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1.	Amare, Azmeraw, et al. (author) Association of Polygenic Score and the involvement of Cholinergic and Glutamatergic Pathways with Lithium Treatment Response in Patients with Bipolar Disorder. 2023 In: Research square. - : Research Square Platform LLC. Journal article (peer-reviewed)abstract Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2,367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<��.
2.	Amare, Azmeraw T, et al. (author) Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder. 2023 In: Molecular psychiatry. - 1476-5578. ; 28, s. 5251-5261 Journal article (peer-reviewed)abstract Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental healthdisorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P=9.8×10-12, R2=1.9%) and continuous (P=6.4×10-9, R2=2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P=3.9×10-4, R2=0.9%), but not for the continuous outcome (P=0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.
3.	Amare, A. T., et al. (author) Association of polygenic score for major depression with response to lithium in patients with bipolar disorder 2021 In: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 26, s. 2457-2470 Journal article (peer-reviewed)abstract Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi(+)Gen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18-2.01) and European sample: OR = 1.75 (95% CI: 1.30-2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61-4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.
4.	Amare, Azmeraw T, et al. (author) Association of Polygenic Score for Schizophrenia and HLA Antigen and Inflammation Genes With Response to Lithium in Bipolar Affective Disorder: A Genome-Wide Association Study. 2018 In: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 75:1, s. 65-74 Journal article (peer-reviewed)abstract Lithium is a first-line mood stabilizer for the treatment of bipolar affective disorder (BPAD). However, the efficacy of lithium varies widely, with a nonresponse rate of up to 30%. Biological response markers are lacking. Genetic factors are thought to mediate treatment response to lithium, and there is a previously reported genetic overlap between BPAD and schizophrenia (SCZ).To test whether a polygenic score for SCZ is associated with treatment response to lithium in BPAD and to explore the potential molecular underpinnings of this association.A total of 2586 patients with BPAD who had undergone lithium treatment were genotyped and assessed for long-term response to treatment between 2008 and 2013. Weighted SCZ polygenic scores were computed at different P value thresholds using summary statistics from an international multicenter genome-wide association study (GWAS) of 36989 individuals with SCZ and genotype data from patients with BPAD from the Consortium on Lithium Genetics. For functional exploration, a cross-trait meta-GWAS and pathway analysis was performed, combining GWAS summary statistics on SCZ and response to treatment with lithium. Data analysis was performed from September 2016 to February 2017.Treatment response to lithium was defined on both the categorical and continuous scales using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. The effect measures include odds ratios and the proportion of variance explained.Of the 2586 patients in the study (mean [SD] age, 47.2 [13.9] years), 1478 were women and 1108 were men. The polygenic score for SCZ was inversely associated with lithium treatment response in the categorical outcome, at a threshold P<5×10-2. Patients with BPAD who had a low polygenic load for SCZ responded better to lithium, with odds ratios for lithium response ranging from 3.46 (95% CI, 1.42-8.41) at the first decile to 2.03 (95% CI, 0.86-4.81) at the ninth decile, compared with the patients in the 10th decile of SCZ risk. In the cross-trait meta-GWAS, 15 genetic loci that may have overlapping effects on lithium treatment response and susceptibility to SCZ were identified. Functional pathway and network analysis of these loci point to the HLA antigen complex and inflammatory cytokines.This study provides evidence for a negative association between high genetic loading for SCZ and poor response to lithium in patients with BPAD. These results suggest the potential for translational research aimed at personalized prescribing of lithium.
5.	Andersson, Ulrika, et al. (author) PERson-centredness in Hypertension management using Information Technology: a randomized controlled trial in primary care 2023 In: Journal of hypertension. - : LIPPINCOTT WILLIAMS & WILKINS. - 1473-5598 .- 0263-6352. ; 41:2, s. 246-253 Journal article (peer-reviewed)abstract OBJECTIVES: To increase the proportion of individuals with hypertension obtaining a blood pressure (BP) of less than 140/90mmHg by improving the management of hypertension in daily life from a person-centred perspective. METHODS: In this unblinded randomized controlled trial, we tested an interactive web-based self-management system for hypertension. A total of 949 patients with hypertension from 31 primary healthcare centres (PHCCs) in Sweden were randomized 1:1 to either the intervention or usual care group. The intervention included daily measurement - via the participant's mobile phone - of BP and pulse and reports of well being, symptoms, lifestyle, medication intake and side effects for eight consecutive weeks. It also included reminders and optional motivational messages. The primary outcome was the proportion of participants obtaining BP of less than 140/90mmHg at 8 weeks and 12months. Significance was tested by Pearson's chi 2 -test. RESULTS: A total of 862 patients completed the trial, 442 in the intervention group and 420 in the control group. The primary outcome (BP <140/90mmHg) at 8 weeks was achieved by 48.8% in the intervention group and 39.9% in the control group ( P =0.006). At 12months, 47.1% (intervention) and 41.0% (control group) had a BP less than 140/90mmHg ( P =0.071). CONCLUSION: The proportion of participants with a controlled BP of less than 140/90mmHg increased after using the interactive system for self-management of hypertension for 8 weeks compared with usual care. Although the trend continued, there was no significant difference after 12months. The results indicate that the effect of the intervention is significant, but the long-term effect is uncertain. TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov (NCT03554382).
6.	Andersson, Ulrika, et al. (author) PERSON-CENTREDNESS IN HYPERTENSION MANAGEMENT USING INFORMATION TECHNOLOGY (PERHIT) : A RANDOMISED CONTROLLED TRIAL IN PRIMARY HEALTH CARE 2022 In: Journal of Hypertension. - : Ovid Technologies (Wolters Kluwer Health). - 1473-5598 .- 0263-6352. ; 40, s. 197-197 Conference paper (other academic/artistic)abstract OBJECTIVE: Few studies address results from use of new technology and patient participation in hypertension management. The PERHIT Study is a multicentre randomised controlled trial with the aim to evaluate the effects of a person-centred approach using a web-based, interactive self-management system through the patient´s own mobile phone on blood-pressure and well-being. Primary aim is the degree of achieved blood pressure (BP) control after eight weeks and one year. In addition, person-centeredness, usefulness, daily life activities in relation to BP values, awareness of risk and health care costs are studied. DESIGN AND METHOD: The PERHIT study was performed in four regions in southern Sweden. Following inclusion, more than 900 patients from 31 primary health care centres were randomised to two groups. In the intervention group (INT), patients were provided with a web-based self-management support system including a home-BP monitor. For eight consecutive weeks, they measured BP and performed self-reports regarding well-being, symptoms, lifestyle, medication intake and side effects every evening via their mobile phone. They could also receive motivational messages and reminders throughout the intervention period. Both patients and professionals had access to graphic feedback of reported values through a secure web portal. Patients in the control (CON) group received standard treatment as usual. RESULTS: The primary outcome (BP < 140/90 mmHg) was achieved by 48.5% and 47.1% in the INT, and by 40.4% and 40.9% in the CON group after 8 weeks (p = 0.016) and 12 months (p = 0.067), respectively. Both patients and professionals experienced the system as a useful resource for communication regarding BP and lifestyle. They described that it could be used to support a constructive and person-centred partnership between patients and professionals. CONCLUSIONS: Blood pressure control was significantly better after eight weeks, but not after one year, following an intervention based on use of mobile phones, feedback and interaction between patients and primary care professionals compared to standard care. The system can be a tool toward a new way of working and help patients reach a controlled BP and play a role in a more person-centred and individually adapted hypertension management.
