Publikationer från Umeå universitet
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PRX004 in variant amyloid transthyretin (ATTRv) amyloidosis : results of a phase 1, open-label, dose-escalation study
No full textBackground: The investigational monoclonal antibody PRX004 is designed to specifically target and deplete TTR amyloid. Here, we report on the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary clinical activity of PRX004 in patients with ATTRv amyloidosis. Methods: This global, multicentre, phase 1 trial comprised a 3 + 3 dose-escalation phase and a long-term extension (LTE) phase (NCT03336580). In the dose-escalation phase, patients received PRX004 (0.1, 0.3, 1, 3, 10 or 30 mg/kg), administered intravenously every 28 days for 3 months. In the LTE, eligible patients could receive up to 15 additional doses. Patients who received doses of ≥3 mg/kg for ≥9 months were assessed for Global Longitudinal Strain (GLS) and Neuropathy Impairment Score (NIS). The primary objective was to determine the maximum tolerated dose (MTD) of PRX004. Results: Overall, 21 patients with ATTRv amyloidosis completed the dose-escalation phase; 17 subsequently enrolled in the LTE. The MTD was not reached. PRX004 was well tolerated at all doses, with dose-proportional exposure. GLS and NIS were improved or maintained over 9 months (n = 7). Conclusions: PRX004 was well tolerated in patients with ATTRv amyloidosis and demonstrated potential clinical activity. A phase 2 randomised controlled trial in ATTR cardiomyopathy is ongoing (NCT05442047)
Leptin and leptin receptor gene polymorphisms and depression treatment response
No full textObjective: Associations between leptin (LEP) and leptin receptor (LEPR) gene polymorphisms and mood disorders have been found but not yet confirmed in multiple studies. The aim of our study was to study the associations between LEP and LEPR single nucleotide polymorphisms (SNPs) and treatment response of depression. Associations between leptin levels and depression severity were also investigated. Methods: The data included 242 depressed patients in secondary psychiatric care. Symptoms of depression were assessed with the Montgomery-Asberg Depression Rating Scale (MADRS). Previously found LEP and LEPR SNPs associated with depression and other mood disorders were studied. Furthermore, all available LEP and LEPR SNPs were clumped using proxy SNPs to represent gene areas in r2 > 0.2 linkage disequilibrium and their association with treatment response was analysed with logistic regression. Results: Two proxy SNPs of LEPR gene, rs12564738 and rs12029311, were associated with MADRS response at 6 weeks (p adjusted = 0.024, p adjusted = 0.024). SNPs from previous studies were not associated with MADRS response, but LEPR rs12145690 from a previous study was strongly associated with rs12564738 (r2 = 0.94). The positive association between leptin levels and MADRS score at baseline after adjusting with age, sex, body mass index (BMI), Alcohol Use Disorders Identification Test score, and smoking was found (p = 0.011). Conclusion: Our findings suggest that LEPR polymorphisms are associated with depression treatment response. We also found associations between leptin levels and depression independently of BMI. Further studies and meta-Analyses are needed to confirm the significance of found SNPs and the role of leptin in depression
Exploring system context contributing to emerging REDD+ collaborative governance regime in Ghana : stakeholders perceptions at the national level
No full textSince its emergence in 2007, the global mechanism for Reducing Emissions from Deforestation and Degradation in developing countries (REDD+) has raised hopes of providing cost-effective solutions to climate change. However, the design and implementation of REDD+ projects in many developing countries, including Ghana, have faced complex governance challenges. In recent years, a collaborative governance approach has been increasingly recommended for effective REDD+ implementation, but the impact of the dynamics of developing countries’ context on collaboration success remains unclear. Using Ghana’s Cocoa Forest REDD+ Programme (GCFRP) as a case study, this paper aims to increase our understanding of how the dynamics of developing countries’ context affect the drivers shaping the initiation of REDD+ collaborative regimes for transforming