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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.

Births involving shoulder dystocia or tight nuchal cords can deteriorate rapidly. The fetus may have had a reassuring tracing just before birth yet may be born without any heartbeat (asystole). Since the publication of our first article on cardiac asystole with two cases, five similar cases have been published. We suggest that these infants shift blood to the placenta due to the tight squeeze of the birth canal during the second stage which compresses the cord. The squeeze transfers blood to the placenta via the firm-walled arteries but prevents blood returning to the infant via the soft-walled umbilical vein. These infants may then be born severely hypovolemic resulting in asystole secondary to the loss of blood. Immediate cord clamping (ICC) prevents the newborn’s access to this blood after birth. Even if the infant is resuscitated, loss of this large amount of blood volume may initiate an inflammatory response that can enhance neuropathologic processes including seizures, hypoxic–ischemic encephalopathy (HIE), and death. We present the role of the autonomic nervous system in the development of asystole and suggest an alternative algorithm to address the need to provide these infants intact cord resuscitation. Leaving the cord intact (allowing for return of the umbilical cord circulation) for several minutes after birth may allow most of the sequestered blood to return to the infant. Umbilical cord milking may return enough of the blood volume to restart the heart but there are likely reparative functions that are carried out by the placenta during the continued neonatal–placental circulation allowed by an intact cord.

We use a case of intact cord resuscitation to argue for the beneficial effects of an enhanced blood volume from placental transfusion for newborns needing resuscitation. We propose that intact cord resuscitation supports the process of physiologic neonatal transition, especially for many of those newborns appearing moribund. Transfer of the residual blood in the placenta provides the neonate with valuable access to otherwise lost blood volume while changing from placental respiration to breathing air. Our hypothesis is that the enhanced blood flow from placental transfusion initiates mechanical and chemical forces that directly, and indirectly through the vagus nerve, cause vasodilatation in the lung. Pulmonary vascular resistance is thereby reduced and facilitates the important increased entry of blood into the alveolar capillaries before breathing commences. In the presented case, enhanced perfusion to the brain by way of an intact cord likely led to regained consciousness, initiation of breathing, and return of tone and reflexes minutes after birth. Paramount to our hypothesis is the importance of keeping the umbilical cord circulation intact during the first several minutes of life to accommodate physiologic neonatal transition for all newborns and especially for those most compromised infants.

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.

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.

Infants are at risk for iron deficiency. Despite research advances, assessing iron stores during infancy remains a challenge to the clinician. Ferritin is the first-choice laboratory marker for measuring iron stores but it is today still unclear how to evaluate reference intervals among infants. We have studied Swedish infants (n = 456), born at term after normal pregnancies. Ferritin was measured at birth (umbilical cord sample), 48-72 h, 4 months and 12 months. Lower and upper reference interval limits were constructed as the 2.5th and 97.5th percentiles. By a large study population, we were able to use more stringent measures to avoid interference from the acute phase response than previous reports on ferritin reference intervals. When we used mathematical transformation we furthermore avoided potential information loss in precision and confirmed earlier reports of sex differences. At the lower reference interval limits there were small differences between sexes. For the higher limits, the differences were more pronounced in the older infant. At 0-3 d of age we observed a difference between the sexes of only 5% at the upper limits. The differences peaked at 12 months, where the boys' upper 97.5th percentile was 56% compared to girls.

We conduct a contest experiment to study if spread seeking and effort can be managed when participants can invest in increasing both the mean and the spread of an uncertain performance variable. Subjects are treated with different prize schemes and in accordance with theory, we observe higher investments in spread for the winner-take-all scheme. Both types of investments can be controlled with a three-level prize scheme. However, the control management is imperfect and behavior is characterized by inertia. We also explore the correlation between effort and spread across subjects and find that is robustly positive.

Decision makers often face incentives to increase risk‐taking on behalf of others through bonus contracts and relative performance contracts. We conduct an experimental study of risk‐taking on behalf of others using a large heterogeneous sample and find that people respond to such incentives without much apparent concern for stakeholders. Responses are heterogeneous and mitigated by personality traits. The findings suggest that lack of concern for others’ risk exposure hardly requires “financial psychopaths” in order to flourish, but is diminished by social concerns.

Our aim was to investigate the effects of timing of cord clamping on the risk of hyperbilirubinaemia.We recruited 540 normal vaginal deliveries at the Paropakar Maternity and Women's Hospital in Kathmandu, Nepal, from October 2 to November 21, 2014. They were randomised into two groups: 257/270 were cord clamped within 60 seconds and 209/270 after 180 seconds. Transcutaneous bilirubin was measured at discharge and 24 hours. At 4 weeks, 506 mothers were successfully contacted by phone, and the health status of the baby and their history of jaundice and treatment was recorded.Based on transcutaneous bilirubin at discharge, 22/261 (8.4%) in the early group and 25/263 (9.5%) in the delayed group (P = 0.76) were at high risk of subsequent hyperbilirubinemia. At the 4-week follow-up, jaundice was reported in 13/253 (5.1%) in the early and 17/253 (6.7%) in the delayed group (P = 0.57) and 3/253 (1.2 %) of the early and 1/253 (0.4%) of the delayed group (P = 0.62) received treatment. All analyses were based on intention-to-treat.Delayed cord clamping was not associated with an increased risk of hyperbilirubinaemia during the first day of life or risk of jaundice within 4 weeks compared with the early group.

