Structures, functions and adaptations of the human LINE-1 ORF2 protein.

The LINE-1 (L1) retrotransposon is an ancient genetic parasite that has written around one-third of the human genome through a 'copy and paste' mechanism catalysed by its multifunctional enzyme, open reading frame 2 protein (ORF2p)1. ORF2p reverse transcriptase (RT) and endonuclease activities have been implicated in the pathophysiology of cancer2,3, autoimmunity4,5 and ageing6,7, making ORF2p a potential therapeutic target. However, a lack of structural and mechanistic knowledge has hampered efforts to rationally exploit it. We report structures of the human ORF2p 'core' (residues 238-1061, including the RT domain) by X-ray crystallography and cryo-electron microscopy in several conformational states. Our analyses identified two previously undescribed folded domains, extensive contacts to RNA templates and associated adaptations that contribute to unique aspects of the L1 replication cycle. Computed integrative structural models of full-length ORF2p show a dynamic closed-ring conformation that appears to open during retrotransposition. We characterize ORF2p RT inhibition and reveal its underlying structural basis. Imaging and biochemistry show that non-canonical cytosolic ORF2p RT activity can produce RNA:DNA hybrids, activating innate immune signalling through cGAS/STING and resulting in interferon production6-8. In contrast to retroviral RTs, L1 RT is efficiently primed by short RNAs and hairpins, which probably explains cytosolic priming. Other biochemical activities including processivity, DNA-directed polymerization, non-templated base addition and template switching together allow us to propose a revised L1 insertion model. Finally, our evolutionary analysis demonstrates structural conservation between ORF2p and other RNA- and DNA-dependent polymerases. We therefore provide key mechanistic insights into L1 polymerization and insertion, shed light on the evolutionary history of L1 and enable rational drug development targeting L1.

Modulation by Neuropeptides with Overlapping Targets Results in Functional Overlap in Oscillatory Circuit Activation.

Neuromodulation lends flexibility to neural circuit operation but the general notion that different neuromodulators sculpt neural circuit activity into distinct and characteristic patterns is complicated by interindividual variability. In addition, some neuromodulators converge onto the same signaling pathways, with similar effects on neurons and synapses. We compared the effects of three neuropeptides on the rhythmic pyloric circuit in the stomatogastric ganglion of male crabs, Cancer borealis Proctolin (PROC), crustacean cardioactive peptide (CCAP), and red pigment concentrating hormone (RPCH) activate the same modulatory inward current, I MI, and have convergent actions on synapses. However, while PROC targets all four neuron types in the core pyloric circuit, CCAP and RPCH target the same subset of only two neurons. After removal of spontaneous neuromodulator release, none of the neuropeptides restored the control cycle frequency, but all restored the relative timing between neuron types. Consequently, differences between neuropeptide effects were mainly found in the spiking activity of different neuron types. We performed statistical comparisons using the Euclidean distance in the multidimensional space of normalized output attributes to obtain a single measure of difference between modulatory states. Across preparations, the circuit output in PROC was distinguishable from CCAP and RPCH, but CCAP and RPCH were not distinguishable from each other. However, we argue that even between PROC and the other two neuropeptides, population data overlapped enough to prevent reliable identification of individual output patterns as characteristic for a specific neuropeptide. We confirmed this notion by showing that blind classifications by machine learning algorithms were only moderately successful.Significance Statement It is commonly assumed that distinct behaviors or circuit activities can be elicited by different neuromodulators. Yet it is unknown to what extent these characteristic actions remain distinct across individuals. We use a well-studied circuit model of neuromodulation to examine the effects of three neuropeptides, each known to produce a distinct activity pattern in controlled studies. We find that, when compared across individuals, the three peptides elicit activity patterns that are either statistically indistinguishable or show too much overlap to be labeled characteristic. We ascribe this to interindividual variability and overlapping subcellular actions of the modulators. Because both factors are common in all neural circuits, these findings have broad significance for understanding chemical neuromodulatory actions while considering interindividual variability.

Mobile interspersed repeats are major structural variants in the human genome.

