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1. Selective MCL-1 inhibitor ABBV-467 is efficacious in tumor models but is associated with cardiac troponin increases in patients

Author

Junichiro Yuda, Christine Will, Darren C. Phillips, Linu Abraham, Cory Alvey, Abraham Avigdor, Wayne Buck, Lauren Besenhofer, Erwin Boghaert, Dong Cheng, Dan Cojocari, Kelly Doyle, T. Matthew Hansen, Kevin Huang, Eric F. Johnson, Andrew S. Judd, Russell A. Judge, John C. Kalvass, Aaron Kunzer, Lloyd T. Lam, Rachel Li, Ruth L. Martin, Anthony Mastracchio, Mike Mitten, Adam Petrich, Jin Wang, James E. Ward, Haichao Zhang, Xilu Wang, Johannes E. Wolff, Katherine M. Bell-McGuinn, and Andrew J. Souers

Subjects
Medicine
Abstract

Abstract Background MCL-1 is a prosurvival B-cell lymphoma 2 family protein that plays a critical role in tumor maintenance and survival and can act as a resistance factor to multiple anticancer therapies. Herein, we describe the generation and characterization of the highly potent and selective MCL-1 inhibitor ABBV-467 and present findings from a first-in-human trial that included patients with relapsed/refractory multiple myeloma (NCT04178902). Methods Binding of ABBV-467 to human MCL-1 was assessed in multiple cell lines. The ability of ABBV-467 to induce tumor growth inhibition was investigated in xenograft models of human multiple myeloma and acute myelogenous leukemia. The first-in-human study was a multicenter, open-label, dose-escalation study assessing safety, pharmacokinetics, and efficacy of ABBV-467 monotherapy. Results Here we show that administration of ABBV-467 to MCL-1-dependent tumor cell lines triggers rapid and mechanism-based apoptosis. In vivo, intermittent dosing of ABBV-467 as monotherapy or in combination with venetoclax inhibits the growth of xenografts from human hematologic cancers. Results from a clinical trial evaluating ABBV-467 in patients with multiple myeloma based on these preclinical data indicate that treatment with ABBV-467 can result in disease control (seen in 1 patient), but may also cause increases in cardiac troponin levels in the plasma in some patients (seen in 4 of 8 patients), without other corresponding cardiac findings. Conclusions The selectivity of ABBV-467 suggests that treatment-induced troponin release is a consequence of MCL-1 inhibition and therefore may represent a class effect of MCL-1 inhibitors in human patients.

Published
2023
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2. Phenotyping Diabetes Mellitus on Aggregated Electronic Health Records from Disparate Health Systems

Author

Hui Xing Tan, Rachel Li Ting Lim, Pei San Ang, Belinda Pei Qin Foo, Yen Ling Koon, Jing Wei Neo, Amelia Jing Jing Ng, Siew Har Tan, Desmond Chun Hwee Teo, Mun Yee Tham, Aaron Jun Yi Yap, Nicholas Kai Ming Ng, Celine Wei Ping Loke, Li Fung Peck, Huilin Huang, and Sreemanee Raaj Dorajoo

Subjects
diabetes, clinical phenotyping, electronic medical record, rule-based algorithm, validation studies, pharmacovigilance, Therapeutics. Pharmacology, RM1-950, Other systems of medicine, RZ201-999, Public aspects of medicine, RA1-1270
Abstract

Background: Identifying patients with diabetes mellitus (DM) is often performed in epidemiological studies using electronic health records (EHR), but currently available algorithms have features that limit their generalizability. Methods: We developed a rule-based algorithm to determine DM status using the nationally aggregated EHR database. The algorithm was validated on two chart-reviewed samples (n = 2813) of (a) patients with atrial fibrillation (AF, n = 1194) and (b) randomly sampled hospitalized patients (n = 1619). Results: DM diagnosis codes alone resulted in a sensitivity of 77.0% and 83.4% in the AF and random hospitalized samples, respectively. The proposed algorithm combines blood glucose values and DM medication usage with diagnostic codes and exhibits sensitivities between 96.9% and 98.0%, while positive predictive values (PPV) ranged between 61.1% and 75.6%. Performances were comparable across sexes, but a lower specificity was observed in younger patients (below 65 versus 65 and above) in both validation samples (75.8% vs. 90.8% and 60.6% vs. 88.8%). The algorithm was robust for missing laboratory data but not for missing medication data. Conclusions: In this nationwide EHR database analysis, an algorithm for identifying patients with DM has been developed and validated. The algorithm supports quantitative bias analyses in future studies involving EHR-based DM studies.

Published
2023
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3. Determinants of synapse diversity revealed by super-resolution quantal transmission and active zone imaging

Author

Zachary L. Newman, Dariya Bakshinskaya, Ryan Schultz, Samuel J. Kenny, Seonah Moon, Krisha Aghi, Cherise Stanley, Nadia Marnani, Rachel Li, Julia Bleier, Ke Xu, and Ehud Y. Isacoff

Subjects
Science
Abstract

Super-resolution quantal imaging relates transmission at excitatory synapses to presynaptic molecular composition. The authors find that evoked transmission varies greatly between synapses and is uncorrelated and physically separate from spontaneous transmission, and identify responsible presynaptic proteins.

Published
2022
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4. Acacia Fiber Protects the Gut from Extended-Spectrum Beta-Lactamase (ESBL)-Producing Escherichia coli Colonization Enabled by Antibiotics

Author

Marlène Maeusli, Nicholas Skandalis, Bosul Lee, Peggy Lu, Sarah Miller, Jun Yan, Yuli Talyansky, Rachel Li, Zeferino Reyna, Noel Guerrero, Amber Ulhaq, Matthew Slarve, Ioannis Theologidis, Brad Spellberg, and Brian Luna

Subjects
ESBL, Escherichia coli, One Health, antibiotic resistance, colicin, fiber, Microbiology, QR1-502
Abstract

ABSTRACT Novel approaches to combating antibiotic resistance are needed given the ever-continuing rise of antibiotic resistance and the scarce discovery of new antibiotics. Little is known about the colonization dynamics and the role of intrinsic plant-food characteristics in this process. We sought to determine whether plant fiber could alter colonization dynamics by antibiotic-resistant bacteria in the gut. We determined that ingestion of antibiotics in mice markedly enhanced gut colonization by a pathogenic extended-spectrum beta-lactamase-producing Escherichia coli strain of human origin, E. coli JJ1886 (ST131-H30Rx). Furthermore, ingestion of soluble acacia fiber before and after antibiotic exposure significantly reduced pathogenic E. coli colonization. 16S rRNA analysis and ex vivo cocultures demonstrated that fiber protected the microbiome by serving as a prebiotic, which induced native gut E. coli to inhibit pathogenic E. coli via colicin M. Fiber may be a useful prebiotic with which to administer antibiotics to protect human and livestock gut microbiomes against colonization from antibiotic-resistant, pathogenic bacteria. IMPORTANCE A One Health-based strategy—the concept that human health and animal health are interconnected with the environment—is necessary to determine the drivers of antibiotic resistance from food to the clinic. Moreover, humans can ingest antibiotic-resistant bacteria on food and asymptomatically, or “silently,” carry such bacteria in the gut long before they develop an opportunistic extraintestinal infection. Here, we determined that fiber-rich foods, in particular acacia fiber, may be a new, promising, and inexpensive prebiotic to administer with antibiotics to protect the mammalian (i.e., human and livestock) gut against such colonization by antibiotic-resistant, pathogenic bacteria.

Published
2022
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7. Temporal Stability of Lipid-Shelled Microbubbles During Acoustically-Mediated Blood-Brain Barrier Opening

Author

Antonios N. Pouliopoulos, Daniella A. Jimenez, Alexander Frank, Alexander Robertson, Lin Zhang, Alina R. Kline-Schoder, Vividha Bhaskar, Mitra Harpale, Elizabeth Caso, Nicholas Papapanou, Rachel Anderson, Rachel Li, and Elisa E. Konofagou

Subjects
focused ultrasound, microbubbles, temporal stability, contrast agents, passive cavitation detection, blood-brain barrier, Physics, QC1-999
Abstract

Non-invasive blood-brain barrier (BBB) opening using focused ultrasound (FUS) is being tested as a means to locally deliver drugs into the brain. Such FUS therapies require injection of pre-formed microbubbles, currently used as contrast agents in ultrasound imaging. Although their behavior during exposure to imaging sequences has been well-described, our understanding of microbubble stability within a therapeutic field is still not complete. Here, we study the temporal stability of lipid-shelled microbubbles during therapeutic FUS exposure in two timescales: the short timescale (i.e., μs of low-frequency ultrasound exposure) and the long timescale (i.e., days post-activation). We first simulated the microbubble response to low-frequency sonication, and found a strong correlation between viscosity and fragmentation pressure. Activated microbubbles had a concentration decay constant of 0.02 d−1 but maintained a quasi-stable size distribution for up to 3 weeks (

Published
2020
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8. Eye Manifestations of Shprintzen–Goldberg Craniosynostosis Syndrome: A Case Report and Systematic Review

Author

Jamie H. Choi, Rachel Li, Rachel Gannaway, Tahnee N. Causey, Anna Harrison, and Natario L. Couser

Subjects
Genetics, QH426-470
Abstract

Shprintzen–Goldberg craniosynostosis syndrome (SGS) is a rare autosomal dominant condition that was first documented in literature in 1982. The disorder is caused by pathogenic variants in the proto-oncogene SKI gene, a known suppressor of TGF-β activity, located on chromosome 1p36. There is considerable phenotypic overlap with Marfan and Loeys–Dietz syndromes. Common clinical features of SGS include craniosynostosis, marfanoid habitus, hypotonia, dysmorphic facies, cardiovascular anomalies, and other skeletal and connective tissue abnormalities. Ocular manifestations may include hypertelorism, downslanting palpebral fissures, proptosis, myopia, and ectopia lentis. We describe a 25-year-old male with the syndrome. Genetic analysis revealed a novel c.350G>A (p.Arg117His) de novo variant, which was predicted to be pathogenic by the CTGT laboratory. The patient presented with dysmorphic features, marfanoid habitus, severe joint contractures, mitral valve insufficiency, aortic root dilatation, and a history of seizures. His ocular manifestations included hypertelorism, downslanting palpebral fissures, bilateral ptosis, and high myopia. Ophthalmic manifestations are an integral component of the syndrome; however, they have not been well characterized in the literature. From a systematic review of previously published cases to date, we summarize the eye and ocular adnexa manifestations reported.

Published
2020
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10. Long-term balancing selection drives evolution of immunity genes in Capsella

Author

Daniel Koenig, Jörg Hagmann, Rachel Li, Felix Bemm, Tanja Slotte, Barbara Neuffer, Stephen I Wright, and Detlef Weigel

Subjects
balancing selection, selfing, bottleneck, immunity, disease resistance, NB-LRR, Medicine, Science, Biology (General), QH301-705.5
Abstract

Genetic drift is expected to remove polymorphism from populations over long periods of time, with the rate of polymorphism loss being accelerated when species experience strong reductions in population size. Adaptive forces that maintain genetic variation in populations, or balancing selection, might counteract this process. To understand the extent to which natural selection can drive the retention of genetic diversity, we document genomic variability after two parallel species-wide bottlenecks in the genus Capsella. We find that ancestral variation preferentially persists at immunity related loci, and that the same collection of alleles has been maintained in different lineages that have been separated for several million years. By reconstructing the evolution of the disease-related locus MLO2b, we find that divergence between ancient haplotypes can be obscured by referenced based re-sequencing methods, and that trans-specific alleles can encode substantially diverged protein sequences. Our data point to long-term balancing selection as an important factor shaping the genetics of immune systems in plants and as the predominant driver of genomic variability after a population bottleneck.

