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1.	Birhanu, Muluken, et al. (author) Antimicrobial susceptibility in Neisseria gonorrhoeae and epidemiological data of gonorrhoea patients in five cities across Ethiopia, 2021-22 2024 In: JAC - Antimicrobial Resistance. - : Oxford University Press. - 2632-1823. ; 6:1 Journal article (peer-reviewed)abstract INTRODUCTION: Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a global public health concern and enhanced global gonococcal AMR surveillance is imperative. As in many African countries, regular, representative and quality-assured gonococcal AMR is lacking in Ethiopia. We describe the AMR in gonococcal isolates from five cities across Ethiopia, 2021-22, and patient epidemiological data.METHODS: Urethral discharge from males and cervical discharge from females were collected from October 2021 to September 2022. Epidemiological data were collected using a questionnaire. MIC determination (ETEST; eight antimicrobials) was performed on gonococcal isolates and EUCAST breakpoints (v13.1) were used.RESULTS: From 1142 urogenital swab samples, 299 species-identified gonococcal isolates were identified; 78.3% were from males and 21.7% from females. The median age for males and females was 25 and 23 years, respectively. Most isolates (61.2%) were identified in Addis Ababa, followed by Gondar (11.4%), Adama (10.4%), Bahir Dar (10.0%) and Jimma (7.0%). The resistance level to ciprofloxacin, tetracycline and benzylpenicillin was 97.0%, 97.0% and 87.6%, respectively, and 87.6% of isolates were producing β-lactamase. All isolates were susceptible to ceftriaxone, cefixime, azithromycin and spectinomycin. Recommended therapy [ceftriaxone (250 mg) plus azithromycin (1 g)] was used for 84.2% of patients.CONCLUSIONS: We present the first national quality-assured gonococcal AMR data from Ethiopia. Resistance levels to ciprofloxacin, tetracycline and benzylpenicillin were exceedingly high. However, all isolates were susceptible to ceftriaxone, cefixime, azithromycin and spectinomycin. In Ethiopia, it is essential to strengthen the gonococcal AMR surveillance by including further epidemiological data, more isolates from different cities, and WGS.
2.	Aberšek, Nina, et al. (author) Calprotectin levels in amniotic fluid in relation to intra-amniotic inflammation and infection in women with preterm labor with intact membranes: A retrospective cohort study 2022 In: European Journal of Obstetrics & Gynecology and Reproductive Biology. - : Elsevier BV. - 1872-7654 .- 0301-2115. ; 272, s. 24-29 Journal article (peer-reviewed)abstract Objective: To evaluate the concentrations of calprotectin in amniotic fluid with respect to intra-amniotic inflammation and infection and to assess the presence or absence of bacteria in the amnio-chorionic niche with respect to presence or absence of intra-amniotic inflammation. Study design: Seventy-nine women with singleton pregnancies and preterm labor with intact membranes (PTL) were included in the study. Amniotic fluid was collected at the time of admission by amniocentesis and calprotectin levels were analyzed from frozen/thawed samples using ELISA. Interleukin (IL)-6 concentration was measured by point-of-care test. Samples from amniotic fluid and the amnio-chorionic niche (space between amniotic and chorionic membranes) were microbiologically analyzed. Microbial invasion of the amniotic cavity (MIAC) was diagnosed based on a positive PCR result for Ureaplasma species, Mycoplasma hominis, 16S rRNA or positive culture. Intra-amniotic inflammation (IAI) was defined as amniotic fluid point-of-care IL-6 concentration ≥ 745 pg/mL. The cohort of included women was divided into 4 subgroups based on the presence or absence of IAI/MIAC; i) intra-amniotic infection, ii) sterile IAI, iii) intra-amniotic colonization and iv) neither MIAC nor IAI. Results: Women with intra-amniotic infection had a significantly higher intra-amniotic calprotectin concentration (median; 101.6 µg/mL) compared with women with sterile IAI (median; 9.2 µg/mL), women with intra-amniotic colonization (median; 2.6 µg/mL) and women with neither MIAC nor IAI (median 4.6 µg/mL) (p = 0.001). Moreover, significantly higher amniotic fluid calprotectin concentration was seen in women who delivered within 7 days (p = 0.003). A significant negative correlation was found between amniotic fluid calprotectin and gestational age at delivery (rho = 0.32, p = 0.003). Relatively more bacteria in the amnio-chorionic niche were found in the sterile IAI group compared with the other groups. Conclusions: Calprotectin concentrations in amniotic fluid were significantly higher in the intra-amniotic infection group compared with the other groups. Moreover, the bacterial presence in the amnio-chorionic niche was higher in IAI group.
3.	Al-Haddad, Benjamin J S, et al. (author) Long-term Risk of Neuropsychiatric Disease After Exposure to Infection In Utero. 2019 In: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 76:6, s. 594-602 Journal article (peer-reviewed)abstract The developmental origins of mental illness are incompletely understood. Although the development of autism and schizophrenia are linked to infections during fetal life, it is unknown whether more common psychiatric conditions such as depression might begin in utero.To estimate the risk of psychopathologic conditions imparted from fetal exposure to any maternal infection while hospitalized during pregnancy.A total of 1791520 Swedish children born between January 1, 1973, and December 31, 2014, were observed for up to 41 years using linked population-based registries. Children were excluded if they were born too late to contribute person-time, died before being at risk for the outcome, or were missing particular model data. Infection and psychiatric diagnoses were derived using codes from hospitalizations. Directed acyclic graphs were developed from a systematic literature review to determine Cox proportional hazards regression models for risk of psychopathologic conditions in the children. Results were evaluated using probabilistic and simple bias analyses. Statistical analysis was conducted from February 10 to October 17, 2018.Hospitalization during pregnancy with any maternal infection, severe maternal infection, and urinary tract infection.Inpatient diagnosis of autism, depression, bipolar disorder, or psychosis among offspring.A total of 1791520 Swedish-born children (48.6% females and 51.4% males) were observed from birth up to age 41 years, with a total of 32125813 person-years. Within the directed acyclic graph framework of assumptions, fetal exposure to any maternal infection increased the risk of an inpatient diagnosis in the child of autism (hazard ratio [HR], 1.79; 95% CI, 1.34-2.40) or depression (HR, 1.24; 95% CI, 1.08-1.42). Effect estimates for autism and depression were similar following a severe maternal infection (autism: HR, 1.81; 95% CI, 1.18-2.78; depression: HR, 1.24; 95% CI, 0.88-1.73) or urinary tract infection (autism: HR, 1.89; 95% CI, 1.23-2.90; depression: HR, 1.30; 95% CI, 1.04-1.61) and were robust to moderate unknown confounding. Within the directed acyclic graph framework of assumptions, the relationship between infection and depression was vulnerable to bias from loss to follow-up, but separate data from the Swedish Death Registry demonstrated increased risk of suicide among individuals exposed to pregnancy infection. No evidence was found for increased risk of bipolar disorder or psychosis among children exposed to infection in utero.These findings suggest that fetal exposure to a maternal infection while hospitalized increased the risk for autism and depression, but not bipolar or psychosis, during the child's life. These results emphasize the importance of avoiding infections during pregnancy, which may impart subtle fetal brain injuries contributing to development of autism and depression.
4.	Al-Haddad, Benjamin J S, et al. (author) The fetal origins of mental illness. 2019 In: American journal of obstetrics and gynecology. - : Elsevier BV. - 1097-6868 .- 0002-9378. ; 221:6, s. 549-562 Research review (peer-reviewed)abstract The impact of infections and inflammation during pregnancy on the developing fetal brain remains incompletely defined, with important clinical and research gaps. Although the classic infectious TORCH pathogens (ie, Toxoplasma gondii, rubella virus, cytomegalovirus [CMV], herpes simplex virus) are known to be directly teratogenic, emerging evidence suggests that these infections represent the most extreme end of a much larger spectrum of injury. We present the accumulating evidence that prenatal exposure to a wide variety of viral and bacterial infections-or simply inflammation-may subtly alter fetal brain development, leading to neuropsychiatric consequences for the child later in life. The link between influenza infections in pregnant women and an increased risk for development of schizophrenia in their children was first described more than 30 years ago. Since then, evidence suggests that a range of infections during pregnancy may also increase risk for autism spectrum disorder and depression in the child. Subsequent studies in animal models demonstrated that both pregnancy infections and inflammation can result in direct injury to neurons and neural progenitor cells or indirect injury through activation of microglia and astrocytes, which can trigger cytokine production and oxidative stress. Infectious exposures can also alter placental serotonin production, which can perturb neurotransmitter signaling in the developing brain. Clinically, detection of these subtle injuries to the fetal brain is difficult. As the neuropsychiatric impact of perinatal infections or inflammation may not be known for decades after birth, our construct for defining teratogenic infections in pregnancy (eg, TORCH) based on congenital anomalies is insufficient to capture the full adverse impact on the child. We discuss the clinical implications of this body of evidence and how we might place greater emphasis on prevention of prenatal infections. For example, increasing uptake of the seasonal influenza vaccine is a key strategy to reduce perinatal infections and the risk for fetal brain injury. An important research gap exists in understanding how antibiotic therapy during pregnancy affects the fetal inflammatory load and how to avoid inflammation-mediated injury to the fetal brain. In summary, we discuss the current evidence and mechanisms linking infections and inflammation with the increased lifelong risk of neuropsychiatric disorders in the child, and how we might improve prenatal care to protect the fetal brain.
5.	Al-Najjar, Basim, 1954-, et al. (author) A Model to Describe the Relationships Man–Machine–Maintenance–Economy (MMME) 2007 In: IMECS 2007. - 9789889867140 ; , s. 2127-2132 Book chapter (peer-reviewed)abstract In the globalisation spirit, one of the major objectives of companies is how to reduce the production losses cost-effectively for continuously enhancement of competitiveness and profitability. However, this area has been neglected by scientists and not given the attention justified considering its obvious link to company profitability. To fill this gap, better understanding of the relations and interactions between man, machine/production process, maintenance and economy is vital. Also, it is important for identifying and eliminating root causes of the losses. In this paper, we develop a model to describe these interactions using the most relevant factors, such as maintenance organisation, personnel commitment, machine condition and characteristics, and the impact of maintenance performance on production time. The use of the model and its potential benefits are tested using an application example. This example illustrates how the above mentioned factors affect the production time and is thereafter derived to financial results. The result is accordingly a model that can help all producing companies categorise the causes behind losses and identify where losses arise and where to focus their work of continuous cost-effective improvements.