Molecular imprinting provides a useful complement to the use of biomolecules for thedevelopment of sensors for the analysis of trace substances on account of their highlyselective recognition characteristics. Moreover, the stabilities make them ideal for use inapplications not normally suitable for the use of biomolecules. The nature of the techniqueand its use in a number of analysis formats suitable for use in environmental monitoring arepresented.

The aim of this communication is to describe the range of applications of GaN-based platforms for trace detection and identification of biological and chemical agents using SERS technique. The methods of nano-structuring of GaN surface for SERS application are briefly described. The results of employing SERS method for analysis of Fentanyl and Bacillus Atrophaeus spores is demonstrated. The arguments are summarized which show the universal feature of GaN-based platforms as SERS sensor.

Background: The outcome for diffuse large B-cell lymphoma (DLBCL) patients has improved with the immunochemotherapy combination R-CHOP. An increased rate of heart failure is well documented following this treatment, whereas incidence and outcome of other cardiac complications, for example myocardial infarction, are less well known. Method: We identified 3548 curatively treated DLBCL patients in Sweden diagnosed between 2007 and 2014, and 35474 matched lymphoma-free general population comparators. The incidence, characteristics and outcome of acute myocardial infarctions (AMIs) were assessed using population-based registers up to 11 years after diagnosis. The rate of AMI was estimated using flexible parametric models. Results: Overall, a 33% excess rate of AMI was observed among DLBCL patients compared with the general population (HR: 1.33, 95% CI: 1.14–1.55). The excess rate was highest during the first year after diagnosis and diminished after 2 years. High age, male sex and comorbidity were the strongest risk factors for AMI. Older patients (>70 years) with mild comorbidities (i.e. hypertension or diabetes) had a 61% higher AMI rate than comparators (HR: 1.61, 95% CI: 1.10–2.35), whereas the corresponding excess rate was 28% for patients with severe comorbidities (HR: 1.28, 95% CI: 1.01–1.64). Among younger patients (≤70), a short-term excess rate of AMI was limited to those with severe comorbidities. There was no difference in AMI characteristics, pharmacological treatment or 30-day survival among patients and comparators. Conclusion: DLBCL patients have an increased risk of AMI, especially during the first 2 years, which calls for improved cardiac monitoring guided by age and comorbidities. Importantly, DLBCL was not associated with differential AMI management or survival. (Less)

Dipicolinic acid (DPA) is an essential component for the protection of DNA in bacterial endospores and is often used as a biomarker for spore detection. Depending upon the pH of the solution, DPA exists in different ionic forms. Therefore, it is important to understand how these ionic forms influence spectroscopic response. In this work, we characterize Raman and absorption spectra of DPA in a pH range of 2.0-10.5. We show that the ring breathing mode Raman peak of DPA shifts from 1003 cm(-1) to 1017 cm (-1) and then to 1000 cm(-1) as pH increases from 2 to 5. The relative peak intensities related to the different ionic forms of DPA are used to experimentally derive the pK(a) values (2.3 and 4.8). We observe using UV-vis spectroscopy that the changes in the absorption spectrum of DPA as a function of pH correlate with the changes observed in Raman spectroscopy, and the same pK(a) values are verified. Lastly, using fluorescence spectroscopy and exciting a DPA solution at between 210-330 nm, we observe a shift in fluorescence emission from 375 nm to 425 nm between pH 2 and pH 6 when exciting at 320 nm. Our work shows that the different spectral responses from the three ionic forms of DPA may have to be taken into account in, e.g., spectral analysis and for detection applications. (C) 2022 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Pregnant women and their newborns may be at particular risk for poor outcomes due to the coronavirus (COVID-19) pandemic. Intrauterine SARS-CoV-2 transmission has been suggested but most reports have not ruled out postpartum infection. We demonstrate a confirmed case of transplacental transmission of SARS-CoV-2 in a neonate born to a mother infected in the third trimester. Comprehensive virological, pathological and genetic investigations establish that intrauterine SARS-CoV-2 transmission occurred via the following chain of events; I) maternal viremia in a seemingly mildly symptomatic patient, II) high viral load in the placenta with massive perivillous fibrin deposition, acute intervillositis in areas with strong positivity for SARS-CoV-2 and chorangiosis in the areas less affected by infection and inflammation, III) intrauterine fetal distress with pathological cardiotocography and acidemia in validated umbilical cord blood gases and IV) mild neonatal COVID-19. Whole genome sequencing of isolates from the mother and placenta revealed a single variant of the virus. Interestingly, the neonate displayed a mixed SARS-CoV-2 population, harboring both an identical strain to the mother as well as a population with one single-nucleotide polymorphism difference, indicating intrapatient genetic drift.

