Early-onset vs late-onset preeclampsia and risk of coronary atherosclerosis later in life: a clinical follow-up study.

BACKGROUND: Younger women with previous preeclampsia have an increased risk of coronary atherosclerosis. It is unknown if this risk is associated with the time of onset of preeclampsia. OBJECTIVE: This study aimed to investigate if women with early-onset preeclampsia have a higher risk of coronary atherosclerosis compared with women with late-onset preeclampsia, independent of other perinatal risk factors. STUDY DESIGN: A total of 911 women with previous preeclampsia aged 35 to 55 years participated in a clinical follow-up study, including clinical examination, comprehensive questionnaires, and cardiac computed tomography scan 13 years (range, 0-28) after index pregnancy. Early- and late-onset preeclampsia were defined as gestational age at delivery of <34+0 and ≥34+0 gestational weeks, respectively. The primary outcome of the study was the presence of coronary atherosclerosis on the cardiac computed tomography. A logistic regression analysis was performed to investigate the association between time of onset of preeclampsia, perinatal risk factors, and the primary outcome. RESULTS: Women with early-onset preeclampsia (N=139) were older (46.2±5.7 vs 44.4±5.5 years; P<.001), more likely to have hypertension (51.1% vs 35.1%; P≤.001), and had a higher body mass index (27.9±6.3 vs 26.9±5.5 kg/m2; P=.051) compared with women with late-onset preeclampsia (N=772) at follow-up. The prevalence of the primary outcome (coronary atherosclerosis) on the cardiac computed tomography among women with early- and late-onset preeclampsia was 28.8% vs 22.2%, respectively (P=.088; adjusted odds ratio, 1.74; 95% confidence interval, 1.01-3.01; P=.045 after adjustment for maternal age at index pregnancy, prepregnancy body mass index, parity, diabetes in pregnancy, smoking in pregnancy, offspring birthweight and sex, and follow-up length). CONCLUSION: Women with early-onset preeclampsia had a slightly higher risk of coronary atherosclerosis compared with women with late-onset preeclampsia. However, according to the current evidence, it does not seem indicated to limit screening, diagnostic, and preventive measures for cardiovascular disease only to women with early-onset preeclampsia.

Early Coronary Atherosclerosis in Women With Previous Preeclampsia.

BACKGROUND: Women with previous preeclampsia have an increased risk of coronary artery disease later in life. OBJECTIVES: This study aimed to determine the prevalence of coronary atherosclerosis in younger women with previous preeclampsia in comparison with women from the general population. METHODS: Women aged 40-55 years with previous preeclampsia were matched 1:1 on age and parity with women from the general population. Participants completed an extensive questionnaire, a clinical examination, and a coronary computed tomography angiography (CTA). The main study outcome was the prevalence of any coronary atherosclerosis on coronary CTA or a calcium score >0 in case of a nondiagnostic coronary CTA. RESULTS: A total of 1,417 women, with a mean age of 47 years, were included (708 women with previous preeclampsia and 709 control subjects from the general population). Women with previous preeclampsia were more likely to have hypertension (284 [40.1%] vs 162 [22.8%]; P < 0.001), dyslipidemia (338 [47.7%] vs 296 [41.7%]; P = 0.023), diabetes mellitus (24 [3.4%] vs 8 [1.1%]; P = 0.004), and high body mass index (27.3 ± 5.7 kg/m2 vs 25.0 ± 4.2 kg/m2; P < 0.001). Cardiac computed tomography was performed in all women. The prevalence of any coronary atherosclerosis was higher in the preeclampsia group (193 [27.4%] vs 141 [20.0%]; P = 0.001) with an OR: 1.41 (95% CI: 1.08-1.85; P = 0.012) after adjustment for age, dyslipidemia, diabetes mellitus, smoking, body mass index, menopause, and parity. CONCLUSIONS: Younger women with previous preeclampsia had a slightly higher prevalence of coronary atherosclerosis compared with age- and parity-matched women from the general population. Preeclampsia remained an independent risk factor after adjustment for traditional cardiovascular risk factors. (The CoPenHagen PREeClampsia and cardIOvascUlar diSease study [CPH-PRECIOUS]; NCT03949829).

Implementing a Standardized Care Pathway Integrating Oncology, Palliative Care and Community Care in a Rural Region of Mid-Norway.

