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The primary mechanism for bone marrow failure in aplastic anaemia (AA) is autoimmune haematopoietic stem cell destruction. AA can be cured with antithymocyte globulin (ATG) treatment, and some smaller studies have indicated that the number of regulatory T cells (Tregs) may be predictive of response. Additionally, AA patients appear to have elevated numbers of Th17 cells and bone marrow macrophages, but outcome data are missing.We performed immunohistochemistry on bone marrow biopsies from 121 ATG-treated AA patients and 14 healthy controls, using antibodies against FOXP3 (for Tregs), IL-17 (for Th17), CD68 (for pan-macrophages), and CD163 (for M2 type macrophages) to study their possible relation to ATG response and AA prognosis.AA patients had significantly fewer Tregs and Th17 cells but significantly more macrophages compared with controls. Treg, Th17, and pan-macrophage cell numbers were not associated with ATG response or differences in survival. Patients with higher levels of M2 macrophages had improved 5-year overall survival: 79.6% vs. 57.4% (p=0.017), and this benefit was primarily seen in AA patients with non-severe disease.We found that Treg and Th17 cell numbers did not predict ATG response or survival, whereas M2 macrophages may be associated with improved survival.

Objectives. There is a paucity of data regarding the association between the use of high-sensitivity troponin (hs-cTn) compared with conventional troponin (cTn) and outcomes in chest pain patients in emergency departments (EDs). This study examined the impact of hs-cTnT on prognosis in chest pain patients in EDs. Design. In an observational cohort study, we included chest pain patients visiting the EDs of 14 hospitals in Sweden from 2011 to 2016. The study population was retrieved from each hospital, and information on characteristics and outcomes was collected from nationwide registries. Cox regression was used to estimate adjusted hazard ratios with 95% confidence intervals (HR, 95% CI) for (1) 1-year all-cause mortality, (2) missed acute coronary syndromes (ACSs), (3) use of coronary angiography, and (4) revascularizations within 30 days. Results. We included 170461 patients with chest pain where 62669 patients were tested with cTn while 107792 patients were tested with hs-cTnT. We found 4149 (4.6%) deaths in the cTn group and 6087 (3.7%) deaths in the hs-cTnT group. Patients in the hs-cTnT group had 9% lower mortality (0.91, 0.87–0.94), and were 14% more likely to undergo coronary angiography (1.14, 1.10–1.17), and 12% more likely to be revascularized (1.12, 1.08–1.17) than patients in the cTn group. Conclusions. Patients with chest pain visiting EDs using hs-cTnT had lower mortality and a higher likelihood of undergoing coronary angiographies and revascularizations than those using cTn. There may be a survival benefit of being tested with hs-cTnT compared with cTn in patients seeking medical attention for chest pain.

Formalin-fixed, paraffin-embedded (FFPE) specimens are an underutilized resource in medical research, particularly in the setting of transcriptome sequencing, as RNA from these samples is often degraded. We took advantage of an exome capture-based RNA-sequencing protocol to explore global gene expression in paired fresh-frozen (FF) and FFPE samples from 16 diffuse large B-cell lymphoma (DLBCL) patients. While FFPE samples generated fewer mapped reads compared to their FF counterparts, these reads captured the same library complexity and had a similar number of genes expressed on average. Furthermore, gene expression demonstrated a high correlation when comparing housekeeping genes only or across the entire transcriptome (r = 0.99 for both comparisons). Differences in gene expression were primarily seen in lowly expressed genes and genes with small or large coding sequences. Using cell-of-origin classifiers and clinically relevant gene expression signatures for DLBCL, FF, and FFPE samples from the same biopsy paired nearly perfectly in clustering analysis. This was further confirmed in a validation cohort of 50 FFPE DLBCL samples. In summary, we found the biological differences between tumors to be far greater than artifacts created as a result of degraded RNA. We conclude that exome capture transcriptome sequencing data from archival samples can confidently be used for cell-of-origin classification of DLBCL samples.

