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2. Waka Taylor

Author

Taylor, Te Wakanui Tureiti

Published
2019

3. DeepSP: Deep learning-based spatial properties to predict monoclonal antibody stability

Author

Lateefat Kalejaye, I-En Wu, Taylor Terry, and Pin-Kuang Lai

Subjects
Monoclonal antibody, Antibody stability, Molecular dynamics simulation, Spatial charge map, Spatial aggregation propensity, Deep learning, Biotechnology, TP248.13-248.65
Abstract

Therapeutic antibody development faces challenges due to high viscosities and aggregation tendencies. The spatial charge map (SCM) and spatial aggregation propensity (SAP) are computational techniques that aid in predicting viscosity and aggregation, respectively. These methods rely on structural data derived from molecular dynamics (MD) simulations, which are computationally demanding. DeepSCM, a deep learning surrogate model based on sequence information to predict SCM, was recently developed to screen high-concentration antibody viscosity. This study further utilized a dataset of 20,530 antibody sequences to train a convolutional neural network deep learning surrogate model called Deep Spatial Properties (DeepSP). DeepSP directly predicts SAP and SCM scores in different domains of antibody variable regions based solely on their sequences without performing MD simulations. The linear correlation coefficient between DeepSP scores and MD-derived scores for 30 properties achieved values between 0.76 and 0.96 with an average of 0.87. DeepSP descriptors were employed as features to build machine learning models to predict the aggregation rate of 21 antibodies, and the performance is similar to the results obtained from the previous study using MD simulations. This result demonstrates that the DeepSP approach significantly reduces the computational time required compared to MD simulations. The DeepSP model enables the rapid generation of 30 structural properties that can also be used as features in other research to train machine learning models for predicting various antibody stability using sequences only. DeepSP is freely available as an online tool via https://deepspwebapp.onrender.com and the codes and parameters are freely available at https://github.com/Lailabcode/DeepSP.

Published
2024
Full Text
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4. Determinants of brain swelling in pediatric and adult cerebral malaria

Author

Sahu, PK, Duffy, FJ, Dankwa, S, Vishnyakova, M, Majhi, M, Pirpamer, L, Vigdorovich, V, Bage, J, Maharana, S, Mandala, W, Rogerson, SJ, Seydel, KB, Taylor, TE, Kim, K, Sather, DN, Mohanty, A, Mohanty, RR, Pattnaik, R, Aitchison, JD, Hoffman, A, Mohanty, S, Smith, JD, Bernabeu, M, Wassmer, SC, Sahu, PK, Duffy, FJ, Dankwa, S, Vishnyakova, M, Majhi, M, Pirpamer, L, Vigdorovich, V, Bage, J, Maharana, S, Mandala, W, Rogerson, SJ, Seydel, KB, Taylor, TE, Kim, K, Sather, DN, Mohanty, A, Mohanty, RR, Pattnaik, R, Aitchison, JD, Hoffman, A, Mohanty, S, Smith, JD, Bernabeu, M, and Wassmer, SC

Abstract

Cerebral malaria (CM) affects children and adults, but brain swelling is more severe in children. To investigate features associated with brain swelling in malaria, we performed blood profiling and brain MRI in a cohort of pediatric and adult patients with CM in Rourkela, India, and compared them with an African pediatric CM cohort in Malawi. We determined that higher plasma Plasmodium falciparum histidine rich protein 2 (PfHRP2) levels and elevated var transcripts that encode for binding to endothelial protein C receptor (EPCR) were linked to CM at both sites. Machine learning models trained on the African pediatric cohort could classify brain swelling in Indian children CM cases but had weaker performance for adult classification, due to overall lower parasite var transcript levels in this age group and more severe thrombocytopenia in Rourkela adults. Subgrouping of patients with CM revealed higher parasite biomass linked to severe thrombocytopenia and higher Group A-EPCR var transcripts in mild thrombocytopenia. Overall, these findings provide evidence that higher parasite biomass and a subset of Group A-EPCR binding variants are common features in children and adult CM cases, despite age differences in brain swelling.

Published
2021

6. Meta-analysis of Plasmodium falciparum var Signatures Contributing to Severe Malaria in African Children and Indian Adults

Author

Miller, LH, Duffy, F, Bernabeu, M, Babar, PH, Kessler, A, Wang, CW, Vaz, M, Chery, L, Mandala, WL, Rogerson, SJ, Taylor, TE, Seydel, KB, Lavstsen, T, Gomes, E, Kim, K, Lusingu, J, Rathod, PK, Aitchison, JD, Smith, JD, Miller, LH, Duffy, F, Bernabeu, M, Babar, PH, Kessler, A, Wang, CW, Vaz, M, Chery, L, Mandala, WL, Rogerson, SJ, Taylor, TE, Seydel, KB, Lavstsen, T, Gomes, E, Kim, K, Lusingu, J, Rathod, PK, Aitchison, JD, and Smith, JD

Abstract

The clinical presentation of severe Plasmodium falciparum malaria differs between children and adults, but the mechanistic basis for this remains unclear. Contributing factors to disease severity include total parasite biomass and the diverse cytoadhesive properties mediated by the polymorphic var gene parasite ligand family displayed on infected erythrocytes. To explore these factors, we performed a multicohort analysis of the contribution of var expression and parasite biomass to severe malaria in two previously published pediatric cohorts in Tanzania and Malawi and an adult cohort in India. Machine learning analysis revealed independent and complementary roles for var adhesion types and parasite biomass in adult and pediatric severe malaria and showed that similar var profiles, including upregulation of group A and DC8 var, predict severe malaria in adults and children. Among adults, patients with multiorgan complications presented infections with significantly higher parasite biomass without significant differences in var adhesion types. Conversely, pediatric patients with specific complications showed distinct var signatures. Cerebral malaria patients showed broadly increased expression of var genes, in particular group A and DC8 var, while children with severe malaria anemia were classified based on high transcription of DC8 var only. This study represents the first large multisite meta-analysis of var expression, and it demonstrates the presence of common var profiles in severe malaria patients of different ages across distant geographical sites, as well as syndrome-specific disease signatures. The complex associations between parasite biomass, var adhesion type, and clinical presentation revealed here represent the most comprehensive picture so far of the relationship between cytoadhesion, parasite load, and clinical syndrome.IMPORTANCEP. falciparum malaria can cause multiple disease complications that differ by patient age. Previous studies have attempted t

Published
2019

7. Measurement of differential cross sections of isolated-photon plus heavy-flavour jet production in pp collisions at root s=8 TeV using the ATLAS detector

