Effect of Inhaled Xenon on Cerebral White Matter Damage in Comatose Survivors of Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial

IMPORTANCE: Evidence from preclinical models indicates that xenon gas can prevent the development of cerebral damage after acute global hypoxic-ischemic brain injury but, thus far, these putative neuroprotective properties have not been reported in human studies. OBJECTIVE: To determine the effect of inhaled xenon on ischemic white matter damage assessed with magnetic resonance imaging (MRI). DESIGN, SETTING, AND PARTICIPANTS: A randomized single-blind phase 2 clinical drug trial conducted between August 2009 and March 2015 at 2 multipurpose intensive care units in Finland. One hundred ten comatose patients (aged 24-76 years) who had experienced out-of-hospital cardiac arrest were randomized. INTERVENTIONS: Patients were randomly assigned to receive either inhaled xenon combined with hypothermia (33°C) for 24 hours (n = 55 in the xenon group) or hypothermia treatment alone (n = 55 in the control group). MAIN OUTCOMES AND MEASURES: The primary end point was cerebral white matter damage as evaluated by fractional anisotropy from diffusion tensor MRI scheduled to be performed between 36 and 52 hours after cardiac arrest. Secondary end points included neurological outcome assessed using the modified Rankin Scale (score 0 [no symptoms] through 6 [death]) and mortality at 6 months. RESULTS: Among the 110 randomized patients (mean age, 61.5 years; 80 men [72.7%]), all completed the study. There were MRI data from 97 patients (88.2%) a median of 53 hours (interquartile range [IQR], 47-64 hours) after cardiac arrest. The mean global fractional anisotropy values were 0.433 (SD, 0.028) in the xenon group and 0.419 (SD, 0.033) in the control group. The age-, sex-, and site-adjusted mean global fractional anisotropy value was 3.8% higher (95% CI, 1.1%-6.4%) in the xenon group (adjusted mean difference, 0.016 [95% CI, 0.005-0.027], P = .006). At 6 months, 75 patients (68.2%) were alive. Secondary end points at 6 months did not reveal statistically significant differences between the groups. In ordinal analysis of the modified Rankin Scale, the median (IQR) value was 1 (1-6) in the xenon group and 1 (0-6) in the control group (median difference, 0 [95% CI, 0-0]; P = .68). The 6-month mortality rate was 27.3% (15/55) in the xenon group and 34.5% (19/55) in the control group (adjusted hazard ratio, 0.49 [95% CI, 0.23-1.01]; P = .053). CONCLUSIONS AND RELEVANCE: Among comatose survivors of out-of-hospital cardiac arrest, inhaled xenon combined with hypothermia compared with hypothermia alone resulted in less white matter damage as measured by fractional anisotropy of diffusion tensor MRI. However, there was no statistically significant difference in neurological outcomes or mortality at 6 months. These preliminary findings require further evaluation in an adequately powered clinical trial designed to assess clinical outcomes associated with inhaled xenon among survivors of out-of-hospital cardiac arrest. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00879892

Metabolomic Profiling of Statin Use and Genetic Inhibition of HMG-CoA Reductase

Background Statins are first-line therapy for cardiovascular disease prevention, but their systemic effects across lipoprotein subclasses, fatty acids, and circulating metabolites remain incompletely characterized. Objectives This study sought to determine the molecular effects of statin therapy on multiple metabolic pathways. Methods Metabolic profiles based on serum nuclear magnetic resonance metabolomics were quantified at 2 time points in 4 population-based cohorts from the United Kingdom and Finland (N = 5,590; 2.5 to 23.0 years of follow-up). Concentration changes in 80 lipid and metabolite measures during follow-up were compared between 716 individuals who started statin therapy and 4,874 persistent nonusers. To further understand the pharmacological effects of statins, we used Mendelian randomization to assess associations of a genetic variant known to mimic inhibition of HMG-CoA reductase (the intended drug target) with the same lipids and metabolites for 27,914 individuals from 8 population-based cohorts. Results Starting statin therapy was associated with numerous lipoprotein and fatty acid changes, including substantial lowering of remnant cholesterol (80% relative to low-density lipoprotein cholesterol [LDL-C]), but only modest lowering of triglycerides (25% relative to LDL-C). Among fatty acids, omega-6 levels decreased the most (68% relative to LDL-C); other fatty acids were only modestly affected. No robust changes were observed for circulating amino acids, ketones, or glycolysis-related metabolites. The intricate metabolic changes associated with statin use closely matched the association pattern with rs12916 in the HMGCR gene (R2 = 0.94, slope 1.00 ± 0.03). Conclusions Statin use leads to extensive lipid changes beyond LDL-C and appears efficacious for lowering remnant cholesterol. Metabolomic profiling, however, suggested minimal effects on amino acids. The results exemplify how detailed metabolic characterization of genetic proxies for drug targets can inform indications, pleiotropic effects, and pharmacological mechanisms