7.	Andersson, Ulrika, et al. (author) Reply to 'Examining the impact of E-health management on hypertension' 2023 In: Journal of Hypertension. - : LIPPINCOTT WILLIAMS & WILKINS. - 0263-6352 .- 1473-5598. ; 41:11, s. 1864-1864 Journal article (other academic/artistic)
8.	Björkman Lundberg, Kerstin, et al. (author) Compliance to National Guidelines for Pharmaceutical Treatment of Sleeping Disorders among Elderly Incident Patients in Sweden in PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, vol 20, issue , pp S203-S203 2011 In: PHARMACOEPIDEMIOLOGY AND DRUG SAFETY. - : John Wiley and Sons. ; , s. S203-S203 Conference paper (peer-reviewed)abstract Background:National guidelines for pharmaceutical treatmentof sleeping disorders among elderly state that zopicloneshould be the first choice and that other hypnotics,such as long acting benzodiazepines and propiomazine,should be avoided. According to aggregated data describingprevalent users compliance to guidelines is fairly high. Objectives:The objective of this study was to investigatechoice and volume (DDD) of substance among incidentusers 75 years and older (75+) of hypnotics (N05C) in Swedenand compare between different county councils andwith incident users below 75 years of age. Methods:Data from the Swedish Prescribed Drug registercovering all dispensed prescriptions in Sweden was analyzedfor incident users of hypnotics (15–44, 45–64, 65–74 and 75+ years of age). Incident users were defined aspeople who filled a prescription (index date) of a hypnotic(N05C) during the period December 2009 - November2010 and had not filled any prescription for a hypnotic duringa wash-out period of 24 months before the index date. Results:Among incident patients 75+ (n= 38,620) zopiclone(52.9%), zolpidem (25.4%), and propiomazine(10.4%) were the most frequently used hypnotics. Therewere however differences between different county councilsin Sweden, with zopiclone ranging from 30 % to 68 %. Theincidence for recommended and appropriate hypnoticsincreased with increasing age, whereas the incidence ofinappropriate hypnotics did not. The prescribed volume ofinappropriate hypnotics was generally larger than the prescribedvolume of recommended hypnotics. Conclusions:The compliance to current guidelines onchoice of hypnotics for the elderly is fairly good, althoughthere is considerable variation between county councils.There are tendencies towards larger mean volumes of inappropriatehypnotics, although further studies are needed toconfirm these findings. Another aspect of quality in treatmentwith sleeping agents is to which extent incident userscontinue their treatment and for how long. This is an issuefor further research.
9.	Blokland, G. A. M., et al. (author) Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders 2022 In: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 91:1, s. 102-117 Journal article (peer-reviewed)abstract Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. Results: Across disorders, genome-wide significant single nucleotide polymorphism–by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10−8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10−6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10−7; rs73033497, p = 8.8 × 10−7; rs7914279, p = 6.4 × 10−7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10−7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10−7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10−7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels. © 2021 Society of Biological Psychiatry
10.	Bäckryd, Emmanuel, et al. (author) Comment on Hauser et al. : Medical use of opioids in Europe - Methodological concerns about data from the International Narcotics Control Board 2022 In: European Journal of Pain. - : Wiley-Blackwell. - 1090-3801 .- 1532-2149. ; 26:4, s. 937-938 Journal article (other academic/artistic)abstract n/a
11.	Bäckryd, Emmanuel, 1974-, et al. (author) Dynamiken i förskrivningen av opioider i Sverige 2000–2015 - Markanta omfördelningar inom opioidgruppen, men ingen »epidemi« 2017 In: Läkartidningen. - : Läkartidningen Förlag. - 0023-7205 .- 1652-7518. ; 114 Journal article (peer-reviewed)abstract Opioid prescription changes in Sweden 2000-2015 In contrast to the well-established »opioid epidemic« in the US, very little is known about how the prescription of opioids in Sweden has developed during the last decade. Aggregated data from the open Statistical database of the Swedish Board of Health and Welfare were analyzed descriptively. The yearly prevalence of opioid prescription did not change 2006-2015, but there were dramatic shifts in the choice of opioids. During this period, dextropropoxyphene was pulled off the market. Tramadol was used by fewer individuals (-54 % over the decade), but dosages expressed as Defined Daily Dose/patient/year (DDD/pat/y) increased (+41 %). In contrast, oxycodone and morphine were used by more individuals (+465 % and +137 %, respectively), but DDD/pat/y decreased during the period (-56% and -54%). Studies on non-aggregated data from available registries are needed to further elucidate the circumstances and possible consequences of these shifts in opioid prescription patterns.
12.	Bäckryd, Emmanuel, Docent, 1974-, et al. (author) Många fallgropar i opioidstatistik 2021 In: Läkartidningen. - Stockholm, Sweden : Läkartidningen förlag AB. - 0023-7205 .- 1652-7518. ; 36/37 Journal article (other academic/artistic)
13.	Bäckryd, Emmanuel, et al. (author) Opioid availability statistics from the International Narcotics Control Board do not reflect the medical use of opioids : comparison with sales data from Scandinavia 2021 In: Scandinavian Journal of Pain. - : Walter de Gruyter GMBH. - 1877-8860 .- 1877-8879. ; 21:4, s. 696-706 Journal article (peer-reviewed)abstract Objectives: Opioid analgesics are essential in clinical practice, but their excessive use is associated with addiction risk. Increases in opioid prescription rates have fuelled an epidemic of opioid addiction in the USA, making statistics on medical opioid use a critical warning signal. A dramatic 150% increase in Swedish opioid access 2001-2013 was recently reported based on data from the International Narcotics Control Board (INCB; Berterame et al. 2016) in conflict with other studies of opioid use in the Nordic countries. This article aims to analyse to what degree published INCB statistics on opioids in Scandinavia (Denmark, Norway and Sweden) reflect actual medical use and study the methodological reasons for putative discrepancies. Methods: Data on aggregated total national sales of opioids for the whole population, including hospitals, were collected from the Swedish e-Health Authority. Total sales data for Denmark and drugs dispensed at pharmacies in Norway are publicly available through the relevant authorities websites. Results: INCB opioid statistics during the period 2001-2013 were markedly inconsistent with sales data from Scandinavia, calling the reliability of INCB data into question. INCB-data were flawed by (a) over-representing the volume of fentanyl, (b) under-reporting of codeine, and (c) by not including tramadol. Conclusions: Opioid availability, as expressed by INCB statistics, does not reflect medical opioid use. It is crucial to underline that INCB statistics are based on the manual compilation of national production, import and export data from manufacturers and drug companies. This is not the same amount that is prescribed and consumed within the health care system. Moreover, there are methodological problems in the INCB reports, in particular concerning fentanyl, codeine and tramadol. We suggest that INCB should carefully review the quality of their data on medical opioids.
