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This paper studies the cross-correlation of two real-valued functions whose common domain is a set on which a finite group acts transitively. Such a group action generalizes, e.g., circular time shifts for discrete periodic time signals or spatial translations in the context of image processing. Cross-correlations can be reformulated as convolutions in group algebras and are thus transformable into the spectral domain via Fast Fourier Transforms. The resulting general discrete cross-correlation theorem will serve as the basis for a unified FFT-based approach to maximum assignment problems related to transitive finite group actions. Our main focus is on those assignment problems arising from the actions of symmetric groups on the cosets of Young subgroups. The "simplest" nontrivial representatives of the latter class of problems are the NP-hard symmetric and asymmetric maximum quadratic assignment problem. We present a systematic spectral approach in terms of the representation theory of symmetric groups to solve such assignment problems. This generalizes and algorithmically improves Kondor's spectral branch-and-bound approach (SODA, 2010) to the exact solution of the asymmetric maximum quadratic assignment problem. [ABSTRACT FROM AUTHOR]

This paper introduces new techniques for the efficient computation of discrete Fourier transforms (DFTs) of S n − k -invariant functions on the symmetric group S n. We uncover diamond- and leaf-rake-like structures in Young's seminormal and orthogonal representations leading to relatively expensive diamond and cheaper leaf-rake computations. These local computations constitute the basis of a reduction/induction process. We introduce a new anticipation technique that avoids diamond computations at the expense of only a small arithmetic overhead for leaf-rake computations. This results in local fast Fourier transforms (FFTs). Combining these local FFTs with a multiresolution scheme close related to the inductive version of Young's branching rule we obtain a global FFT algorithm that computes the DFT of S n − k -invariant functions on S n in linear time. More precisely, we show that for fixed k and all n ≥ 2 k DFTs of S n − k -invariant functions on S n can be computed in at most c k ⋅ [ S n : S n − k ] scalar multiplications and additions, where c k denotes a positive constant depending only on k. This run-time is order-optimal and improves Maslen's algorithm. [ABSTRACT FROM AUTHOR]

We investigated if survival was predicted by nadir neutrophil counts after the first cycle of R-CHOP in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Neutrophil counts (109/L) were categorized in four grades in the nadir time frame. Prognostic indices and comorbidity levels were calculated and used to adjust the Cox regression model. Kaplan–Meier and Cox regression methods were used to estimate and compare survival. We identified 965 patients. Grade 4 neutropenia was present in 432 (45%). Grade 0 patients had a 5-year overall survival of 67%, grade 1–2: 78%, grade 3: 64%, and grade 4: 57%. Compared with grade 0 adjusted hazard ratios (HR) for death were: 0.77 (95% CI 0.49–1.21) for grade 1–2, 1.18 (95% CI 0.82–1.71) for grade 3, and 1.33 (95% CI 1.02–1.73) for grade 4. Grade 4 neutropenia after the 1st cycle of chemotherapy predicted inferior outcome compared with grade 0 and 1–2. Grade 1–2 neutropenia seemed to have superior outcome. [ABSTRACT FROM AUTHOR]

A study published in the British Journal of Haematology examined the impact of COVID-19 on patients with B-cell non-Hodgkin lymphoma (B-NHL) who received bispecific antibodies. The study included 130 Danish patients who were treated with glofitamab or epcoritamab. Of the 43 patients who were infected with COVID-19, the majority were in complete remission at the time of diagnosis. The severity of COVID-19 symptoms varied, with 2 patients experiencing critical symptoms, 2 experiencing severe symptoms, and 30 experiencing non-severe symptoms. Hospitalization was required for 16 patients, and the most common treatments prescribed were sotrovimab and remdesivir. Overall, the study found low mortality rates from COVID-19 infection in patients with B-NHL after bispecific CD20xCD3 therapy. The study also compared the mortality rates of patients who received bispecific antibodies to those treated with CAR-T-cell therapy, finding that bispecific antibody patients had a lower mortality rate. The study concludes that bispecific CD20xCD3 antibodies can be safely prescribed to lymphoma patients who have been vaccinated for COVID-19 with currently circulating virus variants. [Extracted from the article]

Living organisms perceive and respond to a diverse range of mechanical stimuli. A variety of mechanosensitive ion channels have evolved to facilitate these responses, but the molecular mechanisms underlying their exquisite sensitivity to different forces within the membrane remains unclear. TREK-2 is a mammalian two-pore domain (K2P) K+ channel important for mechanosensation, and recent studies have shown how increased membrane tension favors a more expanded conformation of the channel within the membrane. These channels respond to a complex range of mechanical stimuli, however, and it is uncertain how differences in tension between the inner and outer leaflets of the membrane contribute to this process. To examine this, we have combined computational approaches with functional studies of oppositely oriented single channels within the same lipid bilayer. Our results reveal how the asymmetric structure of TREK-2 allows it to distinguish a broad profile of forces within the membrane, and illustrate the mechanisms that eukaryotic mechanosensitive ion channels may use to detect and fine-tune their responses to different mechanical stimuli. [ABSTRACT FROM AUTHOR]

In their journey from the male to the female reproductive tract, spermatozoa are confronted with a constantly changing environment. To cope with the associated challenges, spermatozoa express a distinct set of transporters, channels and pumps. One of the membrane proteins unique to spermatozoa is the α4 isoform of the Na+,K+- ATPase. In addition to α4, spermatozoa express the ubiquous α1 variant. To get a detailed understanding of how α1 and α4 differ, and why spermatozoa need an additional Na+,K+- ATPase, we have conducted an electrophysiological comparison of the rodent isoforms (rat α4 versus mouse α1-3) using the Xenopus oocyte expression system. We demonstrate isoform-specific differences in the voltage sensitivity of steady-state turnover, with α2 being the more sensitive, and α1 and α2 having faster Na+ release kinetics than α3 and α4. Our data further show that the α1 and α2 turnover rates are fast compared with those of α3 and α4. Finally, α4 is less influenced by changes in extracellular Na+ and temperature than α1. Based on these findings, we discuss the possibility that evolution has selected robust activity rather than rapid turnover for α4. [ABSTRACT FROM AUTHOR]