Author

Aaboudd, M, Aad, G, Abbott, B, Abdinov, O, Abeloos, B, Abidi, SH, AbouZeid, OS, Abraham, NL, Abramowicz, H, Abreu, H, Abreu, R, Abulaitia, Y, Acharya, BS, Adachi, S, Adamczyk, L, Adelman, J, Adersberger, M, Adye, T, Affolder, AA, Afik, Y, Agheorghiesei, C, Aguilar-Saavedra, JA, Ahlen, SP, Ahmadov, F, Aiellia, G, Akatsuka, S, Akerstedt, H, Akesson, TPA, Akilli, E, Akimov, AV, Alberghi, GL, Albert, J, Albicocco, P, Alconada Verzini, MJ, Alderweireldt, SC, Aleksa, M, Aleksandrov, IN, Alexa, C, Alexander, G, Alexopoulos, T, Alhroob, M, Ali, B, Aliev, M, Alimonti, G, Alison, J, Alkire, SP, Allbrooke, BMM, Allen, W, Allport, PP, Aloisio, A, Alonso, A, Alonso, F, Alpigiani, C, Alshehri, AA, Alstaty, MI, Alvarez Gonzalez, B, Alvarez Piqueras, D, Alviggi, MG, Amadio, BT, Coutinho, Y Amaral, Amelung, C, Amidei, D, Amor Dos Santos, SP, Amoroso, S, Anastopoulos, C, Ancu, LS, Andari, N, Andeen, T, Anders, CF, Anders, JK, Anderson, KJ, Andreazza, A, Andrei, V, Angelidakis, S, Angelozzi, I, Angerami, A, Anisenkov, AV, Anjos, N, Annovi, A, Antel, C, Antonelli, M, Antonov, A, Antrim, DJ, Anulli, F, Aoki, M, Aperio Bella, L, Arabidze, G, Arai, Y, Araque, JP, Ferraz, V Araujo, Arce, ATH, Ardell, RE, Arduh, FA, Arguin, J-F, Argyropoulos, S, Arika, M, Armbruster, AJ, Armitage, LJ, Arnaez, O, Arnold, H, Arratia, M, Arslan, O, Artamonov, A, Artoni, G, Artz, S, Asai, S, Asbah, N, Ashkenazi, A, Asquith, L, Assamagan, K, Astalos, R, Atkinson, M, Atlay, NB, Augsten, K, Avolio, G, Axen, B, Ayoub, MK, Azuelos, G, Baas, AE, Baca, MJ, Bachacou, H, Bachas, K, Backes, M, Bagnaia, P, Bahmani, M, Bahrasemani, H, Baines, JT, Bajic, M, Baker, OK, Bakker, PJ, Baldin, EM, Balek, P, Balli, F, Balunas, WK, Banas, E, Bandyopadhyay, A, Banerjee, Sw, Bannoura, AAE, Barak, L, Barberio, EL, Barberis, D, Barbero, M, Barillari, T, Barisits, M-S, Barkeloo, JT, Barklow, T, Barlow, N, Barnes, SL, Barnett, BM, Barnett, RM, Barnovska-Blenessy, Z, Baroncelli, A, Barone, G, Barr, AJ, Navarro, L Barranco, Barreiro, F, da Costa, J Barreiro Guimaraes, Bartoldus, R, Barton, AE, Bartos, P, Basalae, A, Bassalat, A, Bates, RL, Batista, SJ, Batley, JR, Battaglia, M, Bauce, M, Bauer, F, Bauer, KT, Bawa, HS, Beacham, JB, Beattie, MD, Beau, T, Beauchemin, PH, Bechtle, P, Beck, HP, Beck, HC, Becker, K, Becker, M, Becot, C, Beddall, AJ, Beddall, A, Bednyakov, VA, Bedognetti, M, Bee, CP, Beermann, TA, Begalli, M, Begel, M, Behr, JK, Bell, AS, Bella, G, Bellagamba, L, Bellerive, A, Bellomo, M, Belotskiy, K, Beltramello, O, Belyaev, NL, Benary, O, Benchekroun, D, Bender, M, Benekos, N, Benhammou, Y, Noccioli, E Benhar, Benitez, J, Benjamin, DP, Benoit, M, Bensinger, JR, Bentvelsen, S, Beresford, L, Beretta, M, Berge, D, Kuutmann, E Bergeaas, Berger, N, Bergsten, J, Beringer, J, Berlendis, S, Bernard, NR, Bernardi, G, Bernius, C, Bernlochner, FU, Berry, T, Berta, P, Bertella, C, Bertoli, G, Bertram, IA, Bertsche, C, Besjes, GJ, Bylund, O Bessidskaia, Bessner, M, Besson, N, Bethani, A, Bethke, S, Betti, A, Bevan, AJ, Beyer, J, Bianchi, RM, Biebel, O, Biedermann, D, Bielski, R, Bierwagen, K, Biesuz, NV, Biglietti, M, Billoud, TRV, Bilokon, H, Bindi, M, Bingul, A, Bini, C, Biondi, S, Bisanz, T, Bittrich, C, Bjergaard, DM, Black, JE, Black, KM, Blair, RE, Blazek, T, Bloch, I, Blocker, C, Blue, A, Blumenschein, U, Blunier, S, Bobbink, GJ, Bobrovnikov, VS, Bocchetta, SS, Bocci, A, Bock, C, Boehler, M, Boerner, D, Bogavac, D, Bogdanchikov, AG, Bohm, C, Boisvert, V, Bokan, P, Bold, T, Boldyrev, AS, Bolz, AE, Bomben, M, Bona, M, Boonekamp, M, Borisov, A, Borissov, G, Bortfeldt, J, Bortoletto, D, Bortolotto, V, Boscherini, D, Bosman, M, Sola, JD Bossio, Boudreau, J, Bouhova-Thacker, EV, Boumediene, D, Bourdarios, C, Boutle, SK, Boveia, A, Boyd, J, Boyko, IR, Bozson, AJ, Bracinik, J, Brandt, A, Brandt, G, Brandt, O, Braren, F, Bratzler, U, Brau, B, Brau, JE, Madden, WD Breaden, Brendlinger, K, Brennan, AJ, Brenner, L, Brenner, R, Bressler, S, Briglin, DL, Bristow, TM, Britton, D, Britzger, D, Brochu, FM, Brock, I, Brock, R, Brooijmans, G, Brooks, T, Brooks, WK, Brost, E, HBroughton, J, de Renstrom, A Bruckman, Bruncko, D, Bruni, A, Bruni, G, Bruni, LS, Bruno, S, Brunt, BH, Bruschi, M, Bruscino, N, Bryant, P, Bryngemark, L, Buanes, T, Buat, Q, Buchholz, P, Buckley, AG, Budagov, IA, Buehrer, F, Bugge, MK, Bulekov, O, Bullock, D, Burch, TJ, Burdin, S, Burgard, CD, Burger, AM, Burghgrave, B, Burka, K, Burke, S, Burmeister, I, Burr, JTP, Buecher, D, Buecher, V, Bussey, P, Butler, JM, Buttar, CM, Butterworth, JM, Butti, P, Buttinger, W, Buzatu, A, Buzykaev, AR, Changqiao, CQ, Cabrera Urban, S, Caforio, D, Cai, H, Cairo, VM, Cakir, O, Calace, N, Calafiura, P, Calandri, A, Calderini, G, Calfayan, P, Callea, G, Caloba, LP, Calvente Lopez, S, Calvet, D, Calvet, TP, CamachoToro, R, Camarda, S, Camarri, P, Cameron, D, Armadans, R Caminal, Camincher, C, Campana, S, Campanelli, M, Camplani, A, Campoverde, A, Canale, V, Bret, M Cano, Cantero, J, Cao, T, Garrido, MDM Capeans, Caprini, I, Caprini, M, Capua, M, Carbone, RM, Cardarelli, R, Cardillo, F, Carli, I, Carli, T, Carlino, G, Carlson, BT, Carminati, L, Carney, RMD, Caron, S, Carquin, E, Carra, S, Carrillo-Montoya, GD, Casadei, D, Casado, MP, Casha, AF, Casolino, M, Casper, DW, Castelijn, R, Gimenez, V Castillo, Castro, NF, Catinaccio, A, Catmore, JR, Cattai, A, Caudron, J, Cavaliere, V, Cavallaro, E, Cavalli, D, Cavalli-Sforza, M, Cavasinni, V, Celebi, E, Ceradini, F, Cerda Alberich, L, Cerqueira, AS, Cerri, A, Cerrito, L, Cerutti, F, Cervelli, A, Cetin, SA, Chafaq, A, Chakraborty, D, Chan, SK, Chan, WS, Chan, YL, Chang, P, Chapman, JD, Charlton, DG, Chau, CC, Barajas, CA Chavez, Che, S, Chegwidden, A, Chekanov, S, Chekulaev, SV, Chelkov, GA, Chelstowska, MA, Chen, C, Chen, H, Chen, J, Chen, S, Chen, X, Chen, Y, Cheng, HC, Cheng, HJ, Cheplakov, A, Cheremushkina, E, Cherkaoui El Moursli, R, Cheu, E, Cheung, K, Chevalier, L, Chiarella, V, Chiarelli, G, Chiodini, G, Chisholm, AS, Chitan, A, Chiu, YH, Chizhov, MV, Choi, K, Chomont, AR, Chouridou, S, Chow, YS, Christodoulou, V, Chu, MC, Chudoba, J, Chuinard, AJ, Chwastowski, JJ, Chytka, L, Ciftci, AK, Cinca, D, Cindro, V, Cioara, IA, Ciocio, A, Cirotto, F, Citron, ZH, Citterio, M, Ciubancan, M, Clark, A, Clark, MR, Clark, PJ, Clarke, RN, Clement, C, Coadou, Y, Cobal, M, Coccaro, A, Cochran, J, Colasurdo, L, Cole, B, Colijn, AP, Collot, J, Colombo, T, Muino, P Conde, Coniavitis, E, Connell, SH, Connelly, IA, Constantinescu, S, Conti, G, Conventi, F, Cooke, M, Cooper-Sarkar, AM, Cormier, F, Cormier, KJR, Corradi, M, Corrigan, EE, Corriveau, F, Cortes-Gonzalez, A, Costa, G, Costa, MJ, Costanzo, D, Cottin, G, Cowan, G, Cox, BE, Cranmer, K, Crawley, SJ, Creager, RA, Cree, G, Crepe-Renaudin, S, Crescioli, F, Cribbs, WA, Cristinziani, M, Croft, V, Crosetti, G, Cueto, A, Donszelmann, T Cuhadar, Cukierman, AR, Cummings, J, Curatolo, M, Cuth, J, Czekierda, S, Czodrowski, P, D'amen, G, D'Auria, S, D'eramo, L, D'Onofrio, M, Da Cunha Sargedas De Sousa, MJ, Da Via, C, Dabrowski, W, Dado, T, Dai, T, Dale, O, Dallaire, F, Dallapiccola, C, Dam, M, Dandoy, JR, Daneri, MF, Dang, NP, Daniells, AC, Dann, NS, Danninger, M, DanoHoffmann, M, Dao, V, Darbo, G, Darmora, S, Dassoulas, J, Dattagupta, A, Daubney, T, Davey, W, David, C, Davidek, T, Davis, DR, Davison, P, Dawe, E, Dawson, I, De, K, de Asmundis, R, De Benedetti, A, De Castro, S, De Cecco, S, De Groot, N, de Jong, P, De la Torre, H, De Lorenzi, F, De Maria, A, De Pedis, D, De Salvo, A, De Sanctis, U, De Santo, A, Corga, K De Vasconcelos, De Regie, JB De Vivie, Debbe, R, Debenedetti, C, Dedovich, DV, Dehghanian, N, Deigaard, I, Del Gaudio, M, Del Peso, J, Delgove, D, Deliot, F, Delitzsch, CM, Dell'Acqua, A, Dell'Asta, L, Dell'Orso, M, Della Pietra, M, della Volpe, D, Delmastro, M, Delporte, C, Delsart, PA, DeMarco, DA, Demers, S, Demichev, M, Demilly, A, Denisov, SP, Denysiuk, D, Derendarz, D, Derkaoui, JE, Derue, F, Dervan, P, Desch, K, Deterre, C, Dette, K, Devesa, MR, Deviveiros, PO, Dewhurst, A, Dhaliwal, S, Di Bello, FA, Di Ciaccio, A, Di Ciaccio, L, Di Clemente, WK, Di Donato, C, Di Girolamo, A, Di Girolamo, B, Di Micco, B, Di Nardo, R, Di Petrillo, KF, Di Simone, A, Di Sipio, R, Di Valentino, D, Diaconu, C, Diamond, M, Dias, FA, Diaz, MA, Dickinson, J, Diehl, EB, Dietrich, J, Cornell, S Diez, Dimitrievska, A, Dingfelder, J, Dita, P, Dita, S, Dittus, F, Djama, F, Djobava, T, Djuvsland, JI, do Vale, MAB, Dobre, M, Dodsworth, D, Doglioni, C, Dolejsi, J, Dolezal, Z, Donadelli, M, Donati, S, Donini, J, Dopke, J, Doria, A, Dova, MT, Doyle, AT, Drechsler, E, Dris, M, Dub, Y, Duarte-Campderros, J, Dubinin, F, Dubreuil, A, Duchovni, E, Duckeck, G, Ducourthial, A, Ducu, OA, Duda, D, Dudarev, A, Dudder, A Chr, Duffield, EM, Duflot, L, Duhrssen, M, Dulsen, C, Dumancic, M, Dumitriu, AE, Duncan, AK, Dunford, M, Duperrin, A, Yildiz, H Duran, Dueren, M, Durglishvili, A, Duschinger, D, Dutta, B, Duvnjak, D, Dyndal, M, Dziedzic, BS, Eckardt, C, Ecker, KM, Edgar, RC, Eifert, T, Eigen, G, Einsweiler, K, Ekelof, T, El Kacimi, M, El Kosseifi, R, Ellajosyula, V, Ellert, M, Elles, S, Ellinghaus, F, Elliot, AA, Ellis, N, Elmsheuser, J, Elsing, M, Emeliyanov, D, Enari, Y, Ennis, JS, Epland, MB, Erdmann, J, Ereditato, A, Ernst, M, Errede, S, Escalier, M, Escobar, C, Esposito, B, Pastor, O Estrada, Etienvre, AI, Etzion, E, Evans, H, Ezhilov, A, Ezzie, M, Fabbri, F, Fabbri, L, Fabiani, V, Facini, G, Fakhrutdinov, RM, Falciano, S, Falla, RJ, Faltova, J, Fang, Y, Fanti, M, Farbin, A, Farilla, A, Farina, EM, Farooque, T, Farrell, S, Farrington, SM, Farthouat, P, Fassi, F, Fassnacht, P, Fassouliotis, D, Giannelli, M Faucci, Favareto, A, Fawcett, WJ, Fayard, L, Fedin, OL, Fedorko, W, Feigl, S, Feligioni, L, Feng, C, Feng, EJ, Feng, M, Fenton, MJ, Fenyuk, AB, Feremenga, L, Martinez, P Fernandez, Ferrando, J, Ferrari, A, Ferrari, P, Ferrari, R, de Lima, DE Ferreira, Ferrer, A, Ferrere, D, Ferretti, C, Fiedler, F, Filipcic, A, Filipuzzi, M, Filthaut, F, Fincke-Keeler, M, Finelli, KD, Fiolhais, MCN, Fiorini, L, Fischer, A, Fischer, C, Fischer, J, Fisher, WC, Flaschel, N, Fleck, I, Fleischmann, P, Fletcher, RRM, Flick, T, Flierl, BM, Castilloa, LR Flores, Flowerdew, MJ, Forcolin, GT, Formica, A, Forster, FA, Forti, A, Foster, AG, Fournier, D, Fox, H, Fracchia, S, Francavilla, P, Franchini, M, Franchino, S, Francis, D, Franconi, L, Franklin, M, Frate, M, Fraternali, M, Freeborn, D, Fressard-Batraneanu, SM, Freund, B, Froidevaux, D, Frost, JA, Fukunaga, C, Fusayasu, T, Fuster, J, Gabizon, O, Gabrielli, A, Gach, GP, Gadatsch, S, Gadomski, S, Gagliardi, G, Gagnon, LG, Galea, C, Galhardo, B, Gallas, EJ, Gallop, BJ, Gallus, P, Galster, G, Gan, KK, Ganguly, S, Gao, Y, Gao, YS, Walls, FM