6.	Aniskevich, Aliaksandra, et al. (author) Antimicrobial resistance in Neisseria gonorrhoeae isolates and gonorrhoea treatment in the Republic of Belarus, Eastern Europe, 2009-2019 2021 In: BMC Infectious Diseases. - : BioMed Central. - 1471-2334. ; 21:1 Journal article (peer-reviewed)abstract BACKGROUND: Limited antimicrobial resistance (AMR) data for Neisseria gonorrhoeae are available in Eastern Europe. We investigated AMR in N. gonorrhoeae isolates in the Republic of Belarus from 2009 to 2019, antimicrobial treatment recommended nationally, and treatment given to patients with gonorrhoea.METHODS: N. gonorrhoeae isolates (n = 522) cultured in three regions of Belarus in 2009-2019 were examined. Determination of minimum inhibitory concentrations (MICs) of eight antimicrobials was performed using Etest. Resistance breakpoints from the European Committee on Antimicrobial Susceptibility Testing were applied where available. A Nitrocefin test identified β-lactamase production. Gonorrhoea treatment for 1652 patients was also analysed. Statistical significance was determined by the Z-test, Fisher's exact test, or Mann-Whitney U test with p-values of < 0.05 indicating significance.RESULTS: In total, 27.8% of the N. gonorrhoeae isolates were resistant to tetracycline, 24.7% to ciprofloxacin, 7.0% to benzylpenicillin, 2.7% to cefixime, and 0.8% to azithromycin. No isolates were resistant to ceftriaxone, spectinomycin, or gentamicin. However, 14 (2.7%) isolates had a ceftriaxone MIC of 0.125 mg/L, exactly at the resistance breakpoint (MIC > 0.125 mg/L). Only one (0.2%) isolate, from 2013, produced β-lactamase. From 2009 to 2019, the levels of resistance to ciprofloxacin and tetracycline were relatively high and stable. Resistance to cefixime was not identified before 2013 but peaked at 22.2% in 2017. Only sporadic isolates with resistance to azithromycin were found in 2009 (n = 1), 2012 (n = 1), and 2018-2019 (n = 2). Overall, 862 (52.2%) patients received first-line treatment according to national guidelines (ceftriaxone 1 g). However, 154 (9.3%) patients received a nationally recommended alternative treatment (cefixime 400 mg or ofloxacin 400 mg), and 636 (38.5%) were given non-recommended treatment.CONCLUSIONS: The gonococcal resistance to ciprofloxacin and tetracycline was high, however, the resistance to azithromycin was low and no resistance to ceftriaxone was identified. Ceftriaxone 1 g can continuously be recommended as empiric first-line gonorrhoea therapy in Belarus. Fluoroquinolones should not be prescribed for treatment if susceptibility has not been confirmed by testing. Timely updating and high compliance with national evidence-based gonorrhoea treatment guidelines based on quality-assured AMR data are imperative. The need for continued, improved and enhanced surveillance of gonococcal AMR in Belarus is evident.
7.	Ankarcrona, Victoria, et al. (author) Delivery outcome after trial of labor in nulliparous women 40 years or older-A nationwide population-based study 2019 In: Acta Obstetricia et Gynecologica Scandinavica. - : WILEY. - 0001-6349 .- 1600-0412. ; 98:9, s. 1195-1203 Journal article (peer-reviewed)abstract Introduction The number of women postponing childbirth until an advanced age is increasing. Our aim was to study the outcome of labor in nulliparous women >= 40 years, compared with women 25-29 years, after both spontaneous onset and induction of labor. Material and methods The nationwide population-based Swedish Medical Birth Register was used to study the perinatal outcome in nulliparous women with a singleton, term (gestational weeks 37-44), live fetus in cephalic presentation and a planned vaginal delivery from 1992 to 2011. We included 7796 nulliparous women >= 40 years and 264 262 nulliparous women 25-29 years. Prevalence and risk of intrapartum cesarean section, operative vaginal delivery, obstetric anal sphincter injury and a 5-minute Apgar score <7 were calculated for women >= 40 years stratified for spontaneous onset and induction of labor, using women 25-29 years as the reference in both strata. Crude and adjusted odds ratios (aOR) were calculated by unconditional logistic regression and presented with 95% confidence intervals (CI). Results Overall, 79% of women >= 40 years with a trial of labor reached a vaginal delivery. After spontaneous onset, intrapartum cesarean section was performed in 15.4% of women >= 40 years compared with 5.4% of women 25-29 years (aOR 3.07, 95% CI 2.81-3.35). Operative vaginal delivery was performed in 22.3% of women >= 40 years compared with 14.2% of women 25-29 years (aOR 1.71, 95% CI 1.59-1.85). After induction of labor, an intrapartum cesarean section was performed in 37.2% women >= 40 years compared with 20.2% women 25-29 years (aOR 2.51, 95% CI 2.24-2.81). Operative vaginal delivery was performed in 22.6% of women >= 40 years compared with 18.4% women 25-29 years (aOR 1.45, 95% CI 1.28-1.65). The risk of obstetric anal sphincter injury or a 5-minute Apgar score <7 was not increased in women >= 40 years, regardless of onset of labor. Conclusions Trial of labor ended in vaginal delivery in 79% of nulliparous women >= 40 years. The risks of intrapartum cesarean section and operative vaginal delivery were higher in women >= 40 years compared with women 25-29 years, after both spontaneous onset and induction of labor. The risk of obstetric anal sphincter injury or a 5-minute Apgar score <7 was not increased.
8.	Beaumont, Robin N, et al. (author) Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth. 2023 In: Nature genetics. - 1546-1718 .- 1061-4036. ; 55:11, s. 1807-19 Journal article (peer-reviewed)abstract A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal (n=65,405), maternal (n=61,228) and paternal (n=52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classified as fetal, four maternal and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1. Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with preeclampsia risk and shorter gestational duration. Moreover, these analyses support the role of fetal insulin in regulating placental weight, providing a key link between fetal and placental growth.
9.	Berçot, Béatrice, et al. (author) Ceftriaxone-resistant, multidrug-resistant Neisseria gonorrhoeae with a novel mosaic penA-237.001 gene, France, June 2022 2022 In: Eurosurveillance. - : European Centre for Disease Prevention and Control. - 1025-496X .- 1560-7917. ; 27:50, s. 17-22 Journal article (peer-reviewed)abstract We report a ceftriaxone-resistant, multidrug-resistant urogenital gonorrhoea case in a heterosexual woman in France, June 2022. The woman was successfully treated with azithromycin 2 g. She had unprotected sex with her regular partner, who developed urethritis following travel to Vietnam and Switzerland. Whole genome sequencing of the gonococcal isolate (F92) identified MLST ST1901, NG-STAR CC- 199, and the novel mosaic penA-237.001, which caused ceftriaxone resistance. penA-237.001 is 98.7% identical to penA-60.001, reported in various ceftriaxone-resistant strains, including the internationally spreading FC428 clone.
10.	Boiko, Iryna, et al. (author) Antimicrobial susceptibility of Neisseria gonorrhoeae isolates and treatment of gonorrhoea patients in Ternopil and Dnipropetrovsk regions of Ukraine, 2013-2018 2019 In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS). - : John Wiley & Sons. - 0903-4641 .- 1600-0463. ; 127:7, s. 503-509 Journal article (peer-reviewed)abstract Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a major public health concern globally. However, recent gonococcal AMR data from Eastern Europe are extremely limited and no AMR data for strains spreading in Ukraine have ever been internationally published. We investigated the AMR of N. gonorrhoeae isolates in two regions of Ukraine (Ternopil 2013-2018, Dnipropetrovsk 2013-2014), and, where information was available, the treatment administered to the corresponding gonorrhoea patients. Determination of minimum inhibitory concentration (MIC) of eight antimicrobials was performed using Etest and resistance breakpoints from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) were applied. Overall, 9.3% of the examined 150 isolates were resistant to ciprofloxacin, 6.0% to tetracycline, 2.0% to azithromycin, and 0.7% to benzylpenicillin. No isolates were resistant to ceftriaxone, cefixime, spectinomycin, or gentamicin. However, one (0.7%) isolate showed a MIC value of 0.125 mg/L for both ceftriaxone and cefixime, i.e., bordering resistance. Eighty-eight (67.2%) of 131 patients were administered dual therapy (ceftriaxone 1 g plus doxycycline/clarithromycin/azithromycin/ofloxacin) and 22 (16.8%) ceftriaxone 1 g monotherapy. Worryingly, 21 (16.0%) patients received monotherapy with clarithromycin/doxycycline/azithromycin/ofloxacin/benzylpenicillin. In conclusion, the antimicrobial susceptibility of gonococcal strains spreading in Ternopil and Dnipropetrovsk, Ukraine during 2013-2018 was high. Low levels of resistance to ciprofloxacin, tetracycline, azithromycin, and benzylpenicillin were found, but no resistance to the internationally recommended ceftriaxone, cefixime, or spectinomycin. Ceftriaxone 1 g should remain as empiric first-line treatment, in dual therapy with azithromycin or doxycycline or in monotherapy. Continued and expanded gonococcal AMR surveillance in Ukraine is essential to monitor the susceptibility to particularly extended-spectrum cephalosporins, azithromycin and doxycycline.
