Relationship between the Clinical Frailty Scale and short-term mortality in patients ≥ 80 years old acutely admitted to the ICU: a prospective cohort study.

BACKGROUND: The Clinical Frailty Scale (CFS) is frequently used to measure frailty in critically ill adults. There is wide variation in the approach to analysing the relationship between the CFS score and mortality after admission to the ICU. This study aimed to evaluate the influence of modelling approach on the association between the CFS score and short-term mortality and quantify the prognostic value of frailty in this context. METHODS: We analysed data from two multicentre prospective cohort studies which enrolled intensive care unit patients ≥ 80 years old in 26 countries. The primary outcome was mortality within 30-days from admission to the ICU. Logistic regression models for both ICU and 30-day mortality included the CFS score as either a categorical, continuous or dichotomous variable and were adjusted for patient's age, sex, reason for admission to the ICU, and admission Sequential Organ Failure Assessment score. RESULTS: The median age in the sample of 7487 consecutive patients was 84 years (IQR 81-87). The highest fraction of new prognostic information from frailty in the context of 30-day mortality was observed when the CFS score was treated as either a categorical variable using all original levels of frailty or a nonlinear continuous variable and was equal to 9% using these modelling approaches (p < 0.001). The relationship between the CFS score and mortality was nonlinear (p < 0.01). CONCLUSION: Knowledge about a patient's frailty status adds a substantial amount of new prognostic information at the moment of admission to the ICU. Arbitrary simplification of the CFS score into fewer groups than originally intended leads to a loss of information and should be avoided. Trial registration NCT03134807 (VIP1), NCT03370692 (VIP2)

Computational Modeling of the AT2 Receptor and AT2 Receptor Ligands : Investigating Ligand Binding, Structure–Activity Relationships, and Receptor-Bound Models

Rational conversion of biologically active peptides to nonpeptide compounds with retained activity is an appealing approach in drug development. One important objective of the work presented in this thesis was to use computational modeling to aid in such a conversion of the peptide angiotensin II (Ang II, Asp-Arg-Val-Tyr-Ile-His-Pro-Phe). An equally important objective was to gain an understanding of the requirements for ligand binding to the Ang II receptors, with a focus on interactions with the AT2 receptor. The bioactive conformation of a peptide can provide important guidance in peptidomimetic design. By designing and introducing well-defined secondary structure mimetics into Ang II the bioactive conformation can be addressed. In this work, both γ- and β-turn mimetic scaffolds have been designed and characterized for incorporation into Ang II. Using conformational analysis and the pharmacophore recognition method DISCO, a model was derived of the binding mode of the pseudopeptide Ang II analogues. This model indicated that the positioning of the Arg side chain was important for AT2 receptor binding, which was also supported when the structure–activity relationship of Ang II was investigated by performing a glycine scan. To further examine ligand binding, a 3D model of the AT2 receptor was constructed employing homology modeling. Using this receptor model in a docking study of the ligands, binding modes were identified that were in agreement with data from point-mutation studies of the AT2 receptor. By investigating truncated Ang II analogues, small pseudopeptides were developed that were structurally similar to nonpeptide AT2 receptor ligands. For further guidance in ligand design of nonpeptide compounds, three-dimensional quantitative structure–activity relationship models for AT1 and AT2 receptor affinity as well as selectivity were derived

Computational Modeling of the AT2 Receptor and AT2 Receptor Ligands : Investigating Ligand Binding, Structure–Activity Relationships, and Receptor-Bound Models

Rational conversion of biologically active peptides to nonpeptide compounds with retained activity is an appealing approach in drug development. One important objective of the work presented in this thesis was to use computational modeling to aid in such a conversion of the peptide angiotensin II (Ang II, Asp-Arg-Val-Tyr-Ile-His-Pro-Phe). An equally important objective was to gain an understanding of the requirements for ligand binding to the Ang II receptors, with a focus on interactions with the AT2 receptor. The bioactive conformation of a peptide can provide important guidance in peptidomimetic design. By designing and introducing well-defined secondary structure mimetics into Ang II the bioactive conformation can be addressed. In this work, both γ- and β-turn mimetic scaffolds have been designed and characterized for incorporation into Ang II. Using conformational analysis and the pharmacophore recognition method DISCO, a model was derived of the binding mode of the pseudopeptide Ang II analogues. This model indicated that the positioning of the Arg side chain was important for AT2 receptor binding, which was also supported when the structure–activity relationship of Ang II was investigated by performing a glycine scan. To further examine ligand binding, a 3D model of the AT2 receptor was constructed employing homology modeling. Using this receptor model in a docking study of the ligands, binding modes were identified that were in agreement with data from point-mutation studies of the AT2 receptor. By investigating truncated Ang II analogues, small pseudopeptides were developed that were structurally similar to nonpeptide AT2 receptor ligands. For further guidance in ligand design of nonpeptide compounds, three-dimensional quantitative structure–activity relationship models for AT1 and AT2 receptor affinity as well as selectivity were derived

Sammanställning av flygets klimatpåverkan och möjlighet till minskning av dessa - alternativa flygrutter för minskade höghöjdseffekter och biobränslen