Contamination of toxic spore-forming bacteria is problematic since spores can survive a plethora of disinfection chemicals. It is also problematic to rapidly detect if the disinfection chemical was active, leaving spores dead. Robust decontamination strategies, as well as reliable detection methods to identify dead from viable spores, are thus critical. Vibrational detection methods such as Raman spectroscopy has been suggested for rapid diagnostics and differentiation of live and dead spores. We investigate in this work, using laser tweezers Raman spectroscopy, the changes in Raman spectra of Bacillus thuringiensis spores treated with sporicidal agents such as chlorine dioxide, peracetic acid, and sodium hypochlorite. We also imaged treated spores using SEM and TEM to verify if any changes to the spore structure can be correlated to the Raman spectra. We found that chlorine dioxide did not change the Raman spectrum or the spore structure; peracetic acid shows a time-dependent decrease in the characteristic DNA/DPA peaks and ∼20 % of the spores were degraded and collapsed; spores treated with sodium hypochlorite show an abrupt drop in DNA and DPA peaks within 20 minutes all though the spore structure was overall intact, however, the exosporium layer was reduced. Structural changes appeared over several minutes, compared to the inactivation time of the spores, which is less than a minute. We conclude that vibrational spectroscopy provides powerful means to detect changes in spores but it might be problematic to identify if spores are live or dead after a decontamination procedure.

Recent studies have identified prognostic mutational clusters for diffuse large B-cell lymphoma (DLBCL) patients, both within and outside the original cell-of-origin (COO) classification. For many of these mutations, there is limited information regarding the corresponding protein expression. With the aim to determine the relationship of protein expression and intensity to COO and prognosis, we used digital image analysis to quantitate immunohistochemical staining of CREBBP, IRF8, EZH2, and TBLR1 in 209 DLBCL patients. We found that patients with strong nuclear expression of TBLR1 had inferior progression-free survival (PFS) and overall survival (OS) in univariable analysis and inferior PFS in multivariable analysis. Patients with higher proportion of intermediate to strong nuclear CREBBP expression had a worse PFS and OS in univariable analysis. CREBBP was expressed with stronger intensity in non-GCB patients and the prognostic impact was restricted to this subgroup. These findings suggest that high nuclear protein expression of TBLR1 and CREBBP is negatively associated with prognosis in DLBCL.

AIM: It has been suggested that intact cord resuscitation can reduce the risk of brain damage. We investigated the effects on neurodevelopment at two years of age.METHODS: This study was performed in Kathmandu, Nepal. In 2016, 231 late preterm and term infants born vaginally and not breathing were randomised to resuscitation with an intact cord or the standard practice of early cord clamping (CC). At two years of age, the World Health Organization's Infant and Young Child Development tool was used to assess the child's neurodevelopment, during telephone interviews with caregivers.RESULTS: We followed up 138 infants (59.7%) at a mean age of 24.8 ±0.8 months. A significant difference was seen in the development for age Z-score, between the group resuscitated with an intact umbilical cord and the group resuscitated with early CC. The median (range) scores were 1.0 (0.1-2.1) versus. 0.9 (-2.0-1.8), respectively (p=0.04). There were no difference in the motor, language-cognitive and socio-emotional domains.CONCLUSION: Neurodevelopment improvements were observed at two years of age in infants resuscitated with an intact rather than early clamped umbilical cord. No definitive conclusions could be drawn due to protocol violations and a low follow-up rate. More research is needed. (Less)

We aimed to evaluate whether serum hepcidin is a useful indicator of iron status in infants.Term infants (n = 400) were randomized to delayed (≥180 s) or early (≤10 s) cord clamping (CC). Iron status was assessed at 4 and 12 months. In all cases with iron depletion or iron deficiency (ID) (as defined in "Methods") (n = 30) and 97 randomly selected iron-replete infants, we analyzed hepcidin and explored its correlation to the intervention, iron status, and perinatal factors.Serum hepcidin concentrations were significantly lower in the early CC group at both time points and in ID infants at 4 months. Median (2.5th-97.5th percentile) hepcidin in non-ID infants in the delayed CC group (suggested reference) was 64.5 (10.9-142.1), 39.5 (3.5-157.7), and 32.9 (11.2-124.2) ng/mL in the cord blood and at 4 and 12 months, respectively. The value of 16 ng/mL was a threshold detecting all cases of iron depletion/ID at 4 months. No similar threshold for ID was observed at 12 months. The strongest predictor of hepcidin at both ages was ferritin.Hepcidin is relevant as iron status indicator in early infancy and may be useful to detect ID. Levels16 ng/mL at 4 months of age indicates ID.Serum hepcidin is a relevant indicator of iron status in early infancy. Normal reference in healthy infants is suggested in this study. Serum hepcidin may be useful in clinical practice to detect iron deficiency.

We show that the anticipation of COVID-19 vaccines reduces voluntary social distancing. In a large-scale preregistered survey experiment with a representative sample, we study whether providing information about the safety, effectiveness, and availability of COVID- 19 vaccines affects compliance with public health guidelines. We find that vaccine information reduces peoples’ voluntary social distancing, adherence to hygiene guidelines, and their willingness to stay at home. Vaccine information induces people to believe in a swifter return to normal life and puts their vigilance at ease. The results indicate an important behavioral drawback of the successful vaccine development: An increased focus on vaccines can lead to bad health behaviors and accelerate the spread of the virus. The results imply that, as vaccinations start and the end of the pandemic feels closer, existing policies aimed at increasing social distancing will be less effective and stricter policies might be required.

This paper reports the results of a choice experiment designed to estimate the private welfare costs of stay-at-home policies during the COVID-19 pandemic. The study is conducted on a large and representative sample of the Swedish population. The results suggest that the welfare cost of a one-month stay-at-home policy, restricting non-working hours away from home, amounts to 9.1 percent of Sweden's monthly GDP. Moreover, we find that stricter and longer lockdowns are disproportionately more costly than lenient ones, indicating that strict policies are cost-effective only if they are much more successful in slowing the spread of the disease.

