Decision-making preceding transcatheter aortic valve implantation in frail older adults : Vulnerable autonomy, novel frailty scoring and clinical outcomes important to treatment strategy. A mixed method study

Introduction: Transcatheter aortic valve implantation (TAVI), also known as transcatheter aortic valve replacement (TAVR), is a new technique for treating severe, symptomatic aortic stenosis. The mean age for TAVI patients is over 80 years and most of the patients have comorbidities and frailty. Some patients may be too frail and have a short life expectancy even after the intervention, and will benefit more from a palliative approach. Established surgical scores have limitations in determining risk among candidates for TAVI. Assessment of frailty might help to estimate the mortality risk and identify patients likely to benefit from treatment. On the other hand, there is a risk of ageism and undertreating older adults. How can we select the right patients for the procedure? Patient autonomy is a leading principle in bioethics and a basis for shared decision-making. In the light of the increasing focus on patient-centred care, this project has explored TAVI patients’ experience of the decision-making process preceding intervention. This thesis consists of three studies focusing on the decision-making process prior to TAVI. Paper 1 focuses on the patient perspective, paper 2 takes the doctors’ viewpoint and paper 3 includes both perspectives. Aims: The aim of paper one was to explore conditions for autonomous choice as experienced by older adults who recently underwent transcatheter aortic valve implantation. The aim of paper two was to develop a frailty score to guide the decision for TAVI. The aim of paper three was to examine baseline characteristics and clinical outcomes important to older adults and their doctors to enhance shared decision-making prior to transcatheter aortic valve implantation.   Materials and methods: We conducted a mixed method study, with one qualitative sub-study (paper 1) and two quantitative sub-studies (papers 2 and 3). All patients underwent TAVI due to severe and symptomatic aortic stenosis. The qualitative study involved semi-structured interviews of a purposive sample of ten older adults after the procedure. Analysis was by systematic text condensation. In paper 2 we conducted a prospective observational study in 82 patients ≥70 years accepted for TAVI from 2013 to 2015 and 65 patients ≥ 80 years (from a concomitant study on delirium) accepted from 2011 to 2013, giving a total of 147 patients. Prior to the procedure, a geriatric assessment (GA) was completed in 142 patients (missing data for calculating frailty score in five patients). Based on this, an eight-element frailty score with a 0–9 (least frail to most frail) scale was developed. In paper 3 we conducted a prospective, observational study of 82 TAVI patients ≥70 years (the last cohort of study 2), with two-year follow-up focusing on baseline frailty status (including cognitive deficits) and outcome measures important for shared decision-making prior to the procedure. Results: In paper 1, the median age of the included patients was 83.5 years (range 73-89 years). Even when choice seemed difficult or lacking, TAVI patients deliberately took the chance presented to them by taking into account risk assessment, ambivalence and fate. They regarded declining the treatment as worse than accepting the risk related to the procedure. The experience of being carefully advised by their doctor formed the basis of autonomous trust. This trust mitigated ambivalence about the procedure and risks. TAVI patients claimed that it had to be their decision and expressed feelings consistent with self-empowerment. Despite this, choosing the procedure as an obligation to their family or passively accepting it were also reported. In paper 2, patients had a mean age of 83 (SD 4) years, and 54% were women. The novel GA frailty score predicted two-year mortality in Cox analysis, also when adjusted for gender, age and logistic EuroSCORE (HR 1.75, 95% CI: 1.28–2.42, P < 0.001). A ROC curve analysis indicated that a GA frailty cut-off score of ≥ 4 predicted two-year mortality with a specificity of 80% (95% CI: 73%–86%) and a sensitivity of 60% (95% CI: 36%–80%), and the area under the curve was 0.81 (CI 0.71–0.90). All-cause two-year mortality was 11%. In paper 3, mean age was 83 years (SD 4.7) and 48% were women. Fifteen patients (18%) had a Mini Mental Status Examination (MMSE) score below 24 points at baseline, indicating cognitive impairment or dementia, while five patients had an MMSE below 20 points. At baseline and six months, mean New York Heart Association (NYHA) class was 2.5 (SD 0.6) and 1.4 (SD 0.6) (p<0.001) respectively. Between baseline and six months there was no change in the mean scores on the Nottingham Extended Activities of Daily Living (NEADL) scale, with 54.2 (SD 11.5) and 54.5 (SD 10.3) points, mean difference 0.3 (p =0.7). At two years, six patients (7%) had died, four (5%, n=79) lived in a nursing home, six (7%) had contracted infective endocarditis, and four (5%) had had a disabling stroke. Conclusion: This study provides empirically-based descriptions of the conditions for TAVI patients’ autonomy as experienced in the decision-making process, to assist clinicians obtaining valid informed consent. We found that a frailty scale based on geriatric assessment predicted two-year mortality in TAVI patients beyond the established risk score. Patients had symptom improvement and could maintain activities of daily living six months after TAVI, and had low mortality after two years. Rarely, severe complications occurred, such as stroke and endocarditis. Some patients had cognitive impairment or dementia at baseline, which might have influenced the decision-making process. Our findings provide support to identify patients with higher risk and lower expected benefit after TAVI, and circumstances under which the procedure might be futile. The decision to offer the procedure should be a careful evaluation by the heart team, and involve considering frailty, symptom burden and technical challenges, and exploring patient preferences, before offering TAVI

Om omstøtelse av tilleggssikkerhet og rekkevidden av unntaket i lov om finansiell sikkerhetsstillelse § 5

Master i rettsvitenskapJUS399MAJU

En kvalitativ studie: ”Foreldre og fagfolks tanker og erfaringer om den tverrfaglige samhandlingen rundt gravide, foreldre og barn 0-2år i Vestre Toten kommune.»

