| 1. |
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| 2. |
- Taddei, C, et al.
(författare)
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Repositioning of the global epicentre of non-optimal cholesterol
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 582:7810, s. 73-
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Tidskriftsartikel (refereegranskat)abstract
- High blood cholesterol is typically considered a feature of wealthy western countries1,2. However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world3 and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health4,5. However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol—which is a marker of cardiovascular risk—changed from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95% credible interval 3.7 million–4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and personal interventions to improve nutrition and enhance access to treatment throughout the world.
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| 3. |
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| 4. |
- Abe, O, et al.
(författare)
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Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials
- 2005
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Ingår i: The Lancet. - 1474-547X. ; 365:9472, s. 1687-1717
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Tidskriftsartikel (refereegranskat)abstract
- Background Quinquennial overviews (1985-2000) of the randomised trials in early breast cancer have assessed the 5-year and 10-year effects of various systemic adjuvant therapies on breast cancer recurrence and survival. Here, we report the 10-year and 15-year effects. Methods Collaborative meta-analyses were undertaken of 194 unconfounded randomised trials of adjuvant chemotherapy or hormonal therapy that began by 1995. Many trials involved CMF (cyclophosphamide, methotrexate, fluorouracil), anthracycline-based combinations such as FAC (fluorouracil, doxombicin, cyclophosphamide) or FEC (fluorouracil, epirubicin, cyclophosphamide), tamoxifen, or ovarian suppression: none involved taxanes, trastuzumab, raloxifene, or modem aromatase inhibitors. Findings Allocation to about 6 months of anthracycline-based polychemotherapy (eg, with FAC or FEC) reduces the annual breast cancer death rate by about 38% (SE 5) for women younger than 50 years of age when diagnosed and by about 20% (SE 4) for those of age 50-69 years when diagnosed, largely irrespective of the use of tamoxifen and of oestrogen receptor (ER) status, nodal status, or other tumour characteristics. Such regimens are significantly (2p=0 . 0001 for recurrence, 2p<0 . 00001 for breast cancer mortality) more effective than CMF chemotherapy. Few women of age 70 years or older entered these chemotherapy trials. For ER-positive disease only, allocation to about 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31% (SE 3), largely irrespective of the use of chemotherapy and of age (<50, 50-69, &GE; 70 years), progesterone receptor status, or other tumour characteristics. 5 years is significantly (2p<0 . 00001 for recurrence, 2p=0 . 01 for breast cancer mortality) more effective than just 1-2 years of tamoxifen. For ER-positive tumours, the annual breast cancer mortality rates are similar during years 0-4 and 5-14, as are the proportional reductions in them by 5 years of tamoxifen, so the cumulative reduction in mortality is more than twice as big at 15 years as at 5 years after diagnosis. These results combine six meta-analyses: anthracycline-based versus no chemotherapy (8000 women); CMF-based versus no chemotherapy (14 000); anthracycline-based versus CMF-based chemotherapy (14 000); about 5 years of tamoxifen versus none (15 000); about 1-2 years of tamoxifen versus none (33 000); and about 5 years versus 1-2 years of tamoxifen (18 000). Finally, allocation to ovarian ablation or suppression (8000 women) also significantly reduces breast cancer mortality, but appears to do so only in the absence of other systemic treatments. For middle-aged women with ER-positive disease (the commonest type of breast cancer), the breast cancer mortality rate throughout the next 15 years would be approximately halved by 6 months of anthracycline-based chemotherapy (with a combination such as FAC or FEC) followed by 5 years of adjuvant tamoxifen. For, if mortality reductions of 38% (age <50 years) and 20% (age 50-69 years) from such chemotherapy were followed by a further reduction of 31% from tamoxifen in the risks that remain, the final mortality reductions would be 57% and 45%, respectively (and, the trial results could well have been somewhat stronger if there had been full compliance with the allocated treatments). Overall survival would be comparably improved, since these treatments have relatively small effects on mortality from the aggregate of all other causes. Interpretation Some of the widely practicable adjuvant drug treatments that were being tested in the 1980s, which substantially reduced 5-year recurrence rates (but had somewhat less effect on 5-year mortality rates), also substantially reduce 15-year mortality rates. Further improvements in long-term survival could well be available from newer drugs, or better use of older drugs.
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| 5. |
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| 6. |
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| 7. |
- Fynbo, J. P. U., et al.
(författare)
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Galaxy counterparts of metal-rich damped Ly alpha absorbers - I. The case of the z=2.35 DLA towards Q2222-0946
- 2010
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 408:4, s. 2128-2136
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Tidskriftsartikel (refereegranskat)abstract
- We have initiated a survey using the newly commissioned X-shooter spectrograph to target candidate relatively metal-rich damped Ly alpha absorbers (DLAs). Our rationale is that high-metallicity DLAs due to the luminosity-metallicity relation likely will have the most luminous galaxy counterparts. In addition, the spectral coverage of X-shooter allows us to search for not only Ly alpha emission, but also rest-frame optical emission lines. We have chosen DLAs where the strongest rest-frame optical lines ([O II], [O III], H beta and H alpha) fall in the near-infrared atmospheric transmission bands. In this first paper resulting from the survey, we report on the discovery of the galaxy counterpart of the z(abs) = 2.354 DLA towards the z = 2.926 quasar Q2222-0946. This DLA is amongst the most metal-rich z > 2 DLAs studied so far at comparable redshifts and there is evidence for substantial depletion of refractory elements on to dust grains. We measure metallicities from Zn II, Si II, Ni II, Mn II and Fe II of -0.46 +/- 0.07, -0.51 +/- 0.06, -0.85 +/- 0.06, -1.23 +/- 0.06 and -0.99 +/- 0.06, respectively. The galaxy is detected in the Ly alpha, [O III] lambda lambda 4959, 5007 and H alpha emission lines at an impact parameter of about 0.8 arcsec (6 kpc at z(abs) = 2.354). Based on the H alpha line, we infer a star formation rate of 10M(circle dot) yr(-1), which is a lower limit due to the possibility of slit loss. Compared to the recently determined H alpha luminosity function for z = 2.2 galaxies, the DLA-galaxy counterpart has a luminosity of L similar to 0.1L*(H alpha). The emission-line ratios are 4.0 (Ly alpha/H alpha) and 1.2 ([O III]/H alpha). In particular, the Ly alpha line shows clear evidence for resonant scattering effects, namely an asymmetric, redshifted (relative to the systemic redshift) component and a much weaker blueshifted component. The fact that the blueshifted component is relatively weak indicates the presence of a galactic wind. The properties of the galaxy counterpart of this DLA are consistent with the prediction that metal-rich DLAs are associated with the most luminous of the DLA-galaxy counterparts.