Published
2019
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11. Respiratory Presentation of Pediatric Patients in the 2014 Enterovirus D68 Outbreak

Author

Georgina Martin, Rachel Li, Victoria E. Cook, Matthew Carwana, Peter Tilley, Laura Sauve, Patrick Tang, Akshat Kapur, and Connie L. Yang

Subjects
Diseases of the respiratory system, RC705-779
Abstract

Background. In the fall of 2014, a North American outbreak of enterovirus D68 resulted in a significant number of pediatric hospital admissions for respiratory illness throughout North America. This study characterized the clinical presentation and risk factors for a severe clinical course in children admitted to British Columbia Children’s Hospital during the 2014 outbreak. Methods. Retrospective chart review of patients with confirmed EV-D68 infection admitted to BCCH with respiratory symptoms in the fall of 2014. Past medical history, clinical presentation, management, and course in hospital was collected and analyzed using descriptive statistics. Comparison was made between those that did and did not require ICU admission to identify risk factors. Results. Thirty-four patients were included (median age 7.5 years). Fifty-three percent of children had a prior history of wheeze, 32% had other preexisting medical comorbidities, and 15% were previously healthy. Ten children (29%) were admitted to the pediatric intensive care unit. The presence of complex medical conditions (excluding wheezing) (P=0.03) and copathogens was associated with PICU admission (P=0.02). Conclusions. EV-D68 infection resulted in severe, prolonged presentations of asthma-like illness in the hospitalized pediatric population. Patients with a prior history of wheeze and preexisting medical comorbidities appear to be most severely affected, but the virus can also cause wheezing in previously well children.

Published
2016
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12. Esthesioneuroblastomas in an Asian population: Similarities and differences

Author

Christopher Hood Keng Goh, Dennis Yu Kim Chua, Rachel Li Wei Ho, and Chumpon Chan

Subjects
craniofacial resection, esthesioneuroblastoma, olfactory neuroblastoma, skull base tumors, Surgery, RD1-811
Abstract

Objective: Esthesioneuroblastoma is an uncommon tumor that is described widely among the Caucasians. In Singapore, we see predominantly Asian patients with esthesioneuroblastomas. From our experience, we note significant and interesting differences between our data on Asian patients and the published ones on the Caucasian patients. Methods: A retrospective review of all patients who underwent craniofacial resection for esthesioneuroblastomas was conducted from January 1997 to January 2010. Relevant data were collected and statistical analyses were carried out to determine factors that predicted mortality or complications. Results: Out of a total of 48 patients who underwent craniofacial resections, half had esthesioneuroblastomas (50%). There was a peak age distribution at the sixth decade of life and 62% of our patients were male. Both local and regional recurrence rate was 50%. Conclusion: Majority of our Asian patients who underwent craniofacial resections had esthesioneuroblastomas. There is a male predilection, and we do not see a bimodal age distribution that is commonly reported.

Published
2012
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19. Development of a Bispecific Antibody Targeting Clinical Isolates of Acinetobacter baumannii

Author

Travis B Nielsen, Jun Yan, Matthew Slarve, Rachel Li, Jason A Junge, Brian M Luna, Ian Wilkinson, Udaya Yerramalla, and Brad Spellberg

Subjects
Infectious Diseases, Immunology and Allergy
Abstract

Background We previously reported developing 2 anticapsular monoclonal antibodies (mAbs) as a novel therapy for Acinetobacter baumannii infections. We sought to determine whether a bispecific mAb (bsAb) could improve avidity and efficacy while maximizing strain coverage in one molecule. Methods Humanized mAb 65 was cloned into a single-chain variable fragment and attached to humanized mAb C8, combining their paratopes into a single bsAb (C73). We tested bsAb C73’s strain coverage, binding affinity, ex vivo opsonic activity, and in vivo efficacy compared to each mAb alone and combined. Results The bsAb demonstrated strain coverage, binding affinity, opsonization, and in vivo efficacy superior to either original mAb alone or combined. Conclusions A humanized bsAb targeting distinct A. baumannii capsule moieties enabled potent and effective coverage of disparate A. baumannii clinical isolates. The bsAb enhances feasibility of development by minimizing the number of components of a promising novel therapeutic for these difficult-to-treat infections.

Published
2023
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22. The High Association of Ophthalmic Manifestations in Individuals With Mucolipidosis Type IV

Author

David Gibson, Vikram Brar, Rachel Li, Arun Kalra, Allison Goodwin, and Natario Couser

Subjects
Strabismus, Ophthalmology, Mucolipidoses, Pediatrics, Perinatology and Child Health, Blepharoptosis, Humans, General Medicine, Nystagmus, Pathologic, Corneal Diseases
Abstract

Purpose: To present a case report of mucolipidosis type IV (ML4) and review the literature for all of the ophthalmic abnormalities associated with this disease. Methods: A systematic review of the literature using PubMed/Medline was conducted, and with the addition of the current case report, the eye and ocular adnexa findings of 93 patients with ML4 are summarized. Results: The most common ophthalmic findings reported among the 93 patients included corneal clouding (90.3%), strabismus (58.1%), optic nerve pallor (52.2%), retinal dystrophy/pigmentary changes (50.5%), and retinal vascular attenuation (38.9%). Other less commonly reported findings included nystagmus, photophobia, ocular pain, excessive lacrimation, ptosis, and cataracts. Conclusions: The ophthalmic findings discussed in the current case report and literature review serve as indicators for ML4. Early diagnosis of ML4 is important in forming a multidisciplinary management plan, genetic counseling strategy, and maximizing the visual development of affected individuals. [ J Pediatr Ophthalmol Strabimus . 2022;59(5):332–337.]

Published
2022
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23. Phenotyping Diabetes Mellitus on Aggregated Electronic Health Records from Disparate Health Systems

Author

Dorajoo, Hui Xing Tan, Rachel Li Ting Lim, Pei San Ang, Belinda Pei Qin Foo, Yen Ling Koon, Jing Wei Neo, Amelia Jing Jing Ng, Siew Har Tan, Desmond Chun Hwee Teo, Mun Yee Tham, Aaron Jun Yi Yap, Nicholas Kai Ming Ng, Celine Wei Ping Loke, Li Fung Peck, Huilin Huang, and Sreemanee Raaj

Subjects
diabetes, clinical phenotyping, electronic medical record, rule-based algorithm, validation studies, pharmacovigilance
Abstract

Background: Identifying patients with diabetes mellitus (DM) is often performed in epidemiological studies using electronic health records (EHR), but currently available algorithms have features that limit their generalizability. Methods: We developed a rule-based algorithm to determine DM status using the nationally aggregated EHR database. The algorithm was validated on two chart-reviewed samples (n = 2813) of (a) patients with atrial fibrillation (AF, n = 1194) and (b) randomly sampled hospitalized patients (n = 1619). Results: DM diagnosis codes alone resulted in a sensitivity of 77.0% and 83.4% in the AF and random hospitalized samples, respectively. The proposed algorithm combines blood glucose values and DM medication usage with diagnostic codes and exhibits sensitivities between 96.9% and 98.0%, while positive predictive values (PPV) ranged between 61.1% and 75.6%. Performances were comparable across sexes, but a lower specificity was observed in younger patients (below 65 versus 65 and above) in both validation samples (75.8% vs. 90.8% and 60.6% vs. 88.8%). The algorithm was robust for missing laboratory data but not for missing medication data. Conclusions: In this nationwide EHR database analysis, an algorithm for identifying patients with DM has been developed and validated. The algorithm supports quantitative bias analyses in future studies involving EHR-based DM studies.

Published
2023
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24. Supplementary Figure S2 from Validation of the 16-Gene Recurrence Score in Patients with Locoregional, High-Risk Renal Cell Carcinoma from a Phase III Trial of Adjuvant Sunitinib

Author

Alain Ravaud, Robert J. Motzer, Michael Staehler, Olga Valota, Xun Lin, Rachel Li, Phillip G. Febbo, Audrey D. Goddard, Dejan Knezevic, Margarita Lopatin, Christer Svedman, Ahmed Magheli, Jean-Francois Martini, Bernard Escudier, and Brian I. Rini

Abstract

Distribution of RS results in T3 patients in the gene signature cohort. Abbreviations: RS, recurrence score; T3, stage III tumor.

Published
2023
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25. Data from Validation of the 16-Gene Recurrence Score in Patients with Locoregional, High-Risk Renal Cell Carcinoma from a Phase III Trial of Adjuvant Sunitinib

Author

Alain Ravaud, Robert J. Motzer, Michael Staehler, Olga Valota, Xun Lin, Rachel Li, Phillip G. Febbo, Audrey D. Goddard, Dejan Knezevic, Margarita Lopatin, Christer Svedman, Ahmed Magheli, Jean-Francois Martini, Bernard Escudier, and Brian I. Rini

Abstract

Purpose: Adjuvant sunitinib prolonged disease-free survival (DFS; HR, 0.76) in patients with locoregional high-risk renal cell carcinoma (RCC) in the S-TRAC trial (ClinicalTrials.gov NCT00375674). The 16-gene Recurrence Score (RS) assay was previously developed and validated to estimate risk for disease recurrence in patients with RCC after nephrectomy. This analysis further validated the prognostic value of RS assay in patients from S-TRAC and explored the association of RS results with prediction of sunitinib benefit.Patients and Methods: The analysis was prospectively designed with prespecified genes, algorithm, endpoints, and analytical methods. Primary RCC was available from 212 patients with informed consent; primary analysis focused on patients with T3 RCC. Gene expression was quantitated by RT-PCR. Time to recurrence (TTR), DFS, and renal cancer–specific survival (RCSS) were analyzed using Cox proportional hazards regression.Results: Baseline characteristics were similar between patients with and those without RS results, and between the sunitinib and placebo arms among patients with RS results. RS results predicted TTR, DFS, and RCSS in both arms, with the strongest results observed in the placebo arm. When high versus low RS groups were compared, HR for recurrence was 9.18 [95% confidence interval (CI), 2.15–39.24; P < 0.001) in the placebo arm; interaction of RS results with treatment was not significant.Conclusions: The strong prognostic performance of the 16-gene RS assay was confirmed in S-TRAC, and the RS assay is now supported by level IB evidence. RS results may help identify patients at high risk for recurrence who may derive higher absolute benefit from adjuvant therapy. Clin Cancer Res; 24(18); 4407–15. ©2018 AACR.

Published
2023
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26. Supplementary Table S1 from Validation of the 16-Gene Recurrence Score in Patients with Locoregional, High-Risk Renal Cell Carcinoma from a Phase III Trial of Adjuvant Sunitinib

Author

Alain Ravaud, Robert J. Motzer, Michael Staehler, Olga Valota, Xun Lin, Rachel Li, Phillip G. Febbo, Audrey D. Goddard, Dejan Knezevic, Margarita Lopatin, Christer Svedman, Ahmed Magheli, Jean-Francois Martini, Bernard Escudier, and Brian I. Rini

Abstract

Patient baseline characteristics in the placebo versus sunitinib arm: all T3 patients in the gene signature cohort. aN0 or NX, any Fuhrman grade, ECOG PS 0 or Fuhrman grade 1 and ECOG PS ï,³1. bN0 or NX, Fuhrman grade {greater than or equal to}2, ECOG PS {greater than or equal to}1. cAny Fuhrman grade, any ECOG PS. Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; SD, standard deviation; RS, Recurrence Score.

Published
2023
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27. Phenotyping Diabetes Mellitus on Aggregated Electronic Health Records from Disparate Health Systems.

Author

Tan, Hui Xing, Lim, Rachel Li Ting, Ang, Pei San, Foo, Belinda Pei Qin, Koon, Yen Ling, Neo, Jing Wei, Ng, Amelia Jing Jing, Tan, Siew Har, Teo, Desmond Chun Hwee, Tham, Mun Yee, Yap, Aaron Jun Yi, Ng, Nicholas Kai Ming, Loke, Celine Wei Ping, Peck, Li Fung, Huang, Huilin, and Dorajoo, Sreemanee Raaj

Subjects
*ELECTRONIC health records, *DIABETES, *ATRIAL fibrillation, *BLOOD sugar, *DATABASES
Abstract

Background: Identifying patients with diabetes mellitus (DM) is often performed in epidemiological studies using electronic health records (EHR), but currently available algorithms have features that limit their generalizability. Methods: We developed a rule-based algorithm to determine DM status using the nationally aggregated EHR database. The algorithm was validated on two chart-reviewed samples (n = 2813) of (a) patients with atrial fibrillation (AF, n = 1194) and (b) randomly sampled hospitalized patients (n = 1619). Results: DM diagnosis codes alone resulted in a sensitivity of 77.0% and 83.4% in the AF and random hospitalized samples, respectively. The proposed algorithm combines blood glucose values and DM medication usage with diagnostic codes and exhibits sensitivities between 96.9% and 98.0%, while positive predictive values (PPV) ranged between 61.1% and 75.6%. Performances were comparable across sexes, but a lower specificity was observed in younger patients (below 65 versus 65 and above) in both validation samples (75.8% vs. 90.8% and 60.6% vs. 88.8%). The algorithm was robust for missing laboratory data but not for missing medication data. Conclusions: In this nationwide EHR database analysis, an algorithm for identifying patients with DM has been developed and validated. The algorithm supports quantitative bias analyses in future studies involving EHR-based DM studies. [ABSTRACT FROM AUTHOR]

Published
2023
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28. Therapeutic, Humanized Monoclonal Antibody Exhibits Broad Binding and Protective Efficacy against Acinetobacter baumannii

Author

Matthew Slarve, Zeferino Reyna, Elizabeth Burk, Juan Ruiz-Delgado, Rachel Li, Jun Yan, Brian Luna, and Brad Spellberg

Subjects
Pharmacology, Infectious Diseases, Pharmacology (medical)
Abstract

Acinetobacter baumannii is an extremely drug-resistant pathogen necessitating the development of new therapies. We seek to generate a cocktail of monoclonal antibodies (MAbs) that can target the full diversity of A. baumannii isolates.

