Real-world experience among patients with relapsed/refractory mantle cell lymphoma after Bruton tyrosine kinase inhibitor failure in Europe: The SCHOLAR-2 retrospective chart review study

Mantle cell lymphoma (MCL) after relapse is associated with poor prognosis. No standard of care exists and available evidence for treatments is limited, particularly in patients who fail Bruton tyrosine kinase inhibitor (BTKi) therapy. This multicentre retrospective chart review study, SCHOLAR-2, addresses this knowledge gap and reports on data collected from 240 patients with relapsed/refractory MCL in Europe who were treated with BTKi-based therapy between July 2012 and July 2018, and had experienced disease progression while on BTKi therapy or discontinued BTKi therapy due to intolerance. The median overall survival (OS) from initiation of first BTKi therapy was 14.6 months (95% confidence interval [CI] 11.6–20.0) in the overall cohort, 5.5 months (95% CI 3.9–8.2) in 91 patients without post-BTKi therapy, and 23.8 months (95% CI 18.9–30.1) in 149 patients who received post-BTKi therapy (excluding chimeric antigen receptor T-cell treatment). In the latter group, patients received a median of one (range, one to seven) line of post-BTKi therapy, with lenalidomide-containing regimens and bendamustine plus rituximab being the most frequently administered; the median OS from initiation of first post-BTKi therapy was 9.7 months (95% CI 6.3–12.7). These results provide a benchmark for survival in patients with R/R MCL receiving salvage therapy after BTKi failure

Multimodal Analgesic Effectiveness on Acute Postoperative Pain Management After Adult Cardiac Surgery

Background Many patients report moderate to severe pain in the acute postoperative period. Enhanced recovery protocols recommend multimodal analgesics, but the optimal combination of these is unknown. Purpose The aim of this study was to synthesize the best available evidence about effectiveness of multimodal analgesics on pain after adult cardiac surgery. Methods A systematic review to determine the effect of multimodal postoperative analgesics is proposed (International Prospective Register of Systematic Reviews Registration CRD42022355834). Multiple databases including the Cochrane Library, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, American Psychological Association, the Education Resources Information Centre, the Excerpta Medica database, the Medical Literature Analysis and Retrieval System Online, Scopus, Web of Science, and clinical trials databases will be searched. Screening in Covidence and quality assessment will be conducted by 2 authors. A grading of recommendations, assessment, development, and evaluation summary of findings will be presented if meta-analysis is possible

State-of-the art data normalization methods improve NMR-based metabolomic analysis

Extracting biomedical information from large metabolomic datasets by multivariate data analysis is of considerable complexity. Common challenges include among others screening for differentially produced metabolites, estimation of fold changes, and sample classification. Prior to these analysis steps, it is important to minimize contributions from unwanted biases and experimental variance. This is the goal of data preprocessing. In this work, different data normalization methods were compared systematically employing two different datasets generated by means of nuclear magnetic resonance (NMR) spectroscopy. To this end, two different types of normalization methods were used, one aiming to remove unwanted sample-to-sample variation while the other adjusts the variance of the different metabolites by variable scaling and variance stabilization methods. The impact of all methods tested on sample classification was evaluated on urinary NMR fingerprints obtained from healthy volunteers and patients suffering from autosomal polycystic kidney disease (ADPKD). Performance in terms of screening for differentially produced metabolites was investigated on a dataset following a Latin-square design, where varied amounts of 8 different metabolites were spiked into a human urine matrix while keeping the total spike-in amount constant. In addition, specific tests were conducted to systematically investigate the influence of the different preprocessing methods on the structure of the analyzed data. In conclusion, preprocessing methods originally developed for DNA microarray analysis, in particular, Quantile and Cubic-Spline Normalization, performed best in reducing bias, accurately detecting fold changes, and classifying samples

Early Adversity and the Prospective Prediction of Depressive and Anxiety Disorders in Adolescents