Garay, Garcia, C, Garcia Navarro, JE, Pascual, JA Garcia, Garcia-Sciveres, M, Gardner, RW, Garelli, N, Garonne, V, Bravo, A Gascon, Gasnikova, K, Gatti, C, Gaudiello, A, Gaudio, G, Gavrilenko, IL, Gay, C, Gaycken, G, Gazis, EN, Gee, CNP, Geisen, J, Geisen, M, Geisler, MP, Gellerstedt, K, Gemme, C, Genest, MH, Geng, C, Gentile, S, Gentsos, C, George, S, Gerbaudo, D, Gessner, G, Ghasemi, S, Ghneimat, M, Giacobbe, B, Giagu, S, Giangiacomi, N, Giannetti, P, Gibson, SM, Gignac, M, Gilchriese, M, Gillberg, D, Gilles, G, Gingrich, DM, Giordani, MP, Giorgi, FM, Giraud, PF, Giromini, P, Giugliarelli, G, Giugni, D, Giuli, F, Giuliani, C, Giulini, M, Gjelsten, BK, Gkaitatzis, S, Gkialas, I, Gkougkousis, EL, Gkountoumis, P, Glasman, C, Glatzer, J, Glaysher, PCF, Glazov, A, Goblirsch-Kolb, M, Godlewski, J, Goldfarb, S, Golling, T, Golubkov, D, Gomes, A, Goncalo, R, Gama, R Goncalves, Da Costa, J Goncalves Pinto Firmino, Gonella, G, Gonella, L, Gongadze, A, Gonnella, F, Gonski, JL, Gonzalez de la Hoz, S, Gonzalez-Sevilla, S, Goossens, L, Gorbounov, PA, Gordon, HA, Gorini, B, Gorini, E, Gorisek, A, Goshaw, AT, Goessling, C, Gostkin, MI, Gottardo, CA, Goudet, CR, Goujdamic, D, Goussiou, AG, Govender, N, Gozani, E, Grabowska-Bold, I, Gradin, POJ, Graham, EC, Gramling, J, Gramstad, E, 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PF, Hartmann, NM, Hasegawa, Y, Hasib, A, Hassani, S, Haug, S, Hauser, R, Hauswald, L, Havener, LB, Havranek, M, Hawkes, CM, Hawkings, RJ, Hayden, D, Hays, CP, Hays, JM, Hayward, HS, Haywood, SJ, Heck, T, Hedberg, V, Heelan, L, Heer, S, Heidegger, KK, Heim, S, Heim, T, Heinemann, B, Heinrich, JJ, Heinrich, L, Heinz, C, Hejbal, J, Helary, L, Held, A, Hellman, S, Helsens, C, Henderson, RCW, Heng, Y, Henkelmann, S, Correia, AM Henriques, Henrot-Versille, S, Herbert, GH, Herde, H, Herget, V, Jimenez, Y Hernandez, Herr, H, Herten, G, Hertenberger, R, Hervas, L, Herwig, TC, Hesketh, GG, Hessey, NP, Hetherly, JW, Higashino, S, Higon-Rodriguez, E, Hildebrand, K, Hill, E, Hill, JC, Hiller, KH, Hillier, SJ, Hils, M, Hinchliffe, I, Hirose, M, Hirschbuehl, D, Hiti, B, Hladik, O, Hlaluku, DR, Hoad, X, Hobbs, J, Hod, N, Hodgkinson, MC, Hodgson, P, Hoecker, A, Hoeferkamp, MR, Hoenig, F, Hohn, D, Holmes, TR, Holzbock, M, Homann, M, Honda, S, Honda, T, Hong, TM, Hooberman, BH, Hopkins, WH, Horii, Y, 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Sadrozinski, HF-W, Sadykov, R, Tehrani, F Safai, Saha, P, Sahinsoy, M, Saimpert, M, Saito, M, Saito, T, Sakamoto, H, Sakurai, Y, Salamanna, G, Loyola, JE Salazar, Salek, D, De Bruin, PH Sales, Salihagic, D, Salnikov, A, Salt, J, Salvatore, D, Salvatore, F, Salvucci, A, Salzburger, A, Sammel, D, Sampsonidis, D, Sampsonidou, D, Sanchez, J, Pineda, A Sanchez, Sandaker, H, Sandbach, RL, Sander, CO, Sandhoff, M, Sandoval, C, Sankey, DPC, Sannino, M, Sano, Y, Sansoni, A, Santoni, C, Santos, H, Castillo, I Santoyo, Sapronov, A, Saraiva, JG, Sasaki, O, Sato, K, Sauvan, E, Savage, G, Savard, P, Savic, N, Sawyer, C, Sawyer, L, Sbarra, C, Sbrizzi, A, Scanlon, T, Scannicchio, DA, Schaarschmidt, J, Schacht, P, Schachtner, BM, Schaefer, D, Schaefer, L, Schaeffer, J, Schaepe, S, Schaetzel, S, Schafer, U, Schaffer, AC, Schaile, D, Schamberger, RD, Schegelsky, VA, Scheirich, D, Schenck, F, Schernau, M, Schiavi, C, Schier, S, Schildgen, LK, Schillo, C, Schioppa, M, Schlenker, S, Schmidt-Sommerfeld, KR, 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Shrestha, S, Shulga, E, Shupe, MA, Sicho, P, Sickles, AM, Sidebo, PE, Haddad, E Sideras, Sidiropoulou, O, Sidoti, A, Siegert, F, Sijacki, Dj, Silva, J, Silverstein, SB, Simak, V, Simic, L, Simion, S, Simioni, E, Simmons, B, Simon, M, Sinervo, P, Sinev, NB, Sioli, M, Siragusa, G, Siral, I, Sivoklokov, S Yu, Sjolin, J, Skinner, MB, Skubic, P, Slater, M, Slavicek, T, Slawinska, M, Sliwa, K, Slovak, R, Smakhtin, V, Smart, BH, Smiesko, J, Smirnov, N, Smirnov, S Yu, Smirnov, Y, Smirnova, LN, Smirnova, O, Smith, JW, Smith, MNK, Smith, W, Smizanska, M, Smolek, K, Snesarev, AA, Snyder, IM, Snyder, S, Sobie, R, Socher, F, Soffer, A, Sogaard, A, Soh, DA, Sokhrannyi, G, SolansSanchez, CA, Solar, M, Soldatov, E Yu, Soldevila, U, Solodkov, AA, Soloshenko, A, Solovyanov, OV, Solovyev, V, Sommer, P, Son, H, Sopczak, A, Sosa, D, Sotiropoulou, CL, Sottocornola, S, Soualah, R, Soukharev, AM, South, D, Sowden, BC, Spagnolo, S, Spalla, M, Spangenberg, M, Spano, F, Sperlich, D, Spettel, F, Spieker, TM, Spighi, R, Spigo, G, Spiller, LA, Spousta, M, St Denis, RD, Stabile, A, Stamen, R, Stamm, S, Stanecka, E, Stanek, RW, Stanescu, C, Stanitzki, MM, Stapf, BS, Stapnes, S, Starchenko, EA, Stark, GH, Stark, J, HStark, S, Staroba, P, Starovoitov, P, Starz, S, Staszewski, R, Stegler, M, Steinberg, P, Stelzer, B, Stelzer, HJ, Stelzer-Chilton, O, Stenzel, H, Stevenson, TJ, Stewart, GA, Stockton, MC, Stoebe, M, Stoicea, G, Stolte, P, Stonjek, S, Stradling, AR, Straessner, A, Stramaglia, ME, Strandberg, J, Strandberg, S, Strauss, M, Strizenec, P, Strohmer, R, Strom, DM, Stroynowski, R, Strubig, A, Stucci, SA, Stugu, B, Styles, NA, Su, D, Su, J, Suchek, S, Sugaya, Y, Suk, M, Sulin, VV, Sultan, DMS, Sultansoy, S, Sumida, T, Sun, S, Sun, X, Suruliz, K, Suster, CJE, Sutton, MR, Suzuki, S, Svatos, M, Swiatlowski, M, Swift, SP, Sykora, I, Sykora, T, Ta, D, Tackmann, K, Taenzer, J, Taffard, A, Tafirout, R, Tahirovic, E, Taiblum, N, Takai, H, Takashima, R, Takasugi, EH, Takeda, K, Takeshita, T, Takubo, Y, Talby, M, Talyshev, AA, Tanaka, J, Tanaka, M, Tanaka, R, Tanioka, R, Tannenwald, BB, Araya, S Tapia, Tapprogge, S, Tarem, S, Tartarelli, GF, Tas, P, Tasevsky, M, Tashiro, T, Tassi, E, Delgado, A Tavares, Tayalati, Y, Taylor, AC, Taylor, AJ, Taylor, GN, Taylor, TE, Taylor, W, Teixeira-Dias, P, Temple, D, Ten Kate, H, Teng, PK, Teoh, JJ, Tepel, F, Terada, S, Terashi, K, Terron, J, Terzo, S, Testa, M, Teuscher, RJ, Thais, SJ, Theveneaux-Pelzer, T, Thiele, F, Thomas, JP, Thomas-Wilsker, J, Thompson, PD, Thompson, AS, Thomsen, LA, Thomson, E, Tian, Y, Tibbetts, MJ, Torres, RE Ticse, Tikhomirov, VO, Tikhonov, Yu A, Timoshenko, S, Tipton, P, Tisserant, S, Todome, K, Todorova-Nova, S, Todt, S, Tojo, J, Tokar, S, Tokushuku, K, Tolley, E, Tomlinson, L, Tomoto, M, Tompkins, L, Toms, K, Tong, B, Tornambe, P, Torrence, E, Torres, H, Pastor, E Torro, Toth, J, Touchard, F, Tovey, DR, Treado, CJ, Trefzger, T, Tresoldi, F, Tricoli, A, Trigger, IM, Trincaz-Duvoid, S, Tripiana, MF, Trischuk, W, Trocme, B, Trofymov, A, Troncon, C, Trovatelli, M, Truong, L, Trzebinski, M, Trzupek, A, Tsang, KW, Tseng, JC-L, Tsiareshka, PV, Tsirintanis, N, Tsiskaridze, S, Tsiskaridze, V, Tskhadadze, EG, Tsukerman, II, Tsulaia, V, Tsuno, S, Tsybychev, D, Tu, Y, Tudorache, A, Tudorache, V, Tulbure, TT, Tuna, AN, Turchikhin, S, Turgeman, D, Cakir, I Turk, Turra, R, Tuts, PM, Ucchielli, G, Ueda, I, Ughetto, M, Ukegawa, F, Unal, G, Undrus, A, Unel, G, Ungaro, FC, Unno, Y, Uno, K, Urbanb, J, Urquijo, P, Urrejola, P, Usai, G, Usui, J, Vacavant, L, Vacek, V, Vachon, B, Vadla, KOH, Vaidya, A, Valderanis, C, Santurio, E Valdes, Valente, M, Valentinetti, S, Valero, A, Valery, L, Vallier, A, Ferrer, JA Valls, Van den Wollenberg, W, Van der Graaf, H, van Gemmeren, P, Van Nieuwkoop, J, vanVulpen, I, vanWoerden, MC, Vanadia, M, Vandelli, W, Vaniachine, A, Vankov, P, Vardanyan, G, Vari, R, Varnes, EW, Varni, C, Varol, T, Varouchas, D, Vartapetian, A, Varvell, KE, Vasquez, JG, Vasquez, GA, Vazeille, F, Vazquez Furelos, D, Schroeder, T Vazquez, Veatch, J, Veeraraghavan, V, Veloce, LM, Veloso, F, Veneziano, S, Ventura, A, Venturi, M, Venturi, N, Vercesi, V, Verducci, M, Verkerke, W, Vermeulen, AT, Vermeulen, JC, Vetterli, MC, Maira, N Viaux, Viazlo, O, Vichou, I, Vickey, T, Boeriu, OE Vickey, Viehhauser, GHA, Viel, S, Vigani, L, Villa, M, Perez, M Villaplana, Vilucchi, E, Vincter, MG, Vinogradov, VB, Vishwakarma, A, Vittori, C, Vivarelli, I, Vlachos, S, Vogel, M, Vokac, P, Volpi, G, von Buddenbrock, SE, von der Schmitt, H, von Toerne, E, Vorobel, V, Vorobev, K, Vos, M, Voss, R, Vossebeld, JH, Vranjes, N, Milosavljevic, M Vranjes, Vrba, V, Vreeswijk, M, Vuillermet, R, Vukotic, I, Wagner, P, Wagner, W, Wagner-Kuhr, J, Wahlberg, H, Wahrmund, S, Wakamiya, K, Walder, J, Walker, R, Walkowiak, W, Wallangen, V, Wang, C, Wang, F, Wang, H, Wang, J, Wang, Q, Wang, R-J, Wang, R, Wang, SM, Wang, T, Wang, W, Wang, Z, Wanotayaroj, C, Warburton, A, Ward, CP, Wardrope, DR, Washbrook, A, Watkins, PM, Watson, AT, Watson, MF, Watts, G, Watts, S, Waugh, BM, Webb, AF, Webb, S, Weber, MS, Weber, SM, Weber, SW, Weber, SA, Webster, JS, Weidberg, AR, Weinert, B, Weingarten, J, Weirich, M, Weiser, C, Wells, PS, Wenaus, T, Wengler, T, Wenig, S, Wermes, N, Werner, MD, Werner, P, Wessels, M, Weston, TD, Whalen, K, Whallon, NL, Wharton, AM, White, AS, White, A, White, MJ, White, R, Whiteson, D, Whitmore, BW, Wickens, FJ, Wiedenmann, W, Wielers, M, Wiglesworth, C, Wiik-Fuchs, LAM, Wildauer, A, Wilk, F, Wilkens, HG, Williams, HH, Williams, S, Willis, C, Willocq, S, Wilson, JA, Wingerter-Seez, I, Winkels, E, Winklmeier, F, Winston, OJ, Winter, BT, Wittgen, M, Wobisch, M, Wolf, A, Wolf, TMH, Wolff, R, Wolter, MW, Wolters, H, Wong, VWS, Woods, NL, Worm, SD, Wosiek, BK, Wotschack, J, Wozniak, KW, Wu, M, Wu, SL, Wu, X, Wu, Y, Wyatt, TR, Wynne, BM, Xella, S, Xi, Z, Xia, L, Xu, D, Xu, L, Xu, T, Xu, W, Yabsley, B, Yacoob, S, Yamaguchi, D, Yamaguchi, Y, Yamamoto, A, Yamamoto, S, Yamanaka, T, Yamane, F, Yamatani, M, Yamazaki, T, Yamazaki, Y, Yan, Z, Yang, H, Yang, Y, Yang, Z, Yao, W-M, Yap, YC, Yasu, Y, Yatsenko, E, Wong, KH Yau, Ye, J, Ye, S, Yeletskikh, I, Yigitbasi, E, Yildirim, E, Yorita, K, Yoshihara, K, Young, C, Young, CJS, Yu, J, Yuen, SPY, Yusuff, I, Zabinski, B, Zacharis, G, Zaidan, R, Zaitsev, AM, Zakharchuk, N, Zalieckas, J, Zaman, A, Zambito, S, Zanzi, D, Zeitnitz, C, Zemaityte, G, Zemla, A, Zeng, JC, Zeng, Q, Zenin, O, Zenis, T, Zerwas, D, Zhang, D, Zhang, F, Zhang, G, Zhang, H, Zhang, J, Zhang, L, Zhang, M, Zhang, P, Zhang, R, Zhang, X, Zhang, Y, Zhang, Z, Zhao, X, Zhao, Y, Zhao, Z, Zhemchugov, A, Zhou, B, Zhou, C, Zhou, L, Zhou, M, Zhou, N, Zhou, Y, Zhu, CG, Zhu, H, Zhu, J, Zhu, Y, Zhuang, X, Zhukov, K, Zibell, A, Zieminska, D, Zimine, NI, Zimmermann, C, Zimmermann, S, Zinonos, Z, Zinser, M, Ziolkowski, M, Zivkovic, L, Zobernig, G, Zoccoli, A, Zou, R, zur Nedden, M, Zwalinski, L, and Collaboration, ATLAS

