This seminar discusses the history and development of techniques for surgical intervention for people with refractory focal epilepsy. Published surgical success rates and prognostic factors ...associated with post‐operative seizure freedom from individual studies have been variable and contradictory. We present here the key findings of a Cochrane systematic review of all evidence published since the introduction of magnetic resonance imaging (MRI) to pre‐operative surgical assessment in 1984. Our findings show the usefulness of uncontrolled case series is now past. Future studies with a prospective controlled design should focus on specific research questions to help improve results and provide better‐informed advice.
Breast cancer brain metastases (BrMs) are defined by complex adaptations to both adjuvant treatment regimens and the brain microenvironment. Consequences of these alterations remain poorly ...understood, as does their potential for clinical targeting. We utilized genome-wide molecular profiling to identify therapeutic targets acquired in metastatic disease.
Gene expression profiling of 21 patient-matched primary breast tumors and their associated brain metastases was performed by TrueSeq RNA-sequencing to determine clinically actionable BrM target genes. Identified targets were functionally validated using small molecule inhibitors in a cohort of resected BrM ex vivo explants (n = 4) and in a patient-derived xenograft (PDX) model of BrM. All statistical tests were two-sided.
Considerable shifts in breast cancer cell-specific gene expression profiles were observed (1314 genes upregulated in BrM; 1702 genes downregulated in BrM; DESeq; fold change > 1.5, Padj < .05). Subsequent bioinformatic analysis for readily druggable targets revealed recurrent gains in RET expression and human epidermal growth factor receptor 2 (HER2) signaling. Small molecule inhibition of RET and HER2 in ex vivo patient BrM models (n = 4) resulted in statistically significantly reduced proliferation (P < .001 in four of four models). Furthermore, RET and HER2 inhibition in a PDX model of BrM led to a statistically significant antitumor response vs control (n = 4, % tumor growth inhibition mean difference; SD, anti-RET = 86.3% 1176; 258.3, P < .001; anti-HER2 = 91.2% 1114; 257.9, P < .01).
RNA-seq profiling of longitudinally collected specimens uncovered recurrent gene expression acquisitions in metastatic tumors, distinct from matched primary tumors. Critically, we identify aberrations in key oncogenic pathways and provide functional evidence for their suitability as therapeutic targets. Altogether, this study establishes recurrent, acquired vulnerabilities in BrM that warrant immediate clinical investigation and suggests paired specimen expression profiling as a compelling and underutilized strategy to identify targetable dependencies in advanced cancers.
Nursing in an age of multimorbidity O'Connor, Siobhan; Deaton, Christi; Nolan, Fiona ...
BMC nursing,
11/2018, Volume:
17, Issue:
1
Journal Article
Peer reviewed
Open access
A changing sociodemographic landscape has seen rising numbers of people with two or more long-term health conditions. Multimorbidity presents numerous challenges for patients and families and those ...who work in healthcare services. Therefore, the nursing profession needs to understand the issues involved in supporting people with multiple chronic conditions and how to prepare the future workforce to care for them.
A descriptive, exploratory study was used to examine the future of nursing in an age of multimorbidity. An hour-long Twitter chat was organised and run by the Florence Nightingale Foundation Chairs of Clinical Nursing Practice Research to discuss this important area of practice and identify what needs to be done to adequately upskill and prepare the nursing profession to care for individuals with more than one long-term illness. Questions were formulated in advance to provide some structure to the online discussion. Data were collected and analysed from the social media platform using NVivo and an analytics tool called Keyhole. Descriptive statistics were used to describe participants and thematic analysis aided the identification of key themes.
Twenty-four people, from a range of nursing backgrounds and organisations, took part in the social media discussion. Five themes encompassing coping with treatment burden, delivering holistic care, developing an evidence base, stimulating learning and redesigning health services were seen as key to ensuring nurses could care for people with multimorbidity and prevent others from developing chronic health conditions.
Multimorbidity is a pressing health issue in today's society. Changes in nursing research, education and practice are required to help the profession work collaboratively with patients, families and multidisciplinary teams to better manage and prevent chronic illness now and in the future.
No uniformly beneficial treatments exist for dogs with non‐lymphomatous nasal tumours (NLNT) that relapse after radiotherapy (RT). Reirradiation may prolong survival and improve quality of life. In ...this retrospective study, we describe outcomes for 11 dogs that had CT‐confirmed locoregional progression of NLNT after an initial course of stereotactic RT (SRT#1; 10 Gy × 3) and were then re‐treated with the same type of protocol (SRT#2, also 10 Gy × 3). The median time between SRT #1 and SRT #2 was 243 days (95% CI: 78–385 days). Ten dogs (91%) had a clinical benefit after SRT#1; five dogs (45%) had clinical benefit after SRT#2. Adverse events after SRT#2 included nasocutaneous or oronasal fistula formation (N = 3 at 180, 270, and 468 days), seizures (N = 2 at 78 and 330 days), bacterial or fungal rhinitis (N = 2 at 240 and 385 days), and facial swelling (N = 1 at 90 days). All 11 dogs have died, due to disease progression, presumed radiotoxicity, or declining quality of life; in most cases, it was difficult to discern between these conditions. The median overall survival time (OST) from SRT#1 was 745 days (95% CI: 360–1132). The median overall survival time (OST) from SRT #2 was 448 days (95% CI: 112–626). For these dogs, survival was prolonged, but adverse events after SRT#2 were common (8/11; 73%). Therefore, before consenting to re‐irradiation with this protocol, pet owners should be counselled about survivorship challenges, including risk for severe toxicities, and persistence of clinical signs.