The current study was a prospective exploration of the specificity of early childhood adversities as predictors of anxiety and depressive disorders in adolescents. Participants were 816 adolescents (414 males, 402 females) with diagnostic information collected at age 15; information on early adversities had been collected from the mothers during pregnancy, at birth, age 6 months, and age 5 years for a related study. Adolescents with "pure" anxiety disorders were compared with adolescents with "pure" depressive disorders (major depressive disorder, dysthymia), and these groups were compared to never-ill controls. Analyses controlled for gender and maternal depression and anxiety disorders. Results indicated that adolescents with anxiety disorders were more likely than depressed youth to have been exposed to various early stressors, such as maternal prenatal stress, multiple maternal partner changes, and more total adversities, whereas few early childhood variables predicted depressive disorders. Even when current family stressors at age 15 were controlled, early adversity variables again significantly predicted anxiety disorders. Results suggest that anxiety disorders may be more strongly related to early strees exposure, while depressive disorders may be related to more proximal stressors or to early stressors not assessed in the current study

Stress sensitization and adolescent depressive severity as a function of childhood adversity: A link to anxiety disorders

The goal of the present study was to determine whether exposure to adversity in childhood contributes to a differential threshold at which stressful life events provoke depressive reactions in adolescence. In addition, to address empirical and conceptual questions about stress effects, the moderating effect of anxiety disorder history was also explored. This examination was conducted in a sample of 816 children of depressed and nondepressed mothers, who were followed from birth to age 15. Information on adversities experienced in childhood was collected both from mothers during the first five years of their youth's life and from the youths themselves at age 15, and included information on the mother's relationship with her partner, maternal psychopathology, as well as youth-reported abuse. Results indicated that youths with both greater exposure to adversity in childhood and a history of an anxiety disorder displayed increased depressive severity following low levels of episodic stress compared to youths with only one or neither of these risk factors. The results are speculated to reflect the possibility that early anxiety disorders associated with exposure to adversity in childhood may be a marker of dysregulated stress responses, and may help to account for the comorbidity of depression and anxiety in some individuals

Understanding the sex difference in vulnerability to adolescent depression: an examination of child and parent characteristics

This study examined sex differences in risk factors associated with adolescent depression in a large sample of boys and girls. Moderation and mediation explanatory models of the sex difference in likelihood of depression were examined. Findings indicate that the factors associated with depression in adolescent boys and girls are quite similar. All of the variables considered were associated with depression, but sex did not moderate the impact of vulnerability factors on likelihood of depression diagnosis. However, negative self-perceptions in the domains of achievement, global self-worth, and physical appearance partially mediated the relationship between sex and depression. Further, girls had higher levels of positive self-perceptions in interpersonal domains that acted as suppressors and reduced the likelihood of depression in girls. These findings suggest that girls' higher incidence of depression is due in part to their higher levels of negative self-perceptions, whereas positive interpersonal factors serve to protect them from depressive episodes

Characterization of Apoptosis-Related Oxidoreductases from Neurospora crassa

The genome from Neurospora crassa presented three open reading frames homologous to the genes coding for human AIF and AMID proteins, which are flavoproteins with oxidoreductase activities implicated in caspase-independent apoptosis. To investigate the role of these proteins, namely within the mitochondrial respiratory chain, we studied their cellular localization and characterized the respective null mutant strains. Efficiency of the respiratory chain was analyzed by oxygen consumption studies and supramolecular organization of the OXPHOS system was assessed through BN-PAGE analysis in the respective null mutant strains. The results demonstrate that, unlike in mammalian systems, disruption of AIF in Neurospora does not affect either complex I assembly or function. Furthermore, the mitochondrial respiratory chain complexes of the mutant strains display a similar supramolecular organization to that observed in the wild type strain. Further characterization revealed that N. crassa AIF appears localized to both the mitochondria and the cytoplasm, whereas AMID was found exclusively in the cytoplasm. AMID2 was detected in both mitochondria and cytoplasm of the amid mutant strain, but was barely discernible in wild type extracts, suggesting overlapping functions for the two proteins

An oribatid mite (Arachnida: Acari) from the Oxford Clay (Jurassic: Upper Callovian) of South Cave Station Quarry, Yorkshire, UK