ObjectiveBlood cell populations, including red blood cells (RBC) unique to the extremely preterm (EPT) infant, are potentially lost due to frequent clinical blood sampling during neonatal intensive care. Currently, neonatal RBC population heterogeneity is not described by measurement of total haemoglobin or haematocrit. We therefore aimed to describe a subpopulation of large RBCs with hyper high haemoglobin content, >49 pg (Hyper-He) following EPT birth.DesignProspective observational cohort study.SettingTwo Swedish study centres.ParticipantsInfants (n=62) born between gestational weeks 22+0to 26+6.MethodsProspective data (n=280) were collected from March 2020 to September 2022 as part of an ongoing randomised controlled trial. Blood was sampled from the umbilical cord, at postnatal day 1–14, 1 month, 40 weeks’ postmenstrual age and at 3 months’ corrected age.ResultsAt birth, there was a considerable inter-individual variation; Hyper-He ranging from 1.5% to 24.9% (median 7.0%). An inverse association with birth weight and gestational age was observed; Spearman’s rho (CI) −0.38 (−0.63 to −0.07) and −0.39 (−0.65 to −0.05), respectively. Overall, Hyper-He rapidly decreased, only 0.6%–5.0% (median 2.2%) remaining 2 weeks postnatally. Adult levels (ConclusionOur results point to gestational age and birth weight-dependent properties of the RBC population. Future work needs to verify results by different measurement techniques and elucidate the potential role of differing properties between endogenous and transfused RBCs in relation to neonatal morbidities during this important time frame of child development.Trial registration numberNCT04239690.

The complexity of the activated B-cell like (ABC) diffuse large B-cell lymphoma (DLBCL) subtype is probably not only explained by genetic alterations and methods to measure global protein expression could bring new knowledge regarding the pathophysiology. We used quantitative proteomics to analyze the global protein expression of formalin-fixed paraffin-embedded (FFPE) tumor tissues from 202 DLBCL patients. We identified 6430 proteins and 498 were significantly regulated between the germinal center B-cell like (GCB) and non-GCB groups. A number of proteins previously not described to be upregulated in non-GCB or ABC DLBCL was found, e.g. CD64, CD85A, guanylate-binding protein 1 (GBP1), interferon-induced proteins with tetratricopeptide repeat (IFIT)2, and mixed lineage kinase domain-like protein (MLKL) and immunohistochemical staining showed higher expression of GBP1 and MLKL. A cluster analysis revealed that the most prominent cluster contained proteins involved in the tumor microenvironment and regulation of the immune system. Our data suggest that the therapeutic focus should be expanded toward the tumor microenvironment in non-GCB/ABC subtype patients.

In follicular lymphoma (FL), progression of disease

Several recent models of choice build on the idea that decision makers are more likely to choose an option if its attributes stand out compared to the attributes of the available alternatives. One example is the model of focusing by Koszegi and Szeidl (2013) where decision makers focus disproportionally on the attributes in which the available options differ more, implying that some attributes will be overweighted. We test this prediction in a controlled experiment. We find that subjects are more likely to make inconsistent choices when we manipulate the choice set by adding new options that are unchosen, but affect the maximal difference in attributes among the options. Hence, our results suggest that there exists a focusing effect.

Background With prelabour caesarean section rates growing globally, there is direct and indirect evidence of negative cognitive outcomes in childhood. The objective of this study was to assess the short-term neurodevelopmental outcomes after prelabour caesarean section as compared to vaginally born infants. Methods We conducted a prospective, observational study of infants delivered by prelabour caesarean section at the Hospital of Halland, Halmstad, Sweden and compared their development with an historical group of infants born by non-instrumental vaginal delivery. Results Infants born by prelabour caesarean section were compared with a group of vaginally born infants. Follow-up assessments were performed at 4 and 12 months. Prelabour caesarean infants (n = 66) had significantly lower Ages and Stages Questionnaire, second edition (ASQ-II) scores in all domains (communication, gross motor, fine motor, problem solving and personal-social) at 4 months of age with an adjusted mean difference (95% CI) of − 20.7 (− 28.7 to − 12.6) in ASQ-II total score as compared to vaginally born infants (n = 352). These differences remained for gross-motor skills at the 12 month assessment, adjusted mean difference (95% CI) -4.7 (− 8.8 to − 0.7), n = 62 and 336. Conclusions Adverse neurodevelopmental outcomes in infants born by prelabour caesarean section may be apparent already a few months after birth. Additional studies are warranted to explore this relationship further.