INTRODUCTION: To improve quality across levels of care, we developed a standardized care pathway (SCP) integrating palliative and oncology services for hospitalized and home-dwelling palliative cancer patients in a rural region. METHODS: A multifaceted implementation strategy was directed towards a combination of target groups. The implementation was conducted on a system level, and implementation-related activities were registered prospectively. Adult patients with advanced cancer treated with non-curative intent were included and interviewed. Healthcare leaders (HCLs) and healthcare professionals (HCPs) involved in the development of the SCP or exposed to the implementation strategy were interviewed. In addition, HCLs and HCPs exposed to the implementation strategy answered standardized questionnaires. Hospital admissions were registered prospectively. RESULTS: To assess the use of the SCP, 129 cancer patients were included. Fifteen patients were interviewed about their experiences with the patient-held record (PHR). Sixty interviews were performed among 1320 HCPs exposed to the implementation strategy. Two hundred and eighty-seven HCPs reported on their training in and use of the SCP. Despite organizational cultural differences, developing an SCP integrating palliative and oncology services across levels of care was feasible. Both HCLs and HCPs reported improved quality of care in the wake of the implementation process. Two and a half years after the implementation was launched, 28% of the HCPs used the SCP and 41% had received training in its use. Patients reported limited use and benefit of the PHR. CONCLUSION: An SCP may be a usable tool for integrating palliative and oncology services across care levels in a rural region. An extensive implementation process resulted in improvements of process outcomes, yet still limited use of the SCP in clinical practice. HCLs and HCPs reported improved quality of cancer care following the implementation process. Future research should address mandatory elements for usefulness and successful implementation of SCPs for palliative cancer patients.

When a patient has incurable cancer, it is beneficial to introduce palliative care early in the disease trajectory along with anti-cancer treatment. A standardized care pathway is a method to improve quality and reduce variation in healthcare. It can promote integrated healthcare services in palliative care, e.g. by specifying action points when the patient's situation is changing. In this study, a standardized care pathway for cancer patients with palliative care needs was developed in a rural region of Norway. The pathway focused on patients' needs and symptoms and on smooth transition between levels of care. An educational program and an information strategy were developed to ensure implementation. To evaluate the implementation, all activity regarding the implementation process was registered. Cancer patients and healthcare professionals were interviewed and answered questionnaires. One thousand three hundred and twenty healthcare professionals were exposed to the implementation strategy. One hundred and twenty-nine cancer patients were followed up according to the standardized care pathway. Despite different perspectives of care, it was feasible to develop a standardized care pathway for palliative cancer patients across care settings. A paper-based patient-held record was only found to be useful by a limited number of patients. An extensive implementation process was completed and resulted in improvements regarding healthcare professionals' experience with the quality of cancer care in the region, but limited use of the care pathway in clinical practice. Further research should identify the most important elements for usefulness and successful implementation of the care pathway.

Degree of pregnancy planning and recommended pregnancy planning behavior among women with and without chronic medical conditions - A large hospital-based cross-sectional study.

INTRODUCTION: Pregnancy planning allows women to engage in pregnancy planning behaviors to optimize health status in the preconception period. Women with chronic medical conditions have a higher risk for adverse pregnancy outcomes and therefore preconception care is recommended. The aim was to compare pregnancy planning among women with and without chronic medical conditions, and to assess adherence to the recommended pregnancy planning behaviors on folic acid intake, physical activity and abstention from smoking and alcohol, among women with and without chronic medical conditions stratified by pregnancy planning. MATERIAL AND METHODS: A cross-sectional study with data from 28 794 pregnancies. Pregnancy planning was measured with the Swedish Pregnancy Planning Scale. Multiple Poisson regression with robust variance estimates was used to assess the associations between chronic medical condition (yes/no and main categories) and pregnancy planning, and chronic medical condition status and pregnancy planning behaviors stratified by pregnancy planning. RESULTS: In the study population, 74% reported high degree of pregnancy planning, and 22% had one or more chronic medical conditions. We found no overall association between chronic medical condition and pregnancy planning (adjusted rate ratio [RR] 1.00, 95% confidence interval [CI] 0.98-1.01). However, women with type 2 diabetes and mental illness were significantly less likely to plan their pregnancies than women without these conditions (aRR 0.73, 95% CI 0.61-0.88; aRR 0.91, 95% CI 0.87-0.96, respectively). Women with chronic medical conditions were more likely to adhere to the recommended planning behaviors; intake of folic acid, abstention from alcohol prior to pregnancy and no binge drinking in early pregnancy. CONCLUSIONS: Overall, pregnancies were highly planned. Women with chronic medical conditions did not show a higher degree of pregnancy planning than women without chronic medical conditions but were, however. more likely to adhere to the generally recommended pregnancy planning behaviors (ie intake of folic acid and abstention from alcohol intake). Only women with mental illness and type 2 diabetes reported a lower degree of pregnancy planning. It is important that we continuously address pregnancy planning and planning behaviors for both women with and women without chronic medical conditions, especially women with type 2 diabetes and mental illness.