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| 8. |
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| 9. |
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| 10. |
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| 11. |
- Fynbo, J. P. U., et al.
(författare)
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Galaxy counterparts of metal-rich damped Ly alpha absorbers - II. A solar-metallicity and dusty DLA at z(abs)=2.58
- 2011
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 413:4, s. 2481-2488
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Tidskriftsartikel (refereegranskat)abstract
- This is the second paper of a series reporting on the results from a survey conducted with the ESO VLT/X-shooter spectrograph. We target high-metallicity damped Lyman alpha absorbers (DLAs) with the aim of investigating the relation between galaxies detected in emission and those detected in absorption. Here, we report on the discovery of the galaxy counterpart of the z(abs) = 2.58 DLA on the line-of-sight to the z = 3.07 quasar SDSS J 091826.16+163609.0 (hereafter Q 0918+1636). The galaxy counterpart of the DLA is detected in the [O iii] lambda 5007 and [O ii] lambda lambda 3726, 3729 emission lines redshifted into the NIR at an impact parameter of 2.0 arcsec (16 kpc at z = 2.58). Ly alpha emission is not detected down to a 3 Sigma detection limit of 5 x 10-18 erg s-1 cm-2, which, compared to the strength of the oxygen lines, implies that Ly alpha emission from this galaxy is suppressed by more than an order of magnitude. The DLA has one of the highest metallicities measured so far at comparable redshifts. We find evidence for substantial depletion of refractory elements on to dust grains. Fitting the main metal line component of the DLA, which is located at z(abs) = 2.5832, we measure the metal abundances from Zn ii, S ii, Si ii, Cr ii, Mn ii, Fe ii and Ni ii to be -0.12 +/- 0.05, -0.26 +/- 0.05, -0.46 +/- 0.05, -0.88 +/- 0.05, -0.92 +/- 0.05, -1.03 +/- 0.05 and -0.78 +/- 0.05, respectively. In addition, we detect absorption in the Lyman and Werner bands of molecular hydrogen (H(2)), which represents the first detection of H(2) molecules with X-shooter. The background quasar Q 0918+1636 is amongst the reddest QSOs at redshifts 3.02 < z < 3.12 from the SDSS catalogue. Its UV to NIR spectrum is well fitted by a composite QSO spectrum reddened by SMC-/LMC-like extinction curves at z(abs) = 2.58 with a significant amount of extinction given by A(V) approximate to 0.2 mag. This supports previous claims that there may be more metal-rich DLAs missing from current samples due to dust reddening of the background QSOs. The fact that there is evidence for dust both in the central emitting regions of the galaxy (as evidenced by the lack of Ly alpha emission) and at an impact parameter of 16 kpc (as probed by the DLA) suggests that dust is widespread in this system.
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| 12. |
- Fynbo, J. P. U., et al.
(författare)
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Galaxy counterparts of metal-rich damped Lyman-alpha absorbers - II. A solar-metallicity and dusty DLA at z_abs=2.58
- 2010
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Annan publikation (populärvet., debatt m.m.)abstract
- [Abridged]. Here, we report on the discovery of the galaxy counterpart of the z_abs=2.58 DLA on the line-of-sight to the z=3.07 quasar SDSS J091826.16+163609.0. The galaxy counterpart of the DLA is detected in the OIII 5007 and OII 3726,3729 emission lines redshifted into the NIR at an impact parameter of 16 kpc. Ly-alpha emission is not detected. The upper limit implies that Ly-alpha emission from this galaxy is suppressed by more than an order of magnitude. The DLA is amongst the most metal-rich DLAs studied so far at comparable redshifts. We find evidence for substantial depletion of refractory elements onto dust grains. Fitting the main metal line component of the DLA, which is located at z_abs=2.5832 and accounts for at least 85% of the total column density of low-ionisation species, we measure metal abundances from ZnII, SII, SiII, CrII, MnII, FeII and NiII of -0.12, -0.26, -0.46, -0.88, -0.92, -1.03 and -0.78, respectively. In addition, we detect absorption in the Lyman and Werner bands of hydrogen, which represents the first detection of H_2 molecules with X-shooter. The background quasar Q0918+1636 is amongst the reddest QSOs at redshifts 3.02<3.12 from the SDSS catalogue. Its UV to NIR spectrum is well fitted by a composite QSO spectrum reddened by SMC/LMC-like extinction curves at z_abs=2.58 with a significant amount of extinction given by A_V = 0.2 mag. This supports previous claims that there may be more metal-rich DLAs missing from current samples due to dust reddening of the background QSOs. The fact that there is evidence for dust both in the central emitting regions of the galaxy (as evidenced by the lack of Ly-alpha emission) and at an impact parameter of 16 kpc (as probed by the DLA) suggests that dust is widespread in this system.
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| 13. |
- Boulakh, L., et al.
