| 1. |
- Dellgren, Goeran, et al.
(författare)
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Effect of once-per-daytacrolimus versus twice-per-day ciclosporin on 3-year incidence of chronic lung allograft dysfunction after lung transplantation in Scandinavia (ScanCLAD): a multicentre randomised controlled trial
- 2024
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Ingår i: LANCET RESPIRATORY MEDICINE. - 2213-2600. ; 12:1, s. 34-44
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Tidskriftsartikel (refereegranskat)abstract
- Background Evidence is low regarding the choice of calcineurin inhibitor for immunosuppression after lung transplantation. We aimed to compare the use of tacrolimus once per day with ciclosporin twice per day according to the current definition of chronic lung allograft dysfunction (CLAD) after lung transplantation. Methods ScanCLAD is an investigator-initiated, open-label, multicentre, randomised, controlled trial in Scandinavia evaluating whether an immunosuppressive protocol based on anti-thymocyte globulin induction followed by tacrolimus (once per day), mycophenolate mofetil, and corticosteroids reduces the incidence of CLAD after de novo lung transplantation compared with a protocol using ciclosporin (twice per day), mycophenolate mofetil, and corticosteroids. Patients aged 18-70 years who were scheduled to undergo double lung transplantation were randomly allocated (1:1) to receive either oral ciclosporin (2-3 mg/kg before transplantation and 3 mg/kg [twice per day] from postoperative day 1) or oral tacrolimus (005-01 mg/kg before transplantation and 01-02 mg/kg from postoperative day 1). The primary endpoint was CLAD at 36 months post transplantation, determined by repeated lung function tests and adjudicated by an independent committee, and was assessed with a competing-risks analysis with death and re-transplantation as competing events. The primary outcome was assessed in the modified intention-to-treat (mITT) population, defined as those who underwent transplantation and received at least one dose of study drug. This study is registered at ClinicalTrials.gov (NCT02936505) and EudraCT (2015-004137-27). Findings Between Oct 21, 2016, and July 10, 2019, 383 patients were screened for eligibility. 249 patients underwent double lung transplantation and received at least one dose of study drug, and were thus included in the mITT population: 125 (50%) in the ciclosporin group and 124 (50%) in the tacrolimus group. The mITT population consisted of 138 (55%) men and 111 (45%) women, with a mean age of 552 years (SD 102), and no patients were lost to follow-up. In the mITT population, CLAD occurred in 48 patients (cumulative incidence 39% [95% CI 31-48]) in the ciclosporin group and 16 patients (13% [8-21]) in the tacrolimus group at 36 months post transplantation (hazard ratio [HR] 028 [95% CI 015-052], log-rank p<00001). Overall survival did not differ between groups at 3 years in the mITT population (74% [65-81] for ciclosporin vs 79% [70-85] for tacrolimus; HR 072 [95% CI 041-127], log-rank p=025). However, in the per protocol CLAD population (those in the mITT population who also had at least one post-baseline lung function test allowing assessment of CLAD), allograft survival was significantly better in the tacrolimus group (HR 049 [95% CI 026-091], log-rank p=0021). Adverse events totalled 1516 in the ciclosporin group and 1459 in the tacrolimus group. The most frequent adverse events were infection (453 events), acute rejection (165 events), and anaemia (129 events) in the ciclosporin group, and infection (568 events), anaemia (108 events), and acute rejection (98 events) in the tacrolimus group. 112 (90%) patients in the ciclosporin group and 108 (87%) in the tacrolimus group had at least one serious adverse event. Interpretation Immunosuppression based on use of tacrolimus once per day significantly reduced the incidence of CLAD compared with use of ciclosporin twice per day. These findings support the use of tacrolimus as the first choice of calcineurin inhibitor after lung transplantation.
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| 2. |
- Bausch, Birke, et al.
