Epidemiological studies of bioprosthetic aortic valves

Background: The use of bioprosthetic valves is common and offers a prosthetic option that does not require anti-coagulant therapy, but with shorter valve longevity compared to mechanical prostheses. Valve model selection might influence the long-term performance of the prosthesis. The research questions in the four studies were 1) Does blood type A-like antigens on porcine valves lead to decreased long-term performance of the valve in blood type B/0 patients, 2) Is there a difference in long-term performance between bovine and porcine valves, 3) Does some aortic valve models perform better or worse compared to other aortic valve models, 4) Does prosthesis-patient mismatch (PPM) impact long-term survival, valve reintervention and heart failure hospitalization. Methods and results: Study I Patients who received a porcine valve between 1995 and 2012 were identified from the Swedish cardiac surgery register and categorized according to blood type B/0 (1693, 49.5%) and A/AB (1724, 50.5%). The groups had similar baseline characteristics. The cumulative incidence of valve reintervention at 15 years was 3.4% (95% CI: 2.5 to 4.4%) and 3.6% (95% CI: 2.6 to 4.6%) in the B/0 and A/AB groups, respectively. After multivariable adjustment, there was no difference in valve reintervention (HR 0.95, 95% CI: 0.62 to 1.45), heart failure hospitalization (HR 0.92, 95% CI: 0.77 to 1.08) and all-cause mortality (HR 0.95, 95% CI: 0.87 to 1.05) rates in patients with blood type B/0 compared to patients with blood type A/AB. Study II: Patients who received a porcine (4194, 33%) or bovine (8647, 67%) aortic valve between 1995 and 2012 were identified from the Swedish cardiac surgery register. Inverse probability of treatment weighting was used to adjust for inter-group differences. Porcine valves were associated with improved survival (HR 0.90, 95% CI: 0.85 to 0.96) and an increased risk for valve reintervention (HR 1.48, 95% CI: 1.11 to 1.98). There was no difference in heart failure hospitalization between porcine and bovine valves. Study III: All patients who underwent primary surgical bioprosthetic aortic valve replacement in Sweden 2003 to 2018 were identified from the Swedish cardiac surgery register. Patients were categorized according to valve model; Perimount, Mosaic/Hancock, Biocor/Epic, Mitroflow/Crown, Soprano and Trifecta. Regression standardization was used to account for differences in baseline characteristics. Perimount had the lowest, and Mitroflow/Crown had the highest cumulative incidence of reintervention (3.6%, 95% CI: 3.1 to 4.2% and 12%, 95% CI: 9.8 to 15%), all-cause mortality (44%, 95% CI: 43 to 45% and 54%, 95% CI: 52 to 57%) and heart failure hospitalization (13%, 95% CI: 12 to 14% and 20%, 95% CI: 18 to 23%) at ten years, respectively. Study IV: All patients who underwent primary surgical bioprosthetic aortic valve replacement in Sweden 2003 to 2018 were identified from the Swedish cardiac surgery register. Patients were categorized according to no (7377, 45%), moderate (8502, 52%) and severe (544, 3%) PPM, estimated by valve model, valve size and the patient’s body surface area. The survival difference at ten years was 4.6% (95% CI: 0.7 to 8.5%) and 1.7% (95% CI: 0.1 to 3.3%) between no versus severe and moderate PPM, respectively. Severe PPM was also associated with a significant increase in heart failure hospitalization, with a ten-year difference of 6.0% (95% CI: 2.2 to 9.7%) compared to no PPM. There was no difference in valve reintervention between different grades of PPM. Conclusions: 1) It is safe to use porcine valves irrespective of blood type, 2) Porcine valves increases the risk for subsequent valve interventions, 3) The widespread use of the Perimount valve is supported by excellent long-term clinical performance, and an increased clinical vigilance is warranted in patients with a Mitroflow/Crown or Soprano valve, 4) Steps should be taken to avoid severe PPM, but the clinical effect of moderate PPM might be negligible

Dual, Photo‐Responsive and Redox‐Active Supramolecular Foldamers

We report on dual, light‐responsive and redox‐active foldamers that demonstrate reversible and robust stimuli‐induced behaviour. Herein, UV/Vis, 1H NMR and circular dichroism (CD) spectroscopy and cyclic voltammetry have been used to establish the reversibility and highly robust nature of the light‐ and redox‐driven behaviour of these new foldamers with minimal levels of fatigue observed even upon multiple cyclic treatments with irradiative/non‐irradiative and oxidative/reductive conditions. This proof‐of‐concept work paves the way towards the creation of novel stimuli‐responsive foldamers of increasing sophistication capable of demonstrating reversible and robust responses to multiple distinct stimuli

Dual, Photo‐Responsive and Redox‐Active Supramolecular Foldamers

We report on dual, light‐responsive and redox‐active foldamers that demonstrate reversible and robust stimuli‐induced behaviour. Herein, UV/Vis, 1H NMR and circular dichroism (CD) spectroscopy and cyclic voltammetry have been used to establish the reversibility and highly robust nature of the light‐ and redox‐driven behaviour of these new foldamers with minimal levels of fatigue observed even upon multiple cyclic treatments with irradiative/non‐irradiative and oxidative/reductive conditions. This proof‐of‐concept work paves the way towards the creation of novel stimuli‐responsive foldamers of increasing sophistication capable of demonstrating reversible and robust responses to multiple distinct stimuli