The sole purpose of a sperm cell is to carry genetic information from a male to a female egg. In order to accomplish this quest, the sperm cell must travel a long distance through a constantly changing environment. The success of this journey depends on membrane proteins that are uniquely expressed in sperm cells. One of these proteins is the α4 isoform of the sodium pump. This pump is optimized to cope with the ionic environment characteristic of the female reproductive tract, and its activity may be tightly coupled with secondary transporters that maintain cytoplasmic pH. Pharmacological inhibition of α4 is sufficient to inhibit sperm motility, and significant differences around the inhibitor-binding site compared with the ubiquitous α1 isoform, make α4 a feasible target in rational drug development. [ABSTRACT FROM AUTHOR]

The management of patients with refractory immune thrombocytopenic purpura (ITP) may be difficult. We describe a rapid-onset very long-term remission (9 years) induced by short-term rituximab monotherapy in a 62-year-old man with treatment-refractory chronic ITP. Over a 30-year period from the original diagnosis to last follow-up, the patient needed renewed treatment twelve times within the first two decades and was subsequently brought in continuous complete remission for the last decade by a single course of rituximab. The effect of rituximab in ITP has previously been described. However, in chronic, treatment-refractory ITP occurring in elderly patients, remission rates tend to be low and of short duration. [ABSTRACT FROM AUTHOR]

Abstract: Let denote the symmetric group on and the stabilizer subgroup of . We derive algorithms for computing Fourier transforms of left and right -invariant signals that require a total of additions and scalar multiplications. Furthermore we show that the convolution of such signals can also be computed in time linear in . [Copyright &y& Elsevier]

Background: The prevalence of adult atopic diseases in Iceland is lower than in other West European countries, despite an affluent lifestyle, but limited data are available on children. The main aim of this study was to investigate the prevalence of atopic diseases and sensitivity to common allergens in 10- to 11-year-old Icelandic schoolchildren as part of phase II of the International Study of Asthma and Allergies in Children (ISAAC). Methods: Nine hundred and forty-six children and their parents answered a questionnaire about atopic diseases. Skin prick tests with six allergens were performed on 773 children and they were examined for signs of atopic dermatitis (AD). Results: The 12-month prevalence of allergic rhinoconjunctivitis and asthma was 11.5% and 8.9% respectively. The reported prevalence of AD was 27%, but only 9.2% had signs when inspected. A positive skin prick test (SPT) was found in 24.4% of the children, that is 18.8% to grass, 12.9% to cat, 3.6% to trees, 3.0% to Dermatophagoides pteronyssinus, 1.4% to D. farinae and 0.5% to Alternaria. Conclusion: The high prevalence of atopic diseases in children at 10–11 years is surprising, as the prevalence in adults is low in Iceland. The findings resemble those in developing countries. Iceland has had an affluent lifestyle for a considerable time, but the absence of dust mites, low pet ownership and relatively low pollen counts in the country raise doubts about the role of exposure levels in the development of sensitization and atopic diseases. [ABSTRACT FROM AUTHOR]

Abstract: By definition, a P2-graph is an undirected graph in which every vertex is contained in a path of length two. For such a graph, denotes the minimum number of paths of length two that cover all vertices of . We prove that and show that these upper and lower bounds are tight. Furthermore we show that every connected P2-graph contains a spanning tree such that . We present a linear time algorithm that produces optimal 2-path covers for trees. This is contrasted by the result that the decision problem is -complete for trivalent graphs. This graph theoretical problem originates from the task of searching a large database of biological molecules such as the Protein Data Bank (PDB) by content. [Copyright &y& Elsevier]

Abstract: In this paper we present approximate algorithms for matching two polygonal curves with respect to the Fréchet distance. We define a discrete version of the Fréchet distance as a distance measure between polygonal curves and show that this discrete version is bounded by the continuous version of the Fréchet distance. For the task of matching with respect to the discrete Fréchet distance, we develop an algorithm that is based on intersecting certain subsets of the transformation group under consideration. Our algorithm for matching two point sequences of lengths m and n under the group of rigid motions has a time complexity of for matching under the discrete Fréchet distance and can be modified for matching subcurves, closed curves and finding longest common subcurves. Group theoretical considerations allow us to eliminate translation components of affine transformations and to consider matching under arbitrary linear algebraic groups. [Copyright &y& Elsevier]

Monitoring is a major component of asthma management in children. Regular monitoring allows for diagnosis confirmation, treatment optimization, and natural history review. Numerous factors that may affect disease activity and patient well‐being need to be monitored: response and adherence to treatment, disease control, disease progression, comorbidities, quality of life, medication side‐effects, allergen and irritant exposures, diet and more. However, the prioritization of such factors and the selection of relevant assessment tools is an unmet need. Furthermore, rapidly developing technologies promise new opportunities for closer, or even "real‐time," monitoring between visits. Following an approach that included needs assessment, evidence appraisal, and Delphi consensus, the PeARL Think Tank, in collaboration with major international professional and patient organizations, has developed a set of 24 recommendations on pediatric asthma monitoring, to support healthcare professionals in decision‐making and care pathway design. [ABSTRACT FROM AUTHOR]

Provides information on a study which examined M-band wavelet packets and a generalized framework for the design and efficient utilization of multirate filter bank trees. M-band wavelet packets; Discussion on filter bank trees; Results of the test.

