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Background: Cognitive deficits are a key source of disability in individuals with major depressive disorder (MDD) and worsen with disease progression. Despite their clinical relevance, the underlying mechanisms of cognitive deficits remain poorly elucidated, hampering effective treatment strategies. Emerging evidence suggests that alterations in white matter microstructure might contribute to cognitive dysfunction in MDD. We aimed to investigate the complex association between changes in white matter integrity, cognitive decline, and disease course in MDD in a comprehensive longitudinal dataset., Methods: In the naturalistic, observational, prospective, case-control Marburg-Münster Affective Disorders Cohort Study, individuals aged 18-65 years and of Caucasian ancestry were recruited from local psychiatric hospitals in Münster and Marburg, Germany, and newspaper advertisements. Individuals diagnosed with MDD and individuals without any history of psychiatric disorder (ie, healthy controls) were included in this subsample analysis. Participants had diffusion-weighted imaging, a battery of neuropsychological tests, and detailed clinical data collected at baseline and at 2 years of follow-up. We used linear mixed-effect models to compare changes in cognitive performance and white matter integrity between participants with MDD and healthy controls. Diffusion-weighted imaging analyses were conducted using tract-based spatial statistics. To correct for multiple comparisons, threshold free cluster enhancement (TFCE) was used to correct α-values at the family-wise error rate (FWE; p tfce-FWE ). Effect sizes were estimated by conditional, partial R 2 values (sr 2 ) following the Nakagawa and Schielzeth method to quantify explained variance. The association between changes in cognitive performance and changes in white matter integrity was analysed. Finally, we examined whether the depressive disease course between assessments predicted cognitive performance at follow-up and whether white matter integrity mediated this association. People with lived experience were not involved in the research and writing process., Findings: 881 participants were selected for our study, of whom 418 (47%) had MDD (mean age 36·8 years [SD 13·4], 274 [66%] were female, and 144 [34%] were male) and 463 (53%) were healthy controls (mean age 35·6 years [13·5], 295 [64%] were female, and 168 [36%] were male). Baseline assessments were done between Sept 11, 2014, and June 3, 2019, and after a mean follow-up of 2·20 years (SD 0·19), follow-up assessments were done between Oct 6, 2016, and May 31, 2021. Participants with MDD had lower cognitive performance than did healthy controls (p<0·0001, sr 2 =0·056), regardless of timepoint. Analyses of diffusion-weighted imaging indicated a significant diagnosis × time interaction with a steeper decline in white matter integrity of the superior longitudinal fasciculus over time in participants with MDD than in healthy controls (p tfce-FWE =0·026, sr 2 =0·002). Furthermore, cognitive decline was robustly associated with the decline in white matter integrity over time across both groups (p tfce-FWE <0·0001, sr 2 =0·004). In participants with MDD, changes in white matter integrity (p=0·0040, β=0·071) and adverse depressive disease course (p=0·0022, β=-0·073) independently predicted lower cognitive performance at follow-up., Interpretation: Alterations of white matter integrity occurred over time to a greater extent in participants with MDD than in healthy controls, and decline in white matter integrity was associated with a decline in cognitive performance across groups. Our findings emphasise the crucial role of white matter microstructure and disease progression in depression-related cognitive dysfunction, making both priority targets for future treatment development., Funding: German Research Foundation (DFG)., Competing Interests: Declaration of interests TK has received unrestricted educational grants from Servier, Janssen, Recordati, Aristo, Otsuka, and neuraxpharm. JR has received speaking honoraria from Janssen, Hexal, and Novartis. MPvdH has worked as a consultant for Roche on an unrelated project and is an editor for Human Brain Mapping. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Brain extraction in magnetic resonance imaging (MRI) data is an important segmentation step in many neuroimaging preprocessing pipelines. Image segmentation is one of the research fields in which deep learning had the biggest impact in recent years. Consequently, traditional brain extraction methods are now being replaced by deep learning-based methods., Method: Here, we used a unique dataset compilation comprising 7837 T1-weighted (T1w) MR images from 191 different OpenNeuro datasets in combination with advanced deep learning methods to build a fast, high-precision brain extraction tool called deepbet., Results: deepbet sets a novel state-of-the-art performance during cross-dataset validation with a median Dice score (DSC) of 99.0 on unseen datasets, outperforming the current best performing deep learning (DSC=97.9) and classic (DSC=96.5) methods. While current methods are more sensitive to outliers, deepbet achieves a Dice score of >97.4 across all 7837 images from 191 different datasets. This robustness was additionally tested in 5 external datasets, which included challenging clinical MR images. During visual exploration of each method's output which resulted in the lowest Dice score, major errors could be found for all of the tested tools except deepbet. Finally, deepbet uses a compute efficient variant of the UNet architecture, which accelerates brain extraction by a factor of ≈10 compared to current methods, enabling the processing of one image in ≈2 s on low level hardware., Conclusions: In conclusion, deepbet demonstrates superior performance and reliability in brain extraction across a wide range of T1w MR images of adults, outperforming existing top tools. Its high minimal Dice score and minimal objective errors, even in challenging conditions, validate deepbet as a highly dependable tool for accurate brain extraction. deepbet can be conveniently installed via "pip install deepbet" and is publicly accessible at https://github.com/wwu-mmll/deepbet., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background and Objective: Flow cytometry is a widely used technique for identifying cell populations in patient-derived fluids, such as peripheral blood (PB) or cerebrospinal fluid (CSF). Despite its ubiquity in research and clinical practice, the process of gating, i.e., manually identifying cell types, is labor-intensive and error-prone. The objective of this study is to address this challenge by introducing GateNet, a neural network architecture designed for fully end-to-end automated gating without the need for correcting batch effects., Methods: For this study a unique dataset is used which comprises over 8,000,000 events from N = 127 PB and CSF samples which were manually labeled independently by four experts. Applying cross-validation, the classification performance of GateNet is compared to the human experts performance. Additionally, GateNet