Preparation and execution of teeth clenching and foot muscle contraction influence on corticospinal hand-muscle excitability

Contraction of a muscle modulates not only the corticospinal excitability (CSE) of the contracting muscle but also that of different muscles. We investigated to what extent the CSE of a hand muscle is modulated during preparation and execution of teeth clenching and ipsilateral foot dorsiflexion either separately or in combination. Hand-muscle CSE was estimated based on motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) and recorded from the first dorsal interosseous (FDI) muscle. We found higher excitability during both preparation and execution of all the motor tasks than during mere observation of a fixation cross. As expected, the excitability was greater during the execution phase than the preparation one. Furthermore, both execution and preparation of combined motor tasks led to higher excitability than individual tasks. These results extend our current understanding of the neural interactions underlying simultaneous contraction of muscles in different body parts.Peer reviewe

Prevention of Biomaterial Infection by Pre-Operative Incubation with Human Cells

Background: Cells of tissues and biofilm forming bacteria compete for the living space on the surface of an implant. We hypothesized the incubation of the implant (titanium, polydimethylsiloxane, and polystyrene surface) with human cells before implantation as a strategy to prevent bacterial adhesion and biofilm formation. Methods: After 24 hours of incubation with human osteogenic sarcoma SaOS-2 cells (1x10(5) cells/mL), the materials were incubated for 4.5 hours or two days with Staphylococcus aureus in serial 1:10 dilutions of 10(8) colony-forming units/mL. The bacterial adherence and biofilm biomass on materials pre-incubated with SaOS-2 cells were compared with our previous results on materials incubated only with bacteria or in simultaneous co-culture of SaOS-2 cells and S. aureus. Fluorescent microscopy and crystal violet stain were used. The number of viable SaOS-2 and bacterial cells present was tested using colorimetric methods (MTT, LDH) and drop plate method, respectively. Results: The pre-treatment with human cells was associated with a reduction of bacterial colonization of the biomaterial at 4.5 hours and 48 hours compared with the non-pre-treated materials. The presence of bacteria decreased the number of viable human cells on all materials. (Supplementary Fig. 1; see online supplementary materials at www.liebertpub.com/sur). Conclusions: These results suggest that the pre-operative incubation of prostheses with host cells could prevent infection of biomaterials.Peer reviewe

Metabolic profiling of alcohol consumption in 9778 young adults

Background: High alcohol consumption is a major cause of morbidity, yet alcohol is associated with both favourable and adverse effects on cardiometabolic risk markers. We aimed to characterize the associations of usual alcohol consumption with a comprehensive systemic metabolite profile in young adults. Methods: Cross-sectional associations of alcohol intake with 86 metabolic measures were assessed for 9778 individuals from three population-based cohorts from Finland (age 24-45 years, 52% women). Metabolic changes associated with change in alcohol intake during 6-year follow-up were further examined for 1466 individuals. Alcohol intake was assessed by questionnaires. Circulating lipids, fatty acids and metabolites were quantified by high-throughput nuclear magnetic resonance metabolomics and biochemical assays. Results: Increased alcohol intake was associated with cardiometabolic risk markers across multiple metabolic pathways, including higher lipid concentrations in HDL subclasses and smaller LDL particle size, increased proportions of monounsaturated fatty acids and decreased proportion of omega-6 fatty acids, lower concentrations of glutamine and citrate (P<0.001 for 56 metabolic measures). Many metabolic biomarkers displayed U-shaped associations with alcohol consumption. Results were coherent for men and women, consistent across the three cohorts and similar if adjusting for body mass index, smoking and physical activity. The metabolic changes accompanying change in alcohol intake during follow-up resembled the cross-sectional association pattern (R-2 = 0.83, slope = 0.7260.04). Conclusions: Alcohol consumption is associated with a complex metabolic signature, including aberrations in multiple biomarkers for elevated cardiometabolic risk. The metabolic signature tracks with long-term changes in alcohol consumption. These results elucidate the double-edged effects of alcohol on cardiovascular risk.Peer reviewe