11.	Boiko, Iryna, et al. (author) Genomic epidemiology and antimicrobial resistance determinants of Neisseria gonorrhoeae isolates from Ukraine, 2013-2018 2020 In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS). - : Wiley-Blackwell. - 0903-4641 .- 1600-0463. ; 128:7, s. 465-475 Journal article (peer-reviewed)abstract Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a major health threat compromising the gonorrhoea treatment globally. AMR surveillance including whole genome sequencing (WGS)-based epidemiology provides ideal resolution to identify and describe AMR gonococcal clones, AMR determinants and populations, which can inform management guidelines and antimicrobial stewardship policies. Our aims were to, for the first time, elucidate the WGS-based epidemiology and characterise AMR determinants of gonococcal strains spreading in Ukraine, 2013-2018. Gonococcal isolates (n=150) from Ternopil and Dnipro, Ukraine (2013-2018) were subjected to AMR testing (Etest) for eight antimicrobials and WGS. Overall, 11.3% of isolates were resistant to ciprofloxacin, 6.0% to tetracycline and 0.7% to benzylpenicillin. No isolates were resistant to azithromycin, spectinomycin, ceftriaxone, or cefixime, but one isolate was bordering resistance to both cephalosporins. Twenty-five MLST STs, 50 NG-MAST STs, and 34 NG-STAR types were identified. The phylogenomic analysis revealed six main clusters, mostly associated with the internationally described multidrug-susceptible gonococcal lineage. Resistance to ciprofloxacin was associated with GyrA S91F and ParC S87R mutations; tetracyclines with rpsJ V57M and tetM; penicillins with mosaic penA-34.001 and β-lactamase; mtrR; PorB1b G101D, and PBP1 L421P mutations. One isolate of the multidrug-resistant NG-MAST ST1407, MLST ST1901 was found, which was bordering resistance to ceftriaxone and cefixime. The susceptibility of gonococcal strains spreading in Ternopil and Dnipro, Ukraine, 2013-2018 was surprisingly high. Continued and expanded gonococcal AMR surveillance, ideally including WGS, in Ukraine is essential. This could inform action plans and public health policies to control the spread of AMR gonococcal strains in Ukraine.
12.	Bolinsson, Jessica, et al. (author) GaAs/AlGaAs heterostructure nanowires studied by cathodoluminescence 2014 In: Nano Reseach. - : Springer Science and Business Media LLC. - 1998-0124 .- 1998-0000. ; 7:4, s. 473-490 Journal article (peer-reviewed)abstract In this report we explore the structural and optical properties of GaAs/AlGaAs heterostructure nanowires grown by metalorganic vapour phase epitaxy using gold seed-particles. The optical studies were done by low-temperature cathodoluminescence (CL) in a scanning electron microscope (SEM). We perform a systematic investigation of how the nanowire growth-temperature affects the total photon emission, and variations in the emission energy and intensity along the length of the nanowires. The morphology and crystal structures of the nanowires were investigated using SEM and transmission electron microscopy (TEM). In order to correlate specific photon emission characteristics with variations in the nanowire crystal structure directly, TEM and spatially resolved CL measurements were performed on the same individual nanowires. We found that the main emission energy was located at around 1.48 eV, and that the emission intensity was greatly enhanced when increasing the GaAs nanowire core growth temperature. The data strongly suggests that this emission energy is related to rotational twins in the GaAs nanowire core. Our measurements also show that radial overgrowth by GaAs on the GaAs nanowire core can have a deteriorating effect on the optical quality of the nanowires. Finally, we conclude that an in situ pre-growth annealing step at a sufficiently high temperature significantly improves the optical quality of the nanowires.
13.	Corrêa, Gregório B., et al. (author) Raman characterization of single-crystalline Ga0.96Mn0.04As:Zn nanowires realized by ion-implantation 2019 In: Nanotechnology. - Bristol : IOP Publishing. - 0957-4484 .- 1361-6528. ; 30:33 Journal article (peer-reviewed)abstract Recent progress in the realization of magnetic GaAs nanowires (NWs) doped with Mn has attracted a lot of attention due to their potential application in spintronics. In this work, we present a detailed Raman investigation of the structural properties of Zn doped GaAs (GaAs:Zn) and Mn-implanted GaAs:Zn (Ga0.96Mn0.04As:Zn) NWs. A significant broadening and redshift of the optical TO and LO phonon modes are observed for these NWs compared to as-grown undoped wires, which is attributed to strain induced by the Zn/Mn doping and to the presence of implantation-related defects. Moreover, the LO phonon modes are strongly damped, which is interpreted in terms of a strong LO phonon-plasmon coupling, induced by the free hole concentration. Moreover, we report on two new interesting Raman phonon modes (191 and 252 cm-1) observed in Mn ion-implanted NWs, which we attribute to Eg (TO) and A1g (LO) vibrational modes in a sheet layer of crystalline arsenic present on the surface of the NWs. This conclusion is supported by fitting the observed Raman shifts for the SO phonon modes to a theoretical dispersion function for a GaAs NW capped with a dielectric shell.
14.	David, Alexandra, et al. (author) In silico gepotidacin target mining among 33 213 global Neisseria gonorrhoeae genomes from 1928 to 2023 combined with gepotidacin MIC testing of 22 gonococcal isolates with different GyrA and ParC substitutions 2024 In: Journal of Antimicrobial Chemotherapy. - : Oxford University Press. - 0305-7453 .- 1460-2091. Journal article (peer-reviewed)abstract Objectives: The novel dual-target triazaacenaphthylene, gepotidacin, recently showed promising results in its Phase III randomized controlled trial for the treatment of gonorrhoea. We investigated alterations in the gepotidacin GyrA and ParC targets in gonococci by in silico mining of publicly available global genomes (n = 33 213) and determined gepotidacin MICs in isolates with GyrA A92 alterations combined with other GyrA and/or ParC alterations.Methods: We examined gonococcal gyrA and parC alleles available at the European Nucleotide Archive. MICs were determined using the agar dilution method (gepotidacin) or Etest (four antimicrobials). Models of DNA gyrase and topoisomerase IV were obtained from AlphaFold and used to model gepotidacin in the binding site.Results: GyrA A92 alterations were identified in 0.24% of genomes: GyrA A92P/S/V + S91F + D95Y/A/N (0.208%), A92P + S91F (0.024%) and A92P (0.003%), but no A92T (previously associated with gepotidacin resistance) was found. ParC D86 alterations were found in 10.6% of genomes: ParC D86N/G (10.5%), D86N + S87I (0.051%), D86N + S88P (0.012%) and D86G + E91G (0.003%). One isolate had GyrA A92P + ParC D86N alterations, but remained susceptible to gepotidacin (MIC = 0.125 mg/L). No GyrA plus ParC alterations resulted in a gepotidacin MIC > 4 mg/L. Modelling of gepotidacin binding to GyrA A92/A92T/A92P suggested that gepotidacin resistance due to GyrA A92T might be linked to the formation of a new polar contact with DNA.Conclusions: In silico mining of 33 213 global gonococcal genomes (isolates from 1928 to 2023) showed that A92 is highly conserved in GyrA, while alterations in D86 of ParC are common. No GyrA plus ParC alterations caused gepotidacin resistance. MIC determination and genomic surveillance of potential antimicrobial resistance determinants are imperative.
15.	Escobar Steinvall, Simon, et al. (author) Visualizing the Mechanism Switching in High-Temperature Au-Catalyzed InAs Nanowire Growth 2023 In: Crystal Growth and Design. - 1528-7483. ; 23:9, s. 6228-6232 Journal article (peer-reviewed)abstract We use environmental transmission electron microscopy to observe in situ the switch from an axial vapor-liquid-solid (VLS) growth mechanism in Au-catalyzed InAs nanowires toward a radial vapor-solid (VS) one, dominated by layers nucleating at the triple-phase line. At elevated temperatures, in addition to high V/III ratios, the affinity for In in the Au catalyst will be greater than that of In in InAs, which in turn reduces the driving force and probability for nucleation at the liquid-solid interface. Consequently, with increased temperature, the catalyst particle stops acting as a sink for incoming material and the decomposition of precursors away from the catalyst increases, making radial vapor-solid growth the dominating growth mechanism. It is further observed that the growth proceeds through multistep propagation rather than a layer-by-layer propagation under these conditions.
16.	Foerster, Sunniva, et al. (author) Genetic Resistance Determinants, In Vitro Time-Kill Curve Analysis and Pharmacodynamic Functions for the Novel Topoisomerase II Inhibitor ETX0914 (AZD0914) in Neisseria gonorrhoeae 2015 In: Frontiers in Microbiology. - : Frontiers Media S.A.. - 1664-302X. ; 6 Journal article (peer-reviewed)abstract Resistance in Neisseria gonorrhoeae to all available therapeutic antimicrobials has emerged and new efficacious drugs for treatment of gonorrhea are essential. The topoisomerase II inhibitor ETX0914 (also known as AZD0914) is a new spiropyrimidinetrione antimicrobial that has different mechanisms of action from all previous and current gonorrhea treatment options. In this study, the N. gonorrhoeae resistance determinants for ETX0914 were further described and the effects of ETX0914 on the growth of N. gonorrhoeae (ETX0914 wild type, single step selected resistant mutants, and efflux pump mutants) were examined in a novel in vitro time-kill curve analysis to estimate pharmacodynamic parameters of the new antimicrobial. For comparison, ciprofloxacin, azithromycin, ceftriaxone, and tetracycline were also examined (separately and in combination with ETX0914). ETX0914 was rapidly bactericidal for all wild type strains and had similar pharmacodynamic properties to ciprofloxacin. All selected resistant mutants contained mutations in amino acid codons D429 or K450 of GyrB and inactivation of the MtrCDE efflux pump fully restored the susceptibility to ETX0914. ETX0914 alone and in combination with azithromycin and ceftriaxone was highly effective against N. gonorrhoeae and synergistic interaction with ciprofloxacin, particularly for ETX0914-resistant mutants, was found. ETX0914, monotherapy or in combination with azithromycin (to cover additional sexually transmitted infections), should be considered for phase III clinical trials and future gonorrhea treatment.