is applied to a publicly available dataset to evaluate generalization. The classification performance is measured using the F1 score., Results: GateNet achieves F1 scores ranging from 0.910 to 0.997 demonstrating human-level performance on samples unseen during training. In the publicly available dataset, GateNet confirms its generalization capabilities with an F1 score of 0.936. Importantly, we also show that GateNet only requires ≈10 samples to reach human-level performance. Finally, gating with GateNet only takes 15 microseconds per event utilizing graphics processing units (GPU)., Conclusions: GateNet enables fully end-to-end automated gating in flow cytometry, overcoming the labor-intensive and error-prone nature of manual adjustments. The neural network achieves human-level performance on unseen samples and generalizes well to diverse datasets. Notably, its data efficiency, requiring only ∼10 samples to reach human-level performance, positions GateNet as a widely applicable tool across various domains of flow cytometry., Competing Interests: Declaration of competing interest We, the undersigned, confirm that the manuscript represents our own work, is original and has not been copyrighted, published, submitted, or accepted for publication elsewhere. We further confirm that we all have fully read the manuscript and give consent to be co-authors of the manuscript., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

A recently developed dynamic mean-field theory for disordered spins (spinDMFT) is shown to capture the spin dynamics of nuclear spins very well. The key quantities are the spin autocorrelations. In order to compute the free induction decay (FID), pair correlations are needed in addition. They can be computed on spin clusters of moderate size which are coupled to the dynamic mean fields determined in a first step by spinDMFT. We dub this versatile approach non-local spinDMFT (nl-spinDMFT). It is a particular asset of nl-spinDMFT that one knows from where the contributions to the FID stem. We illustrate the strengths of nl-spinDMFT in comparison to experimental data for CaF 2 . Furthermore, spinDMFT provides the dynamic mean fields explaining the FID of the nuclear spins of 13 C in adamantane up to some static noise. The spin Hahn echo in adamantane is free from effects of static noise and agrees excellently with the spinDMFT results without further fitting., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Thomas Hahn reports that financial support was provided by the German Academic Exchange Service. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Neuroinflammation affects brain tissue integrity in multiple sclerosis (MS) and may have a role in major depressive disorder (MDD). Whether advanced magnetic resonance imaging characteristics of the gray-to-white matter border serve as proxy of neuroinflammatory activity in MDD and MS remain unknown., Methods: We included 684 participants (132 MDD patients with recurrent depressive episodes (RDE), 70 MDD patients with a single depressive episode (SDE), 222 MS patients without depressive symptoms (nMS), 58 MS patients with depressive symptoms (dMS), and 202 healthy controls (HC)). 3 T-T1w MRI-derived gray-to-white matter contrast (GWc) was used to reconstruct and characterize connectivity alterations of GWc-covariance networks by means of modularity, clustering coefficient, and degree. A cross-validated support vector machine was used to test the ability of GWc to stratify groups according to their depression symptoms, measured with BDI, at the single-subject level in MS and MDD independently., Findings: MS and MDD patients showed increased modularity (ANOVA partial-η 2  = 0.3) and clustering (partial-η 2  = 0.1) compared to HC. In the subgroups, a linear trend analysis attested a gradient of modularity increases in the form: HC, dMS, nMS, SDE, and RDE (ANOVA partial-η 2  = 0.28, p < 0.001) while this trend was less evident for clustering coefficient. Reduced morphological integrity (GWc) was seen in patients with increased depressive symptoms (partial-η 2  = 0.42, P < 0.001) and was associated with depression scores across patient groups (r = -0.2, P < 0.001). Depressive symptoms in MS were robustly classified (88 %)., Conclusions: Similar structural network alterations in MDD and MS exist, suggesting possible common inflammatory events like demyelination, neuroinflammation that are caught by GWc analyses. These alterations may vary depending on the severity of symptoms and in the case of MS may elucidate the occurrence of comorbid depression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The psychopathological syndrome of formal thought disorder (FTD) is not only present in schizophrenia (SZ), but also highly prevalent in major depressive disorder and bipolar disorder. It remains unknown how alterations in the structural white matter connectome of the brain correlate with psychopathological FTD dimensions across affective and psychotic disorders., Methods: Using FTD items of the Scale for the Assessment of Positive Symptoms and Scale for the Assessment of Negative Symptoms, we performed exploratory and confirmatory factor analyses in 864 patients with major depressive disorder (n= 689), bipolar disorder (n = 108), or SZ (n = 67) to identify psychopathological FTD dimensions. We used T1- and diffusion-weighted magnetic resonance imaging to reconstruct the structural connectome of the brain. To investigate the association of FTD subdimensions and global structural connectome measures, we employed linear regression models. We used network-based statistic to identify subnetworks of white matter fiber tracts associated with FTD symptomatology., Results: Three psychopathological FTD dimensions were delineated, i.e., disorganization, emptiness, and incoherence. Disorganization and incoherence were associated with global dysconnectivity. Network-based statistics identified subnetworks associated with the FTD dimensions disorganization and emptiness but not with the FTD dimension incoherence. Post hoc analyses on subnetworks did not reveal diagnosis × FTD dimension interaction effects. Results remained stable after correcting for medication and disease severity. Confirmatory analyses showed a substantial overlap of nodes from both subnetworks with cortical brain regions previously associated with FTD in SZ., Conclusions: We demonstrated white matter subnetwork dysconnectivity in major depressive disorder, bipolar disorder, and SZ associated with FTD dimensions that predominantly comprise brain regions implicated in speech. Results open an avenue for transdiagnostic, psychopathology-informed, dimensional studies in pathogenetic research., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure., Methods: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individual's regional difference and global difference, were used to test for regional differences that diverge from the global difference., Results: For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness., Conclusions: We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanisms involved in altered neurodevelopment., (Copyright © 2023. Published by Elsevier Inc.)

