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Since gaining approval for the treatment of chronic lymphocytic leukemia (CLL), the BCL-2 inhibitor venetoclax has transformed the treatment of this and other blood-related cancers. Reflecting the large and hydrophobic BH3-binding groove within BCL-2, venetoclax has significantly higher molecular weight and lipophilicity than most orally administered drugs, along with negligible water solubility. Although a technology-enabled formulation successfully achieves oral absorption in humans, venetoclax tablets have limited drug loading and therefore can present a substantial pill burden for patients in high-dose indications. We therefore generated a phosphate prodrug (3, ABBV-167) that confers significantly increased water solubility to venetoclax and, upon oral administration to healthy volunteers either as a solution or high drug-load immediate release tablet, extensively converts to the parent drug. Additionally, ABBV-167 demonstrated a lower food effect with respect to venetoclax tablets. These data indicate that beyond-rule-of-5 molecules can be successfully delivered to humans via a solubility-enhancing prodrug moiety to afford robust exposures of the parent drug following oral dosing.

1. Measured pKa values of ABBV-167 (Table S1. Ionization constants of ABBV-167) 2. Preparation of ABBV-167 on large scale (Scheme S1: Synopsis of GMP synthesis of ABBV-167) 3. Preparation of clinical ABBV-167 drug supply 4. Animal pharmacokinetics (Table S2. Single dose pharmacokinetics of prodrug 3 and parent venetoclax in mouse and dog after IV dosing of prodrug 3. Table S3. Single dose pharmacokinetics of 3 after oral dosing in mouse and dog. Table S4. Single dose pharmacokinetics of parent venetoclax in mouse and dog after oral dosing of 3.) 5. Clinical study (Study design, Pharmacokinetic and statistical analysis, Safety and tolerability assessments, Clinical pharmacokinetic results, Table S5. Effect of prodrug and food on venetoclax bioavailability, Safety results) 6. Crystallography methods (Protein preparation. BCL-2 ABBV-167 complex crystallization. X-ray structure determination. Table S6. Diffraction data collection and refinement statistics for BCL-2 in complex with ABBV-167 (PDB code 7LHB))

Objective A high rate of cerebral aneurysm recurrence following endovascular coiling has prompted the use of digital subtraction angiography (DSA) for interval follow-up. However, the utility of skull x-rays as an alternative screening method for aneurysm recurrence is unproperly characterized. Methods Retrospective review of a prospective registry of ruptured and unruptured cerebral aneurysms. Anteroposterior and lateral skull x-rays were obtained immediately at the end of the procedure and at 6-month follow-up. Aneurysm recurrence was defined by comparing post-procedure and 6-month DSA imaging. A true positive was defined as a change in coil mass morphology on at least one projection with aneurysm recurrence on DSA, and a true negative defined as a stable coil mass on both projections and no recurrence on DSA. Receiver operating characteristic area under the curve (AUC) statistics was used to assess the performance of skull x-rays in identifying aneurysm recurrence. Results A total of 118 cerebral aneurysms were evaluated with DSA imaging and skull x-rays. A change in coil mass morphology on one projection of skull x-rays correctly detected all true recurrences with a sensitivity of 100% (95% confidence interval [CI], 91-100%). Skull x-rays failed to identify a stable aneurysm coil mass in 15 cases, with a specificity of 79% (68-88%). Skull x-rays performed with AUC 0.8958 (95% CI, 0.8490-0.9431) in identifying aneurysm recurrence. Conclusions The findings of our study suggest that skull x-rays may represent a low-cost, non-invasive screening tool to rule out aneurysm recurrence, which can potentially aid in decreasing the utilization of DSA in the follow-up of patients with coiled cerebral aneurysms.

Isolated Coronary Artery Stenoses (CAS) involving the ostium of the Left Anterior Descending (LAD) artery is very challenging, especially in a setting of primary Angioplasty in Myocardial Infarction (PAMI). Intimal atherosclerosis in the Left Main Coronary Artery (LMCA) bifurcation is primarily in area of low shear stress which is the lateral wall, close to the LAD and Left Circumflex (LCx). Thus, carina is usually free of disease, which can explain why single-stent strategy can be successful. However, precise stent placement is often difficult due to unwanted stent movement within vessel or its proximity to side branches. A decision must be made at the outset, to decide on the approach to be employed, to treat osteal LAD lesions. Limited data is available on patients undergoing primary PCI of osteal LAD lesions. Here, we present our experience and problems encountered during the management of osteal LAD lesions in the setting of PAMI.

