A prebiotically plausible scenario of an RNA-peptide world.

The RNA world concept1 is one of the most fundamental pillars of the origin of life theory2-4. It predicts that life evolved from increasingly complex self-replicating RNA molecules1,2,4. The question of how this RNA world then advanced to the next stage, in which proteins became the catalysts of life and RNA reduced its function predominantly to information storage, is one of the most mysterious chicken-and-egg conundrums in evolution3-5. Here we show that non-canonical RNA bases, which are found today in transfer and ribosomal RNAs6,7, and which are considered to be relics of the RNA world8-12, are able to establish peptide synthesis directly on RNA. The discovered chemistry creates complex peptide-decorated RNA chimeric molecules, which suggests the early existence of an RNA-peptide world13 from which ribosomal peptide synthesis14 may have emerged15,16. The ability to grow peptides on RNA with the help of non-canonical vestige nucleosides offers the possibility of an early co-evolution of covalently connected RNAs and peptides13,17,18, which then could have dissociated at a higher level of sophistication to create the dualistic nucleic acid-protein world that is the hallmark of all life on Earth.

Association of prehospital lactate levels with base excess in various emergencies - a retrospective study.

OBJECTIVES: Blood gas analysis, including parameters like lactate and base excess (BE), is crucial in emergency medicine but less commonly utilized prehospital. This study aims to elucidate the relationship between lactate and BE in various emergencies in a prehospital setting and their prognostic implications. METHODS: We conducted a retrospective analysis of prehospital emergency patients in Graz, Austria, from October 2015 to November 2020. Our primary aim was to assess the association between BE and lactate. This was assessed using Spearman's rank correlation and fitting a multiple linear regression model with lactate as the outcome, BE as the primary covariate of interest and age, sex, and medical emergency type as confounders. RESULTS: In our analysis population (n=312), lactate and BE levels were inversely correlated (Spearman's ρ, -0.75; p<0.001). From the adjusted multiple linear regression model (n=302), we estimated that a 1 mEq/L increase in BE levels was associated with an average change of -0.35 (95 % CI: -0.39, -0.30; p<0.001) mmol/L in lactate levels. Lactate levels were moderately useful for predicting mortality with notable variations across different emergency types. CONCLUSIONS: Our study highlights a significant inverse association between lactate levels and BE in the prehospital setting, underscoring their importance in early assessment and prognosis in emergency care. Additionally, the findings from our secondary aims emphasize the value of lactate in diagnosing acid-base disorders and predicting patient outcomes. Recognizing the nuances in lactate physiology is essential for effective prehospital care in various emergency scenarios.

Synthesis and Structure Elucidation of Glutamyl-Queuosine.

Queuosine is one of the most complex hypermodified RNA nucleosides found in the Wobble position of tRNAs. In addition to Queuosine itself, several further modified derivatives are known, where the cyclopentene ring structure is additionally modified by a galactosyl-, a mannosyl-, or a glutamyl-residue. While sugar-modified Queuosine derivatives are found in the tRNAs of vertebrates, glutamylated Queuosine (gluQ) is only known in bacteria. The exact structure of gluQ, particularly with respect to how and where the glutamyl side chain is connected to the Queuosine cyclopentene side chain, is unknown. Here we report the first synthesis of gluQ and, using UHPLC-MS-coinjection and NMR studies, we show that the isolated natural gluQ is the α-allyl-connected gluQ compound.

High serum neurofilament light chain levels correlate with brain atrophy and physical disability in multiple sclerosis.

BACKGROUND AND PURPOSE: Serum neurofilament light chain (sNfL) is a promising biomarker of neuroaxonal damage in persons with multiple sclerosis (pwMS). In cross-sectional studies, sNfL has been associated with disease activity and brain magnetic resonance imaging (MRI) changes; however, it is still unclear to what extent in particular high sNfL levels impact on subsequent disease evolution. METHODS: sNfL was quantified by an ultrasensitive single molecule array (Simoa) in 199 pwMS (median age = 34.2 years, 64.3% female) and 49 controls. All pwMS underwent 3-T MRI to assess global and compartmental normalized brain volumes, T2-lesion load, and cortical mean thickness. Follow-up data and serum samples were available in 144 pwMS (median follow-up time = 3.8 years). Linear and binary logistic models were used to estimate the independent contribution of sNfL for changes in MRI and Expanded Disability Status Scale (EDSS). Age-corrected sNfL z-scores from a normative database of healthy controls were used for sensitivity analyses. RESULTS: High sNfL levels at baseline were associated with atrophy measures of the whole brain (standardized beta coefficient ßj = -0.352, p < 0.001), white matter (ßj = -0.229, p = 0.007), thalamus (ßj = -0.372, p = 0.004), and putamen (ßj = -1.687, p = 0.012). pwMS with high levels of sNfL at baseline and follow-up had a greater risk of EDSS worsening (p = 0.007). CONCLUSIONS: Already single time point elevation of sNfL has a distinct effect on brain volume changes over a short-term period, and repeated high levels of sNfL indicate accumulating physical disability. Serial assessment of sNfL may provide added value in the clinical management of pwMS.