(författare)
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Nationwide Incidence of Thyroid Eye Disease and Cumulative Incidence of Strabismus and Surgical Interventions in Denmark
- 2022
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Ingår i: Jama Ophthalmology. - : American Medical Association (AMA). - 2168-6165. ; 140:7, s. 667-673
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE Thyroid eye disease (TED) is a serious condition that can cause proptosis and strabismus and, in rare cases, lead to blindness. Incidence data for TED and strabismus and surgical interventions after TED are sparce. OBJECTIVE To investigate the nationwide incidence of TED, strabismus, and surgical interventions associated with TED. DESIGN, SETTING, AND PARTICIPANTS A Danish nationwide registry-based cohort study between 2000, which marks the beginning of uniform coding for the decompression surgery nationwide, and 2018. The cohort consisted of a mean 4.3 million people aged 18 to 100 years with no prior TED diagnosis each year. Total observation time was 8.22 x 10(7) person-years (women, 4.18 x 10(7) person-years; men, 4.04 x 10(7) person-years). MAIN OUTCOME MEASURES The annual numeric and age-standardized incidence of hospital-treated TED and cumulative incidence of strabismus, strabismus surgery, and orbital decompression surgery in patients with TED. The incidence was stratified by sex, thyroid diagnosis, and age. RESULTS A total of 4106 incident diagnoses of TED were identified during 19 years among 3344 women (81.4%) and 762 men (18.6%). The mean numeric annual nationwide incidence rate of TED was 5,0 per 100 000 person-years overall, 8.0 per 100 000 person-years in women, and 1.9 per 100 000 person-years in men, resulting in a 4:1 ratio of women to men with TED. The age-standardized incidence was similar. The mean (SD) age at onset was 51.3 (14.5) years. At the time of TED diagnosis, 611 patients (14.9%) were euthyroid, 477 (11.6%) were hypothyroid, and 3018 (73.5%) were hyperthyroid. In patients with TED who were euthyroid, the 4-year cumulative incidence was 41% for antithyroid medication and 13% for L-thyroxine. In patients with TED, the 4-year cumulative incidence for strabismus was 10%. The 4-year cumulative incidence of surgical interventions after TED was 8% for strabismus surgery and 5% for orbital decompression. At 4 years, strabismus surgery was more common in men (13.3%; 95% CI, 10.75-15.86) than in women (7.2%; 95% CI, 6.24-8.08), and the absolute difference was 6.1% (95% CI, 3.42-8.14; P < .001). CONCLUSIONS AND RELEVANCE This study in Denmark provides nationwide empirical incidence of TED and strabismus and surgical interventions after TED that required inpatient or outpatient hospital treatment, and might be used for patient information and health care planning.
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| 14. |
- Ekström, Andreas, et al.
(författare)
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Electric quadrupole moments of the 2(1)(+) states in Cd-100,Cd-102,Cd-104
- 2009
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Ingår i: Physical Review C (Nuclear Physics). - 0556-2813. ; 80:5
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Tidskriftsartikel (refereegranskat)abstract
- Using the REX-ISOLDE facility at CERN the Coulomb excitation cross sections for the 0(gs)(+)-> 2(1)(+) transition in the beta-unstable isotopes Cd-100,Cd-102,Cd-104 have been measured for the first time. Two different targets were used, which allows for the first extraction of the static electric quadrupole moments Q(2(1)(+)) in Cd-102,Cd-104. In addition to the B(E2) values in Cd-102,Cd-104, a first experimental limit for the B(E2) value in Cd-100 is presented. The data was analyzed using the maximum likelihood method. The provided probability distributions impose a test for theoretical predictions of the static and dynamic moments. The data are interpreted within the shell-model using realistic matrix elements obtained from a G-matrix renormalized CD-Bonn interaction. In view of recent results for the light Sn isotopes the data are discussed in the context of a renormalization of the neutron effective charge. This study is the first to use the reorientation effect for post-accelerated short-lived radioactive isotopes to simultaneously determine the B(E2) and the Q(2(1)(+)) values.
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| 15. |
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| 16. |
- Schjørring, O. L., et al.
(författare)
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Intensive care doctors’ preferences for arterial oxygen tension levels in mechanically ventilated patients
- 2018
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Ingår i: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172 .- 1399-6576. ; 62:10, s. 1443-1451
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Tidskriftsartikel (refereegranskat)abstract
- Background: Oxygen is liberally administered in intensive care units (ICUs). Nevertheless, ICU doctors’ preferences for supplementing oxygen are inadequately described. The aim was to identify ICU doctors’ preferences for arterial oxygenation levels in mechanically ventilated adult ICU patients. Methods: In April to August 2016, an online multiple-choice 17-part-questionnaire was distributed to 1080 ICU doctors in seven Northern European countries. Repeated reminder e-mails were sent. The study ended in October 2016. Results: The response rate was 63%. When evaluating oxygenation 52% of respondents rated arterial oxygen tension (PaO2) the most important parameter; 24% a combination of PaO2 and arterial oxygen saturation (SaO2); and 23% preferred SaO2. Increasing, decreasing or not changing a default fraction of inspired oxygen of 0.50 showed preferences for a PaO2 around 8 kPa in patients with chronic obstructive pulmonary disease, a PaO2 around 10 kPa in patients with healthy lungs, acute respiratory distress syndrome or sepsis, and a PaO2 around 12 kPa in patients with cardiac or cerebral ischaemia. Eighty per cent would accept a PaO2 of 8 kPa or lower and 77% would accept a PaO2 of 12 kPa or higher in a clinical trial of oxygenation targets. Conclusion: Intensive care unit doctors preferred PaO2 to SaO2 in monitoring oxygen treatment when peripheral oxygen saturation was not included in the question. The identification of PaO2 as the preferred target and the thorough clarification of preferences are important when ascertaining optimal oxygenation targets. In particular when designing future clinical trials of higher vs lower oxygenation targets in ICU patients.
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| 17. |
- van der Laan, Sander W., et al.