17.	Forsberg, Karin, et al. (author) Novel antibodies reveal inclusions containing non-native SOD1 in sporadic ALS patients 2010 In: PLOS ONE. - : Public library of science. - 1932-6203. ; 5:7, s. e11552- Journal article (peer-reviewed)abstract Mutations in CuZn-superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS) and are found in 6% of ALS patients. Non-native and aggregation-prone forms of mutant SOD1s are thought to trigger the disease. Two sets of novel antibodies, raised in rabbits and chicken, against peptides spaced along the human SOD1 sequence, were by enzyme-linked immunosorbent assay and an immunocapture method shown to be specific for denatured SOD1. These were used to examine SOD1 in spinal cords of ALS patients lacking mutations in the enzyme. Small granular SOD1-immunoreactive inclusions were found in spinal motoneurons of all 37 sporadic and familial ALS patients studied, but only sparsely in 3 of 28 neurodegenerative and 2 of 19 non-neurological control patients. The granular inclusions were by confocal microscopy found to partly colocalize with markers for lysosomes but not with inclusions containing TAR DNA binding protein-43, ubiquitin or markers for endoplasmic reticulum, autophagosomes or mitochondria. Granular inclusions were also found in carriers of SOD1 mutations and in spinobulbar muscular atrophy (SBMA) patients and they were the major type of inclusion detected in ALS patients homozygous for the wild type-like D90A mutation. The findings suggest that SOD1 may be involved in ALS pathogenesis in patients lacking mutations in the enzyme.
18.	Golparian, Daniel, 1984-, et al. (author) Complete Reference Genome Sequence of the Clinical Neisseria gonorrhoeae Strain H035, with Resistance to the Novel Antimicrobial Zoliflodacin, Identified in Japan in 2000 2023 In: Microbiology Resource Announcements. - : American Society for Microbiology. - 2576-098X. ; 12:3 Journal article (peer-reviewed)abstract Zoliflodacin is a promising novel antimicrobial in clinical development for treatment of gonorrhea; currently, it is in a global phase 3 randomized controlled clinical trial. High activity against global Neisseria gonorrhoeae strains has been shown. We present the complete reference genome of the zoliflodacin-resistant strain H035, which was identified in Japan in 2000.
19.	Golparian, Daniel, 1984-, et al. (author) Complete Reference Genome Sequence of the Extensively Drug-Resistant Strain Neisseria gonorrhoeae AT159, with Ceftriaxone Resistance and High-Level Azithromycin Resistance, Using Nanopore Q20+ Chemistry and Illumina Sequencing 2022 In: Microbiology Resource Announcements. - : American Society for Microbiology. - 2576-098X. ; 15:11 Journal article (peer-reviewed)abstract Extensively drug-resistant Neisseria gonorrhoeae (XDR-NG) strains with resistance to the last remaining first-line treatments (ceftriaxone monotherapy or combined with azithromycin) represent the emerging threat of untreatable gonorrhea. We present the complete reference genome sequence of the XDR-NG strain AT159, with ceftriaxone and high-level azithromycin resistance, from Austria.
20.	Golparian, Daniel, 1984-, et al. (author) Genomic surveillance and antimicrobial resistance in Neisseria gonorrhoeae isolates in Bangkok, Thailand in 2018 2022 In: Journal of Antimicrobial Chemotherapy. - : Oxford University Press. - 0305-7453 .- 1460-2091. ; 77:8, s. 2171-2182 Journal article (peer-reviewed)abstract OBJECTIVES: Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a substantial global public health problem. Gonococcal infections acquired in or from Asia represent most verified ceftriaxone treatment failures, and several ceftriaxone-resistant strains have emerged in Asia and subsequently spread globally. Additionally, in Thailand the gonorrhoea incidence remains high. Herein, we investigate the genomic diversity, AMR and AMR determinants in gonococcal isolates cultured in 2018 in Bangkok, Thailand.METHODS: Gonococcal isolates from males (n = 37) and females (n = 62) were examined by Etest and WGS. AMR determinants and molecular epidemiological STs were characterized. For phylogenomic comparison, raw sequence data were included from China (432 isolates), Japan (n = 270), Vietnam (n = 229), Thailand (n = 3), a global dataset (n = 12 440) and the 2016 WHO reference strains plus WHO Q (n = 15).RESULTS: In total, 88, 66 and 41 different NG-MAST, NG-STAR and MLST STs, respectively, and 31 different NG-STAR clonal complexes were found. A remarkably high frequency (88%) of β-lactamase TEM genes was detected and two novel TEM alleles were found. The phylogenomic analysis divided the isolates into the previously described lineages A and B, with a large proportion of Thai isolates belonging to the novel sublineage A3.CONCLUSIONS: We describe the first molecular epidemiological study using WGS on gonococcal isolates from Thailand. The high prevalence of AMR and AMR determinants for ciprofloxacin, tetracycline and benzylpenicillin, and some strains belonging to clones/clades especially in sublineage A2 that are prone to develop resistance to extended-spectrum cephalosporins (ESCs) and azithromycin, should prompt continued and strengthened AMR surveillance, including WGS, of N. gonorrhoeae in Thailand.
21.	Golparian, Daniel, 1984-, et al. (author) GyrB in silico mining in 27 151 global gonococcal genomes from 1928-2021 combined with zoliflodacin in vitro testing of 71 international gonococcal isolates with different GyrB, ParC and ParE substitutions confirms high susceptibility 2022 In: Journal of Antimicrobial Chemotherapy. - : Oxford University Press. - 0305-7453 .- 1460-2091. ; 78:1, s. 150-154 Journal article (peer-reviewed)abstract OBJECTIVES: Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a global threat and novel treatment alternatives are imperative. Herein, susceptibility to the novel antimicrobial zoliflodacin, currently in a global Phase 3 randomized controlled clinical trial for gonorrhoea treatment, was investigated by screening for zoliflodacin GyrB target mutations in publicly available gonococcal genomes and, where feasible, determination of the associated zoliflodacin MIC.METHODS: The European Nucleotide Archive was queried using the search term 'Taxon: 485'. DNA sequences from 27 151 gonococcal isolates were analysed and gyrB, gyrA, parC and parE alleles characterized.RESULTS: GyrB amino acid alterations were rare (97.0% of isolates had a wild-type GyrB sequence). GyrB V470L (2.7% of isolates) was the most prevalent alteration, followed by S467N (0.12%), N. meningitidis GyrB (0.092%), V470I (0.059%), Q468R/P (0.015%), A466T (0.0074%), L425I + L465I (0.0037%), L465I (0.0037%), G482S (0.0037%) and D429V (0.0037%). Only one isolate (0.0037%) carried a substitution in a resistance-associated GyrB codon (D429V), resulting in a zoliflodacin MIC of 8 mg/L. None of the other detected gyrB, gyrA, parC or parE mutations caused a zoliflodacin MIC outside the wild-type MIC distribution.CONCLUSIONS: The zoliflodacin target GyrB was highly conserved among 27 151 global gonococcal isolates cultured in 1928-2021. The single zoliflodacin-resistant clinical isolate (0.0037%) was cultured from a male patient in Japan in 2000. Evidently, this strain has not clonally expanded nor has the gyrB zoliflodacin-resistance mutation disseminated through horizontal gene transfer to other strains. Phenotypic and genomic surveillance, including gyrB mutations, of zoliflodacin susceptibility are imperative.
22.	Golparian, Daniel, 1984-, et al. (author) High-level in vitro resistance to gentamicin acquired in a stepwise manner in Neisseria gonorrhoeae 2023 In: Journal of Antimicrobial Chemotherapy. - : Oxford University Press. - 0305-7453 .- 1460-2091. ; 78:7, s. 1769-1778 Journal article (peer-reviewed)abstract OBJECTIVES: Gentamicin is used in several alternative treatments for gonorrhoea. Verified clinical Neisseria gonorrhoeae isolates with gentamicin resistance are mainly lacking and understanding the mechanisms for gonococcal gentamicin resistance is imperative. We selected gentamicin resistance in gonococci in vitro, identified the novel gentamicin-resistance mutations, and examined the biofitness of a high-level gentamicin-resistant mutant.METHODS: Low- and high-level gentamicin resistance was selected in WHO X (gentamicin MIC = 4 mg/L) on gentamicin-gradient agar plates. Selected mutants were whole-genome sequenced. Potential gentamicin-resistance fusA mutations were transformed into WT strains to verify their impact on gentamicin MICs. The biofitness of high-level gentamicin-resistant mutants was examined using a competitive assay in a hollow-fibre infection model.RESULTS: WHO X mutants with gentamicin MICs of up to 128 mg/L were selected. Primarily selected fusA mutations were further investigated, and fusAR635L and fusAM520I + R635L were particularly interesting. Different mutations in fusA and ubiM were found in low-level gentamicin-resistant mutants, while fusAM520I was associated with high-level gentamicin resistance. Protein structure predictions showed that fusAM520I is located in domain IV of the elongation factor-G (EF-G). The high-level gentamicin-resistant WHO X mutant was outcompeted by the gentamicin-susceptible WHO X parental strain, suggesting lower biofitness.CONCLUSIONS: We describe the first high-level gentamicin-resistant gonococcal isolate (MIC = 128 mg/L), which was selected in vitro through experimental evolution. The most substantial increases of the gentamicin MICs were caused by mutations in fusA (G1560A and G1904T encoding EF-G M520I and R635L, respectively) and ubiM (D186N). The high-level gentamicin-resistant N. gonorrhoeae mutant showed impaired biofitness.
23.	Golparian, Daniel, 1984-, et al. (author) Multidrug-resistant Neisseria gonorrhoeae isolate SE690 : mosaic penA-60.001 gene causing ceftriaxone resistance internationally has spread to the more antimicrobial- susceptible genomic lineage, Sweden, September 2022 2023 In: Eurosurveillance. - : European Centre for Disease Prevention and Control. - 1025-496X .- 1560-7917. ; 28:10 Journal article (peer-reviewed)abstract We report a ceftriaxone-resistant, multidrug-resist-ant urogenital Neisseria gonorrhoeae in a female sex worker in Sweden, September 2022, who was treated with ceftriaxone i g, but did not return for test-of-cure. Whole genome sequencing of isolate SE690 identified MLST ST8i30, NG-STAR CCi885 (new NG-STAR ST4859) and mosaic penA-6o.oo1. The latter, causing ceftriax-one resistance in the internationally spreading FC428 clone, has now also spread to the more antimicrobial -susceptible genomic lineage B, showing that strains across the gonococcal phylogeny can develop ceftri-axone resistance.