Phosphonodiamidate prodrugs of phosphoantigens (ProPAgens) exhibit potent Vγ9/Vδ2 T cell activation and eradication of cancer cells

The phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) is an established activator of Vγ9/Vδ2 T cells and stimulates downstream effector functions including cytotoxicity and cytokine production. In order to improve its drug-like properties, we herein report the design, synthesis, serum stability, in vitro metabolism, and biological evaluation of a new class of symmetrical phosphonodiamidate prodrugs of methylene and difluoromethylene monophosphonate derivatives of HMBPP. These prodrugs, termed phosphonodiamidate ProPAgens, were synthesized in good yields, exhibited excellent serum stability (>7 h), and their in vitro metabolism was shown to be initiated by carboxypeptidase Y. These phosphonodiamidate ProPAgens triggered potent activation of Vγ9/Vδ2 T cells, which translated into efficient Vγ9/Vδ2 T cell-mediated eradication of bladder cancer cells in vitro. Together, these findings showcase the potential of these phosphonodiamidate ProPAgens as Vγ9/Vδ2 T cell modulators that could be further developed as novel cancer immunotherapeutic agents

Phosphonodiamidate prodrugs of phosphoantigens (ProPAgens) exhibit potent Vγ9/Vδ2 T cell activation and eradication of cancer cells

The phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) is an established activator of Vγ9/Vδ2 T cells and stimulates downstream effector functions including cytotoxicity and cytokine production. In order to improve its drug-like properties, we herein report the design, synthesis, serum stability, in vitro metabolism, and biological evaluation of a new class of symmetrical phosphonodiamidate prodrugs of methylene and difluoromethylene monophosphonate derivatives of HMBPP. These prodrugs, termed phosphonodiamidate ProPAgens, were synthesized in good yields, exhibited excellent serum stability (>7 h), and their in vitro metabolism was shown to be initiated by carboxypeptidase Y. These phosphonodiamidate ProPAgens triggered potent activation of Vγ9/Vδ2 T cells, which translated into efficient Vγ9/Vδ2 T cell-mediated eradication of bladder cancer cells in vitro. Together, these findings showcase the potential of these phosphonodiamidate ProPAgens as Vγ9/Vδ2 T cell modulators that could be further developed as novel cancer immunotherapeutic agents

Phosphonodiamidate prodrugs of phosphoantigens (ProPAgens) exhibit potent Vγ9/Vδ2 T cell activation and eradication of cancer cells †

The phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) is an established activator of Vγ9/Vδ2 T cells and stimulates downstream effector functions including cytotoxicity and cytokine production. In order to improve its drug-like properties, we herein report the design, synthesis, serum stability, in vitro metabolism, and biological evaluation of a new class of symmetrical phosphonodiamidate prodrugs of methylene and difluoromethylene monophosphonate derivatives of HMBPP. These prodrugs, termed phosphonodiamidate ProPAgens, were synthesized in good yields, exhibited excellent serum stability (>7 h), and their in vitro metabolism was shown to be initiated by carboxypeptidase Y. These phosphonodiamidate ProPAgens triggered potent activation of Vγ9/Vδ2 T cells, which translated into efficient Vγ9/Vδ2 T cell-mediated eradication of bladder cancer cells in vitro. Together, these findings showcase the potential of these phosphonodiamidate ProPAgens as Vγ9/Vδ2 T cell modulators that could be further developed as novel cancer immunotherapeutic agents

En jämförelse mellan Affärsvärldens och Veckans Affärers köprekommendationer

Syfte: Syftet med denna uppsats är att undersöka om det går att påvisa att aktierekommendationerna från Veckans Affärer och Affärsvärlden ger någon effekt på de rekommenderade företagens aktiekurser. Om det skulle visa sig att påverkan sker, har vi för avsikt att närmare undersöka vilken av tidningarna som ger störst inverkan på aktiekursen. Vidare kommer vi att undersöka utfallet på tidningarnas aktierekommendationer på längre sikt genom att jämföra med Affärsvärldens generalindex på 6 respektive 12 månaders sikt. Metod: Undersökningen genomförs i en eventstudie med hjälp av marknadsmodellen. De tidningar, vars köprekommendationer studeras, är Affärsvärlden och Veckans Affärer. Det totala antalet rekommendationer under 2002 och 2003 uppgår till 232 stycken fördelade på 147 stycken för Affärsvärlden och resterande 85 på Veckans Affärer. Undersökningen av aktiens utfall genomförs på kort respektive lång sikt. Slutsats: Under händelsefönstret visar båda tidningarna en överavkastning för sina rekommendationer. På publiceringsdagen kan man statistiskt konstatera en överavkastning på de aktier som rekommenderats av Affärsvärlden och Veckans Affärer. Den förstnämnda ger även en överavkastning för de rekommenderade aktierna dagen efter publiceringsdagen. Således har Affärsvärlden större påverkan på kort sikt. Vidare åskådliggör våra resultat, att Stockholmsbörsen inte uppnår halvstark effektivitet. På lång sikt faller Veckans Affärers rekommendationer bättre ut än Affärsvärldens. Veckans Affärer ger för det totala antalet rekommendationer en statistisk säkerställd överavkastning för aktierna både på 6 och 12 månaders sikt. Affärsvärldens rekommendationer medför däremot inte någon överavkastning för denna tidsperiod