(författare)
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Cystatin C and Cardiovascular Disease : A Mendelian Randomization Study
- 2016
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 68:9, s. 934-945
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Epidemiological studies show that high circulating cystatin C is associated with risk of cardiovascular disease (CVD), independent of creatinine-based renal function measurements. It is unclear whether this relationship is causal, arises from residual confounding, and/or is a consequence of reverse causation. OBJECTIVES The aim of this study was to use Mendelian randomization to investigate whether cystatin C is causally related to CVD in the general population. METHODS We incorporated participant data from 16 prospective cohorts (n = 76,481) with 37,126 measures of cystatin C and added genetic data from 43 studies (n = 252,216) with 63,292 CVD events. We used the common variant rs911119 in CST3 as an instrumental variable to investigate the causal role of cystatin C in CVD, including coronary heart disease, ischemic stroke, and heart failure. RESULTS Cystatin C concentrations were associated with CVD risk after adjusting for age, sex, and traditional risk factors (relative risk: 1.82 per doubling of cystatin C; 95% confidence interval [CI]: 1.56 to 2.13; p = 2.12 x 10(-14)). The minor allele of rs911119 was associated with decreased serum cystatin C (6.13% per allele; 95% CI: 5.75 to 6.50; p = 5.95 x 10(-211)), explaining 2.8% of the observed variation in cystatin C. Mendelian randomization analysis did not provide evidence fora causal role of cystatin C, with a causal relative risk for CVD of 1.00 per doubling cystatin C (95% CI: 0.82 to 1.22; p = 0,994), which was statistically different from the observational estimate (p = 1.6 x 10(-5)). A causal effect of cystatin C was not detected for any individual component of CVD. CONCLUSIONS Mendelian randomization analyses did not support a causal role of cystatin C in the etiology of CVD. As such, therapeutics targeted at lowering circulating cystatin C are unlikely to be effective in preventing CVD.
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| 18. |
- Boulakh, L., et al.
(författare)
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Topical anaesthesia in strabismus surgery for Graves' orbitopathy: a comparative study of 111 patients
- 2022
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Ingår i: Acta Ophthalmologica. - : Wiley. - 1755-375X .- 1755-3768. ; 100:4, s. 447-453
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Tidskriftsartikel (refereegranskat)abstract
- Purpose To evaluate the tolerability and usability of topical anaesthesia in single rectus muscle recession for strabismus caused by Graves' orbitopathy (GO). To compare the perioperative pain score and surgical outcome between GO patients and non-GO patients. Methods A retrospective comparative study of consecutive single rectus muscle recession performed under topical anaesthesia was carried out. All patients scheduled for one-stage single rectus muscle recession under topical anaesthesia were included. Numerical visual analogue pain score scale (NVAS) points, rates of motor success (horizontal deviation < 8 prism diopters (PD) and vertical deviation <= 6 PD) and sensory success (no diplopia without prisms), complications and postoperative adjustment frequencies were compared between GO and non-GO patients. Results A total of 111 patients were included. The mean perioperative pain scores were 2.3 (SD +/- 1.3) in GO and 1.6 (SD +/- 1.1) in non-GO patients (p = 0.06 adjusted for gender). The postoperative mean alignments in GO and non-GO patients were 2 versus 3 PD horizontally and 1 versus 1 PD vertically respectively. Both motor and sensory success rates were 98% in GO patients and 94% versus 93% in non-GO patients. Adjustments as a second procedure the day after surgery was performed in 10% of the GO patients and 15% of the non-GO patients. The oculocardiac reflex was not triggered in any of the GO patients. Conclusion Topical anaesthesia in single muscle recession for GO is safe, well-tolerated and gives comparable surgical outcomes to those achieved in non-GO patients.
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| 19. |
- Heintz, K. E., et al.
(författare)
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The Gas and Stellar Content of a Metal-poor Galaxy at z = 8.496 as Revealed by JWST and ALMA
- 2023
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Ingår i: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 944:2
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Tidskriftsartikel (refereegranskat)abstract
- We present a joint analysis of the galaxy S04590 at z = 8.496 based on NIRSpec, NIRCam, and NIRISS observations obtained as part of the Early Release Observations program of the James Webb Space Telescope (JWST) and the far-infrared [C ii] 158 μm emission line detected by dedicated Atacama Large Millimeter/submillimeter Array (ALMA) observations. We determine the physical properties of S04590 from modeling of the spectral energy distribution (SED) and through the redshifted optical nebular emission lines detected with JWST/NIRSpec. The best-fit SED model reveals a low-mass (M ⋆ = 107.2-108 M ⊙) galaxy with a low oxygen abundance of 12 + log ( O / H ) = 7.16 − 0.12 + 0.10 derived from the strong nebular and auroral emission lines. Assuming that [C ii] effectively traces the interstellar medium, we estimate the total gas mass of the galaxy to be M gas = (8.0 ± 4.0) × 108 M ⊙ based on the luminosity and spatial extent of [C ii]. This yields an exceptionally high gas fraction, f gas = M gas/(M gas + M ⋆) ≳ 90%, though one still consistent with the range expected for low metallicity. We further derive the metal mass of the galaxy based on the gas mass and gas-phase metallicity, which we find to be consistent with the expected metal production from Type II supernovae. Finally, we make the first constraints on the dust-to-gas (DTG) and dust-to-metal (DTM) ratios of galaxies in the epoch of reionization at z ≳ 6, showing overall low mass ratios of logDTG < −3.8 and logDTM < −0.5, though they are consistent with established scaling relations and in particular with those of the local metal-poor galaxy I Zwicky 18. Our analysis highlights the synergy between ALMA and JWST in characterizing the gas, metal, and stellar content of the first generation of galaxies.
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| 20. |
- Lyngso, J., et al.
