Analysis of 3760 hematologic malignancies reveals rare transcriptomic aberrations of driver genes.

BACKGROUND: Rare oncogenic driver events, particularly affecting the expression or splicing of driver genes, are suspected to substantially contribute to the large heterogeneity of hematologic malignancies. However, their identification remains challenging. METHODS: To address this issue, we generated the largest dataset to date of matched whole genome sequencing and total RNA sequencing of hematologic malignancies from 3760 patients spanning 24 disease entities. Taking advantage of our dataset size, we focused on discovering rare regulatory aberrations. Therefore, we called expression and splicing outliers using an extension of the workflow DROP (Detection of RNA Outliers Pipeline) and AbSplice, a variant effect predictor that identifies genetic variants causing aberrant splicing. We next trained a machine learning model integrating these results to prioritize new candidate disease-specific driver genes. RESULTS: We found a median of seven expression outlier genes, two splicing outlier genes, and two rare splice-affecting variants per sample. Each category showed significant enrichment for already well-characterized driver genes, with odds ratios exceeding three among genes called in more than five samples. On held-out data, our integrative modeling significantly outperformed modeling based solely on genomic data and revealed promising novel candidate driver genes. Remarkably, we found a truncated form of the low density lipoprotein receptor LRP1B transcript to be aberrantly overexpressed in about half of hairy cell leukemia variant (HCL-V) samples and, to a lesser extent, in closely related B-cell neoplasms. This observation, which was confirmed in an independent cohort, suggests LRP1B as a novel marker for a HCL-V subclass and a yet unreported functional role of LRP1B within these rare entities. CONCLUSIONS: Altogether, our census of expression and splicing outliers for 24 hematologic malignancy entities and the companion computational workflow constitute unique resources to deepen our understanding of rare oncogenic events in hematologic cancers.

Misfit simulation on implant-supported prostheses with different combinations of engaging and nonengaging titanium bases: Part 3: A radiographic evaluation.

STATEMENT OF PROBLEM: The fit of implant-supported prostheses plays an important role in their mechanical and biological stability. Clinically, the prosthetic fit is typically assessed radiographically, but this method relies on the operator's subjective evaluation. Whether available digital tools could optimize the evaluation of the prosthetic fit is uncertain. PURPOSE: The purpose of this in vitro study was to evaluate the influence of an image processing program on the radiographic detection of discrepancies in the active and passive fit of implant-supported prostheses. Two-implant-supported screw-retained prostheses were analyzed by simulating the vertical and horizontal misfits of 3 different implant abutment configurations. MATERIAL AND METHODS: Seven casts were fabricated using 2 internal-connection titanium implants: 1 control; 3 with vertical (V) misfit of 50 µm, 100 µm, 150 µm; and 3 with horizontal (H) misfit of 35 µm, 70 µm, 100 µm. Thirty bar-shaped zirconia frameworks were fabricated and divided into 3 groups (n=10) according to their attachment to 2 engaging (E-E), 2 nonengaging (NE-NE), and engaging and nonengaging (E-NE) titanium bases. Digital parallel periapical radiographs were made of each specimen in the passive and active fit situation on each cast (1-screw test), except for the E-E specimens, which were only seated on the control, H35, and H70 casts because the fit on the remaining casts was poor. The mean gray value (MGV) was measured at the chosen regions of interest on the second implant (side B) using the ImageJ software program. Differences in the MGV measurements between the passive and active conditions were tested using a t test (α=.05) and compared the different misfit levels using analysis of variance (1-way ANOVA), followed by the Tukey HSD test (α=.05). RESULTS: The highest values for the differences between passive and active fit were found for the V150 and H100 misfit simulations (P<.05). Statistical differences between the MGVs were found with some exceptions: the smallest simulated misfits (H35 and V50) revealed statistically significant MGV differences from the highest simulated misfits (V150, H100) and from the H70 in the groups where an engaging component was present (P>.05). In the horizontal misfit group of NE-NE abutment configuration, H70 revealed no significant difference from the control group cast (P>.05). CONCLUSIONS: Measuring MGV differences between passive and active fit could be a promising alternative for detecting 70- to 150-µm gaps in the implant-abutment connection that result from the misfit. However, the procedure was not adequate for detecting <50 µm gaps, cannot be uniformly applied to all types of implant-abutment connections, and requires 2 exposures to X-radiation.

