Warranties for Your Flat-Screen – Why Not for Your Bypass Surgery?

If Health Care Delivery is a business, and patients are consumers, what is the product they’re buying? Who is liable for that product’s quality? If someone purchases a television set, they get a warranty. That warranty is the manufacturer’s guarantee to the customer that their company will be responsible for repairing or replacing that product should it prove to be defective within a few days of purchase. Could medicine ever be treated the same way? The following article describes Geisinger Health System’s ProvenCareSM program, which establishes flat package pricing and a 90-day “warranty” for Coronary Artery Bypass Grafts (CABGs)

Characterization of novel malaria vaccine candidates representing alpha-helical coiled coil domains

The future vision in the battle against malaria goes beyond controlling the disease. Envisioned is the world-wide eradication of malaria. A substantial contribution to reach this goal is the development of an effective vaccine. Today’s most advanced and most effective malaria vaccine, RTS,S/AS01, showed efficacy of 30 to 66% against all clinical episodes. There is a great need to increase efficacy by the next generation malaria vaccines. A strategy for increasing RTS,S efficacy could be to combine it with an effective blood stage vaccine. The disappointing outcomes of clinical trials conducted for most current blood stage vaccines demands the identification of novel promising candidates. Under persistent exposure individuals develop immunity that protects against clinical disease but not parasitemia. This natural acquired immunity develops slowly and is reached in adolescence. In contrast, immunity against severe disease develops already after few infections. The mechanisms that underlie naturally acquired immunity or severe disease immunity remain poorly understood. Antibodies were demonstrated to play a critical role for controlling blood stage infection. It remains unclear which proteins elicit the production of protective antibodies and through which antibody effector function protection is provided. The relevance of antibodies in blood stage protection has the consequence that the immunogen correctly mimic the three-dimensional structure of the native protein. This PhD thesis has its major focus on immunogens that adopt a stable tertiary structure in aqueous environment. The availability of the P. falciparum genome sequences, transcriptome and proteome data has opened the avenue for the identification of novel targets for vaccine development. However, blood stage vaccine development has focused on only a few candidates. Previously our collaborators in this project have identified promising candidates by genome-wide screening for alpha-helical coiled coil domains in proteins expressed in the erythrocytic parasite stages. The segments with high probability score for coiled coil formation where selected. The 166 coiled coil segments derived from 131 proteins representing 4% of the blood stage proteome. 95 coiled coil fragments of a length of 30-40 amino acids were synthesized and analyzed systematically in a pre-clinical evaluation pathway. The aim of this thesis was to fill the gaps in the preclinical evaluation pathway of novel synthetic peptide vaccine candidates. The extensive polymorphism found in most parasite antigens represents a major obstacle for the development of efficacious blood stage vaccines. The genetic diversity of the identified coiled coil protein segments was studied in great detail. We found that coiled coil segments are well conserved, 82% of all selected 166 segments showed complete sequence conservation. Polymorphism was found predominantly in segments containing almost perfect tandem repeats. Based on these findings an optimized bioinformatic selection strategy was formulated proposing to exclude coiled coil segments consisting of almost perfect tandem repeats. The availability of basic knowledge about vaccine candidates is a prerequisite for vaccine development and is essential to attract further funding for continued clinical development. A detailed cell biological characterization was undertaken for the most promising candidate, PFF0165c (newly termed Trophozoite exported protein 1 (Tex1)) Transcript and protein levels were analyzed throughout the intra-erytrocytic development cycle. Tex1 transcripts were found up-regulated in the early trophozoite stage. This was supported by Tex1 protein levels. Tex1 abundance persisted until parasite egress. Immunofluorescence experiments revealed that Tex1 is exported and associates to parasite-derived structures, termed Maurer’s clefts. Before parasite egress Tex1 resides in close proximity to the red blood cell membrane. In the search of sequence motifs responsible for Tex1 export we found that the actual translational start site is positioned 43 amino acids upstream of the start site previously predicted. The additional 43 amino acids function as signal peptide, directing the protein into the classical secretory pathway. This thesis contributed to the immunological characterization of the intrinsically unstructured region (P27A) of Tex1. P27A was evaluated for vaccine potential and met the principal requirements to be downselected for a phase 1 trial. P27A was recognized by a majority of naturally exposed individuals, highly immunogenic, highly conserved and P27A-specific human and mouse sera were effective in in vitro parasite killing by Antibody-dependent cellular inhibition assay. High P27A-specifc antibody titers were found to positively correlate with protection. Clinical grade P27A peptide is currently produced. In order to validate synthetic peptides as antigens the recognition by sera of adults from endemic region was compared to the recognition of the antigen recombinant expressed in E. coli. Comparable recognition of both types of antigens was observed. This thesis provides evidence that the approach initiated by our collaborators is invaluable. This strategy, if proven successful in clinical trials, could be applied for vaccine development against many other pathogens from which genome data is available