Collecting data under field conditions for forensic investigations of chemical warfare agents calls for the use of portable instruments. In this study, a set of aged, crude preparations of sulfur mustard were characterized spectroscopically without any sample preparation using handheld Raman and portable IR instruments. The spectral data was used to construct Random Forest multivariate models for the attribution of test set samples to the synthetic method used for their production. Colored and fluorescent samples were included in the study, which made Raman spectroscopy challenging although fluorescence was diminished by using an excitation wavelength of 1064 nm. The predictive power of models constructed with IR or Raman data alone, as well as with combined data was investigated. Both techniques gave useful data for attribution. Model performance was enhanced when Raman and IR spectra were combined, allowing correct classification of 19/23 (83%) of test set spectra. The results demonstrate that data obtained with spectroscopy instruments amenable for field deployment can be useful in forensic studies of chemical warfare agents.

IMPORTANCE: The American College of Obstetricians and Gynecologists recommends a delay in umbilical cord clamping in term neonates for at least 30 to 60 seconds after birth. Most literature supporting this practice is from low-risk vaginal deliveries. There are no published data specific to cesarean delivery. OBJECTIVE: To compare maternal blood loss with immediate cord clamping vs delayed cord clamping in scheduled cesarean deliveries at term (≥37 weeks). DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial performed at 2 hospitals within a tertiary academic medical center in New York City from October 2017 to February 2018 (follow-up completed March 15, 2018). A total of 113 women undergoing scheduled cesarean delivery of term singleton gestations were included. INTERVENTIONS: In the immediate cord clamping group (n = 56), cord clamping was within 15 seconds after birth. In the delayed cord clamping group (n = 57), cord clamping was at 60 seconds after birth. MAIN OUTCOMES AND MEASURES: The primary outcome was change in maternal hemoglobin level from preoperative to postoperative day 1, which was used as a proxy for maternal blood loss. Secondary outcomes included neonatal hemoglobin level at 24 to 72 hours of life. RESULTS: All of the 113 women who were randomized (mean [SD] age, 32.6 [5.2] years) completed the trial. The mean preoperative hemoglobin level was 12.0 g/dL in the delayed and 11.6 g/dL in the immediate cord clamping group. The mean postoperative day 1 hemoglobin level was 10.1 g/dL in the delayed group and 9.8 g/dL in the immediate group. There was no significant difference in the primary outcome, with a mean hemoglobin change of −1.90 g/dL (95% CI, −2.14 to −1.66) and −1.78 g/dL (95% CI, −2.03 to −1.54) in the delayed and immediate cord clamping groups, respectively (mean difference, 0.12 g/dL [95% CI, −0.22 to 0.46]; P = .49). Of 19 prespecified secondary outcomes analyzed, 15 showed no significant difference. The mean neonatal hemoglobin level, available for 90 neonates (79.6%), was significantly higher with delayed (18.1 g/dL [95% CI, 17.4 to 18.8]) compared with immediate (16.4 g/dL [95% CI, 15.9 to 17.0]) cord clamping (mean difference, 1.67 g/dL [95% CI, 0.75 to 2.59]; P

Objectives: Antithymocyte globulin (ATG)-based immunosuppression remains a cornerstone in aplastic anaemia (AA) treatment. However, most ATG studies are not population-based and knowledge about real-world results concerning response and outcome could offer important information for treating physicians. Methods: We have recently performed a nationwide retrospective cohort study on all AA patients diagnosed in Sweden in 2000-2011 and now present treatment and outcome data on patients receiving first-line ATG. In total, 158 patients showed a 47.0% response rate which was similar in all age groups (range 41.5%-51.7%) with no difference regarding ATG formulation. The response was significantly associated with severity grade-especially at time of treatment initiation: very severe (VSAA) 22.7%; severe (SAA) 54.5% (P < .001); and non-severe 88.5% (P < .001). A logistic regression-based predictive model indicated that VSAA patients with an absolute reticulocyte count

This paper studies the role of strategic uncertainty in the Nash demand game. A player’s uncertainty about another player’s strategy is modeled as an atomless probability distribution over that player’s strategy set. A strategy profile is robust to strategic uncertainty if it is the limit, as uncertainty vanishes, of some sequence of strategy profiles in which every player’s strategy is optimal under his or her uncertainty about the others (Andersson et al., 2014). In the context of the Nash demand game, we show that robustness to symmetric (asymmetric) strategic uncertainty singles out the (generalized) Nash bargaining solution. The least uncertain party obtains the bigger share.