14.	Carlsson, Per, et al. (author) Prioritering och finansiering av läkemedel för behandling av patienter med sällsynta sjukdomar : Reviderad version 2015 Reports (other academic/artistic)abstract I vilken utsträckning kan särskilda hänsyn tas vid prioritering av särläkemedel och läkemedel för behandling av sällsynta tillstånd? Bör man i vissa speciella situationer kunna acceptera sämre kostnadseffektivitet och lägre krav på vetenskapligt underlag? Om så, vad är det för villkor/kriterier som då bör vara uppfyllda? Hur stämmer ett sådant undantag med den etiska plattformen för prioriteringar? Finns det andra argument som talar för eller mot en särbehandling av sällsynta tillstånd? Detta är frågor som vi diskuterar i denna rapport som tagits fram på uppdrag av Läkemedels- och apoteksutredningen.I rapporten konstaterar vi att särläkemedel är en relativt heterogen grupp av läkemedel och att det finns andra läkemedel med motsvarande egenskaper som inte ansökt eller kunnat ansöka om status som särläkemedel. Ur prioriteringssynpunkt är det därför mer relevant att fokusera på alla typer av läkemedel, som används för sällsynta tillstånd, när vi diskuterar vilka principer för prioriteringar som bör gälla.Utifrån litteratur och erfarenheter i andra länder, som formulerat kriterier för en särskild hantering av läkemedel vid sällsynta sjukdomar, drar vi den preliminära slutsatsen att samhället bör kunna betala mer per hälsovinst (kostnad per kvalitetsjusterat levnadsår (QALY)) och acceptera lägre krav på vetenskapligt underlag vid prioritering av läkemedel för behandling av sällsynta sjukdomar om samtliga följande villkor är uppfyllda:att behandlingen har en hög kostnad per hälsovinst som en konsekvens av att den omfattar endast få patienter,att det rör sig om ett tillstånd med mycket stor svårighetsgrad,att det behandlingsalternativ som övervägs på goda grunder ska antas ha en väsentlig effekt,att det inte finns någon alternativ behandling med en väsentlig effekt som förväntas förebygga, bota, fördröja försämring eller lindra det aktuella tillståndet.Om dessa kriterier anses uppfyllda kan läkemedlet bedömas i relation till ett förhöjt tröskelvärde för kostnadseffektivitet. Hur högt detta värde kan vara för att anses rimligt tar vi inte ställning till i rapporten, men en viktig ståndpunkt är att det måste finnas en övre gräns för hur hög kostnad per QALY samhället kan acceptera. Detta bör gälla även om ovanstående kriterier är uppfyllda, annars riskerar det uppstå oacceptabla undanträngningseffekter av andra prioriterade åtgärder. Även lägre krav på vetenskapligt underlag ska kunna accepteras.Denna preliminära slutsats prövas sedan mot den svenska etiska plattformen och ur ett samhällsekonomiskt perspektiv. Våra slutsatser från den etiska analysen är att:Människovärdesprincipen tillåter att sällsynta tillstånd som ger upphov till höga behandlingskostnader kan särbehandlas och därmed kan vårt första kriterium accepteras utifrån den etiska plattformen. När ett högre tröskelvärde (kostnad per vunnen hälsovinst) för behandling av sällsynta tillstånd accepteras, så ges dessa patienter större likhet i tillgång till hälsa jämfört med andra patienter (under förutsättning att även andra kriterier är uppfyllda). Detta innebär dock inte automatiskt att alla sällsynta tillstånd som ger upphov till höga behandlingskostnader bör särbehandlas.Enligt behovs-solidaritetsprincipen bör samhället sträva efter att alla medborgare i så stor utsträckning som möjligt ges lika möjligheter till vård; men även att de uppnår en så lika nivå av hälsa som möjligt. Det senare förutsätter att vi i första hand prioriterar dem som ligger längst ifrån en sådan lika nivå, dvs. de med störst behov. För att vi ska kunna påverka möjligheter och utfall när det gäller hälsa krävs det att de åtgärder som används faktiskt kan påverka personer till att närma sig ett mer lika utfall, dvs. att dessa åtgärder har en väsentlig effekt på hälsan.Kostnadseffektivitetsprincipen säger att vid val mellan olika verksamhetsområden eller åtgärder bör en rimlig relation mellan kostnader och effekt eftersträvas. Det framgår att mycket svåra tillstånd ska gå före lindrigare tillstånd, även om åtgärderna gentemot de förra är förknippade med förhållandevis högre kostnader per hälsovinst. När ovanstående kriterier är uppfyllda för behandling av ett sällsynt tillstånd innebär det endast att behandlingen kan bli föremål för en bedömning av om ett höjt tröskelvärde kan accepteras. Det innebär alltså inte automatiskt att behandlingen bör erbjudas eller att ett läkemedel till exempel ska inkluderas i läkemedelsförmånerna. Även med dessa kriterier uppfyllda och att det därmed finns skäl för särbehandling av behandlingen, bör beslutfattaren även i det läget komma fram till vad som är en rimlig relation mellan kostnader och effekt, dvs. vilket som är ett acceptabelt tröskelvärde i den aktuella beslutssituationen.Sammanfattningsvis anser vi att dagens etiska plattform tillsammans med den modifiering av kostnadseffektivitetsprincipen, som finns i senare lagstiftning, ger möjlighet att ta särskilda hänsyn vid prioritering av läkemedel riktade till sällsynta och mycket svåra tillstånd. För att en särbehandling av ett läkemedel ska kunna övervägas bör det ha en väsentlig effekt på det aktuella tillståndet. Det är en skillnad mellan behandlingar som har dålig kostnadseffektivitet på grund av liten effekt respektive om de har det på grund av hög kostnad. Skillnaden motiveras utifrån att effektstorleken hos behandlingen påverkar dess möjlighet att bidra till ett utfall som ligger i linje med resten av befolkningens hälsa och livskvalitet, där en större effektstorlek närmar sig detta på ett bättre sätt. Vår tolkning är att om det finns två åtgärder med samma kostnadseffektivitetskvot och samma svårighetsgrad men där den ena har större effekt på tillståndet än den andra, så är den med störst effekt som ska ges företräde.Vi har även undersökt om det finns några argument utifrån samhällsekonomisk effektivitet som talar för eller emot en särbehandling av sällsynta tillstånd. Detta görs utifrån teoretisk och empirisk litteratur i ämnet och preliminära data från en svensk studie. Enligt vissa studier finns det ett samhälleligt värde i vetskapen om att människor blir omhändertagna oavsett situation och det skapar större trygghet och tillit till samhället utifrån dels ett egenintresse eftersom alla människor i ett samhälle löper en risk att drabbas av svåra tillstånd. Det finns också en altruistisk motivering som består i att människor i allmänhet kan påverkas positivt av att bara veta att de lever i ett barmhärtigt samhälle.Det finns dock inget stöd i renodlade empiriska studier för att människor i allmänhet anser att behandling av sällsynta sjukdomar, allt annat lika, ska särbehandlas. Med andra ord saknas empiriskt stöd för att sällsynthet i sig är ett relevant kriterium vid prioritering. Det var även slutsatsen av vår tidigare etiska argumentation kring detta (se Carlsson et al. 2012). Preliminära data från en pågående svensk studie kommer delvis fram till samma slutsats. När analysen i samma studie fördjupas och kompletteras med attitydfrågor och fokusgruppsintervjuer framträder dock en mer nyanserad bild, nämligen att om det rör sig om sällsynta tillstånd med hög svårighetsgrad, och det är den enda behandlingen, så kan stöd finnas för särbehandling.Efter att ha konstaterat att särskild hänsyn kan övervägas vid prioritering av läkemedel som ska användas vid svåra och sällsynta tillstånd utifrån den etiska plattformen och ur ett välfärdsekonomiskt perspektiv återstår att ta ställning till en rad praktiska överväganden vid utformning av procedurer för prioriteringar, nämligen:Utifrån målet att minska olikheter och garantera vård på lika villkor för sällsynta tillstånd är antagligen en modell med ett nationellt beslutsfattande att föredra. Samma principer för prioritering av läkemedel vid sällsynta och svåra tillstånd bör gälla oavsett hur läkemedlet når patienten, dvs. oavsett om detta sker som läkemedel på recept eller rekvisitionsläkemedel. Om prioriteringen görs av en eller flera instanser är en organisatorisk fråga som vi inte tar ställning till i denna rapport.Ur prioriteringssynpunkt bör det inte göras åtskillnad mellan särläkemedel och andra läkemedel som används för sällsynta tillstånd. När det gäller beslut om särläkemedel i allmänhet ska ingå i förmånssystemet bör de utvärderas och beslutas av Tandvård- och läkemedelsförmånsverket (TLV) på sedvanligt sätt medan vid sådana läkemedel som riktas mot tillstånd som både är mycket sällsynta och mycket svåra kan särskild hänsyn behöva tas och handläggas enligt en modifierad ordning. Detta bör avse såväl kostnaden per hälsovinst som hantering av osäkerhet i det vetenskapliga underlaget och bör gälla oavsett status som särläkemedel eller ej.I vissa situationer när det vetenskapliga underlaget är mycket osäkert uppstår problem vid ställningstagande om generell användning av dyra läkemedel för svår sjukdom på gruppnivå. Det förefaller i det läget rimligt att initialt ge visst avkall på evidensunderlaget för kostnadseffektivitet vid svåra sjukdomar när det av olika skäl inte ter sig möjligt av praktiska skäl att få fram ett sådant. Det kan dock finnas en konflikt i att både acceptera en högre betalningsvilja och dessutom acceptera en större osäkerhet i beslutsunderlaget. I sådana fall är det särskilt angeläget att sörja för en adekvat uppföljning för att så snart som möjligt försöka minska osäkerheten och eventuellt ompröva beslutet.De finns olika principer för hur en patientgrupp med mycket svåra och sällsynta tillstånd kan avgränsas. Gruppen kan dels
