المؤلفون: Chen, Benson, Sultan, Mohammad M., Karaletsos, Theofanis

المصدر: Journal of Chemical Information and Modeling; February 2024, Vol. 64 Issue: 4 p1123-1133, 11p

مستخلص: DNA-encoded library (DEL) has proven to be a powerful tool that utilizes combinatorially constructed small molecules to facilitate highly efficient screening experiments. These selection experiments, involving multiple stages of washing, elution, and identification of potent binders via unique DNA barcodes, often generate complex data. This complexity can potentially mask the underlying signals, necessitating the application of computational tools, such as machine learning, to uncover valuable insights. We introduce a compositional deep probabilistic model of DEL data, DEL-Compose, which decomposes molecular representations into their monosynthon, disynthon, and trisynthon building blocks and capitalizes on the inherent hierarchical structure of these molecules by modeling latent reactions between embedded synthons. Additionally, we investigate methods to improve the observation models for DEL count data, such as integrating covariate factors to more effectively account for data noise. Across two popular public benchmark data sets (CA-IX and HRP), our model demonstrates strong performance compared to count baselines, enriches the correct pharmacophores, and offers valuable insights via its intrinsic interpretable structure, thereby providing a robust tool for the analysis of DEL data.

المؤلفون: Shmilovich, Kirill, Chen, Benson, Karaletsos, Theofanis, Sultan, Mohammad M.

المصدر: Journal of Chemical Information and Modeling; May 2023, Vol. 63 Issue: 9 p2719-2727, 9p

مستخلص: DNA-encoded library (DEL) technology has enabled significant advances in hit identification by enabling efficient testing of combinatorially generated molecular libraries. DEL screens measure protein binding affinity though sequencing reads of molecules tagged with unique DNA barcodes that survive a series of selection experiments. Computational models have been deployed to learn the latent binding affinities that are correlated to the sequenced count data; however, this correlation is often obfuscated by various sources of noise introduced in its complicated data-generation process. In order to denoise DEL count data and screen for molecules with good binding affinity, computational models require the correct assumptions in their modeling structure to capture the correct signals underlying the data. Recent advances in DEL models have focused on probabilistic formulations of count data, but existing approaches have thus far been limited to only utilizing 2-D molecule-level representations. We introduce a new paradigm, DEL-Dock, that combines ligand-based descriptors with 3-D spatial information from docked protein–ligand complexes. 3-D spatial information allows our model to learn over the actual binding modality rather than using only structure-based information of the ligand. We show that our model is capable of effectively denoising DEL count data to predict molecule enrichment scores that are better correlated with experimental binding affinity measurements compared to prior works. Moreover, by learning over a collection of docked poses we demonstrate that our model, trained only on DEL data, implicitly learns to perform good docking pose selection without requiring external supervision from expensive-to-source protein crystal structures.

المؤلفون: Fiorella, David, Molyneux, Andy, Coon, Alex, Szikora, Istvan, Saatci, Isil, Baltacioglu, Feyyaz, Aziz-Sultan, Mohammad A, Hoit, Daniel, Delgado Almandoz, Josser E, Elijovich, Lucas, Cekirge, H Saruhan, Byrne, James, Klisch, Joachim, Arthur, Adam S

المصدر: Journal of Neurointerventional Surgery; 2023, Vol. 15 Issue: 12 p1175-1180, 6p

مستخلص: IntroductionThe US Woven EndoBridge Intra-saccular Therapy (WEB-IT) study is a pivotal, prospective, single arm, investigational device exemption study to evaluate the safety and effectiveness of the WEB device for the treatment of wide neck bifurcation aneurysms (WNBAs). We present complete 5 year data for the cohort of 150 patients.Methods150 patients with WNBAs were enrolled at 21 US and six international centers. Imaging from the index procedure, 6 month, 1 year, 3 year, and 5 year follow-up were reviewed by a core laboratory. Adverse events were reviewed and adjudicated by a clinical events adjudicator.Results83 patients had 5 year follow-up imaging and 123 had clinical follow-up. No ruptured (0/9) or unruptured aneurysm (0/141) rebled or bled during follow-up. No new device or procedure related adverse events or serious adverse events were reported after 1 year. At 5 years, using the LOCF method, complete occlusion was observed in 58.1% and adequate occlusion in 87.2% of patients. For patients with both 1 year and 5 year occlusion statuses available, 76.8% (63/82) of aneurysms remained stable or improved with no retreatment. After 1 year, 18 aneurysms were retreated, 11 of which were adequately occluded at 1 year, and 15 of which were retreated in the absence of any deterioration in occlusion grade.ConclusionsFive year follow-up data from the WEB-IT study demonstrated that the WEB device was safe and effective when used in the treatment of WNBAs. Aneurysm occlusion rates achieved at 1 year follow-up were durable, with rates of progressive thrombosis far exceeding rates of recurrence over time.