Subjects
Astrophysics::High Energy Astrophysical Phenomena, High Energy Physics::Phenomenology, High Energy Physics::Experiment, Nuclear Experiment
Abstract

This Letter presents the measurement of differential cross sections of isolated prompt photons produced in association with a b-jet or a c-jet. These final states provide sensitivity to the heavy-flavour content of the proton and aspects related to the modelling of heavy-flavour quarks in perturbative QCD. The measurement uses proton-proton collision data at a centre-of-mass energy of 8 TeV recorded by the ATLAS detector at the LHC in 2012 corresponding to an integrated luminosity of up to 20.2 fb(-1). The differential cross sections are measured for each jet flavour with respect to the transverse energy of the leading photon in two photon pseudorapidity regions: vertical bar eta(gamma)vertical bar < 1.37 and 1.56 < vertical bar eta(gamma)vertical bar < 2.37. The measurement covers photon transverse energies 25 < E-T(gamma) < 400 GeV and 25 < E-T(gamma) < 350 GeV respectively for the two vertical bar eta(gamma)vertical bar regions. For each jet flavour, the ratio of the cross sections in the two vertical bar eta(gamma)vertical bar regions is also measured. The measurement is corrected for detector effects and compared to leading-order and next-to-leading-order perturbative QCD calculations, based on various treatments and assumptions about the heavy-flavour content of the proton. Overall, the predictions agree well with the measurement, but some deviations are observed at high photon transverse energies. The total uncertainty in the measurement ranges between 13% and 66%, while the central gamma+b measurement exhibits the smallest uncertainty, ranging from 13% to 27%, which is comparable to the precision of the theoretical predictions. (c) 2017 The Author. Published by Elsevier B.V.

Published
2018

8. Linking EPCR-Binding PfEMP1 to Brain Swelling in Pediatric Cerebral Malaria

Author

Kessler, A, Dankwa, S, Bernabeu, M, Harawa, V, Danziger, SA, Duffy, F, Kampondeni, SD, Potchen, MJ, Dambrauskas, N, Vigdorovich, V, Oliver, BG, Hochman, SE, Mowrey, WB, MacCormick, IJC, Mandala, WL, Rogerson, SJ, Sather, DN, Aitchison, JD, Taylor, TE, Seydel, KB, Smith, JD, and Kim, K

Subjects
Immunology
Abstract

© 2017 Elsevier Inc. Brain swelling is a major predictor of mortality in pediatric cerebral malaria (CM). However, the mechanisms leading to swelling remain poorly defined. Here, we combined neuroimaging, parasite transcript profiling, and laboratory blood profiles to develop machine-learning models of malarial retinopathy and brain swelling. We found that parasite var transcripts encoding endothelial protein C receptor (EPCR)-binding domains, in combination with high parasite biomass and low platelet levels, are strong indicators of CM cases with malarial retinopathy. Swelling cases presented low platelet levels and increased transcript abundance of parasite PfEMP1 DC8 and group A EPCR-binding domains. Remarkably, the dominant transcript in 50% of swelling cases encoded PfEMP1 group A CIDRα1.7 domains. Furthermore, a recombinant CIDRα1.7 domain from a pediatric CM brain autopsy inhibited the barrier-protective properties of EPCR in human brain endothelial cells in vitro. Together, these findings suggest a detrimental role for EPCR-binding CIDRα1 domains in brain swelling. Brain swelling is associated with cerebral malaria mortality, but the parasite and host factors responsible for development of brain swelling are unknown. Kessler et al. demonstrate an association of low platelet count and EPCR-binding PfEMP1 with brain swelling in children with cerebral malaria.

Published
2017

9. Surgical site infections after pediatric open airway reconstruction—A National Surgical Quality Improvement Program‐Pediatric analysis

Author

Romaine F. Johnson, Taylor Teplitzky, Erin M. Wynings, Yann‐Fuu Kou, and Stephen R. Chorney

Subjects
pediatric airway surgery, surgical site infections, wound dehiscence, Otorhinolaryngology, RF1-547, Surgery, RD1-811
Abstract

Abstract Objectives To determine the rate of surgical site infections (SSI) after pediatric open airway reconstruction using a nationwide database. Study Design Cross‐sectional study of the American College of Surgeons National Surgical Quality Improvement Program‐Pediatric (ACS NSQIP‐P) Database. Methods The ACS NSQIP‐P was queried for open airway surgeries between 2013 and 2019 determining postoperative SSI and wound dehiscence with a random sample of non‐airway cases serving as a control group. Results A total of 637 laryngotracheoplasties (LTP), 411 tracheal resections (TR) and 2100 control procedures were included. LTP and TR were both performed on younger children with more comorbidities than control surgeries (p

Published
2022
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10. Prophylactic relationship between mental health disorder symptoms and physical activity of Royal Canadian Mounted Police Cadets during the cadet training program

Author

Taylor Teckchandani, Rachel L. Krakauer, Katie L. Andrews, J. Patrick Neary, Jolan Nisbet, Robyn E. Shields, Kirby Q. Maguire, Laleh Jamshidi, Tracie O. Afifi, Lisa M. Lix, Shannon Sauer-Zavala, Gordon J. G. Asmundson, Gregory P. Krätzig, and R. Nicholas Carleton

Subjects
posttraumatic stress injuries, exercise, protective factors, Royal Canadian Mounted Police, apple watch, Psychology, BF1-990
Abstract

ObjectiveRoyal Canadian Mounted Police report experiencing extremely frequent potentially psychologically traumatic events (PPTE). In a recent study, approximately half of participating RCMP screened positive for one or more mental disorders, which is approximately five times the diagnostic proportion for the general Canadian population. Increased reporting of mental health symptoms been linked to PPTE exposures. Programs promoting physical activity may be useful interventions to supplement or pair with mental health interventions, providing anxiolytic, antidepressant, and stress-buffering effects. The current study was designed to assess the relationship between physical activity behaviors and reported mental health disorder symptoms of cadets during the Royal Mounted Canadian Police (RCMP) Cadet Training Program (CTP). The current study also examined the relationship between exercise and mental health disorder symptoms of cadets during the CTP.MethodsThe study included data from 394 cadets (76.1% male). An analysis of variance (ANOVA) and a series of t-tests were used to assess several differences across sociodemographic groups. Bivariate Spearman’s Rank correlations were performed between the average number of active calories burned per day, as recorded by Apple Watches, and changes in self-reported mental health disorder symptoms (i.e., Generalized Anxiety Disorder [GAD], Major Depressive Disorder [MDD], Posttraumatic Stress Disorder [PTSD], Social Anxiety Disorder [SAD]. Alcohol Use Disorders [AUD], Panic Disorder [PD]) from pre-training (starting the CTP) to pre-deployment (completing the CTP) 26 weeks later.ResultsThere were statistically significant correlations between physical activity and self-reported mental health disorder symptom scores during CTP. Cadets who performed more physical activity from pre-training to pre-deployment had statistically significantly greater decreases in symptoms of GAD (ρ = −0.472, p 0.05). There were also no statistically significant relationships between pre-CTP mental health disorder symptom scores and the volume of physical activity performed during CTP.ConclusionThere was evidence of a significant relationship between reductions in mental health disorder symptom scores and physical activity during the 26-week CTP. The results highlight the role that exercise can play as an important tool for reducing mental health disorder symptoms, considering there was no relationship between pre-CTP baseline mental health scores and physical activity performed during CTP. Further research is needed to understand differences in physical activity behaviours among cadets and serving RCMP.

