The Global Initiative for Chronic Obstructive Lung Disease (GOLD) provides a comprehensive review and guidance for clinicians managing patients with chronic obstructive pulmonary disease (COPD). ...However, adherence to GOLD guidelines has been suboptimal over the years. The current review summarizes the current body of literature addressing the multitude of reasons for the lack of adherence to GOLD guidelines in clinical practice.
There continue to be several reasons for suboptimal adoption of GOLD guidelines in clinical practice. A primary and recurrent theme appears to be both delayed as well as missed diagnosis of COPD. There are several reasons for this including lack of awareness about current COPD guidelines, lack of availability as well as utilization of office spirometry and improper symptom assessment. Other issues include improper selection of proper pharmacotherapy options, misdiagnosis/mislabeling of COPD phenotypes, lack of smoking cessation counselling as well as enrollment in pulmonary rehabilitation. Potential solutions include adoption of clinical decision support systems, self-care models and careful phenotyping of COPD patients.
There are currently several barriers for the adoption of GOLD guidelines into routine clinical practice. These barriers are all amenable to systematic solutions that will increase adherence to current GOLD guidelines.
OBJECTIVE Patients with hereditary hemorrhagic telangiectasia (HHT) are known to suffer from high rates of cerebral arteriovenous malformations (AVMs). The authors performed a systematic review and ...meta-analysis of the literature examining prevalence rates, characteristics, and clinical presentation of cerebral AVMs in the HHT population. METHODS To identify studies on AVM prevalence and characteristics in the HHT population, 4 databases (MEDLINE, EMBASE, Scopus and Web of Science) were searched by a reference librarian with over 30 years experience in systematic reviews and meta-analysis. The search period was January 1, 1990-March 2016. The following search terms were used: hereditary hemorrhagic telangiectasia, Osler-Weber-Rendu syndrome, AVM, brain AVM, arteriovenous malformation, arteriovenous fistula, prevalence, and epidemiology. The authors identified studies that examined the prevalence rates, characteristics, and clinical presentation of cerebral AVMs in patients with HHT. They assessed overall AVM prevalence rates as well as prevalence rates by age, sex, HHT type, and country/region. They also systematically reviewed the characteristics of AVMs, including rupture status, location, clinical presentation, angioarchitecture, and Spetzler-Martin grade. Data were analyzed using a random-effects meta-analysis model. RESULTS Thirty-nine studies were included in this meta-analysis. Thirty studies examined brain AVM prevalence rates in various HHT patient populations, and 18 studies examined AVM clinical and angiographic characteristics (9 studies examined both prevalence rates and AVM characteristics). The prevalence of brain AVMs in HHT patients was 10.4% (95% CI 7.9%-13.0%) with no significant difference between males (8.5%, 95% CI 4.9%-12.0%) and females (11.0%, 95% CI 5.9%-16.1%). Patients with HHT Type 1 (HHT1) had a significantly higher brain AVM prevalence (13.4%, 95% CI 9.5%-17.4%) compared with those with HHT Type 2 (HHT2) (2.4%, 95% CI 1.0%-3.8%) (p < 0.0001). In 55.2% (95% CI 38.3%-72.1%) of cases, the AVMs were symptomatic. Spetzler-Martin grade was 2 or less in 86.9% (95% CI 67.5%-95.2%) of patients. CONCLUSIONS The prevalence of brain AVMs in the HHT population is about 10%. HHT1 patients are significantly more likely to have brain AVMs than HHT2 patients. Most AVMs in the HHT population are symptomatic. The Spetzler-Martin grade for these lesions is 2 or less in nearly 90% of patients.
