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  • Andre, Malin, et al. (författare)
  • Diagnosis-prescribing surveys in 2000, 2002 and 2005 in Swedish general practice: Consultations, diagnosis, diagnostics and treatment choices
  • 2008
  • Ingår i: Scandinavian Journal of Infectious Diseases. - : Informa Healthcare. - 1651-1980 .- 0036-5548. ; 40:8, s. 648-654
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of this study is to present diagnostic patterns, diagnostics used and antibiotic treatment in relation to guidelines in 3 repeated diagnosis-prescription studies conducted simultaneously in general practice in 5 Swedish counties, during 1 week in November 2000, 2002 and 2005. General practitioners (GPs) at the participating health centres were asked to complete a form for all patients with symptoms of an infectious disease. During the studied periods a total of 15,371 consultations was registered. Consultations with GPs diagnosed as respiratory tract infection (RTI), especially consultations for sore throat, decreased considerably between y 2000 and 2005. The percentage of patients allocated an RTI diagnosis and prescribed an antibiotic declined significantly from 54% to 49% and the decline was most pronounced among children. Penicillin V remained the dominant antibiotic prescribed throughout the study periods. For lower urinary tract infections there was a significant change in choice of prescribed antibiotics with an increase for pivmecillinam and nitrofurantoin and a decrease for trimethoprim, in accordance with recommendations. The results indicate a quite close adherence to current guidelines, with changes in the pattern of consultations as well as in the management of infectious diseases in general practice in Sweden.
  • André, Malin, et al. (författare)
  • Upper respiratory tract infections in general practice: diagnosis, antibiotic prescribing, duration of symptoms and use of diagnostic tests
  • 2002
  • Ingår i: Scandinavian Journal of Infectious Diseases. - : Taylor & Francis. - 2374-4235 .- 0036-5548 .- 1651-1980. ; 34:12, s. 880-886
  • Tidskriftsartikel (refereegranskat)abstract
    • A diagnosis/antibiotic prescribing study was performed in 5 counties in Sweden for 1 week in November 2000. As part of this study, the characteristics and clinical management of patients with upper respiratory tract infections (n = 2899) in primary care were analyzed. Almost half of the patients were aged < 15 y and one-fifth of the patients consulted out of hours. Of all patients seeking primary care for upper respiratory tract infections, 56.0% were prescribed an antibiotic. Almost all patients who were given the diagnoses streptococcal tonsillitis, acute otitis media or acute sinusitis were prescribed antibiotics, compared to 10% of patients with common cold or acute pharyngitis. The most frequently prescribed antibiotic was penicillin V (79.2%) and this was even more pronounced out of hours, when the diagnoses otitis media and streptococcal tonsillitis were more frequently used. In patients with common cold and acute pharyngitis, the percentage who received antibiotics increased with increasing length of symptoms and increasing CRP levels. In patients with acute pharyngitis or streptococcal tonsillitis, antibiotics were prescribed less frequently provided streptococcal tests were performed. The management of patients with upper respiratory tract infections in general practice seems to be in good agreement with current Swedish guidelines. However, the study indicates some areas for improvement. The diagnosis of acute sinusitis seems to have been overestimated and used only to justify antibiotic treatment.
  • Herold, Nikolas, et al. (författare)
  • Targeting SAMHD1 with the Vpx protein to improve cytarabine therapy for hematological malignancies
  • 2017
  • Ingår i: Nature Medicine. - 1078-8956 .- 1546-170X. ; 23:2, s. 256-263
  • Tidskriftsartikel (refereegranskat)abstract
    • The cytostatic deoxycytidine analog cytarabine (ara-C) is the most active agent available against acute myelogenous leukemia (AML). Together with anthracyclines, ara-C forms the backbone of AML treatment for children and adults'. In AML, both the cytotoxicity of ara-C in vitro and the clinical response to ara-C therapy are correlated with the ability of AML blasts to accumulate the active metabolite ara-C triphosphate (ara-CTP)(2-5), which causes DNA damage through perturbation of DNA synthesis(6). Differences in expression levels of known transporters or metabolic enzymes relevant to ara-C only partially account for patient-specific differential ara-CTP accumulation in AML blasts and response to ara-C treatment(7-9). Here we demonstrate that the deoxynucleoside triphosphate (dNTP) triphosphohydrolase SAM domain and HD domain 1 (SAMHD1) promotes the detoxification of intracellular ara-CTP pools. Recombinant SAMHD1 exhibited ara-CTPase activity in vitro, and cells in which SAMHD1 expression was transiently reduced by treatment with the simian immunodeficiency virus (SIV) protein Vpx were dramatically more sensitive to ara-C-induced cytotoxicity. CRISPR-Cas9-mediated disruption of the gene encoding SAMHD1 sensitized cells to ara-C, and this sensitivity could be abrogated by ectopic expression of wild-type (WT), but not dNTPase-deficient, SAMHD1. Mouse models of AML lacking SAMHD1 were hypersensitive to ara-C, and treatment ex vivo with Vpx sensitized primary patient derived AML blasts to ara-C. Finally, we identified SAMHD1 as a risk factor in cohorts of both pediatric and adult patients with de novo AML who received ara-C treatment. Thus, SAMHD1 expression levels dictate patient sensitivity to ara-C, providing proof-of-concept that the targeting of SAMHD1 by Vpx could be an attractive therapeutic strategy for potentiating ara-C efficacy in hematological malignancies.