Changes in the pattern of paracetamol use in the periconception period in a Danish cohort.

Paracetamol is the most commonly used over-the-counter drug in pregnancy. It is generally considered to be safe, but prolonged antenatal exposure has been associated with offspring short- and long-term morbidity. Our aim was to describe the pattern of paracetamol use with a focus on frequent ingestion (more than once a week), 3 months before and in early pregnancy. In this cohort, 8650 pregnant women responded to a web-based clinical questionnaire that included questions about drug use. Paracetamol was the most used drug before and in early pregnancy (35.2% and 6.5% of respondents, respectively). The proportion of frequent users decreased from 3.9% before to 0.9% in early pregnancy. Frequent paracetamol use was associated with smoking, co-morbidities, body mass index ≥ 25 kg/m(2), unplanned pregnancy, no education and inability to understand Danish. A significant decrease in the proportion of women with any paracetamol use in early pregnancy was noted after access to large packs was restricted by legislation.

'In situ simulation' versus 'off site simulation' in obstetric emergencies and their effect on knowledge, safety attitudes, team performance, stress, and motivation: study protocol for a randomized controlled trial.

BACKGROUND: Unexpected obstetric emergencies threaten the safety of pregnant women. As emergencies are rare, they are difficult to learn. Therefore, simulation-based medical education (SBME) seems relevant. In non-systematic reviews on SBME, medical simulation has been suggested to be associated with improved learner outcomes. However, many questions on how SBME can be optimized remain unanswered. One unresolved issue is how 'in situ simulation' (ISS) versus 'off site simulation' (OSS) impact learning. ISS means simulation-based training in the actual patient care unit (in other words, the labor room and operating room). OSS means training in facilities away from the actual patient care unit, either at a simulation centre or in hospital rooms that have been set up for this purpose. METHODS AND DESIGN: The objective of this randomized trial is to study the effect of ISS versus OSS on individual learning outcome, safety attitude, motivation, stress, and team performance amongst multi-professional obstetric-anesthesia teams.The trial is a single-centre randomized superiority trial including 100 participants. The inclusion criteria were health-care professionals employed at the department of obstetrics or anesthesia at Rigshospitalet, Copenhagen, who were working on shifts and gave written informed consent. Exclusion criteria were managers with staff responsibilities, and staff who were actively taking part in preparation of the trial. The same obstetric multi-professional training was conducted in the two simulation settings. The experimental group was exposed to training in the ISS setting, and the control group in the OSS setting. The primary outcome is the individual score on a knowledge test. Exploratory outcomes are individual scores on a safety attitudes questionnaire, a stress inventory, salivary cortisol levels, an intrinsic motivation inventory, results from a questionnaire evaluating perceptions of the simulation and suggested changes needed in the organization, a team-based score on video-assessed team performance and on selected clinical performance. DISCUSSION: The perspective is to provide new knowledge on contextual effects of different simulation settings. TRIAL REGISTRATION: ClincialTrials.gov NCT01792674.

Expression pattern of a single transgene cassette located in endogenous GLIS3 of cloned pigs; a nested situation.

One of the main focus areas in transgenesis is the choice of a promoter driving stable expression over time of the gene of interest. Besides promoter identity, the genomic environment of the transgene plays a pivotal role in transcription regulation. Studies in higher mammals describing transgene expression from a defined locus are very limited. We set out to determine the expression pattern of two transgene promoters, the human PDGFß and the viral SV40, in a single cassette positioned in the largest intron of the porcine GLIS3 locus. The PDGFß promoter drives a variant of the amyloid precursor protein gene named APP695sw and the SV40 promoter drives the neomycin resistant gene, Neo. The nested gene scenario was investigated in three transgenic cloned pigs sacrificed at 3 months, 2 years and 3 years of age. With identical genetic make-up and same environment, the three individual pigs are considered representative of 3 year lifespan of a single pig. Selected organs from the pigs were analyzed by quantitative RT-PCR for transgene promoter activity as well as endogenous GLIS3 promoter activity. No apparent effect of the transgene cassette was observed on endogenous GLIS3 expression. In addition, one year old homozygous pigs showed no phenotypic signs of dysfunctional GLIS3. Both transgene promoters showed and retained their tissue specificity with stable expression over time. Our study indicates that transgenes inserted in a nested situation might be applicable for faithful and long term transgene expression.

