A pilot feasibility, safety and biological efficacy multicentre trial of therapeutic hypercapnia after cardiac arrest: study protocol for a randomized controlled trial.

BACKGROUND: Cardiac arrest causes ischaemic brain injury. Arterial carbon dioxide tension (PaCO2) is a major determinant of cerebral blood flow. Thus, mild hypercapnia in the 24 h following cardiac arrest may increase cerebral blood flow and attenuate such injury. We describe the Carbon Control and Cardiac Arrest (CCC) trial. METHODS/DESIGN: The CCC trial is a pilot multicentre feasibility, safety and biological efficacy randomized controlled trial recruiting adult cardiac arrest patients admitted to the intensive care unit after return of spontaneous circulation. At admission, using concealed allocation, participants are randomized to 24 h of either normocapnia (PaCO2 35 to 45 mmHg) or mild hypercapnia (PaCO2 50 to 55 mmHg). Key feasibility outcomes are recruitment rate and protocol compliance rate. The primary biological efficacy and biological safety measures are the between-groups difference in serum neuron-specific enolase and S100b protein levels at 24 h, 48 h and 72 h. Secondary outcome measure include adverse events, in-hospital mortality, and neurological assessment at 6 months. DISCUSSION: The trial commenced in December 2012 and, when completed, will provide clinical evidence as to whether targeting mild hypercapnia for 24 h following intensive care unit admission for cardiac arrest patients is feasible and safe and whether it results in decreased concentrations of neurological injury biomarkers compared with normocapnia. Trial results will also be used to determine whether a phase IIb study powered for survival at 90 days is feasible and justified. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12612000690853 .

A European survey on current practices in epilepsy monitoring units and implications for patients' safety.

OBJECTIVE: This study aimed to survey current practices in European epilepsy monitoring units (EMUs) with emphasis on safety issues. METHODS: A 37-item questionnaire investigating characteristics and organization of EMUs, including measures for prevention and management of seizure-related serious adverse events (SAEs), was distributed to all identified European EMUs plus one located in Israel (N=150). RESULTS: Forty-eight (32%) EMUs, located in 18 countries, completed the questionnaire. Epilepsy monitoring unit beds are 1-2 in 43%, 3-4 in 34%, and 5-6 in 19% of EMUs; staff physicians are 1-2 in 32%, 3-4 in 34%, and 5-6 in 19% of EMUs. Personnel operating in EMUs include epileptologists (in 69% of EMUs), clinical neurophysiologists trained in epilepsy (in 46% of EMUs), child neurologists (in 35% of EMUs), neurology and clinical neurophysiology residents (in 46% and in 8% of EMUs, respectively), and neurologists not trained in epilepsy (in 27% of EMUs). In 20% of EMUs, patients' observation is only intermittent or during the daytime and primarily carried out by neurophysiology technicians and/or nurses (in 71% of EMUs) or by patients' relatives (in 40% of EMUs). Automatic detection systems for seizures are used in 15%, for body movements in 8%, for oxygen desaturation in 33%, and for ECG abnormalities in 17% of EMUs. Protocols for management of acute seizures are lacking in 27%, of status epilepticus in 21%, and of postictal psychoses in 87% of EMUs. Injury prevention consists of bed protections in 96% of EMUs, whereas antisuffocation pillows are employed in 21%, and environmental protections in monitoring rooms and in bathrooms are implemented in 38% and in 25% of EMUs, respectively. The most common SAEs were status epilepticus reported by 79%, injuries by 73%, and postictal psychoses by 67% of EMUs. CONCLUSIONS: All EMUs have faced different types of SAEs. Wide variation in practice patterns and lack of protocols and of precautions to ensure patients' safety might promote the occurrence and severity of SAEs. Our findings highlight the need for standardized and shared protocols for an effective and safe management of patients in EMUs.

Transfusion sanguine : en toute sécurité d'approvisionnement [Blood transfusion - safety of the inventory].

Over the years, transfusion medicine has been faced to many different problems, notably those related to transmission of pathogens. Major progresses have been accomplished in terms of security. However, nowadays, the discipline is confronted to the day-to-day variability and availability of blood products. More and more donors are excluded from blood donation due to various reasons, and the donor selection criteria have increased over the years, influencing the number of donors able to give blood. This paradox represents one of the constraints that transfusion medicine should resolve in the future. This paper presents some aspects either common or different between France and Switzerland.

Safety profile of prasugrel and clopidogrel in patients with acute coronary syndromes in Switzerland.