Published
2023
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12. Screening unfixed cadavers with handheld ultrasound as a new teaching modality

Author

Min Ji Son, Alexander Thomas, Garrett Jackson, Debini Banh, Taylor Terlizzese, James Oh, Jack Burrows, Rahul Vedantam, Shanon Quach, and John Gibson

Subjects
Special situations and conditions, RC952-1245, Public aspects of medicine, RA1-1270
Abstract

Introduction: With the introduction of portable handheld ultrasounds, higher levels of technology are more easily available for patients in rural and underserved communities. Point-of-care ultrasound (POCUS) increases accessibility for patients with limited resources, thus reducing costs and decreasing the risk of non-compliance or subsequent loss to follow-up. Despite the increasing utility of ultrasonography, literature demonstrates a lack of sufficient training in POCUS and ultrasound-guided techniques for Family Medicine residents. Integrating unfixed cadavers into the preclinical curriculum may be an ideal adjunct to simulating pathologies and screening sensitive regions.Methods: In total, 27 unfixed, de-identified cadavers were scanned with a handheld portable ultrasound. Sixteen body systems were screened: ocular, thyroid, carotid artery/internal jugular vein, brachial plexus, heart, kidneys, pancreas, gallbladder, liver, aorta and inferior vena cava, femoral artery and vein, knee, popliteal vessels, uterus, scrotum, and shoulder.Results: Eight of the sixteen body systems, including the ocular, thyroid, carotid artery/internal jugular vein, brachial plexus, liver, knee, scrotum, and shoulder, consistently showed accurate anatomy and pathology. A physician skilled in ultrasound reviewed images obtained from the cadavers and concluded that differences in anatomy and common pathologies of unfixed cadavers were indiscernible compared with live patient ultrasound images.Discussion: Using unfixed cadavers in POCUS training can be a valuable educational tool in preparing Family Medicine Physicians for rural or remote practices because the cadavers display accurate anatomy and pathology under ultrasound evaluation in multiple body systems. Further studies should explore creating artificial pathologies in cadaveric models to broaden the scope of application.

Published
2023
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13. Mild poikilocapnic hypoxia increases very low frequency haemoglobin oxygenation oscillations in prefrontal cortex

Author

Agnieszka Gruszecka, Monika Waskow, Marta A. Malkiewicz, J. Patrick Neary, Jyotpal Singh, Taylor Teckchandani, Gregory P. Kratzig, Magdalena Wszedybyl-Winklewska, Andrzej F. Frydrychowski, Jacek Rumiński, Natalia Głowacka, Piotr Lass, Pawel J. Winklewski, and Marcin Gruszecki

Subjects
Hypoxia, Wavelet transform, Blood pressure, Subarachnoid space width, Near infrared spectroscopy, Biology (General), QH301-705.5
Abstract

Abstract Background The aim of the study was to investigate the effect of mild cerebral hypoxia on haemoglobin oxygenation (HbO2), cerebrospinal fluid dynamics and cardiovascular physiology. To achieve this goal, four signals were recorded simultaneously: blood pressure, heart rate / electrocardiogram, HbO2 from right hemisphere and changes of subarachnoid space (SAS) width from left hemisphere. Signals were registered from 30 healthy, young participants (2 females and 28 males, body mass index = 24.5 ± 2.3 kg/m2, age 30.8 ± 13.4 years). Results We analysed the recorded signals using wavelet transform and phase coherence. We demonstrated for the first time that in healthy subjects exposed to mild poikilokapnic hypoxia there were increases in very low frequency HbO2 oscillations (

Published
2021
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14. A sensitive and specific LC-MS/MS method for rapid diagnosis of Niemann-Pick C1 disease from human plasma

Author

Jessie Zhang, Hideji Fujiwara, Frances M. Platt, Jean E. Schaffer, Danielle Taylor te Vruchte, Daniel S. Ory, Anneliese O. Speak, Dennis J. Dietzen, Rohini Sidhu, Forbes D. Porter, David E. Scherrer, Nicole M. Yanjanin, and Xuntian Jiang

Subjects
Adult, Male, Time Factors, Adolescent, Oxysterol, QD415-436, Pharmacology, Tandem mass spectrometry, Sensitivity and Specificity, Biochemistry, diagnostic tools, Dimethylglycine, Young Adult, chemistry.chemical_compound, Endocrinology, Tandem Mass Spectrometry, Liquid chromatography–mass spectrometry, hemic and lymphatic diseases, Methods, medicine, Humans, Child, Derivatization, Ketocholesterols, Chromatography, High Pressure Liquid, Niemann–Pick disease, type C, Chromatography, Infant, Newborn, neurodegeneration, Infant, cholesterol, Niemann-Pick Disease, Type C, Sarcosine, Cell Biology, Middle Aged, medicine.disease, chemistry, Case-Control Studies, Child, Preschool, Calibration, oxysterols, Female, lipids (amino acids, peptides, and proteins), NPC1, Niemann–Pick disease, liquid chromatography/tandem mass spectrometry, Niemann-Pick disease, Cholestanols
Abstract

Niemann-Pick type C1 (NPC1) disease is a rare, progressively fatal neurodegenerative disease for which there are no FDA-approved therapies. A major barrier to developing new therapies for this disorder has been the lack of a sensitive and noninvasive diagnostic test. Recently, we demonstrated that two cholesterol oxidation products, specifically cholestane-3β,5α,6β-triol (3β,5α,6β-triol) and 7-ketocholesterol (7-KC), were markedly increased in the plasma of human NPC1 subjects, suggesting a role for these oxysterols in diagnosis of NPC1 disease and evaluation of therapeutics in clinical trials. In the present study, we describe the development of a sensitive and specific LC-MS/MS method for quantifying 3β,5α,6β-triol and 7-KC human plasma after derivatization with N,N-dimethylglycine. We show that dimethylglycine derivatization successfully enhanced the ionization and fragmentation of 3β,5α,6β-triol and 7-KC for mass spectrometric detection of the oxysterol species in human plasma. The oxysterol dimethylglycinates were resolved with high sensitivity and selectivity, and enabled accurate quantification of 3β,5α,6β-triol and 7-KC concentrations in human plasma. The LC-MS/MS assay was able to discriminate with high sensitivity and specificity between control and NPC1 subjects, and offers for the first time a noninvasive, rapid, and highly sensitive method for diagnosis of NPC1 disease.

Published
2011

15. Increased Serum Phospholipase A2 Activity in Malawian Children with Falciparum Malaria

Author

Chimsuku L, Molyneux Me, Peter Vadas, Goldring D, E. Stefanski, W. Pruzanski, and Taylor Te

Subjects
Male, Malawi, Anemia, Plasmodium falciparum, Malaria, Cerebral, Parasitemia, Hematocrit, Phospholipases A, Proinflammatory cytokine, Sepsis, Pathogenesis, Virology, parasitic diseases, medicine, Animals, Humans, Coma, Malaria, Falciparum, Child, medicine.diagnostic_test, biology, Tumor Necrosis Factor-alpha, Infant, medicine.disease, biology.organism_classification, Phospholipases A2, Infectious Diseases, Child, Preschool, Acute Disease, Immunology, Female, lipids (amino acids, peptides, and proteins), Parasitology, Nervous System Diseases, Malaria, Follow-Up Studies
Abstract

Some clinical manifestations of severe malaria resemble those of sepsis and there may be mediators of the host response that are common to both sepsis and malaria. Phospholipase A2 (PLA2), a proinflammatory enzyme whose expression is induced by tumor necrosis factor (TNF), has been implicated in the pathogenesis of complications of the sepsis syndrome. We examined levels of circulating PLA2 in Plasmodium falciparum malaria and studied the association of PLA2 with disease severity. Plasma PLA2 and TNF were measured in 75 Malawian children with P. falciparum malaria. The mean (SD) plasma PLA2 activity in children with acute malaria was 53,804 (37,256) units/ml as compared with 424 (349) units/ml in 34 healthy controls (P < 0.00001). The mean PLA2 activity in 45 convalescent patients was 2,546 (7,372) units/ml (P < 0.00001). In 48 patients with pretreatment PLA2 activity less than 60,000 units/ml, mortality was 8.3%, while in 27 patients with pretreatment PLA2 levels greater than 60,000 units/ml, mortality was 33.3% (P = 0.008). There were significant correlations between PLA2 and TNF (r = 0.471, P < 0.01), density of parasitemia (r = 0.443, P < 0.0001) and a decrease in hematocrit (r = 0.352, P < 0.005). These data show that P. falciparum malaria is associated with a markedly increased circulating PLA2, especially in patients with severe disease, as manifested by high parasite burden, anemia, coma, and death.

Published
1993

16. Differential PfEMP1 Expression Is Associated with Cerebral Malaria Pathology

Author

Smith, J, Tembo, DL, Nyoni, B, Murikoli, RV, Mukaka, M, Milner, DA, Berriman, M, Rogerson, SJ, Taylor, TE, Molyneux, ME, Mandala, WL, Craig, AG, Montgomery, J, Smith, J, Tembo, DL, Nyoni, B, Murikoli, RV, Mukaka, M, Milner, DA, Berriman, M, Rogerson, SJ, Taylor, TE, Molyneux, ME, Mandala, WL, Craig, AG, and Montgomery, J

Abstract

Plasmodium falciparum is unique among human malarias in its ability to sequester in post-capillary venules of host organs. The main variant antigens implicated are the P. falciparum erythrocyte membrane protein 1 (PfEMP1), which can be divided into three major groups (A-C). Our study was a unique examination of sequestered populations of parasites for genetic background and expression of PfEMP1 groups. We collected post-mortem tissue from twenty paediatric hosts with pathologically different forms of cerebral malaria (CM1 and CM2) and parasitaemic controls (PC) to directly examine sequestered populations of parasites in the brain, heart and gut. Use of two different techniques to investigate this question produced divergent results. By quantitative PCR, group A var genes were upregulated in all three organs of CM2 and PC cases. In contrast, in CM1 infections displaying high levels of sequestration but negligible vascular pathology, there was high expression of group B var. Cloning and sequencing of var transcript tags from the same samples indicated a uniformly low expression of group A-like var. Generally, within an organ sample, 1-2 sequences were expressed at dominant levels. 23% of var tags were detected in multiple patients despite the P. falciparum infections being genetically distinct, and two tags were observed in up to seven hosts each with high expression in the brains of 3-4 patients. This study is a novel examination of the sequestered parasites responsible for fatal cerebral malaria and describes expression patterns of the major cytoadherence ligand in three organ-derived populations and three pathological states.