(författare)
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Clinical Characterization of the Pheochromocytoma and Paraganglioma Susceptibility Genes SDHA, TMEM127, MAX, and SDHAF2 for Gene-Informed Prevention
- 2017
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Ingår i: JAMA Oncology. - : AMER MEDICAL ASSOC. - 2374-2437 .- 2374-2445. ; 3:9, s. 1204-1212
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE Effective cancer prevention is based on accurate molecular diagnosis and results of genetic family screening, genotype-informed risk assessment, and tailored strategies for early diagnosis. The expanding etiology for hereditary pheochromocytomas and paragangliomas has recently included SDHA, TMEM127, MAX, and SDHAF2 as susceptibility genes. Clinical management guidelines for patients with germline mutations in these 4 newly included genes are lacking. OBJECTIVE To study the clinical spectra and age-related penetrance of individuals with mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes. DESIGN, SETTING, AND PATIENTS This study analyzed the prospective, longitudinally followed up European-American-Asian Pheochromocytoma-Paraganglioma Registry for prevalence of SDHA, TMEM127, MAX, and SDHAF2 germline mutation carriers from 1993 to 2016. Genetic predictive testing and clinical investigation by imaging from neck to pelvis was offered to mutation-positive registrants and their relatives to clinically characterize the pheochromocytoma/paraganglioma diseases associated with mutations of the 4 new genes. MAIN OUTCOMES AND MEASURES Prevalence and spectra of germline mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes were assessed. The clinical features of SDHA, TMEM127, MAX, and SDHAF2 disease were characterized. RESULTS Of 972 unrelated registrants without mutations in the classic pheochromocytoma- and paraganglioma-associated genes (632 female [65.0%] and 340 male [35.0%]; age range, 8-80; mean [SD] age, 41.0 [13.3] years), 58 (6.0%) carried germline mutations of interest, including 29 SDHA, 20 TMEM127, 8 MAX, and 1 SDHAF2. Fifty-three of 58 patients (91%) had familial, multiple, extra-adrenal, and/or malignant tumors and/or were younger than 40 years. Newly uncovered are 7 of 63 (11%) malignant pheochromocytomas and paragangliomas in SDHA and TMEM127 disease. SDHA disease occurred as early as 8 years of age. Extra-adrenal tumors occurred in 28 mutation carriers (48%) and in 23 of 29 SDHA mutation carriers (79%), particularly with head and neck paraganglioma. MAX disease occurred almost exclusively in the adrenal glands with frequently bilateral tumors. Penetrance in the largest subset, SDHA carriers, was 39% at 40 years of age and is statistically different in index patients (45%) vs mutation-carrying relatives (13%; P amp;lt; .001). CONCLUSIONS AND RELEVANCE The SDHA, TMEM127, MAX, and SDHAF2 genes may contribute to hereditary pheochromocytoma and paraganglioma. Genetic testing is recommended in patients at clinically high risk if the classic genes are mutation negative. Gene-specific prevention and/or early detection requires regular, systematic whole-body investigation.
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| 3. |
- Berg, Johan, et al.
(författare)
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Structural changes at the surface of cytochrome c oxidase alter the proton-pumping stoichiometry
- 2020
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Ingår i: Biochimica et Biophysica Acta - Bioenergetics. - : Elsevier BV. - 0005-2728 .- 1879-2650. ; 1861:2
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Tidskriftsartikel (refereegranskat)abstract
- Data from earlier studies showed that minor structural changes at the surface of cytochrome c oxidase, in one of the proton-input pathways (the D pathway), result in dramatically decreased activity and a lower proton-pumping stoichiometry. To further investigate how changes around the D pathway orifice influence functionality of the enzyme, here we modified the nearby C-terminal loop of subunit I of the Rhodobacter sphaeroides cytochrome c oxidase. Removal of 16 residues from this flexible surface loop resulted in a decrease in the proton-pumping stoichiometry to <50% of that of the wild-type enzyme. Replacement of the protonatable residue Glu552, part of the same loop, by an Ala, resulted in a similar decrease in the proton-pumping stoichiometry without loss of the O2-reduction activity or changes in the proton-uptake kinetics. The data show that minor structural changes at the orifice of the D pathway, at a distance of ~40 Å from the proton gate of cytochrome c oxidase, may alter the proton-pumping stoichiometry of the enzyme.