المؤلفون: Adeeb, Nimer, Dibas, Mahmoud, Diestro, Jose Danilo Bengzon, Phan, Kevin, Cuellar-Saenz, Hugo H, Sweid, Ahmad, Lay, Sovann V, Guenego, Adrien, Aslan, Assala, Renieri, Leonardo, Sundararajan, Sri Hari, Saliou, Guillaume, Mo¨hlenbruch, Markus, Regenhardt, Robert W, Vranic, Justin E, Lylyk, Ivan, Foreman, Paul M, Vachhani, Jay A, Župančić, Vedran, Hafeez, Muhammad U, Rutledge, Caleb, Waqas, Muhammad, Tutino, Vincent M, Rabinov, James D, Ren, Yifan, Schirmer, Clemens M, Piano, Mariangela, Kuhn, Anna L, Michelozzi, Caterina, Elens, Stephanie, Starke, Robert M, Hassan, Ameer, Salehani, Arsalaan, Brehm, Alex, MohammedAli, MajdEddin, Jones, Jesse, Psychogios, Marios, Spears, Julian, Lubicz, Boris, Panni, Pietro, Puri, Ajit S, Pero, Guglielmo, Griessenauer, Christoph J, Asadi, Hamed, Siddiqui, Adnan, Ducruet, Andrew, Albuquerque, Felipe C, Du, Rose, Kan, Peter, Kalousek, Vladimir, Lylyk, Pedro, Stapleton, Christopher J, Boddu, Srikanth, Knopman, Jared, Aziz-Sultan, Mohammad A, Limbucci, Nicola, Jabbour, Pascal, Cognard, Christophe, Patel, Aman B, Dmytriw, Adam A

المصدر: Journal of Neurointerventional Surgery; 2023, Vol. 15 Issue: 6 p558-565, 8p

مستخلص: BackgroundThe Woven EndoBridge (WEB) device has Food and Drug Administration approval for treatment of wide-necked intracranial bifurcation aneurysms. The WEB device has been shown to result in adequate occlusion in bifurcation aneurysms overall, but its usefulness in the individual bifurcation locations has been evaluated separately only in few case series, which were limited by small sample sizes.ObjectiveTo compare angiographic and clinical outcomes after treatment of bifurcation aneurysms at various locations, including anterior communicating artery (AComA), anterior cerebral artery (ACA) bifurcation distal to AComA, basilar tip, internal carotid artery (ICA) bifurcation, and middle cerebral artery (MCA) bifurcation aneurysms using the WEB device.MethodsA retrospective cohort analysis was conducted at 22 academic institutions worldwide to compare treatment outcomes of patients with intracranial bifurcation aneurysms using the WEB device. Data include patient and aneurysm characteristics, procedural details, angiographic and functional outcomes, and complications.ResultsA total of 572 aneurysms were included. MCA (36%), AComA (35.7%), and basilar tip (18.9%) aneurysms were most common. The rate of adequate aneurysm occlusion was significantly higher for basilar tip (91.6%) and ICA bifurcation (96.7%) aneurysms and lower for ACA bifurcation (71.4%) and AComA (80.6%) aneurysms (p=0.04).ConclusionTo our knowledge, this is the most extensive study to date that compares the treatment of different intracranial bifurcation aneurysms using the WEB device. Basilar tip and ICA bifurcation aneurysms showed significantly higher rates of aneurysm occlusion than other locations.

