No major differences in perinatal and maternal outcomes between uninterrupted embryo culture in time-lapse system and conventional embryo culture.

STUDY QUESTION: Is embryo culture in a closed time-lapse system associated with any differences in perinatal and maternal outcomes in comparison to conventional culture and spontaneous conception? SUMMARY ANSWER: There were no significant differences between time-lapse and conventional embryo culture in preterm birth (PTB, <37 weeks), low birth weight (LBW, >2500 g) and hypertensive disorders of pregnancy for singleton deliveries, the primary outcomes of this study. WHAT IS KNOWN ALREADY: Evidence from prospective trials evaluating the safety of time-lapse incubation for clinical use show similar embryo development rates, implantation rates, and ongoing pregnancy and live birth rates when compared to conventional incubation. Few studies have investigated if uninterrupted culture can alter risks of adverse perinatal outcomes presently associated with IVF when compared to conventional culture and spontaneous conceptions. STUDY DESIGN, SIZE, DURATION: This study is a Swedish population-based retrospective registry study, including 7379 singleton deliveries after fresh embryo transfer between 2013 and 2018 from selected IVF clinics. Perinatal outcomes of singletons born from time-lapse-cultured embryos were compared to singletons from embryos cultured in conventional incubators and 71 300 singletons from spontaneous conceptions. Main perinatal outcomes included PTB and LBW. Main maternal outcomes included hypertensive disorders of pregnancy (pregnancy hypertension and preeclampsia). PARTICIPANTS/MATERIALS, SETTING, METHODS: From nine IVF clinics, 2683 singletons born after fresh embryo transfer in a time-lapse system were compared to 4696 singletons born after culture in a conventional incubator and 71 300 singletons born after spontaneous conception matched for year of birth, parity, and maternal age. Patient and treatment characteristics from IVF deliveries were cross-linked with the Swedish Medical Birth Register, Register of Birth Defects, National Patient Register and Statistics Sweden. Children born after sperm and oocyte donation cycles and after Preimplantation Genetic testing cycles were excluded. Odds ratio (OR) and adjusted OR were calculated, adjusting for relevant confounders. MAIN RESULTS AND THE ROLE OF CHANCE: In the adjusted analyses, no significant differences were found for risk of PTB (adjusted OR 1.11, 95% CI 0.87-1.41) and LBW (adjusted OR 0.86, 95% CI 0.66-1.14) or hypertensive disorders of pregnancy; preeclampsia and hypertension (adjusted OR 0.99, 95% CI 0.67-1.45 and adjusted OR 0.98, 95% CI 0.62-1.53, respectively) between time-lapse and conventional incubation systems. A significantly increased risk of PTB (adjusted OR 1.31, 95% CI 1.08-1.60) and LBW (adjusted OR 1.36, 95% CI 1.08-1.72) was found for singletons born after time-lapse incubation compared to singletons born after spontaneous conceptions. In addition, a lower risk for pregnancy hypertension (adjusted OR 0.72 95% CI 0.53-0.99) but no significant difference for preeclampsia (adjusted OR 0.87, 95% CI 0.68-1.12) was found compared to spontaneous conceptions. Subgroup analyses showed that some risks were related to the day of embryo transfer, with more adverse outcomes after blastocyst transfer in comparison to cleavage stage transfer. LIMITATIONS, REASONS FOR CAUTION: This study is retrospective in design and different clinical strategies may have been used to select specific patient groups for time-lapse versus conventional incubation. The number of patients is limited and larger datasets are required to obtain more precise estimates and adjust for possible effect of additional embryo culture variables. WIDER IMPLICATIONS OF THE FINDINGS: Embryo culture in time-lapse systems is not associated with major differences in perinatal and maternal outcomes, compared to conventional embryo culture, suggesting that this technology is an acceptable alternative for embryo incubation. STUDY FUNDING/COMPETING INTEREST(S): The study was financed by a research grant from Gedeon Richter. There are no conflicts of interest for all authors to declare. TRIAL REGISTRATION NUMBER: N/A.

Failure of generic risk assessment model framework to predict groundwater pollution risk at hundreds of metal contaminated sites: Implications for research needs.

