing of type-2 targeting biologics using pooled data from two similarly design randomized, placebo-controlled biologic trials (n = 137).Measurements and Main Results: Simulations demonstrated that narrowing of the small airways had a greater impact on R5 - R20 than narrowing of the larger airways and was associated (above a threshold of approximately 40% narrowing) with marked deterioration in both asthma control and asthma quality of life, above the minimal clinical important difference. The observed treatment effect on R5 - R20 in the pooled trials equated to a predicted small airway narrowing reversal of approximately 40%.Conclusions: We have demonstrated, using computational modeling, that forced oscillation R5 - R20 is a direct measure of anatomical narrowing in the small airways and that small airway narrowing has a marked impact on both asthma control and quality of life and may be modified by biologics.

9.
BMJ Open ; 9(3): e025486, 2019 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-30852546

RESUMO

INTRODUCTION: Patients presenting with acute undifferentiated breathlessness are commonly encountered in admissions units across the UK. Existing blood biomarkers have clinical utility in distinguishing patients with single organ pathologies but have poor discriminatory power in multifactorial presentations. Evaluation of volatile organic compounds (VOCs) in exhaled breath offers the potential to develop biomarkers of disease states that underpin acute cardiorespiratory breathlessness, owing to their proximity to the cardiorespiratory system. To date, there has been no systematic evaluation of VOC in acute cardiorespiratory breathlessness. The proposed study will seek to use both offline and online VOC technologies to evaluate the predictive value of VOC in identifying common conditions that present with acute cardiorespiratory breathlessness. METHODS AND ANALYSIS: A prospective real-world observational study carried out across three acute admissions units within Leicestershire. Participants with self-reported acute breathlessness, with a confirmed primary diagnosis of either acute heart failure, community-acquired pneumonia and acute exacerbation of asthma or chronic obstructive pulmonary disease will be recruited within 24 hours of admission. Additionally, school-age children admitted with severe asthma will be evaluated. All participants will undergo breath sampling on admission and on recovery following discharge. A range of online technologies including: proton transfer reaction mass spectrometry, gas chromatography ion mobility spectrometry, atmospheric pressure chemical ionisation-mass spectrometry and offline technologies including gas chromatography mass spectroscopy and comprehensive two-dimensional gas chromatography-mass spectrometry will be used for VOC discovery and replication. For offline technologies, a standardised CE-marked breath sampling device (ReCIVA) will be used. All recruited participants will be characterised using existing blood biomarkers including C reactive protein, brain-derived natriuretic peptide, troponin-I and blood eosinophil levels and further evaluated using a range of standardised questionnaires, lung function testing, sputum cell counts and other diagnostic tests pertinent to acute disease. ETHICS AND DISSEMINATION: The National Research Ethics Service Committee East Midlands has approved the study protocol (REC number: 16/LO/1747). Integrated Research Approval System (IRAS) 198921. Findings will be presented at academic conferences and published in peer-reviewed scientific journals. Dissemination will be facilitated via a partnership with the East Midlands Academic Health Sciences Network and via interaction with all UK-funded Medical Research Council and Engineering and Physical Sciences Research Council molecular pathology nodes. TRIAL REGISTRATION NUMBER: NCT03672994.

10.
Sci Rep ; 9(1): 2130, 2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30765757

RESUMO

The use of commercialised forced oscillation (FOT) devices to assess impedance in obstructive diseases such as asthma has gained popularity. However, it has yet to be fully established whether resistance and reactance measurements are comparable across different FOT devices, particularly in disease. We compared two commercially available FOT devices: Impulse Oscillometry (IOS) and TremoFlo FOT (Thorasys) in a) clinical adult population of healthy controls (n = 14), asymptomatic smokers (n = 17) and individuals with asthma (n = 73) and b) a 3D printed CT-derived airway tree model resistance, as well as a 3 L standardised volume reactance. Bland-Altman Plots and linear regressions were used to evaluate bias between the devices. Resistance measurements at both 5 and 20 Hz were numerically higher with IOS compared to FOT, with evidence of small and statistically significant proportional systematic bias and a positive Bland-Altman regression slope at both 5 and 20 Hz. In contrast, the IOS device recorded reactances that were less negative at both 5 Hz and 20 Hz and significantly smaller reactance areas when compared to TremoFlo. Larger statistically significant proportional systematic biases were demonstrated with both reactance at 5 Hz and reactance area (AX) between the devices with a negative Bland-Altman regression slope. The printed airway resistance and standardised volume reactance confirmed the observations seen in patients. We have demonstrated that the impulse oscillation system and TremoFlo FOT demonstrate comparative bias, particularly when comparing airway reactance in patients. Our results highlight the need for further standardisation across FOT measurement devices, specifically using variable test loads for reactance standardisation.

