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ABSTRACT The measurement of biomarkers in blood and excreta can enable immune status assessment and provide prognostic information on individual health outcomes. In this respect, the fecal measurement of secretory immunoglobulin A (sIgA), the primary mammalian antibody for mucosal defense, has recently received increased interest in a few anthropoid primates, but a fecal sIgA assay for use in strepsirrhine primates has not yet been reported. Here, we develop and analytically validate a cost‐effective in‐house sandwich enzyme immunoassay for the extraction and measurement of sIgA in feces of redfronted lemurs (Eulemur rufifrons). We also tested a simple method for sIgA extraction that can be used under remote field conditions and undertook experiments to assess the robustness of sIgA concentrations to variation in processing and storage conditions of fecal extracts. Our analytical validation revealed that the assay recognizes immunoreactive sIgA in redfronted lemur feces, that sIgA can be measured accurately with no potential interference from the fecal matrix, and that assay reagents and performance are highly stable over time. The field‐friendly extraction procedure produced sIgA results strongly correlated with those generated by a standard laboratory extraction method. Short‐term storage at room temperature resulted in a slight decline in sIgA concentrations, whereas freezing extracts at −20°C kept sIgA levels stable for at least 3 months. Longer‐term storage of >5 months, however, led to a significant decline of sIgA concentrations. Multiple freeze‐thaw cycles did not affect sIgA levels. This study, therefore, provides the basis for measuring fecal sIgA in lemurs and possibly other strepsirrhines. When samples are processed properly and stored frozen, and when sIgA analysis can be performed within 3 months upon sample collection, fecal sIgA measurements can become a valuable tool for monitoring aspects of immunity and health in both zoo‐housed and wild‐living lemurs. [ABSTRACT FROM AUTHOR]

An older wild female chimpanzee (Pan troglodytes) was found dead with a large calcium oxalate stone in the renal pelvis. Histopathological changes included glomerulosclerosis, interstitial nephritis and fibrosis, focal mineralization, and medial hypertrophy. Urinary albumin‐creatinine‐ratio showed increased values from 15 months before death. Causes of the kidney disease remain unconfirmed. [ABSTRACT FROM AUTHOR]

Fluctuating environments that consist of regular cycles of co-occurring stress are a common challenge faced by cellular populations. For a population to thrive in constantly changing conditions, an ability to coordinate a rapid cellular response is essential. Here, we identify a mutation conferring an arginine-to-histidine (Arg to His) substitution in the transcription terminator Rho. The rho R109H mutation frequently arose in Escherichia coli populations experimentally evolved under repeated long-term starvation conditions, during which the accumulation of metabolic waste followed by transfer into fresh media results in drastic environmental pH fluctuations associated with feast and famine. Metagenomic sequencing revealed that populations containing the rho mutation also possess putative loss-of-function mutations in ydcI, which encodes a recently characterized transcription factor associated with pH homeostasis. Genetic reconstructions of these mutations show that the rho allele confers plasticity via an alkaline-induced reduction of Rho function that, when found in tandem with a ΔydcI allele, leads to intracellular alkalization and genetic assimilation of Rho mutant function. We further identify Arg to His substitutions at analogous sites in rho alleles from species that regularly experience neutral to alkaline pH fluctuations in their environments. Our results suggest that Arg to His substitutions in Rho may serve to rapidly coordinate complex physiological responses through pH sensing and shed light on how cellular populations use environmental cues to coordinate rapid responses to complex, fluctuating environments. [ABSTRACT FROM AUTHOR]

Assessing bone growth trajectories in mammals is crucial for understanding life history dynamics, but the quantification of bone growth in natural settings can be challenging. Bone resorption markers that can be measured in urine, such as C‐telopeptide of type I collagen (CTX‐I), offer a non‐invasive solution to assess bone growth. Although measurement of urinary CTX‐I levels has been applied extensively in human studies, its use in other species is so far limited to a few clinical studies. To validate urinary CTX‐I as a bone resorption marker under less controlled conditions, we investigated within‐individual day‐to‐day variation, diurnal patterns, and sex and age‐specific variation in zoo‐housed bonobos (Pan paniscus). We then also correlated urinary CTX‐I levels with forearm growth velocity measures. We found a day‐to‐day variability in urinary CTX‐I levels of around 25%, comparable to human variation. Diurnally, CTX‐I levels decreased, aligning with observations in humans and other species. Both sexes showed an age‐related decline in urinary CTX‐I levels, with a steady decrease after the age of 10 years. Additionally, we found a positive correlation between forearm growth velocity and urinary CTX‐I levels across age in female, but not in male, bonobos. Our results demonstrate that urinary CTX‐I levels are a meaningful measure of bone growth and highlight its potential to examine bone growth trajectories also in wild populations to investigate life history dynamics. [ABSTRACT FROM AUTHOR]