OBJECTIVE: To assess safety up to 1 year of follow-up associated with prasugrel and clopidogrel use in a prospective cohort of patients with acute coronary syndromes (ACS). METHODS: Between 2009 and 2012, 2286 patients invasively managed for ACS were enrolled in the multicentre Swiss ACS Bleeding Cohort, among whom 2148 patients received either prasugrel or clopidogrel according to current guidelines. Patients with ST-elevation myocardial infarction (STEMI) preferentially received prasugrel, while those with non-STEMI, a history of stroke or transient ischaemic attack, age ≥75 years, or weight <60 kg received clopidogrel or reduced dose of prasugrel to comply with the prasugrel label. RESULTS: After adjustment using propensity scores, the primary end point of clinically relevant bleeding events (defined as the composite of Bleeding Academic Research Consortium, BARC, type 3, 4 or 5 bleeding) at 1 year, occurred at a similar rate in both patient groups (prasugrel/clopidogrel: 3.8%/5.5%). Stratified analyses in subgroups including patients with STEMI yielded a similar safety profile. After adjusting for baseline variables, no relevant differences in major adverse cardiovascular and cerebrovascular events were observed at 1 year (prasugrel/clopidogrel: cardiac death 2.6%/4.2%, myocardial infarction 2.7%/3.8%, revascularisation 5.9%/6.7%, stroke 1.0%/1.6%). Of note, this study was not designed to compare efficacy between prasugrel and clopidogrel. CONCLUSIONS: In this large prospective ACS cohort, patients treated with prasugrel according to current guidelines (ie, in patients without cerebrovascular disease, old age or underweight) had a similar safety profile compared with patients treated with clopidogrel. CLINICAL TRIAL REGISTRATION NUMBER: SPUM-ACS: NCT01000701; COMFORTABLE AMI: NCT00962416.

Relaxation and derelaxation of pure and hydrogenated amorphous silicon during thermal annealing experiments

The structural relaxation of pure amorphous silicon a-Si and hydrogenated amorphous silicon a-Si:H materials, that occurs during thermal annealing experiments, has been analyzed by Raman spectroscopy and differential scanning calorimetry. Unlike a-Si, the heat evolved from a-Si:H cannot be explained by relaxation of the Si-Si network strain but it reveals a derelaxation of the bond angle strain. Since the state of relaxation after annealing is very similar for pure and hydrogenated materials, our results give strong experimental support to the predicted configurational gap between a-Si and crystalline silicon.

Pitkäketjuisten keteenien valmistusreaktiot ja kinetiikka.

Tämän diplomityön tarkoituksena oli tutkia pitkäketjuisten rasvahappokloridien ja alkyyliketeenidimeerien (AKD) valmistusreaktioiden kinetiikkaa. Työn tavoitteena oli saada mittaustuloksia, joiden perusteella voitaisiin kehittää reaktioille kineettinen kineettinen malli ja suorittaa valmistusprosessien alustava optimointi. Teoreettisessa osassa on selvitetty rasvahappokloridien ja alkyyliketeenidimeerien (AKD) eri valmistustapoja. Lisäksi on perehdytty tarkemmin rasvahappokloridien dehydrohalogenointireaktioiden reaktiomekanismeihin ja valmistusprosessin problematiikkaan. Kokeellisessa osassa tutkittiin rasvahappokloridien valmistusta klooraamalla öljyhappoa 30 mol-% fosforitrikloridiylimäärällä lämpötiloissa 45, 50 ja 55OC. Alkyyliketeenidimeerien valmistusta tutkittiin dehydrohalogenoimalla palmitiini- ja öljyhappokloridia 0-30 mol-% trietyyliamiiniylimäärällä inertissä liuottimessa, lämpötiloissa 45 ja 50OC. Reaktiot toteutettiin puolipanosreaktiona, joissa reaktioastiassa olevaan reagenssin ja liuottimen seokseen lisättiin lähtöaine tasaisena massavirtana. Reaktioiden etenemistä seurattiin FT-IR- ja GC-analyysien avulla. Kalorimetrisilla kokeilla tutkittiin öljyhappokloridin dimeroitumisreaktion reaktiolämmön muodostumista ja UV-VIS-analyyseillä seurattiin öljyhappokloridin vanhenemista. Öljyhappokloridin valmistusreaktiolle saatiin hyvä kineettinen malli. Kineettisen mallin puutteena voidaan pitää sitä, ettei kokeissa saatu tietoa mahdollisten sivutuotteiden muodostumisesta. Sovitusohjelmalla saatiin sovitettua estimaatit reaktionopeusvakioille lämpötiloissa 45, 50 ja 55OC. Happokloridien dimeroitumisreaktioiden kineettisen mallin sopivuudelle saatiin suhteellisen hyvä kuva Kuten öljyhappokloridin tapauksessa, myöskään AKD:n valmistusreaktioissa syntynyt sivutuotteita, joten niiden osuutta oletettuun kineettiseen malliin ei tunneta. Sovitusohjelmalla saatiin sovitettua estimaatit reaktionopeusvakioille lämpötiloissa 45 ja 50OC.