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| 4. |
- Berndtsson, Mikael, et al.
(författare)
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13 Organizations' Attempts to Become Data-Driven
- 2020
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Ingår i: International Journal of Business Intelligence Research. - : IGI Global. - 1947-3591 .- 1947-3605. ; 11:1, s. 1-21
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Tidskriftsartikel (refereegranskat)abstract
- Becoming a data-driven organization is a vision for several organizations. It has been frequently mentioned in the literature that data-driven organizations are likely to be more successful than organizations that mostly make decisions on gut feeling. However, few organizations make a successful shift to become data-driven, due to a number of different types of barriers. This article investigates, the initial journey to become a data-driven organization for 13 organizations. Data has been collected via documents and interviews, and then analyzed with respect to: i) how they scaled up the usage of analytics to become data-driven; ii) strategies developed; iii) barriers encountered; and iv) usage of an overall change process. The findings are that most organizations start their journey via a pilot project, take shortcuts when developing strategies, encounter previously reported top barriers, and do not use an overall change management process.
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| 5. |
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| 6. |
- Björklund, Erland, et al.
(författare)
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Förekomst av läkemedel och antibiotika i avloppsvattnet på Skånes Universitetssjukhus (SUS) i Lund
- 2019
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Bok (övrigt vetenskapligt/konstnärligt)abstract
- Under våren 2017 togs prover på avloppsvatten från Skånes Universitetssjukhus (SUS) i Lund i samarbete mellan Region Skåne och Högskolan Kristianstad (HKR). Totalt analyserades fyraprovpunkter med avseende på förekomst av 23 läkemedel, antibiotika och andra mikroföroreningar. De fyra provpunkterna var 1. Pumpgrop för uppsamling, 2. Onkologen, 3. Infektion samt 4. Avlopp från Centralblocket. Resultaten redovisas baserat på olika behandlingsfunktion, vilketinnefattar grupperna J - Antiinfektiva medel för systemiskt bruk, C - Hjärta och Kretslopp, N -Nervsystemet, M - Rörelseapparaten samt övriga ämnen. Resultaten visar att vissa läkemedelsläpps ut från SUS i högre koncentration jämfört med utgående avloppsvatten från ettreningsverk (se rapporten ”Läkemedelsutsläpp från Skånska avloppsreningsverk 2017” nedan). Noterbara ämnen är ciprofloxacin, sulfamethoxazole och trimethoprim, samtligaantibiotika. Resultaten vi-sar också att olika avdelningar medicinerar sina patientgrupper olika och att avdelningarna därmed kan vara lokala punktkällor för vissa typer av antibiotika. Koncentrationen av läkemdelsrester i avloppsvattnet påverkas förstås också av den totala vattenanvändningen, som i sin tur är en konsekvens av antal anställda, antal patienter, antal toaletter och arbetsmetoder/vattenanvänd-ning per avloppsspunkt mm. De uppmätta halternavisar att det är önskvärt, i en uppföljande studie, att analysera och fastställa, företrädesvis för antibiotika, vilka andra preparat som används på SUS, och i vilken omfattning. Det är viktigt att poängtera att resultaten från denna undersökning kommer från ett provtagningstillfälle där provtagningen bestod av ett stickprov. En uppföljande studie behöver innehålla fler analystillfällen samt söka svar på om förekomsten av höga halter av antibiotika kan föranleda resistensutveckling i sjukhusens avloppssystem. Vidare behöver man undersöka vilka eventuella åtgärder som behöver vidtas, vid sjukhusen och/eller vid avloppsreningsverken, för att förhindra att höga halter av läkemedelsrester belastar vattenmiljön med dess djur och växtliv. Hänsyn måste då också tas inte bara till vilka ämnen som specifikt härrör från sjukhuset utan också i vilka mängder och i vilken omfattning de når reningsverket i aktiv form.