24.	Hadad, Ronza, 1984-, et al. (author) Evaluation of the SpeeDx ResistancePlus® GC and SpeeDx GC 23S 2611 (beta) molecular assays for prediction of antimicrobial resistance/susceptibility to ciprofloxacin and azithromycin in Neisseria gonorrhoeae 2021 In: Journal of Antimicrobial Chemotherapy. - : Oxford University Press. - 0305-7453 .- 1460-2091. ; 76:1, s. 84-90 Journal article (peer-reviewed)abstract BACKGROUND: Accurate molecular assays for prediction of antimicrobial resistance (AMR)/susceptibility in Neisseria gonorrhoeae (Ng) can offer individualized treatment of gonorrhoea and enhanced AMR surveillance.OBJECTIVES: We evaluated the new ResistancePlus® GC assay and the GC 23S 2611 (beta) assay (SpeeDx), for prediction of resistance/susceptibility to ciprofloxacin and azithromycin, respectively.METHODS: Nine hundred and sixty-seven whole-genome-sequenced Ng isolates from 20 European countries, 143 Ng-positive (37 with paired Ng isolates) and 167 Ng-negative clinical Aptima Combo 2 (AC2) samples, and 143 non-gonococcal Neisseria isolates and closely related species were examined with both SpeeDx assays.RESULTS: The sensitivity and specificity of the ResistancePlus® GC assay to detect Ng in AC2 samples were 98.6% and 100%, respectively. ResistancePlus® GC showed 100% sensitivity and specificity for GyrA S91 WT/S91F detection and 99.8% sensitivity and specificity in predicting phenotypic ciprofloxacin resistance. The sensitivity and specificity of the GC 23S 2611 (beta) assay for Ng detection in AC2 samples were 95.8% and 100%, respectively. GC 23S 2611 (beta) showed 100% sensitivity and 99.9% specificity for 23S rRNA C2611 WT/C2611T detection and 64.3% sensitivity and 99.9% specificity for predicting phenotypic azithromycin resistance. Cross-reactions with non-gonococcal Neisseria species were observed with both assays, but the analysis software solved most cross-reactions.CONCLUSIONS: The new SpeeDx ResistancePlus® GC assay performed well in the detection of Ng and AMR determinants, especially in urogenital samples. The GC 23S 2611 (beta) assay performed relatively well, but its sensitivity, especially for predicting phenotypic azithromycin resistance, was suboptimal and further optimizations are required, including detection of additional macrolide resistance determinant(s).
25.	Hallingström, Maria, et al. (author) Mid-trimester amniotic fluid proteome’s association with spontaneous preterm delivery and gestational duration 2020 In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203 .- 1932-6203. ; 15:5 Journal article (peer-reviewed)abstract Background Amniotic fluid is clinically accessible via amniocentesis and its protein composition may correspond to birth timing. Early changes in the amniotic fluid proteome could therefore be associated with the subsequent development of spontaneous preterm delivery. Objective The main objective of this study was to perform unbiased proteomics analysis of the association between mid-trimester amniotic fluid proteome and spontaneous preterm delivery and gestational duration, respectively. A secondary objective was to validate and replicate the findings by enzyme-linked immunosorbent assay using a second independent cohort. Methods Women undergoing a mid-trimester genetic amniocentesis at Sahlgrenska University Hospital/Östra between September 2008 and September 2011 were enrolled in this study, designed in three analytical stages; 1) an unbiased proteomic discovery phase using LC-MS analysis of 22 women with subsequent spontaneous preterm delivery (cases) and 37 women who delivered at term (controls), 2) a validation phase of proteins of interest identified in stage 1, and 3) a replication phase of the proteins that passed validation using a second independent cohort consisting of 20 cases and 40 matched controls. Results Nine proteins were nominally significantly associated with both spontaneous preterm delivery and gestational duration, after adjustment for gestational age at sampling, but none of the proteins were significant after correction for multiple testing. Several of these proteins have previously been described as being associated with spontaneous PTD etiology and six of them were thus validated using enzyme linked immunosorbent assay. Two of the proteins passed validation; Neutrophil gelatinase-associated lipocalin and plasminogen activator inhibitor 1, but the results could not be replicated in a second cohort. Conclusions Neutrophil gelatinase-associated lipocalin and Plasminogen activator inhibitor 1 are potential biomarkers of spontaneous preterm delivery and gestational duration but the findings could not be replicated. The negative findings are supported by the fact that none of the nine proteins from the exploratory phase were significant after correction for multiple testing.
26.	Harris, Simon R., et al. (author) Public health surveillance of multidrug-resistant clones of Neisseria gonorrhoeae in Europe : a genomic survey 2018 In: The Lancet - Infectious diseases. - : Elsevier. - 1473-3099 .- 1474-4457. ; 18:7, s. 758-768 Journal article (peer-reviewed)abstract Background: Traditional methods for molecular epidemiology of Neisseria gonorrhoeae are suboptimal. Whole-genome sequencing (WGS) offers ideal resolution to describe population dynamics and to predict and infer transmission of antimicrobial resistance, and can enhance infection control through linkage with epidemiological data. We used WGS, in conjunction with linked epidemiological and phenotypic data, to describe the gonococcal population in 20 European countries. We aimed to detail changes in phenotypic antimicrobial resistance levels (and the reasons for these changes) and strain distribution (with a focus on antimicrobial resistance strains in risk groups), and to predict antimicrobial resistance from WGS data.Methods: We carried out an observational study, in which we sequenced isolates taken from patients with gonorrhoea from the European Gonococcal Antimicrobial Surveillance Programme in 20 countries from September to November, 2013. We also developed a web platform that we used for automated antimicrobial resistance prediction, molecular typing (N gonorrhoeae multi-antigen sequence typing [NG-MAST] and multilocus sequence typing), and phylogenetic clustering in conjunction with epidemiological and phenotypic data.Findings: The multidrug-resistant NG-MAST genogroup G1407 was predominant and accounted for the most cephalosporin resistance, but the prevalence of this genogroup decreased from 248 (23%) of 1066 isolates in a previous study from 2009-10 to 174 (17%) of 1054 isolates in this survey in 2013. This genogroup previously showed an association with men who have sex with men, but changed to an association with heterosexual people (odds ratio=4.29). WGS provided substantially improved resolution and accuracy over NG-MAST and multilocus sequence typing, predicted antimicrobial resistance relatively well, and identified discrepant isolates, mixed infections or contaminants, and multidrug-resistant clades linked to risk groups.Interpretation: To our knowledge, we provide the first use of joint analysis of WGS and epidemiological data in an international programme for regional surveillance of sexually transmitted infections. WGS provided enhanced understanding of the distribution of antimicrobial resistance clones, including replacement with clones that were more susceptible to antimicrobials, in several risk groups nationally and regionally. We provide a framework for genomic surveillance of gonococci through standardised sampling, use of WGS, and a shared information architecture for interpretation and dissemination by use of open access software.
27.	Hjort, Martin, et al. (author) Direct Imaging of Atomic Scale Structure and Electronic Properties of GaAs Wurtzite and Zinc Blende Nanowire Surfaces. 2013 In: Nano Letters. - : American Chemical Society (ACS). - 1530-6992 .- 1530-6984. ; 13:9, s. 4492-4498 Journal article (peer-reviewed)abstract Using scanning tunneling microscopy and spectroscopy we study the atomic scale geometry and electronic structure of GaAs nanowires exhibiting controlled axial stacking of wurtzite (Wz) and zinc blende (Zb) crystal segments. We find that the nonpolar low-index surfaces {110}, {101̅0}, and {112̅0} are unreconstructed, unpinned, and without states in the band gap region. Direct comparison between Wz and Zb GaAs reveal a type-II band alignment and a Wz GaAs band gap of 1.52 eV.
28.	Hu, Tianyi, et al. (author) Direct Observation of Liquid–Solid Two-Phase Seed Particle-Assisted Kinking in GaP Nanowire Growth 2023 In: Small Structures. - 2688-4062. ; 4:9 Journal article (peer-reviewed)abstract In the last decades, the metal-assisted growth approach of semiconductor nanowires (NWs) has shown its potential in controlling crystal properties, such as crystal structure, composition, and morphology. Recently, literature reports have shown successful semiconductor NW growth with multiphase seed particles under growth conditions. Exploring alternative metal seeds and the mechanisms for growing semiconductor NWs is an exciting research field aiming to improve the control over the crystal growth process. Herein, the gallium phosphide (GaP) NW growth using Cu as seed particles inside an environmental transmission electron microscope is studied. In particular, the transformations of the Cu-rich seed particles during the nucleation and growth of GaP NWs are observed. The supply of a relatively high amount of Ga atoms by the precursor mixture led to a solid Cu-rich seed particle core covered by a liquid phase. Different growth dynamics within the two-phase seed particle resulted in local competition in NW growth. As a result, the GaP NW kinked into another growth direction by forming a new interface at the NW growth front. The generated results enable insights into fundamental processes occurring in the seed particle during growth, creating leverage points for controlling the NW morphology.
29.	Jacobsson, Daniel, et al. (author) Crystal structure tuning in GaAs nanowires using HCl. 2014 In: Nanoscale. - : Royal Society of Chemistry (RSC). - 2040-3372 .- 2040-3364. ; 6:14, s. 8257-8264 Journal article (peer-reviewed)abstract The use of HCl during growth of nanowires presents new possibilities for controlling the growth dynamics and resulting nanowire properties. In this paper, we investigate the effects of in situ HCl on the growth of Au-seeded GaAs nanowires in a growth regime where both wurtzite and zinc blende crystal structures are possible to achieve. We find that HCl changes the crystal structure of the nanowires from pure wurtzite to defect-free zinc blende. By comparing the growth of wurtzite-zinc blende heterostructures with and without the addition of HCl, it is deduced that HCl mainly interacts with Ga species prior incorporation, reducing the amount of Ga available to contribute to the growth. We conclude that the change in crystal structure is related to the reduction of Ga adatoms, and demonstrate the realization of wurtzite-zinc blende heterostructures with atomically sharp interfaces achieved only by adding HCl.