Stakeholder needs assessment for developing ageing in place solutions - a qualitative study.

BACKGROUND: Ageing in place is a common desire among older adults and people in need of care. Accessible housing and ambient assisted living (AAL) technologies can help to live independently at home. However, they cannot replace the human support network of informal caregivers, healthcare professionals and social workers. The needs of these stakeholders should be considered and analysed in order to develop user-friendly and acceptable (digital) solutions for ageing in place while supporting human support networks in fulfilling their roles. This paper presents the first step for a comprehensive multi-level needs analysis within the framework of an user-centered design thinking approach. METHODS: Guideline-based interviews were conducted with healthcare professionals, social workers and an informal caregiver to collect data about the needs of older adults as well as people in need of care, and their human support networks. RESULTS: The call for more information that is easier to find is a common desire of the three groups. There is agreement on system-based communication and orientation problems, the existence of physical and psychological stress exacerbated by a lack of human resources, the desire for personalised care, the need to feel safe and supported in emergencies, and the need for advice and help with administrative tasks. Overall, the needs of one group are closely linked to those of the other. CONCLUSION: Stakeholder selection and diversity are decisive for findings about ageing in place. The overlaps between the stakeholders' needs offer chances and challenges at the same time for the development of user-friendly, acceptable (digital) solutions and products that support ageing in place.

Profile of per- and polyfluoroalkyl substances, source appointment, and determinants in Argentinean postpartum women.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are a group of synthetic chemicals with potential adverse health effects. Information concerning PFAS concentrations in relation to pregnancy is scarce in South America and non-existent in Argentina. AIM: We aimed to investigate an extended maternal PFAS profile herein serum concentrations in a regional and global view, source appointment, and determinants in Argentinean women. METHODS: A cross-sectional study with a sampling period from 2011 to 2012 included 689 women from Ushuaia and Salta in Argentina. Serum samples collected two days postpartum were analyzed by ultra-high pressure liquid chromatography coupled to electrospray negative ionisation tandem-quadrupole mass-spectrometry. Principal Component Analysis (PCA) following absolute principal component score-multiple linear regression (APCS-MLR) was used for PFAS source appointments. Determinants of PFAS were explored through a MLR approach. A review of previous studies within the same period was conducted to compare with present levels. RESULTS: Argentinean PFAS concentrations were the lowest worldwide, with PFOS (0.74 ng/mL) and PFOA (0.11 ng/mL) as the dominant substances. Detection frequencies largely aligned with the compared studies, indicating the worldwide PFAS distribution considering the restrictions. The PCA revealed region-specific loading patterns of two component groups of PFAS, a mixture of replaced and legacy substances in Ushuaia and long-chain in Salta. This might relate to a mix of non-diet and diet exposure in Ushuaia and diet in Salta. Region, age, lactation, parity, household members, migration, bottled water, and freshwater fish were among the determinants of various PFAS. CONCLUSION: This is the first study to monitor human PFAS exposure in Argentina. Maternal PFAS concentrations were the lowest observed worldwide in the same period. Exposure contributions are suggested to be affected by restrictions and substitutions. Given the limited population-based studies and the emergence of PFAS, it is essential to conduct further monitoring of PFAS in Argentina and South America.