15.	Carlsson, Per, et al. (author) Prioritering och finansiering av läkemedel för behandling av patienter med sällsynta sjukdomar : Reviderad version 2012 Reports (other academic/artistic)abstract I ett tilläggsdirektiv till utredningen om vissa frågor om prissättning, tillgänglighet och marknadsförutsättningar inom läkemedels- och apoteksområdet (Dir. 2011:82) ingår att analysera behovet av särskilda lösningar vid beslut om subventionering för särläkemedel. Ett särläkemedel är ett läkemedel som uppfyller vissa villkor och därmed omfattas av särskilda stimulansåtgärder innan godkännande av läkemedelsmyndighet samt möjlighet, men inte rätt, till ensamrätt på marknaden under 10 år.I rapporten analyseras den etiska plattformen och läkemedelsförmånslagen, som är Tandvårds- och läkemedelsförmånsverkets (TLV) utgångspunkter för subventionsbeslut. En slutsats som dras är att dagens etiska plattform tillsammans med den modifiering av kostnadseffektivitetsprincipen, som finns i lagen om läkemedelsförmåner, ger möjlighet att komma till slutsatsen att samhället är berett att betala mer per hälsovinst för läkemedel riktade till mycket sällsynta och svåra sjukdomar/tillstånd.Människovärdesprincipen ger uttryck för att irrelevant grupptillhörighet eller gruppegenskap inte ska påverka en patientgrupps lika möjligheter och lika utfall när det gäller hälsa. Huruvida en patientgrupp är liten eller stor är en sådan irrelevant gruppegenskap och gruppens storlek eller tillståndets sällsynthet bör därmed inte påverka gruppens möjligheter till behandling eller till att kunna uppnå ett jämlikt hälsoutfall jämfört med andra större grupper eller grupper med mer vanliga sjukdomar. Däremot kan den konsekvens i form av höga kostnader för behandling som sällsynthet kan medföra, vara en grund för särbehandling.Behovs-solidaritetsprincipen ger dels uttryck för att alla medborgare bör ges lika möjligheter att uppnå god hälsa och dels uttryck för att vi bör uppnå ett så lika hälsoutfall som möjligt för medborgarna. Om vi låter utvecklingskostnaden för läkemedel mot sällsynta tillstånd påverka möjligheten att ta del av dessa läkemedel ges inte medborgarna lika möjligheter till att uppnå god hälsa. Utifrån detta drar vi slutsatsen att sällsynta och svåra tillstånd bör ges likartade möjligheter att uppnå god hälsa som vanliga och allvarliga tillstånd.Kostnadseffektivitetsprincipen. När en sämre kostnadseffektivitet främst beror på höga kostnader som framför allt är kopplade till storleken på den grupp som patienten tillhör dvs. storleken på marknaden för läkemedlet och inte på dålig effekt hos åtgärden finns det av rättviseskäl anledning att dels försöka påverka kostnadsaspekten av läkemedlet, dels i vissa fall acceptera en sämre kostnadseffektivitet. Kostnaden kan påverkas genom t.ex. prissättning på läkemedel efter särskilda avtal med det marknadsförande företaget.　Det finns ett värde i att veta att man lever i ett barmhärtigt samhälle som tar hand om och försöker hjälpa de människor som befinner sig i livshotande eller andra svåra situationer. Detta värde består dels i att vetskapen skapar större trygghet och tillit till samhället utifrån ett egenintresse eftersom vi alla kan löpa risk att drabbas av svåra tillstånd, dels utifrån en mer altruistisk motivering som består i att vi påverkas positivt av att bara veta att vi lever i ett barmhärtigt samhälle. Detta är en faktor som därför även borde vägas in i kostnadseffektivitetskalkyler. Storleken på detta värde är oklart.Särläkemedel är en relativt heterogen grupp och det finns andra läkemedel med motsvarande egenskaper som inte ansökt om status som särläkemedel. Ur prioriteringssynpunkt är det mer relevant att istället fokusera på läkemedel som används för sällsynta och svåra sjukdomar. Läkemedel vid mycket sällsynta och svåra tillstånd, särskilt när annan behandling saknas, bör därför handläggas i sär- skild ordning oavsett status som särläkemedel eller ej. För att säkerställa jämlik tillgång, transparenta beslut och god vård är en modell med nationellt beslutsfattande för sådana läkemedel att föredra. Tre alternativa principer för beslut och finansiering diskuteras: staten som huvudman, samarbete mellan stat och landsting samt samarbete mellan landstingen.
16.	Cearns, M., et al. (author) Using polygenic scores and clinical data for bipolar disorder patient stratification and lithium response prediction: machine learning approach 2022 In: British Journal of Psychiatry. - : Royal College of Psychiatrists. - 0007-1250 .- 1472-1465. ; 220:4, s. 219-228 Journal article (peer-reviewed)abstract Background Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment. Aims To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder. Method This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi(+)Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework. Results The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data. Conclusions Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.
17.	Cearns, Micah, et al. (author) Using polygenic scores and clinical data for bipolar disorder patient stratification and lithium response prediction: machine learning approach - CORRIGENDUM. 2022 In: The British journal of psychiatry : the journal of mental science. - : Royal College of Psychiatrists. - 1472-1465. ; 221:2 Journal article (peer-reviewed)
18.	Coombes, Brandon J, et al. (author) Association of Attention-Deficit/Hyperactivity Disorder and Depression Polygenic Scores with Lithium Response: A Consortium for Lithium Genetics Study. 2021 In: Complex psychiatry. - : S. Karger AG. - 2673-3005 .- 2673-298X. ; 7:3-4, s. 80-89 Journal article (peer-reviewed)abstract Response to lithium varies widely between individuals with bipolar disorder (BD). Polygenic risk scores (PRSs) can uncover pharmacogenomics effects and may help predict drug response. Patients (N = 2,510) with BD were assessed for long-term lithium response in the Consortium on Lithium Genetics using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. PRSs for attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), and schizophrenia (SCZ) were computed using lassosum and in a model including all three PRSs and other covariates, and the PRS of ADHD (β = -0.14; 95% confidence interval [CI]: -0.24 to -0.03; p value = 0.010) and MDD (β = -0.16; 95% CI: -0.27 to -0.04; p value = 0.005) predicted worse quantitative lithium response. A higher SCZ PRS was associated with higher rates of medication nonadherence (OR = 1.61; 95% CI: 1.34-1.93; p value = 2e-7). This study indicates that genetic risk for ADHD and depression may influence lithium treatment response. Interestingly, a higher SCZ PRS was associated with poor adherence, which can negatively impact treatment response. Incorporating genetic risk of ADHD, depression, and SCZ in combination with clinical risk may lead to better clinical care for patients with BD.
19.	de Jong, S, et al. (author) Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder 2018 In: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 1, s. 163- Journal article (peer-reviewed)abstract Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.
20.	Defrere, D., et al. (author) L'-band AGPM vector vortex coronagraph's first light on LBTI/LMIRCam 2014 In: Adaptive Optics Systems IV. - : SPIE. - 9780819496164 Conference paper (peer-reviewed)abstract We present the first observations obtained with the L'-band AGPM vortex coronagraph recently installed on LBTI/LMIRCam. The AGPM (Annular Groove Phase Mask) is a vector vortex coronagraph made from diamond subwavelength gratings. It is designed to improve the sensitivity and dynamic range of high-resolution imaging at very small inner working angles, down to 0.09 arcseconds in the case of LBTI/LMIRCam in the L' band. During the first hours on sky, we observed the young A5V star HR8799 with the goal to demonstrate the AGPM performance and assess its relevance for the ongoing LBTI planet survey (LEECH). Preliminary analyses of the data reveal the four known planets clearly at high SNR and provide unprecedented sensitivity limits in the inner planetary system (down to the diffraction limit of 0.09 arcseconds).
21.	Docherty, Anna R, et al. (author) GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors. 2023 In: The American journal of psychiatry. - : American Psychiatric Association Publishing. - 1535-7228 .- 0002-953X. ; 180:10, s. 723-738 Journal article (peer-reviewed)abstract Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures.This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses.Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors.This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.
22.	Erlandsson, Marcus, et al. (author) Surveillance of Antibiotic Resistance in ICUs in Southeastern Sweden 1999 In: Acta Anaesthesiol Scand. - : Wiley. ; 43:8, s. 815-820 Journal article (peer-reviewed)abstract Background: A study was designed to assess a computer-based program for continuous registration of antibiotic resistance, statistics concerning severity of illness, and consumption of antibacterial drugs. Methods: The frequency of antibiotic resistance among bacteria in eight ICUs in southeastern Sweden was investigated yearly from 1995 through 1997. The antibiotic consumption in the ICUs was registered as defined daily doses (DDD) and compared to severity of illness (APACHE-II scores). Results: There was a statistically significant increase in ampicillin resistance among Enterococcus spp. between 1996 and 1997, which was due to a shift from Enterococcus faecalis to Enterococcus faecium. A high prevalence of resistance among coagulase-negative staphylococci to oxacillin (≈ 70%), ciprofloxacin (≈ 50%), fucidic acid (≈ 50%) and netilmicin (≈ 30%) was seen in all ICUs during the whole study period. There was a statistically significant increase in ciprofloxacin resistance among Escherichia coli and Enterococcus spp. The resistance among Enterobacter spp. to cefotaxime decreased but this change was not statistically significant. Efforts were made to avoid betalactam antibiotics, except carbapenems, for treatment of infections caused by Enterobacter spp. and the consumption of cephalosporins decreased whereas the consumption of carbapenems increased. The total antibiotic consumption decreased by 2.5% during the study period. There was no correlation between APACHE II scores and antibiotic consumption. Conclusions: Each ICU within a hospital ought to have a program for "on-line" antibiotic resistance surveillance of drugs used in that unit so that changes in empirical treatment can be made when there is an increase in antibiotic-resistant isolates within that unit.
