Hematology reference intervals in 6-12-year-old children: the health-oriented pedagogical project (HOPP)

Reference intervals are essential for correct interpretation of laboratory test results, supporting clinicians in distinguishing between healthy and sick individuals. The present study aims to establish pediatric reference intervals for hematological parameters based on a large population of healthy schoolchildren. Blood samples were obtained from 1351 children 6–12 years of age participating in the Health-Oriented Pedagogical Project (HOPP). Reference intervals for hematological parameters were estimated by the nonparametric method following the CLSI C28-A3 guidelines. Reference intervals were estimated as 2.5th and 97.5th percentiles with corresponding 90% confidence intervals. While hematocrit and MCV required age and sex partitioning, hemoglobin and erythrocytes were partitioned for age. The remaining parameters, MCH, MCHC, platelets and white blood cell counts did not require partitioning. While red blood cell parameters exhibited an increasing trend with age, there was a slight decrease in leukocytes, lymphocytes, basophils and platelets with age. The remaining parameters were stable across our age span.publishedVersio

Hematology reference intervals in 6-12-year-old children: the health-oriented pedagogical project (HOPP)

Reference intervals are essential for correct interpretation of laboratory test results, supporting clinicians in distinguishing between healthy and sick individuals. The present study aims to establish pediatric reference intervals for hematological parameters based on a large population of healthy schoolchildren. Blood samples were obtained from 1351 children 6–12 years of age participating in the Health-Oriented Pedagogical Project (HOPP). Reference intervals for hematological parameters were estimated by the nonparametric method following the CLSI C28-A3 guidelines. Reference intervals were estimated as 2.5th and 97.5th percentiles with corresponding 90% confidence intervals. While hematocrit and MCV required age and sex partitioning, hemoglobin and erythrocytes were partitioned for age. The remaining parameters, MCH, MCHC, platelets and white blood cell counts did not require partitioning. While red blood cell parameters exhibited an increasing trend with age, there was a slight decrease in leukocytes, lymphocytes, basophils and platelets with age. The remaining parameters were stable across our age span.publishedVersio

Do Children Who Move Home and School Frequently Have Poorer Educational Outcomes in Their Early Years at School? An Anonymised Cohort Study

Frequent mobility has been linked to poorer educational attainment. We investigated the association between moving home and moving school frequently and the early childhood formal educational achievement. We carried out a cohort analysis of 121,422 children with anonymised linked records. Our exposure measures were: 1) the number of residential moves registered with a health care provider, and 2) number of school moves. Our outcome was the formal educational assessment at age 6–7. Binary regression modeling was used to examine residential moves within the three time periods: 0 – ,1 year; 1 – ,4 years and 4 – ,6 years. School moves were examined from age 4 to age 6. We adjusted for demographics, residential moves at different times, school moves and birth related variables. Children who moved home frequently were more likely not to achieve in formal assessments compared with children not moving. Adjusted odds ratios were significant for 3 or more moves within the time period 1 –,4 years and for any number of residential moves within the time period 4– ,6 years. There was a dose response relationship, with increased odds ratios with increased frequency of residential moves (2 or more moves at 4–,6 years, adjusted odds ratio 1.16 (1.03, 1.29). The most marked effect was seen with frequent school moves where 2 or more moves resulted in an adjusted odds ratio of 2.33 (1.82, 2.98). This is the first study to examine the relationship between residential and school moves in early childhood and the effect on educational attainment. Children experiencing frequent mobility may be disadvantaged and should be closely monitored. Additional educational support services should be afforded to children, particularly those who frequently change school, in order to help them achieve the expected educational standards

MEK Inhibition Induces Canonical WNT Signaling through YAP in KRAS Mutated HCT-15 Cells, and a Cancer Preventive FOXO3/FOXM1 Ratio in Combination with TNKS Inhibition