Low‐load blood‐flow‐restriction resistance training (LL‐BFR‐RT) is gaining popularity, but its physiological effects remain unclear. This study aimed to compare LL‐BFR‐RT with low‐load resistance exercise (LL‐RT) and high‐load resistance exercise (HL‐RT) on metabolism, electrolytes, and ions in the lower extremities by invasive catheter measurements, which are crucial for risk assessment. Ten healthy men (27.6 ± 6.4 years) completed three trials of knee‐extensor exercises with LL‐RT (30% 1RM), LL‐BFR‐RT (30% 1RM, 50% limb occlusion pressure), and HL‐RT (75% 1RM). The exercise protocol consisted of four sets to voluntary muscle failure with 1 min of rest between sets. Blood gas analysis was collected before, during, and after each trial through intravenous catheters at the exercising leg. LL‐BFR‐RT had lower total workload (1274 ± 237 kg, mean ± SD) compared to LL‐RT (1745 ± 604 kg), and HL‐RT (1847 ± 367 kg, p < 0.01), with no difference between LL‐RT and HL‐RT. Pain perception did not differ significantly. Exercise‐induced drop in oxygen partial pressure, lactate accumulation and electrolyte shifts (with increased [K+]) occurred during under all conditions (p < 0.001). Creatine kinase and lactate dehydrogenase increased significantly 24‐ and 48‐h postexercise under all three conditions (p < 0.001). This study, using invasive catheter measurements, found no significant differences in metabolic, ionic, and electrolyte responses among LL‐BFR‐RT, LL‐RT, and HL‐RT when exercised to voluntary muscular failure. LL‐BFR‐RT reduced time to failure without specific physiological responses. [ABSTRACT FROM AUTHOR]

The tumour microenvironment counteracts immune therapy in Glioblastomas. Authors show here, using spatially resolved and single cell transcriptomics, that dysfunctional T cells are induced by a myeloid cell subset via Interleukin-10 signalling, and inhibition of the downstream JAK/STAT pathway might restore glioblastoma immune therapy responsiveness.

Abstract Background Compelling data on clinical emergency medicine is required for healthcare system management. The aim of this survey was to describe the nationwide status quo of emergency care in Germany at the healthcare system level using the Utstein reporting template as the guideline to measure the data collected. Methods This cross-sectional survey collected standardized data from German EDs in 2018. All 759 of the EDs listed in a previously collected ED Directory were contacted in November 2019 using the online-survey tool SoSci Survey. Exclusively descriptive statistical analyses were performed. Absolute as well as relative frequencies, medians, means, ranges, standard deviations (SD) and interquartile ranges (IQR) were reported depending on distribution. Main Results A total of 150 questionnaires of contacted EDs were evaluated (response rate: 19.8%). Hospitals had a median of 403 inpatient beds (n=147). The EDs recorded a median of 30,000 patient contacts (n=136). Eighty-three EDs (55%) had observation units with a median of six beds. The special patient groups were pediatric patients (< 5 years) and older patients (> 75 years) with a median of 1.7% and 25%, respectively. Outpatients accounted for 55%, while 45% were admitted (intensive care unit 5.0%, standard care unit 32.3%, observation unit 6.3%) and 1.2% transferred to another hospital. Conclusions The use of the Utstein reporting template enabled the collection of ED descriptive parameters in Germany. The data can provide a baseline for upcoming reforms on German emergency medicine, and for international comparisons on admission rates, initial triage categories, and patient populations.