Published
2023
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29. Phase I study of anti-epidermal growth factor receptor antibody-drug conjugate serclutamab talirine: Safety, pharmacokinetics, and antitumor activity in advanced glioblastoma

Author

Benedito A Carneiro, Kyriakos P Papadopoulos, John H Strickler, Andrew B Lassman, Saiama N Waqar, Young Kwang Chae, Jyoti D Patel, Einat Shacham-Shmueli, Karen Kelly, Mustafa Khasraw, Christine M Bestvina, Ryan Merrell, Kevin Huang, Harisha Atluri, Peter Ansell, Rachel Li, Janet Jin, Mark G Anderson, Edward B Reilly, Gladys Morrison-Thiele, Kalpesh Patel, Randy R Robinson, Martha R Neagu Aristide, and Hui K Gan

Subjects
Oncology, Surgery, Neurology (clinical)
Abstract

BackgroundSerclutamab talirine (Ser-T, formerly ABBV-321) is an antibody-drug conjugate consisting of an antibody (AM-1-ABT-806) directed against activated epidermal growth factor receptor (EGFR) and a pyrrolobenzodiazepine dimer. We investigated Ser-T monotherapy in a phase I, first-in-human, dose-escalation, and dose-expansion study in patients with advanced solid tumors associated with EGFR overexpression.MethodsEligible patients (≥18 years) had advanced, histologically confirmed solid tumors associated with EGFR overexpression (centralized testing). Patients received Ser-T intravenously once every 4 weeks (Q4W; 5–50 μg/kg) in the dose-escalation phase. Herein, preliminary antitumor activity at the recommended phase II dose (RP2D) is reported only for patients with glioblastoma (n = 24); additional assessments included all treated patients.ResultsSixty-two patients (median age: 58 years) were enrolled within the dose-escalation (n = 43) and dose-expansion (n = 19) phases. One dose-limiting toxicity, grade 3 aspartate aminotransferase and alanine aminotransferase elevation, occurred at 20 μg/kg during dose escalation. The Ser-T RP2D regimen of 50 μg/kg × 1 (loading dose) followed by 25 μg/kg Q4W (maintenance dose) was administered during dose expansion. Fatigue (37%) was the only treatment-emergent adverse event (AE) occurring in >25% of patients. Two patients (3%) reported mild treatment-related ocular AEs (eye pruritus). Responses in patients with glioblastoma included 1 partial response (~33 months), 6 stable disease, and 14 progressive disease (not evaluable: n = 3).ConclusionsSer-T monotherapy at doses up to 50 μg/kg initial dose, followed by 25 μg/kg Q4W demonstrated a tolerable safety profile with minimal antitumor activity observed in patients with glioblastoma. The glioblastoma dose-expansion cohort was closed due to a lack of efficacy (NCT03234712).

Published
2022
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30. Eye and ocular adnexa manifestations of MED12-related disorders

Author

Natario L. Couser, Monika Bapna, Hind Al-Saif, Rachel Li, and Arth H. Shah

Subjects
medicine.medical_specialty, business.industry, Ocular adnexa, medicine.disease, Dermatology, MED12, Ophthalmology, Lujan–Fryns syndrome, Pediatrics, Perinatology and Child Health, Intellectual disability, Medicine, OHDO SYNDROME, business, Genetics (clinical)
Abstract

MED12-related disorders are a rare group of intellectual disability syndromes with a broad range of phenotypic characteristics. The phenotypic spectrum of MED12-related disorders currently includes...

Published
2021
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31. ARF1-related disorder: phenotypic and molecular spectrum

Author

Jean-Madeleine de Sainte Agathe, Ben Pode-Shakked, Sophie Naudion, Vincent Michaud, Benoit Arveiler, Patricia Fergelot, Jean Delmas, Boris Keren, Céline Poirsier, Fowzan S Alkuraya, Brahim Tabarki, Eric Bend, Kellie Davis, Martina Bebin, Michelle L Thompson, Emily M Bryant, Matias Wagner, Iris Hannibal, Jerica Lenberg, Martin Krenn, Kristen M Wigby, Jennifer R Friedman, Maria Iascone, Anna Cereda, Térence Miao, Eric LeGuern, Emanuela Argilli, Elliott Sherr, Oana Caluseriu, Timothy Tidwell, Pinar Bayrak-Toydemir, Caroline Hagedorn, Melanie Brugger, Katharina Vill, Francois-Dominique Morneau-Jacob, Wendy Chung, Kathryn N Weaver, Joshua W Owens, Ammar Husami, Bimal P Chaudhari, Brandon S Stone, Katie Burns, Rachel Li, Iris M de Lange, Margaux Biehler, Emmanuelle Ginglinger, Bénédicte Gérard, Rolf W Stottmann, and Aurélien Trimouille

Subjects
Genetics, Developmental defects, epilepsy, human genetics, sequence analysis, DNA, Genetics (clinical), ddc
Abstract

PurposeARF1was previously implicated in periventricular nodular heterotopia (PVNH) in only five individuals and systematic clinical characterisation was not available. The aim of this study is to provide a comprehensive description of the phenotypic and genotypic spectrum ofARF1-related neurodevelopmental disorder.MethodsWe collected detailed phenotypes of an international cohort of individuals (n=17) withARF1variants assembled through the GeneMatcher platform. Missense variants were structurally modelled, and the impact of several were functionally validated.ResultsDe novo variants (10 missense, 1 frameshift, 1 splice altering resulting in 9 residues insertion) inARF1were identified among 17 unrelated individuals. Detailed phenotypes included intellectual disability (ID), microcephaly, seizures and PVNH. No specific facial characteristics were consistent across all cases, however microretrognathia was common. Various hearing and visual defects were recurrent, and interestingly, some inflammatory features were reported. MRI of the brain frequently showed abnormalities consistent with a neuronal migration disorder.ConclusionWe confirm the role ofARF1in an autosomal dominant syndrome with a phenotypic spectrum including severe ID, microcephaly, seizures and PVNH due to impaired neuronal migration.

Published
2022

32. CEO Succession Roulette

Author

Dragana Cvijanović, Nickolay Gantchev, and Rachel Li

Subjects
Strategy and Management, Management Science and Operations Research
Abstract

Despite intense scrutiny from investors, markets, and regulators, many public companies have no formal succession plans. Anecdotal evidence links succession risk to significant value destruction, but there is limited academic research evaluating the effects of succession planning on chief executive officer (CEO) turnover outcomes. We provide evidence that succession planning reduces the cost of management transitions by improving their efficiency. Firms with succession plans experience not only lower uncertainty around turnover events but also a faster reduction in uncertainty over the incoming CEO’s tenure, consistent with faster learning about CEO-firm fit. Succession planning also raises the quality of the CEO-firm match, as evidenced by longer CEO tenure, and improves the board’s readiness to replace an underperforming CEO, increasing turnover performance sensitivity. This paper was accepted by Suraj Srinivasan, accounting.

Published
2022
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33. The cilia and flagella associated protein CFAP52 orchestrated with CFAP45 is required for sperm motility in mice.

Author

Bingbing Wu, Rachel Li, Shuang Ma, Yanjie Ma, Lijun Fan, Chunxiu Gong, Chao Liu, Ling Sun, and Li Yuan

Subjects
*CILIA & ciliary motion, *SPERM motility, *SPERMATOZOA, *FLAGELLA (Microbiology), *MALE infertility, *KNOCKOUT mice, *PROTEINS
Abstract

Asthenozoospermia characterized by decreased sperm motility is a major cause of male infertility, but the majority of the etiology remains unknown. Here, we showed that the cilia and flagella associated protein 52 (Cfap52) gene was predominantly expressed in testis and its deletion in a Cfap52 knockout mouse model resulted in decreased sperm motility and male infertility. Cfap52 knockout also led to the disorganization of the midpiece-principal piece junction of the sperm tail but had no effect on the axoneme ultrastructure in spermatozoa. Furthermore, we found that CFAP52 interacted with the cilia and flagella associated protein 45 (CFAP45) and knockout of Cfap52 decreased the expression level of CFAP45 in sperm flagellum, which further disrupted the microtubule sliding produced by dynein ATPase. Together, our studies demonstrate that CFAP52 plays an essential role in sperm motility by interacting with CFAP45 in sperm flagellum, providing insights into the potential pathogenesis of the infertility of the human CFAP52 mutations. [ABSTRACT FROM AUTHOR]

Published
2023
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34. Marker-assisted introgression to improve the oleic acid content in the TMV 7 groundnut (Arachis hypogaea L.) variety suitable for the oil industry

Author

Rachel Lissy Vargheese, S. Saravanan, S. Juliet Hepziba, S. Merina Prem Kumari, A. Kavitha Pushpam, Selvaraju Kanagarajan, and M. Arumugam Pillai

Subjects
Quality trait, Backcross breeding, NIR estimation, Allele-specific primers, CAPS marker, Botany, QK1-989
Abstract

Abstract Background Improving the quality and shelf life of groundnut oil is one of the foremost objectives of groundnut breeding programmes. This can be achieved by marker-assisted introgression, a technique that efficiently and precisely enables breeders to develop plants with enhanced qualities. This study focused on improving the oleic acid content of an elite groundnut variety, TMV 7, by introgressing a recessive mutation responsible for the increase in oleic acid from ICG 15419. Hybridization was performed between the donor and recurrent parents to develop the F1, BC1F1, BC2F1 and BC2F2 populations. Introgressed lines with increased oleic acid in the genetic background of TMV 7 were identified using allele-specific marker, F435-F, F435SUB-R and a set of SSR markers were employed to recover the genome of the recurrent parent. Results With two backcrosses, a total of ten homozygous plants in the BC2F2 population were identified with oleic acid content ranging from 54.23 to 57.72% causing an increase of 36% over the recurrent parent. Among the ten lines, the line IL-23 exhibited the highest level of recurrent parent genome recovery of 91.12%. Conclusions The phenotypic evaluation of 10 homozygous introgressed lines indicated fewer differences for all other traits under study compared to the recurrent parent, except for oleic acid and linoleic acid content confirming the genetic background of the recurrent parent. The identified lines will be subjected to multilocation trials before their commercial release.

