Comparative value of dapagliflozin vs empagliflozin in patients with heart failure and preserved ejection fraction: A cost-effectiveness analysis.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) imposes a high disease burden on patients, primarily because of multimorbidity and frequent hospitalizations. Recently, the American College of Cardiology Expert Consensus recommended treating all patients diagnosed with HFpEF with a sodium-glucose cotransporter 2 inhibitor, such as dapagliflozin or empagliflozin, to reduce the risk of cardiovascular death and hospitalization and improve health status. However, managing HFpEF can be expensive, highlighting the need to assess therapeutic alternatives that can minimize health care costs while optimizing patient outcomes. OBJECTIVE: To compare the cost-effectiveness of dapagliflozin vs empagliflozin in managing patients with HFpEF from the US health care system perspective. METHODS: We developed a Markov model to simulate a cohort of patients with HFpEF (defined as having a left ventricular ejection fraction ≥ 50%) treated with dapagliflozin or empagliflozin. Transition probabilities between 3 health states (HFpEF, hospitalization for heart failure, and death), costs, and quality of life weight input variables were obtained from the literature. In the base-case analysis, we estimated total expected costs, quality-adjusted life-years (QALYs) gained, and the incremental cost-effectiveness ratio (ICER) over a lifetime horizon. All future expected costs and QALYs were discounted at the annual rate of 3%. We conducted sensitivity analyses to demonstrate the robustness of the cost-effectiveness model findings. RESULTS: Dapagliflozin had an incremental expected lifetime cost of $29,896 compared with empagliflozin, resulting in an ICER of $36,902/QALY. Value-based price threshold analysis suggested that for empagliflozin to be cost-effective, it would need a 29% discount on its annual price. In a probabilistic sensitivity analysis, dapagliflozin would be the most preferred cost-effective option at willingness-to-pay thresholds of $50,000/QALY about 72% of the time. CONCLUSIONS: This cost-effectiveness analysis showed that, from the US health care system perspective, dapagliflozin was more cost-effective than empagliflozin, and its uptake may enhance long-term outcomes in patients with HFpEF.

Neural stem cell research in Africa: current realities and future prospects.

Neural stem cells (NSCs) are immature progenitor cells that are found in developing and adult brains that have the potential of dividing actively and renewing themselves, with a complex form of gene expression. The generation of new brain cells in adult individuals was initially considered impossible, however, the landmark discovery of human neural stem cells in the hippocampus has been followed by further discoveries in other discreet regions of the brain. Investigation into the current state in Africa of the research and use of NSCs shows relatively limited activities on the continent. Information on the African application of NSCs for modelling disease mechanisms, drug discovery, and therapeutics is still limited. The International Brain Research Organization (IBRO)-African Regional Committee (ARC), with support from the Company of Biologists, and the Movement Disorder Society, sponsored the first African Basic School on NSC in Ibadan, Nigeria, with the vision of bringing together young neuroscientists and physicians across different fields in neuroscience to learn from leaders who have applied NSCs in stem cell research, the pathophysiology of neurodegenerative diseases, neuroanatomy, and neurotherapeutics. Twenty early-career researchers in academic institutions at junior and senior faculty cadres were selected from South Africa, Uganda and Nigeria. The students and organizer of the school, who wrote this review on the state of NSCs research in Africa, recommended the following: (1) other African countries can take a cue from South Africa and Nigeria in probing the phenomena of adult neurogenesis in unique animal species on the continent; (2) Africa should leverage the expertise and facilities of South African scientists and international collaborators in scaling up NSC research into these unique species and (3) Centers of Excellence should be established on the continent to serve as research hubs for training postgraduate students, and facilities for African scientists who trained overseas on NSCs.

SURGE complex of Plasmodium falciparum in the rhoptry-neck (SURFIN4.2-RON4-GLURP) contributes to merozoite invasion.

Plasmodium falciparum invasion into red blood cells (RBCs) is a complex process engaging proteins on the merozoite surface and those contained and sequentially released from the apical organelles (micronemes and rhoptries). Fundamental to invasion is the formation of a moving junction (MJ), a region of close apposition of the merozoite and the RBC plasma membranes, through which the merozoite draws itself before settling into a newly formed parasitophorous vacuole (PV). SURFIN4.2 was identified at the surface of the parasitized RBCs (pRBCs) but was also found apically associated with the merozoite. Using antibodies against the N-terminus of the protein we show the presence of SURFIN4.2 in the neck of the rhoptries, its secretion into the PV and shedding into the culture supernatant upon schizont rupture. Using immunoprecipitation followed by mass spectrometry we describe here a novel protein complex we have named SURGE where SURFIN4.2 forms interacts with the rhoptry neck protein 4 (RON4) and the Glutamate Rich Protein (GLURP). The N-terminal cysteine-rich-domain (CRD) of SURFIN4.2 mediates binding to the RBC membrane and its interaction with RON4 suggests its involvement in the contact between the merozoite apex and the RBC at the MJ. Supporting this suggestion, we also found that polyclonal antibodies to the extracellular domain (including the CRD) of SURFIN4.2 partially inhibit merozoite invasion. We propose that the formation of the SURGE complex participates in the establishment of parasite infection within the PV and the RBCs.

Plasmodium falciparum merozoite surface protein 3: oligomerization, self-assembly, and heme complex formation.