Background: Negative stressful life events and deprivation of social support play critical roles in the development and maintenance of major depressive disorder (MDD). The present study aimed to investigate in a large sample of patients with MDD and healthy control participants (HCs) whether these effects are also reflected in white matter (WM) integrity., Methods: In this diffusion tensor imaging study, 793 patients with MDD and 793 age- and sex-matched HCs were drawn from the Marburg-Münster Affective Disorders Cohort Study (MACS) and completed the Life Events Questionnaire (LEQ) and Social Support Questionnaire (SSQ). Generalized linear models were performed to test voxelwise associations between fractional anisotropy (FA) and diagnosis (analysis 1), LEQ (analysis 2), and SSQ (analysis 3). We examined whether SSQ interacts with LEQ on FA or is independently associated with improved WM integrity (analysis 4)., Results: Patients with MDD showed lower FA in several frontotemporal association fibers compared with HCs (p TFCE-FWE  = .028). Across both groups, LEQ correlated negatively with FA in widely distributed WM tracts (p TFCE-FWE  = .023), while SSQ correlated positively with FA in the corpus callosum (p TFCE-FWE  = .043). Modeling the combined association of both variables on FA revealed significant-and antagonistic-main effects of LEQ (p TFCE-FWE  = .031) and SSQ (p TFCE-FWE  = .037), but no interaction of SSQ × LEQ., Conclusions: Our results indicate that negative stressful life events and social support are both related to WM integrity in opposing directions. The associations did not differ between patients with MDD and HCs, suggesting more general, rather than depression-specific, mechanisms. Furthermore, social support appears to contribute to improved WM integrity independent of stressful life events., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Hepatitis-C virus (HCV) chronically infects 58 million individuals worldwide with variable disease outcome. While a subfraction of individuals exposed to the virus clear the infection, the majority develop chronic infection if untreated. Another subfraction of chronically ill proceeds to severe liver disease. The underlying causes of this interindividual variability include genetic polymorphisms in interferon genes. Here, we review available data on the influence of genetic or pharmacological perturbation of HCV host dependency factors on the clinically observed interindividual differences in disease outcome. We focus on host factors mediating virus entry into human liver cells. We assess available data on genetic variants of the major entry factors scavenger receptor class-B type I, CD81, claudin-1, and occludin as well as pharmacological perturbation of these entry factors. We review cell culture experimental and clinical cohort study data and conclude that entry factor perturbation may contribute to disease outcome of hepatitis C., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships that may be considered as potential competing interests: Gisa Gerold reports financial support was provided by German Research Foundation., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Altered brain structural connectivity has been implicated in the pathophysiology of psychiatric disorders including schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD). However, it is unknown which part of these connectivity abnormalities are disorder specific and which are shared across the spectrum of psychotic and affective disorders. We investigated common and distinct brain connectivity alterations in a large sample (N = 1743) of patients with SZ, BD, or MDD and healthy control (HC) subjects., Methods: This study examined diffusion-weighted imaging-based structural connectome topology in 720 patients with MDD, 112 patients with BD, 69 patients with SZ, and 842 HC subjects (mean age of all subjects: 35.7 years). Graph theory-based network analysis was used to investigate connectome organization. Machine learning algorithms were trained to classify groups based on their structural connectivity matrices., Results: Groups differed significantly in the network metrics global efficiency, clustering, present edges, and global connectivity strength with a converging pattern of alterations between diagnoses (e.g., efficiency: HC > MDD > BD > SZ, false discovery rate-corrected p = .028). Subnetwork analysis revealed a common core of edges that were affected across all 3 disorders, but also revealed differences between disorders. Machine learning algorithms could not discriminate between disorders but could discriminate each diagnosis from HC. Furthermore, dysconnectivity patterns were found most pronounced in patients with an early disease onset irrespective of diagnosis., Conclusions: We found shared and specific signatures of structural white matter dysconnectivity in SZ, BD, and MDD, leading to commonly reduced network efficiency. These results showed a compromised brain communication across a spectrum of major psychiatric disorders., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Morphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre/perinatal periods may be reflected in individual variations in cortical surface area later in life., Methods: Interregional profiles of group differences in surface area between cases and controls were generated using T1-weighted magnetic resonance imaging from 27,359 individuals including those with attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and high general psychopathology (through the Child Behavior Checklist). Similarity of interregional profiles of group differences in surface area and prenatal cell-specific gene expression was assessed., Results: Across the 11 cortical regions, group differences in cortical area for attention-deficit/hyperactivity disorder, schizophrenia, and Child Behavior Checklist were dominant in multimodal association cortices. The same interregional profiles were also associated with interregional profiles of (prenatal) gene expression specific to proliferative cells, namely radial glia and intermediate progenitor cells (greater expression, larger difference), as well as differentiated cells, namely excitatory neurons and endothelial and mural cells (greater expression, smaller difference). Finally, these cell types were implicated in known pre/perinatal risk factors for psychosis. Genes coexpressed with radial glia were enriched with genes implicated in congenital abnormalities, birth weight, hypoxia, and starvation. Genes coexpressed with endothelial and mural genes were enriched with genes associated with maternal hypertension and preterm birth., Conclusions: Our findings support a neurodevelopmental model of vulnerability to mental illness whereby prenatal risk factors acting through cell-specific processes lead to deviations from typical brain development during pregnancy., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Bipolar disorder (BD) is associated with cortical and subcortical structural brain abnormalities. It is unclear whether such alterations progressively change over time, and how this is related to the number of mood episodes. To address this question, we analyzed a large and diverse international sample with longitudinal magnetic resonance imaging (MRI) and clinical data to examine structural brain changes over time in BD., Methods: Longitudinal structural MRI and clinical data from the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) BD Working Group, including 307 patients with BD and 925 healthy control subjects, were collected from 14 sites worldwide. Male and female participants, aged 40 ± 17 years, underwent MRI at 2 time points. Cortical thickness, surface area, and subcortical volumes were estimated using FreeSurfer. Annualized change rates for each imaging phenotype were compared between patients with BD and healthy control subjects. Within patients, we related brain change rates to the number of mood episodes between time points and tested for effects of demographic and clinical variables., Results: Compared with healthy control subjects, patients with BD showed faster enlargement of ventricular volumes and slower thinning of the fusiform and parahippocampal cortex (0.18

Introduction: Reduced testosterone levels due to androgen deprivation therapy (ADT) in prostate cancer patients cause common side effects, such as reduced muscle strength and bone density, increased fat mass, sexual dysfunction and fatigue. Short-term exercise during ADT has proven to be safe and effective in exhibiting a positive impact on body composition, sexual dysfunction and fatigue. However, there are only three randomized controlled trials that investigate one-year supervised impact exercise interventions, none of which examined follow-up effects after the intervention. Therefore, this study will conduct a one-year impact exercise intervention and assess follow-up effects up to one year later., Material and Methods: The aim of the randomized, controlled Burgdorf study is to assess the effects of a supervised 12-month intensive multimodal exercise intervention in comparison to a moderate aerobic exercise intervention, on muscle strength in prostate cancer patients receiving ADT. Additionally, quality of life, fatigue, body composition, erectile dysfunction, bone pain, physical activity level, endurance capacity, body-mass-index, waist and hip circumference and prostate-specific antigen- and testosterone levels will be assessed up to one year later., Discussion: The Burgdorf study is the first study to conduct two different one-year supervised exercise interventions, and follow-up with patients for up to one year after the intervention. Results could provide important insights into the long-term effects of interventions on those parameters negatively affected by ADT, which could specify or newly establish care structures., Trial Registration: German Clinical Trials Register, DRKS00009975. Registered 2016-02-09, https://www.drks.de/drks&#95;web/navigate.do?navigationId=trial.HTML&TRIAL&#95;ID=DRKS00009975., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Potential indications for surgery frequently arise in patients awaiting liver transplantation. There is a risk of hepatic decompensation and death triggered by surgical trauma, but this has not been studied in detail in this unique population. We aimed to quantify the impact of surgical interventions in patients awaiting liver transplantation on hepatic function and identify risk factors for decompensation., Methods: All surgeries between 2000 and 2018 in patients awaiting liver transplantation in a highvolume German liver transplant center were analyzed retrospectively. Change in liver function measured as indicated by MELD score was assessed and complication rates recorded. The primary endpoint was a composite of an increase in MELD score by > 5 points or death. A logistic regression model was used for multivariate analysis to identify risk factors., Results: In total, 177 surgical procedures in 148 patients were analyzed. The primary endpoint was reached in 42 cases (23.7%). The overall in-hospital complication rate (including death) was 44.1%. Multivariate analysis identified elevated leukocyte count, perioperative blood transfusion, preoperative presence of ascites, and preoperative circulatory support as independent risk factors for a decline in liver function or death., Conclusion: Surgery in patients awaiting liver transplantation carries a relevant risk of hepatic decompensation and death that needs to be considered when deciding whether to perform elective surgery prior to or defer until after liver transplantation., (© 2021 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

A fundamental understanding of the protein retention mechanism in preparative ion exchange (IEX) chromatography columns is essential for a model-based process development approach. For the past three decades, the mechanistic description of protein retention has been based predominantly on the steric mass action (SMA) model. In recent years, however, retention profiles of proteins have been reported more frequently for preparative processes that are not consistent with the mechanistic understanding relying on the SMA model. In this work, complex elution behavior of proteins in preparative IEX processes is analyzed using a colloidal particle adsorption (CPA) model. The CPA model is found to be capable of reproducing elution profiles that cannot be described by the traditional SMA model. According to the CPA model, the reported complex behavior can be ascribed to a strong compression and concentration of the elution front in the lower unsaturated part of the chromatography column. As the unsaturated part of the column decreases with increasing protein load density, exceeding a critical load density can lead to the formation of a shoulder in the peak front. The general applicability of the model in describing preparative IEX processes is demonstrated using several industrial case studies including multiple monoclonal antibodies on different IEX adsorber systems. In this context, the work covers both salt controlled and pH-controlled protein elution., Competing Interests: Declaration of Competing Interest The authors affiliated to GoSilico declare that the software ChromX used in this study is a commercial product of GoSilico. The presented research does not depend on the usage of ChromX, the model can be implemented in any kind of modeling software., (Copyright © 2021. Published by Elsevier B.V.)