Published
2024
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37. Decoupling for fractal subsets of the parabola

Author

Jamneshan, Asgar, Chang, Alan; Pont, Jaume de Dios; Greenfeld, Rachel; Li, Zane Kun; Madrid, Jose, College of Sciences, Department of Mathematics, Jamneshan, Asgar, Chang, Alan; Pont, Jaume de Dios; Greenfeld, Rachel; Li, Zane Kun; Madrid, Jose, College of Sciences, and Department of Mathematics

Abstract

We consider decoupling for a fractal subset of the parabola. We reduce studying l(2)L(p) dccoupling for a fractal subset on the parabola {(t , t(2)) : 0 <= t <= 1} to studying l(2)L(p/3) decoupling for the projection of this subset to the interval [0, 1]. This generalizes the decoupling theorem of Bourgain-Demeter in the case of the parabola. Due to the sparsity and fractal like structure, this allows us to improve upon Bourgain-Demeter's decoupling theorem for the parabola. In the case when p/3 is an even integer we derive theoretical and computational tools to explicitly compute the associated decoupling constant for this projection to [0, 1]. Our ideas are inspired by the recent work on ellipsephic sets by Biggs (arXiv:1912.04351, 2019 and Acta Arith. 200(4):331-348, 2021) using nested efficient congruencing., La Caixa Foundation “La Caixa” Fellowship; Eric and Wendy Schmidt Postdoctoral Award; German Research Foundation (DFG); National Science Foundation (NSF)

Published
2022

39. Predictors of study dropout in cognitive-behavioural therapy with a trauma focus for post-traumatic stress disorder in adults: An individual participant data meta-analysis

Author

Eirini Karyotaki, Pim Cuijpers, Sonya B Norman, Davide Papola, Marit Sijbrandij, Soraya Seedat, Miranda Olff, Sudie E Back, Richard Gray, Rolf J Kleber, Francisco Lotufo Neto, Jonathan Bisson, Damion Grasso, Grant J Devilly, Ulrich Schnyder, Marylene Cloitre, Nigel Hunt, Anke B Witteveen, Simonne Wright, Joy M Schmitz, Dana Bichescu-Burian, Liuva Capezzani, Thomas Elbert, Marcelo Mello, Julian D Ford, Pedro Gamito, Moira Haller, Julia König, Claire Kullack, Jonathan Laugharne, Rachel Liebman, Christopher William Lee, Jeannette Lely, John C. Markowitz, Candice Monson, Mirjam J Nijdam, Tahereh Mina Orang, Luca Ostacoli, Nenad Paunovic, Eva Petkova, Patricia Resick, Rita Rosner, Maggie Schauer, Brian N. Smith, Anka A Vujanovic, Yinyin Zang, and Érica Panzani Duran

Subjects
Psychiatry, RC435-571
Abstract

Background Available empirical evidence on participant-level factors associated with dropout from psychotherapies for post-traumatic stress disorder (PTSD) is both limited and inconclusive. More comprehensive understanding of the various factors that contribute to study dropout from cognitive-behavioural therapy with a trauma focus (CBT-TF) is crucial for enhancing treatment outcomes.Objective Using an individual participant data meta-analysis (IPD-MA) design, we examined participant-level predictors of study dropout from CBT-TF interventions for PTSD.Methods A comprehensive systematic literature search was undertaken to identify randomised controlled trials comparing CBT-TF with waitlist control, treatment-as-usual or another therapy. Academic databases were screened from conception until 11 January 2021. Eligible interventions were required to be individual and in-person delivered. Participants were considered dropouts if they did not complete the post-treatment assessment.Findings The systematic literature search identified 81 eligible studies (n=3330). Data were pooled from 25 available CBT-TF studies comprising 823 participants. Overall, 221 (27%) of the 823 dropped out. Of 581 civilians, 133 (23%) dropped out, as did 75 (42%) of 178 military personnel/veterans. Bivariate and multivariate analyses indicated that military personnel/veterans (RR 2.37) had a significantly greater risk of dropout than civilians. Furthermore, the chance of dropping out significantly decreased with advancing age (continuous; RR 0.98).Conclusions These findings underscore the risk of premature termination from CBT-TF among younger adults and military veterans/personnel.Clinical implication Understanding predictors can inform the development of retention strategies tailored to at-risk subgroups, enhance engagement, improve adherence and yield better treatment outcomes.

Published
2024
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40. Structures, processes and outcomes between first referral and referral hospitals in low-income and middle-income countries: a secondary preplanned analysis of the FALCON and ChEETAh randomised trials