Cardiac myxofibrosarcoma (MFS) is an uncommon entity. It is among the most challenging conditions to diagnose due to its rarity, high variability, and non-specific findings. These tumors often simulate left atrial myxoma or mitral stenosis at clinical presentation. Although, the definitive diagnosis of cardiac tumors depends on histopathological examination, various imaging techniques are also useful to study tumor characteristics to plan an appropriate treatment strategy. Here we highlight a case of primary cardiac MFS of left atrium (LA) showing areas of transition to undifferentiated pleomorphic sarcoma (UPS) with bone or osteoid formation, which is extremely rare and not well described.

Patients with cerebral vasospasm caused by aneurysmal subarachnoid hemorrhage (aSAH) are often treated with intra-arterial (IA) vasodilator infusion. However, the optimal drug regimen is yet to be elucidated. A retrospective review of patients with aSAH and cerebral vasospasm treated with IA vasodilator infusion was performed. Patients in group 1 (2008–2011) were treated with a single agent, either nicardipine or verapamil, and patients in group 2 (2010–2016) were treated with a regimen of nitroglycerin, verapamil, and nicardipine. The post-infusion improvement ratio (PIIR) was compared between groups. Adjusted multivariate logistic regression models were utilized to determine whether patients treated with multiple vasodilators had an improved functional outcome, defined by the modified Rankin Scale, at discharge and 90-day follow-up. Among 116 patients from group 1 (N = 47) and group 2 (N = 69), the median age was 54.5 years [IQR, 46–53 years] and 78% were female. Use of multiple-agent therapy resulted in a 24.36% improvement in vessel diameter over single-agent therapy (median PIIR: group 1, 10.5% [IQR, 5.3–21.1%] vs group 2, 34.9% [IQR, 21.4–66.0%]; p < 0.0001). In the adjusted multivariate logistic regression, the use of multiple-agent therapy was associated with a better functional outcome at discharge (OR 0.15, 95% CI [0.04–0.55]; p < 0.01) and at 90-day follow-up (OR 0.20, 95% CI [0.05–0.77]; p < 0.05) when compared to single-agent therapy. In this study, we found that patients treated for cerebral vasospasm with IA infusion of multiple vasodilators had an increased vessel response and better functional outcomes compared to those treated with a single agent.

OSA is considered as an independent risk factor for cardiovascular morbidity and mortality. Hypertension, atrial fibrillation, heart failure with reduced ejection fraction, stroke and metabolic syndrome are also known to be associated with OSA. Each of these conditions are associated with 2D-ECHO abnormalities and often present with increased hospitalization rates or morbidity. However, echocardiographic parameters in newly detected OSA, without any other associated illness, is poorly defined. The aim of this study is to evaluate systolic and diastolic dysfunction using 2D speckle tracking in patients with newly diagnosed OSA and normal left ventricle ejection fraction. The association between diastolic dysfunction, Global Longitudinal Strain (GLS), LV hypertrophy, LV mass, estimated pulmonary artery pressures and severity of OSA was also studied.The results indicated that most of the patients with OSA, without any other cardiovascular diseases, exhibited normal left ventricular (LV) ejection fraction (EF), but had clinical signs and symptoms of LV systolic dysfunction.

In online advertising, an important quality control step is to audit advertising images (“creatives”) before they appear on publishers’ Web pages. This ensures that advertisements only appear on Web pages where the ad is appropriate. If a creative with sensitive content such as gambling and pornography is displayed on the wrong Web page, it can ruin the user’s experience, the publisher’s reputation, and may have legal implications. To protect against this, humans must audit every creative before it is displayed through our ad exchange; this process is costly and time-consuming. To detect sensitive content, we use a pre-trained deep convolutional neural network (Xception Chollet in: The IEEE conference on computer vision and pattern recognition (CVPR), 2017) to process the creative image, and merge its features with the historical distribution of categories associated with the creative’s landing page (the Web page that loads when the ad is clicked, which may also contain sensitive content). This representation is then passed through a series of fully connected layers to predict the sensitive category. The trained model achieves slightly better than human performance (model accuracy 99.92%; human accuracy 99.88%) on a large fraction of creatives (61%), while making 3.5 times fewer mistakes in very sensitive categories. The main challenges we faced were to detect, with high accuracy, creatives from 10 “very sensitive” categories as determined by our Creative Audit team, along with a highly imbalanced data set with 95% of creatives having no sensitive categories. This paper extends the work we described in Austin et al. (in: Proceedings of the 2018 IEEE international conference on data science and advanced analytics (DSAA), DSAA’18, 2018). It demonstrates the successful usage of deep learning in production as a method for detecting sensitive creatives, while respecting the constraints set by business.