Abstract Background Patient handover between prehospital care and the emergency department plays a key role in patient safety. Therefore, we aimed to create a validated tool for measuring quality of communication and interprofessional relations during handover in this specific setting. Methods Based on a theoretical framework a comprehensive item pool on information transfer and human factors in emergency department handovers was created and refined in a modified Delphi survey involving clinical experts. Based on a pre-test, items were again revised. The resulting Emergency Department Human Factors in Handover tool (ED-HFH) was validated in a field test at the emergency department of a German university hospital from July to December 2017. The ED-HFH was completed by emergency department and ambulance service staff participating in handovers and by an external observer. Description of item characteristics, exploratory factor analysis, analyses on internal consistency and interrater reliability by intraclass-correlation. Construct validity was analysed by correlation with an overall rating on quality of the handover. Results The draft of the ED-HFH contained 24 items, 90 of 102 eligible staff members participated in the field test completing 133 questionnaires on 38 observed handovers. Four items were deleted after analysis of item characteristics. Factor analysis supported a single factor explaining 39% of variance in the items. Therefore, a sum-score was calculated with a possible range between 14 and 70. The median value of the sum-score in the sample was 61.5, Cronbach’s α was 0.83, intraclass-correlation was 0.52, the correlation with the overall rating of hand-over quality was ρ = 0.83 (p ≤ 0.001). Conclusions The ED-HFH showed its feasibility, reliability and validity as a measure of quality of information transfer and human factors in handovers between ambulance services and the emergency department. It promises to be a useful tool for quality assurance and staff training.

Tensiomyography (TMG) is a non-invasive method for measuring contractile properties of skeletal muscle that is increasingly being used in research and practice. However, the lack of standardization in measurement protocols mitigates the systematic use in sports medical settings. Therefore, this study aimed to investigate the effects of lower leg fixation and sensor location on TMG-derived parameters. Twenty-two male participants underwent TMG measurements on the m. biceps femoris (BF) in randomized order with and without lower leg fixation (fixed vs. non-fixed). Measurements were conducted at 50% of the muscle's length (BF-mid) and 10 cm distal to this (BF-distal). The sensor location affected the contractile properties significantly, both with and without fixation. Delay time (Td) was greater at BF-mid compared to BF-distal (fixed: 23.2 ± 3.2 ms vs. 21.2 ± 2.7 ms, p = 0.002; non-fixed: 24.03 ± 4.2 ms vs. 21.8 ± 2.7 ms, p = 0.008), as were maximum displacement (Dm) (fixed: 5.3 ± 2.7 mm vs. 3.5 ± 1.7 mm, p = 0.005; non-fixed: 5.4 ± 2.5 mm vs. 4.0 ± 2.0 mm, p = 0.03), and contraction velocity (Vc) (fixed: 76.7 ± 25.1 mm/s vs. 57.2 ± 24.3 mm/s, p = 0.02). No significant differences were revealed for lower leg fixation (all p > 0.05). In summary, sensor location affects the TMG-derived parameters on the BF. Our findings help researchers to create tailored measurement procedures in compliance with the individual goals of the TMG measurements and allow adequate interpretation of TMG parameters.

The organization of the mammalian cerebral cortex shares fundamental features across species. However, while the radial thickness of grey matter varies within one order of magnitude, the tangential spread of the cortical sheet varies by orders of magnitude across species. A broader sample of model species may provide additional clues for understanding mechanisms that drive cortical expansion. Here, we introduce the bat Carollia perspicillata as a new model species. The brain of C. perspicillata is similar in size to that of mouse but has a cortical neurogenic period at least 5 times longer than mouse, and nearly as long as that of the rhesus macaque, whose brain is 100 times larger. We describe the development of laminar and regional structures, neural precursor cell identity and distribution, immune cell distribution, and a novel population of Tbr2+ cells in the caudal ganglionic eminence of the developing neocortex of C. perspicillata. Our data indicate that unique mechanisms guide bat cortical development, particularly concerning cell cycle length. The bat model provides new perspective on the evolution of developmental programs that regulate neurogenesis in mammalian cerebral cortex, and offers insight into mechanisms that contribute to tangential expansion and gyri formation in the cerebral cortex.

BackgroundFrom bat wings to whale flippers, limb diversification has been crucial to the evolutionary success of mammals. We performed the first transcriptome-wide study of limb development in multiple species to explore the hypothesis that mammalian limb diversification has proceeded through the differential expression of conserved shared genes, rather than by major changes to limb patterning. Specifically, we investigated the manner in which the expression of shared genes has evolved within and among mammalian species.ResultsWe assembled and compared transcriptomes of bat, mouse, opossum, and pig fore- and hind limbs at the ridge, bud, and paddle stages of development. Results suggest that gene expression patterns exhibit larger variation among species during later than earlier stages of limb development, while within species results are more mixed. Consistent with the former, results also suggest that genes expressed at later developmental stages tend to have a younger evolutionary age than genes expressed at earlier stages. A suite of key limb-patterning genes was identified as being differentially expressed among the homologous limbs of all species. However, only a small subset of shared genes is differentially expressed in the fore- and hind limbs of all examined species. Similarly, a small subset of shared genes is differentially expressed within the fore- and hind limb of a single species and among the forelimbs of different species.ConclusionsTaken together, results of this study do not support the existence of a phylotypic period of limb development ending at chondrogenesis, but do support the hypothesis that the hierarchical nature of development translates into increasing variation among species as development progresses.