The majority of colorectal cancers are induced by subsequent mutations in APC and KRAS genes leading to aberrant activation of both canonical WNT and RAS signaling. However, due to induction of feedback rescue mechanisms some cancers do not respond well to targeted inhibitor treatments. In this study we show that the APC and KRAS mutant human colorectal cancer cell line HCT-15 induces canonical WNT signaling through YAP in a MEK dependent mechanism. This inductive loop is disrupted with combined tankyrase (TNKS) and MEK inhibition. RNA sequencing analysis suggests that combined TNKS/MEK inhibition induces metabolic stress responses in HCT-15 cells promoting a positive FOXO3/FOXM1 ratio to reduce antioxidative and cryoprotective systems.publishedVersio

A school-based physical activity intervention on psychosocial health outcomes among 11- and 12-year-olds – HOPP-project

The purpose was to investigate the effect of a school-based physical activity (PA)-intervention among 11- and 12-year-olds (6th- and 7th graders) across 4 years. Seven primary schools in Horten municipality in Norway received 45 min daily extra PA as part of the curriculum. The intervention started in 2015 with follow-up in 2016–2019. The effect was measured after 1–4 years of participation, among the same children (6th to 7th grade) and among new children starting in 6th grade. Two control schools received no additional PA beyond the regular PA at school. The Self-reported Strength and Difficulties Questionnaire (SDQ-S) focusing on internalizing and externalizing difficulties were administrated. A statistical model for repeated measurements was used and adjusted for parents' educational level, sex, age, and waist-to-height ratio (WHtR). The significance level was p ≤ 0.01. In total, 1221 children completed the SDQ-S. SDQ-S scores were stable, and difficulties were relatively low. The control group had significantly lower SDQ-S scores than the intervention group at start, indicating fewer difficulties. The adjusted effect within the intervention schools showed a borderline significant increase in total difficulty scores between 2018 and 2019 (mean difference: 1.02, 95% CI: −1.82, −0.23, p ≤ 0.01). Educational level showed a weak negative correlation with total difficulty score (r = −0.1). No significant change was reported within the control schools. Few psychosocial health problems among 11- and 12-year-olds were detected. The borderline increase in total difficulty score that was seen for the intervention schools, is believed to be of limited clinical relevance.publishedVersio

A school-based physical activity intervention on psychosocial health outcomes among 11- and 12-year-olds – HOPP-project

The purpose was to investigate the effect of a school-based physical activity (PA)-intervention among 11- and 12-year-olds (6th- and 7th graders) across 4 years. Seven primary schools in Horten municipality in Norway received 45 min daily extra PA as part of the curriculum. The intervention started in 2015 with follow-up in 2016–2019. The effect was measured after 1–4 years of participation, among the same children (6th to 7th grade) and among new children starting in 6th grade. Two control schools received no additional PA beyond the regular PA at school. The Self-reported Strength and Difficulties Questionnaire (SDQ-S) focusing on internalizing and externalizing difficulties were administrated. A statistical model for repeated measurements was used and adjusted for parents' educational level, sex, age, and waist-to-height ratio (WHtR). The significance level was p ≤ 0.01. In total, 1221 children completed the SDQ-S. SDQ-S scores were stable, and difficulties were relatively low. The control group had significantly lower SDQ-S scores than the intervention group at start, indicating fewer difficulties. The adjusted effect within the intervention schools showed a borderline significant increase in total difficulty scores between 2018 and 2019 (mean difference: 1.02, 95% CI: −1.82, −0.23, p ≤ 0.01). Educational level showed a weak negative correlation with total difficulty score (r = −0.1). No significant change was reported within the control schools. Few psychosocial health problems among 11- and 12-year-olds were detected. The borderline increase in total difficulty score that was seen for the intervention schools, is believed to be of limited clinical relevance.publishedVersio

Rheumatoid arthritis - treatment: 180. Utility of Body Weight Classified Low-Dose Leflunomide in Japanese Rheumatoid Arthritis