cocoa forest landscapes. Through qualitative content analysis of document reviews and semi-structured interviews with national program stakeholder groups, the results indicate that Ghana’s dynamic context facilitates collaboration on REDD+ implementation when stakeholders feel uncertain about the future availability of forest resources and recognize their interdependence in responding to such issues. Additionally, the findings of the study indicate that strong political will for change, along with strategic windows of opportunity created by REDD+ funding mechanisms, play a vital role in shaping consequential incentives essential for aligning stakeholder interests and fostering cross-sector leadership for initiating the REDD+ collaborative governance regime. While the applicability and limitations of the IFCG framework are discussed, further in-depth studies at project levels are crucial to understanding local stakeholders’ perspectives on the key elements necessary for successful collaboration
Swedish parents’ descriptions of giftedness and experiences of home–school collaboration
No full textThere is insufficient Swedish research on giftedness and home-school collaboration and meeting gifted children’s needs in early childhood education. This qualitative study explored these issues by interviewing parents of gifted children. The thematic analysis examined parents’ descriptions of children’s early development, asynchronicity, and differences from their peers. The parents’ stories of their children’s first encounters with the Swedish school system evoked reports of contentment, suffering, and exhaustion. Adopting Bronfenbrenner’s ecological systems theory, the study shows how the parents positioned enabling and limiting factors for their children’s acceptance and further development at different system levels. Positive learning conditions in preschool (unlike primary school), and respectful home–school communication were identified as crucial to gifted children’s development and well-being
Exporting preschool quality assurance : ideational power and legitimation of a Scandinavian edu-business
No full textThis study explores the quest for preschool quality and the ideational foundation it builds on through the work of a Swedish edu-business operating preschools internationally. We analyse associated flows and uses of (global) ideas on preschool quality to understand how such businesses draw on, remould and ‘move’ certain ideas on quality and quality assurance. For this we use data obtained from visits to, interviews with representatives of, and various documents produced by the business and two of its subsidiaries, one Swedish and one Norwegian. The analysis highlights important aspects of three dimensions of ideational power: the power through, over and in ideas. The results show how the business acts, particularly through the Norwegian subsidiary, as a pioneering ideational leader of preschool improvement. In this position it conveys an acclaimed state-of-the-art quality system to the policy domain, thereby legitimising large-scale private preschool provision in policy contexts where it is increasingly questioned.FS 2.1.6-390-21_Lärarhögskolan, Umeå universitet/ Förskola på import och Export
The better choice? : The status quo versus radical human enhancement
No full textCan it be rational to favour the status quo when the alternatives to the status quo promise considerable increases in overall value? For instance, can it be rational to favour the status quo over radical human enhancement? A reasonable response to these questions would be to say that it can only be rational if the status quo is indeed the better choice on some measure. In this paper, I argue that it can be rational to favour the status quo over a radical improvement such as human germline genetic enhancement. First, I distinguish between three different meanings of the “status quo.” Then, I argue that the status quo enjoys modal and epistemic advantages that sometimes translate into other advantages. I propose eight parameters for comparison between the status quo and radical options. These parameters weigh in favour of the status quo but can be outweighed by the benefits of change. Each of these parameters needs to be assessed from case to case. I defend what I refer to as an Open Status Quo position over a Fixed Status Quo position. The former is decision-specific and does not entail a commitment to remaining with the status quo in later decisions. Lastly, I address the objection that an Open Status Quo position risk slipping into a Fixed Status Quo position that would, in turn, block radical progress, change, and discovery