Abstract Background Overall survival remains poor in older patients with acute myeloid leukemia (AML) with less than 10% being alive after 5 years. In recent studies, a significant improvement in event-free, relapse-free and overall survival was shown by adding gemtuzumab ozogamicin (GO), a humanized antibody-drug conjugate directed against CD33, to intensive induction therapy once or in a sequential dosing schedule. Glasdegib, the small-molecule inhibitor of smoothened (SMO), also showed improved overall survival in patients not eligible for intensive chemotherapy when combined with low-dose cytarabine compared to low-dose cytarabine alone. These findings warrant further investigations in the phase III GnG trial. Methods/Design This is a randomized phase III trial with measurable residual disease (MRD) after induction therapy and event-free survival (EFS) as primary endpoints. The two research questions are addressed in a 2 by 2 factorial design. Patients age 60 years and older are upfront randomized 1:1 in one of the two induction arms: GO administered to intensive induction therapy on days 1,4, and 7 versus GO administered once on day 1 (GO-147 versus GO-1), and double-blinded 1:1 in one of the subsequent treatment arms glasdegib vs. placebo as adjunct to consolidation therapy and as single-agent maintenance therapy for six months. Chemotherapy backbone for induction therapy consists of standard 7 + 3 schedule with cytarabine 200 mg/m2 continuously days 1 to 7, daunorubicin 60 mg/m2 days 1, 2, and 3 and high-dose cytarabine (1 g/m2, bi-daily, days 1, 2, and 3) for consolidation therapy. Addressing two primary endpoints, MRD-negativity after induction therapy and event-free survival (EFS), 252 evaluable patients are needed to reject each of the two null hypotheses at a two-sided significance level of 2.5% with a power of at least 85%. Ethics and dissemination Ethical approval and approvals from the local and federal competent authorities were granted. Trial results will be reported via peer-reviewed journals and presented at conferences and scientific meetings. Trial status Protocol version: 1st version 20.10.2020, no amendments yet. Study initiation on February 16, 2021. First patient was recruited on April 1st. Trial registration ClinicalTrials.gov NCT04093505 ; EudraCT 2019-003913-32. Registered on October 30, 2018.

Abstract This study provides a broad phylogenetic analysis for the Eubrachyura, with the inclusion of three new Panopeidae mitochondrial genomes: Eurypanopeus depressus (flatback mud crab) (15,854bp), Panopeus herbstii (Atlantic mud crab) (15,812bp) and Rhithropanopeus harrisii (Harris, or ‘white-fingered’ mud crab) (15,892bp). These new mitogenomes were analyzed alongside all available brachyuran mitochondrial genomes (n = 113), comprising 80 genera from 29 families, to provide an updated phylogenetic analysis of the infra-order Brachyura (“true crabs”). Our analyses support the subsection Potamoida within the Eubrachyura as the sister group to Thoracotremata. The family Panopeidae aligns with the family Xanthidae to form the Xanthoidea branch, which is supported by current morphological and genetic taxonomy. A unique gene arrangement termed ‘XanGO’ was identified for the panopeids and varies relative to other members of the subsection Heterotremata (within the Eubrachyura) via a transposition of the trnV gene. This gene arrangement is novel and is shared between several Xanthoidea species, including Etisus anaglyptus (hairy spooner crab), Atergatis floridus (brown egg crab), and Atergatis integerrimus (red egg crab), suggesting that it is a conserved gene arrangement within the Xanthoidea superfamily. Our study further reveals a need for taxonomic revision of some brachyuran groups, particularly the Sesarmidae. The inclusion of panopeid mitogenomes into the greater brachyuran phylogeny increases our understanding of crab evolution and higher level Eubrachyuran systematics.

Human metaplastic breast cancers (MpBC) are a rare, aggressive subclass of triple-negative breast cancers. Here, the authors show over-expression of histone reader TRIM24 is sufficient to generate tumors with a molecular signature of metabolic dysfunction and EMT in a mouse model of human MpBC.