Early menarche and other endocrine disrupting effects of per- and polyfluoroalkyl substances (PFAS) in adolescents from Northern Norway. The Fit Futures study.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) comprise a large group of chemicals that are ubiquitous in the environment and include recognized persistent organic pollutants. The aim of this cross-sectional study was to investigate possible endocrine disrupting effects of different PFAS in adolescents. METHODS: Serum concentrations of PFAS, thyroid, parathyroid and steroid hormones were measured in 921 adolescents aged 15-19 years in the Fit Futures study, Northern Norway. The questionnaire included data on self-reported age at menarche and puberty development score (PDS). Multiple linear and logistic regression analyses and principle component analyses (PCA) were used to assess associations of PFAS with hormones concentrations and puberty indices. RESULTS: In girls, total PFAS (∑PFAS), perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoate (PFNA), perfluorodecanoate (PFDA) were positively associated with dehydroepiandrosterone sulfate (DHEAS) and negatively associated with 11-deoxycorticosterone (11-DOC)/DHEAS ratio. In boys, the associations with 11-DOC/DHEAS ratio were positive for ∑PFAS, perfluoroheptanoate (PFHpA), perfluoroheptane sulfonate (PFHpS), PFOA, and PFOS. Perfluoroundecanoate (PFUnDA) was negatively associated with free thyroxine (fT4) and free triiodothyronine (fT3) in boys. PFNA and PFDA were also negatively associated with fT3 in boys. Serum parathyroid hormone concentration (PTH) was negatively associated with ∑PFAS and perfluorohexane sulfonate (PFHxS) in girls, and with PFOS in boys. PFDA and PFUnDA were positively associated with early menarche, while ∑PFAS and PFOA were positively associated with PDS in boys. No associations of PFAS with serum testosterone, follicle-stimulating hormone, or luteinizing hormone were found in either sex. In girls, PFOA was positively associated with free testosterone index (FTI). In boys, PFOA was positively associated with androstendione and 17-OH-progesterone, while PFHpA was positively associated with estradiol. CONCLUSIONS: Serum concentrations of several PFAS were associated with parathyroid and steroid hormones in both sexes, and with thyroid hormones in boys, as well as with early menarche in girls and higher PDS in boys.

Should we eat more fish - or less? / Bør vi spise mer fisk ­ eller mindre?

All food contains environmental toxins. The EU has set a new threshold for the level of environmental toxins that can be considered safe in the body. In Norway, the average intake exceeds this threshold, and fatty fish is the main source. Nevertheless, the Norwegian authorities recommend that all age groups eat more fish.

Impact of a family-centred clinical care programme on short-term outcomes of very low-birth weight infants.

AIM: We evaluated the effects of a family-centred clinical care pathway and case management programme on short-term clinical outcome in a cohort of very low-birth weight (VLBW) infants. METHODS: The programme, named NeoPAss, was developed at the Department of Neonatology Children's hospital Passau in 2013. Short-term outcomes of infants were compared to matched controls from the Bavarian neonatology surveillance database before (n = 111; 2008-2012) and after implementation (n = 170; 2014-2017). RESULTS: After implementation the rate of late-onset sepsis was significantly lower (2.5% vs. 10.7%, p = 0.005) and the length of stay was significantly shorter (VLBW 28 to 31 weeks' gestational age (GA) 47.5 vs. 53.1 days, p = 0.047; <28 weeks' GA 79.4 vs. 91.9 days, p = 0.007) in the intervention group compared to controls. Infants were discharged with significantly lower weight (mean 2351 vs. 2539 g, p = 0.013). There was no statistically significant difference in the rate of intraventricular haemorrhage (3.7% vs. 8.2%), necrotizing enterocolitis (0.6% vs. 1.9%) and bronchopulmonary dysplasia (0% vs. 6.9%). CONCLUSION: Our data confirm that of other studies demonstrating a beneficial effect of family-centred care programmes and provides evidence that structured parental involvement is not associated with increased risk of infection in a VLBW cohort.