Long-term real-world results of ibrutinib therapy in patients with relapsed or refractory chronic lymphocytic leukemia : 30-month follow up of the Swedish compassionate use cohort

Purpose: Follicular lymphoma (FL) is generally regarded as an indolent malignancy, yet the clinical outcome is highly variable. In recent years, POD24 (progression of disease within 24 months) has emerged as a potential prognostic marker for overall survival (OS) in FL and other non-Hodgkin lymphomas. The association with survival, however, has mostly been studied in selected clinical trial cohorts and among patients treated with R-CHOP. We aimed to investigate OS by timing of progression and type of primary treatment in a population-based setting in Sweden. Methods: We identified all patients diagnosed with FL in stages II-IV and grade 1-3a between 2007 and 2014, using the population-based Swedish lymphoma register. Data were complemented with information on progression, transformation and second-line treatment through medical charts review up to December 31st, 2017. The analysis covered 4 out of 6 health care regions (75% of all patients diagnosed nationally). The patients were categorized according to type of first-line treatment: R-chemo of any type, R-Benda, R-CHOP (including R-CHOEP), or other (including immunotherapy only). Among patients where it was decided to start first-line treatment within 6 months of diagnosis (and where treatment was started within nine months), POD was defined as either lack of response to first-line therapy (stable [SD] or progressive disease [PD]), or initial response and subsequent relapse/progression/transformation as indication for second-line therapy. To quantify the impact of timing of POD on survival, the five-year OS conditional on either being progression-free (PF) or having experienced POD at different time points during follow-up, was estimated using a flexible parametric illness-death model. Results: Among a total of 970 FL patients, median age at diagnosis was 66 years and patients were followed for a median of 6.4 years (range 0-12 years). The 5-year OS was 75% and progression-free survival was 59%. Six hundred (62%) patients had a first-line treatment within nine months of diagnosis and were hence analyzed further, whereas the remaining 370 (38%) patients were classified as wait-and-watch and were not analyzed further. Among the 600 treated patients, 337 (56%) had R-chemo (R-CHOP or alike (n=210), R-Benda (n=97), other (n=30)), and 263 (44%) received non-R-chemo treatment (mainly R-monotherapy, radiotherapy only, or R-lenalidomide). Patients who received R-Benda were on average older than the other groups. Among patients treated with R-chemo, those who stayed progression-free had a 5-year conditional OS above 75% regardless of PF time point. For patients who progressed, the 5-year conditional OS improved as time point of POD was prolonged (Fig 1a, left panel). Early POD (within 12-24 months) was associated with a particularly poor prognosis (5-year conditional OS below 55%). The OS improvement over time of POD was especially pronounced among R-Benda treated patients (Fig 1b, right panel). Among patients receiving non-R-chemo treatments, early POD was associated with a slightly worse 5-year OS but differences between POD and PF patients were less marked (Fig 1a, right panel). Conclusion: This population-based study of Swedish stage II-IV FL patients shows that among immunochemotherapy-treated patients, progression of disease was always associated with worse survival in comparison to progression-free patients regardless of timing of progression. This reduction in survival was more pronounced the earlier the progression (as described by others). Interestingly, among patients selected for milder non-immunochemotherapy-based treatments, progression of disease did not have a strong effect on survival. Disclosures Weibull: Janssen Cilag: Research Funding. Wahlin:Gilead Sciences: Research Funding; Roche: Consultancy, Research Funding. Smedby:Takeda: Research Funding; Janssen: Research Funding; Celgene: Consultancy.

Background Today, even though most patients with diffuse large B-cell lymphoma (DLBCL) can be cured with standard immunochemotherapy, 20-30% are refractory to primary therapy or relapse during follow-up with a drastic worsening of the prognosis. In recent years, new promising treatment options including CAR-T cell therapy are becoming available for relapsed/refractory (R/R) DLBCL patients although so far with logistic challenges including disease control and toxicities, and a considerable cost. In view of these challenges, we aimed to estimate the proportion of patients with R/R DLBCL that are likely to be eligible for CAR-T cell therapy in clinical routine, and their expected outcome in the pre-CAR-T era. Methods All patients with DLBCL starting primary therapy with curative intent were identified in the Swedish Lymphoma Register for the period 2007-2014 (N=3550). Primary CNS and primary mediastinal B-cell lymphomas were excluded. Data regarding primary treatment response and relapse was validated through medical chart review in the entire cohort during follow-up until Dec 31st 2017, and information about additional treatment lines including disease characteristics, blood test results, and relapse treatment response was collected. Eligibility for CAR-T cell therapy was estimated retrospectively based on eligibility criteria specified in clinical trials, both at first relapse by applying similar criteria as in the ongoing TRANSFORM, ZUMA-7 or PILOT studies (hereafter termed "CAR-T-2ndline"), and at second relapse applying criteria similar to those specified in the JULIET trial (hereafter termed "CAR-T-3rdline"). Administration of second- and third-line therapies and corresponding response rates were considered as proxies for eligibility and response to bridging therapies. Criteria applied for "CAR-T-2ndline" included R/R DLBCL within 12 months of evaluation date of primary treatment, age 18-75 years, ECOG 0-1, and additional criteria as specified in the TRANSFORM trial (see figure footnote). Criteria applied for "CAR-T-3rdline" included relapse following second-line therapy, age 18-76 years, ECOG 0-1, and additional criteria as in the JULIET trial (see figure footnote). Individuals with missing data on performance status were assumed ineligible. We lacked information about other malignancies in the disease history. Overall survival probabilities were estimated with the Kaplan-Meier method among all R/R DLBCL patients in the trial-specified age intervals and separately among those fulfilling all trial criteria. Results In the cohort of 3550 curatively treated DLBCL patients, 847 (cumulative incidence 23%) experienced R/R disease during a median follow-up of 4.3 years. Median age at first relapse was 71 years (range 18-95 years). Overall, 308 patients ≤75 years experienced progression/relapse within 12 months and were able to start second-line therapy. Of these, 148 patients (17% of all R/R DLBCL patients) fulfilled trial eligibility criteria for "CAR-T-2ndline", of whom 60 responded with at least partial remission (overall response rate, ORR, 41%). At second relapse, 370 patients 76 years or younger received third-line therapy, of whom 55 (6.5% of all R/R DLBCL patients) were deemed eligible for "Car-T-3rdline", and 13 responded (ORR 24%, another 5 patients had SD). Two-year overall survival (OS) among all R/R DLBCL patients ≤75 years receiving second-line therapy was 20% (95% confidence interval, CI, 16-25%) (Fig 1). Among those eligible for "CAR-T-2ndline", 2-year OS was 24% (95% CI 17-31%). Among patients ≤76 years at second relapse, 2-year OS was 18% (95% CI 13-24%), and among those eligible for "CAR-T-3rdline", 21% (95% CI 11-32%). Conclusion In the population-based setting, one in six patients (17%) with R/R DLBCL fitted trial eligibility criteria for CAR-T-cell therapy at first relapse and only one in fifteen patients (6.5%) fitted trial criteria at second relapse at retrospective evaluation. Figures were reduced when adding requirement of response to relapse/bridging therapy. These estimates illustrate to what extent current CAR-T cell therapies may be applied in a routine setting when based on trial criteria, and the need for development of modified and additional therapies in this group. Outcome estimation confirmed a poor outcome in these groups and did not indicate that fulfillment of trial criteria led to selection bias in terms of survival. Disclosures Ekstroem Smedby: Janssen Cilag: Research Funding; Celgene: Other: Advisory Board; Takeda: Research Funding. Harrysson:Janssen Cilag: Research Funding. Jerkeman:Janssen: Research Funding; Roche: Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Gilead: Research Funding. Eloranta:Janssen Cilag: Research Funding.