Vesi ja vähähiilinen talous

Tiivistelmä. Tässä kandidaatintyössä tarkastellaan vesi ja vähähiilistä taloutta. Aihe on todella laaja, joten sitä on hieman rajattu. Työssä käydään läpi mitä vesi ja vähähiilinen talous tarkoittavat, miten vähähiiliseen talouteen päästään ja kuinka vesi liittyy tähän. Lyhyesti myös esitetään, mitä ovat uusiutuvat energiamuodot ja kuinka niitä tuotetaan Suomessa ja kansainvälisellä tasolla. Vuonna 2018 Suomessa tuotettiin uusiutuvilla energiamuodoilla sähköä 47 % kokonaissähköntuotannosta, pääosin vesi- ja tuulivoimalla. Työssä myös perehdytään Pariisin ilmastosopimukseen, koska se on yksi tärkeimmistä suunnan näyttäjistä kohti vähähiilistä taloutta. Työ on toteutettu kirjallisuusselvityksenä. Sekä vähän vettä kuluttava, että vähähiilinen talous edellyttävät oikeanlaisten energiamuotojen valitsemista. Molempia talouksia tukevia energiamuotoja ovat ydinvoima, aurinkovoima ja tuulivoima. Näissä kolmessa energiamuodossa on suhteessa tuotettuun energiamäärään pienet kasvihuonepäästöt, mutta myös pieni veden tarveWater and low carbon economy. Abstract. The topic of this thesis is water and low-carbon economy. This topic is extensive, so it has been restricted. This thesis focuses on what water and low-carbon economy mean, how to reach low-carbon economy and how water can be associated with this. This thesis also displays what renewable energy sources are and how they are generated in Finland and internationally. In 2018 Finland generated 47 percent of its total electricity production by renewable energy sources, mainly by hydropower and wind power. This thesis also discusses the Paris Climate Agreement, since it is one of the main predecessors towards low carbon economy. This thesis has been carried out as a literature review. The choice of energy sources is essential for reaching an economy that uses little water and carbon. Energy sources that maintain both economies are nuclear power, solar power, and wind power. These three sources of energy have low greenhouse gas emissions in contrast to the amount of energy produced, but also have low water demand

Effects of hormonal contraception on systemic metabolism : cross-sectional and longitudinal evidence

Background: Hormonal contraception is commonly used worldwide, but its systemic effects across lipoprotein subclasses, fatty acids, circulating metabolites and cytokines remain poorly understood. Methods: A comprehensive molecular profile (75 metabolic measures and 37 cytokines) was measured for up to 5841 women (age range 24-49 years) from three population-based cohorts. Women using combined oral contraceptive pills (COCPs) or progestin-only contraceptives (POCs) were compared with those who did not use hormonal contraception. Metabolomics profiles were reassessed for 869 women after 6 years to uncover the metabolic effects of starting, stopping and persistently using hormonal contraception. Results: The comprehensive molecular profiling allowed multiple new findings on the metabolic associations with the use of COCPs. They were positively associated with lipoprotein subclasses, including all high-density lipoprotein (HDL) subclasses. The associations with fatty acids and amino acids were strong and variable in direction. COCP use was negatively associated with albumin and positively associated with creatinine and inflammatory markers, including glycoprotein acetyls and several growth factors and interleukins. Our findings also confirmed previous results e.g. for increased circulating triglycerides and HDL cholesterol. Starting COCPs caused similar metabolic changes to those observed cross-sectionally: the changes were maintained in consistent users and normalized in those who stopped using. In contrast, POCs were only weakly associated with metabolic and inflammatory markers. Results were consistent across all cohorts and for different COCP preparations and different types of POC delivery. Conclusions: Use of COCPs causes widespread metabolic and inflammatory effects. However, persistent use does not appear to accumulate the effects over time and the metabolic perturbations are reversed upon discontinuation. POCs have little effect on systemic metabolism and inflammation.Peer reviewe