  • Rudd, Sean G., et al. (författare)
  • Ribonucleotide reductase inhibitors suppress SAMHD1 ara-CTPase activity enhancing cytarabine efficacy
  • 2020
  • Ingår i: EMBO Molecular Medicine. - : Blackwell Publishing Ltd. - 1757-4676 .- 1757-4684. ; 12:3
  • Tidskriftsartikel (refereegranskat)abstract
    • The deoxycytidine analogue cytarabine (ara-C) remains the backbone treatment of acute myeloid leukaemia (AML) as well as other haematological and lymphoid malignancies, but must be combined with other chemotherapeutics to achieve cure. Yet, the underlying mechanism dictating synergistic efficacy of combination chemotherapy remains largely unknown. The dNTPase SAMHD1, which regulates dNTP homoeostasis antagonistically to ribonucleotide reductase (RNR), limits ara-C efficacy by hydrolysing the active triphosphate metabolite ara-CTP. Here, we report that clinically used inhibitors of RNR, such as gemcitabine and hydroxyurea, overcome the SAMHD1-mediated barrier to ara-C efficacy in primary blasts and mouse models of AML, displaying SAMHD1-dependent synergy with ara-C. We present evidence that this is mediated by dNTP pool imbalances leading to allosteric reduction of SAMHD1 ara-CTPase activity. Thus, SAMHD1 constitutes a novel biomarker for combination therapies of ara-C and RNR inhibitors with immediate consequences for clinical practice to improve treatment of AML.
  • Andre, Malin, et al. (författare)
  • Management of urinary tract infections in primary care: : a repeated 1-week diagnosis-prescribing study in five counties in Sweden in 2000 and 2002.
  • 2004
  • Ingår i: Scandinavian Journal of Infectious Diseases. - : Informa Healthcare. - 0036-5548 .- 1651-1980. ; 36:2, s. 134-138
  • Tidskriftsartikel (refereegranskat)abstract
    • A diagnosis-antibiotic prescribing study was performed in 5 counties in Sweden during 1 week in November in the y 2000 and 2002, respectively. As part of the study, the characteristics and clinical management of patients who received diagnoses of urinary tract infections (UTIs) (n = 1564) in primary care, were analysed. 85% of the visits were by women, and 74% of all consultations were diagnosed as lower UTIs. One or more diagnostic tests were performed in 98% of the women with suspected lower or recurrent UTIs and 95% were prescribed an antibiotic. The most commonly prescribed antibiotics for lower UTIs were trimethoprim followed by pivmecillinam and a quinolone. The study indicated a change in antibiotic prescribing with improved adherence to the national recommendations. There was an increase of prescribed nitrofurantoin and a decrease of prescribed quinolones to women with lower UTIs between the studied y. Furthermore, 3-d treatment with trimethoprim increased although the prescribed duration was mostly 7 d. In contrast to the guidelines, few urine cultures were performed. The study highlights the necessity of updating the guidelines for the management of lower UTIs in general practice.
  • André, Malin, et al. (författare)
  • The management of infections in children in general practice in Sweden. : a repeated 1-week diagnosis-prescribing study in 5 counties in 2000 and 2002.
  • 2005
  • Ingår i: The Journal of Infectious Diseases. - : Informa Healthcare. - 0022-1899 .- 0036-5548 .- 1651-1980. ; 37:11-12, s. 863-869
  • Tidskriftsartikel (refereegranskat)abstract
    • A diagnosis-prescribing study was performed in 5 Swedish counties during 1 week in November in 2000 and repeated in 2002. The aim of the present study was to analyse data for children 0-15y of age who consulted a general practitioner with symptoms of an infection. During the 2 weeks studied, 4049 children were consulted. Respiratory tract infections (RTI) were the predominant diagnoses, above all among the youngest children, while the proportion of urinary tract infections and skin infections increased with increasing age. Between the y 2000 and 2002, the proportion of children allocated the diagnosis streptococcal tonsillitis and pneumonia decreased (p<0.01 and p<0.001, respectively) while the proportion of common cold increased (p<0.001). Antibiotic prescribing decreased from 55% to 48% (p<0.001) for respiratory infections between the years studied. The only significant changes in type of antibiotics prescribed were the increase of isoxazolylpenicillins (p<0.001) used for skin infection and the decrease of macrolides (p=0.001). A diagnostic test was used in more than half of the consultations. Of children allocated a RTI diagnosis, 36% were prescribed antibiotics when a C-reactive protein test was performed compared to 58% in those not tested. Further studies are needed in general practice to determine the optimal use of near-patient tests in children with RTI.
  • André, Malin, et al. (författare)
  • The use of CRP tests in patients with respiratory tract infections in primary care in Sweden care can be questioned.
  • 2004
  • Ingår i: Scandinavian Journal of Infectious Diseases. - 0036-5548. ; 36:3, s. 192-197
  • Tidskriftsartikel (refereegranskat)abstract
    • A diagnosis-antibiotic prescribing study was performed in 5 counties in Sweden during 1 week in November in 2000 and 2002 respectively. As a part of the study, the use and results of C-reactive protein (CRP) tests in relation to duration of symptoms and antibiotic prescribing in 6778 patients assigned a diagnosis of respiratory tract infections were analysed. In almost half (42%) of the patients, a CRP test was performed. The majority of CRP tests (69%) were performed in patients assigned diagnosis upper respiratory tract infection, where the test is not recommended. Overall, there was a minor decrease in antibiotic prescribing when CRP was used (41%), in comparison to 44% of the patients where no CRP was performed (p < 0.01). Patients assigned diagnoses implying a bacterial aetiology were prescribed antibiotics irrespective of result of CRP or length of symptoms before consultation. For patients assigned viral diagnoses, antibiotic prescribing increased with increasing duration of symptoms and increasing value of CRP. The use of CRP decreased antibiotic prescribing in patients assigned to viral diagnoses and with longstanding symptoms (p < 0.001). However, 59% of the patients assigned viral diagnoses with CRP > or = 25 received antibiotics, which seems to indicate a misinterpretation of CRP and a non-optimal use of antibiotics.
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