Soil pollution constitutes one of the major threats to public health, where spreading to groundwater is one of several critical aspects. In most internationally adopted frameworks for routine risk assessments of contaminated land, generic models and soil guideline values are cornerstones. In order to protect the groundwater at contaminated sites, a common practice worldwide today is to depart from health risk-based limit concentrations for groundwater, and use generic soil-to-groundwater spreading models to back-calculate corresponding equilibrium levels (concentration limits) in soil, which must not be exceeded at the site. This study presents an extensive survey of how actual soil and groundwater concentrations, compiled for all high-priority contaminated sites in Sweden, relate to the national model for risk management of contaminated sites, with focus on As, Cu, Pb and Zn. Results show that soil metal concentrations, as well as total amounts, constitute a poor basis for assessing groundwater contamination status. The evaluated model was essentially incapable of predicting groundwater contamination (i.e. concentrations above limit values) based on soil data, and erred on the "unsafe side" in a significant number of cases, with modelled correlations not being conservative enough. Further, the risk of groundwater contamination was almost entirely independent of industry type. In essence, since neither soil contaminant loads nor industry type is conclusive, there is a need for a supportive framework for assessing metal spreading to groundwater accounting for site-specific, geochemical conditions.

Metal solubility and transport at a contaminated landfill site - From the source zone into the groundwater.

Risks associated with metal contaminated sites are tightly linked to material leachability and contaminant mobility. In this study, metal solubility and transport were characterized within a glass waste landfill through i) lysimeter-collection of pore water and standardized batch leaching tests, ii) soil profiles extending from the landfill surface, through unsaturated soil underneath, and into the groundwater zone, and iii) groundwater samples upstream, at, and downstream of the landfill. The soil analyzes targeted both pseudo-total and geochemically active concentrations of contaminant metals (As, Cd, Pb, Sb) and basic soil geochemistry (pH, org. C, Fe, Mn). Water samples were analyzed for dissolved, colloid-bound and particulate metals, and speciation modelling of the aqueous phase was conducted. The results revealed a highly contaminated system, with mean metal concentrations in the waste zone between 90 and 250 times the regional background levels. Despite severe contamination of the waste zone and high geochemically active fractions (80-100%) of all contaminant metals as well as elevated concentrations in landfill pore water, the concentrations of Cd and Pb decrease abruptly at the transition between landfill and underlying natural soil and no indication of groundwater contamination was found. The efficient cation retention is likely due to the high pH. However, the sorption of As and Sb is weaker at such high pH, which explains their higher mobility from the pore water zone into groundwater. The field soil:solution partitioning (Kd) displayed a high spatial variability within the waste zone (the highest Kd variability was seen for Pb, ranging from 140 to 2,900,000 l kg-1), despite little variability in basic geochemical variables, which we suggest is due to waste material heterogeneity.

The risk of overestimating the risk-metal leaching to groundwater near contaminated glass waste deposits and exposure via drinking water.

This study investigates metal contamination patterns and exposure to Sb, As, Ba, Cd and Pb via intake of drinking water in a region in southeastern Sweden where the production of artistic glass has resulted in a large number of contaminated sites. Despite high total concentrations of metals in soil and groundwater at the glassworks sites properties, all drinking water samples from households with private wells, located at a 30-640m distance from a glassworks site, were below drinking water criteria from the WHO for Sb, As, Ba and Cd. A few drinking water samples showed concentrations of Pb above the WHO guideline, but As was the only element found in concentrations that could result in human exposure near toxicological reference values. An efficient retention of metals in the natural soil close to the source areas, which results in a moderate impact on local drinking water, is implied. Firstly, by the lack of significant difference in metal concentrations when comparing households located upstream and downstream of the main waste deposits, and secondly, by the lack of correlation between the metal concentration in drinking water and distance to the nearest glassworks site. However, elevated Pb and Cd concentrations in drinking water around glassworks sites when compared to regional groundwater indicate that diffuse contamination of the soils found outside the glassworks properties, and not only the glass waste landfills, may have a significant impact on groundwater quality. We further demonstrate that different mobilization patterns apply to different metals. Regarding the need to use reliable data to assess drinking water contamination and human exposure, we finally show that the conservative modelling approaches that are frequently used in routine risk assessments may result in exposure estimates many times higher than those based on measured concentrations in the drinking water that is actually being used for consumption.