Author

Rajeev Sharma, Neha Mishra, Simon Cousens, Sanjay Gupta, Thomas Pinkney, Neil Smart, Jonathan Cook, David Jayne, Hemanth Kumar, Peter Brocklehurst, Mohammed Bashir, Dmitri Nepogodiev, Adesoji O Ademuyiwa, Philip Alexander, Laura Magill, Mark Monahan, Rachel Moore, Stephen Tabiri, Joseph Yorke, Dion Morton, Aneel Bhangu, Bryar Kadir, Naveen Sharma, Punam Mistry, Joshua Arthur, Muneer A Malik, Tracy Roberts, Elisee Rwagahirima, Christian Urimubabo, Ewen Harrison, Vijay Kumar, Julia Brown, Pollyanna Hardy, Amit Mahajan, Pratik Solanki, James Glasbey, Himani Gupta, Omar Omar, Joana Simoes, Sivesh K Kamarajah, Adesoji Ademuyiwa, Felix Alakaloko, Olumide Elebute, Omolara Faboya, Justina Seyi-Olajide, Anita Thomas, David Lissauer, Zainab Imam, George Ihediwa, Zainab O Imam, Felix M Alakaloko, Pradeep Zechariah, Suraj Surendran, Olatunji O Lawal, Mohammed Adnan, Savleen Kaur, Faustin Ntirenganya, JC Allen Ingabire, Lawani Ismaïl, Emmy Runigamugabo, Djifid Morel Seto, Paul Wondoh, Charles Dally, Kwabena Agbedinu, Florence Dedey, Enoch Tackie, Frank Enoch Gyamfi, Anthony Davor, Akinlabi Ajao, Omobolaji Ayandipo, Olalekan Ajai, Mobolaji Oludara, Muhammad Daniyan, Danjuma Sale, Lawal Abdullahi, Olabisi Osagie, Adedeji Fatuga, Muzzammil Abdullahi, Manish Pathak, Prashant Singh, Rita Jain, Kwaku Boakye-Yiadom, Kazeem Atobatele, Ayokunle Ogunyemi, Olabode Oshodi, Christopher Bode, Omobolaji O Ayandipo, Akinlabi E Ajao, Godwin Akaba, Gabriella Hyman, Deepak Singh, Olukemi Akande, Sivesh Kathir Kamarajah, Naseem Akhtar, José A Flores, Donna Smith, Olatunji Lawal, Hadijat Olaide Raji, Zafar Khan, Matthew Francis, Emmanuel Williams, Pardeep Kumar, Oliver Samuel, María Paz Muñoz, Arun Chaturvedi, Sameer Gupta, Puneet Prakash, John Raphael, Funmilola Wuraola, Olalekan Olasehinde, Murlidhar V Pai, Deepak Jain, Anwar Sadat Seidu, Victor Ifeanyichukwu Modekwe, Jideofor Okechukwu Ugwu, Lukmon Amosu, Akan Inyang, Michael Amoah, Boateng Nimako, Dhruva Ghosh, Neil Winkles, Olabisi O Osagie, Karolin Kroese, Olubunmi Ogein, Mustapha Yakubu, Vasanth Mark Samuel, Cecil Thomas, Enono Yhoshu, Vishal Michael, William Bhatti, Swati Daniel, Jyoti Dhiman, Atul Suroy, Christopher O Bode, George C Ihediwa, Adaiah Soibi-Harry, Benedetto Osunwusi, Elizabeth Li, Sonia Mathai, Deepak Singla, Farhanul Huda, Aisha Mustapha, Anisah Yahya, Samuel Mensah, Puneet Pareek, Bernard Ofori, Souliath Lawani, Oluwafunmilayo Adeniyi, Opeyemi Rebecca Akinajo, Richard Ofosu-Akromah, Olumide Adeniyi, Adewale O. Adisa, Natacha Boumas, Fareeda Galley, Frank Enoch Gyamfi Parvez D Haque, Antonio Ramos de la Medina, Chukwuma Okereke, Ronald Tubasime, Felicity Brant, Sohini Chakrabortee, Parvez D Haque, Emily Heritage, Carmela Lapitan, Rachel Lillywhite, Pierre Sodonougbo, Pamphile Assouto, Michel Fiogbe, Houenoukpo Koco, Serge Metchinhoungbe, Hodonou Sogbo, Hulrich Behanzin, Yannick Tandje, Sosthène Kangni, Cyrile Kpangon, Marcelin Akpla, Hugues Herve Chobli, Blaise Kovohouande, Gérard Agboton, Rene Ahossi, Raoul Baderha Ngabo, Nathan Bisimwa, Covalic Melic Bokossa Kandokponou, Mireille Dokponou, Francis Moïse Dossou, Corinne Dzemta, Antoine Gaou, Roland Goudou, Emmanuel Hedefoun, Sunday Houtoukpe, Felix Kamga, Eric Kiki- Migan, Ismaïl Lawani, René Loko, Afissatou Moutaïrou, Pencome Ogouyemi, Fouad Soumanou, Pia Tamadaho, Mack-Arthur Zounon, Luke Aniakwo Adagrah, Bin Baaba Alhaji Alhassan, Mabel Pokuah Amoako-Boateng, Anthony Baffour Appiah, Alvin Asante-Asamani, Benedict Boakye, Samuel A Debrah, Donald Enti, Rahman Adebisi Ganiyu, Patience Koggoh, Richard Kpankpari, Isabella Naa M. Opandoh, Meshach Agyemang Manu, Maison Patrick Opoku Manu, Martin Tangnaa Morna, John Nkrumah, Michael Nortey, Emmanuel Owusu Ofori, Elizaberth Mercy Quartson, Esther Adjei-Acquah, Eric Agyemang Vera Agyekum, Rebecca Adjeibah Akesseh, Forster Amponsah-Manu, Ato Oppong Acquah, Leslie Issa Adam-Zakariah, Esther Asabre, Ruby Acheampong Boateng, Barbara Koomson, Ataa Kusiwaa, Emmanuel Yaw Twerefour, James Ankomah, Frank Assah-Adjei, Anthony Appiah Boakye, Godfred Fosu, Godwin Serbeh, Kofi Yeboah Gyan, Isaac Omane Nyarko, Zelda Robertson, Ralph Armah, Christopher Asare, Delali Akosua Gakpetor, Victoria Sena Gawu, Ambe Obbeng, Doris Ofosuhene, Dorcas Osei-Poku, Diana Puozaa, Arkorful Ebenezer Temitope, Regina Acquah, James Amoako, Akosua Dwamena Appiah, Mark Aseti, Charles Banka, Samuel Dadzie, Derick Essien, Romeo Hussey, Jemima Kwarteng, Naa Anyekaa Sowah, Grace Yeboah, Cynthia Yeboah, Kwame Gyambibi Addo, Enoch Appiah Akosa, Percy Boakye, Christian Larbi Coompson, Brian Gyamfi, Bismark Effah Kontor, Christian Kyeremeh, Ruth Manu, Elijah Mensah, Friko Ibrahim Solae, Gideon Kwasi Toffah, Dorcas Otuo Acheampong, Jane Acquaye, Michael Adinku, Anita Eseenam Agbeko, Emmanuel Gyimah Amankwa, George Amoah, Juliana Appiah, Alex Ayim, Emmanuel Kafui Ayodeji, Jonathan Boakye-Yiadom, Edward Amoah Boateng, Christian Kofi Gyasi-Sarpong, Naabo Nuhu Noel Hamidu, Iddrisu Haruna, Naa Kwarley, Agbenya Kobla Lovi, Bertina Beauty Nyadu, Dominic Opoku, Anita Osabutey, Robert Sagoe, Samuel Tuffour, Yaa Tufour, Francis Akwaw Yamoah, Abiboye Cheduko Yefieye, Nii Armah Adu-Aryee, Faisal Adjei, Erica Akoto, Elikem Ametefe, Joachim Kwaku Amoako, Godsway Solomon Attepor, George Darko Brown, Benjamin Fenu, Philemon Kwame Kumassah, David Olatayo Olayiwola, Theodore Wordui, Nelson Agboadoh, Fatao Abubakari, Cletus Ballu, Charles Gyamfi Barimah, Guy Casskey Boateng, Prosper Tonwisi Luri, Abraham Titigah, Frank Owusu, Raphael Adu-Brobbey, Abdul-Hamid Labaran, Junior Atta Owusu, Vivian Adobea, Amos Bennin, Fred Dankwah, Stanley Doe, Ruth Sarfo Kantanka, Ephraim Kobby, Kennedy Kofi Korankye Hanson Larnyor, Edwin Osei, Prince Yeboah Owusu, Clement Ayum Sie-Broni, Marshall Zume, Francis Atindaana Abantanga, Darling Ramatu Abdulai, Daniel Kwesi Acquah, Emmanuel Ayingayure, Imoro Osman, Sheba Kunfah, Gbana Limann, Shamudeen Alhassan Mohammed, Sheriff Mohammed, Yakubu Musah, Emmanuel Abem Owusu, Abdul-Hafiz Saba, Edwin Mwintiereh Ta-ang Yenli, Arun Gautham, Alice Hepzibah, Grace Mary, Dimple Bhatti, Karan Bir, Tapasya Dhar, Sunita Goyal, Goyal Ankush, Monika Hans, Parvez Haque, Samuel Konda, Anil Luther, Shalini Makkar, Kavita Mandrelle, Partho Mukherjee, Reuben Rajappa, Ravinder Thind, Alen Thomas, Arti Tuli, Sreejith Veetil, Esther Daniel Mark Jesudason, K Priyadarshini, Latha Madankumar, Rohin Mittal, Ida Nagomy, Rajesh Selvakumar, Bharat Shankar, Moonish Sivakumar, Rajeevan Sridhar, Devabalan Titus, Manisha Aggarwal, Parth Dhamija, Vinoth Kanna, Ashwani Kumar, Gurtaj Singh, Josy Thomas, Amos Dasari, Priya Jacob, Elizabeth Kurien, Arpit Mathew, Danita Prakash, Anju Susan, Rose Varghese, Rahul Alpheus, Ashish Choudhrie, Nitin Peters, Subrat Raul, Rakesh Vakil, Wenceslao Ángeles Bueno, Francisco Barbosa Camacho, Aldo Bernal Hernández, Ana Bogurin Arellano, Edgar Cortes Torres, Clotilde Fuentes Orozco, Erick González García de Rojas, Alejandro González Ojeda, Bertha Guzmán Ramírez, Michel Hernández Valadez, Diego Luna Acevedo, Rubén Morán Galaviz, Oscar Olvera Flores, José Pérez Navarro, Kevin Pintor Belmontes, Fernando Ramirez Marbello, Luis Ramírez-González, Laura Reyes Aguirre, Ramona Rojas García, Eduardo Valtierra Robles, Reyes Cervantes Ortiz, Gonzalo Hernandez Gonzalez, Rosa Hernandez Krauss, Luis Hernández Miguelena, Marco Hurtado Romero, Isaac Baltazar Gomez, Celina Cuellar Aguirre, Alejandro Cuevas Avendaño, Luis Dominguez Sansores, Hector Ortiz Mejia, Laura Urdapilleta Gomez del Campo, Claudia Caballero Cerdan, David Dominguez Solano, Rafael Toriz Garcia, Mariana Barreto Gallo, Ana Cortes Flores, Alejandro Gonzalez Ojeda, Monica Jimenez Velasco, Rozana Reyes Gamez, Roque Lincona Menindez, Alberto Navarrete Peón, Irani Durán Sánchez, Diana Gonzalez Vazquez, Maria Martínez Lara, Laura Martinez Perez Maldonado, Alejandra Nayen Sainz de la Fuente, Antonio Ramos De la Medina, Khadija Ado, Mohammed Aliyu, Lofty-John Anyanwu, Mahmoud Magashi, Abubakar Muhammad, Saminu Muhammad, Bello Muideen, Idris Takai, Onyekachi Ukata, Opeoluwa Adesanya, David Awonuga, Olushola Fasiku, Chidiebere Ogo, Moruf Abdulsalam, Abimbola Adeniran, Grace Eke, Esther Momson, Francisca Nwaenyi, Olufunmilade Omisanjo, Yusuf Oshodi, Yemisi Oyewole, Omotade Salami, Omolara Williams, Victoria Adeleye, Opeyemi Akinajo, David Akinboyewa, Iyabo Alasi, Oluwole Atoyebi, Olanrewaju Balogun, Orimisan Belie, Andrew Ekwesianya, Francis Ezenwankwo, Adesola Jimoh, Jubril Kuku, Oluwaseun Ladipo- Ajayi, Ayomide Makanjuola, Olayanju Mokwenyei, Samuel Nwokocha, Rufus Ojewola, Abraham Oladimeji, Thomas Olajide, Oluwaseun Oluseye, Aloy Ugwu, Ochomma Egwuonwu, Okechukwu Ekwunife, Victor Modekwe, Chukwuemeka Okoro, Chisom Uche, Kenneth Ugwuanyi, Chuka Ugwunne, Akeem Adeleke, Wilson Adenikinju, Akinfolarin Adepiti, Adewale Aderounmu, Abdulhafiz Adesunkanmi, Adewale Adisa, Samuel Ajekwu, Olusegun Ajenjfuja, Jerrie Akindojutimi, Akinbolaji Akinkuolie, Olusegun Alatise, Olubukola Allen, Micheal Archibong, Olukayode Arowolo, Deborah Ayantona, Ademola Ayinde, Olusegun Badejoko, Tajudeen Badmus, Amarachukwu Etonyeaku, Emeka Igbodike, Omotade Ijarotimi, Adedayo Lawal, Fayowole Nana, Tunde Oduanafolabi, Olaniyi Olayemi, Stephen Omitinde, Owolabi Oni, Chigozie Onyeze, Ernest Orji, Adewale Rotimi, Abdulkadir Salako, Olufemi Solaja, Oluwaseun Sowemimo, Ademola Talabi, Mohammed Tajudeen, Francis Adebayo, Oseremen Aisuodionoe- Shadrach, Lazarus Ameh, Ndubuisi Mbajiekwe, Felix Ogbo, Samson Olori, Samuel Sani Abu Sadiq, Nancy Tabuanu, Martins Uanikhoba, Godwin Chiejina, Ekpo Edet, Mary Isa, Faith Iseh, Adams Marwa, Sunday Ogbeche, Edima Olory, Gabriel Udie, Joseph Udosen, Usang Usang, Olukayode Abayomi, Rukiyat Abdus-Salam, Sikiru Adebayo, Olanrewaju Amusat, Kelvin Egbuchulem, Hyginus Ekwuazi, Peter Elemile, Taiwo Lawal, Solomon Olagunju, Peter Osuala, Bamidele Suleman, Augustine Takure, Lukman Abdur-Rahman, Nurudeen Adeleke, Muideen Adesola, Rafiat Afolabi, Sulaiman Agodirin, Isiaka Aremu, Jibril Bello, Saheed Lawal, Abdulwahab Lawal, Hadijat Raji, Olayinka Sayomi, Asimiyu Shittu, Jude Ede, Sebastian Ekenze, Vincent Enemuo, Matthew Eze, Uchechukwu Ezomike, Emmanuel Izuka, Okezie Mbadiwe, Ngozi Mbah, Uba Ezinne, Iweha Ikechukwu, Okoi Nnyonno, Philemon Okoro, Igwe Patrick, Oriji Vaduneme, Abhulimen Victor, Salathiel Kanyarukiko, Francine Mukaneza, Deborah Mukantibaziyaremye, Aphrodis Munyaneza, Gibert Ndegamiye, Ronald Tubasiime, Moses Dusabe, Emelyne Izabiriza, Hope Lydia Maniraguha, Christophe Mpirimbanyi, Josiane Mutuyimana, Olivier Mwenedata, Francine Uwizeyimana, Job Zirikana, Aime Dieudonne Hirwa, Elysee Kabanda, Salomee Mbonimpaye, Christine Mukakomite, Piolette Muroruhirwe, Georges Bucyibaruta, Gisele Juru Bunogerane, Sosthene Habumuremyi, Jean de Dieu Haragirimana, Alphonsine Imanishimwe, Violette Mukanyange, Emmanuel Munyaneza, Emmanuel Mutabazi, Isaie Ncogoza, Jeannette Nyirahabimana, Mary Augusta Adams, Richard Crawford, Chikwendu Jeffrey Ede, Maria Fourtounas, Morapedi Kwati, Mpho Nosipho Mathe, Ncamsile Anthea Nhlabathi, Hlengiwe Samkelisiwe Nxumalo, Paddy Pattinson, Nnosa Sentholang, Mmule Evelyn Sethoana, Maria Elizabeth Stassen, Laura Thornley, Cheryl Birtles, Mathete Ivy, Cynthia Mbavhalelo, Zain Ally, Abdus-sami Adewunmi, Maria Picciochi, Michael Bahrami-Hessari, Didier Ahogni Benin, Aristide Ahounou, K. Alassan Boukari, Oswald Gbehade, Thierry K Hessou, Sinama Nindopa, M.J. Bienvenue Nontonwanou, Nafissatou Orou Guessou, Arouna Sambo, Sorekou Victoire Tchati, Affisatou Tchogo, Semevo Romaric Tobome, Parfait Yanto, Isidore Gandaho, Armel Hadonou, Simplice Hinvo, Montcho Adrien Hodonou, Sambo Bio Tamou, Marie-Claire Kouroumta, Enrif Malade, Anne stredy Mkoh Dikao, Joel Nzuwa Nsilu, Nathan Bisimwa Mitima, Cyrille Kpangon, Stephane Laurent Loupeda, Mamonde Victorin Agbangla, Sena Emmanuel Hedefoun, Thierry Mavoha, Juvenal Ngaguene, Janvier Rugendabanga, Rish Romaric Soton, Martin Totin, Mouhamed Agbadebo, Irene Akpo, Hubert Dewamon, Martin Djeto, Aissatou Hada, Monsede Hollo, Albert Houndji, Anasthasie Houndote, Sylvestre Hounsa, Expedit Kpatchassou, Hugues Yome, Mohamed Moussa Alidou, Bonheur Dossou Yovo, Robert Guinnou, Souleymane Hamadou, Nabil Moussa, Boniface Cakpo, Lolyta Etchisse, Emery Hatangimana, Moise Muhindo, Katia Sanni, Agossou Barthelemy Yevide, Hermann Agossou, Fiston Basirwa Musengo, Bill Armstrong Alia, Arnaud Alitonou, Lucien Agbanda, Julien Attinon, Marcel Gbassi, Nounagnon Rene Hounsou, Derick Esssien, Yakubu Mustapha, Kojo Nunoo-Ghartey, Luke A Aniakwo, Margarey N M Adjei, Yvonne Adofo-Asamoah, Meshach M Agyapong, Thomas Agyen, Baba A B Alhassan, Mabel