Midwives are often the first ones to make decisions when a neonate is unexpectedly born non-vigorous. This study aimed to understand how midwives reason and what they experience when deciding what to do when a non-vigorous neonate is born. In present practice, the decision to cut the umbilical cord early is strongly affected bythe decision that the neonate needs resuscitation. To better understand the decisions taken during the first minutes of the non-vigorous neonate’s life, this study focused on the midwives’ decision to cut the umbilical cord.A qualitative study with an inductive and descriptive design using the Critical Incident Technique was chosen to gain a more in-depth understanding of the factors influencing the midwife’s decision-making process concerning cutting the umbilical cord in a critical situation. Semi-structured interviews were conducted, and thematic analysis, as described by Braun and Clarke, was performed.Eligible study participants were midwives currently working in labour wards in Sweden.In total, 14 midwives were interviewed between November 2019 and March 2020. The interviews rendered an understanding about midwives' decision-making on the timing of cord clamping in the non-vigorous neonates. An overarching theme was generated: "The balancing act of clamping the umbilical cord" which consisted of three themes, "Assessing the neonate in need of resuscitation", "Valuing own knowledge and experience" and "Influencing decision-making", and seven sub-themes. Many factors in addition to clinical reasoning influenced the midwives' decision-making processes. Feelings, intuition, and experience also had an effect to varying degrees.

Aim: The hormone osteocalcin influenced neurodevelopment and cognition in mice models; this human study explored potential associations between total serum levels in human infants and neurodevelopment at 4 years of age. Methods: The data were based on two Swedish birth cohorts from 2008 to 2009. We followed 158 healthy full-term vaginal births (51% girls) by measuring serum osteocalcin in cord blood and at 4, 12 and 36 months. The values were compared with neurodevelopment tests at 4 years of age. Results: There was an association between osteocalcin at 4 months and later full-scale intelligence quotient (IQ; r(2) 0.031, p < 0.05). Children with osteocalcin levels in the highest quartile scored 5.6 (95% confidence interval [1.3, 9.9]) points higher than those in the lowest quartile, with mean scores of 118.8 +/- 8.8 and 113.2 +/- 9.2 (p < 0.05). They also scored higher on gross motor skills (p < 0.05) and showed greater ability during the drawing trail test (p < 0.005). Cord levels of osteocalcin were negatively associated with processing speed and fine motor development at 4 years, but levels at 12 and 36 months were not associated with later neurodevelopment. Conclusion: Osteocalcin levels in infancy appeared to be associated with later IQ and motor development, but more research is needed.

ObjectivesThere is a need for updated haematological reference data in infancy. This study aimed to define intervals for haemoglobin and red blood cell biomarkers based on data from a large cohort of longitudinally followed Swedish infants.DesignLongitudinal cohort study.SettingTwo Swedish study centres.ParticipantsThree community-based populations including 442 presumably healthy infants born at term and with umbilical cord clamping delayed to 30 s or more after birth.MethodsBlood samples were collected from umbilical cord blood (a), at 48–118 hours (b), at 4 months (c) and at 12 months (d). Reference intervals as the 2.5th and 97.5th percentiles were calculated in coherence with Clinical and Laboratory Standards Institute guidelines.ResultsReference intervals for haemoglobin (g/L) were: (a) 116–189, (b) 147–218, (c) 99–130, (d) 104–134, and for mean cell volume (fL): (a) 97–118, (b) 91–107, (c) 71–85, (d) 70–83. Reference intervals for erythrocyte counts, reticulocyte counts, reticulocyte haemoglobin, mean cell haemoglobin and mean cell haemoglobin concentration were also estimated. According to the WHO definition of anaemia, a haemoglobin value less than 110 g/L, 16% of this presumably healthy cohort could be classified as anaemic at 12 months.ConclusionWe found mainly narrower reference intervals compared with previously published studies. The reference intervals for each parameter varied according to the infants’ age, demonstrating the necessity of age definitions when presenting infant reference intervals. The discrepancy with the WHO classification for anaemia at 12 months, despite favourable conditions in infancy, needs future investigation.

