DAHEAN: A Danish nationwide study ensuring quality assurance through real-world data for suspected hereditary anemia patients.

BACKGROUND: Hereditary anemias are a group of genetic diseases prevalent worldwide and pose a significant health burden on patients and societies. The clinical phenotype of hereditary anemias varies from compensated hemolysis to life-threatening anemia. They can be roughly categorized into three broad categories: hemoglobinopathies, membranopathies, and enzymopathies. Traditional therapeutic approaches like blood transfusions, iron chelation, and splenectomy are witnessing a paradigm shift with the advent of targeted treatments. However, access to these treatments remains limited due to lacking or imprecise diagnoses. The primary objective of the study is to establish accurate diagnoses for patients with hereditary anemias, enabling optimal management. As a secondary objective, the study aims to enhance our diagnostic capabilities. RESULTS: The DAHEAN study is a nationwide cohort study that collects advanced phenotypic and genotypic data from patients suspected of having hereditary anemias from all pediatric and hematological departments in Denmark. The study deliberates monthly by a multidisciplinary anemia board involving experts from across Denmark. So far, fifty-seven patients have been thoroughly evaluated, and several have been given diagnoses not before seen in Denmark. CONCLUSIONS: The DAHEAN study and infrastructure harness recent advancements in diagnostic tools to offer precise diagnoses and improved management strategies for patients with hereditary anemias.

Mental health and use of psychotropic prescription drugs in adult patients with primary immune thrombocytopenia: a nationwide population-based cohort study.

Patients with primary immune thrombocytopenia (ITP) suffer from reduced survival and quality of life, but the underlying reasons for this are largely undescribed. Mental health and the use of psychotropic drugs in ITP is unknown. We investigated the risk of hospital registered mental health events including fatigue and the use of psychotropic drugs in adult patients with ITP compared with the general population, using nationwide registry-data. We identified 3,749 patients with ITP and 149,849 age-sex matched general population comparators in the Danish Health Registries in the period 1997-2016. The median age was 60 years (IQR 40-73) and 53% were women. We followed the individuals for incident mental health events and estimated the use of psychotropic drugs over calendar-years and in temporal relation to diagnosis of ITP. The first year cumulative incidence of any mental health event was 2.3% (95% confidence interval, 1.9-2.9) in patients and 0.7% (0.6-0.7) in comparators, yielding an adjusted cause-specific hazard ratio (csHR) of 3.57 (2.84-4.50). The corresponding estimates for depression were 1.2% (0.9-1.6) and 0.3% (0.3-0.4) respectively, with an adjusted csHR of 3.53 (2.56-4.85). We found similar findings for anxiety and fatigue, but risks generally diminished after 1-5 years. The use of opioids, antidepressants, and benzodiazepines increased in temporal relation to diagnosis of ITP. The risk of mental health events and the use of psychotropic drugs is higher in adult patients with ITP compared with the general population, and has a temporal relation to diagnosis of ITP emphasizing that mental health in ITP is a concern.

Optimization of Postprocessing parameters for abdominal Forensic CT scans.

Aim: Postmortem Computed Tomography (PMCT) is gradually introduced at forensic institutes. Image reconstruction software can increase diagnostic potential in CT by increasing distinction between structures and reduction of artifacts. The aim of this study was to develop and evaluate novel image reconstruction parameters for postmortem conditions, to increase image quality and diagnostic potential of CT scans. Method: Twenty PMCT scans of deceased hereof two in severe decay were subjected to four reconstruction techniques: a standard reconstruction algorithm, the detail reconstruction algorithm and two novel algorithms based on the standard algorithm, but with different Hounsfield settings. Image quality was evaluated by visual grading analysis (VGA) by four forensic radiologist observers. Results: The VGA did not prove that any of the reconstruction techniques were superior to the others. For standard and detail, the two pre-defined reconstruction algorithms, VGA scores were indiscernible and were superior to the equally indiscernible Hounsfield reconstructions on parameters translated into Sharpness and Low Contrast Resolution. The two alternative Hounsfield settings were superior with respect to Noise and Artifacts/Beam Hardening. Conclusion: The study elucidates the possiblity for multiple reconstructions specialized for PMCT conditions, to accommodate the special conditions when working with the deceased. Despite the lack of clear improvements in the tested reconstructions, this study provides an insight into some of the possibilities of improving PMCT quality using reconstruction techniques.

New expert advice on cancer in pregnancy.