Synthesis of triheptanoin and formulation as a solid diet for rodents

Triheptanoin-enriched diets have been successfully used in the experimental treatment of various metabolic disorders. Maximal therapeutic effect is achieved in the context of a ketogenic diet where triheptanoin oil provides 30-40% of the daily caloric intake. However, pre-clinical studies using triheptanoin-rich diets are hindered by the difficulty of administering to laboratory animals as a solid foodstuff. In the present study, we successfully synthesized triheptanoin to the highest standards of purity from glycerol and heptanoic acid, using sulfonated charcoal as a catalyst. Triheptanoin oil was then formulated as a solid, stable and palatable preparation using a ketogenic base and a combination of four commercially available formulation agents: hydrophilic fumed silica, hydrophobic fumed silica, microcrystalline cellulose, and talc. Diet compliance and safety was tested on C57Bl/6 mice over a 15-week period, comparing overall status and body weight change. Practical applications: This work provides a complete description of (i) an efficient and cost-effective synthesis of triheptanoin and (ii) its formulation as a solid, stable, and palatable ketogenic diet (triheptanoin-rich; 39% of the caloric intake) for rodents. Triheptanoin-rich diets will be helpful on pre-clinical experiments testing the therapeutic efficacy of triheptanoin in different rodent models of human diseases. In addition, using the same solidification procedure, other oils could be incorporated into rodent ketogenic diet to study their dosage and long-term effects on mammal health and development. This approach could be extremely valuable as ketogenic diet is widely used clinically for epilepsy treatment.

Evolutionary Games in Networked Populations: Models and Experiments

Cooperation and coordination are desirable behaviors that are fundamental for the harmonious development of society. People need to rely on cooperation with other individuals in many aspects of everyday life, such as teamwork and economic exchange in anonymous markets. However, cooperation may easily fall prey to exploitation by selfish individuals who only care about short- term gain. For cooperation to evolve, specific conditions and mechanisms are required, such as kinship, direct and indirect reciprocity through repeated interactions, or external interventions such as punishment. In this dissertation we investigate the effect of the network structure of the population on the evolution of cooperation and coordination. We consider several kinds of static and dynamical network topologies, such as Baraba´si-Albert, social network models and spatial networks. We perform numerical simulations and laboratory experiments using the Prisoner's Dilemma and co- ordination games in order to contrast human behavior with theoretical results. We show by numerical simulations that even a moderate amount of random noise on the Baraba´si-Albert scale-free network links causes a significant loss of cooperation, to the point that cooperation almost vanishes altogether in the Prisoner's Dilemma when the noise rate is high enough. Moreover, when we consider fixed social-like networks we find that current models of social networks may allow cooperation to emerge and to be robust at least as much as in scale-free networks. In the framework of spatial networks, we investigate whether cooperation can evolve and be stable when agents move randomly or performing Le´vy flights in a continuous space. We also consider discrete space adopting purposeful mobility and binary birth-death process to dis- cover emergent cooperative patterns. The fundamental result is that cooperation may be enhanced when this migration is opportunistic or even when agents follow very simple heuristics. In the experimental laboratory, we investigate the issue of social coordination between indi- viduals located on networks of contacts. In contrast to simulations, we find that human players dynamics do not converge to the efficient outcome more often in a social-like network than in a random network. In another experiment, we study the behavior of people who play a pure co- ordination game in a spatial environment in which they can move around and when changing convention is costly. We find that each convention forms homogeneous clusters and is adopted by approximately half of the individuals. When we provide them with global information, i.e., the number of subjects currently adopting one of the conventions, global consensus is reached in most, but not all, cases. Our results allow us to extract the heuristics used by the participants and to build a numerical simulation model that agrees very well with the experiments. Our findings have important implications for policymakers intending to promote specific, desired behaviors in a mobile population. Furthermore, we carry out an experiment with human subjects playing the Prisoner's Dilemma game in a diluted grid where people are able to move around. In contrast to previous results on purposeful rewiring in relational networks, we find no noticeable effect of mobility in space on the level of cooperation. Clusters of cooperators form momentarily but in a few rounds they dissolve as cooperators at the boundaries stop tolerating being cheated upon. Our results highlight the difficulties that mobile agents have to establish a cooperative environment in a spatial setting without a device such as reputation or the possibility of retaliation. i.e. punishment. Finally, we test experimentally the evolution of cooperation in social networks taking into ac- count a setting where we allow people to make or break links at their will. In this work we give particular attention to whether information on an individual's actions is freely available to poten- tial partners or not. Studying the role of information is relevant as information on other people's actions is often not available for free: a recruiting firm may need to call a job candidate's refer- ences, a bank may need to find out about the credit history of a new client, etc. We find that people cooperate almost fully when information on their actions is freely available to their potential part- ners. Cooperation is less likely, however, if people have to pay about half of what they gain from cooperating with a cooperator. Cooperation declines even further if people have to pay a cost that is almost equivalent to the gain from cooperating with a cooperator. Thus, costly information on potential neighbors' actions can undermine the incentive to cooperate in dynamical networks.