To find the way back : A qualitative study on the impact of social factors on relapse in substance use, from a social workers perspective
No full textKommuner tillsammans med regioner bär ansvaret för arbetet med Sveriges missbruksvård. Alkohol- och narkotikabruket resulterar i stora samhällskostnader för Sverige varje år. I kommunernas arbete med individer med missbruksproblematik finns det många olika faktorer att ta hänsyn till. Interpersonella egenskaper som exempelvis motivation diskuteras ofta som en framträdande faktor, men även de sociala faktorerna är av stor betydelse. Denna kvalitativa studie har det övergripande syftet att undersöka sociala faktorers påverkan på risken för återfall i missbruk efter frivillig behandling i slutenvård, ur ett socialsekreterarperspektiv. Tidigare forskning visar att de flesta återfall som inträffar sker inom det första året efter avslutat behandling, samt att viktiga faktorer för att lyckas med behandling och hålla sig nykter och drogfri är en kombination av professionellt stöd och individuella handlingar. För att undersöka syftet samt besvara studiens frågeställningar har fyra intervjuer utförts med socialsekreterare som är eller har varit verksamma på socialtjänstens vuxenenheter i olika kommuner i Sverige. För att analysera empirin i studien har systemteoretiskt perspektiv applicerats. Resultatet visar att boende, sysselsättning samt det sociala nätverket främst kan påverka risken för återfall i missbruk efter behandling i slutenvård. Vidare visar resultatet att det finns utmaningar och svårigheter gällande att ta sociala faktorer i beaktning, i form av samverkan med andra enheter inom socialtjänsten gällande planering av eftervården och att planeringen utformas utan att det blir någon typ av "glapp". I resultatet lyfts även svårigheter gällande att ge stöd och insatser för att förändra det sociala nätverket, vilket beskrivs som en viktig del i att vara fortsatt nykter coh drogfri efter behandling. Att ha möjlighet att kunna hjälpa individen att flytta till en annan kommun är enligt empirin önskvärt, men skildras som en utmaning.
Misfolding of transthyretin in vivo is controlled by the redox environment and macromolecular crowding
No full textTransthyretin (TTR) amyloidosis is a progressive disorder characterized by peripheral neuropathy, autonomic dysfunction, and cardiomyopathy. The precise mechanism by which TTR misfolds and forms fibrils in vivo remains incompletely understood, posing challenges to the development of effective therapeutics. In this study, we reveal that the recently identified nonnative pathological species of TTR (NNTTR), which is enriched in the plasma of ttr-val30met gene carriers, exhibits strong amyloidogenic properties, making it a promising therapeutic target. Notably, we demonstrate that NNTTR formation is dependent on an intermolecular disulfide bond and can be promoted by oxidative conditions while being effectively suppressed by reducing agents. The formation of this disulfide bond is incompatible with the native TTR fold, thereby necessitating structural flexibility. We further show that this required flexibility can be constrained using tetramer-stabilizing drugs, thereby suppressing NNTTR formation. Interestingly, the flexibility is also hindered by macromolecular crowding, and NNTTR formation is strongly suppressed by the high protein concentration in plasma. This suppression is released upon dilution, which thus promotes NNTTR formation in areas with lower protein content, highlighting a potential link to the interstitial space, brain, and vitreous body of the eye, where TTR-amyloid is frequently observed. In summary, we demonstrate that NNTTR displays strong amyloidogenic features, underscoring its potential as a therapeutic target. We identify the redox environment and macromolecular crowding as key modulatory factors. Our findings propose a mechanistic explanation for TTR misfolding and suggest a novel therapeutic approach
Sverigedemokraternas regionala politiska kultur i Skåne och Blekinge : vad ligger bakom partiets exceptionella regionala framgångar?