Published
2014

17. Effects of phenylbutazone alone or in combination with a nutritional therapeutic on gastric ulcers, intestinal permeability, and fecal microbiota in horses

Author

Canaan M. Whitfield‐Cargile, Michelle C. Coleman, Noah D. Cohen, Ana M. Chamoun‐Emanuelli, Cristobal Navas DeSolis, Taylor Tetrault, Ryan Sowinski, Amanda Bradbery, and Mattea Much

Subjects
barrier function, gastric ulcers, horses, inflammation, NSAIDs, Veterinary medicine, SF600-1100
Abstract

Abstract Background Gastrointestinal (GI) injury and dysbiosis are adverse events associated with nonsteroidal anti‐inflammatory drug (NSAID) use in horses. Phenylbutazone has been shown to alter GI barrier function both in vitro and ex vivo, but its effects on barrier function have not been assessed in vivo. In addition, the ability of nutritional therapeutics to prevent these changes is not known. Objective Our objectives were to determine whether (a) phenylbutazone affected barrier function in vivo and (b) if phenylbutazone‐induced GI injury could be ameliorated by the use of a nutritional therapeutic. Animals Thirty healthy horses were randomly assigned to 3 groups (n = 10 per group): control, phenylbutazone, or phenylbutazone plus nutritional therapeutic. Methods This study was conducted as a blinded, randomized block design. All horses were managed identically throughout the study period. Samples were collected throughout the study period to monitor fecal microbiota changes and gastric ulcers before and after treatment. Quantification of the bacterial 16S rRNA gene in blood was used as a marker of intestinal permeability. Results Phenylbutazone increased amounts of bacterial 16S rDNA in circulation 3.02‐fold (95% confidence interval [CI], 0.1.89‐4.17), increased gastric ulceration score by a mean of 1.1 grade (P = .02), and induced specific changes in the microbiota, including loss of Pseudobutyrivibrio of family Lachnospiraceae. These changes were attenuated by nutritional treatment. Conclusions and Clinical Importance Collectively, these findings suggest that phenylbutazone induces GI injury, including impaired barrier function, and that nutritional treatment could attenuate these changes.

Published
2021
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20. Pneumocystis pneumonia in HIV-positive adults, Malawi

Author

van Oosterhout, JJG, Laufer, MK, Perez, MA, Graham, SM, Chimbiya, N, Thesing, PC, Alvarez-Martinez, MJ, Wilson, PE, Chagomerana, M, Zijlstra, EE, Taylor, TE, Plowe, CV, Meshnick, SR, van Oosterhout, JJG, Laufer, MK, Perez, MA, Graham, SM, Chimbiya, N, Thesing, PC, Alvarez-Martinez, MJ, Wilson, PE, Chagomerana, M, Zijlstra, EE, Taylor, TE, Plowe, CV, and Meshnick, SR

Abstract

In a prospective study of 660 HIV-positive Malawian adults, we diagnosed Pneumocystis jirovecii pneumonia (PcP) using clinical features, induced sputum for immunofluorescent staining, real-time PCR, and posttreatment follow-up. PcP incidence was highest in patients with the lowest CD4 counts, but PcP is uncommon compared with incidences of pulmonary tuberculosis and bacterial pneumonia.

Published
2007

21. Differential var gene expression in the organs of patients dying of falciparurn malaria

Author

Montgomery, J, Mphande, FA, Berriman, M, Pain, A, Rogerson, SJ, Taylor, TE, Molyneux, ME, Craig, A, Montgomery, J, Mphande, FA, Berriman, M, Pain, A, Rogerson, SJ, Taylor, TE, Molyneux, ME, and Craig, A

Abstract

Sequestration of parasitized erythrocytes in the microcirculation of tissues is thought to be important in the pathogenesis of severe falciparum malaria. A major variant surface antigen, var/Plasmodium falciparum erythrocyte membrane protein 1, expressed on the surface of the infected erythrocyte, mediates cytoadherence to vascular endothelium. To address the question of tissue-specific accumulation of variant types, we used the unique resource generated by the clinicopathological study of fatal paediatric malaria in Blantyre, Malawi, to analyse var gene transcription in patients dying with falciparum malaria. Despite up to 102 different var genes being expressed by P. falciparum populations in a single host, only one to two of these genes were expressed at high levels in the brains and hearts of these patients. These major var types differed between organs. However, identical var types were expressed in the brains of multiple patients from a single malaria season. These results provide the first evidence of organ-specific accumulation of P. falciparum variant types and suggest that parasitized erythrocytes can exhibit preferential binding in the body, supporting the hypothesis of cytoadherence-linked pathogenesis.

Published
2007

23. The effect of quinine on the electroretinograms of children with pediatric cerebral malaria

Author

Lochhead, Jonathan, Movaffaghy, Armand, Falsini, Benedetto, Winstanley, Paul, Mberu, Edward, Riva, Charle, Molyneux, Malcom, Taylor, Te, Harding, Simon, Falsini, Benedetto (ORCID:0000-0002-3569-4968), Riva, Charles, Lochhead, Jonathan, Movaffaghy, Armand, Falsini, Benedetto, Winstanley, Paul, Mberu, Edward, Riva, Charle, Molyneux, Malcom, Taylor, Te, Harding, Simon, Falsini, Benedetto (ORCID:0000-0002-3569-4968), and Riva, Charles

Abstract

To investigate the effects of quinine on the electroretinograms (ERGs) of children with cerebral malaria (CM), we recruited subjects during a single malaria season in Blantyre, Malawi. Seventy ERG investigations were performed, on 34 children with CM. Time recorded from completion of the most recent quinine infusion was termed "quinine elapsed time" (QET). In a subgroup of 16 children, whole-blood quinine concentrations were estimated in a sample of capillary blood, for validation. A significant positive association was found between QET and both maximal-response A-wave amplitude (MRAWA; P=.03) and cone A-wave amplitude (P=.04). Longitudinal analysis demonstrated a significant trend of increasing MRAWA with increasing QET (P=.03). Parenteral quinine administered in therapeutic doses to a pediatric population appears to cause a transient depression in photoreceptor function. No evidence of ocular quinine toxicity was found at the therapeutic doses used.

Published
2003

24. Averting a malaria disaster

Author

White, NJ, primary, Nosten, F, additional, Looareesuwan, S, additional, Watkins, WM, additional, Marsh, K, additional, Snow, RW, additional, Kokwaro, G, additional, Ouma, J, additional, Hien, TT, additional, Molyneux, ME, additional, Taylor, TE, additional, Newbold, CI, additional, Ruebush, TK, additional, Danis, M, additional, Greenwood, BM, additional, Anderson, RM, additional, and Olliaro, P, additional

Published
1999
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29. Tumor necrosis factor and lymphotoxin-alpha polymorphisms and severe malaria in African populations.

Author

Clark TG, Diakite M, Auburn S, Campino S, Fry AE, Green A, Richardson A, Small K, Teo YY, Wilson J, Jallow M, Sisay-Joof F, Pinder M, Griffiths MJ, Peshu N, Williams TN, Marsh K, Molyneux ME, Taylor TE, and Rockett KA

Abstract

The tumor necrosis factor gene (TNF) and lymphotoxin-alpha gene (LTA) have long attracted attention as candidate genes for susceptibility traits for malaria, and several of their polymorphisms have been found to be associated with severe malaria (SM) phenotypes. In a large study involving >10,000 individuals and encompassing 3 African populations, we found evidence to support the reported associations between the TNF -238 polymorphism and SM in The Gambia. However, no TNF/LTA polymorphisms were found to be associated with SM in cohorts in Kenya and Malawi. It has been suggested that the causal polymorphisms regulating the TNF and LTA responses may be located some distance from the genes. Therefore, more-detailed mapping of variants across TNF/LTA genes and their flanking regions in the Gambian and allied populations may need to be undertaken to find any causal polymorphisms. [ABSTRACT FROM AUTHOR]

Published
2009
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30. Effects of HIV-1 serostatus, HIV-1 RNA concentration, and CD4 cell count on the incidence of malaria infection in a cohort of adults in rural Malawi.

Author

Patnaik P, Jere CS, Miller WC, Hoffman IF, Wirima J, Pendame R, Meshnick SR, Taylor TE, Molyneux ME, and Kublin JG

Abstract

BACKGROUND: To assess the effects of human immunodeficiency virus (HIV) infection on susceptibility to malaria, we compared the incidence rates of malaria by HIV type 1 (HIV-1) serostatus, baseline blood HIV-1 RNA concentration, and baseline CD4 cell count, over the course of a malaria season. METHODS: We followed a cohort of 349 adults in Malawi. For the 224 HIV-1-seropositive adults (64% of the cohort), we measured HIV-1 RNA concentration (n=187) and CD4 cell count (n=184) at baseline. Parasitemia was defined as presence of asexual parasites on a thick film of blood and was treated with sulfadoxine/pyrimethamine (SP), in accordance with national policy. Hazard ratios (HRs) of parasitemia were estimated using Cox regression. Demographics were adjusted for. RESULTS: HIV-1 seropositivity was associated with parasitemia (adjusted HR, 1.8 [95% confidence interval {CI}, 1.2-2.7] for a first parasitemia episode; adjusted HR, 2.5 [95% CI, 1.5-4.2] for a second parasitemia episode [> 14 days after the first episode]; adjusted HR, 1.9 [95% CI, 1.4-2.6] for parasitemia overall). Treatment failure (parasitemia < or = 14 days after SP treatment) did not differ by HIV-1 serostatus (risk ratio, 1.3 [95% CI, 0.5-3.2]). HIV-1 RNA concentrations and CD4 cell counts were moderately but inconsistently associated with parasitemia. A high parasite density with fever was associated with HIV-1 seropositivity and low CD4 cell count. CONCLUSION: HIV-infected adults in malaria-endemic areas are at increased risk for malaria. Where possible, additional malaria prevention efforts should be targeted at this population. Copyright © 2005 Infectious Diseases Society of America [ABSTRACT FROM AUTHOR]

Published
2005
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32. Recipes for Determining Doneness in Poultry Do Not Provide Appropriate Information Based on US Government Guidelines

Author

Edgar Chambers, Sandria Godwin, and Taylor Terry

Subjects
food safety, poultry, consumer, cooking, behavior, Chemical technology, TP1-1185
Abstract

Research has shown that consumers use unsafe food handling practices when preparing poultry, which can increase the risk of foodborne illness such as salmonellosis or campylobacteriosis. Recipes from cookbooks, magazines, and the internet commonly are used as sources for consumers to prepare food in homes and the expectation is that food will be safe when prepared. According to the United States Department of Agriculture (USDA), using a thermometer properly is the only way to accurately check for doneness of poultry. The objective of this study was to assess poultry recipes, including recipes for whole birds and poultry parts, to determine if food safety information concerning thermometer use was included within the recipe. Poultry recipes (n = 474) were collected from 217 cookbooks, 28 magazines, 59 websites, and seven blogs. Approximately 33.5% of the recipes contained a specific temperature for doneness, with 73% of those cooked to ≥165 °F/74 °C, as recommended by USDA. Ninety-four percent of recipes used cooking time and about half of the recipes used visual measurements, such as color or juices running clear, to determine doneness. This study showed that most recipes do not contain appropriate information to assure safe cooking of poultry by consumers. Modifying recipes by adding food safety information, such as thermometer use and proper temperatures, could increase the use of proper food preparation behaviors by consumers.