Cancer in pregnancy is rare, and most physicians lack knowledge in handling pregnant cancer patients. This review summarises the present knowledge on this condition. In the Netherlands, an Advisory Board on Cancer in Pregnancy was established in 2012. The board supports Dutch physicians' decisions in the management of pregnant patients with cancer. In 2021 the International Advisory Board on Cancer in Pregnancy was established, and in continuation, the Danish Advisory Board on Cancer in Pregnancy (DABCIP) has now been founded. DABCIP consists of 22 members from 13 different medical disciplines.

Risk of fractures and use of bisphosphonates in adult patients with immune thrombocytopenia-A nationwide population-based study.

Corticosteroids remain the first-line treatment of immune thrombocytopenia (ITP), but increase the risk of osteoporosis and fractures. Bisphosphonates are used for the treatment of osteoporosis, but their usage among patients with ITP has not been systemically described. We investigated the risk of fractures and the use of bisphosphonates in adult patients with primary (pITP) and secondary ITP (sITP) compared with matched comparators in a nationwide registry-based cohort study. We identified 4030 patients with pITP (median age 60 years [IQR, 40-74]), 550 with sITP (median age 59 years [IQR, 43-74]) and 182 939 age-sex-matched general population comparators. All individuals were followed for incident fractures. Bisphosphonate use was estimated for calendar-years and in temporal relation to the ITP diagnosis. Adjusted cause-specific hazard ratio (csHR) for any fracture was 1.37 (95% confidence interval [CI] 1.23; 1.54) for pITP and 1.54 (1.17; 2.03) for sITP. The first-year csHR was 1.82 (1.39; 2.40) for pITP and 2.78 (1.58; 4.91) for sITP. Bisphosphonate use over calendar-years and in the early years following ITP diagnosis was higher among patients with ITP diagnosis compared with the general population. In conclusion, the risk of fractures and the use of bisphosphonates are higher in patients with ITP compared with the general population.

Primary autoimmune haemolytic anaemia is associated with increased risk of ischaemic stroke: A binational cohort study from Denmark and France.

Primary autoimmune haemolytic anaemia (AIHA) causes the destruction of red blood cells and a subsequent pro-thrombotic state, potentially increasing the risk of ischaemic stroke. We investigated the risk of ischaemic stroke in patients with AIHA in a binational study. We used prospectively collected data from nationwide registers in Denmark and France to identify cohorts of patients with primary AIHA and age- and sex-matched general population comparators. We followed the patient and comparison cohorts for up to 5 years, with the first hospitalization of a stroke during follow-up as the main outcome. We estimated cumulative incidence, cause-specific hazard ratios (csHR) and adjusted for comorbidity and exposure to selected medications. The combined AIHA cohorts from both countries comprised 5994 patients and the 81 525 comparators. There were 130 ischaemic strokes in the AIHA cohort and 1821 among the comparators. Country-specific estimates were comparable, and the overall adjusted csHR was 1.36 [95% CI: 1.13-1.65], p = 0.001; the higher rate was limited to the first year after AIHA diagnosis (csHR 2.29 [95% CI: 1.77-2.97], p < 10-9 ) and decreased thereafter (csHR 0.89 [95% CI: 0.66-1.20], p = 0.45) (p-interaction < 10-5 ). The findings indicate that patients diagnosed with primary AIHA are at higher risk of ischaemic stroke in the first year after diagnosis.

Genome Characterisation of Invasive Haemophilus influenzae in Pregnancy: The Noticeable Placental Tissue Tropism Is Distributed across the Species Rather Than Linked with Capsulation or Particular Clones.

Pregnancy is associated with a 5-26 times increased risk of invasive Haemophilus influenzae infection and subsequent adverse pregnancy outcomes. Incidence rate and outcome are published in some regions, but the characterisation of bacterial isolates is limited. We performed comparative genomic analyses of isolates from 12 pregnancy-associated cases, cultured from maternal bacteraemia in pregnancy (nine), postpartum bacteraemia (one), neonatal bacteraemia (one), and placental tissue (one). In two bacteraemia cases, identical isolates were also cultured from cervical swabs. Eight cases occurred early in pregnancy (gestational week 7-26), and seven of them resulted in miscarriage or neonatal death. All bacterial genomes were devoid of capsule loci, and they were evenly distributed in the major phylogenetic group I of the species. The conspicuous tropism of H. influenzae for pregnancy and placental tissue is associated with the species rather than specific clonal subtypes.

TMEM106B reduction does not rescue GRN deficiency in iPSC-derived human microglia and mouse models.