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| 7. |
- Christofer Juhlin, C., et al.
(författare)
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Whole-exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT2D as a recurrently mutated gene
- 2015
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley: 12 months. - 1045-2257 .- 1098-2264. ; 54:9, s. 542-554
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Tidskriftsartikel (refereegranskat)abstract
- As subsets of pheochromocytomas (PCCs) lack a defined molecular etiology, we sought to characterize the mutational landscape of PCCs to identify novel gene candidates involved in disease development. A discovery cohort of 15 PCCs wild type for mutations in PCC susceptibility genes underwent whole-exome sequencing, and an additional 83 PCCs served as a verification cohort for targeted sequencing of candidate mutations. A low rate of nonsilent single nucleotide variants (SNVs) was detected (6.1/sample). Somatic HRAS and EPAS1 mutations were observed in one case each, whereas the remaining 13 cases did not exhibit variants in established PCC genes. SNVs aggregated in apoptosis-related pathways, and mutations in COSMIC genes not previously reported in PCCs included ZAN, MITF, WDTC1, and CAMTA1. Two somatic mutations and one constitutional variant in the well-established cancer gene lysine (K)-specific methyltransferase 2D (KMT2D, MLL2) were discovered in one sample each, prompting KMT2D screening using focused exome-sequencing in the verification cohort. An additional 11 PCCs displayed KMT2D variants, of which two were recurrent. In total, missense KMT2D variants were found in 14 (11 somatic, two constitutional, one undetermined) of 99 PCCs (14%). Five cases displayed somatic mutations in the functional FYR/SET domains of KMT2D, constituting 36% of all KMT2D-mutated PCCs. KMT2D expression was upregulated in PCCs compared to normal adrenals, and KMT2D overexpression positively affected cell migration in a PCC cell line. We conclude that KMT2D represents a recurrently mutated gene with potential implication for PCC development. (c) 2015 The Authors. Genes, Chromosomes and Cancer Published by Wiley Periodicals, Inc.
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| 8. |
- Damm, Margareta, 1946, et al.
(författare)
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Minskad sjukfrånvaro : en fråga om arbetsgivarincitament? Medfinansieringsreformen ur ett arbetsgivarperspektiv
- 2008
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Studien utvärderar medfinansieringsreformen som kom att gälla 2004-2006 och vars intention var att med ekonomiska incitament få arbetsgivare att ta ett ökat ansvar för att minska den sjukfrånvaro som i början av seklet ansågs mycket stor. För att förklara ar-betsgivarnas förhållningssätt besvaras först följande frågor: • Vad gör arbetsgivarna för att de anställda inte skall vara frånvarande från arbetet? Hur har de på denna punkt eventuellt förändrat sitt handlande på grund av refor-men? • Hur påverkas jämställdheten av de nya incitamenten, till exempel med hänsyn taget till att kvinnor vanligtvis står för högre andel av sjukfrånvaro? • Hur förhåller sig arbetsgivarna till ekonomiska analyser och kalkyler av sjukfrånvaron och reformen? Vilka ekonomiska resultat kan skönjas? • Hur ser arbetsgivarna efter reformens genomförande på sitt ansvar att förebygga ohälsa och vidta rehabiliterande insatser? Har reformen förändrat synsättet? Frågorna besvaras dels med hjälp av en enkät och dels med en serie fallstudier från företag och förvaltningar. I analysen dras slutsatsen att arbetsgivare, oavsett reformen, tar ansvar för att åtgärder som antas förebygga ohälsa eller rehabilitera sjuka genomförs, men att de vare sig kan eller vill, annat än marginellt, ta ansvar för sjukfrånvaron och dess orsaker.
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