Predictors of Maternal Serum Concentrations for Selected Persistent Organic Pollutants (POPs) in Pregnant Women and Associations with Birth Outcomes: A Cross-Sectional Study from Southern Malawi.

Population exposure to persistent organic pollutants (POPs) may result in detrimental health effects, especially to pregnant women, developing foetuses and young children. We are reporting the findings of a cross-sectional study of 605 mothers in their late pregnancy, recruited between August 2020 and July 2021 in southern Malawi, and their offspring. The aim was to measure the concentrations of selected POPs in their maternal serum and indicate associations with social demographic characteristics and birth outcomes. A high level of education was the main predictor of p,p'-DDE (p = 0.008), p,p'-DDT (p < 0.001), cis-NC (p = 0.014), o,p'-DDT (p = 0.019) and o,p'-DDE (p = 0.019) concentrations in maternal serum. Multiparity was negatively associated with o,p'-DDE (p = 0.021) concentrations. Maternal age was also positively associated (p,p'-DDE (p = 0.013), o,p'-DDT (p = 0.017) and o,p'-DDE (p = 0.045) concentrations. Living in rural areas was inversely associated with high maternal serum concentrations of p,p'-DDT (p < 0.001). Gestational age was positively associated with p,p'-DDE (p = 0.031), p,p'-DDT (p = 0.010) and o,p'-DDT (p = 0.022) concentrations. Lastly, an inverse association was observed between head circumference and t-NC (p = 0.044), Oxychlordane (p = 0.01) and cis-NC (p = 0.048). These results highlight the need to continue monitoring levels of POPs among vulnerable populations in the southern hemisphere.

AML classification in the year 2023: How to avoid a Babylonian confusion of languages.

In parallel to the 5th edition of the World Health Organization Classification of Haematolymphoid Tumours (WHO 2022), an alternative International Consensus Classification (ICC) has been proposed. To evaluate the impact of the new classifications on AML diagnoses and ELN-based risk classification, we analyzed 717 MDS and 734 AML non-therapy-related patients diagnosed according to the revised 4th WHO edition (WHO 2017) by whole genome and transcriptome sequencing. In both new classifications, the purely morphologically defined AML entities decreased from 13% to 5%. Myelodysplasia-related (MR) AML increased from 22% to 28% (WHO 2022) and 26% (ICC). Other genetically-defined AML remained the largest group, and the abandoned AML-RUNX1 was mainly reclassified as AML-MR (WHO 2022: 77%; ICC: 96%). Different inclusion criteria of AML-CEBPA and AML-MR (i.a. exclusion of TP53 mutated cases according to ICC) were associated with differences in overall survival. In conclusion, both classifications focus on more genetics-based definitions with similar basic concepts and a large degree of agreement. The remaining non-comparability (e.g., TP53 mutated AML) needs additional studies to definitely answer open questions on disease categorization in an unbiased way.

Polybrominated diphenyl ethers in type 2 diabetes mellitus cases and controls: Repeated measurements prior to and after diagnosis.

BACKGROUND: Previous studies have reported associations between certain persistent organic pollutants (POPs) and type 2 diabetes mellitus (T2DM). Polybrominated diphenyl ethers (PBDEs) are a class of POPs that are found in increasing concentrations in humans. Although obesity is a known risk factor for T2DM and PBDEs are fat-soluble, very few studies have investigated associations between PBDEs and T2DM. No longitudinal studies have assessed associations between repeated measurements of PBDE and T2DM in the same individuals and compared time trends of PBDEs in T2DM cases and controls. OBJECTIVES: To investigate associations between pre- and post-diagnostic measurements of PBDEs and T2DM and to compare time trends of PBDEs in T2DM cases and controls. METHODS: Questionnaire data and serum samples from participants in the Tromsø Study were used to conduct a longitudinal nested case-control study among 116 T2DM cases and 139 controls. All included study participants had three pre-diagnostic blood samples (collected before T2DM diagnosis in cases), and up to two post-diagnostic samples after T2DM diagnosis. We used logistic regression models to investigate pre- and post-diagnostic associations between PBDEs and T2DM, and linear mixed-effect models to assess time trends of PBDEs in T2DM cases and controls. RESULTS: We observed no substantial pre- or post-diagnostic associations between any of the PBDEs and T2DM, except for BDE-154 at one of the post-diagnostic time-points (OR = 1.65, 95% CI: 1.00, 2.71). The overall time trends of PBDE concentrations were similar for cases and controls. DISCUSSION: The study did not support PBDEs increasing the odds of T2DM, prior to or after T2DM diagnosis. T2DM status did not influence the time trends of PBDE concentrations.