30.	Jacobsson, Daniel, et al. (author) Crystal structure tuning in GaAs nanowires using HCl 2014 Conference paper (other academic/artistic)
31.	Jacobsson, Daniel (author) Crystal Structures in GaAs Nanowires: Growth and Characterization 2015 Doctoral thesis (other academic/artistic)abstract With their nanometer size cross-section and high aspect ratio, semiconducting nanowires have properties that make them promising as building blocks in future electronic and optoelectronic devices. Because of their small size, their optical and electrical properties can differ from their bulk counterparts, and their geometry allows for material combinations not accessible in thin films. Moreover, nanowires are possible to grow with crystal structures which are different from their stable phase in the bulk. The focus of this thesis is on tuning the crystal structure of Au-seeded GaAs nanowires between the zincblende (ZB) structure, which is stable in the bulk, and the metastable wurtzite (WZ) structure. Metal-organic vapor phase epitaxy (MOVPE) has been used to demonstrate a single temperature approach to achieving high quality WZ-ZB heterostructures. To increase the complexity of the nanowires, heterostructures with controlled ZB inclusions in WZ nanowires were also grown. Detailed post-growth analysis of the seed particle composition suggested a Ga-rich growth environment for WZ, whereas it is possible to grow defect-free ZB in As-rich conditions. To achieve a sharp interface between ZB grown with As-rich conditions and a following WZ segment, the local growth environment has to be returned to Ga-rich before growth is continued. To gain further control of the growth of polytypic GaAs nanowires, the possibility of using HCl as an additive during growth has been explored. Using in situ transmission electron microscopy, real time growth studies of GaAs WZ-ZB nanowires revealed distinct differences between the two polytypes for the growth dynamics at the seed particle-nanowire interface. By increasing or decreasing the Ga content within the Au-Ga alloy seed particle, crystal structure tuning was achieved, with the wetting angle of the seed particle as the trigger changing between growth of ZB and WZ. The different atomic arrangements in WZ and ZB GaAs mean that the two polytypes have different electronic, optical and surface properties, even though they have the same composition. This thesis work has determined the nature of the faceting of WZ-ZB heterostructures and the lattice parameters of WZ and the higher order polytype 4H, as well as the band gap of WZ and its and band alignment with ZB.
32.	Jacobsson, Daniel, et al. (author) High Quality GaAs WZ-ZB Nanowire Heterostructures 2012 Conference paper (peer-reviewed)
33.	Jacobsson, Daniel, et al. (author) In-Situ TEM Growth Studies on Polytypic GaAs Nanowires 2014 Conference paper (other academic/artistic)
34.	Jacobsson, Daniel, et al. (author) Interface dynamics and crystal phase switching in GaAs nanowires 2016 In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 531:7594, s. 317-322 Journal article (peer-reviewed)abstract Controlled formation of non-equilibrium crystal structures is one of the most important challenges in crystal growth. Catalytically grown nanowires are ideal systems for studying the fundamental physics of phase selection, and could lead to new electronic applications based on the engineering of crystal phases. Here we image gallium arsenide (GaAs) nanowires during growth as they switch between phases as a result of varying growth conditions. We find clear differences between the growth dynamics of the phases, including differences in interface morphology, step flow and catalyst geometry. We explain these differences, and the phase selection, using a model that relates the catalyst volume, the contact angle at the trijunction (the point at which solid, liquid and vapour meet) and the nucleation site of each new layer of GaAs. This model allows us to predict the conditions under which each phase should be observed, and use these predictions to design GaAs heterostructures. These results could apply to phase selection in other nanowire systems.
35.	Jacobsson, Daniel, et al. (author) Particle-assisted GaxIn1-xP nanowire growth for designed bandgap structures 2012 In: Nanotechnology. - : IOP Publishing. - 0957-4484 .- 1361-6528. ; 23:24 Journal article (peer-reviewed)abstract Non-tapered vertically straight GaxIn1-xP nanowires were grown in a compositional range from Ga0.2In0.8P to pure GaP in particle-assisted mode by controlling the trimethylindium, trimethylgallium and hydrogen chloride flows in metal-organic vapor phase epitaxy. X-ray energy dispersive spectroscopy in transmission electron microscopy revealed homogeneous radial material composition in single nanowires, whereas variations in the material composition were found along the nanowires. High-resolution x-ray diffraction indicates a variation of the material composition on the order of about 19% measuring an entire sample area, i.e., including edge effects during growth. The non-capped nanowires emit room temperature photoluminescence strongly in the energy range of 1.43-2.16 eV, correlated with the bandgap expected from the material composition.
36.	Jacobsson, Daniel, et al. (author) Phase Transformation in Radially Merged Wurtzite GaAs Nanowires. 2015 In: Crystal Growth & Design. - : American Chemical Society (ACS). - 1528-7483 .- 1528-7505. ; 15:10, s. 4795-4803 Journal article (peer-reviewed)abstract III-V Nanowires (NWs) grown with metal-organic chemical vapor deposition commonly show a polytypic crystal structure, allowing growth of structures not found in the bulk counterpart. In this paper we studied the radial overgrowth of pure wurtzite (WZ) GaAs nanowires and characterized the samples with high resolution X-ray diffraction (XRD) to reveal the crystal structure of the grown material. In particular, we investigated what happens when adjacent WZ NWs radially merge with each other by analyzing the evolution of XRD peaks for different amounts of radial overgrowth and merging. By preparing cross-sectional lamella samples we also analyzed the local crystal structure of partly merged NWs by transmission electron microscopy. Once individual NWs start to merge, the crystal structure of the merged segments is transformed progressively from initial pure WZ to a mixed WZ/ZB structure. The merging process is then modeled using a simple combinatorial approach, which predicts that merging of two or more WZ NWs will result in a mixed crystal structure containing WZ, ZB, and 4H. The existence large and relaxed segments of 4H structure within the merged NWs was confirmed by XRD, allowing us to accurately determine the lattice parameters of GaAs 4H. We compare the measured WZ and 4H unit cells with an ideal tetrahedron and find that both the polytypes are elongated in the c-axis and compressed in the a-axis compared to the geometrically converted cubic ZB unit cell.
37.	Jacobsson, Daniel, et al. (author) Zincblende-to-wurtzite interface improvement by group III loading in Au-seeded GaAs nanowires 2013 In: Physica Status Solidi. Rapid Research Letters. - : Wiley. - 1862-6254. ; 7:10, s. 855-859 Journal article (peer-reviewed)abstract Achieving control of the crystal structure is essential in III-V nanowires, since twin defects, stacking faults and uncontrolled zincblende-wurtzite polytypism could have detrimental effects on the physical properties. In addition, precise control of the crystal phases also opens up the possibility of homomaterial bandgap engineering. Here, we show by ex situ chemical analysis of the alloy seed particle that Ga-rich conditions are required for growth of wurtzite GaAs nanowires using Au seed particles in MOVPE. Based on this understanding, we propose and demonstrate a growth procedure to significantly improve the crystal structure quality of the zincblende-to-wurtzite transition in GaAs nanowire heterostructures. ((c) 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)
38.	Jacobsson, Hanna, et al. (author) Hypoxia-induced secretion stimulates breast cancer stem cell regulatory signalling pathways 2019 In: Molecular Oncology. - : Wiley. - 1574-7891 .- 1878-0261. ; 13:8, s. 1693-1705 Journal article (peer-reviewed)abstract It is well known that tumour cells are dependent on communication with the tumour microenvironment. Previously, it has been shown that hypoxia (HX) induces pronounced, diverse and direct effects on cancer stem cell (CSC) qualities in different breast cancer subtypes. Here, we describe the mechanism by which HX-induced secretion influences the spreading of CSCs. Conditioned media (CM) from estrogen receptor (ER)-α-positive hypoxic breast cancer cell cultures increased the fraction of CSCs compared to normal growth conditions, as determined using sets of CSC assays and model systems. In contrast, media from ERα-negative hypoxic cell cultures instead decreased this key subpopulation of cancer cells. Further, there was a striking overrepresentation of JAK-STAT-associated cytokines in both the ERα-positive and ERα-negative linked hypoxic responses as determined by a protein screen of the CM. JAK-STAT inhibitors and knockdown experiments further supported the hypothesis that this pathway is critical for the CSC-activating and CSC-inactivating effects induced by hypoxic secretion. We also observed that the interleukin-6-JAK2-STAT3 axis was specifically central for the ERα-negative hypoxic behaviour. Our results underline the importance of considering breast cancer subtypes in treatments targeting JAK-STAT or HX-associated processes and indicate that HX is not only a confined tumour biological event, but also influences key tumour properties in widespread normoxic microenvironments. © 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.