Merozoite surface protein 3 of Plasmodium falciparum, a 40-kDa protein that also binds heme, has been biophysically characterized for its tendency to form highly elongated oligomers. This study aims to systematically analyze the regions in MSP3 sequence involved in oligomerization and correlate its aggregation tendency with its high affinity for binding with heme. Through size exclusion chromatography, dynamic light scattering, and transmission electron microscopy, we have found that MSP3, previously known to form elongated oligomers, actually forms self-assembled filamentous structures that possess amyloid-like characteristics. By expressing different regions of MSP3, we observed that the previously described leucine zipper region at the C terminus of MSP3 may not be the only structural element responsible for oligomerization and that other peptide segments like MSP3(192-196) (YILGW) may also be required. MSP3 aggregates on incubation were transformed to long unbranched amyloid fibrils. Using immunostaining methods, we found that 5-15-µm-long fibrillar structures stained by anti-MSP3 antibodies were attached to the merozoite surface and also associated with erythrocyte membrane. We also found MSP3 to bind several molecules of heme by UV spectrophotometry, HPLC, and electrophoresis. This study suggested that its ability to bind heme is somehow related to its inherent characteristics to form oligomers. Moreover, heme interaction with a surface protein like MSP3, which does not participate in hemozoin formation, may suggest a protective role against the heme released from unprocessed hemoglobin released after schizont egress. These studies point to the other roles that MSP3 may play during the blood stages of the parasite, in addition to be an important vaccine candidate.

Low admission serum albumin as prognostic determinant of 30-day case fatality and adverse functional outcome following acute ischemic stroke.

INTRODUCTION: Over 80% of stroke deaths occur in low-income and middle-income regions of the world. Identification of predictors of mortality is vital so that prompt therapeutic measures could be instituted to improve outcome. Previous studies have identified factors such as stroke severity, stroke type, older age, impairment of consciousness and hyperglycaemia as predictors of mortality for acute stroke but mortality remain high among patients hospitalized for acute stroke. The study objective was to determine the association between admission serum albumin levels and short-term outcome following acute ischaemic stroke in Nigerians. METHODS: Consecutive first-ever acute ischaemic stroke patients were prospectively enrolled between February 2009 and May 2010. Stroke severity at presentation was determined using National Institute of Heath Stroke Score (NIHSS). Admission serum chemistry including albumin, were measured. Patients were then followed up for 30 days and outcome measures applied at the end of the study were 30-day mortality and functional outcome using the Modified Rankin Scale (MRS) and graded as favourable(MRS 0-3) or unfavourable(MRS 4-6). Relationship between serum albumin and stroke outcome was determined. RESULTS: 75 acute stroke cases were studied. Mean age was 57.68±12.4 years. Outcome was favourable in 48% while 30-day case fatality was 17.3%. The mean age (61.13 years) of those with poor outcome was significantly higher than those with favourable outcome. Mean serum albumin (3.03 g/dL) of those with favourable outcome was also significantly higher than (2.08 g/dL) of those with unfavourable outcome (p=0.0001). Patients that died had significantly lower serum albumin (1.66 g/dl) than survivors (p=0.0001).Receiver operating characteristics curve for optimal cut off point of serum albumin to predict survival or death within 30 days revealed area under the cure (AUC) of 0.870, p-value 0.0001, 95% C/I=0.759-0.982. Serum albumin of 1.55 g /dL has sensitivity of 100% and specificity of 61.5%. NIHSS and serum albumin were predictors of poor outcome using multiple regression. CONCLUSION: Low admission serum albumin was an independent determinant of poor outcome.

Pyrano[4,3-b]quinolines library generation via iodocyclization and palladium-catalyzed coupling reactions.

Synthesis of a 80-member library of novel pyrano[4,3-b]quinolines in solution-phase is reported. The key intermediate, 4-iodopyrano[4,3-b]quinolines were synthesized by the electrophilic iodocyclization of corresponding ortho-alkynyl aldehydes in good to excellent yields under mild reaction conditions. Subsequently a diverse set of libraries was generated by employing palladium-catalyzed Suzuki-Miyaura, Heck, and Sonogashira coupling reactions on 4-iodopyrano[4,3-b]quinolines. In this way, a series of structurally different and biologically interesting molecules were obtained. Some of the selected compounds were screened against 3D7 strains of Plasmodium falciparum for antimalarial activity. Suzuki coupling products 6{3} and 6{21} and Heck coupling product 8{12} exhibit promising antimalarial activity.

Comparative Immunogenicities of full-length Plasmodium falciparum merozoite surface protein 3 and a 24-kilodalton N-terminal fragment.

Recombinant Plasmodium falciparum merozoite surface protein 3 (PfMSP3F) and a 24-kDa fragment from its N terminus (MSP3N) that includes the essential conserved domain, which elicits the maximum antibody (Ab)-dependent cellular inhibition (ADCI), were expressed as soluble proteins in Escherichia coli. Both proteins were found to be stable in both soluble and lyophilized forms. Immunization with MSP3F and MSP3N formulated separately with two human-compatible adjuvants, aluminum hydroxide (Alhydrogel) and Montanide ISA 720, produced significant antibody responses in mice and rabbits. Polyclonal Abs against both antigens recognized native MSP3 in the parasite lysate. These two Abs also recognized two synthetic peptides, previously characterized to possess B cell epitopes from the N-terminal region. Antibody depletion assay showed that most of the IgG response is directed toward the N-terminal region of the full protein. Anti-MSP3F and anti-MSP3N rabbit antibodies did not inhibit merozoite invasion or intraerythrocytic development but significantly reduced parasitemia in the presence of human monocytes. The ADCI demonstrated by anti-MSP3N antibodies was comparable to that exhibited by anti-MSP3F antibodies (both generated in rabbit). These results suggest that the N-terminal fragment of MSP3 can be considered a vaccine candidate that can form part of a multigenic vaccine against malaria.