11.
Trends Hear ; 23: 2331216518821449, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30803416

RESUMO

Noninvasive transcranial or minimally invasive transtympanic electric stimulation may offer a desirable treatment option for tinnitus because it can activate the deafferented auditory nerve fibers while posing little to no risk to hearing. Here, we built a flexible research interface to generate and control accurately charge-balanced current stimulation as well as a head-mounted instrument capable of holding a transtympanic electrode steady for hours. We then investigated the short-term effect of a limited set of electric stimulation parameters on tinnitus in 10 adults with chronic tinnitus. The preliminary results showed that 63% of conditions of electric stimulation produced some degree of tinnitus reduction, with total disappearance of tinnitus in six subjects in response to at least one condition. The present study also found significant side effects such as visual, tactile, and even pain sensations during electric stimulation. In addition to masking and residual inhibition, neuroplasticity is likely involved in the observed tinnitus reduction. To translate the present electric stimulation into a safe and effective tinnitus treatment option, we need to optimize stimulation parameters that activate the deafferented auditory nerve fibers and reliably suppress tinnitus, with minimal side effects and tolerable sensations. Noninvasive or minimally invasive electric stimulation can be integrated with sound therapy, invasive cochlear implants, or other forms of coordinated stimulation to provide a systematic strategy for tinnitus treatment or even a cure.


Assuntos
Implantes Cocleares , Terapia por Estimulação Elétrica/métodos , Zumbido/terapia , Idoso , Estudos de Viabilidade , Feminino , Audição/fisiologia , Testes Auditivos , Humanos , Masculino , Pessoa de Meia-Idade , Projetos de Pesquisa , Resultado do Tratamento
12.
J Allergy Clin Immunol ; 144(1): 83-93, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30682455

RESUMO

BACKGROUND: Asthma is a disease characterized by ventilation heterogeneity (VH). A number of studies have demonstrated that VH markers derived by using impulse oscillometry (IOS) or multiple-breath washout (MBW) are associated with key asthmatic patient-related outcome measures and airways hyperresponsiveness. However, the topographical mechanisms of VH in the lung remain poorly understood. OBJECTIVES: We hypothesized that specific regionalization of topographical small-airway disease would best account for IOS- and MBW-measured indices in patients. METHODS: We evaluated the results of paired expiratory/inspiratory computed tomography in a cohort of asthmatic (n = 41) and healthy (n = 11) volunteers to understand the determinants of clinical VH indices commonly reported by using IOS and MBW. Parametric response mapping (PRM) was used to calculate the functional small-airways disease marker PRMfSAD and Hounsfield unit (HU)-based density changes from total lung capacity to functional residual capacity (ΔHU); gradients of ΔHU in gravitationally perpendicular (parallel) inferior-superior (anterior-posterior) axes were quantified. RESULTS: The ΔHU gradient in the inferior-superior axis provided the highest level of discrimination of both acinar VH (measured by using phase 3 slope analysis of multiple-breath washout data) and resistance at 5 Hz minus resistance at 20 Hz measured by using impulse oscillometry (R5-R20) values. Patients with a high inferior-superior ΔHU gradient demonstrated evidence of reduced specific ventilation in the lower lobes of the lungs and high levels of PRMfSAD. A computational small-airway tree model confirmed that constriction of gravitationally dependent, lower-zone, small-airway branches would promote the largest increases in R5-R20 values. Ventilation gradients correlated with asthma control and quality of life but not with exacerbation frequency. CONCLUSIONS: Lower lobe-predominant small-airways disease is a major driver of clinically measured VH in adults with asthma.

13.
Behav Cogn Psychother ; 47(4): 421-430, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30654853

RESUMO

BACKGROUND: There is an emerging evidence base that mindfulness for psychosis is a safe and effective intervention. However, empirical data on the within-session effects of mindfulness meditation was hitherto lacking. AIMS: The aim of the study was to assess the impact of taking part in a mindfulness for psychosis group, using a within-session self-report measure of general stress, and symptom-related distress. METHOD: Users of a secondary mental health service (n = 34), who experienced enduring psychotic symptoms, took part in an 8-week mindfulness for psychosis group in a community setting. Mindfulness meditations were limited to 10 minutes and included explicit reference to psychotic experience arising during the practice. Participants self-rated general stress, and symptom-related distress, before and after each group session using a visual analogue scale. RESULTS: Average ratings of general stress and symptom-related distress decreased from pre- to post-session for all eight sessions, although not all differences were statistically significant. There was no increase in general stress, or symptom-related distress across any session. CONCLUSIONS: There was evidence of positive effects and no evidence of any harmful effects arising from people with psychotic symptoms taking part in a mindfulness for psychosis session.