For mechanistic modeling of ion exchange (IEX) processes, a profound understanding of the adsorption mechanism is important. While the description of protein adsorption in IEX processes has been dominated by stoichiometric models like the steric mass action (SMA) model, discrepancies between experimental data and model results suggest that the conceptually simple stoichiometric description of protein adsorption provides not always an accurate representation of nonlinear adsorption behavior. In this work an alternative colloidal particle adsorption (CPA) model is introduced. Based on the colloidal nature of proteins, the CPA model provides a non-stoichiometric description of electrostatic interactions within IEX columns. Steric hindrance at the adsorber surface is considered by hard-body interactions between proteins using the scaled-particle theory. The model's capability of describing nonlinear protein adsorption is demonstrated by simulating adsorption isotherms of a monoclonal antibody (mAb) over a wide range of ionic strength and pH. A comparison of the CPA model with the SMA model shows comparable model results in the linear adsorption range, but significant differences in the nonlinear adsorption range due to the different mechanistic interpretation of steric hindrance in both models. The results suggest that nonlinear adsorption effects can be overestimated by the stoichiometric formalism of the SMA model and are generally better reproduced by the CPA model., Competing Interests: Declaration of Competing Interest The authors affiliated to GoSilico declare that the software ChromX used in this study is a commercial product of GoSilico. The presented research does not depend on the usage of ChromX, the model can be implemented in any kind of modeling software., (Copyright © 2021. Published by Elsevier B.V.)

Apolipoprotein E (APOE) genotype is the strongest single gene predictor of Alzheimer's disease (AD) and has been frequently associated with AD-related brain structural alterations before the onset of dementia. While previous research has primarily focused on hippocampal morphometry in relation to APOE, sporadic recent findings have questioned the specificity of the hippocampus and instead suggested more global effects on the brain. With the present study we aimed to investigate associations between homozygous APOE ε4 status and cortical gray matter structure as well as white matter microstructure. In our study, we contrasted n = 31 homozygous APOE ε4 carriers (age=34.47 years, including a subsample of n = 12 subjects with depression) with a demographically matched sample without an ε4 allele (resulting total sample: N = 62). Morphometry analyses included a) Freesurfer based cortical segmentations of thickness and surface area measures and b) tract based spatial statistics of DTI measures. We found pronounced and widespread reductions in cortical surface area of ε4 homozygotes in 57 out of 68 cortical brain regions. In contrast, no differences in cortical thickness were observed. Furthermore, APOE ε4 homozygous carriers showed significantly lower fractional anisotropy in the corpus callosum, the right internal and external capsule, the left corona radiata and the right fornix. The present findings support a global rather than regionally specific effect of homozygous APOE ε4 allele status on cortical surface area and white matter microstructure. Future studies should aim to delineate the clinical implications of these findings., Competing Interests: Declaration of Competing Interests Biomedical financial interests or potential conflicts of interest: Tilo Kircher received unrestricted educational grants from Servier, Janssen, Recordati, Aristo, Otsuka, neuraxpharm. Markus Wöhr is scientific advisor of Avisoft Bioacoustics. No further potential conflicts of interest are declared by the authors., (Copyright © 2021. Published by Elsevier B.V.)

Social determinants of health, including poverty, contribute significantly to health outcomes in the United States; however, their impact on pediatric hematopoietic cell transplantation (HCT) outcomes is poorly understood. We aimed to identify the association between neighborhood poverty and HCT outcomes for pediatric allogeneic HCT recipients in the Center for International Blood and Marrow Transplant Research database. We assembled 2 pediatric cohorts undergoing first allogeneic HCT from 2006 to 2015 at age ≤18 years, including 2053 children with malignant disease and 1696 children with nonmalignant disease. Neighborhood poverty exposure was defined a priori per the US Census definition as living in a high-poverty ZIP code (≥20% of persons below 100% federal poverty level) and used as the primary predictor in all analyses. Our primary outcome was overall survival (OS), defined as the time from HCT until death resulting from any cause. Secondary outcomes included relapse and transplantation-related mortality (TRM) in malignant disease, acute and chronic graft-versus-host disease, and infection in the first 100 days post-HCT. Among children undergoing transplantation for nonmalignant disease, neighborhood poverty was not associated with any HCT outcome. Among children undergoing transplantation for malignant disease, neighborhood poverty conferred an increased risk of TRM but was not associated with inferior OS or any other transplantation outcome. Among children with malignant disease, a key secondary finding was that children with Medicaid insurance experienced inferior OS and increased TRM compared with those with private insurance. These data suggest opportunities for future investigation of the effects of household-level poverty exposure on HCT outcomes in pediatric malignant disease to inform care delivery interventions., (© 2021 by The American Society of Hematology.)