23.	Farnocchia, Davide, et al. (author) The Second International Asteroid Warning Network Timing Campaign: 2005 LW3 2023 In: The Planetary Science Journal. - : Institute of Physics (IOP). - 2632-3338. ; 4:11 Journal article (peer-reviewed)abstract The Earth close approach of near-Earth asteroid 2005 LW3 on 2022 November 23 represented a good opportunity for a second observing campaign to test the timing accuracy of astrometric observation. With 82 participating stations, the International Asteroid Warning Network collected 1046 observations of 2005 LW3 around the time of the close approach. Compared to the previous timing campaign targeting 2019 XS, some individual observers were able to significantly improve the accuracy of their reported observation times. In particular, U.S. surveys achieved good timing performance. However, no broad, systematic improvement was achieved compared to the previous campaign, with an overall negative bias persisting among the different observers. The calibration of observing times and the mitigation of timing errors should be important future considerations for observers and orbit computers, respectively.
24.	Godman, Brian, et al. (author) Utilisation Trend of Long-Acting Insulin Analogues including Biosimilars across Europe : Findings and Implications 2021 In: BioMed Research International. - : Hindawi Publishing Corporation. - 2314-6133 .- 2314-6141. ; 2021 Journal article (peer-reviewed)abstract Background. Diabetes mellitus rates and associated costs continue to rise across Europe enhancing health authority focus on its management. The risk of complications is enhanced by poor glycaemic control, with long-acting insulin analogues developed to reduce hypoglycaemia and improve patient convenience. There are concerns though with their considerably higher costs, but moderated by reductions in complications and associated costs. Biosimilars can help further reduce costs. However, to date, price reductions for biosimilar insulin glargine appear limited. In addition, the originator company has switched promotional efforts to more concentrated patented formulations to reduce the impact of biosimilars. There are also concerns with different devices between the manufacturers. As a result, there is a need to assess current utilisation rates for insulins, especially long-acting insulin analogues and biosimilars, and the rationale for patterns seen, among multiple European countries to provide future direction.Methodology. Health authority databases are examined to assess utilisation and expenditure patterns for insulins, including biosimilar insulin glargine. Explanations for patterns seen were provided by senior-level personnel.Results. Typically increasing use of long-acting insulin analogues across Europe including both Western and Central and Eastern European countries reflects perceived patient benefits despite higher prices. However, activities by the originator company to switch patients to more concentrated insulin glargine coupled with lowering prices towards biosimilars have limited biosimilar uptake, with biosimilars not currently launched in a minority of European countries. A number of activities were identified to address this. Enhancing the attractiveness of the biosimilar insulin market is essential to encourage other biosimilar manufacturers to enter the market as more long-acting insulin analogues lose their patents to benefit all key stakeholder groups.Conclusions. There are concerns with the availability and use of insulin glargine biosimilars among European countries despite lower costs. This can be addressed.
25.	Gudex, Claire, et al. (author) Praktiserende lægers opfattelse afInstitut for Rationel Farmakoterapi [GPs' perceptions of the Institute for Rational Pharmacotherapy] 2009 In: Ugeskrift for laeger. - 1603-6824. ; 171:7, s. 522-526 Journal article (peer-reviewed)abstract INTRODUCTION: A questionnaire study was conducted among Danish general practitioners (GPs) as part of an international evaluation of the Institute for Rational Pharmacotherapy (IRF). The aim was to investigate GPs' use and opinion of the IRF's activities. MATERIAL AND METHODS: A questionnaire was sent to a random sample of 500 GPs, who were asked about their level of knowledge and frequency of use of IRF's activities, as well as their opinion on the relevance, credibility and independence of the IRF's activities. RESULTS: The response rate was 59%. IRF is generally not the first source of information about new drugs, but is frequently used in the search for information about comparability between drugs and in relation to sudden drug warnings. IRF's Rational Pharmacotherapy bulletin and its GP courses, which nine out of ten GPs knew about, were considered to be highly relevant by 80% and 71%, respectively. All of IRF's activities were considered highly credible. Most GPs felt that the IRF's information increased their confidence in prescribing decisions (84%) and supported them in their role as a GP (88%). CONCLUSION: IRF's activities support the GP's prescribing role through the production of credible, neutral and evidence-based pharmacotherapeutic information that is not available elsewhere. IRF could further refine its dissemination methods, however, in order to reach more GPs and to increase the use of its information.
26.	Hammar, Tora, 1984-, et al. (author) Challenges with Medication Management and the National Medication List in Sweden : An Interview Study from a Human, Organizational, and Technology Perspective 2023 In: Caring is Sharing – Exploiting the Value in Data for Health and Innovation. - : IOS Press. - 9781643683881 ; , s. 287-291 Conference paper (peer-reviewed)abstract Sweden is in the process of implementing the National Medication List (NLL). The aim of this study was to explore the challenges with the medication management process, as well as expectation for NLL, from a human, organizational, and technology perspective. This study included interviews with prescribers, nurses, pharmacists, patients, and their relatives and was conducted during March to June 2020, before the implementation of NLL. Challenges were (1) feeling lost with several different medication lists, (2) spending time searching for information, (3) being frustrated at parallel information systems, (4) patients being the carriers of information, and (5) the feeling of being responsible in an indistinct process. The expectations for NLL in Sweden were high, but there were several fears.
27.	Herrera-Rivero, Marisol, et al. (author) Exploring the genetics of lithium response in bipolar disorders. 2023 In: Research square. Other publication (other academic/artistic)abstract Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N=2,064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II.We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism.Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.
28.	Herrera-Rivero, Marisol, et al. (author) Immunogenetics of lithium response and psychiatric phenotypes in patients with bipolar disorder. 2023 In: Research square. Other publication (other academic/artistic)abstract The link between bipolar disorder (BP) and immune dysfunction remains controversial. While epidemiological studies have long suggested an association, recent research has found only limited evidence of such a relationship. To clarify this, we investigated the contributions of immune-relevant genetic factors to the response to lithium (Li) treatment and the clinical presentation of BP. First, we assessed the association of a large collection of immune-related genes (4,925) with Li response, defined by the Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale), and clinical characteristics in patients with BP from the International Consortium on Lithium Genetics (ConLi+Gen, N = 2,374). Second, we calculated here previously published polygenic scores (PGSs) for immune-related traits and evaluated their associations with Li response and clinical features. We found several genes associated with Li response at p < 1×10- 4 values, including HAS3, CNTNAP5 and NFIB. Network and functional enrichment analyses uncovered an overrepresentation of pathways involved in cell adhesion and intercellular communication, which appear to converge on the well-known Li-induced inhibition of GSK-3β. We also found various genes associated with BP's age-at-onset, number of mood episodes, and presence of psychosis, substance abuse and/or suicidal ideation at the exploratory threshold. These included RTN4, XKR4, NRXN1, NRG1/3 and GRK5. Additionally, PGS analyses suggested serum FAS, ECP, TRANCE and cytokine ligands, amongst others, might represent potential circulating biomarkers of Li response and clinical presentation. Taken together, our results support the notion of a relatively weak association between immunity and clinically relevant features of BP at the genetic level.
