Moving Towards Universal Health Coverage in Haiti.

Haiti announced in 2018 its aim to achieve universal health coverage. In this paper, we discuss what this objective means for the country and what next steps should be taken. To contextualize the notion, we framed Haiti en route to the 2030 goal and analyzed qualitatively the status quo in terms of geographic, financial, and service access. For each dimension, we focused on the context, the government's policies and political agendas, their implementation progress, and key influential factors. Our analysis found little progress and numerous challenges. Geographic access was limited due principally to the insufficient number of facilities, difficulties in reaching health facilities, and local customs. Financial coverage was low because of the government's insufficient budgets, inefficient budget allocation, and ineffective management. Service access also had room for significant improvement for a lack of basic infrastructure and resources, gaps between the essential service package guidelines, health professionals' skills, and the needs, as well as deficiencies in people-centered care. These factors affected not only health service coverage but also its quality. We found that the root causes of these issues were composed of unstable financing mechanisms, opportunistic resource allocation, and ineffective management control systems. We suggest that to overcome these issues and achieve universal health coverage with decent service quality, Haiti's health system needs to be reformed by implementing strategic financing, decentralized management systems, and community engagement in primary health care.

Enhanced intravenous transgene expression in mouse lung using cyclic-head cationic lipids.

Herein, we report enhanced intravenous mouse lung transfection using novel cyclic-head-group analogs of usually open-head cationic transfection lipids. Design and synthesis of the new cyclic-head lipid N,N-di-n-tetradecyl-3,4-dihydroxy-pyrrolidinium chloride (lipid 1) and its higher alkyl-chain analogs (lipids 2-4) and relative in vitro and in vivo gene transfer efficacies of cyclic-head lipids 1-4 to their corresponding open-head analogs [lipid 5, namely N,N-di-n-tetradecyl-N,N-(2-hydroxyethyl)ammonium chloride and its higher alkyl-chain analogs, lipids 6-8] have been described. In stark contrast to comparable in vitro transfection efficacies of both the cyclic- and open-head lipids, lipids 1-4 with cyclic heads were found to be significantly more efficient (by 5- to 11-fold) in transfecting mouse lung than their corresponding open-head analogs (5-8) upon intravenous administration. The cyclic-head lipid 3 with di-stearyl hydrophobic tail was found to be the most promising for future applications.

On the gene delivery efficacies of pH-sensitive cationic lipids via endosomal protonation: a chemical biology investigation.

In an effort to probe the importance of endosomal protonation in pH-sensitive, cationic, lipid-mediated, non-viral gene delivery, we have designed and synthesized a novel cholesterol-based, endosomal pH-sensitive, histidylated, cationic amphiphile (lipid 1), its less pH-sensitive counterpart with an electron-deficient, tosylated histidine head group (lipid 2) as well as a third new cholesterol-based, cationic lipid containing no histidine head group (lipid 3). For all the novel liposomes and lipoplexes, we evaluated hysicochemical characteristics, including lipid:DNA interactions, global surface charge, and sizes. As anticipated, lipid 2 showed lower efficacies than lipid 1 for the transfection of 293T7 cells with the cytoplasmic gene expression vector pT7Luc at lipid:DNA mole ratios of 3.6:1 and 1.8:1; both lipids were greatly inhibited in the presence of Bafilomycin A1. This demonstrates the involvement of imidazole ring protonation in the endosomal escape of DNA. Conversely, endosome escape of DNA with lipid 3 seemed to be independent of endosome acidification. However, with nuclear gene expression systems in 293T7, HepG2, and HeLa cells, the transfection efficacies of lipid 2 at a lipid:DNA mole ratio of 3.6:1 were found to be either equal to or somewhat lower than those of lipids 1 and 3. Interestingly, at a lipid:DNA mole ratio of 1.8:1, lipids 2 and 3 were remarkably more transfection efficient than lipid 1 in both HepG2 and HeLa cells. Mechanistic implications of such contrasting relative transfection profiles are delineated.

Single additional methylene group in the head-group region imparts high gene transfer efficacy to a transfection-incompetent cationic lipid.

In combination with equimolar 1,2-dioleoyl-L-alpha-glycero-3-phosphatidyl ethanolamine, a novel cholesterol-based cationic lipid with beta-alanine head-group (2) has been demonstrated to be strikingly more efficacious (10-24-fold) in transfecting CHO, COS-1 and HepG2 cells than its glycine analog (1) containing just one less methylene unit in its head-group region. Syntheses, characterizations and in vitro transfection biology of lipids 1 and 2 are described. Present findings demonstrate that even truly minor structural alterations, such as inclusion of just one additional methylene functionality in the polar head-group region, can convert an essentially transfection-incompetent cholesterol-based cationic amphiphile to a remarkably efficient cationic transfection lipid.

Cationic transfection lipids in gene therapy: successes, set-backs, challenges and promises.

The clinical success of gene therapy is critically dependent on the development of efficient and safe gene delivery reagents, popularly known as "Transfection Vectors". The transfection vectors commonly used in gene therapy are mainly of two types: viral and non-viral. The efficiencies of viral transfection vectors are, in general, superior to their non-viral counterparts. However, the myriads of potentially adverse immunogenic aftermaths associated with the use of viral vectors are increasingly making the non-viral gene delivery reagents as the vectors of choice. Among the existing arsenal of non-viral gene delivery reagents, the distinct advantages associated with the use of cationic transfection lipids include their: (a) robust manufacture; (b) ease in handling & preparation techniques; (c) ability to inject large lipid:DNA complexes and (d) low immunogenic response. The present review will highlight the successes, set-backs, challenges and future promises of cationic transfection lipids in non-viral gene therapy.

Anchor dependency for non-glycerol based cationic lipofectins: mixed bag of regular and anomalous transfection profiles.

Although detailed structure-activity, physicochemical and biophysical investigations in probing the anchor influence in liposomal gene delivery have been reported for glycerol-based transfection lipids, the corresponding investigation for non-glycerol based simple monocationic transfection lipids have not yet been undertaken. Towards this end, herein, we delineate our structure-activity and physicochemical approach in deciphering the anchor dependency in liposomal gene delivery using fifteen new structural analogues (lipids 1-15) of recently reported non-glycerol based monocationic transfection lipids. The C(14) analogues in both series 1 (lipids 1-6) and series 2 (lipids 7-15) showed maximum efficiency in transfecting COS-1 and CHO cells. However, the C(12) analogue of the ether series (lipid 3) exhibited a seemingly anomalous behavior compared with its transfection efficient C(10) and C(14) analogues (lipids 2 and 4) in being completely inefficient to transfect both COS-1 and CHO cells. The present structure-activity investigation also convincingly demonstrates that enhancement of transfection efficiencies through incorporation of membrane reorganizing unsaturation elements in the hydrophobic anchor of cationic lipids is not universal but cell dependent. The strength of the interaction of lipids 1-15 with DNA was assessed by their ability to exclude ethidium bromide bound to the DNA. Cationic lipids with long hydrophobic tails were found, in general, to be efficient in excluding EtBr from DNA. Gel to liquid crystalline transition temperatures of the lipids was measured by fluorescence anisotropy measurement technique. In general (lipid 2 being an exception), transfection efficient lipids were found to have their mid transition temperatures at or below physiological temperatures (37 degrees C).