Out-of-Hospital Arterial to End-Tidal Carbon Dioxide Gradient in Patients With Return of Spontaneous Circulation After Out-of-Hospital Cardiac Arrest: A Retrospective Study.

STUDY OBJECTIVE: End-tidal carbon dioxide (etCO2) is used to guide ventilation after achieving return of spontaneous circulation (ROSC) in certain out-of-hospital systems, despite an unknown difference between arterial and end-tidal CO2 (partial pressure of carbon dioxide [paCO2]-etCO2 difference) levels in this population. The primary aim of this study was to evaluate and quantify the paCO2-etCO2 difference in out-of-hospital patients with ROSC after nontraumatic cardiac arrest. METHODS: This retrospective single-center study included patients aged 18 years and older with sustained ROSC after nontraumatic out-of-hospital cardiac arrest. In patients with an existing out-of-hospital arterial blood gas analysis within 30 minutes after achieving ROSC, matching etCO2 values were evaluated. Linear regression and Bland-Altman plot analysis were performed to ascertain the primary endpoint of interest. RESULTS: We included data of 60 patients in the final analysis. The mean paCO2-etCO2 difference was 32 (±18) mmHg. Only a moderate correlation (R2=0.453) between paCO2 and etCO2 was found. Bland-Altman analysis showed a bias of 32 mmHg (95% confidence interval [CI], 27 to 36) [the upper limit of agreement of 67 mmHg (95% CI, 59 to 74) and the lower limit of agreement of -3 mmHg (95% CI, -11 to 5)]. CONCLUSION: The paCO2-etCO2 difference in patients with ROSC after out-of-hospital cardiac arrest is far from physiologic ranges, and the between-patient variability is high. Therefore, etCO2-guided adaption of ventilation might not provide adequate accuracy in this setting.

Long-term course and morphological MRI correlates of cognitive function in multiple sclerosis.

BACKGROUND: Cognitive impairment frequently occurs in patients with MS (pwMS). Magnetic resonance imaging (MRI) markers could help to identify patients at risk for decline. OBJECTIVE: To characterize the long-term course and morphological MRI correlates of cognitive function in pwMS. METHODS: We invited 116 pwMS who had undergone clinical, cognitive, and MRI evaluations between 2006 and 2012 (baseline, BL) to attend follow-up (FU) testing between 2016 and 2018. Disability (expanded disability status scale (EDSS)), cognition (brief repeatable battery of neuropsychological test (BRB-N)), global and regional T2-lesion load (T2-LL), brain volumes, and cortical thickness were assessed. RESULTS: Sixty-three pwMS were willing to attend the FU (54%; median EDSS = 2, interquartile range (IQR) = 2) and did not differ from non-participating pwMS regarding BL characteristics. At BL, half of the participants showed cognitive deficits in at least one domain. Across the entire group, we observed no relevant changes in physical disability and cognition over 10 years. BL thalamic volume best predicted cognitive function at FU, in addition to age and BL cognition, explaining 67% of variance. Cognitive decliners (23.8%) were older, had longer disease duration, and a tendency for lower thalamic volume at BL. CONCLUSION: Thalamic volume predicted FU cognitive function and distinguished declining from stable pwMS, underlining the potential of MRI to define risk groups.

The role of pontine lesion location in differentiating multiple sclerosis from vascular risk factor-related small vessel disease.

BACKGROUND: Differentiating multiple sclerosis (MS) from vascular risk factor (VRF)-small vessel disease (SVD) can be challenging. OBJECTIVE AND METHODS: In order to determine whether or not pontine lesion location is a useful discriminator of MS and VRF-SVD, we classified pontine lesions on brain magnetic resonance imaging (MRI) as central or peripheral in 93 MS cases without VRF, 108 MS patients with VRF and 43 non-MS cases with VRF. RESULTS: MS without VRF were more likely to have peripheral pons lesions (31.2%, 29/93) than non-MS with VRF (0%, 0/43) (Exp(B) = 29.8; 95% confidence interval (CI) = (1.98, 448.3); p = 0.014) but there were no significant differences regarding central pons lesions between MS without VRF (5.4%, 5/93) and non-MS with VRF patients (16.3%, 7/43) (Exp(B) = 0.89; 95% CI = (0.2, 3.94); p = 0.87). The presence of peripheral pons lesions discriminated between MS and VRF-SVD with 100% (95% CI = (91.8, 100)) specificity. The proportion of peripheral pons lesions in MS with VRF (30.5%, 33/108) was similar to that seen in MS without VRF (31.2%, 29/93, p = 0.99). Central lesions occurred in similar frequency in MS with VRF (8.3%, 9/108) and non-MS with VRF (16.3%, 7/43, p = 0.15). CONCLUSION: Peripheral pons lesion location is a good discriminator of MS from vascular lesions.