29.	Hoffmann, Mikael, et al. (author) Changes in women’s attitudes towards and use of hormone therapy after HERS and WHI 2005 In: Maturitas. - : Elsevier. - 0378-5122 .- 1873-4111. ; 52:1, s. 11-17 Journal article (peer-reviewed)abstract Objectives:To assess changes in women's attitudes towards risk and benefits of, and use of hormone treatment in the menopausal transition (HT) before and after Heart and Estrogen/Progestin Replacement Study (HERS) and the oestrogen and progestin trial of Women's Health Initiative (WHI).Methods:Postal questionnaires to all women 53 and 54 years of age in a Swedish community in 1999 (n = 1.760) and 2003 (n = 1.733). Data on sales of HT were collected from the database of the National Corporation of Swedish Pharmacies.Results:The fraction of women reporting current use of HT fell from 40.5 to 25.3% (p < 0.001, χ2-test) both by fewer women starting and more women discontinuing treatment. This corresponded to a decrease in dispensation of HT in Linköping and nationwide for the same age group. The fraction of women who had tried complementary treatment for climacteric discomfort, increased from 9.6 to 18.1% for natural remedies (p < 0.001, χ2-test).Women perceived HT as more risky and less beneficial in 2003 as compared with 1999 (both p < 0.001, χ2-test). The most frequent source of information about HT during the last year before the 2003 questionnaire were newspaper or magazines (43.8%) and television or radio (31.7%).Conclusions:The decreased use of HT in the community correlated with pronounced changes in the attitudes towards HT. Media were a more frequent source of information than health care personnel. This indicates that media reports about major clinical studies might have influenced the use of HT among women.
30.	Hoffmann, Mikael, et al. (author) Do patients or their physicians more accurately assess long-term risk associated with hypertension? A population-based study 2020 In: Scandinavian Journal of Primary Health Care. - : Informa UK Limited. - 0281-3432 .- 1502-7724. ; 38:2, s. 166-175 Journal article (peer-reviewed)abstract Objective: To compare the assessments of 10-year probability by patients and their physicians of cardiovascular complications of hypertension with actual outcomes. Design: Patients with uncomplicated hypertension treated with at least one antihypertensive drug at inclusion were followed for 10 years through mandatory national health registers. Setting: 55 primary health care centres, 11 hospital outpatient clinics in Sweden Patients: 848 patient, 212 physicians. Main outcome measures: Patients and physicians estimated the probability of hypertension-related complications with treatment (death, heart failure, acute myocardial infarction/AMI, and stroke) for each patient in 848 pairs. Estimates were compared with the clinical outcomes 10 years later using data from the Mortality Register and the National Patient Register. Results: Patients were significantly better (p < 0.001) than their physicians in estimating the average probability of heart failure compared with actual outcome data (14% vs. 24%, outcome 15%), AMI (16% vs. 26%, outcome 8%), and stroke (15% vs. 25%, outcome 11%). Patients were significantly worse (p < 0.001) at estimating the average probability of death (10% vs. 18%, actual outcome 20%). Neither the patients nor the physicians were able to distinguish reliably between low-risk and high-risk patients after adjustment for age and sex. Conclusions: Patients were better than their physicians in estimating the average probability of morbidity due to hypertension. Both the patients and their attending physicians had difficulty in estimating the individual patient’s risk of complications. The results support the use of evidence-based tools in consultations for assessing the risk of cardiovascular complications associated with hypertension.Key points •Shared decision making relies on a common understanding of risks and benefits. Tools for risk assessment of hypertension have been introduced in the last two decades. •Without tools for risk assessment, both patients and physicians had difficulties in estimating the individual patient’s risk of cardiovascular morbidity. •Patients were better than physicians in estimating actual average cardiovascular morbidity due to hypertension during a follow-up of 10 years. •The results support the use of evidence-based tools in consultations for assessing the risk of cardiovascular complications associated with hypertension. © 2020, © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
31.	Hoffmann, Mikael, et al. (author) Guiding principles for the use of knowledge bases and real-world data in clinical decision support systems : report by an international expert workshop at Karolinska Institutet 2020 In: Expert Review of Clinical Pharmacology. - : Taylor & Francis. - 1751-2433 .- 1751-2441. ; 13:9, s. 925-934 Journal article (peer-reviewed)abstract Introduction Technical and logical breakthroughs have provided new opportunities in medicine to use knowledge bases and large-scale clinical data (real-world) at point-of-care as part of a learning healthcare system to diminish the knowledge-practice gap. Areas covered The article is based on presentations, discussions and recommendations from an international scientific workshop. Value, research needs and funding avenues of knowledge bases and access to real-world data as well as transparency and incorporation of patient perspectives are discussed. Expert opinion Evidence-based, publicly funded, well-structured and curated knowledge bases are of global importance. They ought to be considered as a public responsibility requiring transparency and handling of conflicts of interest. Information has to be made accessible for clinical decision support systems (CDSS) for healthcare staff and patients. Access to rich and real-world data is essential for a learning health care ecosystem and can be augmented by data on patient-reported outcomes and preferences. This field can progress by the establishment of an international policy group for developing a best practice guideline on the development, maintenance, governance, evaluation principles and financing of open-source knowledge bases and handling of real-world data.
32.	Hoffmann, Mikael, et al. (author) Hormone replacement therapy in the menopause - structure and content of risk talk 2005 In: Maturitas. - : Elsevier BV. - 0378-5122 .- 1873-4111. ; 50:1, s. 8-18 Journal article (peer-reviewed)abstract Objective: To investigate how risks and benefits of hormone replacement therapy (HRT) are communicated to women in clinical practice. To evaluate the usefulness of a risk classification based on context framing, i.e. whether the risk is discussed for one or several alternative treatments, and/or in the same context as possible benefits. Design: Analysis of structure and content of transcribed consultations (n=20) from first-time visits for discussion of climacteric discomfort and/or HRT with five physicians at three different out-patient clinics of gynecology. Results: All women received a prescription of HRT. An alternative to HRT was discussed in seven of the consultations. No decision aids were used. Risk discussion was dominated by the physicians giving information about long-time risk and benefits. The decision to prescribe was made either before the risk discussion was initiated, or before it was finished, in 8 of the 18 consultations where risk discussion was present. Risk classification according to context framing was performed and indicated use of different communication strategies by the physicians.Conclusions: The perspective of the physicians was mainly on prevention while the women were more focused on symptom alleviation. Each physician had a strategy of his/her own for the risk discussion. Thus, the major differences found between the consultations were between physicians, and not between the women. Risk discussion seemed to be aimed at motivating the woman to follow the physician’s decision rather than to help her participate in the decision-making process.
33.	Hoffmann, Mikael, 1960-, et al. (author) Incidence in pharmacoepidemiology : A conceptual framework for incidence of a single substance or group of substances with statins as an example 2023 In: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7835 .- 1742-7843. ; 132:2, s. 171-179 Journal article (peer-reviewed)abstract A framework for analysing incidence in pharmacoepidemiology and drug statistics is suggested using statins as an example. A new case of statin use (first-ever use or recurrence of treatment) can be defined as new on the group (NoG), new on substance whether new on the group or not (NoS), new on substance and new on the group (NoS_and_NoG), new on substance and not new on the group (NoS_not_NoG). MethodIndividual-level dispensations of statins 2006-2019 for 1 017 058 individuals with at least one dispensation 2019 in Sweden. ResultsWith 12-month run-in, corresponding to at least 8 months without treatment, the incidence proportion of NoG was 13.39 new cases per 1000 inhabitants and 8.40 with 10-year run-in. Thus, 37% had first been treated with any statin between 12 months and 10 years before the index date.For atorvastatin, NoS was 10.69, NoS_and_NoG 9.99, and NoS_not_NoG 0.70 per 1000 inhabitants. 0.70 per 1000 inhabitants or 6.6% of new cases of atorvastatin represented a change from another statin during the run-in. ConclusionIt is essential to separate new cases that are new both on the substance and on the group from those that represent a change of therapy during the run-in.
34.	Hoffmann, Mikael, et al. (author) Incidence in pharmacoepidemiology - Basic definitions and types of misclassification 2022 In: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7835 .- 1742-7843. ; 130:6, s. 632-643 Journal article (peer-reviewed)abstract The definition of a new case is a vital step in incidence studies in both epidemiology and pharmacoepidemiology, although with significant differences in methodology between the fields. We define and apply a framework for two different types of new cases of drug use, first-ever and recurrent, and show how the associated misclassifications related to length of run-in period can be expressed by the positive predictive value (PPV). In the study, we consider individual-level dispensations of statins 2006-2019 for 1,017,058 individuals with at least one dispensation in 2019 in Sweden. The incidence proportion for statins for both sexes of all ages in Sweden 2019 varied from 17.4/1000 with a run-in of 8 months, 9.45/1000 with 5 years and 8.4/1000 with 10 years. The PPV was 49% with 8 months and 89% for 5 years using 10 years as gold standard. We conclude that the interpretation of incidence and thus the selection of an appropriate run-in period, in pharmacoepidemiology, depends on whether first-ever use, recurrent treatment or both together (new cases) is the focus of the research question studied. At least five different misclassifications can be introduced depending on how incidence is defined.