Heterozygous mutations in the granulin (GRN) gene are a leading cause of frontotemporal lobar degeneration with TDP-43 aggregates (FTLD-TDP). Polymorphisms in TMEM106B have been associated with disease risk in GRN mutation carriers and protective TMEM106B variants associated with reduced levels of TMEM106B, suggesting that lowering TMEM106B might be therapeutic in the context of FTLD. Here, we tested the impact of full deletion and partial reduction of TMEM106B in mouse and iPSC-derived human cell models of GRN deficiency. TMEM106B deletion did not reverse transcriptomic or proteomic profiles in GRN-deficient microglia, with a few exceptions in immune signaling markers. Neither homozygous nor heterozygous Tmem106b deletion normalized disease-associated phenotypes in Grn -/-mice. Furthermore, Tmem106b reduction by antisense oligonucleotide (ASO) was poorly tolerated in Grn -/-mice. These data provide novel insight into TMEM106B and GRN function in microglia cells but do not support lowering TMEM106B levels as a viable therapeutic strategy for treating FTD-GRN.

Early Mortality in Paroxysmal Nocturnal Hemoglobinuria.

OBJECTIVES:  The elevated mortality risk among patients with paroxysmal nocturnal hemoglobinuria (PNH) has been suggested to derive from a high risk of thromboembolism (TE); however, the risks of coexisting cardiovascular risk factors are not well described. We studied mortality associated with PNH taking comorbidity and treatment into account. METHODS: Patients with PNH (n=115) were identified in the 1977-2016 Danish National Patient Register (DNPR). For each patient with PNH, we identified 50 age- and sex-matched general population comparators. Using the Kaplan-Meier estimator and Cox regression, we compared the overall survival of patients with comparators. Cumulative incidences were used to analyze the effects of comorbidity and the causes of death. RESULTS: One-year survival among patients and comparators was 92.2% and 99.4%, and after 10 years, it was 68.4% and 85.8%, respectively. Early mortality was associated with older age, higher levels of comorbidity, and solid malignancies prior to PNH diagnosis. The leading causes of death were infections and associated hematological diseases. Patients with early mortality were less likely to have received treatment with eculizumab and/or warfarin. Cardiovascular risk factors were evenly distributed between patients and comparators at diagnosis. CONCLUSION: We conclude that early mortality in PNH is associated with older age, cardiovascular comorbidity, and hematological malignancies.

Clinical challenges in the treatment of a patient with decompensated heart failure and glucose-6-phosphate dehydrogenase deficiency (G6PDd).

We present a case of a man in his 60s, known with glucose-6-phosphate dehydrogenase deficiency (G6PDd) and cor pulmonale, admitted to the department of cardiology due to cardiac decompensation and anaemia. The main complaint was dyspnoea. Echocardiography confirmed severe cor pulmonale with compression of the left ventricle. G6PDd has been linked with pulmonary hypertension which could contribute to aforementioned echocardiographic findings. Diuretics are the first line of treatment when it comes to cardiac decompensation, but sulfonamide diuretics can induce or exacerbate haemolysis in patients with G6PDd. Due to the respiratory distress of the patient, a treatment plan including sulfonamide diuretics was initiated in collaboration with the haematologists. Unfortunately, the patient died 2 days after admission. This case emphasises that not all cardiac patients can tolerate standard treatment with sulfonamide diuretics; despite this, they remain essential in the acute setting, and they are associated with foreseeable but only partly manageable complications in susceptible patients.

Characterization of biochar produced from sewage sludge and its potential use as a substrate and plant growth improver.

Biochar is a product rich in carbon produced by pyrolysis of different kinds of biomass and it modifies the physical, chemical, and biological properties of soil. In this study, biochar, produced at different pyrolysis temperatures (590 °C, 665 °C, and 765 °C), was physico-chemically characterized. It was explored whether biochar made from sewage sludge can become an alternative solution for future water and phosphorus management in agricultural production. A pot experiment was conducted using Chinese cabbage (Brassica rapa subsp. pekinensis) to investigate the effect of applying different biochars to the substrate, taking into account different growth parameters and the biochemical composition of the plants, as well as the physico-chemical properties of the substrate. According to the results, pyrolysis temperature influences the content of elements in biochar and their availability to plants, with total phosphorus contents in biochar ranging from 4.6% to 4.9%. In addition, applying biochar to the substrate significantly increases the volumetric water content up to 4.5 fold more compared to the control, which indicates a promising application in drought stress conditions and, at the same time, is a source of nutrients and can help to reduce the amount of mineral fertilizer application.