39.	Jacobsson, Lars, et al. (author) The functioning of flange joints – findings from full scale experiments and FEM analyses 2012 In: Proceedings of PPXVI. Conference paper (peer-reviewed)
40.	Jacobsson, Lars, et al. (author) Tightness of flange joints for large polyethylene pipes – Part 1 Numerical simulations 2011 Reports (peer-reviewed)abstract Tightness of flange joints for large polyethylene pipes – Part 1 Numerical simulations Leaks occasionally occur in flange joints in plastic pipelines, predominantly large dimension ones. Such pipelines are normally of importance for e g water supply, and repair is expensive. A better understanding is vital since a clear background is missing for the existing design and mounting recommendations, which also are differing. Analysis of plastic flanges is more complicated than for metal ones since the material is time dependent, and much softer than the backing rings and bolts. The aim of this work was to be able to assess on one hand if presently standardized flange geometries mean smaller safety margins when the size of the pipe is increased, and on the other hand if the instructions for mounting have to be improved. First, an analysis was made by manual calculations, without consideration of the time dependent properties of the material, in order to assess the stresses just after tightening of the joint but before pressurizing and start of service time of the pipeline. The manual analysis is of course misleading for assessment of the compression stresses in the flange surfaces over time, although it seems that such calculations often are used for design. The value of the manual analysis was mainly that it showed that the nominal stresses are similar for different sizes, except for the 630 mm pipe where they are significantly higher. Further it was established that pressurizing of the pipe means a moderate influence on the flange stresses and bolt forces, 10-15%, and that the bolt and backing ring are much stiffer than the plastic flange, meaning that it is mainly relaxation that is responsible for unloading of the joint over time. Computer simulations (FEM) were then made of both the tightening and the service phase for a set of geometries, and with a material model including time dependent properties of the plastic parts of the joint using material data from in-house experiments. Although the computer simulations are approximate too, they give a much better impression both of the principal function of the joint and of the magnitude of the stresses over time. It appears that the geometry of the flange joint means that the contact is lost over large parts of the flange surfaces already at pressurizing and that a triangular distribution of pressure covering a part of the flange surface corresponding to the width of the backing ring is developed over time which should be sufficient to keep the joint tight. The effects of gaskets and profiled, softer, backing rings are clarified, and it is indicated that re-tightening is an efficient way to improve the function of the joint over time. Further, it seems that there is no significant difference in behaviour, as regards flange pressure, between SDR 11 and SDR 17 geometries. So, the FEM investigation has revealed that intuitive thoughts about reasons for inferior functioning of large size flange joints in plastic pipes are not well founded. The most efficient way to improve the joint is to increase the bolt force and to keep it up, by re-tightening or by flexible backing rings. Gaskets, soft ones, may be beneficial for reducing unevenness of the plastic joint surfaces.
41.	Jacobsson, Maritha, et al. (author) Akademisering av examensmålet våld i nära relation i socialt arbete 2021 In: Socialmedicinsk Tidskrift. - 0037-833X. ; 98:4, s. 615-623 Journal article (peer-reviewed)abstract Enligt det nya examensmålet skall studenter inom socionomutbildningen visa kunskap om mäns våld mot kvinnor och våld i nära relation. Implementeringen av kunskapsmålet har i hög grad lämnats åt respektive lärosäte att uppfylla avseende innehåll och utformning i utbildningen. Vid Centrum för socialt arbete, Cesar, utvecklades en särskild kurs för ändamålet: Våld i nära relation, på 7,5 högskolepoäng. Kursen innefattade kunskap om företeelsen i allmänhet men även fördjupande avsnitt i relation till särskilt utsatta grupper. Med hjälp av case-metodik fick studenterna möjlighet att analysera, argumentera och diskutera komplexa problem. Vid utvärderingen i samband med kursavslut identifierades fortsatta utvecklingsområden för kursen, bland annat behovet av att följa studentgruppen närmare då vissa kan ha egna obearbetade erfarenheter av våld. En annan aspekt som berörts i lärarlaget är vikten av att reflektera över ämnets (eventuella) politisering.
42.	Jacobsson, Susanne, 1974-, et al. (author) High In Vitro Activity of the Novel Spiropyrimidinetrione AZD0914, a DNA Gyrase Inhibitor, against Multidrug-Resistant Neisseria gonorrhoeae Isolates Suggests a New Effective Option for Oral Treatment of Gonorrhea 2014 In: Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 58:9, s. 5585-5588 Journal article (peer-reviewed)abstract We evaluated the activity of the novel spiropyrimidinetrione AZD0914 (DNA gyrase inhibitor) against clinical gonococcal isolates and international reference strains (n = 250), including strains with diverse multidrug resistance and extensive drug resistance. The AZD0914 MICs were substantially lower than those of most other currently or previously recommended antimicrobials. AZD0914 should be further evaluated, including in vitro selection, in vivo emergence and mechanisms of resistance, pharmacokinetics/pharmacodynamics in humans, optimal dosing, and performance, in appropriate randomized and controlled clinical trials.
43.	Jacobsson, Susanne, 1974-, et al. (author) In Vitro Activity of the Novel Pleuromutilin Lefamulin (BC-3781) and Effect of Efflux Pump Inactivation on Multidrug-Resistant and Extensively Drug-Resistant Neisseria gonorrhoeae 2017 In: Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 61:11 Journal article (peer-reviewed)abstract We evaluated the activity of the novel semisynthetic pleuromutilin lefamulin, inhibiting protein synthesis and growth, and the effect of efflux pump inactivation on clinical gonococcal isolates and reference strains (n = 251), including numerous multidrug-resistant and extensively drug-resistant isolates. Lefamulin showed potent activity against all gonococcal isolates, and no significant cross-resistance to other antimicrobials was identified. Further studies of lefamulin are warranted, including in vitro selection and mechanisms of resistance, pharmacokinetics/pharmacodynamics, optimal dosing, and performance in randomized controlled trials.
44.	Jacobsson, Susanne, 1974-, et al. (author) In vitro activity of the novel triazaacenaphthylene gepotidacin (GSK2140944) against MDR Neisseria gonorrhoeae 2018 In: Journal of Antimicrobial Chemotherapy. - : Oxford University Press. - 0305-7453 .- 1460-2091. ; 73:8, s. 2072-2077 Journal article (peer-reviewed)abstract Objectives: Increased antimicrobial resistance surveillance and new effective antimicrobials are crucial to maintain treatable gonorrhoea. We examined the in vitro activity of gepotidacin, a novel triazaacenaphthylene, and the effect of efflux pump inactivation on clinical Neisseria gonorrhoeae isolates and international reference strains (n = 252) and compared gepotidacin with antimicrobials currently or previously recommended for gonorrhoea treatment.Methods: MICs (mg/L) were determined by agar dilution (gepotidacin) or by Etest (seven other antimicrobials). The gyrA and parC genes were sequenced and the impact of inactivation of the MtrCDE, MacAB and NorM efflux pumps on gepotidacin MICs was examined.Results: Gepotidacin showed potent in vitro activity against all gonococcal isolates (n = 252; MIC <= 4 mg/L). The modal MIC, MIC50 , MIC90 and MIC range of gepotidacin were 0.5, 0.5, 1 and 0.032-4 mg/L, respectively. Inactivation of the MtrCDE efflux pump, but not MacAB or NorM, decreased the gepotidacin MICs for most strains. No significant cross-resistance between gepotidacin and any other antimicrobials, including the fluoroquinolone ciprofloxacin, was identified. However, the ParC D86N mutation (possibly together with additional antimicrobial resistance mutation), which is associated with fluoroquinolone resistance, was associated with increased gepotidacin MICs.Conclusions: Gepotidacin demonstrated high in vitro activity against gonococcal strains, indicating that gepotidacin could potentially be an effective option for gonorrhoea treatment, particularly in a dual antimicrobialtherapy regimen and for patients with resistance or allergy to extended-spectrum cephalosporins. Nevertheless, elucidating in vitro and in vivo resistance emergence and mechanisms in detail, together with further gonorrhoea clinical studies, ideally also including chlamydia and Mycoplasma genitalium are essential.
45.	Jacobsson, Susanne, 1974-, et al. (author) Pharmacodynamic Evaluation of Dosing, Bacterial Kill, and Resistance Suppression for Zoliflodacin Against Neisseria gonorrhoeae in a Dynamic Hollow Fiber Infection Model 2021 In: Frontiers in Pharmacology. - : Frontiers Media S.A.. - 1663-9812. ; 12 Journal article (peer-reviewed)abstract Antimicrobial resistance in Neisseria gonorrhoeae is threatening the treatment and control of gonorrhea globally, and new treatment options are imperative. Utilizing our dynamic in vitro hollow fiber infection model (HFIM), we examined the pharmacodynamics of the first-in-class spiropyrimidinetrione (DNA gyrase B inhibitors), zoliflodacin, against the N. gonorrhoeae reference strains World Health Organization F (susceptible to all relevant antimicrobials) and WHO X (extensively drug resistant, including resistance to ceftriaxone) over 7 days. Dose-range experiments with both strains, simulating zoliflodacin single oral dose regimens of 0.5-8 g, and dose-fractionation experiments with WHO X, simulating zoliflodacin oral dose therapy with 1-4 g administered as q12 h and q8 h for 24 h, were performed. A kill-rate constant that reflected a rapid bacterial kill during the first 6.5 h for both strains and all zoliflodacin doses was identified. In the dose-range experiments, the zoliflodacin 2-8 g single-dose treatments successfully eradicated both WHO strains, and resistance to zoliflodacin was not observed. However, zoliflodacin as a single 0.5 g dose failed to eradicate both WHO strains, and a 1 g single dose failed to eradicate WHO X in one of two experiments. The zoliflodacin 1 g/day regimen also failed to eradicate WHO X when administered as two and three divided doses given at q12 h and q8 h in the dose-fractionation studies, respectively. All failed regimens selected for zoliflodacin-resistant mutants. In conclusion, these data demonstrate that zoliflodacin should be administered at >2 g as a single oral dose to provide effective killing and resistance suppression of N. gonorrhoeae. Future studies providing pharmacokinetic data for zoliflodacin (and other gonorrhea therapeutic antimicrobials) in urogenital and extragenital infection sites, particularly in the pharynx, and evaluation of gonococcal strains with different gyrB mutations would be important.