Serum Concentrations of Selected Poly- and Perfluoroalkyl Substances (PFASs) in Pregnant Women and Associations with Birth Outcomes. A Cross-Sectional Study from Southern Malawi.

Pervasive exposure to per-and polyfluoroalkyl substances (PFASs) shows associations with adverse pregnancy outcomes. The aim of the present study was to examine the determinants of different serum PFAS concentrations in late pregnancy and their relationship with birth outcomes in southern Malawi. The sample included 605 pregnant women with a mean age of 24.8 years and their offspring from three districts in the southern region of Malawi. Six PFAS were measured in serum from third-trimester women. The serum PFAS concentrations were assessed with head circumference, birth length, birth weight, gestational age and ponderal index. Participants living in urban areas had significantly higher serum levels of PFOA, PFNA and SumPFOS, while SumPFHxS concentrations were higher in women from rural settings. High PFOA, PFNA and SumPFHxS concentrations were generally inversely associated with head circumference. Birth length was negatively associated with PFOA and PFNA while SumPFHxS was negatively associated with birth weight. SumPFOS was inversely associated with gestational age. Urban area of residence was the strongest predictor for high PFAS concentrations in the maternal serum and was generally associated with adverse birth outcomes. The results highlight the need to investigate SumPFHxS further as it follows a pattern that is different to similar compounds and cohorts.

One-year follow-up of young people with ME/CFS following infectious mononucleosis by Epstein-Barr virus.

Background: Infectious mononucleosis after primary infection with Epstein-Barr virus (EBV-IM) has been linked to the development of myalgic encephalomyelitis/chronic fatigue-syndrome (ME/CFS) in children, adolescents, and young adults. Here, we present clinical phenotypes and follow-up data from a first German cohort of young people with ME/CFS following EBV-IM. Methods: 12 adolescents and 13 young adults were diagnosed with IM-triggered ME/CFS at our specialized tertiary outpatient service by clinical criteria requiring post-exertional malaise (PEM) and a history of confirmed EBV primary infection as triggering event. Demographic information, laboratory findings, frequency and severity of symptoms, physical functioning, and health-related quality of life (HRQoL) were assessed and re-evaluated 6 and 12 months later. Results: Young adults displayed more severe symptoms as well as worsening of fatigue, physical and mental functioning, and HRQoL throughout the study, compared to adolescents. After one year, 6/12 (54%) adolescents no longer met the diagnostic criteria for ME/CFS while all young adults continued to fulfill the Canadian consensus criteria. Improvement in adolescents was evident in physical functioning, symptom frequency and severity, and HRQoL, while young adults showed little improvement. EBV serology and EBV DNA load did not correlate with distinct clinical features of ME/CFS, and clinical chemistry showed no evidence of inflammation. Remarkably, the median time from symptom onset to ME/CFS diagnosis was 13.8 (IQR: 9.1-34.9) months. Conclusions: ME/CFS following EBV-IM is a severely debilitating disease often diagnosed late and with limited responses to conventional medical care, especially in adults. Although adolescents may have a better prognosis, their condition can fluctuate and significantly impact their HRQoL. Our data emphasize that biomarkers and effective therapeutic options are also urgently needed to improve medical care and pave the way to recovery.