While the hippocampus remains a region of high interest for neuropsychiatric research, the precise contributors to hippocampal morphometry are still not well understood. We and others previously reported a hippocampus specific effect of a tescalcin gene (TESC) regulating single nucleotide polymorphism (rs7294919) on gray matter volume. Here we aimed to replicate and extend these findings. Two complementary morphometric approaches (voxel based morphometry (VBM) and automated volumetric segmentation) were applied in a well-powered cohort from the Marburg-Münster Affective Disorder Cohort Study (MACS) including N=1137 participants (n=636 healthy controls, n=501 depressed patients). rs7294919 homozygous T-allele genotype was significantly associated with lower hippocampal gray matter density as well as with reduced hippocampal volume. Exploratory whole brain VBM analyses revealed no further associations with gray matter volume outside the hippocampus. No interaction effects of rs7294919 with depression nor with childhood trauma on hippocampal morphometry could be detected. Hippocampal subfield analyses revealed similar effects of rs7294919 in all hippocampal subfields. In sum, our results replicate a hippocampus specific effect of rs7294919 on brain structure. Due to the robust evidence for a pronounced association between the reported polymorphism and hippocampal morphometry, future research should consider investigating the potential clinical and functional relevance of the reported association., Competing Interests: Conflict of interest Tilo Kircher received unrestricted educational grants from Servier, Janssen, Recordati, Aristo, Otsuka, neuraxpharm. Markus Wöhr is scientific advisor of Avisoft Bioacoustics. No further conflicts of interest are declared., (Copyright © 2020 Elsevier B.V. and ECNP. All rights reserved.)

Mechanistic modeling of protein adsorption has gained increasing importance in the development of ion-exchange (IEX) chromatography processes. The most common adsorption models use a stoichiometric representation of the adsorption process based on the law of mass action. Despite the importance of these models in model-based development, the stoichiometric representation of the adsorption process is not accurate for the description of long-range electrostatic interactions in IEX chromatography, limiting the application and mechanistic extension of these models. In this work an adsorption model is introduced describing the non-stoichiometric electrostatic interaction in IEX chromatography based on the linear Poisson-Boltzmann equation and a simplified colloidal representation of the protein. In contrast to most recent non-stoichiometric models, the introduced model accounts for charge regulation during the adsorption process. Its capability of describing the adsorption equilibrium is demonstrated by simulating partitioning coefficients of multiple proteins on different adsorber systems as a function of ionic strength and pH. Despite model simplifications the physical meaning and predictive value of the model could be preserved. By transferring model parameters of a monoclonal antibody (mAb) from one adsorber system to another, it could be demonstrated that protein parameters are theoretically not only valid on a specific adsorber system but freely transferable to other adsorbers. The predictive value of the mechanistic model on the new adsorber system was highlighted by predicting the elution behavior of charge variants of the mAb., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background & Aims: Hepatitis delta virus (HDV) infection is the most severe form of viral hepatitis. Although HDV-associated liver disease is considered immune-mediated, adaptive immune responses against HDV are weak. Thus, the role of several other cell-mediated mechanisms such as those driven by mucosa-associated invariant T (MAIT) cells, a group of innate-like T cells highly enriched in the human liver, has not been extensively studied in clinical HDV infection., Methods: MAIT cells from a sizeable cohort of patients with chronic HDV were analyzed ex vivo and in vitro after stimulation. Results were compared with MAIT cells from hepatitis B virus (HBV) monoinfected patients and healthy controls., Results: Circulating MAIT cells were dramatically decreased in the peripheral blood of HDV-infected patients. Signs of decline were also observed in the liver. In contrast, only a modest decrease of circulating MAIT cells was noted in HBV monoinfection. Unsupervised high-dimensional analysis of residual circulating MAIT cells in chronic HDV infection revealed the appearance of a compound phenotype of CD38 hi PD-1 hi CD28 lo CD127 lo PLZF lo Eomes lo Helios lo cells indicative of activation. Corroborating these results, MAIT cells exhibited a functionally impaired responsiveness. In parallel to MAIT cell loss, HDV-infected patients exhibited signs of monocyte activation and increased levels of proinflammatory cytokines IL-12 and IL-18. In vitro, IL-12 and IL-18 induced an activated MAIT cell phenotype similar to the one observed ex vivo in HDV-infected patients. These cytokines also promoted MAIT cell death, suggesting that they may contribute to MAIT cell activation and subsequent loss during HDV infection., Conclusions: These results suggest that chronic HDV infection engages the MAIT cell compartment causing activation, functional impairment, and subsequent progressive loss of MAIT cells as the HDV-associated liver disease progresses., Lay Summary: Hepatitis delta virus (HDV) infection is the most severe form of viral hepatitis. We found that in patients with HDV, a subset of innate-like T cells called mucosa-associated invariant T cells (or MAIT cells), which are normally abundant in peripheral blood and the liver, are activated, functionally impaired and severely depleted., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: The lipid-binding protein, SEC14L2, is crucial for the efficient viral replication of clinical hepatitis C virus (HCV) isolates in cell culture. Given the role of SEC14L2 in HCV replication, we aimed to study a large number of HCV positive sera carrying genotypes 1-4, to identify viral factors associated with efficient replication in culture. Additionally, we investigated whether 13 single nucleotide polymorphisms (SNPs) of SEC14L2 have an impact on RNA replication of naturally occurring HCV isolates., Methods: We generated Huh-7.5 cell lines overexpressing SEC14L2 or 13 coding SNPs and tested 73 different HCV positive sera for in vitro replication. Furthermore, we genotyped a cohort of 262 patients with chronic HCV for the common SNP (rs757660) and investigated its effect on the clinical phenotype., Results: HCV isolates from genotype 1, 2, 3 and 4 replicate in Huh-7.5 cells overexpressing SEC14L2. Interestingly, only subgenomic replicons from genotypes 1 and 3 showed enhanced replication whereas genotypes 2 and 4 remained unaffected. Furthermore, replication was independent of viral load. Importantly, all tested SNPs supported HCV RNA replication in vitro, while 1 SNP was associated with decreased SEC1L2 expression and viral RNA. All SNPs exhibited comparable cellular cholesterol and vitamin E abundance in naïve Huh-7.5 cells., Conclusions: This large screen of natural HCV isolates of 4 genotypes underscores the relevance of SEC14L2 as an in vitro HCV host factor. Additionally, SEC14L2 variants appear to recapitulate the wild-type enhancement of HCV replication. Variant rs191341134 showed a decreased effect due to lowered stability, whereas variant rs757660, a high prevalence mutant, showed a similar phenotype to the wild-type., Lay Summary: Until the year 2015, consistent replication of patient-derived isolates of hepatitis C virus (HCV) in an in vitro model remained a limitation in HCV research. In 2015 a group of authors identified a protein named SEC14L2 that enabled the replication of HCV isolates in cell culture. We performed a large