Assuntos
Atenção Plena , Transtornos Psicóticos/psicologia , Transtornos Psicóticos/terapia , Estresse Psicológico/complicações , Estresse Psicológico/terapia , Adulto , Idoso , Feminino , Humanos , Masculino , Meditação/psicologia , Serviços de Saúde Mental , Pessoa de Meia-Idade , Transtornos Psicóticos/complicações , Autorrelato , Estresse Psicológico/psicologia
14.
Thorax ; 74(7): 705-706, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30630892

RESUMO

Asthma exacerbations are a common reason for hospital admission. We sought to identify whether patterns of inhaler prescribing are significantly associated with regional asthma admission rates. Asthma admission rates were obtained for English Clinical Commissioning Group (CCG) regions from 2013/2014 to 2016/2017. Raw prescribing data were obtained from OpenPrescribing.net, based on monthly general practice-level data published by the National Health Service Business Services Authority. Data were analysed using a linear mixed effects model. The ratio of salbutamol to inhaled corticosteroid prescriptions within a CCG was positively associated with asthma admission rates, independently of median age, asthma prevalence and socioeconomic deprivation.

15.
NPJ Prim Care Respir Med ; 28(1): 39, 2018 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-30356047

RESUMO

The Royal College of Physicians three questions (RCP3Q) is widely used for assessing asthma control within primary care in the UK, despite limited evidence in children. This study compared the RCP3Q as a tool for assessing asthma control in children (5-16 years) against the validated Asthma Control Test (ACT), Childhood Asthma Control Test (C-ACT), and Mini-Paediatric Quality of Life Questionnaire (MiniPAQLQ). We conducted a prospective observational cohort study involving children from eight primary care practices in Leicestershire. Children with doctor diagnosed asthma, or receiving regular asthma medication, were invited to participate. A total of 319 participants completed the MiniPAQLQ and the C-ACT/ACT questionnaires, before RCP3Q responses were collected as part of their routine asthma review conducted immediately afterwards. RCP3Q sensitivity for detecting uncontrolled asthma ranged from 43-60% and specificity from 80-82%. Using an RCP3Q score ≥2 to predict uncontrolled asthma and an RCP3Q score of zero to predict well-controlled asthma resulted in 10% of participants misclassified as uncontrolled and 8% as well-controlled, respectively. Using an RCP3Q threshold score of ≥1 resulted in 25% of participants being misclassified as uncontrolled. Our data suggests limited utility of the RCP3Q to assess asthma control in children. Alternative indicators of asthma control, such as the validated Asthma Control Test and the Children's Asthma Control Test should be considered instead.

16.
Hum Mutat ; 39(11): 1553-1568, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30311375

RESUMO

The variant curation guidelines published in 2015 by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) provided the genetics community with a framework to assess variant pathogenicity; however, these rules are not gene specific. Germline pathogenic variants in the CDH1 gene cause hereditary diffuse gastric cancer and lobular breast cancer, a clinically challenging cancer predisposition syndrome that often requires a multidisciplinary team of experts to be properly managed. Given this challenge, the Clinical Genome Resource (ClinGen) Hereditary Cancer Domain prioritized the development of the CDH1 variant curation expert panel (VCEP) to develop and implement rules for CDH1 variant classifications. Here, we describe the CDH1 specifications of the ACMG/AMP guidelines, which were developed and validated after a systematic evaluation of variants obtained from a cohort of clinical laboratory data encompassing ∼827,000 CDH1 sequenced alleles. Comparing previously reported germline variants that were classified using the 2015 ACMG/AMP guidelines to the CDH1 VCEP recommendations resulted in reduced variants of uncertain significance and facilitated resolution of variants with conflicted assertions in ClinVar. The ClinGen CDH1 VCEP recommends the use of these CDH1-specific guidelines for the assessment and classification of variants identified in this clinically actionable gene.

17.
J Breath Res ; 12(4): 046012, 2018 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-30102246

RESUMO

RATIONALE: Asthma is often characterised by inflammation, damage and dysfunction of the small airways, but no standardised biomarkers are available. OBJECTIVES: Using a novel approach-particles in exhaled air (PExA)-we sought to (a) sample and analyse abundant protein biomarkers: surfactant protein A (SPA) and albumin in adult asthmatic and healthy patients and (b) relate protein concentrations with physiological markers using phenotyping. METHODS: 83 adult asthmatics and 21 healthy volunteers were recruited from a discovery cohort in Leicester, UK, and 32 adult asthmatics as replication cohort from Sweden. Markers of airways closure/small airways dysfunction were evaluated using forced vital capacity, impulse oscillometry and multiple breath washout. SPA/albumin from PEx (PExA sample) were analysed using ELISA and corrected for acquired particle mass. Topological data analysis (TDA) was applied to small airway physiology and PExA protein data to identify phenotypes. RESULTS: PExA manoeuvres were feasible, including severe asthmatic subjects. TDA identified a clinically important phenotype of asthmatic patients with multiple physiological markers of peripheral airway dysfunction, and significantly lower levels of both SPA and albumin. CONCLUSION: We report that the PExA method is feasible across the spectrum of asthma severity and could be used to identify small airway disease phenotypes.