(författare)
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Menstrual cycle characteristics in fertile women from Greenland, Poland and Ukraine exposed to perfluorinated chemicals: a cross-sectional study
- 2014
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Ingår i: Human Reproduction. - : Oxford University Press (OUP). - 0268-1161 .- 1460-2350. ; 29:2, s. 359-367
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Tidskriftsartikel (refereegranskat)abstract
- Does perfluorooctane sulfonate (PFOS) and perfluorooctanate (PFOA) exposure disrupt the menstrual cyclicity? The female reproductive system may be sensitive to PFOA exposure, with longer menstrual cycle length at higher exposure. PFOS and PFOA are persistent man-made chemicals. Experimental animal studies suggest they are reproductive toxicants but epidemiological findings are inconsistent. A cross-sectional study including 1623 pregnant women from the INUENDO cohort enrolled during antenatal care visits between June 2002 and May 2004 in Greenland, Poland and Ukraine. Information on menstrual cycle characteristics was obtained by questionnaires together with a blood sample from each pregnant woman. Serum concentrations of PFOS and PFOA were measured by liquid chromatography tandem mass spectrometry. Multiple imputations were performed to account for missing data. The association between PFOS/PFOA and menstrual cycle length (short cycle: 24 days, long cycle: 32 days) and irregularities (7 days in difference between cycles) was analyzed using logistic regression with tertiles of exposure. Estimates are given as adjusted odds ratios (ORs) with 95 confidence intervals (CIs). Higher exposure levels of PFOA were associated with longer menstrual cycles in pooled estimates of all three countries. Compared with women in the lowest exposure tertile, the adjusted OR of long cycles was 1.8 (95 CI: 1.0; 3.3) among women in the highest tertile of PFOA exposure. No significant associations were observed between PFOS exposure and menstrual cycle characteristics. However, we observed a tendency toward more irregular cycles with higher exposure to PFOS [OR 1.7 (95 CI: 0.8; 3.5)]. The overall response rate was 45.3 with considerable variation between countries (91.3 in Greenland, 69.1 in Poland and 26.3 in Ukraine). Possible limitations in our study include varying participation rates across countries; a selected study group overrepresenting the most fertile part of the population; retrospective information on menstrual cycle characteristics; the determination of cut-points for all three outcome variables; and lacking information on some determinants of menstrual cycle characteristics, such as stress, physical activity, chronic diseases and gynecological disorders, thus confounding cannot be excluded. The generalizability of the study results is restricted to fertile women who manage to conceive and women who do not use oral contraceptives when getting pregnant or within 2 months before getting pregnant. To our knowledge only one previous epidemiological study has addressed the possible association between perfluorinated chemical exposure and menstrual disturbances. Though pointing toward different disturbances in cyclicity, both studies suggest that exposure to PFOA may affect the female reproductive function. This study contributes to the limited knowledge on effects of exposure to PFOA and PFOS on female reproductive function and suggests that the female reproductive system may be affected by environmental exposure to PFOA. Supported by a scholarship from Aarhus University Research Foundation. The collection of questionnaire data and blood samples was part of the INUENDO project supported by The European Commission (Contract no. QLK4-CT-2001-00 202), . The Ukrainian part of the study was possible by a grant from INTAS (project 012 2205). Determination of PFOA and PFOS in serum was part of the CLEAR study () supported by the European Commissions 7th Framework Program (FP7-ENV-2008-1-226217). No conflict of interest declared.
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| 21. |
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| 22. |
- Smit, L. A. M., et al.
(författare)
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Prenatal exposure to environmental chemical contaminants and asthma and eczema in school-age children
- 2015
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Ingår i: Allergy. - : Wiley. - 1398-9995 .- 0105-4538. ; 70:6, s. 653-660
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundEmerging evidence suggests that prenatal or early-life exposures to environmental contaminants may contribute to an increased risk of asthma and allergies in children. We aimed to the explore associations of prenatal exposures to a large set of environmental chemical contaminants with asthma and eczema in school-age children. MethodsWe studied 1024 mother-child pairs from Greenland and Ukraine from the INUENDO birth cohort. Data were collected by means of an interview-based questionnaire when the children were 5-9years of age. Questions from the ISAAC study were used to define asthma, eczema, and wheeze. We applied principal components analysis (PCA) to sixteen contaminants in maternal serum sampled during pregnancy, including perfluoroalkyl substances (PFASs), metabolites of diethylhexyl (DEHP) and diisononyl (DiNP) phthalates, PCB-153, and p,p-DDE. Scores of five principal components (PCs) explaining 70% of the variance were included in multiple logistic regression models. ResultsIn a meta-analysis that included both populations, the PC2 score, reflecting exposure to DiNP, was negatively associated with current eczema (OR 0.71, 95% CI 0.52-0.96). Other associations were not consistent between the two populations. In Ukrainian children, the PC3 score (DEHP) was positively associated with current wheeze (adjusted OR 1.56, 95% CI 1.03-2.37), whereas the PC5 score, dominated by perfluorooctanoic acid (PFOA), was inversely associated with current wheeze (OR 0.64, 0.41-0.99). In Greenlandic children, a negative association of PC4 (organochlorines) with ever eczema (OR 0.78, 0.61-0.99) was found. ConclusionsWe found limited evidence to support a link between prenatal exposure to environmental chemical contaminants and childhood asthma and eczema.
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| 23. |
- Toft, P. B., et al.
(författare)
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Microbial dietary protein metabolism regulates GLP-1 mediated intestinal transit
- 2023
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Ingår i: Faseb Journal. - 0892-6638. ; 37:10
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Tidskriftsartikel (refereegranskat)abstract
- Depletion of gut microbiota is associated with inefficient energy extraction and reduced production of short-chain fatty acids from dietary fibers, which regulates colonic proglucagon (Gcg) expression and small intestinal transit in mice. However, the mechanism by which the gut microbiota influences dietary protein metabolism and its corresponding effect on the host physiology is poorly understood. Enteropeptidase inhibitors block host protein digestion and reduce body weight gain in diet-induced obese rats and mice, and therefore they constitute a new class of drugs for targeting metabolic diseases. Enteroendocrine cells (EECs) are dispersed throughout the gut and possess the ability to sense dietary proteins and protein-derived metabolites. Despite this, it remains unclear if enteropeptidase inhibition affects EECs function. In this study, we fed conventional and antibiotic treated mice a western style diet (WSD) supplemented with an enteropeptidase inhibitor (WSD-ETPi), analyzed the expression of gut hormones along the length of the intestine, and measured small intestinal transit under different conditions. The ETPi-supplemented diet promoted higher Gcg expression in the colon and increased circulating Glucagon like peptide-1 (GLP-1) levels, but only in the microbiota-depleted mice. The increase in GLP-1 levels resulted in slower small intestinal transit, which was subsequently reversed by administration of GLP-1 receptor antagonist. Interestingly, small intestinal transit was normalized when an amino acid-derived microbial metabolite, p-cresol, was supplemented along with WSD-ETPi diet, primarily attributed to the reduction of colonic Gcg expression. Collectively, our data suggest that microbial dietary protein metabolism plays an important role in host physiology by regulating GLP-1-mediated intestinal transit.