screen encompassing 73 isolates of 4 different HCV genotypes. Additionally, we replaced the natural SEC14L2 with 13 different mutants to test if the protein variation significantly altered its HCV replication enhancing functions. We showed that different genotypes of HCV react differently to the presence of this protein and the variants of the protein mimic the behavior of the wild-type., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Childhood maltreatment is a leading environmental risk factor for an unfavourable course of disease in major depressive disorder. Both maltreatment and major depressive disorder are associated with similar brain structural alterations suggesting that brain structural changes could mediate the adverse influence of maltreatment on clinical outcome in major depressive disorder. However, longitudinal studies have not been able to confirm this hypothesis. We therefore aimed to clarify the relationship between childhood trauma, brain structural alterations, and depression relapse in a longitudinal design., Methods: We recruited participants at the Department of Psychiatry, University of Münster, Germany, from the Münster Neuroimage Cohort for whom 2-year longitudinal clinical data were available. Baseline data acquisition comprised clinical assessments, structural MRI, and retrospective assessment of the extent of childhood maltreatment experiences using the Childhood Trauma Questionnaire. Clinical follow-up assessments were conducted in all participants 2 years after initial recruitment., Findings: Initial recruitment was March 21, 2010-Jan 29, 2016; follow-up reassessment Sept 7, 2012-March 9, 2018. 110 patients with major depressive disorder participated in this study. 35 patients were relapse-free, whereas 75 patients had experienced depression relapse within the 2-year follow-up period. Childhood maltreatment was significantly associated with depression relapse during follow-up (odds ratio [OR] 1·035, 95% CI 1·001-1·070; p=0·045). Both previous childhood maltreatment experiences and future depression relapse were associated with reduced cortical surface area (OR 0·996, 95% CI 0·994-0·999; p=0·001), primarily in the right insula at baseline (r=-0·219, p=0·023). Insular surface area was shown to mediate the association between maltreatment and future depression relapse (indirect effect: coefficient 0·0128, SE 0·0081, 95% CI 0·0024-0·0333)., Interpretation: Early life stress has a detrimental effect on brain structure, which increases the risk of unfavourable disease courses in major depression. Clinical and translational research should explore the role of childhood maltreatment as causing a potential clinically and biologically distinct subtype of major depressive disorder., Funding: The German Research Foundation, the Interdisciplinary Centre for Clinical Research, and the Deanery of the Medical Faculty of the University of Münster., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Hippocampal enlargements are commonly reported after electroconvulsive therapy (ECT). To clarify mechanisms, we examined if ECT-induced hippocampal volume change relates to dose (number of ECT sessions and electrode placement) and acts as a biomarker of clinical outcome., Methods: Longitudinal neuroimaging and clinical data from 10 independent sites participating in the Global ECT-Magnetic Resonance Imaging Research Collaboration (GEMRIC) were obtained for mega-analysis. Hippocampal volumes were extracted from structural magnetic resonance images, acquired before and after patients (n = 281) experiencing a major depressive episode completed an ECT treatment series using right unilateral and bilateral stimulation. Untreated nondepressed control subjects (n = 95) were scanned twice., Results: The linear component of hippocampal volume change was 0.28% (SE 0.08) per ECT session (p < .001). Volume change varied by electrode placement in the left hippocampus (bilateral, 3.3 ± 2.2%, d = 1.5; right unilateral, 1.6 ± 2.1%, d = 0.8; p < .0001) but not the right hippocampus (bilateral, 3.0 ± 1.7%, d = 1.8; right unilateral, 2.7 ± 2.0%, d = 1.4; p = .36). Volume change for electrode placement per ECT session varied similarly by hemisphere. Individuals with greater treatment-related volume increases had poorer outcomes (Montgomery-Åsberg Depression Rating Scale change -1.0 [SE 0.35], per 1% volume increase, p = .005), although the effects were not significant after controlling for ECT number (slope -0.69 [SE 0.38], p = .069)., Conclusions: The number of ECT sessions and electrode placement impacts the extent and laterality of hippocampal enlargement, but volume change is not positively associated with clinical outcome. The results suggest that the high efficacy of ECT is not explained by hippocampal enlargement, which alone might not serve as a viable biomarker for treatment outcome., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Social anxiety is known to impair interpersonal relationships. These impairments are thought to partly arise from difficulties to engage in affiliative interactions with others, such as sharing favors or reciprocating prosocial acts. Here, we examined whether individuals high compared to low in social anxiety differ in giving towards strangers in an economic game paradigm., Methods: One hundred and twenty seven non-clinical participants who had been pre-screened to be either particularly high or low in social anxiety played an incentivized Trust Game to assess trustful and reciprocal giving towards strangers in addition to providing information on real life interpersonal functioning (perceived social support and attachment style)., Results: We found that reciprocal, but not trustful giving, was significantly decreased among highly socially anxious individuals. Both social anxiety and reciprocal giving furthermore showed significant associations with self-reported real life interpersonal functioning., Limitations: Participants played the Trust Game with the strategy method; results need replication with a clinical sample., Conclusions: Individuals high in social anxiety showed reduced reciprocal, but intact trustful giving, pointing to a constraint in responsiveness. The research may contribute to the development of new treatment and prevention programs to reduce the interpersonal impairments in socially anxious individuals., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Although survival outcomes have significantly improved, up to 40% of patients die within 1 year of HLA-matched unrelated-donor blood and marrow transplantation (BMT). To identify non-HLA genetic contributors to mortality after BMT, we performed the first exome-wide association study in the DISCOVeRY-BMT cohorts using the Illumina HumanExome BeadChip. This study includes 2473 patients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome and 2221 10/10 HLA-matched donors treated from 2000 to 2011. Single-variant and gene-level analyses were performed on overall survival (OS), transplantation-related mortality (TRM), and disease-related mortality (DRM). Genotype mismatches between recipients and donors in a rare nonsynonymous variant of testis-expressed gene TEX38 significantly increased risk of TRM, which was more dramatic when either the recipient or donor was female. Using the SKAT-O test to evaluate gene-level effects, variant genotypes of OR51D1 in recipients were significantly associated with OS and TRM. In donors, 4 ( ALPP , EMID1 , SLC44A5 , LRP1 ), 1 ( HHAT ), and 2 genes ( LYZL4 , NT5E ) were significantly associated with OS, TRM, and DRM, respectively. Inspection of NT5E crystal structures showed 4 of the associated variants affected the enzyme structure and likely decreased the catalytic efficiency of the enzyme. Further confirmation of these findings and additional functional studies may provide individualized risk prediction and prognosis, as well as alternative donor selection strategies., (© 2018 by The American Society of Hematology.)