46.	Jacobsson, Susanne, 1974-, et al. (author) Pharmacodynamic evaluation of lefamulin in the treatment of gonorrhea using a hollow fiber infection model simulating Neisseria gonorrhoeae infections 2022 In: Frontiers in Pharmacology. - : Frontiers Media S.A.. - 1663-9812. ; 13 Journal article (peer-reviewed)abstract The emergence and spread of antimicrobial resistance in Neisseria gonorrhoeae is seriously threatening the treatment and control of gonorrhea globally. Novel treatment options are essential, coupled with appropriate methods to pharmacodynamically examine the efficacy and resistance emergence of these novel drugs. Herein, we used our dynamic in vitro hollow fiber infection model (HFIM) to evaluate protein-unbound lefamulin, a semisynthetic pleuromutilin, against N. gonorrhoeae. Dose-range and dose-fractionation experiments with N. gonorrhoeae reference strains: WHO F (susceptible to all relevant antimicrobials), WHO X (extensively drug-resistant, including ceftriaxone resistance), and WHO V (high-level azithromycin resistant, and highest gonococcal MIC of lefamulin (2 mg/l) reported), were performed to examine lefamulin gonococcal killing and resistance development during treatment. The dose-range experiments, simulating a single oral dose of lefamulin based on human plasma concentrations, indicated that ≥1.2 g, ≥2.8 g, and ≥9.6 g of lefamulin were required to eradicate WHO F, X, and V, respectively. Dose-fractionation experiments, based on human lefamulin plasma concentrations, showed that WHO X was eradicated with ≥2.8 g per day when administered as q12 h (1.4 g twice a day) and with ≥3.6 g per day when administered as q8 h (1.2 g thrice a day), both for 7 days. However, when simulating the treatment with 5-10 times higher concentrations of free lefamulin in relevant gonorrhea tissues (based on urogenital tissues in a rat model), 600 mg every 12 h for 5 days (approved oral treatment for community-acquired bacterial pneumonia) eradicated all strains, and no lefamulin resistance emerged in the successful treatment arms. In many arms failing single or multiple dose treatments for WHO X, lefamulin-resistant mutants (MIC = 2 mg/l), containing an A132V amino acid substitution in ribosomal protein L3, were selected. Nevertheless, these lefamulin-resistant mutants demonstrated an impaired biofitness. In conclusion, a clinical study is warranted to elucidate the clinical potential of lefamulin as a treatment option for uncomplicated gonorrhea (as well as several other bacterial STIs).
47.	Jacobsson, Susanne, 1974-, et al. (author) Pharmacodynamic evaluation of zoliflodacin dosing,bacterial kill and resistance suppression in Neisseria gonorrhoeae using a dynamichollow fiber infection model 2022 Conference paper (other academic/artistic)
48.	Jacobsson, Susanne, 1974-, et al. (author) Pharmacodynamic Evaluation of Zoliflodacin Treatment of Neisseria gonorrhoeae Strains With Amino Acid Substitutions in the Zoliflodacin Target GyrB Using a Dynamic Hollow Fiber Infection Model 2022 In: Frontiers in Pharmacology. - : Frontiers Media S.A.. - 1663-9812. ; 13 Journal article (peer-reviewed)abstract Novel antimicrobials for effective treatment of uncomplicated gonorrhea are essential, and the first-in-class, oral spiropyrimidinetrione DNA gyrase B inhibitor zoliflodacin appears promising. Using our newly developed Hollow Fiber Infection Model (HFIM), the pharmacodynamics of zoliflodacin was examined. A clinical zoliflodacin-susceptible N. gonorrhoeae strain, SE600/18 (harbouring a GyrB S467N amino acid substitution; MIC = 0.25 mg/L), and SE600/18-D429N (zoliflodacin-resistant mutant with a second GyrB substitution, D429N, selected in the HFIM experiments; zoliflodacin MIC = 2 mg/L), were examined. Dose-range experiments, simulating zoliflodacin single oral dose regimens of 0.5, 1, 2, 3, and 4 g, were performed for SE600/18. For SE600/18-D429N, dose-range experiments, simulating zoliflodacin single oral 2, 3, 4, and 6 g doses, and zoliflodacin oral dose-fractionation experiments with 4, 6, and 8 g administered as q12 h were performed. Both strains grew well in the untreated HFIM growth control arms and mostly maintained growth at 1010-1011 CFU/ml for 7 days. Zoliflodacin 3 and 4 g single dose oral regimens successfully eradicated SE600/18 and no growth was recovered during the 7-days experiments. However, the single oral 0.5, 1, and 2 g doses failed to eradicate SE600/18, and zoliflodacin-resistant populations with a GyrB D429N substitution were selected with all these doses. The zoliflodacin-resistant SE600/18-D429N mutant was not eradicated with any examined treatment regimen. However, this in vitro-selected zoliflodacin-resistant mutant was substantially less fit compared to the zoliflodacin-susceptible SE600/18 parent strain. In conclusion, the rare clinical gonococcal strains with GyrB S467N substitution are predisposed to develop zoliflodacin resistance and may require treatment with zoliflodacin ≥3 g. Future development may need to consider the inclusion of diagnostics directed at identifying strains resistant or predisposed to resistance development at a population level and to strengthen surveillance (phenotypically and genetically), and possibly also at the patient level to guide treatment.
49.	Jacobsson, Susanne, 1974-, et al. (author) Pharmacodynamics of zoliflodacin plus doxycycline combination therapy against Neisseria gonorrhoeae in a gonococcal hollow-fiber infection model 2023 In: Frontiers in Pharmacology. - : Frontiers Media S.A.. - 1663-9812. ; 14 Journal article (peer-reviewed)abstract Antimicrobial resistance in the sexually transmitted bacterium Neisseria gonorrhoeae is compromising the management and control of gonorrhea globally. Optimized use and enhanced stewardship of current antimicrobials and development of novel antimicrobials are imperative. The first in class zoliflodacin (spiropyrimidinetrione, DNA Gyrase B inhibitor) is a promising novel antimicrobial in late-stage clinical development for gonorrhea treatment, i.e., the phase III randomized controlled clinical trial (ClinicalTrials.gov Identifier: NCT03959527) was recently finalized, and zoliflodacin showed non-inferiority compared to the recommended ceftriaxone plus azithromycin dual therapy. Doxycycline, the first-line treatment for chlamydia and empiric treatment for non-gonococcal urethritis, will be frequently given together with zoliflodacin because gonorrhea and chlamydia coinfections are common. In a previous static in vitro study, it was indicated that doxycycline/tetracycline inhibited the gonococcal killing of zoliflodacin in 6-h time-kill curve analysis. In this study, our dynamic in vitro hollow-fiber infection model (HFIM) was used to investigate combination therapies with zoliflodacin and doxycycline. Dose-range experiments using the three gonococcal strains WHO F (susceptible to relevant therapeutic antimicrobials), WHO X (extensively drug-resistant, including ceftriaxone-resistant; zoliflodacin-susceptible), and SE600/18 (zoliflodacin-susceptible strain with GyrB S467N substitution) were conducted simulating combination therapy with a single oral dose of zoliflodacin 0.5-4 g combined with a doxycycline daily oral dose of 200 mg administered as 100 mg twice a day, for 7 days (standard dose for chlamydia treatment). Comparing combination therapy of zoliflodacin (0.5-4 g single dose) plus doxycycline (200 mg divided into 100 mg twice a day orally, for 7 days) to zoliflodacin monotherapy (0.5-4 g single dose) showed that combination therapy was slightly more effective than monotherapy in the killing of N. gonorrhoeae and suppressing emergence of zoliflodacin resistance. Accordingly, WHO F was eradicated by only 0.5 g single dose of zoliflodacin in combination with doxycycline, and WHO X and SE600/18 were both eradicated by a 2 g single dose of zoliflodacin in combination with doxycycline; no zoliflodacin-resistant populations occurred during the 7-day experiment when using this zoliflodacin dose. When using suboptimal (0.5-1 g) zoliflodacin doses together with doxycycline, gonococcal mutants with increased zoliflodacin MICs, due to GyrB D429N and the novel GyrB T472P, emerged, but both the mutants had an impaired biofitness. The present study shows the high efficacy of zoliflodacin plus doxycycline combination therapy using a dynamic HFIM that more accurately and comprehensively simulate gonococcal infection and their treatment, i.e., compared to static in vitro models, such as short-time checkerboard experiments or time-kill curve analysis. Based on our dynamic in vitro HFIM work, zoliflodacin plus doxycycline for the treatment of both gonorrhea and chlamydia can be an effective combination.
50.	Jacobsson, Susanne, 1974-, et al. (author) WGS analysis and molecular resistance mechanisms of azithromycin-resistant (MIC >2 mg/L) Neisseria gonorrhoeae isolates in Europe from 2009 to 2014 2016 In: Journal of Antimicrobial Chemotherapy. - Oxford, United Kingdom : Oxford University Press. - 0305-7453 .- 1460-2091. ; 71:11, s. 3109-3116 Journal article (peer-reviewed)abstract Objectives: To elucidate the genome-based epidemiology and phylogenomics of azithromycin-resistant (MIC >2 mg/L) Neisseria gonorrhoeae strains collected in 2009-14 in Europe and clarify the azithromycin resistance mechanisms.Methods: Seventy-five azithromycin-resistant (MIC 4 to >256 mg/L) N. gonorrhoeae isolates collected in 17 European countries during 2009-14 were examined using antimicrobial susceptibility testing and WGS.Results: Thirty-six N. gonorrhoeae multi-antigen sequence typing STs and five phylogenomic clades, including 4-22 isolates from several countries per clade, were identified. The azithromycin target mutation A2059G (Escherichia coli numbering) was found in all four alleles of the 23S rRNA gene in all isolates with high-level azithromycin resistance (n = 4; MIC ≥256 mg/L). The C2611T mutation was identified in two to four alleles of the 23S rRNA gene in the remaining 71 isolates. Mutations in mtrR and its promoter were identified in 43 isolates, comprising isolates within the whole azithromycin MIC range. No mutations associated with azithromycin resistance were found in the rplD gene or the rplV gene and none of the macrolide resistance-associated genes [mef(A/E), ere(A), ere(B), erm(A), erm(B), erm(C) and erm(F)] were identified in any isolate.Conclusions: Clonal spread of relatively few N. gonorrhoeae strains accounts for the majority of the azithromycin resistance (MIC >2 mg/L) in Europe. The four isolates with high-level resistance to azithromycin (MIC ≥256 mg/L) were widely separated in the phylogenomic tree and did not belong to any of the main clades. The main azithromycin resistance mechanisms were the A2059G mutation (high-level resistance) and the C2611T mutation (low- and moderate-level resistance) in the 23S rRNA gene.

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