Teachers\u27 Perceptions of a One-to-One Teacher Laptop Program and Teacher Technology Efficacy

Schools all over the world are embracing technology because they view technology as a catalyst to improve teaching and learning, leading to further investment in technology initiatives for school improvement. The 1:1 teacher laptop program is one such initiative that continues to gain interest and momentum. Despite widespread adoption, teachers continue to face challenges with the use of technology. Furthermore, while research has indicated that teacher technology efficacy is a significant enabling factor for technology use, there is limited evidence for how the 1:1 teacher laptop program has influenced teacher technology efficacy. The purpose of this qualitative pragmatic study was to describe the perceptions and experiences of teachers who participated in a 1:1 teacher laptop program at an international school in relation to teachers\u27 technology efficacy. The study was framed through the model of adult learning proposed by Knowles and the construct of self-efficacy posited by Bandura. Thematic analysis was used to analyze data. Findings from this study identified 7 overarching themes: access to the teacher laptop, change in practice, support structures, concerns and barriers, attitude towards technology, self-directed learning, and perceived value. Interpretations revealed that while participants were positive about the program and acknowledged that the program helped raise their technology efficacy, participants also shared concerns. This study adds to the body of knowledge for an understudied topic and provides teachers a voice to influence implementation fidelity. This study also contributes to social change by adding a global perspective through experiences at an international school to inform school leaders to prepare teachers to use technology effectively to improve student learning

First Aid and Emergency Preparedness: Improving Health Outcomes Among Aging Adults

As the United States population demographic shifts and the baby boomer population enters seniority, the health sector must adjust and prepare to provide efficient and adequate healthcare to the people. The Silver Tsunami, a metaphor for the expected wave of aging adults, will inevitably strain healthcare professionals and can be partly relieved by promoting risk-minimizing behavior in baby boomers before severe conditions develop. Through this effort, a health education course, titled First Aid and Emergency Preparedness, was developed and taught twice at a local senior center to target senior citizens and promote proactivity and healthy behaviors. Course development founded largely on existing literature specific to the target population, led to the creation of a curriculum consisting of four units: (1) Fall Prevention, (2) Pharmacology, (3) Burn Care, and (4) Identifying Medical Emergencies. The workshops were delivered with supplementary handouts, resources and demonstrations to promote proactivity and information retention. The seminars were then evaluated based on knowledge gained, self-reported perceptions of preparedness, and participant feedback. Findings included potential improvements in relevant course content and educational delivery that promotes optimal student engagement. The insights discovered through this health initiative were valuable in their contribution to literature regarding health initiatives that target older adults and can help to relieve the threat of the Silver Tsunami against healthcare

Poly(ADP-ribose) polymerase-1 (PARP-1) and RNA interference (RNAI) during cell death