Background: Cardiac involvement is a major cause of mortality in Beta-Thalassaemia Major (ß-TM) patients. Despite many advances in therapeutic management of ß-TM, cardiac involvement remains the primary cause of mortality in ~70% of the cases. Chronic iron overloading results in thalassaemic cardiomyopathy, leading to diastolic dysfunction and overt heart failure (HF). Serial electrocardiography (ECG), 2D-echocardiography (2DECHO) and cardiovascular magnetic resonance (CMR) help in early detection and risk stratification of ß-TM patients, to prevent complications, such as arrhythmias and sudden cardiac death. An established network of care between thalassaemia centres and local health providers is essential for optimal management. Case presentation: We report 2 cases of HF in ß-TM of varied etiology, and different approaches undertaken for its early diagnosis and treatment. Conclusion: It is important to differentiate various phenotypes of cardiomyopathy in ß-TM. Since, the management of each varies accordingly. ß-TM patients require a multi-disciplinary approach that includes HF specialists, haematologist, hepatologist, endocrinologist, psychologist, transfusion experts and nursing personnel to maximise benefits from the application of the modern HF therapeutic strategies in evaluation, monitoring and treatment.

This study presents a descriptive overview of assessment and verification techniques used and emergent in contemporary online learning platforms. The Covid-19 pandemic has encouraged many institutions to move to online examinations at scale. Verification of learner identity is thus increasingly important for online education in examination and proctoring. Here we review state of the art approaches to ID verification, recognition, and assessment in Massive Open Online Courses (MOOC). Desktop research included research publications, grey literature, and direct interactions with MOOC platforms to identify current practices. The main focus was on public data from course pages on MOOC platforms, and particularly courses that had been grouped to offer a single academic program. Four approaches to verification of identity are described: basic identity checks; checks made by the university; external proctoring; and various types of interview. Our review demonstrates the absence of any universal approach. However, the emergent picture indicates increasing co-ordination across relevant stakeholders (including higher education institutions, employment services and the private sector). There remain significant challenges for online proctoring, including overcoming learner preferences and meeting the increased resourcing needed for human-led processes of identity verification. There remain significant ethical challenges regarding the use of learner data (especially biometrics). As a result, MOOC platforms may benefit from adopting identity verification strategies that are well-established in higher education institutions, such as plagiarism checking software and pedagogies like e-portfolios.

Stent infection after drug-eluting stent implantation is uncommon but is a critical event. In this study, we describe two such cases of coronary stent infection but with varied presentation. The first patient presented with recurrent stent thrombosis and acute coronary syndrome while the second patient was erroneously diagnosed as having tubercular pericarditis and was started on anti-tubercular therapy. Due to their possible fatal outcome, we herein report our experience with this uncommon clinical entity to help in rapid diagnosis and treatment. .

INTRODUCTION: Prior retrospective and case-control studies have shown that the use of general anesthesia (GA) during endovascular therapy (EVT) for acute ischemic stroke with large vessel occlusion (AIS-LVO) was independently associated with poor clinical outcomes compared with cases performed under conscious sedation (CS). Conversely, recent small randomized clinical trials (RCT) demonstrated a trend toward better outcome in cases performed under GA. METHODS: We submitted an online survey to 193 Society of Vascular Interventional Neurology and 78 American Association of Neurological Surgeons and Congress of Neurological Surgeons – Cerebrovascular Section neuroendovascular practitioners. Questions were aimed at understanding the current state of anesthesia practice during EVT, and to determine if there is clinical equipoise for a large multicenter RCT comparing GA versus CS during EVT. RESULTS: Between March and May of 2017, we received 116 (43%) responses. Anesthesiologists were responsible for managing 96% of the GA cases as compared to only 51% of the CS cases (P < 0.0001). Notable 56% of providers reported performing less than a quarter of their cases under GA. Only 7% performed all cases under GA compared with 17% who used solely CS (P = 0.048). More than half of respondents thought a new RCT was necessary, of whom 61% were interested in participating. Among interested responders, 59% were located in centers with 3 or more neurointerventionalists. CONCLUSION: The significant variation among neuroendovascular providers, added with the lack of consensus among recent trials and meta-analyses, demonstrate clinical equipoise for further studies to explore the effects of anesthesia during EVT in AIS-LVO.