Background
Little is known regarding the comparative efficacy of various irradiation strategies used to treat intranasal carcinomas (INC) in cats.
Objectives
Investigate outcomes and prognostic ...factors associated with survival for cats with INC.
Animals
Forty‐two cats with INC that underwent radiotherapy (RT).
Methods
Single‐arm retrospective study. Medical record review for cats with INC that underwent RT at 1 of 7 veterinary RT facilities. Irradiation protocols categorized as: definitive‐intent fractionated RT (FRT), definitive‐intent stereotactic RT (SRT), and palliative‐intent RT (PRT). Median overall survival time (OST) and disease progression‐free survival (PFS; documented by advanced transverse imaging, or recurrence of symptoms) were calculated. Associations between tumor stage, RT protocol/intent, and adjunctive treatment usage and outcome were calculated.
Results
Cats underwent SRT (N = 18), FRT (N = 8), and PRT (N = 16). In multivariate modeling, cats received definitive‐intent treatment (DRT; FRT/SRT) had significantly longer median PFS (504 days, 95% confidence interval (CI): 428–580 days vs PRT 198 days 95% CI: 62–334 days; p = 0.006) and median OST 721 days (95% CI: 527–915 days) vs 284 days (95% CI: 0–570 days); p = 0.001). Cats that underwent second DRT course at time of recurrence lived significantly longer than cats that received 1 RT course (either DRT or PRT median OST 824 days (95% CI: 237–1410 days) vs 434 days (95% CI: 277–591 days); p = .028).
Conclusion
In cats with INC, DRT is associated with prolonged OST and PFS as compared to PRT. If tumor progression occurs, a second course of DRT should be considered.
Steroid regulated cancer cells use nuclear receptors and associated regulatory proteins to orchestrate transcriptional networks to drive disease progression. In primary breast cancer, the coactivator ...AIB1 promotes estrogen receptor (ER) transcriptional activity to enhance cell proliferation. The function of the coactivator in ER
metastasis however is not established. Here we describe AIB1 as a survival factor, regulator of pro-metastatic transcriptional pathways and a promising actionable target. Genomic alterations and functional expression of AIB1 associated with reduced disease-free survival in patients and enhanced metastatic capacity in novel CDX and PDX ex-vivo models of ER
metastatic disease. Comparative analysis of the AIB1 interactome with complementary RNAseq characterized AIB1 as a transcriptional repressor. Specifically, we report that AIB1 interacts with MTA2 to form a repressive complex, inhibiting CDH1 (encoding E-cadherin) to promote EMT and drive progression. We further report that pharmacological and genetic inhibition of AIB1 demonstrates significant anti-proliferative activity in patient-derived models establishing AIB1 as a viable strategy to target endocrine resistant metastasis. This work defines a novel role for AIB1 in the regulation of EMT through transcriptional repression in advanced cancer cells with a considerable implication for prognosis and therapeutic interventions.
Viruses are increasingly recognised as important components of the human microbiome, fulfilling numerous ecological roles including bacterial predation, immune stimulation, genetic diversification, ...horizontal gene transfer, microbial interactions, and augmentation of metabolic functions. However, our current view of the human gut virome is tainted by previous sequencing requirements that necessitated the amplification of starting nucleic acids. In this study, we performed an original longitudinal analysis of 40 healthy control, 19 Crohn's disease, and 20 ulcerative colitis viromes over three time points without an amplification bias, which revealed and highlighted the interpersonal individuality of the human gut virome. In contrast to a 16 S rRNA gene analysis of matched samples, we show that α- and β-diversity metrics of unamplified viromes are not as efficient at discerning controls from patients with inflammatory bowel disease. Additionally, we explored the intrinsic properties of unamplified gut viromes and show there is considerable interpersonal variability in viral taxa, infrequent longitudinal persistence of intrapersonal viruses, and vast fluctuations in the abundance of temporal viruses. Together, these properties of unamplified faecal viromes confound the ability to discern disease associations but significantly advance toward an unbiased and accurate representation of the human gut virome.