A Click-Chemistry Linked 2'3'-cGAMP Analogue.

2'3'-cGAMP is an uncanonical cyclic dinucleotide where one A and one G base are connected via a 3'-5' and a unique 2'-5' linkage. The molecule is produced by the cyclase cGAS in response to cytosolic DNA binding. cGAMP activates STING and hence one of the most powerful pathways of innate immunity. cGAMP analogues with uncharged linkages that feature better cellular penetrability are currently highly desired. Here, the synthesis of a cGAMP analogue with one amide and one triazole linkage is reported. The molecule is best prepared via a first CuI -catalyzed click reaction, which establishes the triazole, while the cyclization is achieved by macrolactamization.

The impact of vascular risk factors on brain volume and lesion load in patients with early multiple sclerosis.

BACKGROUND: Vascular risk factors (VRF) in multiple sclerosis (MS) patients have been associated with lower brain volumes. It is currently unknown if this association already exists in early MS and how it develops over time. METHODS: We identified 82 patients with clinically isolated syndrome (CIS) ( n = 61) or with early relapsing-remitting MS ( n = 21) and assessed their VRF including arterial hypertension, hyperlipidaemia, diabetes mellitus and smoking. We analysed T2-lesion load, normalized brain volume (NBV), cortical grey (cGMV) and white matter volumes (WMV), thalamic and basal ganglia volumes at baseline and follow-up magnetic resonance imaging (MRI) and assessed the percentage of brain volume change (PBVC) using SIENA. RESULTS: Patient mean age was 32.4 (±8.7) years and 54 (65%) were women. Median follow-up period was 42 (29-54) months. In total, 26 patients (31.7%) had one or more VRF (VRF+). At baseline, VRF+ patients had a lower NBV (1530.9 cm3 vs 1591.2 cm3, p = 0.001), a lower cGMV (628.5 cm3 vs 668.6 cm3, p = 0.002) and WMV (752.2 cm3 vs 783.9 cm3, p = 0.009) than VRF-negative patients. Similar results were obtained at follow-up. PBVC was comparable between patients with and without VRF. CONCLUSION: VRF are associated with lower brain volume already in early MS but do not lead to increased brain volume loss during 3.5 years of follow-up.

Genetic variants influencing elevated myeloperoxidase levels increase risk of stroke.

Primary intracerebral haemorrhage and lacunar ischaemic stroke are acute manifestations of progressive cerebral microvascular disease. Current paradigms suggest atherosclerosis is a chronic, dynamic, inflammatory condition precipitated in response to endothelial injury from various environmental challenges. Myeloperoxidase plays a central role in initiation and progression of vascular inflammation, but prior studies linking myeloperoxidase with stroke risk have been inconclusive. We hypothesized that genetic determinants of myeloperoxidase levels influence the development of vascular instability, leading to increased primary intracerebral haemorrhage and lacunar stroke risk. We used a discovery cohort of 1409 primary intracerebral haemorrhage cases and 1624 controls from three studies, an extension cohort of 12 577 ischaemic stroke cases and 25 643 controls from NINDS-SiGN, and a validation cohort of 10 307 ischaemic stroke cases and 29 326 controls from METASTROKE Consortium with genome-wide genotyping to test this hypothesis. A genetic risk score reflecting elevated myeloperoxidase levels was constructed from 15 common single nucleotide polymorphisms identified from prior genome-wide studies of circulating myeloperoxidase levels (P < 5 × 10-6). This genetic risk score was used as the independent variable in multivariable regression models for association with primary intracerebral haemorrhage and ischaemic stroke subtypes. We used fixed effects meta-analyses to pool estimates across studies. We also used Cox regression models in a prospective cohort of 174 primary intracerebral haemorrhage survivors for association with intracerebral haemorrhage recurrence. We present effects of myeloperoxidase elevating single nucleotide polymorphisms on stroke risk per risk allele, corresponding to a one allele increase in the myeloperoxidase increasing genetic risk score. Genetic determinants of elevated circulating myeloperoxidase levels were associated with both primary intracerebral haemorrhage risk (odds ratio, 1.07, P = 0.04) and recurrent intracerebral haemorrhage risk (hazards ratio, 1.45, P = 0.006). In analysis of ischaemic stroke subtypes, the myeloperoxidase increasing genetic risk score was strongly associated with lacunar subtype only (odds ratio, 1.05, P = 0.0012). These results, demonstrating that common genetic variants that increase myeloperoxidase levels increase risk of primary intracerebral haemorrhage and lacunar stroke, directly implicate the myeloperoxidase pathway in the pathogenesis of cerebral small vessel disease. Because genetic variants are not influenced by environmental exposures, these results provide new support for a causal rather than bystander role for myeloperoxidase in the progression of cerebrovascular disease. Furthermore, these results support a rationale for chronic inflammation as a potential modifiable stroke risk mechanism, and suggest that immune-targeted therapies could be useful for treatment and prevention of cerebrovascular disease.