المؤلفون: Diestro, Jose Danilo Bengzon, Dibas, Mahmoud, Adeeb, Nimer, Regenhardt, Robert W, Vranic, Justin E, Guenego, Adrien, Lay, Sovann V, Renieri, Leonardo, Al Balushi, Ali, Shotar, Eimad, Premat, Kevin, El Naamani, Kareem, Saliou, Guillaume, Mo¨hlenbruch, Markus A., Lylyk, Ivan, Foreman, Paul M, Vachhani, Jay A, Župančić, Vedran, Hafeez, Muhammad U, Rutledge, Caleb, Rai, Hamid, Tutino, Vincent M, Mirshani, Shervin, Ghozy, Sherief, Harker, Pablo, Alotaibi, Naif M, Rabinov, James D, Ren, Yifan, Schirmer, Clemens M, Goren, Oded, Piano, Mariangela, Kuhn, Anna Luisa, Michelozzi, Caterina, Elens, Stephanie, Starke, Robert M, Hassan, Ameer, Salehani, Arsalaan, Nguyen, Anh, Jones, Jesse, Psychogios, Marios, Spears, Julian, Parra-Fariñas, Carmen, Bres Bullrich, Maria, Mayich, Michael, Salem, Mohamed M, Burkhardt, Jan-Karl, Jankowitz, Brian T, Domingo, Ricardo A, Huynh, Thien, Tawk, Rabih, Ulfert, Christian, Lubicz, Boris, Panni, Pietro, Puri, Ajit S, Pero, Guglielmo, Griessenauer, Christoph J, Asadi, Hamed, Siddiqui, Adnan, Ducruet, Andrew F, Albuquerque, Felipe C, Du, Rose, Kan, Peter, Kalousek, Vladimir, Lylyk, Pedro, Boddu, Srikanth Reddy, Stapleton, Christopher J, Knopman, Jared, Jabbour, Pascal, Tjoumakaris, Stavropoula, Clarencon, Frédéric, Limbucci, Nicola, Aziz-Sultan, Mohammad A, Cuellar-Saenz, Hugo H, Cognard, Christophe, Patel, Aman B, Dmytriw, Adam A

المصدر: Journal of Neurointerventional Surgery; 2023, Vol. 15 Issue: 9 p844-850, 7p

مستخلص: BackgroundThe Woven EndoBridge (WEB) device is a novel intrasaccular flow disruptor tailored for bifurcation aneurysms. We aim to describe the degree of aneurysm occlusion at the latest follow-up, and the rate of complications of aneurysms treated with the WEB device stratified according to rupture status.MethodsOur data were taken from the WorldWideWeb Consortium, an international multicenter cohort including patients treated with the WEB device. Aneurysms were classified into two groups: ruptured and unruptured. We compared clinical and radiologic outcomes of both groups. Propensity score matching (PSM) was done to match according to age, gender, bifurcation, location, prior treatment, neck, height, dome width, daughter sac, incorporated branch, pretreatment antiplatelets, and last imaging follow-up.ResultsThe study included 676 patients with 691 intracranial aneurysms (529 unruptured and 162 ruptured) treated with the WEB device. The PSM analysis had 55 pairs. In both the unmatched (85.8% vs 84.3%, p=0.692) and matched (94.4% vs 83.3%, p=0.066) cohorts there was no significant difference in the adequate occlusion rate at the last follow-up. Likewise, there were no significant differences in both ischemic and hemorrhagic complications between the two groups. There was no documented aneurysm rebleeding after WEB device implantation.ConclusionThere was no significant difference in both the radiologic outcomes and complications between unruptured and ruptured aneurysms. Our findings support the feasibility of treatment of ruptured aneurysms with the WEB device.

المؤلفون: Adeeb, Nimer, Dibas, Mahmoud, Diestro, Jose Danilo Bengzon, Cuellar-Saenz, Hugo H., Sweid, Ahmad, Kandregula, Sandeep, Lay, Sovann V., Guenego, Adrien, Renieri, Leonardo, Sundararajan, Sri Hari, Saliou, Guillaume, Aslan, Assala, Möhlenbruch, Markus, Vranic, Justin E., Regenhardt, Robert W., Savardekar, Amey, Mamilly, Ahmed, Lylyk, Ivan, Foreman, Paul M., Vachhani, Jay A., Župančić, Vedran, Hafeez, Muhammad U., Rutledge, Caleb, Waqas, Muhammad, Parra Farinas, Carmen, Tutino, Vincent M., Inoue, Yasuaki, Mirshahi, Shervin, Rabinov, James D., Ren, Yifan, Schirmer, Clemens M., Piano, Mariangela, Kühn, Anna L., Michelozzi, Caterina, Elens, Stéphanie, Starke, Robert M., Hassan, Ameer, Salehani, Arsalaan, Sporns, Peter, Brehm, Alex, Jones, Jesse, Psychogios, Marios, Spears, Julian, Lubicz, Boris, Panni, Pietro, Puri, Ajit S., Pero, Guglielmo, Griessenauer, Christoph J., Asadi, Hamed, Stapleton, Christopher J., Siddiqui, Adnan, Ducruet, Andrew F., Albuquerque, Felipe C., Kan, Peter, Kalousek, Vladimir, Lylyk, Pedro, Boddu, Srikanth, Knopman, Jared, Aziz-Sultan, Mohammad A., Limbucci, Nicola, Jabbour, Pascal, Cognard, Christophe, Patel, Aman B., Dmytriw, Adam A.