High metal reactivity and environmental risks at a site contaminated by glass waste.

This study addresses the reactivity and risks of metals (Ba, Cd, Co, Cr, Cu, Ni, Pb, Zn, As and Sb) at a Swedish site with large glass waste deposits. Old glassworks sites typically have high total metal concentrations, but as the metals are mainly bound within the glass waste and considered relatively inert, environmental investigations at these kinds of sites are limited. In this study, soil and landfill samples were subjected to a sequential chemical extraction procedure. Data from batch leaching tests and groundwater upstream and downstream of the waste deposits were also interpreted. The sequential extraction revealed that metals in <2 mm soil/waste samples were largely associated with geochemically active fractions, indicating that metals are released from pristine glass and subsequently largely retained in the surrounding soil and/or on secondary mineral coatings on fine glass particles. From the approximately 12,000 m(3) of coarse glass waste at the site, almost 4000 kg of Pb is estimated to have been lost through corrosion, which, however, corresponds to only a small portion of the total amount of Pb in the waste. Metal sorption within the waste deposits or in underlying soil layers is supported by fairly low metal concentrations in groundwater. However, elevated concentrations in downstream groundwater and in leachates of batch leaching tests were observed for several metals, indicating on-going leaching. Taken together, the high metal concentrations in geochemically active forms and the high amounts of as yet uncorroded metal-rich glass, indicate considerable risks to human health and the environment.

Outcome after HSCT in Philadelphia chromosome positive acute lymphoblastic leukemia in Sweden: a population-based study.

Even in the tyrosine kinase inhibitor era, allogeneic hematopoietic stem cell transplantation (HSCT) is regarded as standard care for adult Philadelphia (Ph) positive acute lymphoblastic leukemia (ALL). In this retrospective national study, we have reviewed the outcome after HSCT in Sweden for adult Ph-positive ALL between 2000 and 2009. In total, 51 patients with median age 42 (range 20-66) years underwent HSCT. Mainly allogeneic HSCT was performed (24 related donor, 24 unrelated donor and one cord blood), and only two patients were treated with an autologous HSCT. The 5-year OS was 51 (37-64) %. The probabilities of morphological relapse and non-relapse mortality (NRM) at 5 years were 36 (23-49) and 18 (9-29) %, respectively. For the allogeneic transplanted, the 5-year OS was for patients <40 years 70 (50-90) % and for patients ≥40 years 34 (16-52) %, p = 0.002. The 5-year probability of NRM was for patients <40 years 10 (2-28) % compared to 25 (11-42) % for patients ≥40 years (p = 0.04). Patients with chronic graft-versus-host disease (GVHD) had a 5-year morphological relapse probability of 20 (6-40) % compared to 59 (35-77) % for patients without chronic GVHD (p = 0.03). Age ≥40 years and the absence of chronic GVHD were confirmed as independent negative prognostic factors for relapse and non-relapse mortality in a multivariate analysis although the impact of chronic GVHD was significant only in the older age cohort.

Stimulation-induced side effects in the posterior subthalamic area: distribution, characteristics and visualization.

OBJECTIVE: The posterior subthalamic area (PSA) is an emerging but relatively unexplored target for DBS treatment of tremor. The aim of the study was to explore the area further by evaluating the spatial distribution and the characteristics of stimulation-induced side effects in this area. METHODS: Twenty-eight patients with essential tremor (ET) implanted with 33 DBS electrodes were evaluated concerning stimulation-induced side effects by testing each contact separately one year after surgery. The location of the side effects were plotted on axial slides of the Morel Stereotactic Atlas and a 3-dimensional model of the area for visualization was created. RESULTS: Visualization of the contacts eliciting stimulation-induced side effects demonstrated that identical responses can be elicited from various points in the PSA and its vicinity. The majority of contacts inducing muscular affection and cerebellar symptoms, including dysarthria, could not be attributed to an effect on the internal capsule. Paresthesias, affecting various body parts were elicited throughout the area without a clear somatotopic pattern. CONCLUSION: Stimulation-induced side effects in the PSA and its vicinity were difficult to attribute to certain anatomical areas as the same response was induced from various locations. Therefore, this study could not provide a meaningful somatotopic map with regard to stimulation-induced side effects in the PSA.

Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMP-activated protein kinase.

AIMS/HYPOTHESIS: Brain-derived neurotrophic factor (BDNF) is produced in skeletal muscle, but its functional significance is unknown. We aimed to determine the signalling processes and metabolic actions of BDNF. METHODS: We first examined whether exercise induced BDNF expression in humans. Next, C2C12 skeletal muscle cells were electrically stimulated to mimic contraction. L6 myotubes and isolated rat extensor digitorum longus muscles were treated with BDNF and phosphorylation of the proteins AMP-activated protein kinase (AMPK) (Thr(172)) and acetyl coenzyme A carboxylase beta (ACCbeta) (Ser(79)) were analysed, as was fatty acid oxidation (FAO). Finally, we electroporated a Bdnf vector into the tibialis cranialis muscle of mice. RESULTS: BDNF mRNA and protein expression were increased in human skeletal muscle after exercise, but muscle-derived BDNF appeared not to be released into the circulation. Bdnf mRNA and protein expression was increased in muscle cells that were electrically stimulated. BDNF increased phosphorylation of AMPK and ACCbeta and enhanced FAO both in vitro and ex vivo. The effect of BDNF on FAO was AMPK-dependent, since the increase in FAO was abrogated in cells infected with an AMPK dominant negative adenovirus or treated with Compound C, an inhibitor of AMPK. Electroporation of a Bdnf expression vector into the tibialis cranialis muscle resulted in increased BDNF protein production and tropomyosin-related kinase B (TrkB(Tyr706/707)) and extracellular signal-regulated protein kinase (p44/42 Thr(202)/Tyr(204)) phosphorylation in these muscles. In addition, phosphorylation of ACCbeta was markedly elevated in the Bdnf electroporated muscles. CONCLUSIONS/INTERPRETATION: These data identify BDNF as a contraction-inducible protein in skeletal muscle that is capable of enhancing lipid oxidation in skeletal muscle via activation of AMPK.

Attitude towards remission induction for elderly patients with acute myeloid leukemia influences survival.

Combination chemotherapy may induce remission from acute myeloid leukemia (AML), but validated criteria for treatment of elderly are lacking. The remission intention (RI) rate for elderly patients, as reported to the Swedish Leukemia Registry, was known to be different when comparing the six health care regions, but the consequences of different management are unknown. The Leukemia Registry, containing 1672 AML patients diagnosed between 1997 and 2001, with 98% coverage and a median follow-up of 4 years, was completed with data from the compulsory cancer and population registries. Among 506 treated and untreated patients aged 70-79 years with AML (non-APL), there was a direct correlation between the RI rate in each health region (range 36-76%) and the two-year overall survival, with no censored observations (6-21%) (chi-squared for trend=11.3, P<0.001; r2=0.86, P<0.02, nonparametric). A 1-month landmark analysis showed significantly better survival in regions with higher RI rates (P=0.003). Differences could not be explained by demographics, and was found in both de novo and secondary leukemias. The 5-year survival of the overall population aged 70-79 years was similar between the regions. Survival of 70-79-year-old AML patients is better in regions where more elderly patients are judged eligible for remission induction.

Granulocyte-macrophage colony-stimulating factor to increase efficacy of mitoxantrone, etoposide and cytarabine in previously untreated elderly patients with acute myeloid leukaemia: a Swedish multicentre randomized trial.

A total of 110 patients, aged 64 years or over, with de novo acute myeloid leukaemia (AML) and white blood cell counts <50 x 109/l were treated with 3 d of cytarabine 1 g/m2 twice daily, mitoxantrone 12 mg/m2 and etoposide 200 mg/m2, randomized with or without the addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) 200 microg/m2. The primary aim was to evaluate the effect of GM-CSF on the remission rate. Secondary aims included comparison of duration of remission, survival and infectious complications and the impact of maintenance therapy with thioguanine. Complete remission (CR) was achieved by 64% of patients without GM-CSF, and by 65% of patients who received GM-CSF, the median remission duration was 13 vs. 6 months, the median overall survival (OS) was 14 vs. 9 months, the mean time to neutrophil recovery was 25 vs. 17 d (P = 0.03) and the number of positive blood cultures was 46 vs. 39 (P = 0.05) respectively. The impact of thioguanine remains unanswered since only 30 patients remained in CR after consolidation therapy. We conclude that induction therapy is feasible with acceptable toxicity in elderly patients with AML, albeit with a high relapse rate and short OS. GM-CSF prior to, and in combination with, induction treatment reduced the time to neutrophil recovery and the number of neutropenic septicaemia cases but did not improve the OS of AML in the elderly.