Physical and Oxidative Stability of Emulsions Stabilized with Fractionated Potato Protein Hydrolysates Obtained from Starch Production Side Stream.

This work studies the emulsifying and antioxidant properties of potato protein hydrolysates (PPHs) fractions obtained through enzymatic hydrolysis of potato protein using trypsin followed by ultrafiltration. Unfractionated (PPH1) and fractionated (PPH2 as >10 kDa, PPH3 as 10-5 kDa, PPH4 as 5-0.8 kDa, and PPH5 as <0.8 kDa) protein hydrolysates were evaluated. Pendant drop tensiometry and dilatational rheology were applied for determining the ability of PPHs to reduce interfacial tension and affect the viscoelasticity of the interfacial films at the oil-water interface. Peptides >10 kDa showed the highest ability to decrease oil-water interfacial tension. All PPH fractions predominantly provided elastic, weak, and easily stretchable interfaces. PPH2 provided a more rigid interfacial layer than the other hydrolysates. Radical scavenging and metal chelating activities of PPHs were also tested and the highest activities were provided by the unfractionated hydrolysate and the fractions with peptides >5 kDa. Furthermore, the ability of PPHs to form physically and oxidatively stable 5% fish oil-in-water emulsions (pH 7) was investigated during 8-day storage at 20 °C. Our results generally show that the fractions with peptides >5 kDa provided the highest physicochemical stability, followed by the fraction with peptides between 5 and 0.8 kDa. Lastly, promising sensory results with mostly mild attributes were obtained even at protein concentration levels that are higher than needed to obtain functional properties. The more prominent attributes (e.g., bitterness and astringency) were within an acceptable range for PPH3 and PPH4.

Bone marrow biopsy can be omitted in the diagnostic workup of CNS lymphoma of DLBCL origin: a population-based retrospective study in the PET-CT era.

Currently, bone marrow (BM) biopsy (BMB) is recommended in the initial staging of patients with the presumed primary central nervous system (CNS) lymphoma (PCNSL). However, the added value of BMB in the era of positron emission tomography (PET-CT) has been challenged in other lymphoma subtypes. We analyzed BM findings in patients with biopsy-proven CNS lymphoma and a negative PET-CT scan for disease outside CNS. A comprehensive Danish population-based registry search was performed to identify all patients with CNS lymphoma of diffuse large B cell lymphoma (DLBCL) histology with available BMB results and staging PET-CT without systemic lymphoma. A total of 300 patients fulfilled the inclusion criteria. Of them, 16% had a previous history of lymphoma, while 84% were diagnosed with PCNSL. None of the patients had DLBCL in the BM. A minority (8.3%) had discordant BMB findings, mainly low-grade histologies that did not influence treatment choice in any case. In conclusion, the risk of overlooking concordant BM infiltration in patients with CNS lymphoma of DLBCL histology and negative PET-CT scan is negligible. As we did not find any patient with DLBCL in the BMB, our results suggest that BMB can be safely omitted in the diagnostic workup in patients with CNS lymphoma and a negative PET-CT.

Interferon alpha-2 treatment reduces circulating neutrophil extracellular trap levels in myeloproliferative neoplasms.

Neutrophil extracellular traps (NETs) may play a pathogenic role in the thrombosis associated with myeloproliferative neoplasms (MPNs). We measured serum NET levels in 128 pretreatment samples from patients with MPNs and in 85 samples taken after 12 months of treatment with interferon alpha-2 (PEG-IFNα-2) formulations or hydroxyurea (HU). No differences in NET levels were observed across subdiagnoses or phenotypic driver mutations. In PV, a JAK2V617F+ allele burden ≥50% associated with increased NET levels (p = 0.006). Baseline NET levels correlated with neutrophil count (r = 0.29, p = 0.001), neutrophil-to-lymphocyte ratio (r = 0.26, p = 0.004) and JAK2V617F allele burden (r = 0.22, p = 0.03), particularly in patients with PV and with allele burden ≥50% (r = 0.50, p = 0.01, r = 0.56, p = 0.002 and r = 0.45, p = 0.03 respectively). In PV, after 12 months of treatment, NET levels decreased on average by 60% in patients with allele burden ≥50%, compared to only 36% in patients with an allele burden <50%. Overall, treatment with PEG-IFNα-2a or PEG-IFNα-2b reduced NETs levels in 77% and 73% of patients, respectively, versus only 53% of HU-treated patients (average decrease across treatments: 48%). Normalization of blood counts did not per se account for these reductions. In conclusion, baseline NET levels correlated with neutrophil count, NLR and JAK2V617F allele burden, and IFNα was more effective at reducing prothrombotic NET levels than HU.

