Probing the past: historical case study analysis to inform more just and sustainable global health partnerships in education.

Introduction: Disparities of power between high-income (HICs) and low- and middle-income countries (LMICs) have long characterised the structures of global health, including knowledge production and training. Historical case study analysis is an often-overlooked tool to improve our understanding of how to mitigate inequalities.

Methods: Drawing from the contemporary experience of collaborators from Canada and Ethiopia, we chose to examine the historical relationship between Ethiopian Emperor Haile Selassie and Canadian Jesuit Lucien Matte as a case study for international collaborations based on the model of an 'invited guest'.

Data-Exchange Between Electronic Medical Record and Viral-Load Laboratory Database Towards Improving HIV Care in Ethiopia.

Electronic viral load (VL) Test Ordering and Result Reporting System (ETORRS) was introduced to create data exchange between the existing VL database and the electronic medical record (EMR) system, with the aim of reducing laboratory test results turnaround time (TAT), improving data quality, and supporting timely clinical response for patients with high VL. This use case is an illustrative example of initiating and adopting the principles of health information exchange for a priority health program.

Identifying critical gaps in research to advance global surgery by 2030: a systematic mapping review.

Progress on surgical system strengthening has been slow due to a disconnect between evidence generation and the information required for effective policymaking. This systematic mapping review sought to assess critical research gaps in the field of global surgery guided by the World Health Organisation Health Systems building block framework, analysis of authorship and funding patterns, and an exploration of emerging research partnership networks. Literature was systematically mapped to identify, screen, and synthesize results of publications in the global surgery field between 2015 and March 2022.

Ethiopia National Food and Nutrition Survey to inform the Ethiopian National Food and Nutrition Strategy: a study protocol.

Introduction: Ethiopia has made significant progress in reducing malnutrition in the past two decades. Despite such improvements, a substantial segment of the country's population remains chronically undernourished and suffers from micronutrient deficiencies and from increasing diet-related non-communicable diseases such as diabetes, hypertension and cancer. This survey aims to assess anthropometric status, dietary intake and micronutrient status of Ethiopian children, women and adolescent girls.

Effect of enhanced nutrition services with community-based nutrition services on the diet quality of young children in Ethiopia.

Poor diet quality related to inadequate complementary feeding is a major public health problem in low and middle-income countries including Ethiopia. Low dietary diversity has been linked to negative health outcomes in children. To provide a package of interventions to close nutritional gaps through agriculture, the Sustainable Undernutrition Reduction in Ethiopia (SURE) programme was set up as a multi-sectoral initiative and the results of combined effects of community-based and enhanced nutrition services, compared to community-based alone, on diet diversity and diet quality of complementary feeding of young children are presented.

Efficiently driving protein-based fragment screening and lead discovery using two-dimensional NMR.

Fragment-based drug discovery (FBDD) and validation of small molecule binders using NMR spectroscopy is an established and widely used method in the early stages of drug discovery. Starting from a library of small compounds, ligand- or protein-observed NMR methods are employed to detect binders, typically weak, that become the starting points for structure-activity relationships (SAR) by NMR. Unlike the more frequently used ligand-observed 1D NMR techniques, protein-observed 2D H-N or H-C heteronuclear correlation (HSQC or HMQC) methods offer insights that include the mechanism of ligand engagement on the target and direct binding affinity measurements in addition to routine screening.

Identification and structure-based drug design of cell-active inhibitors of interleukin 17A at a novel C-terminal site.

Anti-IL17A therapies have proven effective for numerous inflammatory diseases including psoriasis, axial spondylitis and psoriatic arthritis. Modulating and/or antagonizing protein-protein interactions of IL17A cytokine binding to its cell surface receptors with oral therapies offers the promise to bring forward biologics-like efficacy in a pill to patients. We used an NMR-based fragment screen of recombinant IL17A to uncover starting points for small molecule IL17A antagonist discovery.

Insights into the Conformation and Self-Association of a Concentrated Monoclonal Antibody using Isothermal Chemical Denaturation and Nuclear Magnetic Resonance.

The purpose of this investigation was to highlight the utility of nuclear magnetic resonance (NMR) as a multi-attribute method for the characterization of therapeutic antibodies. In this case study, we compared results from isothermal chemical denaturation (ICD) and NMR with standard methods to relate conformational states of a model monoclonal antibody (mAb1) with protein-protein interactions (PPI) that lead to self - association in concentrated solutions. The increase in aggregation rate and relative viscosity for mAb1 was found to be both concentration and pH dependent.

Determinants of hypertension among patients with type 2 diabetes mellitus on follow-up at Tikur Anbessa Specialized Hospital, Addis Ababa: A case-control study.

Introduction: Hypertension (HTN) in patients with diabetes mellitus (DM) is a common problem that increases the risk of mortality and morbidity, and lowers the quality of life. Despite the disproportionately high burden of HTN in DM patients, determinants for the comorbidity have not been sufficiently explored. Therefore, this study aimed to identify the determinants of HTN among patients with type 2 diabetes mellitus on follow-up at Tikur Anbessa Specialized Hospital.

Incidence and pattern of stroke among patients admitted to medical ward at Yirgalem General Hospital, Sidama Regional State, Southern-Ethiopia.

Introduction: In the current days, stroke has become one of the common reasons for admission in many health care setups and becoming an alarming public health problem in Ethiopia. Hence, this study aimed to assess the incidence and associated factors of stroke among patients admitted to the medical wards in Yirgalem hospital.

Methods: An institution-based retrospective cross-sectional study design was carried out from 01 January 2017, to 30 December 2019.