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| 24. |
- Toft, P. B., et al.
(författare)
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Microbial metabolite p-cresol inhibits gut hormone expression and regulates small intestinal transit in mice
- 2023
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Ingår i: FRONTIERS IN ENDOCRINOLOGY. - 1664-2392. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- p-cresol is a metabolite produced by microbial metabolism of aromatic amino acid tyrosine. p-cresol and its conjugated forms, p-cresyl sulfate and p-cresyl glucuronide, are uremic toxins that correlate positively with chronic kidney disease and diabetes pathogenesis. However, how p-cresol affects gut hormones is unclear. Here, we expose immortalized GLUTag cells to increasing concentrations of p-cresol and found that p-cresol inhibited Gcg expression and reduced glucagon-like peptide-1 (GLP-1) secretion in vitro. In mice, administration of p-cresol in the drinking water for 2 weeks reduced the transcript levels of Gcg and other gut hormones in the colon; however, it did not affect either fasting or glucose-induced plasma GLP-1 levels. Furthermore, it did not affect glucose tolerance but promoted faster small intestinal transit in mice. Overall, our data suggest that microbial metabolite p-cresol suppresses transcript levels of gut hormones and regulates small intestinal transit in mice.
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| 25. |
- Tulstrup, M., et al.
(författare)
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NT5C2 germline variants alter thiopurine metabolism and are associated with acquired NT5C2 relapse mutations in childhood acute lymphoblastic leukaemia
- 2018
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 32:12, s. 2527-2535
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Tidskriftsartikel (refereegranskat)abstract
- The antileukaemic drug 6-mercaptopurine is converted into thioguanine nucleotides (TGN) and incorporated into DNA (DNA-TG), the active end metabolite. In a series of genome-wide association studies, we analysed time-weighted means ((wm)) of erythrocyte concentrations of TGN (Ery-TGN) and DNA-TG in 1009 patients undergoing maintenance therapy for acute lymphoblastic leukaemia (ALL). In discovery analyses (454 patients), the propensity for DNA-TG incorporation ((wm)DNA-TG/(wm)Ery-TGN ratio) was significantly associated with three intronic SNPs in NT5C2 (top hit: rs72846714; P - 2.09 x 10(-10), minor allele frequency 15%). In validation analyses (555 patients), this association remained significant during both early and late maintenance therapy (P - 8.4 x 10(-6) and 1.3 x 10(-3), respectively). The association was mostly driven by differences in (wm)Ery-TGN, but in regression analyses adjusted for wmEry-TGN (P < 0.0001), rs72846714-A genotype was also associated with a higher (wm)DNA-TG (P - 0.029). Targeted sequencing of NT5C2 did not identify any missense variants associated with rs72846714 or (wm)Ery-TGN/(wm)DNA-TG. rs72846714 was not associated with relapse risk, but in a separate cohort of 180 children with relapsed ALL, rs72846714-A genotype was associated with increased occurrence of relapse-specific NT5C2 gain-of-function mutations that reduce cytosol TGN levels (P = 0.03). These observations highlight the impact of both germline and acquired mutations in drug metabolism and disease trajectory.
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| 26. |
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| 27. |
- Allen, David B, et al.
(författare)
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GH Safety Workshop Position Paper: a critical appraisal of recombinant human growth hormone therapy in children and adults.
- 2016
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Ingår i: European Journal of Endocrinology. - 1479-683X. ; 174:2, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- Recombinant human growth hormone (rhGH) has been in use for 30 years, and over that time its safety and efficacy in children and adults has been subject to considerable scrutiny. In 2001, a statement from the GH Research Society (GRS) concluded that 'for approved indications, GH is safe'; however, the statement highlighted a number of areas for on-going surveillance of long-term safety including; cancer risk, impact on glucose homeostasis and use of high dose pharmacological rhGH treatment. Over the intervening years, there have been a number of publications addressing the safety of rhGH with regard to mortality, cancer and cardiovascular risk and the need for longterm surveillance of the increasing number of adults who were treated with rhGH in childhood. Against this backdrop of interest in safety, the European Society of Paediatric Endocrinology (ESPE), the GRS and the Pediatric Endocrine Society (PES) convened a meeting to reappraise the safety of rhGH. The ouput of the meeting is a concise position statement.
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| 28. |
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| 29. |
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| 30. |
- Fujimoto, Seiji, et al.
(författare)
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JWST and ALMA Multiple-line Study in and around a Galaxy at z =8.496: Optical to Far-Infrared Line Ratios and the Onset of an Outflow Promoting Ionizing Photon Escape
- 2024
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Ingår i: Astrophysical Journal. - 1538-4357 .- 0004-637X. ; 964:2
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Tidskriftsartikel (refereegranskat)abstract
- We present Atacama Large Millimeter/submillimeter Array (ALMA) deep spectroscopy for a lensed galaxy at z(spec) = 8.496 with log(M-star/M-circle dot) similar to 7.8 whose optical nebular lines and stellar continuum are detected by JWST/NIRSpec and NIRCam Early Release Observations in the field of SMACS J0723.3-7327. Our ALMA spectrum shows [O III] 88 mu m and [C II] 158 mu m line detections at 4.0 sigma and 4.5 sigma, respectively. The redshift and position of the [O III] line coincide with those of the JWST source, while the [C II] line is blueshifted by 90 km s(-1) with a spatial offset of 0.'' 5 (approximate to 0.5 kpc in the source plane) from the centroid of the JWST source. The NIRCam F444W image, including [O III] lambda 5007 and H beta line emission, spatially extends beyond the stellar components by a factor of >8. This indicates that the z = 8.5 galaxy has already experienced strong outflows as traced by extended [O III] lambda 5007 and offset [C II] emission, which would promote ionizing photon escape and facilitate reionization. With careful slit-loss corrections and the removal of emission spatially outside the galaxy, we evaluate the [O III] 88 mu m/lambda 5007 line ratio, and derive the electron density n (e) by photoionization modeling to be 220(-130)(+230) cm(-3), which is comparable with those of z similar to 2-3 galaxies. We estimate an [O III] 88 mu m/[C II] 158 mu m line ratio in the galaxy of >4, as high as those of known z similar to 6-9 galaxies. This high [O III] 88 mu m/[C II] 158 mu m line ratio is generally explained by the high n(e) as well as the low metallicity (Z(gas)/Z(circle dot)=0.04(-0.02)(+0.02)), high ionization parameter (log U > -2.27), and low carbon-to-oxygen abundance ratio (log(C/O) = [-0.52: -0.24]) obtained from the JWST/NIRSpec data; further [C II] follow-up observations will constrain the covering fraction of photodissociation regions.