Aim: The main objective of this study was to see how many of the children, with a suspected antibiotic allergy, developed an allergic or adverse reaction to a drug provocation test. Methods: Data on children that had undergone a drug provocation test for a suspected antibiotic allergy were compiled retrospectively for the period from 2007–2018. The median age at the first provocation was 2.25 years (1.5–5.7). Standardised questionnaires, the children's parents had answered before the provocation, were used to evaluate the originally suspected allergic reaction, previous health, atopic diseases and family history. Results: Ninety‐two (6.4%) of the 1440 children showed a possible mild allergic reaction. Sixty‐four of the 92 children underwent a second drug provocation test 1–2 years later. At that time, only eleven developed a positive‐ or a possible‐delayed reaction. Conclusion: An immediate moderate or severe allergic reaction was excluded in all cases of suspected antibiotic allergy in this study. Our study indicates that an oral drug provocation test is safe. It may be appropriate to wait for 6 months or more after the initial event of ADR before these tests are performed. A second oral provocation 1–2 years after the first one shows that ADRs are outgrown in most children. [ABSTRACT FROM AUTHOR]

Summary: Outcome data of patients with relapsed/refractory (R/R) diffuse large B‐cell lymphoma (DLBCL) beyond the second line are scarce outside of clinical trials. Novel therapies in the R/R setting have been approved based on single‐arm trials, but results need to be contextualized by real‐world outcomes. Medical records from 3753 Danish adults diagnosed with DLBCL were reviewed. Patients previously treated with rituximab and anthracycline‐based chemotherapy who received the third or later line (3 L+) of treatment after 1 January 2015, were included. Only 189 patients with a median age of 71 years were eligible. The median time since the last line of therapy was 6 months. Patients were treated with either best supportive care (22%), platinum‐based salvage therapy (13%), low‐intensity chemotherapy (22%), in clinical trial (14%) or various combination treatments (32%). The 2‐year OS‐/PFS estimates were 25% and 12% for all patients and 49% and 17% for those treated with platinum‐based salvage therapy. Age ≥70, CNS involvement, elevated LDH and ECOG ≥2 predicted poor outcomes, and patients with 0–1 of these risk factors had a 2‐year OS estimate of 65%. Only a very small fraction of DLBCL patients received third‐line treatment and were eligible for inclusion. Outcomes were generally poor, but better in intensively treated, fit young patients with limited disease. [ABSTRACT FROM AUTHOR]

Background: Patients with relapsed or refractory B-cell non-Hodgkin lymphoma have few treatment options. We aimed to establish the safety and recommended phase 2 dose of epcoritamab, a novel bispecific antibody that targets CD3 and CD20 and induces T-cell-mediated cytotoxic activity against CD20+ malignant B cells.Methods: For the dose-escalation part of this phase 1/2 study, we enrolled adults (aged ≥18 years) with relapsed or refractory CD20+ B-cell non-Hodgkin lymphoma at ten sites across four countries (Denmark, the Netherlands, the UK, and Spain). Eligible patients received priming and intermediate doses followed by full doses of subcutaneous epcoritamab administered in 28-day cycles; each subsequent cohort involved escalation of the priming, intermediate, or full dose (0·0128-60 mg). The primary objectives were to determine the maximum tolerated dose and the recommended phase 2 dose. Safety, antitumour activity, pharmacokinetics, and immune biomarkers were also assessed. This study is registered with ClinicalTrials.gov, NCT03625037, with the dose-expansion part ongoing.Findings: Between June 26, 2018, and July 14, 2020, we enrolled 73 patients with relapsed, progressive, or refractory CD20+ mature B-cell non-Hodgkin lymphoma. 68 patients received escalating full doses (0·0128-60 mg) of subcutaneous epcoritamab. No dose-limiting toxic effects were observed, and the maximum tolerated dose was not reached; the full dose of 48 mg was identified as the recommended phase 2 dose. All 68 patients received at least one dose of epcoritamab and were included in safety analyses: common adverse events were pyrexia (47 patients [69%]), primarily associated with cytokine release syndrome (CRS; 40 [59%], all grade 1-2), and injection site reactions (32 [47%]; 31 grade 1). There were no grade 3 or higher CRS events. No discontinuations occurred due to treatment-related adverse events or treatment-related deaths. Overall response rate in patients with relapsed or refractory diffuse large B-cell lymphoma was 68% (95% CI 45-86), with 45% achieving a complete response at full doses of 12-60 mg. At 48 mg, the overall response rate was 88% (47-100), with 38% achieving a complete response. Patients with relapsed or refractory follicular lymphoma had an overall response rate of 90% (55-100), with 50% achieving a complete response at full doses of 0·76-48 mg. Epcoritamab induced robust and sustained B-cell depletion, and CD4+ and CD8+ T-cell activation and expansion, with modest increases in cytokine levels.Interpretation: Single-agent subcutaneous epcoritamab for treatment of patients with relapsed or refractory B-cell non-Hodgkin lymphoma merits investigation in ongoing phase 2 and phase 3 studies.Funding: Genmab and AbbVie. [ABSTRACT FROM AUTHOR]

Background: Coexistence of childhood asthma, eczema and allergic rhinitis is higher than can be expected by chance, suggesting a common mechanism. Data on allergic multimorbidity from a pan‐European, population‐based birth cohort study have been lacking. This study compares the prevalence and early‐life risk factors of these diseases in European primary school children. Methods: In the prospective multicentre observational EuroPrevall‐iFAAM birth cohort study, we used standardized questionnaires on sociodemographics, medical history, parental allergies and lifestyle, and environmental exposures at birth, 12 and 24 months. At primary school age, parents answered ISAAC‐based questions on current asthma, rhinitis and eczema. Allergic multimorbidity was defined as the coexistence of at least two of these. Results: From 10,563 children recruited at birth in 8 study centres, we included data from 5,572 children (mean age 8.2 years; 51.8% boys). Prevalence estimates were as follows: asthma, 8.1%; allergic rhinitis, 13.3%; and eczema, 12.0%. Allergic multimorbidity was seen in 7.0% of the whole cohort, ranging from 1.2% (Athens, Greece) to 10.9% (Madrid, Spain). Risk factors for allergic multimorbidity, identified with AICc, included family‐allergy‐score, odds ratio (OR) 1.50 (95% CI 1.32–1.70) per standard deviation; early‐life allergy symptoms, OR 2.72 (2.34–3.16) for each symptom; and caesarean birth, OR 1.35 (1.04–1.76). Female gender, OR 0.72 (0.58–0.90); older siblings, OR 0.79 (0.63–0.99); and day care, OR 0.81 (0.63–1.06) were protective factors. Conclusion: Allergic multimorbidity should be regarded as an important chronic childhood disease in Europe. Some of the associated early‐life factors are modifiable and may be considered for prevention strategies. [ABSTRACT FROM AUTHOR]

