Superior efficacy of co-targeting GFI1/KDM1A and BRD4 against AML and post-MPN secondary AML cells

There is an unmet need to overcome nongenetic therapy-resistance to improve outcomes in AML, especially post-myeloproliferative neoplasm (MPN) secondary (s) AML. Studies presented describe effects of genetic knockout, degradation or small molecule targeted-inhibition of GFI1/LSD1 on active enhancers, altering gene-expressions and inducing differentiation and lethality in AML and (MPN) sAML cells. A protein domain-focused CRISPR screen in LSD1 (KDM1A) inhibitor (i) treated AML cells, identified BRD4, MOZ, HDAC3 and DOT1L among the codependencies. Our findings demonstrate that co-targeting LSD1 and one of these co-dependencies exerted synergistic in vitro lethality in AML and post-MPN sAML cells. Co-treatment with LSD1i and the JAKi ruxolitinib was also synergistically lethal against post-MPN sAML cells. LSD1i pre-treatment induced GFI1, PU.1 and CEBPα but depleted c-Myc, overcoming nongenetic resistance to ruxolitinib, or to BETi in post-MPN sAML cells. Co-treatment with LSD1i and BETi or ruxolitinib exerted superior in vivo efficacy against post-MPN sAML cells. These findings highlight LSD1i-based combinations that merit testing for clinical efficacy, especially to overcome nongenetic therapy-resistance in AML and post-MPN sAML.Subject terms: Acute myeloid leukaemia, Targeted therapies     

Long-term Implications of Tracheostomy in Cardiac Surgery Patients: Decannulation and Mortality

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Black beans and red kidney beans induce positive postprandial vascular responses in healthy adults: A pilot randomized cross-over study

Background and aimsConsuming pulses (dry beans, dry peas, chickpeas, lentils) over several weeks can improve vascular function and decrease cardiovascular disease risk; however, it is unknown whether pulses can modulate postprandial vascular responses. The objective of this study was to compare different bean varieties (black, navy, pinto, red kidney) and white rice for their acute postprandial effects on vascular and metabolic responses in healthy individuals.Methods and resultsThe study was designed as a single-blinded, randomized crossover trial with a minimum 6 days between consumption of the food articles. Vascular tone (primary endpoint), haemodynamics and serum biochemistry (secondary endpoints) were measured in 8 healthy adults before and at 1, 2, and 6 h after eating ¾ cup of beans or rice. Blood pressure and pulse wave velocity (PWV) were lower at 2 h following red kidney bean and pinto bean consumption compared to rice and navy bean, respectively (p < 0.05). There was greater vasorelaxation 6 h following consumption of darker-coloured beans, as shown by decreased vascular tone: PWV was lower after consuming black bean compared to pinto bean, augmentation pressure was lower after consuming black bean compared to rice and pinto bean, and wave reflection magnitude was lower after consuming red kidney bean and black bean compared to rice, navy bean, and pinto bean (p < 0.05). LDL-cholesterol concentrations were lower 6 h after black bean consumption compared to rice (p < 0.05).ConclusionOverall, red kidney and black beans, the darker-coloured beans, elicited a positive effect on the tensile properties of blood vessels, and this acute response may provide insight for how pulses modify vascular function.     

The fibrotic and immune microenvironments as targetable drivers of metastasis

Although substantial progress has been made over the past 40 years in treating patients with cancer, effective therapies for those who are diagnosed with advanced metastatic disease are still few and far between. Cancer cells do not exist in isolation: rather, they exist within a complex microenvironment composed of stromal cells and extracellular matrix. Within this tumour microenvironment exists an interplay between the two main stromal cell subtypes, cancer-associated fibroblasts (CAFs) and immune cells, that are important in controlling metastasis. A complex network of paracrine signalling pathways between CAFs, immune cells and tumour cells are involved at multiple stages of the metastatic process, from invasion and intravasation at the primary tumour site to extravasation and colonisation in the metastatic site. Heterogeneity and plasticity within stromal cell populations also contribute to the complexity. Although many of these processes are likely to be common to a number of metastatic sites, we will describe in detail the interplay within the liver, a preferred site of metastasis for many tumours. A greater understanding of these networks provides opportunities for the design of new therapeutic approaches for targeting the metastatic disease.Subject terms: Cancer microenvironment, Mechanisms of disease     