Työnaikaisten siltojen aukkomitoitus

Tiivistelmä. Tämän työn tavoitteena on tehdä selvitys työnaikaisten siltojen aukkomitoituksesta kirjallisuuskatsauksen ja kyselytutkimuksen avulla. Työssä perehdytään Suomessa käytettävään varasiltakalustoon, jota käytetään yleensä väliaikaisena siltana varsinaisen sillan rakentamisen tai sen korjauksen aikana, tilapäisratkaisujen rakenteisiin sekä luonnossa tapahtuviin erikoistilanteisiin, kuten jääpatoihin sekä hyydetulviin. Työn keskivaiheilla avataan aukkomitoituksen periaatteet, ongelmat sekä yleisimmät mitoitusmenetelmät. Työn lopussa esitetään johtopäätökset ja suositukset tulevaa tutkimusta varten. Työnaikaisen sillan aukkomitoituksen määrittelyyn vaikuttaa monia eri tekijöitä. Näitä ovat ympäristötekijät, rakenteelliset ratkaisut sekä ilmastonmuutoksen aiheuttamat ääriolosuhteet. Ympäristötekijät sisältävät vesistön luonteen, kuten alttiuden tulville, mutta myös suppojään esiintymisen. Rakenteelliset ratkaisut ja päätökset vaikuttavat rakentamisen aikana, esimerkiksi kuinka tukirakenteet ja siltaosat suunnataan kohti pysyvää siltaa. Ilmaston lämpeneminen aiheuttaa ääriolosuhteita, jotka johtavat muutoksiin rankkasateiden ja kuivien jaksojen esiintymiseen. Sähköpostikysely työtä varten tehtiin lokakuussa 2022. Sähköposti lähetettiin yhteensä seitsemälle henkilölle, jotka työskentelevät työnaikaisten siltojen parissa, joko suunnittelijoina tai rakennuttajina. Monet vastanneista vastasivat kollegoiden kanssa yhdessä, jolloin vastauksia tuli lopulta yhdeksältä henkilöltä. Kyselyn avulla kartoitettiin työnaikaisen sillan suunnittelun ja rakentamisen ongelmakohdat sekä tarve mahdolliselle ohjeistukselle. Kyselyn tulosten analyysimenetelmänä toimi sisällönanalyysi. Kyselyn perusteella valtaosa henkilöistä on tietoisia tärkeimmistä tekijöistä ja ongelmakohdista työnaikaisten siltojen suunnittelussa hydrologian ja hydraulisen puolen näkökulmista. Samalla selvisi, että työnaikaisen sillan aukkomitoitukseen ei ole Suomessa riittävää ohjeistusta tai opasta. Ohjeistuksen uupuessa lähtötietoja ja menetelmiä joudutaan arvaamaan ja soveltamaan, jolloin aukkomitoituksessa virheen mahdollisuus on suuri.Gap sizing of temporary bridges. Abstract. The aim of this work is to investigate the gap sizing of temporary bridges through a literature review and a questionnaire survey. The work examines the emergency bridge equipment used in Finland. Emergency bridges are usually used as temporary solutions during the construction or mending of the main permanent bridge. They are also used as temporary structures, and during some special natural phenomena, e.g., ice jams and slush floods. In the middle section of the work the principles, problems and most common sizing methods of gap sizing are explained. Conclusions and recommendations for future research are presented at the end of the work. There is a plethora of factors that affect the gap sizing of bridges. These include environmental factors, structural decisions, and extreme weather conditions caused by climate change. Environmental factors include the nature of the body of water such as its susceptibility to flooding, and the occurrence of frazil ice. Structural decisions and solutions have an impact during construction, an example being how the supports and bridge span are directed to the permanent bridge. Global warming causes extreme weather conditions, which result in changes in the occurrence of heavy rain and droughts. An e-mail questionnaire for the work was conducted in October 2022. The e-mail was sent to a total of seven people, who work with temporary bridges as either designers or contractors. Many of the respondents wrote their responses with their colleagues, which meant that in total nine people responded. The questionnaire was used to define the problem areas in the design and construction of temporary bridges, as well as the need for possible guidelines. Content analysis was used as the analysis method for the results of the questionnaire. Based on the questionnaire, the majority of people are aware of the major factors and problem areas in designing temporary bridges, from the hydrologic and hydraulic perspectives. At the same time, it was found that the gap sizing of temporary bridges does not have adequate guidelines or instructions in Finland. In the absence of an overall guide, the initial information must be guessed, and methods adapted. This causes a major chance of error in gap sizin