Characterizing structural variants in the human genome is of great importance, but a genome wide analysis to detect interspersed repeats has not been done. Thus, the degree to which mobile DNAs contribute to genetic diversity, heritable disease, and oncogenesis remains speculative. We perform transposon insertion profiling by microarray (TIP-chip) to map human L1(Ta) retrotransposons (LINE-1 s) genome-wide. This identified numerous novel human L1(Ta) insertional polymorphisms with highly variant allelic frequencies. We also explored TIP-chip's usefulness to identify candidate alleles associated with different phenotypes in clinical cohorts. Our data suggest that the occurrence of new insertions is twice as high as previously estimated, and that these repeats are under-recognized as sources of human genomic and phenotypic diversity. We have just begun to probe the universe of human L1(Ta) polymorphisms, and as TIP-chip is applied to other insertions such as Alu SINEs, it will expand the catalog of genomic variants even further.

Remembering the Work of Phillip L. Geissler: A Coda to His Scientific Trajectory.

Phillip L. Geissler made important contributions to the statistical mechanics of biological polymers, heterogeneous materials, and chemical dynamics in aqueous environments. He devised analytical and computational methods that revealed the underlying organization of complex systems at the frontiers of biology, chemistry, and materials science. In this retrospective we celebrate his work at these frontiers.

Cerebroprotection in the endovascular era: an update.

Despite advances in clinical diagnosis and increasing numbers of patients eligible for revascularisation, ischaemic stroke remains a significant public health concern accounting for 3.3 million deaths annually. In addition to recanalisation therapy, patient outcomes could be improved through cerebroprotection, but all translational attempts have remained unsuccessful. In this narrative review, we discuss potential reasons for those failures. We then outline the diverse, multicellular effects of ischaemic stroke and the complex temporal sequences of the pathophysiological cascade during and following ischaemia, reperfusion, and recovery. This evidence is linked with findings from prior cerebroprotective trials and interpreted for the modern endovascular era. Future cerebroprotective agents that are multimodal and multicellular, promoting cellular and metabolic health to different targets at time points that are most responsive to treatment, might prove more successful.

Primary and secondary data in emergency medicine health services research - a comparative analysis in a regional research network on multimorbid patients.

BACKGROUND: This analysis addresses the characteristics of two emergency department (ED) patient populations defined by three model diseases (hip fractures, respiratory, and cardiac symptoms) making use of survey (primary) and routine (secondary) data from hospital information systems (HIS). Our aims were to identify potential systematic inconsistencies between both data samples and implications of their use for future ED-based health services research. METHODS: The research network EMANET prospectively collected primary data (n=1442) from 2017-2019 and routine data from 2016 (n=9329) of eight EDs in a major German city. Patient populations were characterized using socio-structural (age, gender) and health- and care-related variables (triage, transport to ED, case and discharge type, multi-morbidity). Statistical comparisons between descriptive results of primary and secondary data samples for each variable were conducted using binomial test, chi-square goodness-of-fit test, or one-sample t-test according to scale level. RESULTS: Differences in distributions of patient characteristics were found in nearly all variables in all three disease populations, especially with regard to transport to ED, discharge type and prevalence of multi-morbidity. Recruitment conditions (e.g., patient non-response), project-specific inclusion criteria (e.g., age and case type restrictions) as well as documentation routines and practices of data production (e.g., coding of diagnoses) affected the composition of primary patient samples. Time restrictions of recruitment procedures did not generate meaningful differences regarding the distribution of characteristics in primary and secondary data samples. CONCLUSIONS: Primary and secondary data types maintain their advantages and shortcomings in the context of emergency medicine health services research. However, differences in the distribution of selected variables are rather small. The identification and classification of these effects for data interpretation as well as the establishment of monitoring systems in the data collection process are pivotal. TRIAL REGISTRATION: DRKS00011930 (EMACROSS), DRKS00014273 (EMAAGE), NCT03188861 (EMASPOT).

Effort-reward imbalance and its association with sociocultural diversity factors at work: findings from a cross-sectional survey among physicians and nurses in Germany.