A Dedicated Mycosis Flask Increases the Likelihood of Identifying Candidemia Sepsis.

INTRODUCTION: Candidemia is a severe condition associated with high mortality, and fungi are often not covered by empiric antimicrobial regimes for sepsis. Therefore, the shortest possible time to detection of yeast in the blood is of the essence. MATERIALS AND METHODS: We performed a cohort study of blood culture flasks drawn from patients aged 18 or older in the capital region of Denmark. In 2018 a blood cultures set consisted of two aerobic and two anaerobic flasks. This was changed in 2020 to two aerobic, one anaerobic, and one mycosis flask. We used time-to-event statistics to model time to positivity and compared 2018 with 2020; further, we stratified analyses on the blood culture system used (BacTAlert™ vs. BACTEC™) and high-risk vs. low-risk departments. RESULTS: We included 175,416 blood culture sets and 107,077 unique patients. We found an absolute difference in the likelihood of identifying fungi in a blood culture set of 1.2 (95% CI: 0.72; 1.6) pr. 1.000 blood culture sets corresponding to the number needed to treat 853 (617; 1382). In high-risk departments, the absolute difference was profound, whereas it was negligible and statistically non-significant in low-risk departments 5.2 (95% CI: 3.4; 7.1) vs. 0.16 (-0.17; 0.48) pr. 1.000 blood culture sets. CONCLUSIONS: We found that including a mycosis flask in a blood culture set increases the likelihood of identifying candidemia. The effect was mainly seen in high-risk departments.

High level of colonization with third-generation cephalosporin-resistant Enterobacterales in African community settings, Ghana.

A cross-sectional survey was conducted in eight Ghanaian communities to investigate the extent of intestinal colonization with 3rd-generation cephalosporin-resistant Enterobacterales. The study collected faecal samples and corresponding lifestyle data from 736 healthy residents to assess the occurrence of cephalosporin-resistant Escherichia coli and Klebsiella pneumoniae, with a focus on genotypes of plasmid-mediated ESBLs, AmpCs, and carbapenemases. The results showed that 371 participants (50.4%) carried 3rd-generation cephalosporin-resistant E. coli (n=362) and K. pneumoniae (n=9). Most of these were ESBL-producing E. coli (n=352, 94.9%), carrying CTX-M genes (96.0%, n=338/352), mostly for CTX-M-15 (98.9%, n=334/338). Nine participants (1.2%) carried AmpC-producing E. coli that harboured blaDHA-1 or blaCMY-2 genes, and two participants (0.3%) each carried a carbapenem-resistant E. coli that harboured both blaNDM-1 and blaCMY-2. Quinolone-resistant O25b: ST131 E. coli were recovered from six participants (0.8%) and were all CTX-M-15 ESBL-producers. Having a household toilet facility was significantly associated with a reduced risk of intestinal colonization (adjusted odds ratio, 0.71; 95% CI, 0.48-0.99; P-value=0.0095) in multivariate analysis. These findings raise serious public health concerns, and effective control of the spread of antibiotic-resistant bacteria is possible by providing better sanitary conditions for communities.

Elevated Hemolysis Index is associated with higher risk of cardiovascular diseases.

OBJECTIVES: In vivo hemolysis is associated with thromboembolism. Although an increased Hemolysis Index (HI) can be due to in vitro as well as in vivo hemolysis, both reflects a more fragile erythrocyte population. We therefore hypothesized that HI above upper reference limit would be associated with an increased risk of cardiovascular disease (CVD). METHODS: We identified persons with two elevated HI (HI+) from blood samples analyzed at a university hospital laboratory from 2012 to 2017. We compared their risk of CVD with the risk in matched comparators with normal HI and from the general population. HI+ persons and comparators were followed from start date (date of the second elevated HI) until the first of the main outcome: CVD, emigration, death, or end of observation time on December 31, 2018. RESULTS: In 43,102 unique HI+ persons, the risk of developing CVD was 40% higher compared with the general population and 13% higher compared with the matched blood sample cohort. HI+ was associated with a significantly increased cumulative incidence of both arterial and venous CVD compared with the matched blood sample cohort and the general population (respectively 47 and 14% for arterial CVD; 78 and 24% for venous CVD). Moreover, overall mortality risk was significantly higher in patients with HI+ than in the two comparator groups. CONCLUSIONS: Elevated HI is associated with increased risk of arterial and venous CVD and with increased mortality. Our findings imply that HI may contribute as a CVD risk biomarker.