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| 31. |
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| 32. |
- Karlsson, J, et al.
(författare)
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Cardioprotective effects of the MR contrast agent MnDPDP and its metabolite MnPLED upon reperfusion of the ischemic porcine myocardium
- 2001
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Ingår i: Acta Radiologica. - 0284-1851 .- 1600-0455. ; 42:6, s. 540-547
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To evaluate whether manganese dipyridoxyl diphosphate (MnDPDP) or its metabolite manganese dipyridoxyl ethyldiamine (MnPLED) reduces post-ischemic myocardial injury. Material and Methods: Left anterior descending artery (LAD) in anesthetized pigs was occluded (30 min) followed by reperfusion (120 min) during hemodynamic monitoring and infarct assessment. Three ╡mol/kg MnDPDP, 1 ╡mol/kg MnPLED (or a mixture of both) or saline was injected i.v. 10 min before reperfusion followed by infusion of either 3 ╡mol/kg/h MnDPDP, 1 ╡mol/kg/h MnPLED (or a mixture of both) or saline. The plasma concentrations of MnDPDP, MnPLED and other metabolites (e.g., ZnDPDP and ZnPLED) were analyzed. Results: Femoral blood flow was reduced by 60% during early reperfusion in controls, whereas only 23 and 31% reductions were seen in animals treated with MnDPDP and MnPLED During that time, +LV/dP and -LV/dP (maximum rate of left ventricular isovolumic contraction and relaxation, respectively), systolic pressure and diastolic pressure fell significantly less in animals treated with MnDPDP or MnPLED. Three out of 5 control animals experienced ventricular fibrillation (VF) during reperfusion, whereas VF was not seen in any of the pigs treated with MnPLED or/and MnDPDP. The infarct sizes in saline- and MnPLED-treated animals were 39▒6 and 16▒5%, respectively, of the occluded areas. MnDPDP did not reduce the infarct size. A mixture of MnDPDP and MnPLED significantly reduced infarct size (10▒4%). When reperfusion started and throughout reperfusion, almost all injected MnDPDP was present as Zn-metabolites. Conclusion: MnPLED seems to reduce reperfusion-induced cardiac dysfunction and infarct size in pigs. MnDPDP does not reduce infarct size in the pig, probably because of the rapid exchange of Mn2+ for Zn2+ taking place in the pig.
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| 33. |
- Mikkelsen, L. H., et al.
(författare)
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Genomic and immunohistochemical characterisation of a lacrimal gland oncocytoma and review of literature
- 2017
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Ingår i: Oncology Letters. - : Spandidos Publications. - 1792-1074 .- 1792-1082. ; 14:4, s. 4176-4182
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to report the genetic and immunohistochemical profile of a rare case of lacrimal gland oncocytoma. A 20-year-old male underwent magnetic resonance imaging (MRI) due to viral encephalitis. Notably, the MRI revealed a multicystic tumor in the left lacrimal gland. A lateral orbitotomy was performed and the tumor was completely excised. Four months following surgery, the patient was free of symptoms. Histopathologically, the tumor was composed of large, eosinophilic and polyhedral cells with small round nuclei. The tumor cells stained strongly for antimitochondrial antibody MU213-UC, cytokeratin (CK) 5/6, CK 7, CK 17, CK 8/18 and CK 19. The final diagnosis was an oncocytoma of the lacrimal gland without any signs of malignancy. Array-based comparative genomic hybridisation demonstrated a gain of one copy of chromosome 8 and loss of one copy of chromosome 22 as the sole genomic imbalances. These chromosomal alterations have not previously been identified in oncocytoma and may be specific to lacrimal gland oncocytoma. Sequencing of the mitochondrial genome demonstrated multiple alterations of the NADH-ubiquinone oxidoreductase chain 5 (ND5) gene involved in mitochondrial oxidative phosphorylation. This may support the notion of a common genetic background of oncocytic lesions in the lacrimal gland and other anatomical sites. © 2017, Spandidos Publications. All rights reserved.
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| 34. |
- Pihlstrom, L., et al.
(författare)
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Fine mapping and resequencing of the PARK16 locus in Parkinson's disease
- 2015
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Ingår i: Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1434-5161 .- 1435-232X. ; 60:7, s. 357-362
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Tidskriftsartikel (refereegranskat)abstract
- The PARK16 locus, spanning five genes on chromosome 1, was among the first genetic regions to show genome-wide association in Parkinson's disease (PD). Subsequent investigations have found variability in PARK16 top-hits and association patterns across populations, and the implicated genes and mechanisms are currently unclear. In the present study, we aimed to explore the contribution of PARK16 variability to PD risk in a Scandinavian population. We genotyped 17 single-nucleotide polymorphisms in a case-control sample set of 2570 individuals from Norway and Sweden to fine map the locus. Targeted resequencing of the full coding regions of SLC45A3, NUCKS1, RAB7L1, SLC41A1 and PM20D1 was performed in DNA pools from a subset of 387 patient samples. We find evidence for an association with PD for rs1775143 as well as a haplotype located around the 5' region of RAB7L1, implicating variants which are not in high linkage disequilibrium with the strongest signal from a recent large meta-analysis in Caucasians. We also provide suggestive support for epistasis between RAB7L1 and LRRK2 as previously hypothesized by others. Comparing our results with previous work, allelic heterogeneity at PARK16 appears likely, and further studies are warranted to disentangle the complex patterns of association and pinpoint the functionally relevant variants.