18.
Trials ; 19(1): 436, 2018 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-30103785

RESUMO

BACKGROUND: Bipolar disorder is a chronic and disabling psychiatric condition, characterised by recurrent episodes of mania, hypomania and depression. It places a heavy burden on sufferers and families, with high societal and healthcare costs. Many service users with a diagnosis of bipolar disorder also experience prominent psychotic symptoms, with differential diagnoses of schizoaffective disorder, and relapses characterised by repeated manic psychotic episodes and grandiosity. Such presentations require specific adaptations to standard bipolar disorder interventions in order to address their psychosis, alongside mood regulation, with a particular emphasis on impulsivity, irritability, disinhibition and elation. The Balancing ACT study aims to evaluate an innovative group intervention combining Acceptance and Commitment Therapy and psychoeducation approaches (ACT/PE) with individuals experiencing bipolar disorder and/or symptoms within community psychosis services. METHODS: The Balancing ACT study is a randomised controlled trial comparing Balancing ACT groups (ACT/PE) plus routine care to routine care alone. Balancing ACT (ACT/PE) comprises ten group sessions, each lasting 2 hours, delivered weekly. The primary outcome is psychological wellbeing; secondary outcomes are mental health relapses (measured by service use averages for the 12 months pre baseline and 3 months post baseline). We will also measure mood, distress, recovery and psychological change processes. Participants will be randomised in a 1:1 ratio, after baseline assessment. Outcomes will be assessed by trained assessors blind to treatment condition at 0, 10 and 14 weeks. Recruitment began in April 2017 and is on-going until the end of October 2017. DISCUSSION: The Balancing ACT study will contribute to the currently limited evidence base for psychological interventions for people experiencing bipolar disorder and/or symptoms in the context of community psychosis services. TRIAL REGISTRATION: ISRCTN73327972 . Registered on 27 March 2017. Balancing ACT: evaluating the effectiveness of psychoeducation and Acceptance and Commitment Therapy (ACT) groups for people with bipolar disorder.

19.
Nat Commun ; 9(1): 2308, 2018 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-29921861

RESUMO

Whole blood transcriptional signatures distinguishing active tuberculosis patients from asymptomatic latently infected individuals exist. Consensus has not been achieved regarding the optimal reduced gene sets as diagnostic biomarkers that also achieve discrimination from other diseases. Here we show a blood transcriptional signature of active tuberculosis using RNA-Seq, confirming microarray results, that discriminates active tuberculosis from latently infected and healthy individuals, validating this signature in an independent cohort. Using an advanced modular approach, we utilise the information from the entire transcriptome, which includes overabundance of type I interferon-inducible genes and underabundance of IFNG and TBX21, to develop a signature that discriminates active tuberculosis patients from latently infected individuals or those with acute viral and bacterial infections. We suggest that methods targeting gene selection across multiple discriminant modules can improve the development of diagnostic biomarkers with improved performance. Finally, utilising the modular approach, we demonstrate dynamic heterogeneity in a longitudinal study of recent tuberculosis contacts.

20.
BMC Cancer ; 18(1): 588, 2018 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-29793444

RESUMO

BACKGROUND: High Dose Rate Brachytherapy (HDRB) boost is a well-established treatment for prostate cancer (PC). We describe the PROstate Multicentre External beam radioTHErapy Using Stereotactic boost (PROMETHEUS) study. Non-surgical stereotactic techniques are used to deliver similar doses to HDRB boost regimens with a dose escalation sub-study. METHODS: Eligible patients have intermediate or high risk PC. PROMETHEUS explores the safety, efficacy and feasibility of multiple Australian centres cooperating in the delivery of Prostate Stereotactic Body Radiotherapy (SBRT) technology. A SBRT boost component Target Dose (TD) of 19Gy in two fractions is to be delivered, followed by a subsequent EBRT component of 46Gy in 23 fractions. Once accrual triggers have been met, SBRT doses can be escalated in 1 Gy increments to a maximum of 22Gy in two fractions. Patient safety will also be measured with the rate of both acute and late moderate to severe Gastro-Intestinal (GI) and Genito-Urinary (GU) Common Terminology Criteria for Adverse Events (CTCAE) toxicities as well as patient reported quality of life. Efficacy will be assessed via biochemical control after 3 years. DISCUSSION: PROMETHEUS aims to generate evidence for a non-surgical possible future alternative to HDRB boost regimens, and introduce advanced radiotherapy techniques across multiple Australian cancer centres. TRIAL REGISTRATION: The study was retrospectively registered on the ANZCTR (Australian New Zealand Clinical Trials Registry) with trial ID: ACTRN12615000223538 .

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