Vestre Toten kommune prøver ut et tverrfaglig tilbud for gravide, foreldre og barn. Tilbudet er plassert på helsestasjonen, og kalles «Trygghet og trivsel for småbarnsfamilien». Hensikten med tilbudet er å finne fram til barn som står i fare for skjevutvikling, en skjevutvikling som kan føre til at de kan utvikle sårbarheter og senere psykiske lidelser. I de siste tiår, er det forsket mye på hva som skjer vedrørende samhandling mellom foreldrene og spedbarnet. Spesielt med tanke på barnets utvikling av hjernen og av tilknytningsmønstre til de voksne. Videre er det fokus på hvilken foreldrekompetanse det er viktig å ha når man får et barn. Det første året i spedbarnets liv, er det viktigste året med hensyn til tilknytningsutvikling. Derfor ønsker fagmiljøene å prioritere veiledning og tiltak allerede fra livets begynnelse der dette trengs. I Vestre Toten kommune finnes mye kompetanse hos fagpersonene i de forskjellige tjenestene. Flere av fagmiljøene i kommunen ønsker i dag å finne fram til barna som fødes med sårbarheter, de gravide og de foreldrene som trenger oppfølging. Den nye Folkehelseloven, vedtatt 24.06.11 nr.29 lovfester prinsippet om at det er «helse i alt vi gjør», og tydeliggjør ansvaret for å bruke virkemidler i alle sektorer. Loven skal sikre at «Forvaltningsorganene på alle nivå setter i verk tiltak og samordner innsatsen». Når det gjelder kommunens ansvar, blir helsestasjonen nevnt vedrørende det å identifisere spesielle utfordringer. Samhandlingsreformen beskriver de fremtidige oppgavene kommunehelsetjenesten kan ha ansvar for, og regjeringen ønsker å styrke forebyggingsarbeidet (St.meld. nr.47,2008-2009). Samtidig beskriver NOU’en «Det du gjør, gjør det helt» kommunenes ansvar for å identifisere barn og familier med risikofaktorer ved at det gjennomføres generelle kartlegginger (NOU, 2009:22, kap.1, s.11). Det som kommer fram her, er ansvaret 1.linjen har. Siktemålet med min master er å finne ut om Vestre Toten sitt tilbud «Trygghet og trivsel for småbarnsfamilien», når ut til de gravide, foreldrene og barna som trenger det. Får fagpersonene i dette tverrfaglige tilbudet til en god samhandling med hverandre, eller blir denne samhandlingen vanskelig? Og hvorfor blir dette vanskelig når man i utgangspunktet har så mange dyktige fagpersoner i kommunen? Videre ønsker jeg å finne ut om dette er en samhandling som foreldrene har bruk for, og om fagpersonene klarer å gi en god informasjon om tilbudet. Studien foretas gjennom en kvalitativ tilnærming, fenomenologisk, hermeneutisk rettet, for å få frem de ulike fagpersoners og de ulike foreldres refleksjoner, tolkninger og erfaringer. Metoden i studien er fokusintervjuer. Disse gjennomføres i en faggruppe og i to foreldregrupper. I fokusintervjuene kommer det fram hvordan en tverrfaglig samhandling vil fungere på helsestasjonens arena. De forskjellige fagpersonene og foreldrene synliggjør utfordringer rundt den tverrfaglige samhandlingen, og begge grupper har klare formeninger om hvilke foreldregrupper et tverrfaglig tilbud burde nå ut til. Det ble diskutert om foreldre uten definerte problemer har behov for slike tiltak, eller om tilbudene kun skal rette seg mot de som har spesielle behov i sin foreldrerolle. Den teoretiske referanserammen i studien er tidlig intervensjon, barnets utvikling, risiko, resiliens, psykisk helse, forebygging, kartlegging, mentalisering, brukermedvirkning, tverrfaglig samhandling og samtykkekompetanse

Baseline frailty status and outcomes important for shared decision-making in older adults receiving transcatheter aortic valve implantation, a prospective observational study.