The metabolome, which is the final down-stream global product of metabolic processes in organisms, is not sufficiently described in multiple myeloma (MM) patients. The aim of this study was, therefore, to study the serum metabolomic profile using proton nuclear magnetic resonance (1H-NMR) spectroscopy, and its relationship to clinical characteristics and patient outcome. Serum samples, which were taken at diagnosis, from 201 MM patients who underwent high-dose melphalan followed by autologous stem cell transplantation as the first-line therapy, were analyzed. We found that the metabolomic profile differed between patients with different MM International Staging System (ISS) stages. The profile revealed increased levels of cholesterol, phospholipids, high-density lipoprotein, low-density lipoprotein, apolipoproteins A1 and A2, valine, and leucine in ISS I patients compared with ISS III patients. The metabolomic profile also differed between patients with IgA and IgG paraproteins, predominantly because of higher levels of high- and low-density lipoprotein subfractions in IgA patients. The exact pathway of metabolism leading to accumulation of these metabolites is still elusive, but this study indicates an area of interest for further investigation in the search for new therapy targets and prognostic markers for this disease.

Picric acid (PA) is a severe environmental and security risk due to its unstable, toxic, and explosive properties. It is also challenging to detect in trace amounts and in situ because of its highly acidic and anionic character. Here, we assess sensing of PA under nonlaboratory conditions using surface-enhanced Raman scattering (SERS) silver nanopillar substrates and hand-held Raman spectroscopy equipment. The advancing elasto-capillarity effects are explained by molecular dynamics simulations. We obtain a SERS PA detection limit on the order of 20 ppt, corresponding attomole amounts, which together with the simple analysis methodology demonstrates that the presented approach is highly competitive for ultrasensitive analysis in the field.

Background Experiments have shown improved cardiovascular stability in lambs if umbilical cord clamping is postponed until positive pressure ventilation is started. Studies on intact cord resuscitation on human term infants are sparse. The purpose of this study was to evaluate differences in clinical outcomes in non-breathing infants between groups, one where resuscitation is initiated with an intact umbilical cord (intervention group) and one group where cord clamping occurred prior to resuscitation (control group). Methods Randomized controlled trial, inclusion period April to August 2016 performed at a tertiary hospital in Kathmandu, Nepal. Late preterm and term infants born vaginally, non-breathing and in need of resuscitation according to the ‘Helping Babies Breathe’ algorithm were randomized to intact cord resuscitation or early cord clamping before resuscitation. Main outcome measures were saturation by pulse oximetry (SpO2), heart rate and Apgar at 1, 5 and 10 minutes after birth. Results At 10 minutes after birth, SpO2 (SD) was significantly higher in the intact cord group compared to the early cord clamping group, 90.4 (8.1) vs 85.4 (2.7) %, P

We have earlier demonstrated sensitive detection of low the volatile nerve agents Tabun, Cyclosarin and VX by using handheld Raman instrumentation in conjunction with surface-enhanced Raman scattering (SERS) attained with gold and silver coated Si nanopillar substrates. In the present proof-of-concept study, the gold substrates chemically are functionalized to realize selectivity towards organophosphorus compounds (OPs) with high sensitivity. A potential capturer and reporter molecule, chemical nerve agent antidote, 4-pyridine amide oxime, is evaluated due to its high Raman cross section, high chemical affinity towards gold, and binding specificity to the target substances Tabun, VX and Cyclosarin via the oxime group. Upon selective and covalent binding, the SERS probe undergoes structural changes which are reflected in the spectral SERS responses, making it suitable for indirect monitoring of nerve agents in aqueous solution. With the probe attached to the hotspots of Au-coated Si nanopillars, the SERS signals distinctly discriminate between specific and non-specific analyte binding of Tabun, Cyclosarin and VX down to sub ppm levels. SERS spectrum of 4-PAO is measured after microliter drop coating of aqueous sample solution onto the functionalized substrates and subsequent water evaporation from surfaces. This binding assay is complemented by letting functionalized substrates being immersed into sample solutions 1 h before measuring. Binding specific SERS response decreases in following order: Tabun > VX > Cyclosarin. Overall, the concept looks promising, as expected the candidate probe 4-PAO introduces selectivity to the nanopillar gold substrates without loss of sensitivity.