The purpose of this bi‐institutional retrospective study was to determine whether survival for dogs with extremity osteosarcoma (OS) is improved through the use of stereotactic radiotherapy (SRT; a ...single fraction of 25 Gy, or 36 Gy total given in three consecutive daily fractions) plus chemotherapy, vs lower dose conventionally planned and delivered hypofractionated radiotherapy (CHRT; 14‐20 Gy total in 1‐2 consecutive daily fractions) plus chemotherapy. We also sought to determine whether baseline pain severity influences oncologic outcomes following radiotherapy for canine extremity OS. The medical records of 82 dogs undergoing radiotherapy for confirmed or presumed OS were reviewed. In dogs receiving combinations of both chemotherapy and radiotherapy, survival was significantly longer with SRT vs CHRT (median overall survival time: 350 vs 147 days; P = .031). In a univariate analysis, dogs with pulmonary metastases and high pain at the time of irradiation had short overall survival times; use of high radiation doses and chemotherapy were associated with improved survival. Separate multivariable models were built to assess the predictive nature of various factors that might influence event‐free or overall survival in dogs treated with radiotherapy, with or without chemotherapy; for dogs treated with both chemotherapy and radiotherapy, overall survival times were significantly longer when baseline pain scores were ‘low’ (vs ‘high’; hazard ratio: 0.258; P = .030), radiation doses were high (hazard ratio: 0.943; P = .034). Neither pain nor radiation dose were associated with survival in dogs treated with radiotherapy, without chemotherapy.
Background
Respiratory syncytial virus (RSV) is the world's leading cause of viral acute lower respiratory infections (ALRI) in infants. WHO has identified maternal RSV vaccination a priority and ...candidate vaccines are in development; however, vaccine hesitancy remains an impediment to successful implementation of maternal immunization. This study, the largest antenatal survey conducted to‐date, aimed to examine maternal RSV awareness, likely acceptance of RSV vaccination in pregnancy, and attitudes to maternal vaccination.
Methods
Pregnant women of all gestations attending antenatal clinic of a university maternity hospital in Ireland were invited to participate. An information leaflet provided, consent obtained, and survey administered examining RSV awareness, willingness to avail of antenatal RSV vaccination, factors influencing acceptability and preferred sources of assistance. Research Ethics Committee (REC) approval obtained, and general data protection regulation (GDPR) guidelines followed.
Results
528 women completed the survey. A large proportion (75.6%) had never heard of RSV, yet 48.5% would still avail of a vaccine, 45.8% were undecided and only 5.3% would not. The main factor making vaccination acceptable to women (76.4%) was that it protects their infant from illness (p < .001, CV 0.336 for association with acceptance) and general practitioner (GP) was the preferred guidance source in decision‐making (57.7%).
Conclusions
Despite low levels of maternal awareness of RSV, pregnant women in Ireland are open to availing of antenatal vaccination. Maternal immunization strategies need to focus on infant's protection from RSV‐associated ALRI along with vaccine safety, and build on an interdisciplinary collaboration of maternal, neonatal, primary care and public health services.
A study of maternal awareness, acceptability and willingness towards antenatal respiratory syncytial virus (RSV) vaccination in Ireland showed low levels of awareness of RSV but an openness to this approach to protect infants. Collaborative working will be required to raise awareness and facilitate maternal vaccine uptake, as part of a life‐course immunization strategy.
Cognitive impairment is prevalent in older ages. Associations with sleep are well established; however, ambiguity remains in which sleep characteristics contribute to this impairment. We examined ...cross-sectional associations between both self-reported and actigraphy-based sleep and cognitive performance across a number of domains in community-dwelling older adults.
1520 participants aged 50 and older with self-reported and actigraphy-based total sleep time (TST) (≤5, 6, 7-8, 9 and ≥10 h) and self-reported sleep problems were analysed. Cognitive function was assessed using the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), verbal fluency, immediate and delayed recall memory, colour trails tests, and choice reaction tests (CRT). Associations between sleep and cognition were modelled using linear and negative binomial regression.
Negative associations were found between ≥10 h of self-reported TST and MoCA error rate (incidence rate ratio IRR = 1.42; 95% confidence interval CI = 1.18, 1.71; p < 0.001); verbal fluency (beta B = -2.32 words; 95% CI = -4.00, -0.65; p < 0.01); and delayed recall (B = -0.91 words; 95% CI = -1.58, -0.25; p < 0.05) compared to 7-8 h. Significant associations with actigraphy-based TST were limited to MoCA error rate in ≤5 h (IRR = 1.22; 95% CI = 1.02, 1.45; p < 0.05) compared to 7-8 h. Higher numbers of sleep problems were associated with slower performance in CRT cognitive response time (IRR = 1.02; 95% CI = 1.00, 104; p < 0.05) and total response time (IRR = 1.02; 95% CI = 1.00, 1.04; p < 0.05).
Self-reported long sleep duration was consistently associated with worse cognitive performance across multiple domains. Marginal associations between cognition and both actigraphy-based sleep and self-reported sleep problems were also apparent. These results further affirm poor sleep as a risk factor for cognitive impairment.
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