Ionising radiation (IR) is a recognised carcinogen responsible for cancer development in patients previously treated using radiotherapy, and in individuals exposed as a result of accidents at nuclear ...energy plants. However, the mutational signatures induced by distinct types and doses of radiation are unknown. Here, we analyse the genetic architecture of mammary tumours, lymphomas and sarcomas induced by high (
Fe-ions) or low (gamma) energy radiation in mice carrying Trp53 loss of function alleles. In mammary tumours, high-energy radiation is associated with induction of focal structural variants, leading to genomic instability and Met amplification. Gamma-radiation is linked to large-scale structural variants and a point mutation signature associated with oxidative stress. The genomic architecture of carcinomas, sarcomas and lymphomas arising in the same animals are significantly different. Our study illustrates the complex interactions between radiation quality, germline Trp53 deficiency and tissue/cell of origin in shaping the genomic landscape of IR-induced tumours.
CRISPR-Cas9 technologies have transformed genome-editing of experimental organisms and have immense therapeutic potential. Despite significant advances in our understanding of the CRISPR-Cas9 system, ...concerns remain over the potential for off-target effects. Recent studies have addressed these concerns using whole-genome sequencing (WGS) of gene-edited embryos or animals to search for de novo mutations (DNMs), which may represent candidate changes introduced by poor editing fidelity. Critically, these studies used strain-matched, but not pedigree-matched controls and thus were unable to reliably distinguish generational or colony-related differences from true DNMs. Here we used a trio design and whole genome sequenced 8 parents and 19 embryos, where 10 of the embryos were mutagenised with well-characterised gRNAs targeting the coat colour Tyrosinase (Tyr) locus. Detailed analyses of these whole genome data allowed us to conclude that if CRISPR mutagenesis were causing SNV or indel off-target mutations in treated embryos, then the number of these mutations is not statistically distinguishable from the background rate of DNMs occurring due to other processes.
Hereditary hemorrhagic telangiectasia (HHT, Osler-Weber-Rendu disease) is a rare multisystem vascular disorder causing chronic gastrointestinal bleeding, epistaxis, and severe anemia. Bevacizumab, an ...anti-vascular endothelial growth factor antibody, may be effective to treat bleeding in HHT. This international, multicenter, retrospective study evaluated the use of systemic bevacizumab to treat HHT-associated bleeding and anemia at 12 HHT treatment centers. Hemoglobin, epistaxis severity score, red cell units transfused, and intravenous iron infusions before and after treatment were evaluated using paired means testing and mixed-effects linear models. 238 HHT patients received bevacizumab for a median of 12 (range, 1-96) months. Compared with pretreatment, bevacizumab increased mean hemoglobin by 3.2 g/dL (95% CI, 2.9-3.5 g/dL) mean hemoglobin 8.6 (8.5, 8.8) g/dL versus 11.8 (11.5, 12.1) g/dL, p<0.0001) and decreased the epistaxis severity score (ESS) by 3.4 (3.2-3.7) points mean ESS 6.8 (6.6-7.1) versus 3.4 (3.2-3.7), P<0.0001 during the first year of treatment. Compared with 6 months pretreatment, RBC units transfused decreased by 82% median of 6.0 (IQR 0.0-13.0) units versus 0 (IQR, 0.0-1.0) units, P<0.0001 and iron infusions decreased by 70% median of 6.0 (1.0-18.0) infusions versus 1.0 (0.0-4.0) infusions, P<0.0001 during the first 6 months of bevacizumab treatment. Outcomes were similar regardless of underlying pathogenic mutation. Following initial induction infusions, continuous/scheduled bevacizumab maintenance achieved higher hemoglobin and lower ESS than intermittent/as needed maintenance but with more drug exposure. Bevacizumab was well tolerated: hypertension, fatigue, and proteinuria were the most common adverse events. Venous thromboembolism occurred in 2% of patients. In conclusion, systemic bevacizumab was safe and effective to manage chronic bleeding and anemia in HHT.