AIMS The objective of this study was to examine baseline frailty status (including cognitive deficits) and important clinical outcomes, to inform shared decision-making in older adults receiving transcatheter aortic valve implantation (TAVI). METHODS AND RESULTS We conducted a prospective, observational study of 82 TAVI patients, recruited 2013 to 2015, with 2-year follow-up. Mean age was 83 years (standard deviation (SD) 4.7). Eighteen percent of the patients were frail, as assessed with an 8-item frailty scale. Fifteen patients (18%) had a Mini-Mental Status Examination (MMSE) score below 24 points at baseline, indicating cognitive impairment or dementia and five patients had an MMSE below 20 points. Mean New York Heart Association (NYHA) class at baseline and 6 months was 2.5 (SD 0.6) and 1.4 (SD 0.6), (p < 0.001). There was no change in mean Nottingham Extended Activities of Daily Living (NEADL) scale between baseline and 6 months, 54.2 (SD 11.5) and 54.5 (SD 10.3) points, respectively, mean difference 0.3 (p = 0.7). At 2 years, six patients (7%) had died, four (5%, n = 79) lived in a nursing home, four (5%) suffered from disabling stroke, and six (7%) contracted infective endocarditis. CONCLUSIONS TAVI patients had improvement in symptoms and maintenance of activity of daily living at 6 months. They had low mortality and most patients lived in their own home 2 years after TAVI. Complications like death, stroke, and endocarditis occurred. Some patients had cognitive impairment before the procedure which might influence decision-making. Our findings may be used to develop pre-TAVI decision aids

Alpha-2-adrenergic receptor agonists for the prevention of delirium and cognitive decline after open heart surgery (ALPHA2PREVENT): protocol for a multicentre randomised controlled trial

INTRODUCTION: Postoperative delirium is common in older cardiac surgery patients and associated with negative short-term and long-term outcomes. The alpha-2-adrenergic receptor agonist dexmedetomidine shows promise as prophylaxis and treatment for delirium in intensive care units (ICU) and postoperative settings. Clonidine has similar pharmacological properties and can be administered both parenterally and orally. We aim to study whether repurposing of clonidine can represent a novel treatment option for delirium, and the possible effects of dexmedetomidine and clonidine on long-term cognitive trajectories, motor activity patterns and biomarkers of neuronal injury, and whether these effects are associated with frailty status. METHODS AND ANALYSIS: This five-centre, double-blind randomised controlled trial will include 900 cardiac surgery patients aged 70+ years. Participants will be randomised 1:1:1 to dexmedetomidine or clonidine or placebo. The study drug will be given as a continuous intravenous infusion from the start of cardiopulmonary bypass, at a rate of 0.4 µg/kg/hour. The infusion rate will be decreased to 0.2 µg/kg/hour postoperatively and be continued until discharge from the ICU or 24 hours postoperatively, whichever happens first.Primary end point is the 7-day cumulative incidence of postoperative delirium (Diagnostic and Statistical Manual of Mental Disorders, fifth edition). Secondary end points include the composite end point of coma, delirium or death, in addition to delirium severity and motor activity patterns, levels of circulating biomarkers of neuronal injury, cognitive function and frailty status 1 and 6 months after surgery. ETHICS AND DISSEMINATION: This trial is approved by the Regional Committee for Ethics in Medical Research in Norway (South-East Norway) and by the Norwegian Medicines Agency. Dissemination plans include publication in peer-reviewed medical journals and presentation at scientific meetings. TRIAL REGISTRATION NUMBER: NCT05029050

The emergence of lean construction in the Norwegian AEC industry

publishedVersio

Crystal structure of the P2 C-repressor: a binder of non-palindromic direct DNA repeats

As opposed to the vast majority of prokaryotic repressors, the immunity repressor of temperate Escherichia coli phage P2 (C) recognizes non-palindromic direct repeats of DNA rather than inverted repeats. We have determined the crystal structure of P2 C at 1.8 Å. This constitutes the first structure solved from the family of C proteins from P2-like bacteriophages. The structure reveals that the P2 C protein forms a symmetric dimer oriented to bind the major groove of two consecutive turns of the DNA. Surprisingly, P2 C has great similarities to binders of palindromic sequences. Nevertheless, the two identical DNA-binding helixes of the symmetric P2 C dimer have to bind different DNA sequences. Helix 3 is identified as the DNA-recognition motif in P2 C by alanine scanning and the importance for the individual residues in DNA recognition is defined. A truncation mutant shows that the disordered C-terminus is dispensable for repressor function. The short distance between the DNA-binding helices together with a possible interaction between two P2 C dimers are proposed to be responsible for extensive bending of the DNA. The structure provides insight into the mechanisms behind the mutants of P2 C causing dimer disruption, temperature sensitivity and insensitivity to the P4 antirepressor

Topology Optimization for Unsteady Flow with Applications in Biomedical Flows

In this thesis, we will apply a topology optimization method to unsteady fluid flow, using a density model and level set method, in order to optimize the shape of a coronary artery bypass anastomosis. The fluid movement is described by the unsteady, incompressible Navier-Stokes equations combined with Darcy's equation. These equations are discretized using a finite element approach in space and a backward Euler method in time, and solved using an incremental pressure correction scheme (IPCS). We will consider different objective functionals for the optimization problems. The topological derivative will be calculated based on an adjoint formulation of the Navier-Stokes equations combined with Darcy's equation, and used as a search direction in a gradient-based algorithm, in order to find the optimal channel shape