Diffuse large B-cell lymphoma is an aggressive disease occurring primarily in elderly patients. Despite high curative rates with doxorubicin-containing treatment, some elderly patients receive less intensive treatments, mainly due to advanced age, comorbidities, and concerns of cardiotoxicity from doxorubicin-containing regimens. We analyzed 1009 patients aged 75 years or older and 10,090 age- and sex-matched comparisons. We aimed to evaluate long-term cardiovascular side effects in elderly patients treated with doxorubicin. Approximately, 64% of patients received doxorubicin-containing treatment. These patients had a persistently increased risk of new-onset heart failure with a hazard ratio of 1.5 and 1.7 when conditioning on survival without heart failure to 6 and 24 months, respectively. Moreover, we observed an increased risk of venous thromboembolism during the first six months following the lymphoma diagnosis. On the contrary, no difference in risk of developing ischemic heart disease or stroke following doxorubicin-containing treatment was observed. [ABSTRACT FROM AUTHOR]

Background: The Danish National Lymphoma Register (LYFO) prospectively includes information on all lymphoma patients newly diagnosed at hematology departments in Denmark. The validity of the clinical information in the LYFO has never been systematically assessed. Aim: To test the coverage and data quality of the LYFO. Methods: The coverage was tested by merging data of the LYFO with the Danish Cancer Register and the Danish National Patient Register, respectively. The validity of the LYFO was assessed by crosschecking with information from medical records in subgroups of patients. A random sample of 3% (N = 364) was made from all patients in the LYFO. In addition, four subtypes of lymphomas were validated: CNS lymphomas, diffuse large B-cell lymphomas, peripheral T-cell lymphomas, and Hodgkin lymphomas. A total of 1,706 patients from the period 2000–2012 were included. The positive predictive values (PPVs) and completeness of selected variables were calculated for each subgroup and for the entire cohort of patients. Results: The comparison of data from the LYFO with the Danish Cancer Register and the Danish National Patient Register revealed a high coverage. In addition, the data quality was good with high PPVs (87% to 100%), and high completeness (92% to 100%). Conclusion: The LYFO is a unique, nationwide clinical database characterized by high validity, good coverage and prospective data entry. It represents a valuable resource for future lymphoma research. [ABSTRACT FROM AUTHOR]

Background: The heterogeneity and lack of validation of existing severity scores for food allergic reactions limit standardization of case management and research advances. We aimed to develop and validate a severity score for food allergic reactions. Methods: Following a multidisciplinary experts consensus, it was decided to develop a food allergy severity score (FASS) with ordinal (oFASS) and numerical (nFASS) formats. oFASS with 3 and 5 grades were generated through expert consensus, and nFASS by mathematical modeling. Evaluation was performed in the EuroPrevall outpatient clinic cohort (8232 food reactions) by logistic regression with request of emergency care and medications used as outcomes. Discrimination, classification, and calibration were calculated. Bootstrapping internal validation was followed by external validation (logistic regression) in 5 cohorts (3622 food reactions). Correlation of nFASS with the severity classification done by expert allergy clinicians by Best‐Worst Scaling of 32 food reactions was calculated. Results: oFASS and nFASS map consistently, with nFASS having greater granularity. With the outcomes emergency care, adrenaline and critical medical treatment, oFASS and nFASS had a good discrimination (receiver operating characteristic area under the curve [ROC‐AUC]>0.80), classification (sensitivity 0.87–0.92, specificity 0.73–0.78), and calibration. Bootstrapping over ROC‐AUC showed negligible biases (1.0 × 10−6–1.23 × 10−3). In external validation, nFASS performed best with higher ROC‐AUC. nFASS was strongly correlated (R 0.89) to best‐worst scoring of 334 expert clinicians. Conclusion: FASS is a validated and reliable method to measure severity of food allergic reactions. The ordinal and numerical versions that map onto each other are suitable for use by different stakeholders in different settings. [ABSTRACT FROM AUTHOR]

The Na,K-ATPase, or sodium pump, is well known for its role in ion transport across the plasma membrane of animal cells. It carries out the transport of Na ions out of the cell and of K ions into the cell and thus maintains electrolyte and fluid balance. In addition to the fundamental ion-pumping function of the Na,K-ATPase, recent work has suggested additional roles for Na,K-ATPase in signal transduction and biomembrane structure. Several signaling pathways have been found to involve Na,K-ATPase, which serves as a docking station for a fast-growing number of protein interaction partners. In this review, we focus on Na,K-ATPase as a signal transducer, but also briefly discuss other Na,K-ATPase protein-protein interactions, providing a comprehensive overview of the diverse signaling functions ascribed to this well-known enzyme. [ABSTRACT FROM AUTHOR]

Significant digitization efforts have resulted in large multimodal music collections, which comprise music-related documents of various types and formats including text, symbolic data, audio, image, and video. The challenge is to organize, understand, and search musical content in a robust, efficient, and intelligent manner. Key issues concern the development of methods for analysing, correlating, and annotating the available multimodal material, thus identifying and establishing semantic relationships across various music representations and formats. Here, one important task is referred to as music synchronization, which aims at identifying and linking semantically corresponding events present in different versions of the same underlying musical work. In this paper, we give an introduction to music synchronization and show how synchronization techniques can be integrated into novel user interfaces that allow music lovers and researchers to access and explore music in all its different facets thus enhancing human involvement with music and deepening music understanding. [ABSTRACT FROM AUTHOR]