Allogeneic stem cell transplantation (SCT) as primary treatment for aplastic anemia (AA) is being increasingly used. Yet, age, stem cell source, and donor type are important outcome factors. We have recently performed a nationwide cohort study of all patients with AA in Sweden diagnosed from 2000 to 2011 and now present outcome data on SCT patients. In total, 68 patients underwent SCT, and 63% of them had failed immunosuppressive therapy. We found that, with a median follow-up of 109 months (range, 35 to 192 months), 5-year overall survival (OS) for all patients was 86.8%, whereas graft-versus-host disease-free, relapse/rejection-free survival (GRFS) at 5 years was 69.1%. There was no survival impact regarding the donor type or stem cell source. Patients aged ≥40 years had a higher transplant-related mortality (29.4% versus 7.8%; P = .023), which translated into a lower 5-year OS: 70.6% versus 92.2% (P = .022) and a trend of lower GRFS (52.9% versus 74.5%; P = .069). In conclusion, we found in this real-world setting that both OS and GRFS were high, but SCT for patients with AA aged ≥40 years is problematic, and clinical trials addressing this issue are warranted.

Additional file 1. Additional figures 1 to 3 and the list of all additional files and contents

We experimentally subliminally prime subjects prior to charity donation decisions by showing words that have connotations of pro-social values for a very brief time (17ms). Our main fnding is that, compared to a baseline condition, the pro-social prime increases donations by approximately 10-17 percent among subjects with strong pro-social preferences (universalism values). We find a similar effect when interacting the prime with the Big 5 personality characteristic of agreeableness. We furthermore introduce a novel method for testing for priming, "subliminity". This method reveals that some subjects are capable of recognizing prime words, and the overall results are weaker when we control for this capacity.

Recent experimental studies suggest that risk aversion is negatively related to cognitive ability. In this paper we report evidence that this relation may be spurious. We recruit a large subject pool drawn from the general Danish population for our experiment. By presenting subjects with choice tasks that vary the bias induced by random choices, we are able to generate both negative and positive correlations between risk aversion and cognitive ability. Our results suggest that cognitive ability is related to random decision making rather than to risk preferences. (JEL: C81, C91, D12, D81)

Background Our knowledge of the outcome of patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) in the rituximab era is mostly derived from randomised controlled trials or specialized center cohorts presenting selected patient materials. With new targeted therapies being evaluated in the relapsed/refractory setting such as CART therapy, there is a need for a better understanding of the expected survival in real-world cohorts of R/R DLBCL and the likelihood of patients being selected for established intensive treatment schedules and consolidation with autologous stem cell transplantation (ASCT). Here we investigated timing of relapse, treatment intensity and outcome among patients with R/R DLBCL in a nationwide population-based cohort. Methods Patients with R/R DLBCL (N=713) were identified among all patients with a first incident DLBCL diagnosed 2007-2014 recorded in the Swedish Lymphoma Register and treated with primary anthracycline-based immunochemotherapy (N=3528), with follow-up until December 31st 2018. The register holds information about clinical characteristics at diagnosis, primary treatment, treatment response and relapse. Data regarding treatment response and relapse was validated through medical chart review in the entire cohort and information about second-line treatment and ASCT was collected. Timing of progression/relapse was categorized by time interval in months from diagnosis (0-12, 12-24, 24+). Treatment intensity was categorized in four groups: intensive chemotherapy (e.g., DHAP, ICE, GDP) with intent of ASCT, remission-inducing chemotherapy (e.g., GemOx, IME, Benda), palliative therapy (oral chemotherapy, radiotherapy) and no active antitumoral treatment (e.g., steroids, best supportive care). Second-line treatments could have been given with or without immunotherapy. Overall survival probabilities were estimated in the entire cohort and by age >/≤ 70 years using the Kaplan-Meier method. Results In the study population of 713 patients (59% men), median age at relapse was 71 years (range 18 to 95) and 61% had stage IV disease. Most patients relapsed within 12 months (N=428, 60%) whereas 135 patients (19%) relapsed 12-24 months from diagnosis and 148 patients (21%) after 24 months. In patients ≤70 years of age, intensive chemotherapy with intent of ASCT was started in 206 out of 354 patients (58%) and 124 (35%) subsequently received a consolidative ASCT. Remission-inducing chemotherapy was given to 95 patients (27%), 22 (6%) received palliative treatment directly and 31 (9%) were deemed unfit for any active treatment. Among patients >70 years at relapse, 63 patients started intensive chemotherapy (18%) and 4 (1%) were eventually transplanted, whereas another 127 (35%) received remission-inducing chemotherapy, 92 (26%) palliative therapy directly and 77 (21%) no active therapy. Overall survival in the entire cohort was 26% at 2 years (Figure 1A). Timing of relapse strongly correlated with survival, primarily among patients 50% in relapse 12 months or after). Among patients >70 years, outcomes were strikingly poor in all treatment intensity groups (2-year OS 23% or lower). Conclusion In the population-based setting, less than 60% of patients with R/R DLBCL ≤70 years at relapse could go on to receive curative intent second-line treatment and only about one third were consolidated with ASCT (even fewer among those with early relapse). Among patients >70 years, outcomes were very poor and second-line treatment intensity seemed to have little impact on outcome, although there were a few longer-term survivors in all treatment groups. More efficient and less toxic therapies are urgently needed for R/R DLBCL at all ages. Figure 1 A-C Overall survival of patients with relapsed/refractory diffuse large B-cell lymphoma in Sweden 2007-2014 (N=713) in the entire cohort (1A), by age >/≤ 70 years and timing of relapse (0-/≤ 70 years and treatment intensity categorized in 4 groups (1C). Disclosures Ekstroem Smedby: Janssen Cilag: Honoraria, Other: Grant funding, Research Funding; Celgene: Honoraria, Other: Grant funding, Research Funding; Takeda: Honoraria, Other: Grant funding, Research Funding. Ekberg:Swedish Cancer Society: Other: This project was partly funded by the Swedish Cancer Society; Janssen Pharmaceuticals: Other: This project was partly funded through a private-public collaboration between KI and Janssen pharmaceuticals.. Eloranta:Karolinska Institutet: Other: coordinator for a public-private real world evidence; Janssen Pharmaceuticals.: Other: project coordinator for a public-private real world evidence. Enblad:Kite/Gilead: Membership on an entity's Board of Directors or advisory committees. Jerkeman:Janssen: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Acerta: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Andersson:Gilead: Research Funding; Gilead, Janssen and Roche: Consultancy; Abbvie and Janssen: Membership on an entity's Board of Directors or advisory committees. Harrysson:Swedish Cancer Society: Other: This project was partly funded by the Swedish Cancer Society.; Janssen pharmaceuticals: Other: This project was partly funded through a private-public collaboration between KI and Janssen pharmaceuticals..