P Amoako-Boateng, Josephine Ashong, Joseph K Awindaogo, Benjamin B Brimpong, Makafui S C J K Dayie, Wendy W Ghansah, Jude E Gyamfi, Vincent Kudoh, Philip Mensah, Isabella N Morkor Opandoh, Martin T Morna, Emelia Odame, Emmanuel O Ofori, Sandra Quaicoo, Elizabert M Quartson, Cynthia Teye-Topey, Makafui Yigah, Safia Yussif, Vera O Agyekum-Gyimah, Eric Agyemang, Arko Akoto- Ampaw, Temitope E Arkorful, Moses A Dokurugu, Nanabanyin Essel, Aja Ijeoma, Emmanuel L Obiri, Karen N D Quarchey, Leslie Adam-Zakariah, Aaron B Andoh, Ruby A Boateng, Atta Kusiwaa, Adeline Naah, Ato Oppon-Acquah, Benjamin A Oppong, Emma A Agbowada, Ameley Akosua, O Lawrence Dorcas Acheampong, Frank E Gyamfi, Bertina B Nyadu, Samira Abdulai, Nii A Adu-Aryee, Joachim K Amoako, Nicholas T Aperkor, Wilfred K Asman, Godsway S Attepor, Antoinette A Bediako-Bowan, George D Brown, Victor K Etwire, Benjamin S Fenu, Philemon K Kumassah, Linda A Larbi-Siaw, Josephine Nsaful, David O Olatola, Sandra E Tsatsu, Iddrisu I A Abdul-Aziz, Johnson Akunyam, Gilbert A G Anasara, Charles G Barimah, Guy C Boateng, Ponala W Kwabena, Seidu M Kwarteng, Prosper T Luri, Kennedy Ngaaso, David K D Ogudi, Collins Kyeremeh, Clement Sie-Broni, Saba Abdul-Hafiz, Daniel K Acquah, Shamsudeen M Adams, Mohammed S Alhassan, Munira Amadu, Samuel A Asirifi, Martin Awe, Millicent Azanlerigu, Mathias K Dery, Yenli Edwin, Abantanga Atindaana Francis, Aloysius Maalekuu, Hawa Malechi, Ibrahim Mohammed, Kareem Mumuni, Bernard A Ofori, Jonathan I K Quansah, Napoleon Bellua Sam, Anwar S Seidu, Shekira Yahaya, Emmanuel Kojo Acquah, Jaabir Alhassan, Christian L Coompson, Addo K Gyambibi, Ametepe Jeffery-Felix, Bismark E Kontor, Gifty Naah, Carmen Noufuentes, Abraham Sakyi, Ramkaran Chaudhary, Sanjeev Misra, Dharma R Poonia, Kirti K Rathod, Mahaveer S Rodha, Nivedita Sharma, Subhash C Soni, Vaibhav K Varsheney, Jeevan R Vishnoi, Deepak K Garnaik, Manoj J Lokavarapu, Rohit Ranjan, Rajkumar K Seenivasagam, Shanky Singh, Raunak Verma, Suzan John, Jeffery A Kalyanapu, Ananta Kutma, Sanish Philips, Arun K Gautham, Deepak S Singh, Eunice S Abraham, Chetana Chetana, Prashant Dummala, Chinta S Gold, Jurgen Jacob, Jeremiah N Joseph, Elizabeth N Kurien, Priya Mary, Arpit J Mathew, Amy E Mathew, Danita D Prakash, Ashwin Sukumar, Niyah Syam, Alisha Bhatt, Dhruva N Ghosh, Ankush Goyal, Monika A Hans, Jyoti Jyoti, Karan Kumar, Vivin Daniel Sam, Ravinder Singh Thind, Sreejith K Veetil, Rahul Williams, D Sreekar, Esther R Daniel, Smitha E Jacob, Mark R Jesudason, Pushplatha Kumari, Soosan Prasad, Srujan Sharma, Moonish V Sivakumar, Paul Trinity, Sudheer Kanchodu, K Leshiini, Sundeep S Saluja, Ashok K Attri, Ishan Bansal, Monika Gureh, Simran Kapoor, Harmanjot Kaur, Simrandeep Singh, Viju John, Nivesh Agrawal, Uttkarsh Kumar, S Abhishek, Vikram Sehrawat, Gaurav Thami, Stanley Mathew, P S Prabhu, P T Sundeep, Shiv Rajan, Mohit Singh, Abhilasha Tripathi, Philip V Alexander, A Vijay, Moloti Kichu* Ismavel, Carolin V Solomi, Rahul A Alpheus, Ashish Victor Choudhrie, Rashmi Jacob Gunny, Susan Joseph, Nitin J Peters, Neha Pundir, Ram Samujh, Hafsa I Ahmed, Gowhar Aziz, Nisar A Chowdri, Rayees A Dar, Robindera Kour, Imtiyaz Mantoo, Asif Mehraj, Fazl Q Parray, Najmus Saqib, Zamir A Shah, Rauf A Wani, Komal Rautela, Nishu Singh, Priyanka Chowdhury, Sona Chowdhury, Pragyanmai Nayak, Bipradas Roy, Andrea S Alvarez Villaseñor, Kriscia V Ascencio Díaz, Victor J Avalos Herrera, Francisco J Barbosa, Elyoenai Bonilla Ahumada, Irma V Brancaccio, Miguel A Calderón, Guadalupe Castillo Cardiel, Guillermo A Cervantes, Gabino Cervantes Guevara, Enrique Cervantes Perez, Maria Chávez, Jonathan M Chejfec, Luis R Cifuentes, Ana O Cortés, Edgar J Cortes, Tania A Cueto, Andrea E Cueto, Esteban Cueva Martinez, Paulina Domínguez Barradas, Isaac Esparza Estrada, Paola Flores Becerril, Luis A García, Benjamín García Reyna, Eduardo Gómez Sánchez, Jaime L González, Eduardo González Espinoza, Fanny Y González, Cristhian S Guerrero, José A Guzmán, Bertha G Guzmán, Mario J Guzmán, DanielA Hérnandez Alva, SilviaA Ibarra Camargo, JuanC Ibarrola Peña, Martin Islas Torres, Jorge Jiménez Tornero, ZayraM Lara Pérez, Roberto Mares País, MelP Mellado Tellez, RobertoC Miranda Ackerman, Damián Mora Santana, Gilberto Morgan Villela, Rodrigo Nájar Hinojosa, Cesar Nuño Escobar, Itzel Ochoa Rodríguez, Angelica Ortega Barreiro, Jacqueline Osuna Rubio, Luis RPacheco Vallejo, VíctorH Pérez Bocanegra, JoseV Pérez Navarro, Francisco JPlascencia Posada, MaríaA Quirarte Hernández, LuisR Ramirez Gonzalez, Emilio AReyes Elizalde, EveliaV Romo Ascencio, Cornelio Ruelas Bravo, CarlosB Ruiz Velasco, JoséA Sánchez Martínez, Guillermo Sanchez Villaseñor, JoséI Sandoval Pulido, AlejandroG Serrano García, LuisO Suárez Carreón, JuanJ Tijerina Ávila, JesusO Vega Gastelum, MelissaL Vicencio Ramirez, MariaF Zarate Casas, CarlosJ Zuloaga, Fernández del Valle, JesusAntonion Aguilar Mata, MiguelAntonio Calderon Vanegas, RocioGuadalupe Cano Arias, Carlos Colunga Tinajero, Fernanda Diaz Samano, Fernando Duque Zepeda, BrendaVanessa Enriquez Barajas, Gerardo Gallardo Banuelos, MarijoseDe CristoGonzalez Calvillo, Francisco Ibanez Ortiz, Maryzela Lazo Ramirez, Gerardo Lopez Arroyo, LauraOlivia Montano Angeles, DavidGiovannyI Morales Iriarte, AngeloFernando Mortola Lomeli, Jose EstebanOrozco Navarro, Jaime Orozco Perez, Damaris Orozco Ramirez, LauraGabriela Pena Baolboa, Jesus Pizarro Lozano, Guillermo Yanowsky Reyes, Monica N Castillo, Ana CamilleG Dominguez, Dorihela H Mellado, Jesus FlavioM Morales, Luzdel CarmenM Namur, Jose AlbertoA Pesquera, LauraMartinez Perez Maldonado, Antonio RamosDe laMedina, Katya Bozada-Gutierrez, AnaFlorencia Casado-Zarate, Roberto Delano-Alonso, Jose Herrera-Esquivel, Mucio Moreno-Portillo, Mario Trejo-Avila, Roland Kevin CethorthFonseca, Edgard Efren LozadaHernandez, Bruno Crocco Quiros, JairoArturo Rodriguez Ramirez, Gabriela Ambriz-González, MitziR Becerra Moscoso, Ishtar Cabrera-Lozano, AnaB Calderón-Alvarado, FranciscoJ León-Frutos, ErickE Villanueva-Martínez, Aisha Abdullahi, Maimuna Abubakar, MohammedS Aliyu, Mudi Awaisu, Fadimatu Bakari, Abigail Olajumoke Balogun, Ahmad Bello, Kehinde Michael Duromola, Stephen G Gana, Mukoro Duke George, Justina Gimba, Isaac Gundu, Lambert Onahi Iji, Aminat O Jimoh, Afolabi K Koledade, Ahmad T Lawal, Bilkisu K Lawal, Stanley Emeka Nwabuoku, Oluseyi O Ogunsua, Ifeanyi Fidelis Okafor, Ethos Ike Okorie, Nasir Oyelowo, Ibrahim A Saidu, Tunde T Sholadoye, Ibrahim Sufyan, Musliu Adetola Tolani, Aliyu Muhammad Tukur, Ahmad Shehu Umar, Aminatu M Umar, Hajara Umaru-Sule, Mohammed Usman, Alfa Yakubu, Salisu Abeku Yusuf, Abdulhafiz A Abdulkarim, Lawal Barau Abdullahi, Khadija A Ado, Nura U Aliyu, Lofty-John Chukwuemeka Anyanwu, Sulaiman M Daneji, Mahmoud Kawu Magashi, Mohammad A Mohammad, Abubakar Bala Muhammad, Saminu S Muhammad, Bello Abodunde Muideen, Calistus U Nwachukwu, Suleiman B Sallau, Abdulrahman A Sheshe, Abdulmajeed Soladoye, Idris Usman Takai, Garzali I Umar, Abubakar Yahaya, Lubabatu Abdulrasheed, Joel A Adze, Lydia R Airede, Bashiru Aminu, Stephen B Bature, Firdaws Bello-Tukur, Damai Chinyio, SharonA N Duniya, Moses C Galadima, Babatunde K Hamza, Samaila Joshua, Stephen A Kache, Williams Y Kagomi, Ifeanyi A Kene, Jamila Lawal, Jerry G Makama, Caleb Mohammed, Amina A Mohammed-Durosinlorun, Deborah Nuwam, Abdulrasheed Sani, Salome Tabara, Mathew C Taingson, Emmanuel Usam, Josiah Yakubu, Folasade Adegoke, Oluwasuyi Ige, Tunde A Odunafolabi, Chukwuma E Okereke, Oluwafemi O Oladele, Oluwaseun H Olaleye, Oyetunde O Olubayo, Olukayode P Abiola, Henry O Abiyere, Idowu O Adebara, GbadeboT C Adeleye, Adebayo A Adeniyi, Olumide E Adewara, Olabisi T Adeyemo, Ademola A Adeyeye, Abimbola L Ariyibi, Babatunde S Awoyinka, Olumide M Ayankunle, Olakunle F Babalola, Adewumi Bakare, TajudeenI B Bakare, Oluseyi O Banjo, Peter A Egharevba, Oluwafemi S Fatudimu, John A Obateru, Oluremi J Odesanya, Owolabi D Ojo, Abiodun I Okunlola, Cecilia K Okunlola, Adewale T Olajide, Tesleem O Orewole, Adedayo I Salawu, Moruf A Abdulsalam, Aderinsola T Adelaja, Olalekan T Ajai, Noble Anyanwu, Kazeem M Atobatele, Oludayo Oluwaseyi Bakare, Omolara M Faboya, Francisca C Nwaenyi, Ayokunle A Ogunyemi, Mobolaji A Oludara, Olufunmilade A Omisanjo, Chinonso U Onyeka, Olabode A Oshodi, Yusuf A Oshodi, Omotade S Salami, Omolara M Williams, Esther Abunimye, Adebunmi Adeoluwa, Adedotun Adesiyakan, Victoria Ibukunoluwa Adeyeye, Moses Vincent Agbulu, David O Akinboyewa, Iyabo O Alasi, Michael Amao, Christiana Ashley-Osuzoka, Oluwole A Atoyebi, Olanrewaju S Balogun, Maryam Oluwatobi Busari, Nnamdi Jonathan Duru, Glory Bassey Edet, Olumide A Elebute, Francis Chinonso Ezenwankwo, Adedeji L Fatuga, Christianah Gbenga-Oke, Emmanuel Sylvester Inyang, Adesola I Jimoh, Jubril Oladayo Kuku, OluwaseunA Ladipo-Ajayi, Abdulrazzaq O Lawal, Christian Chigoze Makwe, Chinelo Victoria Mgbemena, Samuel U Nwokocha, Moses Adebisi Ogunjimi, Ephraim Okwudiri Ohazurike, Rufus W Ojewola, Moyosoluwa Eunice Badedale, Chike J Okeke, Adeyemi A Okunowo, Abraham T Oladimeji, Thomas O Olajide, Olabisi Olanrewaju, Olawunmi Olayioye, Oluwaseun O Oluseye, Stephen Olutola, Kenneth Onyekachi, Adeola Ayoola Orowale, Emili Osariemen, Adedapo Olumide Osinowo, Emmanuel Owie, Christianah Bidemi Oyegbola, Justina OSeyi-Olajide, AdaiahP Soibi-Harry, Manuella Talla Timo, Aloy Okechukwu Ugwu, Emmanuel Ojo Williams, Innocent O Duruewuru, Ochonma A Egwuonwu, Okechukwu Hyginus Ekwunife, James J Emeka, Chimdiebele Daisy Nwosu, Sylvester O Obiechina, Ahuizechukwu E Obiesie, Celestine I Okafor, Theophilus O Okonoboh, Odili A Okoye, Onyekachi A Onu, Chukwudubem C Onyejiaka, Chisom Faith Uche, JosephO Ugboajah, Akeem A Adeleke, Akinfolarin C Adepiti, Adewale A Aderounmu, Abdulhafiz O Adesunkanmi, Adewale O Adisa, Samuel C Ajekwu, Olusegun K Ajenifuja, Olusegun I Alatise, Tajudeen A Badmus, Tajudeen O Mohammed, Abdulkadir A Salako, Oludayo A Sowande, Ademola O Talabi, Funmilola O Wuraola, Paul Aderemi Adegoke, Abidemi Akinloye, Ayodeji Akinniyi, Joseph Ejimogu, Ideyonbe Samuel Eseile, Olakayode Olaolu Ogundoyin, Amos Okedare, Dare Isaac Olulana, Omolara Omotola, Francis Sanwo, Collins C Adumah, Adewale O Ajagbe, Olugbenga P Akintunde, Opeyemi Q Asafa, Kehinde Awodele, Amogu K Eziyi, Adeniyi O Fasanu, Olufemi O Ojewuyi, Abiodun R Ojewuyi, Abisola E Oyedele, Oluwaseun A Taiwo, Habiba I Abdullahi, Nathaniel D Adewole, Teddy E Agida, Eunice E Ailunia, Oseremen Aisuodionoe-Shadrach, Godwin O Akaba, Janet Alfred, Terkaa Atim, Kehinde G Bawa, John Y Chinda, Esther B Daluk, Sefiu B Eniola, Augusta O Ezenwa, Stephen E Garba, Philip M Mshelbwala, Ngozi O Ndukwe, Idoko P Ogolekwu, Alexander A Ohemu, Samuel A Sani, Salisu Suleiman, Helen Sunday, Nancy O Tabuanu, Aminu M Umar, Peter I Agbonrofo, Alexander I Arekhandia, Morrison E Edena, Raymond A Eghonghon, Joel E Enaholo, Genesis Ida, Stanley N Ideh, Oseihie I Iribhogbe, Omorodion O Irowa, Maradona E Isikhuemen, Oluwatomi R Odutola, Kester O Okoduwa, Scott O Omorogbe, David Oruade, Osasumwen T Osagie, Osarenkhoe Osemwegie, RukiyatA Abdus-Salam, Sikiru Adekola Adebayo, Oluwasanmi A Ajagbe, Gboyega Ajibola, Kelvin I Egbuchulem, Hyginus O Ekwuazi, Adegbolahan Fakoya, Oluwasegun C Idowu, David O Irabor, Taiwo A Lawal, Olakayode O Ogundoyin, Oluwabukade Ojediran, Naomi Olagunju, Akinsola T Sanusi, Augustine O Takure, Lukman Olajide Abdur-Rahman, Mary Oluwadamilola Adebisi, Nurudeen Abiola Adeleke, Rafiat Tinuola Afolabi, Isiaka Ishola Aremu, Jibril Oyekunle Bello, Robiat Bello, Saheed Abolade Lawal, Adeolu Ojajuni, Sabur Oyewale, Victor Abhulimen, Patrick O Igwe, Ikechukwu Enyinnaya Iweha, Raphael E John, Nnyonno Okoi, Philemon E Okoro, Vaduneme Kingsley Oriji, Ibiene T Oweredaba, Japhet Mizero, Immaculee Mutimamwiza, Francoise Nirere, Irenee Niyongombwa, Jean Paul Majyabere, Anastase Byaruhanga, Rongin Dukuzimana, Jean Aimable Habiyakare, Marie Gloriose Nabada, Marcel Uwizeye, Mathias Ruhosha, Joselyne Igiraneza, Faustine Ingabire, Aloys Karekezi, Jean pierre Masengesho, Lydia Mukamazera, Clemence Mukangabo, Jean Paul Niyomuremyi, Gabriel Ntwari, Celestin Seneza, Divine Umuhoza, Pierrine Nyirangeri, Jean Claude Uwimana, Isaie Sibomana, Desire Rubanguka, Josine Umuhoza, Roda Uwayezu, Leoncie Uzikwambara, Herbert Butana, Moise Dusabeyezu, Athanasie Mukasine, Jean N Utumatwishima, Mediatrice Batangana, Jeande Dieu Haragirimana, AllenJ C Ingabire, Espoir Mwungura, Dancilla Nyirasebura, Christian Jean Urimubabo, Anaclet Dusabimana, Sam Kanyesigye, Robert Munyaneza, Jean Yves Shyirakera, Aimee Domingo, Philip Munda, Chido Nyatsambo, Victor Ojo, Rudo Pswarayi, and Soeren Laurberg