OBJECTIVE: Due to staff shortages and reports of high work stress, work conditions of hospital physicians and nurses receive wide attention. Additionally, sociocultural diversity of the workforce and patient population is increasing. Our study aim is to analyze how individual and organizational diversity-related factors are associated with the experience of staff's work stress. METHODS: A cross-sectional online survey was conducted with healthcare staff from 22 acute hospitals operated by two healthcare organizations in Germany in 2018. Sociodemographic, occupational and organizational factors were surveyed. Participants further reported work conditions related to the sociocultural diversity of colleagues and patients. Effort-reward imbalance (ERI) was measured with the German short version. Multivariable regression models were calculated with ER ratio as an outcome. RESULTS: N = 800 healthcare staff were included. Variables associated with higher ERI were longer work experience (ß = 0.092, p < 0.05), not holding a leading position (0.122, < 0.01), being a witness (0.149, < 0.001) or victim (0.099, < 0.05) of discrimination at one's own ward, reporting frequent burden due to language barriers with patients (0.102, < 0.01) and colleagues (0.127, < 0.001), and having restricted access to translators at work (0.175, < 0.001). Factors associated with lower ERI were having a first generation migration background (- 0.095, < 0.05) and being a physician (- 0.112, < 0.05). CONCLUSIONS: Catering to the needs of healthcare personnel in dealing with the additional effort related to language barriers at work, e.g., readily available translator services, and creating non-discriminatory work environments might be one cornerstone for the prevention of work-related ill health and retention of qualified hospital staff.

Cost-Effectiveness of Mobile Stroke Unit Care in Norway.

BACKGROUND: Acute ischemic stroke treatment in mobile stroke units (MSUs) reduces time-to-treatment and increases thrombolytic rates, but implementation requires substantial investments. We wanted to explore the cost-effectiveness of MSU care incorporating novel efficacy data from the Norwegian MSU study, Treat-NASPP (the Norwegian Acute Stroke Prehospital Project). METHODS: We developed a Markov model linking improvements in time-to-treatment and thrombolytic rates delivered by treatment in an MSU to functional outcomes for the patients in a lifetime perspective. We estimated incremental costs, health benefits, and cost-effectiveness of MSU care as compared with conventional care. In addition, we estimated a minimal MSU utilization level for the intervention to be cost-effective in the publicly funded health care system in Norway. RESULTS: MSU care was associated with an expected quality-adjusted life-year-gain of 0.065 per patient, compared with standard care. Our analysis suggests that about 260 patients with ischemic stroke need to be treated with MSU annually to result in an incremental cost-effectiveness ratio of about NOK385 000 (US$43 780) per quality-adjusted life-year for MSU compared with standard care. The incremental cost-effectiveness ratio varies between some NOK1 000 000 (US$113 700) per quality-adjusted life-year if an MSU treats 100 patients per year and to about NOK340 000 (US$38 660) per quality-adjusted life-year if 300 patients with acute ischemic stroke are treated. CONCLUSIONS: MSU care in Norwegian settings is potentially cost-effective compared with conventional care, but this depends on a relatively high annual number of treated patients with acute ischemic stroke per vehicle. These results provide important information for MSU implementation in government-funded health care systems.

Megaporous monolithic adsorbents for bioproduct recovery as prepared on the basis of nonwoven fabrics.