المصدر: Radiology; August 2022, Vol. 304 Issue: 2 p372-382, 11p

مستخلص: No significant difference in the angiographic and clinical outcomes was observed for the treatment of sidewall versus bifurcation intracranial aneurysms with use of Woven EndoBridge.

المؤلفون: Srinivasan, Visish M., Dmytriw, Adam A., Regenhardt, Robert W., Vicenty-Padilla, Juan, Alotaibi, Naif M., Levy, Elad, Waqas, Muhammad, Cherian, Jacob, Johnson, Jeremiah N., Jabbour, Pascal, Sweid, Ahmad, Gross, Bradley, Starke, Robert M., Puri, Ajit, Massari, Francesco, Griessenauer, Christoph J., Catapano, Joshua S., Rutledge, Caleb, Tanweer, Omar, Yashar, Parham, Cortez, Gustavo M., Aziz-Sultan, Mohammad A., Patel, Aman B., Ducruet, Andrew F., Albuquerque, Felipe C., Hanel, Ricardo A., Lawton, Michael T., Kan, Peter

المصدر: Neurosurgery; May 2022, Vol. 90 Issue: 5 p569-580, 12p

المؤلفون: Lai, Pui Man Rosalind, Caragher, Seamus, Patel, Nirav J., Du, Rose, Ali Aziz-Sultan, Mohammad

المصدر: Neurosurgery; February 2022, Vol. 90 Issue: 2 p233-239, 7p

المؤلفون: Nawabi, Noah L A, Duey, Akiro H, Kilgallon, John L, Jessurun, Charissa, Doucette, Joanne, Mekary, Rania A, Aziz-Sultan, Mohammad Ali

المصدر: Journal of Neurointerventional Surgery; 2022, Vol. 14 Issue: 7 p642-649, 8p

مستخلص: ObjectivesCOVID-19 presents a risk for delays to stroke treatment. We examined how COVID-19 affected stroke response times.MethodsA literature search was conducted to identify articles covering stroke during COVID-19 that included time metrics data pre- and post-pandemic. For each outcome, pooled relative change from baseline and 95% CI were calculated using random-effects models. Heterogeneity was explored through subgroup analyses comparing comprehensive stroke centers (CSCs) to non-CSCs.Results38 included studies reported on 6109 patients during COVID-19 and 14 637 patients during the pre-COVID period. Pooled increases of 20.9% (95% CI 5.8% to 36.1%) in last-known-well (LKW) to arrival times, 1.2% (−2.9% to 5.3%) in door-to-imaging (DTI), 0.8% (–2.9% to 4.5%) in door-to-needle (DTN), 2.8% (−5.0% to 10.6%) in door-to-groin (DTG), and 19.7% (11.1% to 28.2%) in door-to-reperfusion (DTR) times were observed during COVID-19. At CSCs, LKW increased by 24.0% (−0.3% to 48.2%), DTI increased by 1.6% (−3.0% to 6.1%), DTN increased by 3.6% (1.2% to 6.0%), DTG increased by 4.6% (−5.9% to 15.1%), and DTR increased by 21.2% (12.3% to 30.1%). At non-CSCs, LKW increased by 12.4% (−1.0% to 25.7%), DTI increased by 0.2% (−2.0% to 2.4%), DTN decreased by −4.6% (−11.9% to 2.7%), DTG decreased by −0.6% (−8.3% to 7.1%), and DTR increased by 0.5% (−31.0% to 32.0%). The increases during COVID-19 in LKW (p=0.01) and DTR (p=0.00) were statistically significant, as was the difference in DTN delays between CSCs and non-CSCs (p=0.04).ConclusionsFactors during COVID-19 resulted in significantly delayed LKW and DTR, and mild delays in DTI, DTN, and DTG. CSCs experience more pronounced delays than non-CSCs.