35.	Hoffmann, Mikael, 1960-, et al. (author) Nationell process för värdering av off label-användning behövs 2020 In: Läkartidningen. - Stockholm, Sweden : Sveriges Läkarförbund. - 0023-7205 .- 1652-7518. ; 117 Journal article (peer-reviewed)abstract Läkemedelsverket rapporterar att man inte, utifrån sitt etablerade arbetssätt, kan genomföra nytta–riskvärdering av läkemedel utanför godkänd indikation. Sjukvården har ett behov av en nationell process för värdering av off label-användning av vissa läkemedel. Sjukvården behöver också fler och innovativa akademiskt drivna läkemedelsstudier.
36.	Hoffmann, Mikael, et al. (author) Risk communication in consultations about hormone therapy in the menopause – concordance in risk assessment and framing due to the context 2006 In: Climacteric. - : Informa UK Limited. - 1369-7137 .- 1473-0804. ; 9:5, s. 347-354 Journal article (peer-reviewed)abstract BackgroundIt is important for the physician and the patient to have a mutual understanding of the possible consequences of different treatment alternatives in order to achieve a partnership in decision making.ObjectiveThe aim of this study was to explore to which degree first-time consultations for discussion of climacteric discomfort achieved shared understanding of the risks and benefits associated with hormone therapy in the menopausal transition (HT).MethodsAnalysis of structure and content of transcribed consultations (n=20), and follow-up interviews of the women (n=19 pairs of consultations and interviews), from first-time visits for discussion of climacteric discomfort and/or HT with five physicians at three different out-patient clinics of gynaecology in Sweden.ResultsFour distinctively different interpretations of risk, depending on whether or not benefits were discussed in the same context, emerged from the analysis. On average 5 advantages (range 0-11) and 2 (0-3) disadvantages were mentioned during the consultations. In the interviews the women expressed on average 4 advantages (0-7) and 1 disadvantage (0-3). There were major variations between advantages and disadvantages expressed in the consultation and the following interview.ConclusionEven though the consultations scored high in patient involvement, the information in most consultations was not structured in a way that made it possible to achieve a shared or an informed decision making.
37.	Hoffmann, Mikael, et al. (author) Risk talk : rhetorical strategies in consultations on hormone replacement therap 2005 In: Health, Risk and Society. - Hants, UK : Carfax Publishing. - 1369-8575 .- 1469-8331. ; 5:2, s. 139-154 Journal article (peer-reviewed)abstract When analysing risk discussions in medical settings it is important to consider the specific activity type. In this qualitative study 20 first-time consultations by healthy women regarding hormone replacement therapy (HRT) in the menopause the risk discussion is asymmetrical with the doctors dominating. Despite being set up as a specific opportunity for women in the menopause to discuss problems and risks, it comes forth as a decision-making activity in a traditional medical setting. The consultations fulfil to a high extent the demands for informed decision making, but the risk discussions are recontextualised into a cost-benefit discourse with a typical implicit quantitative bias. The doctors use several different rhetorical strategies such as positive introduction of HRT, embedding drawbacks in positive introductions and/or exits thereby diminishing them. The word risk is avoided to a considerable extent and the term 'drawbacks' is used instead. The most obvious strategy is to move from the woman's symptoms to aspects of prevention, thus changing the discussion from the menopause and different strategies to cope with menopausal problems into a medically oriented discussion of pharmacological treatment alternatives. The 'change of life' in these talks is entirely conceptualised within a 'medical model'.
38.	Hoffmann, Mikael (author) Risk Talk : On Communicating Benefits and Harms in Health Care 2006 Doctoral thesis (other academic/artistic)abstract One of the most critical elements in empowering the patient, and ensuring concordance, is communication of the possible benefits and harms of different actions in health care. Risk assessment is a complex task due both to the different interpretations of the concept of risk, and the common lack of hard facts. Hormone, or hormone replacement, therapy (HT) is used by many women in, and after, the menopause. The benefits and possible harms associated with short and long term treatment with HT have been extensively discussed the last decade and the use of HT has decreased dramatically internationally the last few years.The aims of this thesis were to study the interaction between patient and physician when discussing risks and benefits of different treatment alternatives, and to suggest strategies to improve risk communication in clinical practice. The studies have focused on how risks and benefits with HT were communicated between women and physicians during firsttime consultations in 1999- 2000 on this subject (20 women, 5 gynaecologists), and through questionnaires how attitudes towards HT have changed between 1999 (n=1,760) and 2003 (n=1,733) among women entering the menopause (53-54 years).Through a qualitative analysis of the risk communication in the consultations a system was constructed to classify how risk is communicated in relation to benefits. This was used to assess and present differences in risk communication in the consultations. Different rhetorical strategies by the physicians were identified and the dominating tendency was a move from the woman’s current problems to the long-term effects of HT.The questionnaires showed a marked difference in attitudes towards HT between the years. In 2003 women perceived HT to be associated with higher risk and less benefits than in 1999. This correlated to a drastic reduction in the use of HT over the same period. Media was the most frequent source of information about HT during the last twelve months before the questionnaire in 2003.Possible explanations for the different attitudes towards HT between women entering the menopause and gynaecologist; how this difference might have influenced the results; and how they may have implications for future communication strategies are discussed. This thesis illustrates the importance of a deeper understanding in health care of the concept of risk in order to achieve an adequate communication of risk. This is important both in consultations and in campaigns to educate and inform the public.
39.	Hoffmann, Mikael (author) Slutreplik angående virtuell vård : Dags att skynda på införandet av telemedicin i all offentlig vård 2017 In: Läkartidningen. - : Sveriges Läkarforbund. - 0023-7205 .- 1652-7518. ; 114 Journal article (pop. science, debate, etc.)
40.	Hoffmann, Mikael (author) Timeline of and Expectations for the National Medication List in Sweden 2023 In: CARING IS SHARING-EXPLOITING THE VALUE IN DATA FOR HEALTH AND INNOVATION-PROCEEDINGS OF MIE 2023. - : IOS PRESS. - 9781643683898 ; , s. 327-331 Conference paper (peer-reviewed)abstract It is important to separate the continuous chains of medications orders (or decisions by the prescriber) in modern electronic health records from the one-way communication of prescriptions from healthcare to pharmacies. To support the self-administration of prescribed drugs the patient needs a continuously updated list of medication orders. For the NLL to function as a safe resource for the patient, it is necessary to have the information updated, curated, and documented by prescribers in a one-step process within the electronic health record. Four of the Nordic countries have chosen separate ways trying to achieve this. The experiences and obstacles during the introduction of the mandatory National Medication List (NLL) in Sweden and the resulting delays are described. The planned integration for 2022 is now delayed to 2025 and will probably only be achieved in 2028 or even 2030 in some regions.
41.	Hoffmann, Mikael, 1960-, et al. (author) Vårdpersonal bör vara öppna för att dra nytta av e-hälsa 2018 In: Läkartidningen. - Stockholm, Sweden : Läkartidningen Förlag AB. - 0023-7205 .- 1652-7518. ; 115 Journal article (other academic/artistic)abstract n/a
42.	Holmbom, Martin, et al. (author) 14-Year Survey in a Swedish County Reveals a Pronounced Increase in Bloodstream Infections (BSI). Comorbidity : An Independent Risk Factor for Both BSI and Mortality 2016 In: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 11:11 Journal article (peer-reviewed)abstract Objectives: we assessed the incidence, risk factors and outcome of BSI over a 14-year period (2000-2013) in a Swedish county.Methods: retrospective cohort study on culture confirmed BSI among patients in the county of Östergötland, Sweden, with approximately 440,000 inhabitants. A BSI was defined as either community-onset BSI (CO-BSI) or hospital-acquired BSI (HA-BSI).Results: of a total of 11,480 BSIs, 67% were CO-BSI and 33% HA-BSI. The incidence of BSI increased by 64% from 945 to 1,546 per 100,000 hospital admissions per year during the study period. The most prominent increase, 83% was observed within the CO-BSI cohort whilst HA-BSI increased by 32%. Prescriptions of antibiotics in outpatient care decreased with 24% from 422 to 322 prescriptions dispensed/1,000 inhabitants/year, whereas antibiotics prescribed in hospital increased by 67% (from 424 to 709 DDD per 1,000 days of care). The overall 30-day mortality for HA-BSIs was 17.2%, compared to 10.6% for CO-BSIs, with an average yearly increase per 100,000 hospital admissions of 2 and 5% respectively. The proportion of patients with one or more comorbidities, increased from 20.8 to 55.3%. In multivariate analyses, risk factors for mortality within 30 days were: HA-BSI (2.22); two or more comorbidities (1.89); single comorbidity (1.56); CO-BSI (1.21); male (1.05); and high age (1.04).Conclusion: this survey revealed an alarming increase in the incidence of BSI over the 14-year study period. Interventions to decrease BSI in general should be considered together with robust antibiotic stewardship programmes to avoid both over- and underuse of antibiotics.