Postprocedural Antiplatelet Treatment after Emergent Carotid Stenting in Tandem Lesions Stroke: Impact on Stent Patency beyond Day 1

BACKGROUND AND PURPOSE:Postprocedural dual-antiplatelet therapy is frequently withheld after emergent carotid stent placement during stroke thrombectomy. We aimed to assess whether antiplatelet regimen variations increase the risk of stent thrombosis beyond postprocedural day 1.MATERIALS AND METHODS:Retrospective review was undertaken of all consecutive thrombectomies for acute stroke with tandem lesions in the anterior circulation performed in a single comprehensive stroke center between January 9, 2011 and March 30, 2020. Patients were included if carotid stent patency was confirmed at day 1 postprocedure. The group of patients with continuous dual-antiplatelet therapy from day 1 was compared with the group of patients with absent/discontinued dual-antiplatelet therapy.RESULTS:Of a total of 109 tandem lesion thrombectomies, 96 patients had patent carotid stents at the end of the procedure. The early postprocedural stent thrombosis rate during the first 24 hours was 14/96 (14.5%). Of 82 patients with patent stents at day 1, in 28 (34.1%), dual-antiplatelet therapy was either not initiated at day 1 or was discontinued thereafter. After exclusion of cases without further controls of stent patency, there was no significant difference in the rate of subacute/late stent thrombosis between the 2 groups: 1/50 (2%) in patients with continuous dual-antiplatelet therapy versus 0/22 (0%) in patients with absent/discontinued dual-antiplatelet therapy (P = 1.000). In total, we observed 88 patient days without any antiplatelet treatment and 471 patient days with single antiplatelet treatment.CONCLUSIONS:Discontinuation of dual-antiplatelet therapy was not associated with an increased risk of stent thrombosis beyond postprocedural day 1. Further studies are warranted to better assess the additional benefit and optimal duration of dual-antiplatelet therapy after tandem lesion stroke thrombectomy.

In around 15% of endovascular procedures for anterior circulation stroke,¹ there is a tight stenosis or occlusion of the cervical carotid artery in addition to the intracranial artery occlusion. The optimal endovascular management of tandem lesions has yet to be defined; however, there is mounting evidence^2,3 that emergent stent placement in the carotid artery associated with at least 1 antiplatelet agent could lead to better recanalization rates and improved clinical outcomes. A more definitive answer should be provided by the Thrombectomy In TANdem lesions (TITAN) randomized multicenter trial,⁴ designed to assess the safety and efficacy of emergent internal carotid artery stent placement in tandem lesion thrombectomy. This study recently enrolled the first patient in early 2020.In patients undergoing emergent carotid stent placement, there is no consensus regarding the optimal periprocedural antiplatelet therapy. Many groups^5,6 chose to avoid dual-antiplatelet therapy (DAPT) during the first 24 hours in an attempt to reduce the risk of hemorrhagic transformation. Conversely, less aggressive antiplatelet regimens might increase the risk of carotid stent thrombosis.Stent thrombosis was recently identified as a predictor of unfavorable clinical outcome.^7,8 To date, available data regarding stent patency rates remain scarce. Most case series of endovascular management for tandem lesions^5,9-11 do not report postprocedural stent patency, while some publications^12-15 offer partial data for a subgroup of patients for whom carotid imaging controls were available. Reported rates of stent thrombosis ranged between 1.2% and 22.0%.^{6-8,12-14,16,17}To date, no study has attempted to differentiate between early (first 24 hours) and subacute/late postprocedural stent thrombosis. During the first 24 hours, protection against stent thrombosis is conferred by antiplatelet agents administered during the procedure (periprocedural antiplatelets). Beyond 24 hours, the recommended antiplatelet regimen is DAPT for 4–12 weeks,^9,17 but in reality, antiplatelets are often tailored in view of neurological and extra-neurological hemorrhagic events. It is currently unknown whether discontinuation of DAPT is associated with an increased risk of late stent thrombosis.Thus, we aimed to describe the variations in the postprocedural antiplatelet regimen in a large consecutive cohort of tandem lesion thrombectomies with emergent carotid artery stent placement and to assess whether discontinuation of DAPT was associated with an increased risk of carotid stent thrombosis.     