In this paper, we perform a choice experiment assessing the impact of stay-at-home policies on individual welfare. We estimate the willingness to accept compensation (WTA) for restricting non-working hours in Sweden during the COVID-19 pandemic. The WTA for a one-month stay-at-home policy is about US$480 per person, or 9.1 percent of Sweden's monthly per capita GDP. Stricter lockdowns require disproportionately higher compensation than more lenient ones, indicating that strict policies are cost-effective only if they are much more successful in slowing the spread of the disease. Moreover, older people have a higher WTA of staying home than the rest of the population.

The 71–82 fragment of the non-amyloid-β component (NAC) region of the Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) related protein α-Synuclein, has been reported to be important during protein misfolding. Although reports have demonstrated the importance of this fragment for the aggregation properties of the full-length protein, its exact role in pre-fibrillar oligomerisation, fibrillar growth and morphology has not yet been fully elucidated. Here, we provide evidence that fibrils prepared from an acetylated and methyl amidated peptide of the NAC 71–82 amino acid stretch of α-Synuclein are amyloid and contain, in addition to the cross-β structure detected in the full-length protein fibrils, a cross-β structure previously observed in prion proteins. These results shed light on the aggregation propensity of the NAC 71–82 amino acid stretch of the full-length protein but also the roles of the N- and C-terminal domains of α-Synuclein in balancing this aggregation propensity. The results also suggest that early aggregated forms of the capped NAC 71–82 peptide generated structures were stabilised by an anti-parallel and twisted β-sheet motif. Due to its expected toxicity, this β-sheet motif may be a promising molecular target for the development of therapeutic strategies for PD and DLB.

Delaying cord clamping (CC) for 3-5 minutes reduces iron deficiency and improves neurodevelopment. Data on the effects of CC beyond 3 minutes in relation to short-term neonatal outcomes and maternal risk of postpartum hemorrhage are scarce.This was a prospective observational study performed in two delivery departments. Pregnant women with vaginal deliveries were included. Time to CC, estimated postpartum blood loss, and perinatal data were recorded. Spearman's correlation analysis and comparisons between newborns clamped before and after 3 minutes were performed.In total, 904 dyads were included. The mean gestational age ± standard deviation was 40.1 ± 1.2 weeks. CC was performed at a median time of 6 minutes (range 0-23.5). Apgar scores at 5 and 10 minutes were positively correlated with time to CC (correlation coefficient .140, P lt; .001 and .161, lt; .001). There was no correlation between CC time and bilirubin level (correlation coefficient .021, P = .54). The median postpartum blood loss was 300 mL (70-2550 mL), with a negative correlation between CC time and postpartum blood loss (-0.115, P = .001). The postpartum blood loss was larger in the group clamped at ≤3 minutes (median [interquartile range] 400 mL [300-600] vs 300 mL [250-450], [P = .003]].Umbilical CC times beyond 3 minutes in vaginal deliveries were not associated with negative short-term outcomes in newborns and were associated with a smaller maternal postpartum blood loss. Although CC time as long as 6 minutes could be considered as safe, further research is needed to decide the optimal timing.

Keeping the umbilical cord intact after delivery facilitates transition from fetal to neonatal circulation and allows a placental transfusion of a considerable amount of blood. A delay of at least 3 minutes improves neurodevelopmental outcomes in term infants. Although regarded as common sense and practiced by many midwives, implementation of delayed cord clamping into practice has been unduly slow, partly because of beliefs regarding theoretic risks of jaundice and lack of understanding regarding the long-term benefits. This article provides arguments for delaying cord clamping for a minimum of 3 minutes.