Background: EAACI guidelines emphasize the importance of patient history in diagnosing food allergy (FA) and the need for studies investigating its value using standardized allergy‐focused questionnaires. Objective: To determine the contribution of reaction characteristics, allergic comorbidities and demographics to prediction of FA in individuals experiencing food‐related adverse reactions. Methods: Adult and school‐age participants in the standardized EuroPrevall population surveys, with self‐reported FA, were included. Penalized multivariable regression was used to assess the association of patient history determinants with "probable" FA, defined as a food‐specific case history supported by relevant IgE sensitization. Results: In adults (N = 844), reproducibility of reaction (OR 1.35 [95% CI 1.29‐1.41]), oral allergy symptoms (OAS) (4.46 [4.19‐4.75]), allergic rhinitis (AR) comorbidity (2.82 [2.68‐2.95]), asthma comorbidity (1.38 [1.30‐1.46]) and male sex (1.50 [1.41‐1.59]) were positively associated with probable FA. Gastrointestinal symptoms (0.88 [0.85‐0.91]) made probable FA less likely. The AUC of a model combining all selected predictors was 0.85 after cross‐validation. In children (N = 670), OAS (2.26 [2.09‐2.44]) and AR comorbidity (1.47 [CI 1.39‐1.55]) contributed most to prediction of probable FA, with a combined cross‐validation‐based AUC of 0.73. When focusing on plant foods, the dominant source of FA in adults, the pediatric model also included gastrointestinal symptoms (inverse association), and the AUC increased to 0.81. Conclusions: In both adults and school‐age children from the general population, reporting of OAS and of AR comorbidity appear to be the strongest predictors of probable FA. Patient history particularly allows for good discrimination between presence and absence of probable plant FA. [ABSTRACT FROM AUTHOR]

Low absolute lymphocyte counts (ALC) and high absolute monocyte counts (AMC) are associated with poor survival in patients with diffuse large B-cell lymphoma (DLBCL). We studied the prognostic impact of the ALC and AMC in patients with testicular DLBCL (T-DLBCL). T-DLBCL patients were searched using Southern Finland University Hospital databases and the Danish lymphoma registry. The progression free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier and Cox proportional hazards methods. We identified 178 T-DLBCL patients, of whom 78 (44%) had a low ALC at diagnosis. The ALC did not correlate with survival in the whole cohort. However, among the patients treated with rituximab (R) containing regimen, a pre-therapeutic low ALC was associated with an increased risk of progression (HR 1.976, 95% CI 1.267–3.086, p = 0.003). Conversely, intravenous (iv) CNS directed chemotherapy translated to favorable outcome. In multivariate analyses, the advantage of an iv CNS directed chemotherapy was sustained (PFS, HR 0.364, 95% CI 0.175–0.757, p = 0.007). The benefit of R and intravenous CNS directed chemotherapy was observed only in non-lymphopenic patients. The AMC did not correlate with survival. A low ALC is an adverse prognostic factor in patients with T-DLBCL. Alternative treatment options for lymphopenic patients are needed. [ABSTRACT FROM AUTHOR]

Background: The prevalence of food allergy (FA) among European school children is poorly defined. Estimates have commonly been based on parent‐reported symptoms. We aimed to estimate the frequency of FA and sensitization against food allergens in primary school children in eight European countries. Methods: A follow‐up assessment at age 6‐10 years of a multicentre European birth cohort based was undertaken using an online parental questionnaire, clinical visits including structured interviews and skin prick tests (SPT). Children with suspected FA were scheduled for double‐blind, placebo‐controlled oral food challenges (DBPCFC). Results: A total of 6105 children participated in this school‐age follow‐up (57.8% of 10 563 recruited at birth). For 982 of 6069 children (16.2%), parents reported adverse reactions after food consumption in the online questionnaire. Of 2288 children with parental face‐to‐face interviews and/or skin prick testing, 238 (10.4%) were eligible for a DBPCFC. Sixty‐three foods were challenge‐tested in 46 children. Twenty food challenges were positive in 17 children, including seven to hazelnut and three to peanut. Another seventy‐one children were estimated to suffer FA among those who were eligible but refused DBPCFC. This yielded prevalence estimates for FA in school age between 1.4% (88 related to all 6105 participants of this follow‐up) and 3.8% (88 related to 2289 with completed eligibility assessment). Interpretation: In primary school children in eight European countries, the prevalence of FA was lower than expected even though parents of this cohort have become especially aware of allergic reactions to food. There was moderate variation between centres hampering valid regional comparisons. [ABSTRACT FROM AUTHOR]

High-dose prednisolone is used in first-line treatment for lymphoma, but the potential adverse impact on bone health is unclear. Danish patients with diffuse large B-cell lymphoma or follicular lymphoma diagnosed between 2000 and 2012 were matched to the background population. Osteoporotic events (osteoporosis treatment or low-energy fracture) were identified using the Danish National Patient Registry and Prescription Registry. In total, 2589 patients and 12,945 controls were included. Lymphoma patients had increased risk of osteoporotic events compared to the matched population (hazard ratio 1.61 [95% confidence interval 1.40;1.84]). The 5- and 10-year cumulative risks of osteoporotic events for lymphoma patients were 10.0% [8.6;11.4] and 16.3% [13.8;18.7], whereas corresponding risks in the background population were 6.8% [6.3;7.3] and 13.5% [12.4;14.6]. Patients without osteoporotic event in the first two years after treatment were not at higher risk of osteoporotic events in subsequent years. Risk factors for osteoporotic events were female sex and age >70 years. [ABSTRACT FROM AUTHOR]

Richter's transformation (RT) refers to the development of an aggressive lymphoma in patients with chronic lymphocytic leukemia (CLL). Approximately, 2–10% of patients with CLL develop RT, most often as diffuse large B-cell lymphoma. To assess the incidence of RT, we examined risk factors for RT and death among patients with RT in a nationwide CLL cohort (from 2008 to 2016). Among 3772 patients, 113 had biopsy-proven RT. With a median follow-up of 4.3 years, the 5-year cumulative incidence of RT was 2.8%. Advanced Binet stage (B/C) (p<.001), unmutated IGHV (p<.001), and del(17p) (p<.001) were independently associated with risk of developing RT. Half of the patients with RT (49%) were treatment-naïve prior to transformation and demonstrated longer survival after RT compared to patients previously treated for CLL (6.1 vs. 2.8 years, p=.03). Whether this finding could be explained by a higher proportion of clonally unrelated RT among treatment-naïve patients, remain to be addressed. [ABSTRACT FROM AUTHOR]