Idag står den globala flygtrafiken för ca 2-3% av det fossila CO2-utsläppet härlett från mänskliga aktiviteter. Flygtrafikens bidrag till global uppvärmningen i form av strålningsdrivning är dock 4.9% om man tar hänsyn till effekt från kortlivade klimatföroreningar (short-lived climate pollutants, SLCP) relaterade till flyget, även kallade höghöjdseffekter. Dessa innefattar utsläpp av vattenånga, sot och andra partiklar, bildning av kondensstrimmor och flyginducerade cirrusmoln samt utsläpp av NOX som leder till förändringar av halter av ozon och metan i atmosfären. Det relativa bidraget av SLCP från flyget varierar kraftigt beroende på vilket mått man använder, med GWP20 (Global Warming Potential på en tidshorisont 20 år) ligger total effekt av flygemissionerna relativt till CO2 inom intervallet 2.1-4.8, för GWP100 ligger samma proportion mellan 1.3 och 2.0, använder man Global TemperaturPotential GTP ligger proportionen mellan 1.0 och 1.1 för GTP100. Klimatpåverkan av SLCP är starkt beroende av atmosfäriska förhållanden där utsläppen sker. Persistenta kondensstrimmor bildas och värmer upp klimatet när flygplan rör sig i områden som har luftfuktighet övermättad mot is och som är molnfri. Även utsläpp av NOx kan ge olika effekter beroende på förhållandena vid utsläpp. Flera studier har utvärderat möjligheterna att optimera flygrutter med hänsyn till både CO2 utsläpp och effekter från SLCP genom att justera var/när största delen av utsläppen sker. Man har visat att trots en högre bränsleförbrukning vid alternativa flygrutter kunde man uppnå en minskad klimatpåverkan med mått GWP100. Klimatmålet med max. 2° temperaturhöjning kräver mer än en halvering av utsläppen av växthusgaser till år 2050 vilket kräver en bred övergång till alternativa bränslen fria från fossilt kol. För flyget finns ett flertal alternativa jetbränslen (AJF) med lägre halter fossilt kol i sin well-to-wake cykel (WTWk). WTWk minskningen varierar kraftigt med processen som bränslet framställts genom samt vilket råmaterial som använts. Det finns flera negativa effekter kring ändrad markanvändning som är en mycket viktigt hållbarhetsaspekt. Det alternativ som ger störst WTWk minskning är att producera AJF från restprodukter som avfallsolja och skogsrester. För vissa alternativ, som sojabönor och palmolja, ligger WTWk högre hos AJF än hos de konventionella jetbränslena. Dessutom kopplas AJF-produktionen till en konflikt mellan matproduktion och bränsleproduktion, potentiellt minskad biodiversitet, vattenkonsumtion samt föroreningar som uppstår vid produktion vilka inte går att ignorera ur ett hållbarhetsperspektiv.Idag står den globala flygtrafiken för ca 2-3% av det fossila CO2-utsläppet härlett från mänskliga aktiviteter. Flygtrafikens bidrag till global uppvärmningen i form av strålningsdrivning är dock 4.9% om man tar hänsyn till effekt från kortlivade klimatföroreningar (short-lived climate pollutants, SLCP) relaterade till flyget, även kallade höghöjdseffekter. Dessa innefattar utsläpp av vattenånga, sot och andra partiklar, bildning av kondensstrimmor och flyginducerade cirrusmoln samt utsläpp av NOX som leder till förändringar av halter av ozon och metan i atmosfären. Det relativa bidraget av SLCP från flyget varierar kraftigt beroende på vilket mått man använder, med GWP20 (Global Warming Potential på en tidshorisont 20 år) ligger total effekt av flygemissionerna relativt till CO2 inom intervallet 2.1-4.8, för GWP100 ligger samma proportion mellan 1.3 och 2.0, använder man Global TemperaturPotential GTP ligger proportionen mellan 1.0 och 1.1 för GTP100. Klimatpåverkan av SLCP är starkt beroende av atmosfäriska förhållanden där utsläppen sker. Persistenta kondensstrimmor bildas och värmer upp klimatet när flygplan rör sig i områden som har luftfuktighet övermättad mot is och som är molnfri. Även utsläpp av NOx kan ge olika effekter beroende på förhållandena vid utsläpp. Flera studier har utvärderat möjligheterna att optimera flygrutter med hänsyn till både CO2 utsläpp och effekter från SLCP genom att justera var/när största delen av utsläppen sker. Man har visat att trots en högre bränsleförbrukning vid alternativa flygrutter kunde man uppnå en minskad klimatpåverkan med mått GWP100. Klimatmålet med max. 2° temperaturhöjning kräver mer än en halvering av utsläppen av växthusgaser till år 2050 vilket kräver en bred övergång till alternativa bränslen fria från fossilt kol. För flyget finns ett flertal alternativa jetbränslen (AJF) med lägre halter fossilt kol i sin well-to-wake cykel (WTWk). WTWk minskningen varierar kraftigt med processen som bränslet framställts genom samt vilket råmaterial som använts. Det finns flera negativa effekter kring ändrad markanvändning som är en mycket viktigt hållbarhetsaspekt. Det alternativ som ger störst WTWk minskning är att producera AJF från restprodukter som avfallsolja och skogsrester. För vissa alternativ, som sojabönor och palmolja, ligger WTWk högre hos AJF än hos de konventionella jetbränslena. Dessutom kopplas AJF-produktionen till en konflikt mellan matproduktion och bränsleproduktion, potentiellt minskad biodiversitet, vattenkonsumtion samt föroreningar som uppstår vid produktion vilka inte går att ignorera ur ett hållbarhetsperspektiv.Denna rapport är nummer 1 av tre leveranser i projektet och kartlägger kunskapsläget kring hur flygets utsläpp, inklusive introducerade k-strimmor och cirrusmoln påverkar klimatet och möjligheten att minska flygets klimatpåverkan genom alternativa flygrutter. Den innehåller även en sammanställning av kunskapsläget när det gäller biojetbränslen, deras ”well-to-wake”-klimatpåverkan och emissioner av luftföroreningar, i jämförelse med fossila jetbränslen