Object-vector (OV) cells are cells in the medial entorhinal cortex (MEC) that track an animal’s distance and direction to objects in the environment. Their firing fields are defined by vectorial relationships to free-standing 3-dimensional (3D) objects of a variety of identities and shapes. However, the natural world contains a panorama of objects, ranging from discrete 3D items to flat two-dimensional (2D) surfaces, and it remains unclear what are the most fundamental features of objects that drive vectorial responses. Here we address this question by systematically changing features of experimental objects. Using an algorithm that robustly identifies OV firing fields, we show that the cells respond to a variety of 2D surfaces, with visual contrast as the most basic visual feature to elicit neural responses. The findings suggest that OV cells use plain visual features as vectorial anchoring points, allowing vector-guided navigation to proceed in environments with few free-standing landmarks.

Precision diagnostics and therapy have been implemented rather early in clinical hematology due to the easy accessibility of blood and bone marrow, allowing not only for consecutive genetic analysis at diagnosis, remission and relapse, but also for culturing these cells and testing new drugs in vitro. One contributing factor has also been the relatively low number of »driver« mutations in hematologic malignancies and that some of them are gain of function mutations that are relatively easy to target by drugs. Examples of this development are ABL1-, JAK2-, and FLT3-inhibitors for the treatment of chronic myeloid leukemia, myeloproliferative neoplasms, and acute myeloid leukemia, respectively. More recently, gene panel sequencing has been introduced in clinical routine to identify genetic alterations with diagnostic, prognostic and predictive impact, and more sensitive techniques to monitor minimal residual disease are emerging. Whole genome and transcriptome sequencing are currently evaluated as the next diagnostic tool. Finally, a large number of targeted therapies are currently under development and/or undergoing clinical trials.

Introduction: Iron deficiency (ID) is associated with poor neurodevelopment. We have previously shown that delayed umbilical cord clamping (CC) improves iron stores at 8 months and neurodevelopment at 1 year in term, healthy infants in Nepal. Objective: The aim of this study was to assess the effects of delayed CC (≥180 s) compared to early CC (≤60 s) on neurodevelopment using the Ages and Stages Questionnaire (ASQ) at age 3 years. Methods: In 2014, 540 healthy Nepalese infants born at term were randomized in a 1:1 ratio to delayed or early CC. At 3 years of age, ASQ assessment was performed by phone interviews with parents. A score >1 standard deviation below the mean was defined as “at risk” for developmental impairment. Results: At 3 years of age, 350 children were followed up, 170 (63.0%) in the early CC group and 180 (66.7%) in the delayed CC group. No significant differences in ASQ scores in any domains between groups were found. However, more girls were “at risk” for affected gross motor development in the early CC group: 14 (18.9%) versus 6 (6.3%), p = 0.02. Conclusion: There were no significant differences in ASQ scores in any domains between groups. In the subgroup analysis, fewer girls who underwent delayed CC were “at risk” for delayed gross motor development. Due to the pronounced difference in iron stores at 8 months postpartum in this cohort, follow-up studies at an older age are motivated since neurodevelopmental impairment after early ID may be more detectable with increasing age.

Purpose: To develop an artificial intelligence (AI)-based method for the detection of focal skeleton/bone marrow uptake (BMU) in patients with Hodgkin´s lymphoma (HL) undergoing staging with FDG-PET/CT. The results of the AI in a separate test group were compared to the interpretations of independent physicians. Methods: The skeleton and bone marrow were segmented using a convolutional neural network. The training of AI was based on 153 un-treated patients. Bone uptake significantly higher than the mean BMU was marked as abnormal, and an index, based on the total squared abnormal uptake, was computed to identify the focal uptake. Patients with an index above a predefined threshold were interpreted as having focal uptake. As the test group, 48 un-treated patients who had undergone a staging FDG-PET/CT between 2017-2018 with biopsy-proven HL were retrospectively included. Ten physicians classified the 48 cases regarding focal skeleton/BMU. Results: The majority of the physicians agreed with the AI in 39/48 cases (81%) regarding focal skeleton/bone marrow involvement. Inter-observer agreement between the physicians was moderate, Kappa 0.51 (range 0.25-0.80). Conclusion: An AI-based method can be developed to highlight suspicious focal skeleton/BMU in HL patients staged with FDG-PET/CT. Inter-observer agreement regarding focal BMU is moderate among nuclear medicine physicians.