Efficacy and safety of once-daily aclidinium in chronic obstructive pulmonary disease

Background: The long-term efficacy and safety of aclidinium bromide, a novel, long-acting muscarinic antagonist, were investigated in patients with moderate to severe chronic obstructive pulmonary disease (COPD). Methods: In two double-blind, 52-week studies, ACCLAIM/COPD I (n = 843) and II (n = 804), patients were randomised to inhaled aclidinium 200 μg or placebo once-daily. Patients were required to have a postbronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity ratio of ≤70% and FEV1 <80% of the predicted value. The primary endpoint was trough FEV1 at 12 and 28 weeks. Secondary endpoints were health status measured by St George"s Respiratory Questionnaire (SGRQ) and time to first moderate or severe COPD exacerbation. Results: At 12 and 28 weeks, aclidinium improved trough FEV1 versus placebo in ACCLAIM/COPD I (by 61 and 67 mL; both p < 0.001) and ACCLAIM/COPD II (by 63 and 59 mL; both p < 0.001). More patients had a SGRQ improvement ≥4 units at 52 weeks with aclidinium versus placebo in ACCLAIM/COPD I (48.1% versus 39.5%; p = 0.025) and ACCLAIM/COPD II (39.0% versus 32.8%; p = 0.074). The time to first exacerbation was significantly delayed by aclidinium in ACCLAIM/COPD II (hazard ratio [HR] 0.7; 95% confidence interval [CI] 0.55 to 0.92; p = 0.01), but not ACCLAIM/COPD I (HR 1.0; 95% CI 0.72 to 1.33; p = 0.9). Adverse events were minor in both studies. Conclusion: Aclidinium is effective and well tolerated in patients with moderate to severe COPD. Trial registration: ClinicalTrials.gov: NCT00363896 ACCLAIM/COPD I) and NCT00358436 (ACCLAIM/COPD II).