Megaporous adsorbents were prepared based on nonwoven polyethylene terephthalate (PET) fabrics and functionalized by covalent modification with polyvinylamine (PVAm) or monotriazinyl-ß-cyclodextrin-substituted polyvinylamine (PVAm-MCT-ß-CD). Mechanical properties of the resulting fabrics were maintained, as judged by tensile strength tests and scanning electron microscopy. Exceptional porosity (≥82%) and preserved hydrodynamic characteristics (Pe ≥ 63) indicated excellent structural stability when packed. The performance of the constructed adsorbents was evaluated with high molecular weight (proteins) and low molecular weight (dyes) model compounds. The static binding capacity (SBC) for bovine serum albumin (BSA) was 79.7 ± 1.3 and 92.9 ± 8.2 mg/g for PVAm-modified and PVAm-MCT-ß-CD-modified fabrics, respectively. The mentioned materials also adsorbed Orange II, an acidic dye (92.4 ± 2.6 and 101.9 ± 2.6 mg/g, respectively), indicating that the hydrophobicity was a prevailing binding mechanism operating at a pH close to isoelectric point. SBC for lysozyme and toluidine blue O (TBO, a basic dye) onto PVAm-MCT-ß-CD functionalized PET was 52.7 ± 5.1 and 73.3 ± 0.6 mg/g, respectively. TBOs have also shown some affinity for PVAm functionalized PET, but this was most likely to be mediated by hydrophobicity. On the other hand, operating at a superficial velocity of 90 cm/h, dynamic binding capacity for BSA was 11.4 ± 3.5 and 2.5 ± 0.6 mg/g indicating the importance of possible aggregation mechanisms during protein binding at equilibrium. Thus, PET-based adsorbents require further functional improvement for chromatography applications. However, the easy-to-construct, scalable nonwoven adsorbents deserve further attention as a potential alternative to packed-bed-chromatography adsorbents.

Childhood obesity prevention: what can be achieved?

PURPOSE OF REVIEW: Childhood obesity is a pandemic generating an enormous individual and socioeconomic burden worldwide. This narrative review summarizes recent evidence on successful and recommended prevention strategies according to age groups and different levels of interventions. RECENT FINDINGS: Effective prevention of childhood obesity is feasible and most successful early in life up to preschool age, and it should include a multicomponent approach, integrating individuals, family and society. Trials that improve nutrition and/or enhance physical activity are the cornerstones of childhood obesity prevention on an individual level. However, their efficacy is determined by the combination of interventions for the target age group. Further, improving family support and sleep, as well as reducing screen time, lead to favourable results. Many research gaps remain, including a lack of effective interventions for high-risk groups. SUMMARY: As a multifactorial condition, childhood obesity requires a multicomponent approach. Interventions should be developmental stage-specific and adjusted to the setting. Current research gaps need to be targeted by future trials, with a special focus on the benefit of the most vulnerable groups. From a systems response perspective, a paradigm shift from interventions focusing on the individual to approaches that target society as a whole is warranted.

Safety and Potential Efficacy of Escalating Dose of Ustekinumab in Pediatric Crohn Disease (the Speed-up Study): A Multicenter Study from the Pediatric IBD Porto Group of ESPGHAN.

OBJECTIVES: Escalation of the ustekinumab (UST) maintenance dosage was effective in adults with Crohn disease (CD), but no data are available for children. We evaluated the effectiveness and safety of dose escalation of UST in pediatric CD. METHODS: This was a retrospective multicenter study from 25 centers affiliated with the IBD Interest and Porto groups of ESPGHAN. We included children with CD who initiated UST at a standard dosing and underwent either dose escalation to intervals shorter than 8 weeks or re-induction of UST due to active disease. Demographic, clinical, laboratory, endoscopic, imaging, and safety data were collected up to 12 months of follow-up. RESULTS: Sixty-nine children were included (median age 15.8 years, interquartile range 13.8-16.9) with median disease duration of 4.3 years (2.9-6.3). Most children were biologic (98.6%)- and immunomodulator (86.8%)- experienced. Clinical response and remission were observed at 3 months after UST escalation in 46 (67%) and 29 (42%) children, respectively. The strongest predictor for clinical remission was lower weighted Pediatric Crohn Disease Activity Index (wPCDAI) at escalation ( P = 0.001). The median C-reactive protein level decreased from 14 (3-28.03) to 5 (1.1-20.5) mg/L ( P = 0.012), and the fecal calprotectin level from 1100 (500-2300) to 515 (250-1469) µg/g ( P = 0.012) 3 months post-escalation. Endoscopic and transmural healing were achieved in 3 of 19 (16%) and 2 of 15 (13%) patients, respectively. Thirteen patients (18.8%) discontinued therapy due to active disease. No serious adverse events were reported. CONCLUSIONS: Two-thirds of children with active CD responded to dose escalation of UST. Milder disease activity may predict a favorable outcome following UST dose escalation.

Association between alanine aminotransferase as surrogate of fatty liver disease and physical activity and sedentary time in adolescents with obesity.