Published
2018
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35. Clinical manifestations of new versus recrudescent malaria infections following anti-malarial drug treatment

Author

Shaukat Ayesha M, Gilliams Elizabeth A, Kenefic Leo J, Laurens Matthew B, Dzinjalamala Fraction K, Nyirenda Osward M, Thesing Phillip C, Jacob Christopher G, Molyneux Malcolm E, Taylor Terrie E, Plowe Christopher V, and Laufer Miriam K

Subjects
Malaria, Sulphadoxine-pyrimethamine, Drug efficacy, Genotyping, Recrudescent infections, New infections, Malawi, Anaemia, Arctic medicine. Tropical medicine, RC955-962, Infectious and parasitic diseases, RC109-216
Abstract

Abstract Background Distinguishing new from recrudescent infections in post-treatment episodes of malaria is standard in anti-malarial drug efficacy trials. New infections are not considered malaria treatment failures and as a result, the prevention of subsequent episodes of malaria infection is not reported as a study outcome. However, in moderate and high transmission settings, new infections are common and the ability of a short-acting medication to cure an initial infection may be outweighed by its inability to prevent the next imminent infection. The clinical benefit of preventing new infections has never been compared to that of curing the initial infection. Methods Children enrolled in a sulphadoxine-pyrimethamine efficacy study in Blantyre, Malawi from 1998–2004 were prospectively evaluated. Six neutral microsatellites were used to classify new and recrudescent infections in children aged less than 10 years with recurrent malaria infections. Children from the study who did not experience recurrent parasitaemia comprised the baseline group. The odds of fever and anaemia, the rate of haemoglobin recovery and time to recurrence were compared among the groups. Results Fever and anemia were more common among children with parasitaemia compared to those who remained infection-free throughout the study period. When comparing recrudescent vs. new infections, the incidence of fever was not statistically different. However, children with recrudescent infections had a less robust haematological recovery and also experienced recurrence sooner than those whose infection was classified as new. Conclusions The results of this study confirm the paramount importance of providing curative treatment for all malaria infections. Although new and recrudescent infections caused febrile illnesses at a similar rate, recurrence due to recrudescent infection did have a worsened haemological outcome than recurrence due to new infections. Local decision-makers should take into account the results of genotyping to distinguish new from recrudescent infections when determining treatment policy on a population level. It is appropriate to weigh recrudescent malaria more heavily than new infection in assessing treatment efficacy.

Published
2012
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36. Human cerebral malaria and Plasmodium falciparum genotypes in Malawi

Author

Milner Danny A, Vareta Jimmy, Valim Clarissa, Montgomery Jacqui, Daniels Rachel F, Volkman Sarah K, Neafsey Daniel E, Park Daniel J, Schaffner Stephen F, Mahesh Nira C, Barnes Kayla G, Rosen David M, Lukens Amanda K, Van-Tyne Daria, Wiegand Roger C, Sabeti Pardis C, Seydel Karl B, Glover Simon J, Kamiza Steve, Molyneux Malcolm E, Taylor Terrie E, and Wirth Dyann F

Subjects
Plasmodium falciparum, Cerebral malaria, Genotyping, Molecular barcode, Histopathology, Autopsy, Arctic medicine. Tropical medicine, RC955-962, Infectious and parasitic diseases, RC109-216
Abstract

Abstract Background Cerebral malaria, a severe form of Plasmodium falciparum infection, is an important cause of mortality in sub-Saharan African children. A Taqman 24 Single Nucleotide Polymorphisms (SNP) molecular barcode assay was developed for use in laboratory parasites which estimates genotype number and identifies the predominant genotype. Methods The 24 SNP assay was used to determine predominant genotypes in blood and tissues from autopsy and clinical patients with cerebral malaria. Results Single genotypes were shared between the peripheral blood, the brain, and other tissues of cerebral malaria patients, while malaria-infected patients who died of non-malarial causes had mixed genetic signatures in tissues examined. Children with retinopathy-positive cerebral malaria had significantly less complex infections than those without retinopathy (OR = 3.7, 95% CI [1.51-9.10]).The complexity of infections significantly decreased over the malaria season in retinopathy-positive patients compared to retinopathy-negative patients. Conclusions Cerebral malaria patients harbour a single or small set of predominant parasites; patients with incidental parasitaemia sustain infections involving diverse genotypes. Limited diversity in the peripheral blood of cerebral malaria patients and correlation with tissues supports peripheral blood samples as appropriate for genome-wide association studies of parasite determinants of pathogenicity.

Published
2012
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37. Pentoxifylline as an adjunct therapy in children with cerebral malaria

Author

Kokwaro Gilbert, Kivaya Esther, Olola Christopher HO, Wamola Betty, Köhler Carsten, Lell Bertrand, Wypij David, Mithwani Sadik, Taylor Terrie E, Kremsner Peter G, and Newton Charles RJC

Subjects
Arctic medicine. Tropical medicine, RC955-962, Infectious and parasitic diseases, RC109-216
Abstract

Abstract Background Pentoxifylline (PTX) affects many processes that may contribute to the pathogenesis of severe malaria and it has been shown to reduce the duration of coma in children with cerebral malaria. This pilot study was performed to assess pharmacokinetics, safety and efficacy of PTX in African children with cerebral malaria. Methods Ten children admitted to the high dependency unit of the Kilifi District Hospital in Kenya with cerebral malaria (Blantyre coma score of 2 or less) received quinine plus a continuous infusion of 10 mg/kg/24 hours PTX for 72 hours. Five children were recruited as controls and received normal saline instead of PTX. Plasma samples were taken for PTX and tumour necrosis factor (TNF) levels. Blantyre Coma Score, parasitemia, hematology and vital signs were assessed 4 hourly. Results One child (20%) in the control group died, compared to four children (40%) in the PTX group. This difference was not significant (p = 0.60). Laboratory parameters and clinical data were comparable between groups. TNF levels were lower in children receiving PTX. Conclusions The small sample size does not permit definitive conclusions, but the mortality rate was unexpectedly high in the PTX group.

Published
2010
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38. Malaria in infants below six months of age: retrospective surveillance of hospital admission records in Blantyre, Malawi

Author

ter Kuile Feiko O, Molyneux Elizabeth, Larru Beatriz, Taylor Terrie, Molyneux Malcolm, and Terlouw Dianne J

Subjects
Arctic medicine. Tropical medicine, RC955-962, Infectious and parasitic diseases, RC109-216
Abstract

Abstract Background Information on the burden of malaria in early infancy is scarce. Young infants are relatively protected against clinical malaria during the first six months of life due to the presence of maternal antibodies and foetal haemoglobin, and have received relatively little attention with respect to research and treatment guidelines. The World Health Organization provides treatment guidelines for children from six months onwards, without specific treatment guidelines for the younger infants. A number of recent reports however suggest that the burden in this young age group may be underestimated. Methods A retrospective review of paediatric hospital records at the Queen Elizabeth Central Hospital in Blantyre from 1998 to 2008 from three data sources was carried out. The number of admitted infants Results Retrospective analysis of hospital records showed that over the course of these years, the average annual proportion of paediatric admissions in children ≤ 15 years with confirmed malaria aged Conclusions These findings are consistent with recent reports suggesting that the burden of malaria during the six first months of life may be substantial, and highlight that more research is needed on dose-optimization, safety and efficacy of anti-malarials that are currently used off-label in this vulnerable patient group.

Published
2009
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39. TLR9 polymorphisms in African populations: no association with severe malaria, but evidence of cis-variants acting on gene expression

Author

Pinder Margaret, Sisay-Joof Fatou, Jallow Muminatou, Hull Jeremy, Richardson Anna, Diakite Mahamadou, Fry Andrew, Auburn Sarah, Forton Julian, Campino Susana, Molyneux Malcolm E, Taylor Terrie E, Rockett Kirk, Clark Taane G, and Kwiatkowski Dominic P

Subjects
Arctic medicine. Tropical medicine, RC955-962, Infectious and parasitic diseases, RC109-216
Abstract

Abstract Background During malaria infection the Toll-like receptor 9 (TLR9) is activated through induction with plasmodium DNA or another malaria motif not yet identified. Although TLR9 activation by malaria parasites is well reported, the implication to the susceptibility to severe malaria is not clear. The aim of this study was to assess the contribution of genetic variation at TLR9 to severe malaria. Methods This study explores the contribution of TLR9 genetic variants to severe malaria using two approaches. First, an association study of four common single nucleotide polymorphisms was performed on both family- and population-based studies from Malawian and Gambian populations (n>6000 individual). Subsequently, it was assessed whether TLR9 expression is affected by cis-acting variants and if these variants could be mapped. For this work, an allele specific expression (ASE) assay on a panel of HapMap cell lines was carried out. Results No convincing association was found with polymorphisms in TLR9 for malaria severity, in either Gambian or Malawian populations, using both case-control and family based study designs. Using an allele specific expression assay it was observed that TLR9 expression is affected by cis-acting variants, these results were replicated in a second experiment using biological replicates. Conclusion By using the largest cohorts analysed to date, as well as a standardized phenotype definition and study design, no association of TLR9 genetic variants with severe malaria was found. This analysis considered all common variants in the region, but it is remains possible that there are rare variants with association signals. This report also shows that TLR9 expression is potentially modulated through cis-regulatory variants, which may lead to differential inflammatory responses to infection between individuals.

Published
2009
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41. Tissue distribution of migration inhibitory factor and inducible nitric oxide synthase in falciparum malaria and sepsis in African children

Author

Liomba N George, Harper Clive G, Whitten Richard O, Awburn Melissa M, Clark Ian A, Molyneux Malcolm E, and Taylor Terrie E

Subjects
Arctic medicine. Tropical medicine, RC955-962, Infectious and parasitic diseases, RC109-216
Abstract

Abstract Background The inflammatory nature of falciparum malaria has been acknowledged since increased circulating levels of tumour necrosis factor (TNF) were first measured, but precisely where the mediators downstream from this prototype inflammatory mediator are generated has not been investigated. Here we report on the cellular distribution, by immunohistochemistry, of migration inhibitory factor (MIF) and inducible nitric oxide synthase (iNOS) in this disease, and in sepsis. Methods We stained for MIF and iNOS in tissues collected during 44 paediatric autopsies in Blantyre, Malawi. These comprised 42 acutely ill comatose patients, 32 of whom were diagnosed clinically as cerebral malaria and the other 10 as non-malarial diseases. Another 2 were non-malarial, non-comatose deaths. Other control tissues were from Australian adults. Results Of the 32 clinically diagnosed cerebral malaria cases, 11 had negligible histological change in the brain, and no or scanty intravascular sequestration of parasitised erythrocytes, another 7 had no histological changes in the brain, but sequestered parasitised erythrocytes were present (usually dense), and the remaining 14 brains showed micro-haemorrhages and intravascular mononuclear cell accumulations, plus sequestered parasitised erythrocytes. The vascular walls of the latter group stained most strongly for iNOS. Vascular wall iNOS staining was usually of low intensity in the second group (7 brains) and was virtually absent from the cerebral vascular walls of 8 of the 10 comatose patients without malaria, and also from control brains. The chest wall was chosen as a typical non-cerebral site encompassing a range of tissues of interest. Here pronounced iNOS staining in vascular wall and skeletal muscle was present in some 50% of the children in all groups, including septic meningitis, irrespective of the degree of staining in cerebral vascular walls. Parasites or malarial pigment were rare to absent in all chest wall sections. While MIF was common in chest wall vessels, usually in association with iNOS, it was absent in brain vessels. Conclusions These results agree with the view that clinically diagnosed cerebral malaria in African children is a collection of overlapping syndromes acting through different organ systems, with several mechanisms, not necessarily associated with cerebral vascular inflammation and damage, combining to cause death.