A single specimen of a new species of oribatid mite belonging to the genus Jureremus Krivolutsky, in Krivolutsky and Krassilov 1977, previously described from the Upper Jurassic of the Russian Far East, is described as J. phippsi sp. nov. The mite is preserved by iron pyrite replacement, and was recovered by sieving from the Oxford Clay Formation (Jurassic: Upper Callovian) of South Cave, Yorkshire. It is the first record of a pre-Pleistocene mite, and the second species record of the family Cymbaeremaeidae, from the British Isles; also, it is only the third record of Acari from the Jurassic Period. The presence of a terrestrial mite in a sedimentary sequence of open marine origin is noteworthy, and suggestions for its mode of transport to the site of deposition are discussed

mSep: investigating physiological and immune-metabolic biomarkers in septic and healthy pregnant women to predict feto-maternal immune health – a prospective observational cohort study protocol

Introduction: Maternal sepsis remains a leading cause of death in pregnancy. Physiological adaptations to pregnancy obscure early signs of sepsis and can result in delays in recognition and treatment. Identifying biomarkers that can reliably diagnose sepsis will reduce morbidity and mortality and antibiotic overuse. We have previously identified an immune-metabolic biomarker network comprising three pathways with a >99% accuracy for detecting bacterial neonatal sepsis. In this prospective study, we will describe physiological parameters and novel biomarkers in two cohorts—healthy pregnant women and pregnant women with suspected sepsis—with the aim of mapping pathophysiological drivers and evaluating predictive biomarkers for diagnosing maternal sepsis. Methods and analysis: Women aged over 18 with an ultrasound-confirmed pregnancy will be recruited to a pilot and two main study cohorts. The pilot will involve blood sample collection from 30 pregnant women undergoing an elective caesarean section. Cohort A will follow 100 healthy pregnant women throughout their pregnancy journey, with collection of blood samples from participants at routine time points in their pregnancy: week 12 ‘booking’, week 28 and during labour. Cohort B will follow 100 pregnant women who present with suspected sepsis in pregnancy or labour and will have at least two blood samples taken during their care pathway. Study blood samples will be collected during routine clinical blood sampling. Detailed medical history and physiological parameters at the time of blood sampling will be recorded, along with the results of routine biochemical tests, including C reactive protein, lactate and white blood cell count. In addition, study blood samples will be processed and analysed for transcriptomic, lipidomic and metabolomic analyses and both qualitative and functional immunophenotyping. Ethics and dissemination: Ethical approval has been obtained from the Wales Research Ethics Committee 2 (SPON1752-19, 30 October 2019). Trial registration number: NCT05023954

Support for maternal manipulation of developmental nutrition in a facultatively eusocial bee, Megalopta genalis (Halictidae)

Developmental maternal effects are a potentially important source of phenotypic variation, but they can be difficult to distinguish from other environmental factors. This is an important distinction within the context of social evolution, because if variation in offspring helping behavior is due to maternal manipulation, social selection may act on maternal phenotypes, as well as those of offspring. Factors correlated with social castes have been linked to variation in developmental nutrition, which might provide opportunity for females to manipulate the social behavior of their offspring. Megalopta genalis is a mass-provisioning facultatively eusocial sweat bee for which production of males and females in social and solitary nests is concurrent and asynchronous. Female offspring may become either gynes (reproductive dispersers) or workers (non-reproductive helpers). We predicted that if maternal manipulation plays a role in M. genalis caste determination, investment in daughters should vary more than for sons. The mass and protein content of pollen stores provided to female offspring varied significantly more than those of males, but volume and sugar content did not. Sugar content varied more among female eggs in social nests than in solitary nests. Provisions were larger, with higher nutrient content, for female eggs and in social nests. Adult females and males show different patterns of allometry, and their investment ratio ranged from 1.23 to 1.69. Adult body weight varied more for females than males, possibly reflecting increased variation in maternal investment in female offspring. These differences are consistent with a role for maternal manipulation in the social plasticity observed in M. genalis