The addition of the antibody rituximab to CHOP (R-CHOP) has improved the outcome of diffuse large B-cell lymphoma (DLBCL) and is the current standard of care [[1]]. On the contrary, preliminary results from a trial randomizing stage II-IV DLBCL patients to R-CHOP14 and R-CHOP14 plus additional rituximab on day 8 during the first four treatment cycles did not confirm a benefit of intensified rituximab in male patients [[12]]. Consistent with this study, a more recent Swedish study including >7000 DLBCL patients reported comparable improvements in life expectancy for male and female patients during the rituximab introduction period, although no direct comparison between male and female patients was performed [[15]]. As the survival in the general population is gender-specific (5-year OS, 94% for a female and 90% for a male Danish person aged 65 in 2010), crude OS differences between male and female patients may be sensitive to excess deaths in male patients unrelated to DLBCL. [Extracted from the article]

In Hodgkin lymphoma (HL) bleomycin can induce pulmonary toxicity (BPT). BPT consists of respiratory tract symptoms during bleomycin-exposure and radiologic pulmonary lesions without concomitant infection. Older age, bleomycin dose, smoking history and the use of granulocyte-colony stimulating factor (G-CSF) have been suggested as possible risk factors for BPT. It is still debated whether BPT affects overall (OS) and progression-free survival (PFS). We investigated the incidence of BPT along with possible risk factors in 412 HL patients treated in 1990-2014. BPT occurred in 34 patients (8%) and was significantly associated with disseminated disease and B-symptoms. It was more frequent in elderly patients (p =.05) but not significantly correlated with a history of smoking. BPT occurred more often in patients receiving G-CSF (p =.03), particularly the poly-ethylenglycol-bound molecule. All significant risk correlations were limited to the age group >45 years. In the present cohort, BPT did not influence OS or PFS regardless of age. [ABSTRACT FROM AUTHOR]

Background: Of the major peanut allergens, sensitivity to Ara h 2 has the highest prediction for clinical allergy. In this study, we evaluated sensitization to peanut components in Iceland and related Ara h 2-negative sensitization to clinical allergy. Methods: Ara h 1, Ara h 2, Ara h 3, Ara h 8, and Bet v 1 IgEs were measured (ImmunoCAP) in 220 peanut IgE (Pn-IgE)-positive serum samples. Ara h 2 IgE-negative individuals were invited to an open peanut challenge and evaluated for Ara h 6 and 9 sensitization (ISAC microarray). Results: The Ara h 2 IgE-negative group (52.3%, 115/220) was older (p = 0.04) and more likely to have a history of pollen allergy than the Ara h 2-positive group (p < 0.001). Of the Ara h 2-negative participants, 24.3% were already consuming peanuts and 38.3% were unavailable. Of the 43 who underwent an open peanut challenge, 79% were negative, 14% were positive, and 7% were inconclusive. Those who reacted to peanuts had a higher Ara h 1 IgE than that of the tolerant participants, and 3 were positive to Ara h 6 IgE, and 2 of those subjects were monosensitized. Ara h 8 may have caused a positive reaction, while Ara h 9 did not. Conclusions: Half of the peanut-sensitized individuals in Iceland were not sensitized to the major allergen Ara h 2. Ara h 1, Ara h 3, and Ara h 6 sensitizations resulted in a positive open peanut challenge and they are therefore clinically important for individuals with a peanut allergy in Iceland. [ABSTRACT FROM AUTHOR]

Background Optimal treatment strategy for the oldest patients with diffuse large B-cell lymphoma (DLBCL) remains controversial, as this group often is precluded from clinical trials, and population-based studies are limited. Methods All Danish DLBCL-patients ≥75 years diagnosed from 2003 to 2012 were identified, using the Danish National Lymphoma Registry (LYFO). Information regarding baseline characteristics, treatment, comorbidities and outcomes was retrieved from LYFO, the Danish National health registries and medical records. Patients were stratified by age (75–79; 80–84 and 85 + years), comorbidity score and treatment modality (standard treatment [R-CHOP/CHOP-like], less intensive regimens or palliative treatment). Findings A total of 1011 patients were included. Standard treatment was initiated in 64%, ranging from 83% among patients aged 75–79 years to 32% among patient aged 85 + years. With standard treatment, median overall survival (OS) estimates were 4·6, 2·6, and 1·9 years for the age groups 75–79, 80–84 and 85+ years. Among patient aged 75–79 and 80–84 years, OS was superior with standard treatment, although high comorbidity scores attenuated this association. Among patients aged 85+ years, survival was not influenced by treatment intensity. Patients ≥80 years had similar OS regardless of intended (R-)CHOP dosing, whereas patients of 75–79 years scheduled for full dose had higher OS. Standard treatment was not associated with increased hospitalisation. Interpretation Standard treatment is feasible with good outcomes in a large proportion of elderly DLBCL-patients. Planned dose reduction in patients aged ≥80 years had no negative impact on OS. [ABSTRACT FROM AUTHOR]

Summary The mechanosensitive two-pore domain (K2P) K + channels (TREK-1, TREK-2, and TRAAK) are important for mechanical and thermal nociception. However, the mechanisms underlying their gating by membrane stretch remain controversial. Here we use molecular dynamics simulations to examine their behavior in a lipid bilayer. We show that TREK-2 moves from the “down” to “up” conformation in direct response to membrane stretch, and examine the role of the transmembrane pressure profile in this process. Furthermore, we show how state-dependent interactions with lipids affect the movement of TREK-2, and how stretch influences both the inner pore and selectivity filter. Finally, we present functional studies that demonstrate why direct pore block by lipid tails does not represent the principal mechanism of mechanogating. Overall, this study provides a dynamic structural insight into K2P channel mechanosensitivity and illustrates how the structure of a eukaryotic mechanosensitive ion channel responds to changes in forces within the bilayer. [ABSTRACT FROM AUTHOR]