Subjects
Medicine (General), R5-920, Infectious and parasitic diseases, RC109-216
Published
2024
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41. Measuring Environmental and Behavioral Drivers of Chronic Diseases Using Smartphone-Based Digital Phenotyping: Intensive Longitudinal Observational mHealth Substudy Embedded in 2 Prospective Cohorts of Adults

Author

Li Yi, Jaime E Hart, Marcin Straczkiewicz, Marta Karas, Grete E Wilt, Cindy R Hu, Rachel Librett, Francine Laden, Jorge E Chavarro, Jukka-Pekka Onnela, and Peter James

Subjects
Public aspects of medicine, RA1-1270
Abstract

BackgroundPrevious studies investigating environmental and behavioral drivers of chronic disease have often had limited temporal and spatial data coverage. Smartphone-based digital phenotyping mitigates the limitations of these studies by using intensive data collection schemes that take advantage of the widespread use of smartphones while allowing for less burdensome data collection and longer follow-up periods. In addition, smartphone apps can be programmed to conduct daily or intraday surveys on health behaviors and psychological well-being. ObjectiveThe aim of this study was to investigate the feasibility and scalability of embedding smartphone-based digital phenotyping in large epidemiological cohorts by examining participant adherence to a smartphone-based data collection protocol in 2 ongoing nationwide prospective cohort studies. MethodsParticipants (N=2394) of the Beiwe Substudy of the Nurses’ Health Study 3 and Growing Up Today Study were followed over 1 year. During this time, they completed questionnaires every 10 days delivered via the Beiwe smartphone app covering topics such as emotions, stress and enjoyment, physical activity, access to green spaces, pets, diet (vegetables, meats, beverages, nuts and dairy, and fruits), sleep, and sitting. These questionnaires aimed to measure participants’ key health behaviors to combine them with objectively assessed high-resolution GPS and accelerometer data provided by participants during the same period. ResultsBetween July 2021 and June 2023, we received 11.1 TB of GPS and accelerometer data from 2394 participants and 23,682 survey responses. The average follow-up time for each participant was 214 (SD 148) days. During this period, participants provided an average of 14.8 (SD 5.9) valid hours of GPS data and 13.2 (SD 4.8) valid hours of accelerometer data. Using a 10-hour cutoff, we found that 51.46% (1232/2394) and 53.23% (1274/2394) of participants had >50% of valid data collection days for GPS and accelerometer data, respectively. In addition, each participant submitted an average of 10 (SD 11) surveys during the same period, with a mean response rate of 36% across all surveys (SD 17%; median 41%). After initial processing of GPS and accelerometer data, we also found that participants spent an average of 14.6 (SD 7.5) hours per day at home and 1.6 (SD 1.6) hours per day on trips. We also recorded an average of 1046 (SD 1029) steps per day. ConclusionsIn this study, smartphone-based digital phenotyping was used to collect intensive longitudinal data on lifestyle and behavioral factors in 2 well-established prospective cohorts. Our assessment of adherence to smartphone-based data collection protocols over 1 year suggests that adherence in our study was either higher or similar to most previous studies with shorter follow-up periods and smaller sample sizes. Our efforts resulted in a large dataset on health behaviors that can be linked to spatial datasets to examine environmental and behavioral drivers of chronic disease.

Published
2024
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42. Enhanced production of taxadiene in Saccharomyces cerevisiae

Author

Lungang Liang, Behnaz Nowrouzi, Laura E. Walls, Albert Isaac Lerma-Escalera, Jay D. Keasling, Jose Ruben Morones-Ramirez, Nestor Jonguitud-Borrego, Rachel Li, Koray Malcı, Leo d'Espaux, and Leonardo Rios-Solis

Subjects
0106 biological sciences, lcsh:QR1-502, Applied Microbiology and Biotechnology, 01 natural sciences, lcsh:Microbiology, chemistry.chemical_compound, Bioreactors, Solubility, Isomerases, Shake flask, 0303 health sciences, Strain (chemistry), biology, Chemistry, Taxadiene, Temperature, Yeast metabolic engineering, Biochemistry, Metabolic Engineering, Taxadiene synthase, Production (computer science), Taxol&#8482, Diterpenes, Biotechnology, Paclitaxel, Stereochemistry, Minibioreactor, Saccharomyces cerevisiae, Paclitaxel, Taxol™, Bioengineering, Antineoplastic Agents, Alkenes, Microbiology, Industrial Biotechnology, 03 medical and health sciences, SDG 3 - Good Health and Well-being, 010608 biotechnology, Bioreactor, Escherichia coli, Bioprocess, 030304 developmental biology, 010405 organic chemistry, Research, biology.organism_classification, 0104 chemical sciences, biology.protein, Taxol™
Abstract

Background Cost-effective production of the highly effective anti-cancer drug, paclitaxel (Taxol®), remains limited despite growing global demands. Low yields of the critical taxadiene precursor remains a key bottleneck in microbial production. In this study, the key challenge of poor taxadiene synthase (TASY) solubility in S. cerevisiae was revealed, and the strains were strategically engineered to relieve this bottleneck. Results Multi-copy chromosomal integration of TASY harbouring a selection of fusion solubility tags improved taxadiene titres 22-fold, up to 57 ± 3 mg/L at 30 °C at microscale, compared to expressing a single episomal copy of TASY. The scalability of the process was highlighted through achieving similar titres during scale up to 25 mL and 250 mL in shake flask and bioreactor cultivations, respectively at 20 and 30 °C. Maximum taxadiene titres of 129 ± 15 mg/L and 127 mg/L were achieved through shake flask and bioreactor cultivations, respectively, of the optimal strain at a reduced temperature of 20 °C. Conclusions The results of this study highlight the benefit of employing a combination of molecular biology and bioprocess tools during synthetic pathway development, with which TASY activity was successfully improved by 6.5-fold compared to the highest literature titre in S. cerevisiae cell factories.

Published
2020
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44. Eye and ocular adnexa manifestations of

Author

Arth, Shah, Monika, Bapna, Hind, Al-Saif, Rachel, Li, and Natario L, Couser

Subjects
Mediator Complex, Intellectual Disability, Astigmatism, Humans, Female
Abstract

We performed a systematic literature review of previously published cases to highlight the key ocular features in individuals withOur patient presented with developmental delay, mild hypotonia and dysmorphic features including frontal bossing, high arched palate, and syndactyly of the 2Ocular manifestations identified in this patient included intermittent esotropia, hyperopic astigmatism, epicanthal folds and ptosis bilaterally.

Published
2021

45. Monoclonal Antibody Therapy against Acinetobacter baumannii

Author

Travis B. Nielsen, Elizabeth Burk, Brian Luna, Matthew Slarve, Peter Oelschlaeger, William Win, Kyle Hurth, Robert A. Bonomo, Yuli Talyansky, Rachel Li, Bosul Lee, Peggy Lu, Brad Spellberg, Juan Ruiz, and Jun Yan

Subjects
Acinetobacter baumannii, medicine.drug_class, Immunology, Antibiotics, Microbial Sensitivity Tests, Monoclonal antibody, Microbiology, Sepsis, Mice, Drug Resistance, Multiple, Bacterial, medicine, Animals, Monoclonal antibody therapy, biology, Colistin, Antibodies, Monoclonal, biology.organism_classification, medicine.disease, Antibodies, Bacterial, Anti-Bacterial Agents, Infectious Diseases, Microbial Immunity and Vaccines, biology.protein, Hybridoma technology, Cytokines, Parasitology, Antibody, Biomarkers, medicine.drug, Acinetobacter Infections
Abstract

Extremely drug-resistant (XDR) Acinetobacter baumannii is a notorious and frequently encountered pathogen demanding novel therapeutic interventions. An initial monoclonal antibody (MAb), C8, raised against A. baumannii capsule, proved a highly effective treatment against a minority of clinical isolates. To overcome this limitation, we broadened coverage by developing a second antibody for use in a combination regimen. We sought to develop an additional anti-A. baumannii MAb through hybridoma technology by immunizing mice with sublethal inocula of virulent, XDR clinical isolates not bound by MAb C8. We identified a new antibacterial MAb, 65, which bound to strains in a pattern distinct from and complementary to that of MAb C8. MAb 65 enhanced macrophage opsonophagocytosis of targeted strains and markedly improved survival in lethal bacteremic sepsis and aspiration pneumonia murine models of A. baumannii infection. MAb 65 was also synergistic with colistin, substantially enhancing protection compared to monotherapy. Treatment with MAb 65 significantly reduced blood bacterial density, ameliorated cytokine production (interleukin-1β [IL-1β], IL-6, IL-10, and tumor necrosis factor), and sepsis biomarkers. We describe a novel MAb targeting A. baumannii that broadens immunotherapeutic strain coverage, is highly potent and effective, and synergistically improves outcomes in combination with antibiotics.