To compare patterns of sedentary (SED) time (more sedentary, SED + vs less sedentary, SED-), moderate to vigorous physical activity (MVPA) time (more active, MVPA + vs less active, MVPA-), and combinations of behaviors (SED-/MVPA + , SED-/MVPA-, SED + /MVPA + , SED + /MVPA-) regarding nonalcoholic fatty liver diseases (NAFLD) markers. This cross-sectional study included 134 subjects (13.4 ± 2.2 years, body mass index (BMI) 98.9 ± 0.7 percentile, 48.5% females) who underwent 24-h/7-day accelerometry, anthropometric, and biochemical markers (alanine aminotransferase (ALT) as first criterion, and aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), AST/ALT ratio as secondary criteria). A subgroup of 39 patients underwent magnetic resonance imaging-liver fat content (MRI-LFC). Hepatic health was better in SED- (lower ALT, GGT, and MRI-LFC (p < 0.05), higher AST/ALT (p < 0.01)) vs SED + and in MVPA + (lower ALT (p < 0.05), higher AST/ALT (p < 0.01)) vs MVPA- groups after adjustment for age, gender, and Tanner stages. SED-/MVPA + group had the best hepatic health. SED-/MVPA- group had lower ALT and GGT and higher AST/ALT (p < 0.05) in comparison with SED + /MVPA + group independently of BMI. SED time was positively associated with biochemical (high ALT, low AST/ALT ratio) and imaging (high MRI-LFC) markers independently of MVPA. MVPA time was associated with biochemical markers (low ALT, high AST/ALT) but these associations were no longer significant after adjustment for SED time. CONCLUSION: Lower SED time is associated with better hepatic health independently of MVPA. Reducing SED time might be a first step in the management of pediatric obesity NAFLD when increasing MVPA is not possible. WHAT IS KNOWN: • MVPA and SED times are associated with cardiometabolic risks in youths with obesity. • The relationships between NAFLD markers and concomitant MVPA and SED times have not been studied in this population. WHAT IS NEW: • Low SED time is associated with healthier liver enzyme profiles and LFC independent of MVPA. • While low SED/high MVPA is the more desirable pattern, low SED/low MVPA pattern would have healthier liver enzyme profile compared with high MVPA/high SED, independent of BMI, suggesting that reducing SED time irrespective of MVPA is needed to optimize liver health.

Observed and personally experienced discrimination: findings of a cross-sectional survey of physicians and nursing staff.

BACKGROUND: Discrimination against hospital staff based on ascribed features is prevalent in healthcare systems worldwide. Detrimental effects on health and quality of patient care have been shown. Our study aims to describe and analyse the discrimination experiences of both physicians and nurses, specifically for the German hospital context. METHODS: A cross-sectional online survey on observed and personally experienced discrimination at work addressed staff from 22 hospitals of two organizations in Germany. Sociodemographic and occupational as well as institutional characteristics served as independent variables. In multivariable analyses, block- and stepwise logistic regressions were calculated for the two dependent variables (witness and victim of discrimination). Sensitivity analyses with imputed data for missings were performed. RESULTS: N = 800 healthcare professionals (n = 243 physicians, n = 557 nurses; response rate: 5.9%) participated in the survey. 305 respondents (38.1%) were witnesses of discrimination, while 108 respondents (13.5%) were victims of discrimination in their wards. Reasons for observed discriminatory acts were predominantly attributed to the ethnicity of the person concerned, their appearance and language, whereas personally affected staff most frequently cited gender as a reason, followed by ethnicity, and physical appearance. In multivariable models, cultural competence significantly increased the likelihood of witnessing discrimination (ß = .575; p = .037). In terms of the likelihood of being a victim of discrimination, in addition to cultural competence (ß = 2.838; p = < .001), the interaction of the effects of gender and professional group was statistically significant (ß = .280; p = .010). CONCLUSIONS: Given the extent of experienced and observed discrimination, appropriate institutional responses are needed. Further research on discriminatory structures in the German-speaking health care system should focus on discrimination at the intersection of ethnicity, gender and occupation.