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| 35. |
- Pihlstrom, L., et al.
(författare)
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Supportive evidence for 11 loci from genome-wide association studies in Parkinson's disease
- 2013
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 34:6
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Tidskriftsartikel (refereegranskat)abstract
- enome-wide association studies have identified a number of susceptibility loci in sporadic Parkinson's disease (PD). Recent larger studies and meta-analyses have greatly expanded the list of proposed association signals. We performed a case-control replication study in a Scandinavian population, analyzing samples from 1345 unrelated PD patients and 1225 control subjects collected by collaborating centers in Norway and Sweden. Single-nucleotide polymorphisms representing 18 loci previously reported at genome-wide significance levels were genotyped, as well as 4 near-significant, suggestive, loci. We replicated 11 association signals at p < 0.05 (SNCA, STK39, MAPT, GPNMB, CCDC62/HIP1R, SYT11, GAK, STX1B, MCCC1/LAMP3, ACMSD, and FGF20). The more recently nominated susceptibility loci were well represented among our positive findings, including 3 which have not previously been validated in independent studies. Conversely, some of the more well-established loci failed to replicate. While future meta-analyses should corroborate disease associations further on the level of common markers, efforts to pinpoint functional variants and understand the biological implications of each risk locus in PD are also warranted.
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| 36. |
- Rank, CU, et al.
(författare)
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Asparaginase-Associated Pancreatitis in ALL: Results from the NOPHO ALL2008 Treatment of Patients 1-45 Years
- 2019
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Ingår i: Blood. 134 (Suppl. 1), 3820.. - : American Society of Hematology. - 0006-4971 .- 1528-0020.
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Konferensbidrag (refereegranskat)abstract
- Premature discontinuation of asparaginase reduces cure rate in contemporary acute lymphoblastic leukemia (ALL) treatment. One of the commonest causes of asparaginase truncation is asparaginase-associated pancreatitis (AAP). We prospectively registered AAP during treatment of 2,448 consecutive Nordic/Baltic ALL patients aged 1.0-45.9 years treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol (7/2008-10/2018). The Day 280 cumulative incidence of first-time AAP (including 99% (167/168) of AAP events at this time point) was 8.3% (95% confidence interval (CI) 7.0-9.9) with a median time of 104 days (interquartile range (IQR) 70-145) from ALL diagnosis to AAP, with a median of 10 days (IQR 6-13) from last asparaginase exposure, and after a median number of five asparaginase doses (IQR 3-7, max 14 doses). All patients received polyethylene glycol conjugated Escherichia coli-derived asparaginase as standard treatment. Eighty-five percent (140/164, unknown in N=4) of AAP events were severe (AAP-associated symptoms and/or pancreatic enzymes >3x upper normal limit lasting >72 hours or with hemorrhagic pancreatitis, pancreatic abscess, or pseudocyst). Four age groups were defined: 1.0-4.9, 5.0-8.9, 9.0-16.9, and 17.0-45.9 years-each containing approximately 25% of the AAP events. Compared with patients aged 1.0-4.9 years, adjusted (sex, immunophenotype, and white blood cell count) hazard ratios (HR) of AAP were associated with higher age (5.0-8.9 years: HR 2.3, 95% CI 1.5-3.6, P<.0001; 9.0-16.9 years: HR 2.5, 95% CI 1.6-3.8, P<.0001; and 17.0-45.9 years: HR 2.5, 95% CI 1.6-3.8, P<.0001). When analyzing the odds of developing any AAP-related complication among patients with ≥100 days of follow-up after the AAP diagnosis, older children (≥5.0 years) and adolescents had increased odds of developing any complication compared with younger children aged 1.0-4.9 years, notably a more than six-fold increase among adolescents (5.0-8.9 years: odds ratio (OR) 2.67, 95% CI 1.07-6.68, P=.04 and 9.0-16.9 years: OR 6.52, 95% CI 2.35-18.1, P=.0003)-including acute and permanent insulin need; intensive care unit admission; pancreatic pseudocyst development; recurrent abdominal pain; elevated pancreatic enzymes at last-follow-up; imaging compatible with pancreatitis (pancreatic inflammation/edema/pseudocysts/hemorrhage) at last follow-up; and AAP-related death. Adult age was not associated with development of any AAP-related complication (17.0-45.9 years: OR 2.3, 95% CI 0.9-5.9, P=.07). Three patients aged 8.6, 17.3, and 18.6 years died of first-time AAP within 0-29 days from AAP diagnosis. Of 168 AAP patients, 34 (20%) were re-challenged with asparaginase. Fifty percent (17/34) developed a second episode of AAP-41% being severe (7/17). The median time to a second AAP event from asparaginase re-exposure was 29 days (IQR 16-94) and occurred after a median of two asparaginase doses (range 0-7). Neither age group nor severity of the first AAP was associated with increased hazard of a second AAP event. None of the patients with a second AAP were further re-exposed to asparaginase, and none died of the second AAP. Among a total of 196 ALL relapses, 21 patients have had AAP including 17 patients with asparaginase truncation. However, the hazard of relapse (age- and sex-adjusted) was not increased among AAP patients with asparaginase truncation versus AAP patients with asparaginase re-exposure (5.0-year cumulative incidence of relapse: 13.2% versus 14.2%) (HR 1.0, 95% CI 0.3-3.1, P=1.0). When analyzing time to relapse among AAP patients versus non-AAP patients, no difference in hazard of relapse was found (HR 2.0, 95% CI 0.8-4.9, P=.2). In conclusion, adolescents and young adults tolerated asparaginase treatment as well as children; however, the risk of AAP was higher for patients older than 5.0 years of age with no difference with increasing age. Despite a low AAP-related mortality, the morbidity was considerable and most profound for patients aged 9.0-16.9 years. Since asparaginase re-exposure was associated with a high risk of a second AAP event and neither AAP development nor AAP-related asparaginase truncation was associated with increased relapse risk, asparaginase re-exposure should be attempted only in patients with a high risk of leukemic relapse. Finally, there is an unmet need for preventive strategies toward AAP
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