Background: In Japan, more than 20 rheumatoid arthritis (RA) patients died of interstitial pneumonia (IP) caused by leflunomide (LEF) were reported, but many of them were considered as the victims of opportunistic infection currently. In this paper, efficacy and safety of low-dose LEF classified by body weight (BW) were studied. Methods: Fifty-nine RA patients were started to administrate LEF from July 2007 to July 2009. Among them, 25 patients were excluded because of the combination with tacrolimus, and medication modification within 3 months before LEF. Remaining 34 RA patients administered 20 to 50 mg/week of LEF were followed up for 1 year and enrolled in this study. Dose of LEF was classified by BW (50 mg/week for over 50 kg, 40 mg/week for 40 to 50 kg and 20 to 30 mg/week for under 40 kg). The average age and RA duration of enrolled patients were 55.5 years old and 10.2 years. Prednisolone (PSL), methotrexate (MTX) and etanercept were used in 23, 28 and 2 patients, respectively. In case of insufficient response or adverse effect, dosage change or discontinuance of LEF were considered. Failure was defined as dosages up of PSL and MTX, or dosages down or discontinuance of LEF. Last observation carried forward method was used for the evaluation of failed patients at 1 year. Results: At 1 year after LEF start, good/ moderate/ no response assessed by the European League Against Rheumatism (EULAR) response criteria using Disease Activity Score, including a 28-joint count (DAS28)-C reactive protein (CRP) were showed in 14/ 10/ 10 patients, respectively. The dosage changes of LEF at 1 year were dosage up: 10, same dosage: 5, dosage down: 8 and discontinuance: 11 patients. The survival rate of patients in this study was 23.5% (24 patients failed) but actual LEF continuous rate was 67.6% (11 patients discontinued) at 1 year. The major reason of failure was liver dysfunction, and pneumocystis pneumonia was occurred in 1 patient resulted in full recovery. One patient died of sepsis caused by decubitus ulcer infection. DAS28-CRP score was decreased from 3.9 to 2.7 significantly. Although CRP was decreased from 1.50 to 0.93 mg/dl, it wasn't significant. Matrix metalloproteinase (MMP)-3 was decreased from 220.0 to 174.2 ng/ml significantly. Glutamate pyruvate transaminase (GPT) was increased from 19 to 35 U/l and number of leukocyte was decreased from 7832 to 6271 significantly. DAS28-CRP, CRP, and MMP-3 were improved significantly with MTX, although they weren't without MTX. Increase of GPT and leukopenia were seen significantly with MTX, although they weren't without MTX. Conclusions: It was reported that the risks of IP caused by LEF in Japanese RA patients were past IP history, loading dose administration and low BW. Addition of low-dose LEF is a potent safe alternative for the patients showing unsatisfactory response to current medicines, but need to pay attention for liver function and infection caused by leukopenia, especially with MTX. Disclosure statement: The authors have declared no conflicts of interes

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Discovery of Therapeutic Approaches for Polyglutamine Diseases: A Summary of Recent Efforts

Polyglutamine (PolyQ) diseases are a group of neurodegenerative disorders caused by the expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the coding region of specific genes. This leads to the production of pathogenic proteins containing critically expanded tracts of glutamines. Although polyQ diseases are individually rare, the fact that these nine diseases are irreversibly progressive over 10 to 30 years, severely impairing and ultimately fatal, usually implicating the full-time patient support by a caregiver for long time periods, makes their economic and social impact quite significant. This has led several researchers worldwide to investigate the pathogenic mechanism(s) and therapeutic strategies for polyQ diseases. Although research in the field has grown notably in the last decades, we are still far from having an effective treatment to offer patients, and the decision of which compounds should be translated to the clinics may be very challenging. In this review, we provide a comprehensive and critical overview of the most recent drug discovery efforts in the field of polyQ diseases, including the most relevant findings emerging from two different types of approaches-hypothesis-based candidate molecule testing and hypothesis-free unbiased drug screenings. We hereby summarize and reflect on the preclinical studies as well as all the clinical trials performed to date, aiming to provide a useful framework for increasingly successful future drug discovery and development efforts.Project ON.2 SR&TD Integrated Program (NORTE-07-0124-FEDER-000021), co-funded by North Portugal Regional Operational Program (ON.2-O Novo Norte), under the National Strategic Reference Framework, through the European Regional Development Fund (ERDF) and also supported by Fundação para a Ciência e Tecnologia through the project POCI-01-0145-FEDER-016818 (PTDC/NEU-NMC/3648/2014)info:eu-repo/semantics/publishedVersio