Multiple candidate gene-association studies of non-HLA single-nucleotide polymorphisms (SNPs) and outcomes after blood or marrow transplant (BMT) have been conducted. We identified 70 publications reporting 45 SNPs in 36 genes significantly associated with disease-related mortality, progression-free survival, transplant-related mortality, and/or overall survival after BMT. Replication and validation of these SNP associations were performed using DISCOVeRY-BMT (Determining the Influence of Susceptibility COnveying Variants Related to one-Year mortality after BMT), a well-powered genome-wide association study consisting of 2 cohorts, totaling 2888 BMT recipients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome, and their HLA-matched unrelated donors, reported to the Center for International Blood and Marrow Transplant Research. Gene-based tests were used to assess the aggregate effect of SNPs on outcome. None of the previously reported significant SNPs replicated at P < .05 in DISCOVeRY-BMT. Validation analyses showed association with one previously reported donor SNP at P < .05 and survival; more associations would be anticipated by chance alone. No gene-based tests were significant at P < .05. Functional annotation with publicly available data shows these candidate SNPs most likely do not have biochemical function; only 13% of candidate SNPs correlate with gene expression or are predicted to impact transcription factor binding. Of these, half do not impact the candidate gene of interest; the other half correlate with expression of multiple genes. These findings emphasize the peril of pursing candidate approaches and the importance of adequately powered tests of unbiased genome-wide associations with BMT clinical outcomes given the ultimate goal of improving patient outcomes., (© 2017 by The American Society of Hematology.)

In protein chromatography, process variations, such as aging of column or process errors, can result in deviations of the product and impurity levels. Consequently, the process performance described by purity, yield, or production rate may decrease. Based on visual inspection of the UV signal, it is hard to identify the source of the error and almost unfeasible to determine the quantity of deviation. The problem becomes even more pronounced, if multiple root causes of the deviation are interconnected and lead to an observable deviation. In the presented work, a novel method based on the combination of mechanistic chromatography models and the artificial neural networks is suggested to solve this problem. In a case study using a model protein mixture, the determination of deviations in column capacity and elution gradient length was shown. Maximal errors of 1.5% and 4.90% for the prediction of deviation in column capacity and elution gradient length respectively demonstrated the capability of this method for root cause investigation., (Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background & Aims: There are numerous coding and non-coding variants in the SCARB1 gene that encodes scavenger receptor class B member 1 (SR-BI), a key receptor for both high density lipoproteins and hepatitis C virus (HCV). Many have been linked to clinical phenotypes, yet their impact on the HCV replication cycle is incompletely understood. The aim of this study was to analyze the impact of these variants on the molecular biology and clinical course of HCV., Methods: We analyzed key coding non-synonymous as well as non-coding SCARB1 variants using virological in vitro and human genetics approaches., Results: Non-synonymous variants: S112F and T175A have greatly reduced HCV receptor function. When present on the cell surface, these variants are impaired in their ability to interact with HCV E2. Non-coding variants: The G allele in rs3782287 is associated with decreased viral load. Haplotype analysis confirmed these findings and identified haplotype rs3782287 A/rs5888 C as a risk allele associated with increased viral load. We also detected a trend towards lower hepatic SR-BI expression in individuals with the rs3782287 GG genotype associated with low viral load suggesting a potential underlying mechanism., Conclusion: Coding and non-coding genetic SCARB1 variants modulate the HCV replication cycle and possibly clinical features of hepatitis C. These findings underscore the relevance of SR-BI as an HCV receptor and contribute to our understanding of inter-individual variation in HCV infection., Lay Summary: The cell surface receptor SR-BI (scavenger receptor class B member 1), is essential for hepatitis C virus (HCV) entry into hepatocytes. Variations in the gene coding this receptor influence infectivity and viral load. We analyzed these variations to gain a better understanding of inter-individual differences over the course of HCV infection., (Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Hepatitis delta virus (HDV) is a minimalistic satellite virus of hepatitis B virus (HBV). HBV/HDV co-infection, i.e. "hepatitis D", is the most severe form of viral hepatitis. No effective therapy for HDV infection is available partly due to the fact that HDV is a highly host-dependent virus devoid of any potentially drugable enzyme encoded in its small genome. In this study we present a semi-automated method to evaluate HDV infection and replication under the influence of different drugs. We utilized a Huh-7/hNTCP cell culture based system in a 96-well plate format, an automated microscope and image acquisition as well as analysis with the CellProfiler software to quantify the impact of these drugs on HDV infection. For validation, three groups of potential anti-HDV agents were evaluated: To target ribozyme activity of HDV RNA, we screened ribozyme inhibitors but only observed marked toxicity. Testing innate antiviral mediators showed that interferons alpha-2a and beta-1a had a specific inhibitory effect on HDV infection. Finally, we screened a library of 160 human kinase inhibitors covering all parts of the human kinome. Overall, only inhibitors targeting the tyrosine kinase-like group had significant average anti-HDV activity. Looking at individual substances, kenpaullone, a GSK-3β and Cdk inhibitor, had the highest selective index of 3.44. Thus, we provide a potentially useful tool to screen for substances with anti-HDV activity and novel insights into interactions between HDV replication and the human kinome., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Mechanistic modeling has been repeatedly successfully applied in process development and control of protein chromatography. For each combination of adsorbate and adsorbent, the mechanistic models have to be calibrated. Some of the model parameters, such as system characteristics, can be determined reliably by applying well-established experimental methods, whereas others cannot be measured directly. In common practice of protein chromatography modeling, these parameters are identified by applying time-consuming methods such as frontal analysis combined with gradient experiments, curve-fitting, or combined Yamamoto approach. For new components in the chromatographic system, these traditional calibration approaches require to be conducted repeatedly. In the presented work, a novel method for the calibration of mechanistic models based on artificial neural network (ANN) modeling was applied. An in silico screening of possible model parameter combinations was performed to generate learning material for the ANN model. Once the ANN model was trained to recognize chromatograms and to respond with the corresponding model parameter set, it was used to calibrate the mechanistic model from measured chromatograms. The ANN model's capability of parameter estimation was tested by predicting gradient elution chromatograms. The time-consuming model parameter estimation process itself could be reduced down to milliseconds. The functionality of the method was successfully demonstrated in a study with the calibration of the transport-dispersive model (TDM) and the stoichiometric displacement model (SDM) for a protein mixture., (Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Comprehensive studies on neutropenia and infection-related complications in patients with acute lymphoblastic leukemia (ALL) are lacking., Patients and Methods: We evaluated infection-related complications that were grade ≥3 on National Cancer Institute's Common Terminology Criteria for Adverse Events (version 3.0) and their risk factors in 409 children with newly diagnosed ALL throughout the treatment period., Results: Of the 2420 infection episodes, febrile neutropenia and clinically or microbiologically documented infection were seen in 1107 and 1313 episodes, respectively. Among documented infection episodes, upper respiratory tract was the most common site (n = 389), followed by ear (n = 151), bloodstream (n = 147), and gastrointestinal tract (n = 145) infections. These episodes were more common during intensified therapy phases such as remission induction and reinduction, but respiratory and ear infections, presumably viral in origin, also occurred during continuation phases. The 3-year