Published
2021

46. Clinical findings and outcome predictors for multinodular pulmonary fibrosis in horses: 46 cases (2009‐2019)

Author

Amanda Craven, Amy Todd‐Donato, Tracy Stokol, Rachel Liepman, Ilana Glasberg, Pamela Wilkins, Daniela Luethy, David Wong, Angelika Schoster, Astrid J. van denBrom ‐ Spierenburg, and Joy E. Tomlinson

Subjects
asthma, equine herpesvirus‐5 (EHV‐5), bronchoalveolar lavage, tracheal wash, Veterinary medicine, SF600-1100
Abstract

Abstract Background Prognostic indicators for equine multinodular pulmonary fibrosis (EMPF), an interstitial fibrosing lung disease, are poorly described. Hypothesis/Objectives Describe diagnostic findings and outcome predictors for EMPF. Animals Forty‐six adult horses with EMPF. Methods Retrospective multicenter case series from 2009 to 2019. Radiographic (n = 27) and ultrasonographic studies (n = 19) from EMPF horses and bronchoalveolar lavage fluid (BALF) cytology from 6 EMPF and 13 asthma cases were independently reviewed and blinded to diagnosis and outcome. Associations between predictor variables and survival were assessed by predictor screening followed by Fisher's exact and Wilcoxon rank sum tests. Results Primary clinical findings were weight loss (36/46, 78%), increased respiratory effort (33/46, 72%), tachypnea (32/46, 70%), and fever (18/46, 39%). Macrophage atypia was seen in more EMPF than asthmatic horse BALF (67% vs. 8%; P = .02). Equine herpesvirus 5 (EHV‐5) was detected in 24 of 30 (80%) and hyperfibrinogenemia in 25 of 28 (89%) cases. Twenty‐seven of 46 horses (59%) and 11 of 45 (24%) survived to discharge and to 3 months, respectively. Three‐month survival was associated with lower median (range) respiratory rates (30 [24‐36] vs. 41 [30‐60] breaths per minute; P = .04), and higher BALF lymphocyte:neutrophil ratios (4.7 [1.4‐22] vs. 0.47 [0.11‐1.9]; P = .01) and blood lymphocyte counts (1.25 [0.93‐2.55] vs. 0.90 [0.70‐1.24] × 109/L; P = .03). Imaging findings, EHV‐5 detection, and corticosteroid treatment were not associated with survival. Conclusions and Clinical Importance Fever is not a sensitive clinical sign of EMPF. Diagnostic testing should be pursued for horses with increased respiratory rate and effort and weight loss. The prognosis for EMPF horses is poor. Corticosteroid treatment does not improve 3‐month survival.

Published
2024
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47. Cost‐effectiveness of Resonance® metallic ureteral stent compared with standard polyurethane ureteral stents in malignant ureteric obstruction: A cost‐utility analysis

Author

Dawn M. Cooper, Rachel Lines, and Iqbal Shergill

Subjects
cost‐effectiveness, double‐J stents, malignant ureteric obstruction, metallic stents, Diseases of the genitourinary system. Urology, RC870-923
Abstract

Abstract Background Malignant ureteral obstruction (MUO) is a frequent challenge for urologists. Patients have poor prognoses, treatment aims to improve quality‐of‐life while optimising renal function. Standard practice in the United Kingdom is to use polyurethane stents, which require frequent surgical replacements for blockages and encrustation. More durable metallic stents are available, although these incur an increased initial purchase price. Aims We aim to assess whether the use of polyurethane double‐J (JJ) or metallic stent, Resonance® is more cost‐effective for managing MUO in the UK healthcare setting. Methods A Markov model was parameterised to 5 years with costs and health‐related quality‐of‐life consequences for treating MUO with Resonance metallic stent (Cook Medical), versus standard JJ stents, from the UK care system perspective, with 3.5% discounting. Deterministic and probabilistic sensitivity analyses were undertaken to assess the effect of uncertainty. Results Over 5 years, approximately four fewer repeat surgical interventions were estimated in the metallic stent arm compared with the JJ stent, driving a 23.4% reduction in costs. The mean estimates of costs and benefits indicate that treatment of MUO with Resonance for 5 years is dominant over JJ stents. Over 5 years a cost‐saving of £2164.74 and a health gain of +0.046 quality‐adjusted life years (QALYs) per patient is estimated. With a maximum willingness to pay of £20 k per QALY, a net monetary benefit (NMB) of £3077.83 is estimated. Probabilistic sensitivity analysis at a willingness to pay threshold of £20 000 indicates an 89.3% probability of Resonance being cost‐effective over JJ stents. Within 1‐year savings of £726.53 are estimated driven by a reduction of two fewer repeat surgical interventions when using the metallic stent. Conclusions Resonance metallic stents for the treatment of MUO reduce the number of repeat procedures and could be a cost‐effective option for the treatment, potentially offering efficiencies to the healthcare system.

Published
2024
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48. Ophthalmic abnormalities in Wieacker-Wolff syndrome

Author

Tien Comlekoglu, Virang Kumar, Kayla King, Hind Al Saif, Rachel Li, and Natario Couser

Subjects
Ophthalmology, Muscular Atrophy, Contracture, Ophthalmoplegia, Apraxias, Pediatrics, Perinatology and Child Health, Intracellular Signaling Peptides and Proteins, Humans, Nuclear Proteins, Female, Genetic Diseases, X-Linked
Abstract

Wieacker-Wolff syndrome is an X-linked condition caused by variants of the ZC4H2 gene that results in in utero muscular weakness that manifests clinically as arthrogryposis congenita as well as facial and bulbar weakness. We report the case of a young girl with a de novo pathogenic deletion in the ZC4H2 gene and clinical features consistent with Wieacker-Wolff syndrome. Common eye manifestations of the syndrome reported in the literature include ptosis, strabismus, and oculomotor apraxia. The overall incidence of these manifestations is 56%.

Published
2021

49. Vaginal fungi are associated with treatment-induced shifts in the vaginal microbiota and with a distinct genital immune profile

Author

Eric Armstrong, Anke Hemmerling, Steve Miller, Sanja Huibner, Maria Kulikova, Rachel Liu, Emily Crawford, Gloria R. Castañeda, Bryan Coburn, Craig R. Cohen, and Rupert Kaul

Subjects
genital immunology, vaginal microbiome, fungi, Candida, inflammation, Microbiology, QR1-502
Abstract

ABSTRACT Vaginal colonization by fungi may elicit genital inflammation and enhance the risk of adverse reproductive health outcomes, such as HIV acquisition. Cross-sectional studies have linked fungi with an absence of bacterial vaginosis (BV), but it is unclear whether shifts in vaginal bacteria alter the abundance of vaginal fungi. Vaginal swabs collected following topical metronidazole treatment for BV during the phase 2b, placebo-controlled trial of LACTIN-V, a Lactobacillus crispatus-based live biotherapeutic, were assayed with semi-quantitative PCR for the relative quantitation of fungi and key bacterial species and multiplex immunoassay for immune factors. Vaginal fungi increased immediately following metronidazole treatment for BV (adjusted P = 0.0006), with most of this increase attributable to Candida albicans. Vaginal fungi were independently linked to elevated levels of the proinflammatory cytokine interleukin (IL) 17A, although this association did not remain significant after correcting for multiple comparisons. Fungal relative abundance by semi-quantitative PCR returned to baseline levels within 1 month of metronidazole treatment and was not affected by LACTIN-V or placebo administration. Fungal abundance was positively associated with Lactobacillus species, negatively associated with BV-associated bacteria, and positively associated with a variety of proinflammatory cytokines and chemokines, including IL-17A, during and after study product administration. Antibiotic treatment for BV resulted in a transient expanded abundance of vaginal fungi in a subset of women which was unaffected by subsequent administration of LACTIN-V. Vaginal fungi were positively associated with Lactobacillus species and IL-17A and negatively associated with BV-associated bacteria; these associations were most pronounced in the longer-term outcomes.IMPORTANCEVaginal colonization by fungi can enhance the risk of adverse reproductive health outcomes and HIV acquisition, potentially by eliciting genital mucosal inflammation. We show that standard antibiotic treatment for bacterial vaginosis (BV) results in a transient increase in the absolute abundance of vaginal fungi, most of which was identified as Candida albicans. Vaginal fungi were positively associated with proinflammatory immune factors and negatively associated with BV-associated bacteria. These findings improve our understanding of how shifts in the bacterial composition of the vaginal microbiota may enhance proliferation by proinflammatory vaginal fungi, which may have important implications for risk of adverse reproductive health outcomes among women.

Published
2024
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50. Mycobacterium dormancy and antibiotic tolerance within the retinal pigment epithelium of ocular tuberculosis

Author

Rachel Liu, Joshua N. Dang, Rhoeun Lee, Jae Jin Lee, Niranjana Kesavamoorthy, Hossein Ameri, Narsing Rao, and Hyungjin Eoh

Subjects
Mycobacterium tuberculosis, ocular tuberculosis, metabolomics, chemotherapy, Microbiology, QR1-502
Abstract

ABSTRACT Tuberculosis (TB) is a leading cause of death among infectious diseases worldwide due to latent TB infection, which is the critical step for the successful pathogenic cycle. In this stage, Mycobacterium tuberculosis resides inside the host in a dormant and antibiotic-tolerant state. Latent TB infection can also lead to multisystemic diseases because M. tuberculosis invades virtually all organs, including ocular tissues. Ocular tuberculosis (OTB) occurs when the dormant bacilli within the ocular tissues reactivate, originally seeded by hematogenous spread from pulmonary TB. Histological evidence suggests that retinal pigment epithelium (RPE) cells play a central role in immune privilege and in protection from antibiotic effects, making them an anatomical niche for invading M. tuberculosis. RPE cells exhibit high tolerance to environmental redox stresses, allowing phagocytosed M. tuberculosis bacilli to maintain viability in a dormant state. However, the microbiological and metabolic mechanisms determining the interaction between the RPE intracellular environment and phagocytosed M. tuberculosis are largely unknown. Here, liquid chromatography-mass spectrometry metabolomics were used to illuminate the metabolic state within RPE cells reprogrammed to harbor dormant M. tuberculosis bacilli and enhance antibiotic tolerance. Timely and accurate diagnosis as well as efficient chemotherapies are crucial in preventing the poor visual outcomes of OTB patients. Unfortunately, the efficacy of current methods is highly limited. Thus, the results will lead to propose a novel therapeutic option to synthetically kill the dormant M. tuberculosis inside the RPE cells by modulating the phenotypic state of M. tuberculosis and laying the foundation for a new, innovative regimen for treating OTB.IMPORTANCEUnderstanding the metabolic environment within the retinal pigment epithelium (RPE) cells altered by infection with Mycobacterium tuberculosis and mycobacterial dormancy is crucial to identify new therapeutic methods to cure ocular tuberculosis. The present study showed that RPE cellular metabolism is altered to foster intracellular M. tuberculosis to enter into the dormant and drug-tolerant state, thereby blunting the efficacy of anti-tuberculosis chemotherapy. RPE cells serve as an anatomical niche as the cells protect invading bacilli from antibiotic treatment. LC-MS metabolomics of RPE cells after co-treatment with H2O2 and M. tuberculosis infection showed that the intracellular environment within RPE cells is enriched with a greater level of oxidative stress. The antibiotic tolerance of intracellular M. tuberculosis within RPE cells can be restored by a metabolic manipulation strategy such as co-treatment of antibiotic with the most downstream glycolysis metabolite, phosphoenolpyruvate.

Published
2024
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