Analysis of Stroke Detection during the COVID-19 Pandemic Using Natural Language Processing of Radiology Reports

BACKGROUND AND PURPOSE:The coronavirus disease 2019 (COVID-19) pandemic has led to decreases in neuroimaging volume. Our aim was to quantify the change in acute or subacute ischemic strokes detected on CT or MR imaging during the pandemic using natural language processing of radiology reports.MATERIALS AND METHODS:We retrospectively analyzed 32,555 radiology reports from brain CTs and MRIs from a comprehensive stroke center, performed from March 1 to April 30 each year from 2017 to 2020, involving 20,414 unique patients. To detect acute or subacute ischemic stroke in free-text reports, we trained a random forest natural language processing classifier using 1987 randomly sampled radiology reports with manual annotation. Natural language processing classifier generalizability was evaluated using 1974 imaging reports from an external dataset.RESULTS:The natural language processing classifier achieved a 5-fold cross-validation classification accuracy of 0.97 and an F1 score of 0.74, with a slight underestimation (−5%) of actual numbers of acute or subacute ischemic strokes in cross-validation. Importantly, cross-validation performance stratified by year was similar. Applying the classifier to the complete study cohort, we found an estimated 24% decrease in patients with acute or subacute ischemic strokes reported on CT or MR imaging from March to April 2020 compared with the average from those months in 2017–2019. Among patients with stroke-related order indications, the estimated proportion who underwent neuroimaging with acute or subacute ischemic stroke detection significantly increased from 16% during 2017–2019 to 21% in 2020 (P = .01). The natural language processing classifier performed worse on external data.CONCLUSIONS:Acute or subacute ischemic stroke cases detected by neuroimaging decreased during the COVID-19 pandemic, though a higher proportion of studies ordered for stroke were positive for acute or subacute ischemic strokes. Natural language processing approaches can help automatically track acute or subacute ischemic stroke numbers for epidemiologic studies, though local classifier training is important due to radiologist reporting style differences.

There is much concern regarding the impact of the coronavirus disease 2019 (COVID-19) pandemic on the quality of stroke care, including issues with hospital capacity, clinical resource re-allocation, and the safety of patients and clinicians.^1,2 Previous reports have shown that there have been substantial decreases in stroke neuroimaging volume during the pandemic.^3,4 In addition, acute ischemic infarcts have been found on neuroimaging studies in many hospitalized patients with COVID-19, though the causal relationship is unclear.^5,6 Studies like these and other epidemiologic analyses usually rely on the creation of manually curated databases, in which identification of cases can be time-consuming and difficult to update in real-time. One way to facilitate such research is to use natural language processing (NLP), which has shown utility for automated analysis of radiology report data.⁷ NLP algorithms have been developed previously for the classification of neuroradiology reports for the presence of ischemic stroke findings and acute ischemic stroke subtypes.^8,9 Thus, NLP has the potential to facilitate COVID-19 research.In this study, we developed an NLP machine learning model that classifies radiology reports for the presence or absence of acute or subacute ischemic stroke (ASIS), as opposed to chronic stroke. We used this model to quantify the change in ASIS detected on all CT or MR imaging studies performed at a large comprehensive stroke center during the COVID-19 pandemic in the United States. We also evaluated NLP model generalizability and different training strategies using a sample of radiology reports from a second stroke center.     

Rapid behavioral assessment of barriers and opportunities to improve vaccination coverage among displaced Rohingyas in Bangladesh,January 2018

Background

In November 2017, the World Health Organization received initial reports of suspected diphtheria cases in camps established for displaced Rohingyas in Cox’s Bazar district, Bangladesh. By January 11, 2018, over 4,000 suspected cases of diphtheria and 30 deaths were reported. The Bangladesh government and partners implemented a diphtheria vaccination campaign in December 2017. Outbreak response staff reported anecdotal evidence of vaccine hesitancy. Our assessment aimed to understand vaccination barriers and opportunities to enhance vaccine demand among displaced Rohingyas in Bangladesh.