The Effect of Load Follow Operation on Fuel Behaviour in Loviisa NPP

Työn tarkoituksena oli analysoida polttoainesauvojen käyttäytymistä Loviisan ydinvoimalaitoksen tehonsäätöajossa. Sähkömarkkinoiden vapautuminen Pohjoismaissa sekä tämän seurauksena vaihteleva sähkön markkinahinta ovat ajaneet sähkötuottajat tilanteeseen, jossa tuotanto aiempaa enemmän mukautuu markkinatilanteeseen. Näin ollen myös Loviisan ydinvoimalaitoksen osallistuminen sähkön tuotannon säätelyyn saattaa tulevaisuudessa olla ajankohtaista. Ennen kuin reaktorin tehonsäätöajoa voidaan alkaa toteuttaa, tulee varmistua siitä, että polttoainesauvassa tehonsäätöjen seurauksena tapahtuvat muutokset eivät aiheuta epäsuotuisia käyttäytymisilmiöitä. Työssä tarkastellaan kahden Loviisan ydinvoimalaitoksen polttoainetoimittajan, British Nuclear Fuels plc:n ja venäläisen TVEL:n ensinippujen polttoainesauvan käyttäytymistä tehonsäätötapauksissa. Työssä tarkastellut tehonsäätötapaukset on pyritty valitsemaan niin, että ne kuvaisivat tulevaisuudessa mahdollisesti toteutettavia tehonsäätöjä. Laskentatapauksien sauvatehohistoriat on generoitu HEXBU-3D sydänsimulaattoriohjelmalla lasketun nelivuotisen perustehohistorian pohjalta lisäämällä säätösauvan aiheuttama reaktoritehon muutos, säätösauvan viereisen polttoainenipun aksiaalitehon muutos sekä säätösauvan rakenteen aiheuttama paikallinen tehopiikki säätösauvan vieressä. Työssä tarkastellaan tehonsäätöjen toteuttamista eri tehotasoille ja vaihtelevilla määrillä tehonsäätösyklejä. Työssä käsitellyt laskentatapaukset on jaoteltu reaktorin ajotavan mukaan seuraavasti: peruskuorma-ajo, viikonloppusäätö ja päiväsäätö. Laskenta suoritettiin ydinpolttoaineen käyttäytymistä kuvaavaa ENIGMA-B 7.3.0 ohjelmaa apuna käyttäen. Laskelmien tulokset osoittavat, että molempien polttoainetoimittajien ensinippujen sauvat kestävät reaktorin tehonsäätöajoa rajoituksetta tarkastelluissa laskentatapauksissa. ENIGMA-ohjelman sisältämät mallit, jotka ennustavat polttoainesauvan suojakuoren vaurioitumistodennäköisyyden jännityskorroosion tai väsymismurtuman kautta, eivät näytä mitään merkkejä vaurioitumisesta. BNFL:n polttoainesauva saavuttaa kuitenkin suurempia väsymismurtumatodennäköisyyden arvoja. Tämä johtuu siitä, että polttoainepelletin ja suojakuoren välinen mekaaninen vuorovaikutus syntyy BNFL:n sauvassa aikaisemmin, joka taas johtaa suurempaan määrään sauvaa rasittavia muodonmuutoksia tehonnostotilanteissa. TVEL:n Zr1%Nb -materiaalista valmistetun suojakuoren käyttäytymistä ei voida kuitenkaan suoraan näiden laskujen perusteella arvioida, sillä ENIGMA-ohjelman mallit perustuvat Zircaloy-suojakuorimateriaaleilla suoritettuihin kokeisiin.

Synthesis of triheptanoin and formulation as a solid diet for rodents

Triheptanoin-enriched diets have been successfully used in the experimental treatment of various metabolic disorders. Maximal therapeutic effect is achieved in the context of a ketogenic diet where triheptanoin oil provides 30-40% of the daily caloric intake. However, pre-clinical studies using triheptanoin-rich diets are hindered by the difficulty of administering to laboratory animals as a solid foodstuff. In the present study, we successfully synthesized triheptanoin to the highest standards of purity from glycerol and heptanoic acid, using sulfonated charcoal as a catalyst. Triheptanoin oil was then formulated as a solid, stable and palatable preparation using a ketogenic base and a combination of four commercially available formulation agents: hydrophilic fumed silica, hydrophobic fumed silica, microcrystalline cellulose, and talc. Diet compliance and safety was tested on C57Bl/6 mice over a 15-week period, comparing overall status and body weight change. Practical applications: This work provides a complete description of (i) an efficient and cost-effective synthesis of triheptanoin and (ii) its formulation as a solid, stable, and palatable ketogenic diet (triheptanoin-rich; 39% of the caloric intake) for rodents. Triheptanoin-rich diets will be helpful on pre-clinical experiments testing the therapeutic efficacy of triheptanoin in different rodent models of human diseases. In addition, using the same solidification procedure, other oils could be incorporated into rodent ketogenic diet to study their dosage and long-term effects on mammal health and development. This approach could be extremely valuable as ketogenic diet is widely used clinically for epilepsy treatment.

Quality and safety requirements for sustainable phage therapy products.

The worldwide antibiotic crisis has led to a renewed interest in phage therapy. Since time immemorial phages control bacterial populations on Earth. Potent lytic phages against bacterial pathogens can be isolated from the environment or selected from a collection in a matter of days. In addition, phages have the capacity to rapidly overcome bacterial resistances, which will inevitably emerge. To maximally exploit these advantage phages have over conventional drugs such as antibiotics, it is important that sustainable phage products are not submitted to the conventional long medicinal product development and licensing pathway. There is a need for an adapted framework, including realistic production and quality and safety requirements, that allowsa timely supplying of phage therapy products for 'personalized therapy' or for public health or medical emergencies. This paper enumerates all phage therapy product related quality and safety risks known to the authors, as well as the tests that can be performed to minimize these risks, only to the extent needed to protect the patients and to allow and advance responsible phage therapy and research.