Published
2003
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42. A sensitive and specific LC-MS/MS method for rapid diagnosis of Niemann-Pick C1 disease from human plasma[S]

Author

Xuntian Jiang, Rohini Sidhu, Forbes D. Porter, Nicole M. Yanjanin, Anneliese O. Speak, Danielle Taylor te Vruchte, Frances M. Platt, Hideji Fujiwara, David E. Scherrer, Jessie Zhang, Dennis J. Dietzen, Jean E. Schaffer, and Daniel S. Ory

Subjects
cholesterol, diagnostic tools, liquid chromatography/tandem mass spectrometry, Niemann-Pick disease, oxysterols, neurodegeneration, Biochemistry, QD415-436
Abstract

Niemann-Pick type C1 (NPC1) disease is a rare, progressively fatal neurodegenerative disease for which there are no FDA-approved therapies. A major barrier to developing new therapies for this disorder has been the lack of a sensitive and noninvasive diagnostic test. Recently, we demonstrated that two cholesterol oxidation products, specifically cholestane-3β,5α,6β-triol (3β,5α,6β-triol) and 7-ketocholesterol (7-KC), were markedly increased in the plasma of human NPC1 subjects, suggesting a role for these oxysterols in diagnosis of NPC1 disease and evaluation of therapeutics in clinical trials. In the present study, we describe the development of a sensitive and specific LC-MS/MS method for quantifying 3β,5α,6β-triol and 7-KC human plasma after derivatization with N,N-dimethylglycine. We show that dimethylglycine derivatization successfully enhanced the ionization and fragmentation of 3β,5α,6β-triol and 7-KC for mass spectrometric detection of the oxysterol species in human plasma. The oxysterol dimethylglycinates were resolved with high sensitivity and selectivity, and enabled accurate quantification of 3β,5α,6β-triol and 7-KC concentrations in human plasma. The LC-MS/MS assay was able to discriminate with high sensitivity and specificity between control and NPC1 subjects, and offers for the first time a noninvasive, rapid, and highly sensitive method for diagnosis of NPC1 disease.

Published
2011
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43. Return of chloroquine antimalarial efficacy in Malawi.

Author

Laufer MK, Thesing PC, Eddington ND, Masonga R, Dzinjalamala FK, Takala SL, Taylor TE, Plowe CV, Laufer, Miriam K, Thesing, Phillip C, Eddington, Nicole D, Masonga, Rhoda, Dzinjalamala, Fraction K, Takala, Shannon L, Taylor, Terrie E, and Plowe, Christopher V

Abstract

Background: In 1993, Malawi became the first country in Africa to replace chloroquine with the combination of sulfadoxine and pyrimethamine for the treatment of malaria. At that time, the clinical efficacy of chloroquine was less than 50%. The molecular marker of chloroquine-resistant falciparum malaria subsequently declined in prevalence and was undetectable by 2001, suggesting that chloroquine might once again be effective in Malawi.Methods: We conducted a randomized clinical trial involving 210 children with uncomplicated Plasmodium falciparum malaria in Blantyre, Malawi. The children were treated with either chloroquine or sulfadoxine\#8211;pyrimethamine and followed for 28 days to assess the antimalarial efficacy of the drug.Results: In analyses conducted according to the study protocol, treatment failure occurred in 1 of 80 participants assigned to chloroquine, as compared with 71 of 87 participants assigned to sulfadoxine\#8211;pyrimethamine. The cumulative efficacy of chloroquine was 99% (95% confidence interval [CI], 93 to 100), and the efficacy of sulfadoxine\#8211;pyrimethamine was 21% (95% CI, 13 to 30). Among children treated with chloroquine, the mean time to parasite clearance was 2.6 days (95% CI, 2.5 to 2.8) and the mean time to the resolution of fever was 10.3 hours (95% CI, 8.1 to 12.6). No unexpected adverse events related to the study drugs occurred.Conclusions: Chloroquine is again an efficacious treatment for malaria, 12 years after it was withdrawn from use in Malawi. (ClinicalTrials.gov number, NCT00125489 [ClinicalTrials.gov].). [ABSTRACT FROM AUTHOR]

Published
2006

45. Mixing costs and mixing benefits in naming words, pictures, and sums.

Author

Lupker SJ, Kinoshita S, Coltheart M, and Taylor TE

Abstract

When two types of stimuli are mixed in a trial block, each stimulus type is typically responded to more slowly than when those stimuli are presented by themselves in pure blocks (a 'mixing cost,' [Los, 1996]). In word/non-word naming tasks, however, mixing two types of stimuli leads to a different, 'homogenization,' pattern. There is a mixing cost for the easier stimuli and a mixing benefit for the more difficult stimuli ( [Lupker et al., 1997]). In the present research we investigated the generality of this homogenization pattern by examining picture naming and a sum-naming task involving addition problems (e.g., 10+7=?). In Experiments 1 and 2, the homogenization pattern was observed for both pictures and sums. In Experiments 3 and 4, qualitatively different stimulus types (words and pictures, words and sums) were mixed. The mixing cost pattern was observed. Experiments 5 (words and pictures) and 6 (words and sums), however, demonstrated that a homogenization-type pattern can be obtained even when qualitatively different stimulus types are mixed. These results indicate that theoretical mechanisms like those proposed by [Los, 1996] and theoretical mechanisms like those proposed by [Lupker et al., 1997] are both active in reaction time experiments. Copyright © 2003 by Elsevier Science (USA). [ABSTRACT FROM AUTHOR]

Published
2003
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48. A systems serology approach to identifying key antibody correlates of protection from cerebral malaria in Malawian children.

Author

Walker IS, Dini S, Aitken EH, Damelang T, Hasang W, Alemu A, Jensen ATR, Rambhatla JS, Opi DH, Duffy MF, Takashima E, Harawa V, Tsuboi T, Simpson JA, Mandala W, Taylor TE, Seydel KB, Chung AW, and Rogerson SJ

Subjects
Humans, Malawi, Child, Preschool, Male, Female, Child, Infant, Intercellular Adhesion Molecule-1 immunology, Endothelial Protein C Receptor immunology, Phagocytosis, Erythrocytes parasitology, Erythrocytes immunology, Malaria, Falciparum immunology, Antigens, Protozoan immunology, Malaria, Cerebral immunology, Antibodies, Protozoan immunology, Antibodies, Protozoan blood, Protozoan Proteins immunology, Plasmodium falciparum immunology
Abstract

Background: Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) proteins are expressed on the surface of infected erythrocytes, mediating parasite sequestration in the vasculature. PfEMP1 is a major target of protective antibodies, but the features of the antibody response are poorly defined., Methods: In Malawian children with cerebral or uncomplicated malaria, we characterized the antibody response to 39 recombinant PfEMP1 Duffy binding like (DBL) domains or cysteine-rich interdomain regions (CIDRs) in detail, including measures of antibody classes, subclasses, and engagement with Fcγ receptors and complement. Using elastic net regularized logistic regression, we identified a combination of seven antibody targets and Fc features that best distinguished between children with cerebral and uncomplicated malaria. To confirm the role of the selected targets and Fc features, we measured antibody-dependent neutrophil and THP-1 cell phagocytosis of intercellular adhesion molecule-1 (ICAM-1) and endothelial protein C (EPCR) co-binding infected erythrocytes., Results: The selected features distinguished between children with cerebral and uncomplicated malaria with 87% accuracy (median, 80-96% interquartile range) and included antibody to well-characterized DBLβ3 domains and a less well-characterized CIDRγ12 domain. The abilities of antibodies to engage C1q and FcγRIIIb, rather than levels of IgG, correlated with protection. In line with a role of FcγRIIIb binding antibodies to DBLβ3 domains, antibody-dependent neutrophil phagocytosis of ICAM-1 and EPCR co-binding IE was higher in uncomplicated malaria (15% median, 8-38% interquartile range) compared to cerebral malaria (7%, 30-15%, p < 0.001)., Conclusions: Antibodies associated with protection from cerebral malaria target a subset of PfEMP1 domains. The Fc features of protective antibody response include engagement of FcγRIIIb and C1q, and ability to induce antibody-dependent neutrophil phagocytosis of infected erythrocytes. Identifying the targets and Fc features of protective immunity could facilitate the development of PfEMP1-based therapeutics for cerebral malaria., (© 2024. The Author(s).)

Published
2024
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49. Murine model captures evolution of edema in experimental cerebral malaria.

Author

Taylor TE

Subjects
Animals, Mice, Humans, Malaria, Cerebral physiopathology, Malaria, Cerebral parasitology, Disease Models, Animal, Brain Edema parasitology
Abstract

A complex series of studies by Oelschlegel et al. in a murine model of cerebral malaria establishes a temporal sequence of events linking decreased venous efflux to impaired perfusion, edema, and neuroinflammation. The relevance to human cerebral malaria is discussed, including the heterogeneity recognized in recent investigations of cerebrovascular hemodynamics., Competing Interests: Declaration of interests I serve as a member of the Malaria Advisory Council for Novartis Pharma AG and a member of the Strategic Advisory Committee for Global Health, Novartis Institutes for BioMedical Research., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Published
2024
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50. Prothrombotic autoantibodies targeting platelet factor 4/polyanion are associated with pediatric cerebral malaria.

Author

Vera IM, Kessler A, Harawa V, Ahmadu A, Keller TE, Ray ST, Taylor TE, Rogerson SJ, Mandala WL, Reyes Gil M, Seydel KB, and Kim K

Subjects
Humans, Female, Male, Child, Child, Preschool, Infant, Polyelectrolytes, Thrombosis immunology, Thrombosis blood, Malaria, Cerebral immunology, Malaria, Cerebral blood, Autoantibodies blood, Autoantibodies immunology, Platelet Factor 4 immunology, Platelet Factor 4 blood
Abstract

BACKGROUNDFeatures of consumptive coagulopathy and thromboinflammation are prominent in cerebral malaria (CM). We hypothesized that thrombogenic autoantibodies contribute to a procoagulant state in CM.METHODSPlasma from children with uncomplicated malaria (UM) (n = 124) and CM (n = 136) was analyzed by ELISA for a panel of 8 autoantibodies including anti-platelet factor 4/polyanion (anti-PF4/P), anti-phospholipid, anti-phosphatidylserine, anti-myeloperoxidase, anti-proteinase 3, anti-dsDNA, anti-β-2-glycoprotein I, and anti-cardiolipin. Plasma samples from individuals with nonmalarial coma (NMC) (n = 49) and healthy controls (HCs) (n = 56) were assayed for comparison. Associations with clinical and immune biomarkers were determined using univariate and logistic regression analyses.RESULTSMedian anti-PF4/P and anti-PS IgG levels were elevated in individuals with malaria infection relative to levels in HCs (P < 0.001) and patients with NMC (PF4/P: P < 0.001). Anti-PF4/P IgG levels were elevated in children with CM (median = 0.27, IQR: 0.19-0.41) compared with those with UM (median = 0.19, IQR: 0.14-0.22, P < 0.0001). Anti-PS IgG levels did not differ between patients with UM and those with CM (P = 0.39). When patients with CM were stratified by malaria retinopathy (Ret) status, the levels of anti-PF4/P IgG correlated negatively with the peripheral platelet count in patients with Ret+ CM (Spearman's rho [Rs] = 0.201, P = 0.04) and associated positively with mortality (OR = 15.2, 95% CI: 1.02-275, P = 0.048). Plasma from patients with CM induced greater platelet activation in an ex vivo assay relative to plasma from patients with UM (P = 0.02), and the observed platelet activation was associated with anti-PF4/P IgG levels (Rs= 0.293, P = 0.035).CONCLUSIONSThrombosis mediated by elevated anti-PF4/P autoantibodies may be one mechanism contributing to the clinical complications of CM.

Published
2024
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