Background: The cell-of-origin (COO) concept, based on gene expression profiling (GEP), dividing diffuse large B-cell lymphoma (DLBCL) patients into germinal center B cell (GCB) or activated B cell (ABC) subtypes, is a well-established subclassification where ABC patients have an inferior survival. The hallmark the ABC-type is constitutive activation of nuclear factor kappa B (NF-κB), often due to mutations in the B-cell receptor (BCR) signaling pathway. This has been the underlying rationale for adding newer drugs, such as bortezomib, ibrutinib or lenalidomide, to R-CHOP for ABC patients. However, none of these combinations studied in phase III trials have shown any clinical benefit. So, the complexity of ABC DLBCL is probably not only explained by genetic alterations and transcriptional changes as gene expression not necessarily correlate with protein expression, and protein action and dynamics are not caught by genomics-based techniques. Instead, using methods to measure global protein expression and interactions could offer new insights into the ABC subtype and possibly aid in the identification of novel drug targets. Aim: To study possible differences in global protein expression between ABC and GCB DLBCL subtypes using quantitative proteomics. Patients: A total of 213 adult DLBCL patients in western Sweden diagnosed between 1/1 2004 and 31/12 2016, were included. All patients received immunochemotherapy (R-CHOP). Primary mediastinal large B-cell lymphoma, primary CNS lymphoma, HIV-related lymphoma and transformed lymphoma were excluded. From archived formalin-fixed, paraffin-embedded (FFPE) tissue sections, from the time of diagnosis, a core biopsy (1 mm diameter) were obtained from each patient sample. Methods: COO was determined using the Hans immunohistochemistry algorithm. For 92 of the 213 patients, COO was also determined using the gene expression Lymph2cx chip: 14% changed subtype group from either non-GCB to GCB (n=8), GCB to ABC (n=4) or GCB to unclassified (n=1). From the FFPE samples a proteomic analysis was performed. In short, peptides were labelled using tandem mass tag (TMT) according to the manufacturer instructions and samples were analysed on an Orbitrap Fusion Tribrid mass spectrometer. The data files were merged for identification and relative quantification using Proteome Discoverer version 1.4.The search used the Human Swissprot Database version August 2016 using Mascot 2.3 as a search engine. The differentially expressed proteins were analysed using STRING version 10.0, for pathway analysis we used the Reactome database resource, and for potentially druggable proteins we used the Human Protein Atlas website which holds protein information of the current FDA approved drugs directed to 672 separate human proteins. Results: In all, 3078 proteins could be identified in all patients and 793 proteins were differentially expressed (p Conclusions: In this large proteomic study we found a number of overexpressed proteins in the ABC subtype, previously not described in DLBCL. Even though functional studies aimed at individual proteins and protein interactions to evaluate potential clinical effect are needed, our findings reveal novel proteins that could be potential druggable targets in ABC DLBCL patients. Figure 1 Disclosures Enblad: Kite/Gilead: Membership on an entity's Board of Directors or advisory committees. Mellqvist:Amgen, Janssen, Oncopeptides, Sanofi, Sandoz, Takeda: Honoraria. Andersson:Abbvie and Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead, Janssen and Roche: Consultancy; Gilead: Research Funding.