cumulative incidence of infection-related death was low (1.0±0.9%, n = 4), including 2 from Bacillus cereus bacteremia. There was no fungal infection-related mortality. Age 1-9.9 years at diagnosis was associated with febrile neutropenia (P = 0.002) during induction and febrile neutropenia and documented infection (both P < 0.001) during later continuation. White race was associated with documented infection (P = 0.034) during induction. Compared with low-risk patients, standard- and high-risk patients received more intensive therapy during early continuation and had higher incidences of febrile neutropenia (P < 0.001) and documented infections (P = 0.043). Furthermore, poor neutrophil surge after dexamethasone pulses during continuation, which can reflect the poor bone marrow reserve, was associated with infections (P < 0.001)., Conclusions: The incidence of infection-related death was low. However, young age, white race, intensive chemotherapy, and lack of neutrophil surge after dexamethasone treatment were associated with infection-related complications. Close monitoring for prompt administration of antibiotics and modification of chemotherapy should be considered in these patients., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Fibers are prominent among novel stationary phase supports for preparative chromatography. Several recent studies have highlighted the potential of fiber-based adsorbents for high productivity downstream processing in both batch and continuous mode, but so far the development of these materials and of processes employing these materials has solely been based on experimental data. In this study we assessed whether mechanistic modeling can be performed on fiber-based adsorbents. With a column randomly filled with short cut hydrogel grafted anion exchange fibers, we tested whether tracer, linear gradient elution, and breakthrough data could be reproduced by mechanistic models. Successful modeling was achieved for all of the considered experiments, for both non-retained and retained molecules. For the fibers used in this study the best results were obtained with a transport-dispersive model in combination with a steric mass action isotherm. This approach accurately accounted for the convection and dispersion of non-retained tracers, and the breakthrough and elution behaviors of three different proteins with sizes ranging from 6 to 160kDa were accurately modeled, with simulation results closely resembling the experimental data. The estimated model parameters were plausible both from their physical meaning, and from an analysis of the underlying model assumptions. Parameters were determined within good confidence levels; the average confidence estimate was below 7% for confidence levels of 95%. This shows that fiber-based adsorbents can be modeled mechanistically, which will be valuable for the future design and evaluation of these novel materials and for the development of processes employing such materials., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Previous studies have identified single-nucleotide polymorphisms (SNPs) associated with the risk of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation. The current study determined whether these associations could be replicated in large cohorts of donors and recipients. Each SNP was tested with cohorts of patients having the same donor type (HLA-matched related, unrelated, or both) reported in the original publication, and testing was limited to the same genome (recipient or donor) and genetic model (dominant, recessive, or allelic) reported in the original study. The 21 SNPs reported in this study represent 19 genes, and the analysis encompassed 22 SNP association tests. The hazard ratio (HR) point estimates and risk ratio point estimates corresponding to odds ratios in previous studies consistently fall outside the 95% confidence intervals of HR estimates in the current study. Despite the large size of the cohorts available for the current study, the 95% confidence intervals for most HRs did not exclude 1.0. Three SNPs representing CTLA4, HPSE, and IL1R1 showed evidence of association with the risk of chronic GVHD in unrelated donor-recipient pairs from 1 cohort, but none of these associations was replicated when tested in unrelated donor-recipient pairs from an independent cohort. Two SNPs representing CCR6 and FGFR1OP showed possible associations with the risk of chronic GVHD in related donor-recipient pairs but not in unrelated donor-recipient pairs. These results remain to be tested for replication in other cohorts of related donor-recipient pairs., (© 2016 by The American Society of Hematology.)

Background: Although dysimmunity is considered an important link between multiple sclerosis (MS), family history and cancer risk, their relationship to the use of disease modifying therapies (DMT) is not fully understood., Objective: To assess the observed versus expected number of cancers in MS patients, and family history of cancer, among DMT users and DMT naïve patients., Methods: Cancer, DMT use, and family history of cancer were assessed using the New York State Multiple Sclerosis Consortium (NYSMSC) registry. Self-reported cancers in MS patients were tested for associations with DMT use, family history of cancer and other factors. Expected number of cancer cases was estimated using age- and gender-specific prevalence and incidence rates from the general population., Results: The prevalence of cancer in males and females in the NYSMSC cohort was lower than expected (p<0.001). Patients with cancer were older at MS diagnosis and more likely to be female (p<0.001). MS patients with a personal history of cancer were more likely to report DMT use (p<0.001) and family history of cancer (p<0.001). Multivariable analysis did not support a higher risk of cancer after DMT initiation., Conclusions: We report a lower than expected number of cancer cases in MS patients compared to the general population. MS patients with a personal history of cancer were more likely to report DMT use suggesting that DMTs may abrogate the lower incidence of cancer in MS., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Mechanistic models are successfully used for protein purification process development as shown for ion-exchange column chromatography (IEX). Modeling and simulation of hydrophobic interaction chromatography (HIC) in the column mode has been seldom reported. As a combination of these two techniques is often encountered in biopharmaceutical purification steps, accurate modeling of protein adsorption in HIC is a core issue for applying holistic model-based process development, especially in the light of the Quality by Design (QbD) approach. In this work, a new mechanistic isotherm model for HIC is derived by consideration of an equilibrium between well-ordered water molecules and bulk-like ordered water molecules on the hydrophobic surfaces of protein and ligand. The model's capability of describing column chromatography experiments is demonstrated with glucose oxidase, bovine serum albumin (BSA), and lysozyme on Capto™ Phenyl (high sub) as model system. After model calibration from chromatograms of bind-and-elute experiments, results were validated with batch isotherms and prediction of further gradient elution chromatograms., (Copyright © 2016 Elsevier B.V. All rights reserved.)

In chromatographic protein purification, process variations, aging of columns, or processing errors can lead to deviations of the expected elution behavior of product and contaminants and can result in a decreased pool purity or yield. A different elution behavior of all or several involved species leads to a deviating chromatogram. The causes for deviations are however hard to identify by visual inspection and complicate the correction of a problem in the next cycle or batch. To overcome this issue, a tool for root cause investigation in protein chromatography was developed. The tool combines a spectral deconvolution with inverse mechanistic modelling. Mid-UV spectral data and Partial Least Squares Regression were first applied to deconvolute peaks to obtain the individual elution profiles of co-eluting proteins. The individual elution profiles were subsequently used to identify errors in process parameters by curve fitting to a mechanistic chromatography model. The functionality of the tool for root cause investigation was successfully demonstrated in a model protein study with lysozyme, cytochrome c, and ribonuclease A. Deviating chromatograms were generated by deliberately caused errors in the process parameters flow rate and sodium-ion concentration in loading and elution buffer according to a design of experiments. The actual values of the three process parameters and, thus, the causes of the deviations were estimated with errors of less than 4.4%. Consequently, the established tool for root cause investigation is a valuable approach to rapidly identify process variations, aging of columns, or processing errors. This might help to minimize batch rejections or contribute to an increased productivity., (Copyright © 2016 Elsevier B.V. All rights reserved.)