Mucosal melanoma is a rare and poorly characterized subtype of human melanoma. Here we perform a cross-species analysis by sequencing tumor-germline pairs from 46 primary human muscosal, 65 primary ...canine oral and 28 primary equine melanoma cases from mucosal sites. Analysis of these data reveals recurrently mutated driver genes shared between species such as NRAS, FAT4, PTPRJ, TP53 and PTEN, and pathogenic germline alleles of BRCA1, BRCA2 and TP53. We identify a UV mutation signature in a small number of samples, including human cases from the lip and nasal mucosa. A cross-species comparative analysis of recurrent copy number alterations identifies several candidate drivers including MDM2, B2M, KNSTRN and BUB1B. Comparison of somatic mutations in recurrences and metastases to those in the primary tumor suggests pervasive intra-tumor heterogeneity. Collectively, these studies suggest a convergence of some genetic changes in mucosal melanomas between species but also distinctly different paths to tumorigenesis.
The rapid development of CRISPR-Cas9 mediated genome editing techniques has given rise to a number of online and stand-alone tools to find and score CRISPR sites for whole genomes. Here we describe ...the Wellcome Trust Sanger Institute Genome Editing database (WGE), which uses novel methods to compute, visualize and select optimal CRISPR sites in a genome browser environment. The WGE database currently stores single and paired CRISPR sites and pre-calculated off-target information for CRISPRs located in the mouse and human exomes. Scoring and display of off-target sites is simple, and intuitive, and filters can be applied to identify high-quality CRISPR sites rapidly. WGE also provides a tool for the design and display of gene targeting vectors in the same genome browser, along with gene models, protein translation and variation tracks. WGE is open, extensible and can be set up to compute and present CRISPR sites for any genome.
The WGE database is freely available at www.sanger.ac.uk/htgt/wge
: vvi@sanger.ac.uk or skarnes@sanger.ac.uk
Supplementary data are available at Bioinformatics online.
Abstract Objective To assess the incidence of new-onset atrial fibrillation (NOAF) in the medical intensive care unit (MICU) setting and describe associated characteristics and implications for long ...term outcomes. Materials and Methods Single-center, retrospective study of patients admitted to a MICU from January 1, 2008 to December 31, 2013. Atrial fibrillation (AF) diagnosis was categorized as NOAF or pre-existing (PEAF). ICU characteristics along with in-hospital and long term outcomes were compared. Results 10 836 patients were included, 582 (5%) NOAF, 2368 (22%) PEAF, and 7886 (73%) non-AF. Adjusted ICU management differed (P < .001) between all groups (NOAF vs PEAF vs non-AF) in regards to incidence of vasopressor use, mechanical ventilation, and renal replacement therapy, occurring more frequently in NOAF. While ICU mortality was greater for NOAF (OR =1.40; 95% CI 1.03–1.87; P = .03) , NOAF was not predictive of in-hospital mortality after adjustment for greater disease severity. One-year survival after ICU discharge was similar for both AF groups when compared to non-AF, (54%, 52%, 75%, P < .001, log-rank). Conclusions Risk factors for AF were less common in NOAF than PEAF, yet NOAF incidence was associated with greater ICU disease severity and poorer short term ICU outcomes. NOAF was not independently predictive of in-hospital mortality.
While oncogenes promote tumorigenesis, they also induce deleterious cellular stresses, such as apoptosis, that cancer cells must combat by coopting adaptive responses. Whether tumor suppressor gene ...haploinsufficiency leads to such phenomena and their mechanistic basis is unclear. Here, we demonstrate that elevated levels of the anti-apoptotic factor, CASP8 and FADD-like apoptosis regulator (CFLAR), promotes apoptosis evasion in acute myeloid leukemia (AML) cells haploinsufficient for the cut-like homeobox 1 (CUX1) transcription factor, whose loss is associated with dismal clinical prognosis. Genome-wide CRISPR/Cas9 screening identifies CFLAR as a selective, acquired vulnerability in CUX1-deficient AML, which can be mimicked therapeutically using inhibitor of apoptosis (IAP) antagonists in murine and human AML cells. Mechanistically, CUX1 deficiency directly alleviates CUX1 repression of the CFLAR promoter to drive CFLAR expression and leukemia survival. These data establish how haploinsufficiency of a tumor suppressor is sufficient to induce advantageous anti-apoptosis cell survival pathways and concurrently nominate CFLAR as potential therapeutic target in these poor-prognosis leukemias.
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