Purpose Development of secondary central nervous system involvement (SCNS) in patients with diffuse large B-cell lymphoma is associated with poor outcomes. The CNS International Prognostic Index (CNS-IPI) has been proposed for identifying patients at greatest risk, but the optimal model is unknown. Methods We retrospectively analysed patients with diffuse large B-cell lymphoma diagnosed between 2001 and 2013, staged with PET/CT and treated with R-CHOP(-like) regimens. Baseline clinicopathologic characteristics, treatments, and outcome data were collected from clinical databases and medical files. We evaluated the association between candidate prognostic factors and modelled different risk models for predicting SCNS. Results Of 1532 patients, 62 (4%) subsequently developed SCNS. By multivariate analysis, disease stage III/IV, elevated serum LDH, kidney/adrenal and uterine/testicular involvement were independently associated with SCNS. There was a strong correlation between absolute number of extranodal sites and risk of SCNS; the 144 patients (9%) with >2 extranodal sites had a 3-year cumulative incidence of SCNS of 15.2% (95% confidence interval [CI] 9.2–21.2%) compared with 2.6% (95% CI 1.7–3.5) among those with ≤2 sites ( P < 0.001). The 3-year cumulative risks of SCNS for CNS-IPI defined risk groups were 11.2%, 3.1% and 0.4% for high-, intermediate- and low-risk patients, respectively. All risk models analysed had high negative predictive values, but only modest positive predictive values. Conclusions Patients with >2 extranodal sites or high-risk disease according to the CNS-IPI should be considered for baseline CNS staging. Clinical risk prediction models suffer from limited positive predictive ability, highlighting the need for more sensitive biomarkers to identify patients at highest risk of this devastating complication. [ABSTRACT FROM AUTHOR]

Involvement of the internal female reproductive organs by diffuse large B-cell lymphoma ( DLBCL) is uncommon, and there are sparse data describing the outcomes of such cases. In total, 678 female patients with DLBCL staged with positron emission tomography/computed tomography and treated with rituximab-containing chemotherapy were identified from databases in Denmark, Great Britain, Australia, and Canada. Overall, 27/678 (4%) had internal reproductive organ involvement: uterus ( n = 14), ovaries ( n = 10) or both ( n = 3). In multivariate analysis, women with uterine DLBCL experienced inferior progression-free survival and overall survival compared to those without reproductive organ involvement, whereas ovarian DLBCL was not predictive of outcome. Secondary central nervous system ( CNS) involvement ( SCNS) occurred in 7/17 (41%) women with uterine DLBCL (two patients with concomitant ovarian DLBCL) and 0/10 women with ovarian DLBCL without concomitant uterine involvement. In multivariate analysis adjusted for other risk factors for SCNS, uterine involvement by DLBCL remained strongly associated with SCNS (Hazard ratio 14·13, 95% confidence interval 5·09-39·25, P < 0·001). Because involvement of the uterus by DLBCL appears to be associated with a high risk of SCNS, those patients should be considered for CNS staging and prophylaxis. However, more studies are needed to determine whether the increased risk of secondary CNS involvement also applies to women with localized reproductive organ DLBCL. [ABSTRACT FROM AUTHOR]

The tumour microenvironment in classical Hodgkin's lymphoma ( cHL) is characterised by a minor population of neoplastic Hodgkin and Reed-Sternberg cells within a heterogeneous background of non-neoplastic bystanders cells, including mast cells. The number of infiltrating mast cells in cHL has been reported to correlate with poor prognosis. We used immunohistochemistry to assess the degree of tumour-infiltrating mast cells in cHL tissue microarrays and correlated this with clinico-pathological features and prognosis in a cohort of homogeneously treated patients with Hodgkin's disease. A high degree of tumour mast cells was associated with nodular sclerosis ( NS) subtype histology ( P = 0.0002). Moreover, the number of mast cells was inversely correlated with the numbers of CD68+ and CD163+ macrophages ( P = 0.0001 and P = 0.003, respectively) and with the number of granzyme+ cytotoxic cells ( P = 0.004). The degree of mast cell infiltration was not a prognostic factor in cHL of nodular sclerosis subtype. In contrast, in mixed cellularity cHL a high number of intratumoral mast cells correlated with significantly poorer outcome both in terms of overall ( P = 0.03) and event-free survival ( P = 0.01). Further studies are warranted into the biological mechanisms underlying this adverse outcome and their possible therapeutic implications. [ABSTRACT FROM AUTHOR]

Background: The FAST (food allergy-specific immunotherapy) project aims at developing safe and effective subcutaneous immunotherapy for fish allergy, using recombinant hypoallergenic carp parvalbumin, Cyp c 1. Objectives: Preclinical characterization and good manufacturing practice (GMP) production of mutant Cyp (mCyp) c 1. Methods:Escherichia coli-produced mCyp c 1 was purified using standard chromatographic techniques. Physicochemical properties were investigated by gel electrophoresis, size exclusion chromatography, circular dichroism spectroscopy, reverse-phase high-performance liquid chromatography and mass spectrometry. Allergenicity was assessed by ImmunoCAP inhibition and basophil histamine release assay, immunogenicity by immunization of laboratory animals and stimulation of patients' peripheral blood mononuclear cells (PBMCs). Reference molecules were purified wild-type Cyp c 1 (natural and/or recombinant). GMP-compliant alum-adsorbed mCyp c 1 was tested for acute toxicity in mice and rabbits and for repeated-dose toxicity in mice. Accelerated and real-time protocols were used to evaluate stability of mCyp c 1 as drug substance and drug product. Results: Purified mCyp c 1 behaves as a folded and stable molecule. Using sera of 26 double-blind placebo-controlled food-challenge-proven fish-allergic patients, reduction in allergenic activity ranged from 10- to 5,000-fold (1,000-fold on average), but with retained immunogenicity (immunization in mice/rabbits) and potency to stimulate human PBMCs. Toxicity studies revealed no toxic effects and real-time stability studies on the Al(OH)3-adsorbed drug product demonstrated at least 20 months of stability. Conclusion: The GMP drug product developed for treatment of fish allergy has the characteristics targeted for in FAST: i.e. hypoallergenicity with retained immunogenicity. These results have warranted first-in-man immunotherapy studies to evaluate the safety of this innovative vaccine. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