Detection of body position changes using the surface electrocardiogram.

A method for detecting body position changes that uses the surface vectorcardiogram (VCG) is presented. Such changes are often manifested as sudden shifts in the electrical axis of the heart and can erroneously be interpreted as acute ischaemic events. Axis shifts were detected by analysing the rotation angles obtained from the alignment of successive VCG loops to a reference loop. Following the rejection of angles originating from noise events, the detection of body position changes was performed on the angle series using a Bayesian approach. On a database of ECG recordings from normal subjects performing a predefined sequence of body position changes, a detection rate of 92% and a false alarm rate of 7% was achieved.

Effect of ditching operations on stream-water chemistry in a boreal forested catchment.

The effects of ditching of boreal forest land on stream-water quality and quantity was assessed by comparing, over a 4-year-period, the physicochemical properties of the water in two small streams (western Finland), one whose catchment was ditched for forestry halfway through the sampling period and another nearby (control) stream whose catchment was not ditched ('paired catchment method'). While the artificial drainage did not have any significant effect on the hydrograph, it resulted in an increase in the aquatic concentrations of Mn, Ca, Mg, suspended material and alkalinity, a decrease in the concentrations of TOC and H3O+, while for Al and Fe there was a change in control mechanisms. The concentration and control changes after ditching are related to changes in hydrological pathways and to the exposure of both organic (peat) and inorganic (mineral soil) layers on the ditch slopes.

Patients with psychiatric disorders in gynecologic practice.

OBJECTIVE: The relationship between different gynecologic complaints and somatic symptoms was studied in a gynecologic population in which the prevalence of psychiatric disorders had been established. STUDY DESIGN: The prevalence of depression and anxiety in the unselected population of 1013 subjects was 27.2% and 12.1%, respectively, as assessed by the Primary Care Evaluation of Mental Disorders (PRIME-MD). The subjects' medical charts were reviewed after the PRIME-MD diagnosis was made. RESULTS: Depression and anxiety disorders were significantly more common among those seeking care for abdominal pain, those who made frequent and unscheduled visits, and those who were hospitalized for acute care. All the physical symptoms indicated in the PRIME-MD Patient Health Questionnaire were more common among women with a psychiatric diagnosis compared with controls. CONCLUSIONS: The majority of cases of depression and anxiety in women are undiagnosed and untreated, and patients with these disorders often present with physical symptoms. Because gynecologic outpatients with abdominal pain, frequent and unscheduled visits, and admissions due to acute illness are more likely to have a psychiatric disorder, it is desirable that gynecologists recognize and treat these problems.

Adjustment of incidence rates after an estimate of completeness and accuracy in registration of acute leukemias in a Swedish population.

Earlier studies have revealed undernotification of hematological malignancies in Swedish and other Cancer Registries. We present epidemiological data on AML, ALL and unspecified AL in adults diagnosed 1987-1992 in a well-defined population. Blast crises of CML were excluded. The Swedish Cancer Registry and Cause of Death Registry were compared and patient records reviewed for validation. When available, listings of pathology bone marrow reports and inpatient discharge diagnoses were utilized for casefinding. 260 cases of acute leukemias could be verified in a population of 663,135 adults, corresponding to a yearly incidence of 6.5/100,000. The median age of the patients was 69.2 years. 214 cases were AML, 38 ALL and eight unspecified AL. Undernotification in the Cancer Registry was found to be 15.4%, greater for AML and unspecified AL than for ALL. In addition the coding was not uniform, resulting in an incidence rate in adults of 5.3/100,000 for the Cancer Registry which is 18.5% lower than that of our study. A significant survival advantage was seen for notified patients. Combination of the Cancer Registry and Cause of Death Registry gave acceptable coverage, omitting only four patients. As the incidence of acute leukemias in our study is comparatively high, we hypothesize that underestimation of incidence and overestimation of survival are general problems for cancer registries.