Development of Orally Efficacious Allosteric Inhibitors of TNFα via Fragment-Based Drug Design.

Tumor necrosis factor α (TNFα) is a soluble cytokine that is directly involved in systemic inflammation through the regulation of the intracellular NF-κB and MAPK signaling pathways. The development of biologic drugs that inhibit TNFα has led to improved clinical outcomes for patients with rheumatoid arthritis and other chronic autoimmune diseases; however, TNFα has proven to be difficult to drug with small molecules. Herein, we present a two-phase, fragment-based drug discovery (FBDD) effort in which we first identified isoquinoline fragments that disrupt TNFα ligand-receptor binding through an allosteric desymmetrization mechanism as observed in high-resolution crystal structures.

NMR-based fragment screening and lead discovery accelerated by principal component analysis.

Protein-based NMR spectroscopy has proven to be a very robust method for finding fragment leads to protein targets. However, one limitation of protein-based NMR is that the data acquisition and analysis can be time consuming. In order to streamline the scoring of protein-based NMR fragment screening data and the determination of ligand affinities using 2D NMR experiments we have developed a data analysis workflow based on principal component analysis (PCA) within the TREND NMR Pro software package.

Fragment-Based Discovery of an Apolipoprotein E4 (apoE4) Stabilizer.

Apolipoprotein E is a 299-residue lipid carrier protein produced in both the liver and the brain. The protein has three major isoforms denoted apoE2, apoE3, and apoE4 which differ at positions 112 and 158 and which occur at different frequencies in the human population. Genome-wide association studies indicate that the possession of two apoE4 alleles is a strong genetic risk factor for late-onset Alzheimer's disease (LOAD).

Targeting lysine specific demethylase 4A (KDM4A) tandem TUDOR domain - A fragment based approach.

The tandem TUDOR domains present in the non-catalytic C-terminal half of the KDM4A, 4B and 4C enzymes play important roles in regulating their chromatin localizations and substrate specificities. They achieve this regulatory role by binding to different tri-methylated lysine residues on histone H3 (H3-K4me3, H3-K23me3) and histone H4 (H4-K20me3) depending upon the specific chromatin environment. In this work, we have used a 2D-NMR based fragment screening approach to identify a novel fragment (1a), which binds to the KDM4A-TUDOR domain and shows modest competition with H3-K4me3 binding in biochemical as well as in vitro cell based assays.

Fragment-based discovery of a potent NAMPT inhibitor.

NAMPT expression is elevated in many cancers, making this protein a potential target for anticancer therapy. We have carried out both NMR based and TR-FRET based fragment screens against human NAMPT and identified six novel binders with a range of potencies. Co-crystal structures were obtained for two of the fragments bound to NAMPT while for the other four fragments force-field driven docking was employed to generate a bound pose.

Linkages between health and agriculture sectors in Ethiopia: a formative research study exploring barriers, facilitators and opportunities for local level coordination to deliver nutritional programmes and services.

Background: In Ethiopia, poor infant and young child feeding practices and low household dietary diversity remain widespread. The Government has adopted the National Nutrition Programme that emphasizes the need for multi-sectoral collaboration to effectively deliver nutrition-sensitive and nutrition-specific interventions. The Sustainable Undernutrition Reduction in Ethiopia (SURE) programme is one such Government-led initiative that will be implemented jointly by the health and agriculture sectors across 150 districts in Ethiopia.

Hydrogen Sulfide in Exhaled Gases From Ventilated Septic Neonates and Children: A Preliminary Report.

Objectives: There is increasing interest in hydrogen sulfide as a marker of pathologic conditions or predictors of outcome. We speculate that as hydrogen sulfide is a diffusible molecule, if there is an increase in plasma hydrogen sulfide in sepsis, it may accumulate in the alveolar space and be detected in exhaled gas. We wished to determine whether we could detect hydrogen sulfide in exhaled gases of ventilated children and neonates and if the levels changed in sepsis.

Fragment-Based, Structure-Enabled Discovery of Novel Pyridones and Pyridone Macrocycles as Potent Bromodomain and Extra-Terminal Domain (BET) Family Bromodomain Inhibitors.

Members of the BET family of bromodomain containing proteins have been identified as potential targets for blocking proliferation in a variety of cancer cell lines. A two-dimensional NMR fragment screen for binders to the bromodomains of BRD4 identified a phenylpyridazinone fragment with a weak binding affinity (1, K = 160 μM). SAR investigation of fragment 1, aided by X-ray structure-based design, enabled the synthesis of potent pyridone and macrocyclic pyridone inhibitors exhibiting single digit nanomolar potency in both biochemical and cell based assays.

Methylpyrrole inhibitors of BET bromodomains.

An NMR fragment screen for binders to the bromodomains of BRD4 identified 2-methyl-3-ketopyrroles 1 and 2. Elaboration of these fragments guided by structure-based design provided lead molecules with significant activity in a mouse tumor model. Further modifications to the methylpyrrole core provided compounds with improved properties and enhanced activity in a mouse model of multiple myeloma.

The EED protein-protein interaction inhibitor A-395 inactivates the PRC2 complex.

Polycomb repressive complex 2 (PRC2) is a regulator of epigenetic states required for development and homeostasis. PRC2 trimethylates histone H3 at lysine 27 (H3K27me3), which leads to gene silencing, and is dysregulated in many cancers. The embryonic ectoderm development (EED) protein is an essential subunit of PRC2 that has both a scaffolding function and an H3K27me3-binding function.