Mind the gap: Teachers’ conceptions of student-staff partnership and its potential to enhance educational quality

Abstract

Introduction: Student-staff partnerships as a concept to improve medical education have received a growing amount of attention. Such partnerships are collaborations in which students and teachers seek to improve education by each adding their unique contribution to decision-making and implementation processes. Although previous research has demonstrated that students are favourable to this concept, teachers remain hesitant. The present study investigated teachers’ conceptions of student-staff partnerships and of the prerequisites that are necessary to render such partnerships successful and enhance educational quality.

Method: We conducted semi-structured interviews with 14 course coordinators who lead course design teams and also teach in 4 bachelor health programmes, using Bovill and Bulley’s levels of student participation as sensitising concepts during data analysis.

Results: The results pointed to three different conceptions of student-staff partnerships existing among teachers: Teachers teach and students study; teachers teach and value students’ feedback; and teachers and students co-create. The prerequisites for effective co-creation teachers identified were: Teachers must be open to involve students and create dialogues; students must be motivated and have good communication skills; the organisation must be supportive; and teachers should have the final say.

Conclusion: We conclude that teachers’ conceptions are consistent with Bovill and Bulley’s levels of student participation. Under certain conditions, teachers are willing to co-create and reach the highest levels of student participation.     

Managing invasive aspergillosis in haematological patients in the era of resistance polymerase chain reaction and increasing triazole resistance: A modelling study of different strategies

Objectives

Triazole resistance in Aspergillus spp. is emerging and complicates prophylaxis and treatment of invasive aspergillosis (IA) worldwide. New polymerase chain reaction (PCR) tests on broncho-alveolar lavage (BAL) fluid allow for detection of triazole resistance at a genetic level, which has opened up new possibilities for targeted therapy. In the absence of clinical trials, a modelling study delivers estimates of the added value of resistance detection with PCR, and which empiric therapy would be optimal when local resistance rates are known.

Does ablation of atrial fibrillation at the time of septal myectomy improve survival of patients with obstructive hypertrophic cardiomyopathy?

ObjectiveTo evaluate the outcomes after septal myectomy in patients with obstructive hypertrophic cardiomyopathy according to atrial fibrillation and surgical ablation of atrial fibrillation.MethodsWe reviewed patients with obstructive hypertrophic cardiomyopathy who underwent septal myectomy at the Mayo Clinic from 2001 to 2016. History of atrial fibrillation was obtained from patient histories and electrocardiograms. All-cause mortality was the primary end point.ResultsA total of 2023 patients underwent septal myectomy, of whom 394 (19.5%) had at least 1 episode of atrial fibrillation preoperatively. Among patients with atrial fibrillation, 76 (19.3%) had only 1 known episode, 278 (70.6%) had recurrent paroxysmal atrial fibrillation, and 40 (10.2%) had persistent atrial fibrillation. Surgical ablation was performed in 190 patients at the time of septal myectomy, including 148 with pulmonary vein isolation and 42 with the classic maze procedure. Among all patients, operative mortality was 0.4%, and there were no early deaths in patients undergoing surgical ablation. Over a median follow-up of 5.6 years, patients with preoperative atrial fibrillation had increased mortality (hazard ratio, 1.36; 95% confidence interval, 0.97-1.91; P = .070) after multivariable adjustment for comorbidities. When considering the impact of atrial fibrillation with or without surgical treatment, the adjusted hazard ratio for mortality in patients undergoing ablation compared with no ablation was 0.93 (95% confidence interval, 0.52-1.69; P = .824).ConclusionsAtrial fibrillation is present preoperatively in one-fifth of patients with obstructive hypertrophic cardiomyopathy undergoing myectomy and showed a trend toward higher all-cause mortality. Survival of patients undergoing septal myectomy with preoperative atrial fibrillation was similar between those who did and did not receive concomitant surgical ablation.