L’activation de la poly(ADP-ribose) polymérase-1 (PARP-1) en réponse aux dommages à l’ADN est impliquée dans diverses réponses cellulaires, de la réparation de l’ADN à la mort cellulaire. Dans l'annexe I, nous avons décrit différentes techniques indispensables pour détecter le métabolisme de PARP-1 en réponse aux dommages à l’ADN in vitro et in vivo. Les travaux de cette thèse se concentrent sur le rôle de PARP-1 dans la mort cellulaire. PARP-1 est clivée et inactivée par des caspases pendant l’apoptose ; j’ai donc utilisé une PARP-1 non-clivable pour étudier le rôle de l’activation et de la fragmentation de PARP-1 dans la mort cellulaire induite par les UVB. Nous avons observé que, contrairement aux fibroblastes de peau humaine exprimant la PARP-1, les fibroblastes avec un "knockdown" de PARP-1 sont résistants à l’apoptose induite par les UVB, phénotype pouvant être totalement inversé par ré-expression de PARP-1 sauvage mais pas de PARP-1 non-clivable par les caspases, suggérant un rôle significatif du clivage de PARP-1 en réponse à la mort cellulaire induite par les UVB (chapitre 2). Dans ce contexte, nous avons récemment passé en revue comment les substrats non clivables par des caspases peuvent être utilisés comme outil important pour démystifier le rôle de ce clivage pour la mort comme pour la vie, avec l’exemple spécifique de PARP-1 non-clivable par les caspases (chapitre 3). Curieusement, en utilisant l’ARNi comme outil d’étude du rôle de PARP-1 dans la mort cellulaire, nous avons observé que l’ARNi stable (shRNA) de nombreux gènes, incluant PARP-1, échoue lors de l’apoptose, en raison de l’inactivation catalytique par clivage par une caspase de l’endoribonucléase Dicer-1, indispensable pour la régulation de l’ARNi et des miARN (chapitre 4). Cependant, nous avons découvert que l’ARNi transitoire persiste plusieurs jours même après induction de l’apoptose, soulignant des différences entre les ARNi stable et transitoire dans la dynamique de "knockdown" génétique et dans la dépendance de la fonction de Dicer-1 (chapitre 5). En résumé, mon travail a permis la découverte des avantages et des limites de l’ARNi durant l’apoptose et le rôle de PARP-1 dans la mort cellulaire induite par les UVB

Teachers\u27 Perceptions of a One-to-One Teacher Laptop Program and Teacher Technology Efficacy

Schools all over the world are embracing technology because they view technology as a catalyst to improve teaching and learning, leading to further investment in technology initiatives for school improvement. The 1:1 teacher laptop program is one such initiative that continues to gain interest and momentum. Despite widespread adoption, teachers continue to face challenges with the use of technology. Furthermore, while research has indicated that teacher technology efficacy is a significant enabling factor for technology use, there is limited evidence for how the 1:1 teacher laptop program has influenced teacher technology efficacy. The purpose of this qualitative pragmatic study was to describe the perceptions and experiences of teachers who participated in a 1:1 teacher laptop program at an international school in relation to teachers\u27 technology efficacy. The study was framed through the model of adult learning proposed by Knowles and the construct of self-efficacy posited by Bandura. Thematic analysis was used to analyze data. Findings from this study identified 7 overarching themes: access to the teacher laptop, change in practice, support structures, concerns and barriers, attitude towards technology, self-directed learning, and perceived value. Interpretations revealed that while participants were positive about the program and acknowledged that the program helped raise their technology efficacy, participants also shared concerns. This study adds to the body of knowledge for an understudied topic and provides teachers a voice to influence implementation fidelity. This study also contributes to social change by adding a global perspective through experiences at an international school to inform school leaders to prepare teachers to use technology effectively to improve student learning

Povezanost novog polimorfizma pojedinačnog nukleotida u eksonu 2 gena za inzulinu sličan faktor rasta 1 (IGF1) s fenotipskim varijantama u koza

The Insulin-Like Growth Factor 1 plays a key role in foetal development and post natal growth. The objectives of this study were to characterise the complete coding sequence of caprine IGF1 gene in two indigenous goat breeds of India: Malabari and Attappady Black, to detect polymorphisms of IGF1 gene, to investigate their effects on body size traits and to ascertain the relative expression of IGF1 mRNA in muscle tissues of goats belonging to low and high body weight groups. All the four exons of caprine IGF1 gene were amplified and characterized by PCR-SSCP in 298 goats, revealing two genotypes (CC and CT) at exon 2. Sequencing of the PCR products from each genotype revealed a novel SNP, g.80C>T (GenBank accession No. KM974180), which caused a non-synonymous mutation (Thr48Met),causing differences in IGF1 protein structure. Association analysis of the loci indicated CT genotypes have higher body length (P0.05). The results of the present study suggest that the alleles of the IGF1 gene could be considered as strong targets for improvement of growth traits in goats.Inzulinu sličan faktor rasta 1 (IGF1) ima ključnu ulogu u razvoju ploda i postnatalnom rastu. Cilj je ovog istraživanja bio okarakterizirati cijelu kodirajuću sekvenciju IGF1 gena koza u dvije autohtone pasmine iz Indije: malabari i crna atapadi. S tim u vezi željelo se utvrditi polimorfizme IGF1 gena i istražiti njihove učinke na obilježja tjelesne razvijenosti, te ustanoviti relativnu ekspresiju IGF1 mRNA u mišićnom tkivu koza s malom i velikom tjelesnom masom. Kod 298 koza umnožena su sva 4 eksona IGF1 gena i okarakterizirana uz pomoć PCR-SSCP. Na eksonu 2 utvrđena su dva genotipa (CC i CT). Analiza sekvencije PCR produkata od svakog genotipa pokazala je novi polimorfizam pojedinačnog nukleotida, g. 80C>T (GenBank No. KM974180) koja je uzrokovala neistovjetnu mutaciju (Thr48Met) i razlike u strukturi proteina IGF1. Analiza povezanosti lokusa pokazala je da CT genotipovi imaju u odnosu na CC genotipove veću dužinu tijela (P0,05) u ekspresiji IGF1 mRNA u mišićnom tkivu koza s malim i velikim tjelesnim masama. Rezultati istraživanja upućuju da bi alele IGF1 gena mogli smatrati ciljanom skupinom za unaprjeđenju obilježja rasta u koza