Two fatal autochthonous cases of airport malaria, Belgium, 2020.

We report an outbreak investigation of two fatal cases of autochthonous Plasmodium falciparum malaria that occurred in Belgium in September 2020. Various hypotheses of the potential source of infection were investigated. The most likely route of transmission was through an infectious exotic Anopheles mosquito that was imported via the international airport of Brussels or the military airport Melsbroek and infected the cases who lived at 5 km from the airports. Based on genomic analysis of the parasites collected from the two cases, the most likely origin of the Plasmodium was Gabon or Cameroon. Further, the parasites collected from the two Belgian patients were identical by descent, which supports the assumption that the two infections originated from the bite of the same mosquito, during interrupted feeding. Although airport malaria remains a rare event, it has significant implications, particularly for the patient, as delayed or missed diagnosis of the cause of illness often results in complications and mortality. Therefore, to prevent such severe or fatal outcomes, we suggest a number of public health actions including increased awareness among health practitioners, especially those working in the vicinity of airports, and increased surveillance of exotic mosquito species at airports.

Somatic variants for seed and fruit set in grapevine.

BACKGROUND: Grapevine reproductive development has direct implications on yield. It also impacts on berry and wine quality by affecting traits like seedlessness, berry and bunch size, cluster compactness and berry skin to pulp ratio. Seasonal fluctuations in yield, fruit composition and wine attributes, which are largely driven by climatic factors, are major challenges for worldwide table grape and wine industry. Accordingly, a better understanding of reproductive processes such as gamete development, fertilization, seed and fruit set is of paramount relevance for managing yield and quality. With the aim of providing new insights into this field, we searched for clones with contrasting seed content in two germplasm collections. RESULTS: We identified eight variant pairs that seemingly differ only in seed-related characteristics while showing identical genotype when tested with the GrapeReSeq_Illumina_20K_SNP_chip and several microsatellites. We performed multi-year observations on seed and fruit set deriving from different pollination treatments, with special emphasis on the pair composed by Sangiovese and its seedless variant locally named Corinto Nero. The pollen of Corinto Nero failed to germinate in vitro and gave poor berry set when used to pollinate other varieties. Most berries from both open- and cross-pollinated Corinto Nero inflorescences did not contain seeds. The genetic analysis of seedlings derived from occasional Corinto Nero normal seeds revealed that the few Corinto Nero functional gametes are mostly unreduced. Moreover, three genotypes, including Sangiovese and Corinto Nero, were unexpectedly found to develop fruits without pollen contribution and occasionally showed normal-like seeds. Five missense single nucleotide polymorphisms were identified between Corinto Nero and Sangiovese from transcriptomic data. CONCLUSIONS: Our observations allowed us to attribute a seedlessness type to some variants for which it was not documented in the literature. Interestingly, the VvAGL11 mutation responsible for Sultanina stenospermocarpy was also discovered in a seedless mutant of Gouais Blanc. We suggest that Corinto Nero parthenocarpy is driven by pollen and/or embryo sac defects, and both events likely arise from meiotic anomalies. The single nucleotide polymorphisms identified between Sangiovese and Corinto Nero are suitable for testing as traceability markers for propagated material and as functional candidates for the seedless phenotype.

Self-reported health and life satisfaction in older emergency department patients: sociodemographic, disease-related and care-specific associated factors.