TREK-2 (KCNK10/K2P10), a two-pore domain potassium (K2P) channel, is gated by multiple stimuli such as stretch, fatty acids, and pH and by several drugs. However, the mechanisms that control channel gating are unclear. Here we present crystal structures of the human TREK-2 channel (up to 3.4 angstrom resolution) in two conformations and in complex with norfluoxetine, the active metabolite of fluoxetine (Prozac) and a state-dependent blocker of TREK channels. Norfluoxetine binds within intramembrane fenestrations found in only one of these two conformations. Channel activation by arachidonic acid and mechanical stretch involves conversion between these states through movement of the pore-lining helices. These results provide an explanation for TREK channel mechanosensitivity, regulation by diverse stimuli, and possible off-target effects of the serotonin reuptake inhibitor Prozac. [ABSTRACT FROM AUTHOR]

Introduction: Food allergy is a recognized health problem, but little has been reported on its cost for health services. The EuroPrevall project was a European study investigating the patterns, prevalence and socio-economic cost of food allergy. Aims: To investigate the health service cost for food-allergic Europeans and the relationship between severity and cost of illness. Methods: Participants recruited through EuroPrevall studies in a case–control study in four countries, and cases only in five countries, completed a validated economics questionnaire. Individuals with possible food allergy were identified by clinical history, and those with food-specific immunoglobulin E were defined as having probable allergy. Data on resource use were used to estimate total health care costs of illness. Mean costs were compared in the case–control cohorts. Regression analysis was conducted on cases from all 9 countries to assess impact of country, severity and age group. Results: Food-allergic individuals had higher health care costs than controls. The mean annual cost of health care was international dollars (I$)2016 for food-allergic adults and I$1089 for controls, a difference of I$927 (95% confidence interval I$324–I$1530). A similar result was found for adults in each country, and for children, and was not sensitive to baseline demographic differences. Cost was significantly related to severity of illness in cases in nine countries. Conclusions: Food allergy is associated with higher health care costs. Severity of allergic symptoms is a key explanatory factor. [ABSTRACT FROM AUTHOR]

At least 5% of individuals with hypertension have adrenal aldosterone-producing adenomas (APAs). Gain-of-function mutations in KCNJ5 and apparent loss-of-function mutations in ATP1A1 and ATP2A3 were reported to occur in APAs. We find that KCNJ5 mutations are common in APAs resembling cortisol-secreting cells of the adrenal zona fasciculata but are absent in a subset of APAs resembling the aldosterone-secreting cells of the adrenal zona glomerulosa. We performed exome sequencing of ten zona glomerulosa-like APAs and identified nine with somatic mutations in either ATP1A1, encoding the Na+/K+ ATPase α1 subunit, or CACNA1D, encoding Cav1.3. The ATP1A1 mutations all caused inward leak currents under physiological conditions, and the CACNA1D mutations induced a shift of voltage-dependent gating to more negative voltages, suppressed inactivation or increased currents. Many APAs with these mutations were <1 cm in diameter and had been overlooked on conventional adrenal imaging. Recognition of the distinct genotype and phenotype for this subset of APAs could facilitate diagnosis. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients are diagnosed with myeloproliferative neoplasia (MPN) and lymphoma more frequently in the population than expected, which has led to the hypothesis that the two malignancies may, in some cases, be pathogenetically related. In this study, lymphoma patients with and without MPN show subtle but important differences in the protein expression that enables the clustering of the lymphomas, thus indicating the differences at the molecular level between the lymphoma malignancies with and without MPN, and strengthening the hypothesis that the lymphoma and MPN may be biologically related. Myeloproliferative neoplasia (MPN) and lymphoma are regarded as distinct diseases with different pathogeneses. However, patients that are diagnosed with both malignancies occur more frequently in the population than expected. This has led to the hypothesis that the two malignancies may, in some cases, be pathogenetically related. Using a mass spectrometry-based proteomic approach, we show that pre-treatment lymphoma samples from patients with both MPN and lymphoma, either angioimmunoblastic T-cell lymphoma (MPN-AITL) or diffuse large B-cell lymphoma (MPN-DLBCL), show differences in protein expression compared with reference AITL or DLBCL samples from patients without MPN. A distinct clustering of samples from patients with and without MPN was evident for both AITL and DLBCL. Regarding MPN-AITL, a pathway analysis revealed disturbances of cellular respiration as well as oxidative metabolism, and an immunohistochemical evaluation further demonstrated the differential expression of citrate synthase and DNAJA2 protein (p = 0.007 and p = 0.015). Interestingly, IDH2 protein also showed differential expression in the MPN-AITL patients, which contributes to the growing evidence of this protein's role in both myeloid neoplasia and AITL. In MPN-DLBCL, the disturbed pathways included a significant downregulation of protein synthesis as well as a perturbation of signal transduction. These results imply an underlying disturbance of tumor molecular biology, and in turn an alternative pathogenesis for tumors in these patients with both myeloid and lymphoid malignancies. [ABSTRACT FROM AUTHOR]

In this paper, we present a digital library system for managing heterogeneous music collections. The heterogeneity refers to various document types and formats as well as to different modalities, e. g., CD-audio recordings, scanned sheet music, and lyrics. The system offers a full-fledged, widely automated document processing chain: digitization, indexing, annotation, access, and presentation. Our system is implemented as a generic and modular music repository based on a service-oriented software architecture. As a particular strength of our approach, the various documents representing aspects of a piece of music are jointly considered in all stages of the document processing chain. Our user interfaces allow for a multimodal and synchronized presentation of documents (WYSIWYH: what you see is what you hear), a score- or lyrics-based navigation in audio, as well as a cross- and multimodal retrieval. Hence, our music repository may be called a truly cross-modal library system. In our paper, we describe the system components, outline the techniques of the document processing chain, and illustrate the implemented functionalities for user interaction. We describe how the system is put into practice at the Bavarian State Library (BSB) Munich as a part of the German PROBADO Digital Library Initiative (PDLI). [ABSTRACT FROM AUTHOR]

Reports of a possible relationship between Aleutian mink disease parvovirus (AMDV) and human infection are rare. However, 2 mink farmers with vascular disease and microangiopathy similar to that in mink with Aleutian disease were found to have AMDV-specific antibodies and AMDV DNA. These findings raise the suspicion that AMDV may play a role in human disease. [ABSTRACT FROM AUTHOR]