43.	Hou, Liping, et al. (author) Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study. 2016 In: Lancet (London, England). - 1474-547X. ; 387:10023, s. 1085-1093 Journal article (peer-reviewed)abstract Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified.
44.	Hou, Liping, et al. (author) Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder. 2016 In: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 25:15, s. 3383-94 Journal article (peer-reviewed)abstract Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behavior. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ∼2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, p=5.87×10(-9); odds ratio=1.12) and markers within ERBB2 (rs2517959, p=4.53×10(-9); odds ratio=1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.
45.	Hughes, T., et al. (author) Elevated expression of a minor isoform of ANK3 is a risk factor for bipolar disorder 2018 In: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 8 Journal article (peer-reviewed)abstract Ankyrin-3 (ANK3) is one of the few genes that have been consistently identified as associated with bipolar disorder by multiple genome-wide association studies. However, the exact molecular basis of the association remains unknown. A rare loss-of-function splice-site SNP (rs41283526*G) in a minor isoform of ANK3 (incorporating exon ENSE00001786716) was recently identified as protective of bipolar disorder and schizophrenia. This suggests that an elevated expression of this isoform may be involved in the etiology of the disorders. In this study, we used novel approaches and data sets to test this hypothesis. First, we strengthen the statistical evidence supporting the allelic association by replicating the protective effect of the minor allele of rs41283526 in three additional large independent samples (meta-analysis pvalues: 6.8E-05 for bipolar disorder and 8.2E-04 for schizophrenia). Second, we confirm the hypothesis that both bipolar and schizophrenia patients have a significantly higher expression of this isoform than controls (p-values: 3.3E-05 for schizophrenia and 9.8E-04 for bipolar type I). Third, we determine the transcription start site for this minor isoform by Pacific Biosciences sequencing of full-length cDNA and show that it is primarily expressed in the corpus callosum. Finally, we combine genotype and expression data from a large Norwegian sample of psychiatric patients and controls, and show that the risk alleles in ANK3 identified by bipolar disorder GWAS are located near the transcription start site of this isoform and are significantly associated with its elevated expression. Together, these results point to the likely molecular mechanism underlying ANK3's association with bipolar disorder.
46.	Jacobs, Maartje S., et al. (author) Secondary adherence to non-vitamin-K antagonist oral anticoagulants in patients with atrial fibrillation in Sweden and the Netherlands 2018 In: Current Medical Research and Opinion. - : TAYLOR & FRANCIS LTD. - 0300-7995 .- 1473-4877. ; 34:10, s. 1839-1847 Journal article (peer-reviewed)abstract Objective: There is limited evidence on patients adherence and the impact of the prescribed dosing regimen in non-vitamin-K oral anticoagulants (NOACs). We aimed to assess secondary adherence to NOACs and to determine the impact of the dosing regimen in patients with atrial fibrillation. Methods: Patients using a NOAC between 2009 and 2013 were identified from the nation-wide Swedish Prescribed Drug Register and the Dutch regional IADB.nl database. Patients using a consistent dosage for at least 180 consecutive days were included. Adherence was calculated using the medication possession ratio (MPR) and adjusted for overlapping dates. Adherence was defined as a MPR amp;gt;= 0.8. Sensitivity analyses were performed using a MPR amp;gt;= 0.9. Logistic regression was performed to compare secondary adherence and to explore the influence of the dosing regimen. Results: A total of 5254 Swedish and 430 Dutch NOAC users were included. The mean MPR was 96.0% (SD 7.8%) in Sweden and 95.1% (SD 10.1%) in the Netherlands. Multivariable logistic regression analysis showed that a twice daily regimen had a lower likelihood of being secondary adherent compared to a once daily regimen in Sweden (odds ratio [OR] 0.21 [95% CI 0.12-0.35]). Limitations: The influence of selection bias introduced by the inclusion criterion of amp;gt;= 2 dispensations covering at least 180 days could not be excluded. Conclusions: This study demonstrated that secondary adherence was high in this specific setting among patients with at least two initial dispensations of a NOAC covering a minimum of 180 days. The use of NOACs in a once daily regimen showed higher adherence compared to a twice daily regimen.
47.	Järvstråt, Lotta, et al. (author) Use of hormone therapy in Swedish women aged 80 years or older 2015 In: Menopause. - 1072-3714 .- 1530-0374. ; 22:3, s. 275-278 Journal article (peer-reviewed)abstract Objective: Menopausal symptoms such as hot flashes and night sweats may persist for 10 to 20 years or even longer. Information about the extent to which older women use hormone therapy is limited. The aim of this study was to determine the use of hormone therapy in Swedish women aged 80 years or older.Methods: The study is based on national register data on dispensed drug prescriptions (ie, prescribed therapy that has been provided to individuals by pharmacies) for hormone therapy and local low-dose estrogens.Results: Of 310,923 Swedish women who were aged at least 80 years, 609 (0.2%) were new users of hormone therapy. A total of 2,361 women (0.8%) were current users of hormone therapy. The median duration of hormone therapy use in new users was 257 days (25th to 75th percentiles, 611-120 d). About one in six women aged 80 years or older had used local vaginal estrogen therapy for at least four 3-month periods. The drugs were mainly prescribed by gynecologists and general practitioners.Conclusions: Our results show that a number of women aged 80 years or older still use hormone therapy and that most women who started a new treatment period had only one or two dispensations despite the median duration of treatment being more than half a year. Because at least some of the women aged 80 years or older who used hormone therapy probably did so owing to persistent climacteric symptoms, vasomotor symptoms and hormone therapy are still relevant issues that need to be discussed when counseling women around and after age 80.
48.	Kalman, Janos L, et al. (author) Investigating polygenic burden in age at disease onset in bipolar disorder: Findings from an international multicentric study. 2019 In: Bipolar disorders. - : Wiley. - 1399-5618 .- 1398-5647. ; 21:1, s. 68-75 Journal article (peer-reviewed)abstract Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early-onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD- and schizophrenia (SCZ)-associated risk variants is associated with an earlier AAO in BD patients.A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn-Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18years] vs adulthood [>18years]) or considered as a continuous measure. The associations between BD- and SCZ-PRSs and AAO were evaluated with regression models.BD- and SCZ-PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment.The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype.
49.	Kelsoe, John, et al. (author) Lithium Response in Bipolar Disorder is Associated with Focal Adhesion and PI3K-Akt Networks: A Multi-omics Replication Study. 2023 In: Research square. Other publication (other academic/artistic)abstract Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2,039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.
50.	Kuimova, M. K., et al. (author) Determination of the triplet state energies of a series of conjugated porphyrin oligomers 2007 In: Photochemical and Photobiological Sciences. - : Springer Science and Business Media LLC. - 1474-9092 .- 1474-905X. ; 6:6, s. 675-682 Journal article (peer-reviewed)abstract We report a systematic study of the photophysical parameters relevant to photodynamic therapy (PDT) by a new type of sensitizers, conjugated porphyrin oligomers. Due to the strong nonlinear properties of oligomers containing 2, 4 and 8 porphyrin units, these molecules are attractive candidates for PDT via multiphoton excitation. The triplet state energy levels for all molecules have been determined by the triplet quenching method, phosphorescence measurements and DFT calculations. We find that the triplet energies of all the oligomers are sufficient to generate singlet oxygen, > 94 kJ mol(-1). However, low singlet oxygen quantum yields are observed for the tetramer and the octamer, as compared to the conjugated dimer and monomeric porphyrin, reflecting the decrease in triplet yield. Thus the conjugated porphyrin dimer is the most promising core structure for PDT applications via multiphoton excitation.

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