BACKGROUND: Self-reported health (SRH) and life satisfaction (LS) are patient-reported outcomes (PROs) that independently predict mortality and morbidity in older adults. Emergency department (ED) visits due to serious health problems or accidents might pose critical life events for patients. This study aimed (a) to characterize older patients' SRH and LS during the distinct event of an ED stay, and (b) to analyze concomitant associations of PROs with ED patients' sociodemographic, disease-specific and care-related variables. METHODS: Study personnel recruited mostly older ED patients from three disease groups during a two-year period (2017-2019) in eight EDs in central Berlin, Germany, in the context of the health services research network EMANet. Cross-sectional data from the baseline patient survey and associated secondary data from hospital information systems were analyzed. Multilevel linear regression models with random intercept were applied to assess concomitant associations with SRH (scale: 0 (worst) to 100 (best)) and LS (scale: 0 (not at all satisfied) to 10 (completely satisfied)) as outcomes, including sensitivity analyses. RESULTS: The final sample comprised N = 1435 participants. Mean age was 65.18 (SD: 16.72) and 50.9% were male. Mean ratings of SRH were 50.10 (SD: 23.62) while mean LS scores amounted to 7.15 (SD: 2.50). Better SRH and higher LS were found in patients with cardiac symptoms (SRH: ß = 4.35, p = .036; LS: ß = 0.53, p = .006). Worse SRH and lower LS were associated with being in need of nursing care (SRH: ß = - 7.52, p < .001; LS: ß = - 0.59, p = .003) and being unemployed (SRH: ß = - 8.54, p = .002; LS: ß = - 1.27, p < .001). Sex, age, number of close social contacts, and hospital stays in the previous 6 months were additionally related to the outcomes. Sensitivity analyses largely supported results of the main sample. CONCLUSIONS: SRH and LS were associated with different sociodemographic and disease-related variables in older ED patients. Nursing care dependency and unemployment emerged as significant factors relating to both outcomes. Being able to identify especially vulnerable patients in the ED setting might facilitate patient-centered care and prevent negative health outcomes. However, further longitudinal research needs to analyze trajectories in both outcomes and suitable intervention possibilities in the ED setting. TRIAL REGISTRATION: EMANet sub-studies were registered separately: German Clinical Trials Register (EMAAge: DRKS00014273, registration date: May 16, 2018; https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00014273; EMACROSS: DRKS00011930, registration date: April 25, 2017; https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00011930); ClinicalTrials.gov (EMASPOT: NCT03188861, registration date: June 16, 2017; https://clinicaltrials.gov/ct2/show/NCT03188861?term=NCT03188861&draw=2&rank=1).

Physicians' and nurses' work time allocation and workflow interruptions in emergency departments: a comparative time-motion study across two countries.

BACKGROUND: Globally, emergency department (ED) work is fast-paced and subject to interruptions, placing high coordination and communication demands on staff. Our study aimed to compare ED staffs' work time allocation and interruption rates across professional roles and two national settings. METHODS: We conducted a time-motion study with standardised expert observations of ED physicians and nurses in Germany and the USA. Observers coded ED staffs' activities and workflow interruptions. General and generalised linear models were used to examine differences in activities and interruption rates between countries and ED professions. RESULTS: 28 observations were conducted in the USA and 30 in Germany. Overall, the largest portion of time spent by ED staff in both settings was in documentation (22.0%). Physicians spent more time in verbal interaction with patients (9.9% vs 5.2% in nurses; p=0.006), in documentation (29.4% vs 15.6%; p<0.001) and other professional activities (13.0% vs 4.8%; p=0.002). Nurses allocated significantly more time to therapeutic (22.3% vs 6.0% in physicians; p<0.001) and organisational activities (20.4% vs 9.5%; p<0.001). Overall mean interruption rate per hour was 10.16 (US ED: 8.15, German ED: 12.04; p<0.001). American physicians and German nurses were most often disrupted by colleagues of the same profession (country: B=-.27, p=0.027; profession: B=0.35, p=0.006). German ED staff were interrupted more often by patients (B=-.78, p=0.001) and other sources (B=-.76, p<0.001) than American ED staff. DISCUSSION: Our findings corroborate that professional roles largely determine time allocation to specific activities. However, interruption rates indicate differences between countries, suggesting the need for context-specific solutions to work stressors.

Rapamycin Induces an eNOS (Endothelial Nitric Oxide Synthase) Dependent Increase in Brain Collateral Perfusion in Wistar and Spontaneously Hypertensive Rats.