Computational studies of molecular pre-organization through macrocyclization : Conformational distribution analysis of closely related non-macrocyclic and macrocyclic analogs

Macrocycles form an important compound class in medicinal chemistry due to their interesting structural and biological properties. To help design macrocycles, it is important to understand how the conformational preferences are affected upon macrocyclization of a lead compound. To address this, we collected a unique data set of protein-ligand complexes containing "non-macrocyclic" ("linear") ligands matched with macrocyclic analogs binding to the same protein in a similar pose. Out of the 39 co-crystallized ligands considered, 10 were linear and 29 were macrocyclic. To enable a more general analysis, 128 additional ligands from the publications associated with these protein data bank entries were added to the data set. Using in total 167 collected ligands, we investigated if the conformers in the macrocyclic conformational ensembles were more similar to the bioactive conformation in comparison to the conformers of their linear counterparts. Unexpectedly, in most cases the macrocycle conformational ensemble distributions were not very different from those of the linear compounds. Thus, care should be taken when designing macrocycles with the aim to focus their conformational preference towards the bioactive conformation. We also set out to investigate potential conformational flexibility differences between the two compound classes, computational energy window settings and evaluate a literature metric for approximating the conformational focusing on the bioactive conformation

Physical Disturbance by Bottom Trawling Suspends Particulate Matter and Alters Biogeochemical Processes on and Near the Seafloor

Bottom trawling is known to affect benthic faunal communities but its effects on sediment suspension and seabed biogeochemistry are less well described. In addition, few studies have been carried out in the Baltic Sea, despite decades of trawling in this unique brackish environment and the frequent occurrence of trawling in areas where hypoxia and low and variable salinity already act as ecosystem stressors. We measured the physical and biogeochemical impacts of an otter trawl on a muddy Baltic seabed. Multibeam bathymetry revealed a 36 m-wide trawl track, comprising parallel furrows and sediment piles caused by the trawl doors and shallower grooves from the groundgear, that displaced 1,000 m3 (500 t) sediment and suspended 9.5 t sediment per km of track. The trawl doors had less effect than the rest of the gear in terms of total sediment mass but per m2 the doors had 5× the displacement and 2× the suspension effect, due to their greater penetration and hydrodynamic drag. The suspended sediment spread >1 km away over the following 3–4 days, creating a 5–10 m thick layer of turbid bottom water. Turbidity reached 4.3 NTU (7 mgDW L−1), 550 m from the track, 20 h post-trawling. Particulate Al, Ti, Fe, P, and Mn were correlated with the spatio-temporal pattern of suspension. There was a pulse of dissolved N, P, and Mn to a height of 10 m above the seabed within a few hundred meters of the track, 2 h post-trawling. Dissolved methane concentrations were elevated in the water for at least 20 h. Sediment biogeochemistry in the door track was still perturbed after 48 h, with a decreased oxygen penetration depth and nutrient and oxygen fluxes across the sediment-water interface. These results clearly show the physical effects of bottom trawling, both on seabed topography (on the scale of km and years) and on sediment and particle suspension (on the scale of km and days- weeks). Alterations to biogeochemical processes suggest that, where bottom trawling is frequent, sediment biogeochemistry may not have time to recover between disturbance events and elevated turbidity may persist, even outside the trawled area

Brandteknisk riskvärdering av Nattklubben Cleo, Luleå

This report has been made as a part of the fire safety engineering education at Lund University. The report analyses the safety regarding evacuation in case of fire in a nightclub in Luleå, Sweden. The nightclub Cleo is located in the basement of a central hotel in Luleå, a town in the northern part of Sweden. The club is large and can hold maximum 600 persons. The aim of this report has been to evaluate different fire scenarios and compare ASET (available safe egress time) calculated with the software C-FAST with RSET (required safe egress time), calculated with the software SIMULEX. Cleo, that recently has gone through some major changes, need to be further modified to reach the demands of fire safety. Suggestions for changes are included in the report