المؤلفون: Dmytriw, Adam A, Dibas, Mahmoud, Phan, Kevin, Efendizade, Aslan, Ospel, Johanna, Schirmer, Clemens, Settecase, Fabio, Heran, Manraj K S, Ku¨hn, Anna Luisa, Puri, Ajit S, Menon, Bijoy K, Sivakumar, Sanjeev, Mowla, Askan, Vela-Duarte, Daniel, Linfante, Italo, Dabus, Guilherme C, Regenhardt, Robert W, D'Amato, Salvatore, Rosenthal, Joseph A, Zha, Alicia, Talukder, Nafee, Sheth, Sunil A, Hassan, Ameer E, Cooke, Daniel L, Leung, Lester Y, Malek, Adel M, Voetsch, Barbara, Sehgal, Siddharth, Wakhloo, Ajay K, Goyal, Mayank, Wu, Hannah, Cohen, Jake, Ghozy, Sherief, Turkel-Parella, David, Farooq, Zerwa, Vranic, Justin E, Rabinov, James D, Stapleton, Christopher J, Minhas, Ramandeep, Velayudhan, Vinodkumar, Chaudhry, Zeshan Ahmed, Xavier, Andrew, Bullrich, Maria Bres, Pandey, Sachin, Sposato, Luciano A, Johnson, Stephen A, Gupta, Gaurav, Khandelwal, Priyank, Ali, Latisha, Liebeskind, David S, Farooqui, Mudassir, Ortega-Gutierrez, Santiago, Nahab, Fadi, Jillella, Dinesh V, Chen, Karen, Aziz-Sultan, Mohammad Ali, Abdalkader, Mohamad, Kaliaev, Artem, Nguyen, Thanh N, Haussen, Diogo C, Nogueira, Raul G, Haq, Israr Ul, Zaidat, Osama O, Sanborn, Emma, Leslie-Mazwi, Thabele M, Patel, Aman B, Siegler, James E, Tiwari, Ambooj

المصدر: Journal of Neurology, Neurosurgery, & Psychiatry (JNNP); 2022, Vol. 93 Issue: 4 p360-368, 9p

مستخلص: BackgroundTo analyse the clinical characteristics of COVID-19 with acute ischaemic stroke (AIS) and identify factors predicting functional outcome.MethodsMulticentre retrospective cohort study of COVID-19 patients with AIS who presented to 30 stroke centres in the USA and Canada between 14 March and 30 August 2020. The primary endpoint was poor functional outcome, defined as a modified Rankin Scale (mRS) of 5 or 6 at discharge. Secondary endpoints include favourable outcome (mRS ≤2) and mortality at discharge, ordinal mRS (shift analysis), symptomatic intracranial haemorrhage (sICH) and occurrence of in-hospital complications.ResultsA total of 216 COVID-19 patients with AIS were included. 68.1% (147/216) were older than 60 years, while 31.9% (69/216) were younger. Median [IQR] National Institutes of Health Stroke Scale (NIHSS) at presentation was 12.5 (15.8), and 44.2% (87/197) presented with large vessel occlusion (LVO). Approximately 51.3% (98/191) of the patients had poor outcomes with an observed mortality rate of 39.1% (81/207). Age >60 years (aOR: 5.11, 95% CI 2.08 to 12.56, p<0.001), diabetes mellitus (aOR: 2.66, 95% CI 1.16 to 6.09, p=0.021), higher NIHSS at admission (aOR: 1.08, 95% CI 1.02 to 1.14, p=0.006), LVO (aOR: 2.45, 95% CI 1.04 to 5.78, p=0.042), and higher NLR level (aOR: 1.06, 95% CI 1.01 to 1.11, p=0.028) were significantly associated with poor functional outcome.ConclusionThere is relationship between COVID-19-associated AIS and severe disability or death. We identified several factors which predict worse outcomes, and these outcomes were more frequent compared to global averages. We found that elevated neutrophil-to-lymphocyte ratio, rather than D-Dimer, predicted both morbidity and mortality.