BACKGROUND AND PURPOSE: Rapamycin is a clinically approved mammalian target of rapamycin inhibitor that has been shown to be neuroprotective in animal models of stroke. However, the mechanism of rapamycin-induced neuroprotection is still being explored. Our aims were to determine if rapamycin improved leptomeningeal collateral perfusion, to determine if this is through eNOS (endothelial nitric oxide synthase)-mediated vessel dilation and to determine if rapamycin increases immediate postreperfusion blood flow. METHODS: Wistar and spontaneously hypertensive rats (≈14 weeks old, n=22 and n=15, respectively) were subjected to ischemia by middle cerebral artery occlusion (90 and 120 minutes, respectively) with or without treatment with rapamycin at 30-minute poststroke. Changes in middle cerebral artery and collateral perfusion territories were measured by dual-site laser Doppler. Reactivity to rapamycin was studied using isolated and pressurized leptomeningeal anastomoses. Brain injury was measured histologically or with triphenyltetrazolium chloride staining. RESULTS: In Wistar rats, rapamycin increased collateral perfusion (43±17%), increased reperfusion cerebral blood flow (16±8%) and significantly reduced infarct volume (35±6 versus 63±8 mm3, P<0.05). Rapamycin dilated leptomeningeal anastomoses by 80±9%, which was abolished by nitric oxide synthase inhibition. In spontaneously hypertensive rats, rapamycin increased collateral perfusion by 32±25%, reperfusion cerebral blood flow by 44±16%, without reducing acute infarct volume 2 hours postreperfusion. Reperfusion cerebral blood flow was a stronger predictor of brain damage than collateral perfusion in both Wistar and spontaneously hypertensive rats. CONCLUSIONS: Rapamycin increased collateral perfusion and reperfusion cerebral blood flow in both Wistar and comorbid spontaneously hypertensive rats that appeared to be mediated by enhancing eNOS activation. These findings suggest that rapamycin may be an effective acute therapy for increasing collateral flow and as an adjunct therapy to thrombolysis or thrombectomy to improve reperfusion blood flow.

New Horizons in the use of routine data for ageing research.

The past three decades have seen a steady increase in the availability of routinely collected health and social care data and the processing power to analyse it. These developments represent a major opportunity for ageing research, especially with the integration of different datasets across traditional boundaries of health and social care, for prognostic research and novel evaluations of interventions with representative populations of older people. However, there are considerable challenges in using routine data at the level of coding, data analysis and in the application of findings to everyday care. New Horizons in applying routine data to investigate novel questions in ageing research require a collaborative approach between clinicians, data scientists, biostatisticians, epidemiologists and trial methodologists. This requires building capacity for the next generation of research leaders in this important area. There is a need to develop consensus code lists and standardised, validated algorithms for common conditions and outcomes that are relevant for older people to maximise the potential of routine data research in this group. Lastly, we must help drive the application of routine data to improve the care of older people, through the development of novel methods for evaluation of interventions using routine data infrastructure. We believe that harnessing routine data can help address knowledge gaps for older people living with multiple conditions and frailty, and design interventions and pathways of care to address the complex health issues we face in caring for older people.

A combination of combat experience, early abduction, and severe traumatization fuels appetitive aggression and violence among abductees of rebel war in Northern Uganda.

Individuals who perpetrate violence may likely perceive violence as appealing and infliction of violence to derive pleasure is termed as appetitive aggression. Individuals who were abducted as children into an armed group often experience a higher number of traumatic event types, that is traumatic load and are usually socialized in a violence-endorsing environment. This study aims to investigate the interaction between age at initial abduction with that of traumatic load, and their influence on appetitive aggression along with perpetration of violent acts by former members of an armed rebel group of both sexes. Semi-structured interviews were conducted among a target group of formerly abducted rebel-war survivors (including participants with and without combat experience) from Northern Uganda. Participants included 596 women and 570 men with N = 1,166 (Mage = 32.58, SDage = 9.76, range: 18-80 years). We conducted robust linear regression models to investigate the influence of age at initial abduction, traumatic load, combat experience, and biological sex on appetitive aggression as well as their perpetrated violent acts. Our study shows, appetitive aggression and the number of perpetrated violent acts were specifically increased in individuals who were abducted young, experienced several traumatic events in their lifetime, and with previous combat experience. For perpetrated violence men showed increased levels whereas for appetitive aggression the association was independent of biological sex. Therefore, early abducted individuals with a higher traumatic load, who have combat experience, need to be given special intervention to prevent any further violence.