Mycobacterial lipoarabinomannans modulate cytokine production in human T helper cells by interfering with raft/microdomain signalling

Abstract.: Lipoarabinomannans (LAMs) are major lipoglycans of the mycobacterial envelope and constitute immunodominant epitopes of mycobacteria. In this paper, we show that mannose-capped (ManLAM) and non-mannose- capped (PILAM) mycobacterial lipoglycans insert into T helper cell rafts without apparent binding to known receptors. T helper cells modified by the insertion of PILAM responded to CD3 cross-linking by decreasing type 1 (IL-2 and IFN-γ) and increasing type 2 (IL-4 and IL-5) cytokine production. Modification by the mannose-capped ManLAMs had similar, but more limited effects on T helper cell cytokine production. When incorporated into isolated rafts, PILAMs modulated membrane-associated kinases in a dose-dependent manner, inducing increased phosphorylation of Src kinases and Cbp/PAG in Th1 rafts, while decreasing phosphorylation of the same proteins in Th2 rafts. Mycobacterial lipoglycans thus modify the signalling machineries of rafts/microdomains in T helper cells, a modification of the membrane organization that eventually leads to an overall enhancement of type 2 and inhibition of type 1 cytokine productio

Aligned and Electrospun Piezoelectric Polymer Fiber Assembly and Scaffold

A method of manufacturing and/or using a scaffold assembly for stem cell culture and tissue engineering applications is disclosed. The scaffold at least partially mimics a native biological environment by providing biochemical, topographical, mechanical and electrical cues by using an electroactive material. The assembly includes at least one layer of substantially aligned, electrospun polymer fiber having an operative connection for individual voltage application. A method of cell tissue engineering and/or stem cell differentiation that uses the assembly seeded with a sample of cells suspended in cell culture media, incubates and applies voltage to one or more layers, and thus produces cells and/or a tissue construct. In another aspect, the invention provides a method of manufacturing the assembly including the steps of providing a first pre-electroded substrate surface; electrospinning a first substantially aligned polymer fiber layer onto the first surface; providing a second pre-electroded substrate surface; electrospinning a second substantially aligned polymer fiber layer onto the second surface; and, retaining together the layered surfaces with a clamp and/or an adhesive compound

Aligned and Electrospun Piezoelectric Polymer Fiber Assembly and Scaffold

A scaffold assembly and related methods of manufacturing and/or using the scaffold for stem cell culture and tissue engineering applications are disclosed which at least partially mimic a native biological environment by providing biochemical, topographical, mechanical and electrical cues by using an electroactive material. The assembly includes at least one layer of substantially aligned, electrospun polymer fiber having an operative connection for individual voltage application. A method of cell tissue engineering and/or stem cell differentiation uses the assembly seeded with a sample of cells suspended in cell culture media, incubates and applies voltage to one or more layers, and thus produces cells and/or a tissue construct. In another aspect, the invention provides a method of manufacturing the assembly including the steps of providing a first pre-electroded substrate surface; electrospinning a first substantially aligned polymer fiber layer onto the first surface; providing a second pre-electroded substrate surface; electrospinning a second substantially aligned polymer fiber layer onto the second surface; and, retaining together the layered surfaces with a clamp and/or an adhesive compound