No full textRapporten syftar till att undersöka varför Sverigedemokraterna lyckats så bra i just Skåne och Blekinge och vad som kännetecknar den regionala politiska kultur som dominerar i detta område. Vid 2022 års val fick man 30 procent av rösterna i detta område, mot drygt 20 procent i Sverige som helhet. Den politiska regionen Skåne-Blekinge (SD) innefattar 25 av de 38 kommunerna i dessa län. Partiet har där gjort inbrytningar i alla samhällsgrupper, men särskilt i dess kärngrupper av män, arbetare, lågutbildade och lågavlönade. Den kanske viktigaste förklaringen till Sverigedemokraternas framgångar i denna politiska region är att medborgarna redan innan detta parti dök upp hade mer konservativa och nationalistiska åsikter, som motsvarade Sverigedemokraternas. De hade också svag tillit till andra människor och var särskilt missnöjda med det politiska systemet. Detta mönster präglade både arbetarklass och medelklass. Särskilt de socialdemokratiska sympatisörerna hade sådana uppfattningar och lockades snabbt över till det nya partiet. Det historiska ursprunget till detta åsikts- och handlingsmönster är höjt i dunkel, men en negativ inställning till invandrare har djupa rötter och är dokumenterat inom både fackföreningsrörelsen och på den skånska landsbygden. Skånsk separatism och närheten till kontinenten har också angivits som skäl. Detta förhållningssätt överförs också alltjämt från generation till generation.The report aims to investigate why the Sweden Democrats have succeeded so well in Skåne and Blekinge and what characterizes the regional political culture that dominates in this area. In the 2022 general elections, the party received 30 percent of the votes this area, compared to 20 percent in the country as a whole. The political region Skåne-Blekinge (SD) includes 25 of the 38 municipalities in these two counties. The party has made inroads into all social groups, but especially into its core groups of men, manual workers, people with limited education and the low-paid.Perhaps the most important explanation for the Sweden Democrats' success in this political region is that even before this party appeared, the citizens had more conservative and nationalist views, which corresponded with those of the Sweden Democrats. Citizens also had little trust in other people and were particularly dissatisfied with the political system. This pattern characterized both the working class and the middle class. The Social Democratic sympathizers in particular held such views and were quickly attracted to the new party.The historical origins of this pattern of opinion and action are shrouded in mystery, but a negative attitude towards immigrants has deep roots and is documented within both the trade union movement and in the Skåne countryside. Regional separatism and proximity to the continent have also been cited as reasons. This attitude is continues to be transmitted from generation to generation.</p
The Wayqecha Amazon Cloud Curtain Ecosystem Experiment : A new experimental method to manipulate fog water inputs in terrestrial systems
No full textFog makes a significant contribution to the hydrology of a wide range of important terrestrial ecosystems. The amount and frequency of fog immersion are affected by rapid ongoing anthropogenic changes but the impacts of these changes remain relatively poorly understood compared with changes in rainfall. Here, we present the design and performance of a novel experiment to actively manipulate low lying fog abundance in an old-growth tropical montane cloud forest (TMCF) in Peru—the Wayqecha Amazon Cloud Curtain Ecosystem Experiment (WACCEE). The treatment consists of a 30 m high, 40 m wide mesh curtain suspended between two towers and extending down to the ground, and two supplementary curtains orientated diagonally inwards from the top of each tower and secured to the ground upslope. The curtains divert and intercept airborne water droplets in fog moving upslope, thereby depriving a ~420 m2 patch of forest immediately behind the curtains of this water source. We monitored inside the treatment and a nearby unmodified control plot various metrics of water availability (air humidity, vapour pressure deficit, leaf wetness and soil moisture) and other potentially confounding variables (radiation, air and soil temperature) above and below the forest canopy. The treatment caused a strong reduction in both air humidity and leaf wetness, and an increase in vapour pressure deficit, above the canopy compared to the control plot. This effect was most pronounced during the nighttime (20:00–05:00). Below-canopy shifts within the treatment were more subtle: relative humidity at 2 m height above the ground was significantly suppressed during the daytime, while soil moisture was apparently elevated. The treatment caused a small but significant increase in air temperature above the canopy but a decrease in temperature in and near the soil, while mixed effects were observed at 2 m height above the ground. Above-canopy radiation was slightly elevated on the treatment relative to the control, particularly during the dry season. Further application of the method in other systems where fog plays a major role in ecosystem processes could improve our understanding of the ecological impacts of this important but understudied climate driver