Prediction of response to preoperative chemoradiotherapy in rectal cancer by multiplex kinase activity profiling.

PURPOSE: Tumor response of rectal cancer to preoperative chemoradiotherapy (CRT) varies considerably. In experimental tumor models and clinical radiotherapy, activity of particular subsets of kinase signaling pathways seems to predict radiation response. This study aimed to determine whether tumor kinase activity profiles might predict tumor response to preoperative CRT in locally advanced rectal cancer (LARC). METHODS AND MATERIALS: Sixty-seven LARC patients were treated with a CRT regimen consisting of radiotherapy, fluorouracil, and, where possible, oxaliplatin. Pretreatment tumor biopsy specimens were analyzed using microarrays with kinase substrates, and the resulting substrate phosphorylation patterns were correlated with tumor response to preoperative treatment as assessed by histomorphologic tumor regression grade (TRG). A predictive model for TRG scores from phosphosubstrate signatures was obtained by partial-least-squares discriminant analysis. Prediction performance was evaluated by leave-one-out cross-validation and use of an independent test set. RESULTS: In the patient population, 73% and 15% were scored as good responders (TRG 1-2) or intermediate responders (TRG 3), whereas 12% were assessed as poor responders (TRG 4-5). In a subset of 7 poor responders and 12 good responders, treatment outcome was correctly predicted for 95%. Application of the prediction model on the remaining patient samples resulted in correct prediction for 85%. Phosphosubstrate signatures generated by poor-responding tumors indicated high kinase activity, which was inhibited by the kinase inhibitor sunitinib, and several discriminating phosphosubstrates represented proteins derived from signaling pathways implicated in radioresistance. CONCLUSIONS: Multiplex kinase activity profiling may identify functional biomarkers predictive of tumor response to preoperative CRT in LARC.

Vorinostat, a histone deacetylase inhibitor, combined with pelvic palliative radiotherapy for gastrointestinal carcinoma: the Pelvic Radiation and Vorinostat (PRAVO) phase 1 study.

BACKGROUND: Histone deacetylase (HDAC) inhibitors have shown radiosensitising activity in preclinical tumour models. This phase 1 study assessed the use of vorinostat combined with pelvic palliative radiotherapy for gastrointestinal carcinoma. METHODS: Between Feb 14, 2007, and May 18, 2009, eligible patients with histologically confirmed carcinoma, scheduled to receive pelvic palliative radiation to 30 Gy in 3 Gy daily fractions over 2 weeks, were enrolled into cohorts of escalating vorinostat dose. Vorinostat was administered orally once daily, 3 h before each radiotherapy fraction, at the following dose levels: 100 mg (n=1), 200 mg (n=4), 300 mg (n=6), and 400 mg (n=6). Endpoints included safety, tolerability, and biological activity (tumour histone acetylation). This study is registered with ClinicalTrials.gov, number NCT00455351. FINDINGS: One patient withdrew consent after one treatment day, leaving 16 patients evaluable for tolerability. Most recorded adverse events were grade 1 and 2, among which fatigue (all patients) and gastrointestinal events (all patients) were most common. Grade 3 adverse events included fatigue (n=5), anorexia (n=3), diarrhoea (n=2), hyponatraemia (n=1), hypokalaemia (n=1), and acneiform rash (n=1). Of these, treatment-related grade 3 events (ie, dose-limiting toxicities) were observed in one of six patients at vorinostat 300 mg once daily (fatigue and anorexia), and in two of six patients at vorinostat 400 mg once daily (two events of diarrhoea and one each of fatigue, anorexia, hyponatraemia, and hypokalaemia). The maximum-tolerated dose of vorinostat in combination with palliative radiotherapy was thus determined to be 300 mg once daily. Histone hyperacetylation was detected, indicating biological activity of vorinostat. INTERPRETATION: Vorinostat can be safely combined with short-term pelvic palliative radiotherapy. This study highlights the potential use of HDAC inhibitors with radiation, and suggests investigation of vorinostat in long-term curative pelvic radiotherapy--eg, as a component of preoperative chemoradiotherapy for rectal cancer. FUNDING: Merck & Co, Inc, Norwegian Cancer Society, Norwegian Health and Rehabilitation Foundation.