Prevalence of psychiatric disorders in gynecologic outpatients.

OBJECTIVE: This study was undertaken to determine the point prevalence of psychiatric disorders in an unselected gynecologic population. STUDY DESIGN: Participants were 1013 consecutive women attending 2 outpatient gynecology clinics in northern Sweden between November 16 and December 15, 1998. The Primary Care Evaluation of Mental Disorders (PRIME-MD) was used as a diagnostic tool for evaluating mood, anxiety, and eating disorders. RESULTS: Overall, 897 patients (88.5%) filled in the diagnostic tool's patient questionnaire. Psychiatric disorders were present in 30.5% of the patients. Mood disorders were most common; major depression was prevalent in 10.1% of patients and minor depression was seen in 12.4% of patients. Anxiety disorders were also common and were encountered in 12.1% of patients. Among patients with a diagnosis, only 21.4% had some form of treatment. CONCLUSIONS: The prevalence of mood and anxiety disorders in an outpatient gynecology clinic is high. The majority of women with a diagnosis based on the diagnostic tool did not have a previous diagnosis and were untreated.

Laser Doppler flowmetry in the assessment of tendon blood flow.

This review of laser Doppler flowmetry (LDF) focuses on indications and limitations in general and the author's experience of LDF in the assessment of tendon perfusion in particular. LDF is easy to use, minimally invasive and well suited for the study of relative changes in perfusion during rapid events. Problems specifically related to LDF include motion artifacts, a non-flow dependent output of unknown significance and uncertainty regarding the spatial resolution. The human Achilles tendon has a lower perfusion at the insertion but otherwise an even distribution of blood flow. Male gender, advancing age and mechanical loading of the tendon are associated with diminished tendon blood flow. The lesion in chronic degenerative Achilles tendinopathy is associated with hyperemia of uncertain origin.

Treatment, long-term outcome and prognostic variables in 214 unselected AML patients in Sweden.

With the aim of describing an unselected series of acute myeloid leukaemias (AML) in adults, patients diagnosed 1987-1992 in the Orebro region of central Sweden were reviewed by investigating hospital records. By utilizing: (1) The Swedish Cancer Registry, (2) The Cause of Death Registry, (3) listings of pathology bone marrow reports and (4) listings of inpatient discharge diagnoses, we attempted to find all patients. Among secondary AML, only blast-crises of CML were excluded. A total of 214 cases of AML with a median age of 69.5 years were verified corresponding to a mean yearly incidence in adults of 5.4/100 000. Of all patients, 56% had received 'high-dose' induction treatment, 28% 'low-dose' treatment and 16% no cytostatic treatment. Median survival for all patients was 5.8 months and the probability of survival at 5 years was 9.3%. The 120 'high-dose' treated patients had a total CR rate of 67%, median CR duration 10.1 months and median survival 11.4 months. Age, LDH and kidney function were found to be independent prognostic variables for survival. The inclusion of patients unreferred from district hospitals makes this study unique as an example of unselected AML.

Vectorcardiographic loop alignment and the measurement of morphologic beat-to-beat variability in noisy signals.

The measurement of subtle morphologic beat-to-beat variability in the electrocardiogram (ECG)/vectorcardiogram (VCG) is complicated by the presence of noise which is caused by, e.g., respiration and muscular activity. A method was recently presented which reduces the influence of such noise by performing spatial and temporal alignment of VCG loops. The alignment is performed in terms of scaling, rotation and time synchronization of the loops. Using an ECG simulation model based on propagation of action potentials in cardiac tissue, the ability of the method to separate morphologic variability of physiological origin from respiratory activity was studied. Morphologic variability was created by introducing a random variation in action potential propagation between different compartments. The results indicate that the separation of these two activities can be done accurately at low to moderate noise levels (less than 10 microV). At high noise levels, the estimation of the rotation angles was found to break down in an abrupt manner. It was also shown that the breakdown noise level is strongly dependent on loop morphology; a planar loop corresponds to a lower breakdown noise level than does a nonplanar loop.