Meta-analysis of genome-wide association studies identifies 1q22 as a susceptibility locus for intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 × 10(-6) was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 × 10(-8)); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 × 10(-8)). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 × 10(-4); meta-analysis p = 2.2 × 10(-10)) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 × 10(-5)). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly.

Genetic variants in CETP increase risk of intracerebral hemorrhage.

OBJECTIVE: In observational epidemiologic studies, higher plasma high-density lipoprotein cholesterol (HDL-C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein (CETP) gene activity increase plasma HDL-C; as such, medicines that inhibit CETP and raise HDL-C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL-C also increase risk for ICH. METHODS: We performed 2 candidate-gene analyses of CETP. First, we tested individual CETP variants in a discovery cohort of 1,149 ICH cases and 1,238 controls from 3 studies, followed by replication in 1,625 cases and 1,845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL-C as well as ICH risk. RESULTS: Twelve variants within CETP demonstrated nominal association with ICH, with the strongest association at the rs173539 locus (odds ratio [OR] = 1.25, standard error [SE] = 0.06, p = 6.0 × 10-4 ) with no heterogeneity across studies (I2 = 0%). This association was replicated in patients of European ancestry (p = 0.03). A genetic score of CETP variants found to increase HDL-C by ∼2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR = 1.86, SE = 0.13, p = 1.39 × 10-6 ). INTERPRETATION: Genetic variants in CETP associated with increased HDL-C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL-raising strategies, further exploration of potential adverse cerebrovascular outcomes may be warranted. Ann Neurol 2016;80:730-740.

Multiple scattering in grazing-incidence X-ray diffraction: impact on lattice-constant determination in thin films.

Dynamical scattering effects are observed in grazing-incidence X-ray diffraction experiments using an organic thin film of 2,2':6',2''-ternaphthalene grown on oxidized silicon as substrate. Here, a splitting of all Bragg peaks in the out-of-plane direction (z-direction) has been observed, the magnitude of which depends both on the incidence angle of the primary beam and the out-of-plane angle of the scattered beam. The incident angle was varied between 0.09° and 0.25° for synchrotron radiation of 10.5 keV. This study reveals comparable intensities of the split peaks with a maximum for incidence angles close to the critical angle of total external reflection of the substrate. This observation is rationalized by two different scattering pathways resulting in diffraction peaks at different positions at the detector. In order to minimize the splitting, the data suggest either using incident angles well below the critical angle of total reflection or angles well above, which sufficiently attenuates the contributions from the second scattering path. This study highlights that the refraction of X-rays in (organic) thin films has to be corrected accordingly to allow for the determination of peak positions with sufficient accuracy. Based thereon, a reliable determination of the lattice constants becomes feasible, which is required for crystallographic structure solutions from thin films.

Periventricular lesions correlate with cortical thinning in multiple sclerosis.

OBJECTIVE: It has been suggested recently that cortical pathology in multiple sclerosis (MS) may, at least partly, be caused by factors in cerebrospinal fluid (CSF). We thus hypothesized that MS-related tissue changes in compartments close to the CSF, such as periventricular lesions, might correlate with cortical pathology. METHODS: We investigated a cohort of 160 patients, comprising 91 with a clinically isolated syndrome (CIS) and 69 with relapsing-remitting MS (RRMS; mean age: CIS: 31.4 ± 9.0; RRMS: 33.0 ± 8.7 years; mean disease duration: CIS: 7.2 ± 15 months; RRMS: 8.0 ± 6.5 years, Expanded Disability Status Scale (median, min-max): CIS: 1, 0-3.5; RRMS: 1.25, 0-4) with 3.0T magnetic resonance imaging. MS lesions were segmented semiautomatically on fluid-attenuated inversion recovery images. To quantify periventricular lesion load (PV-LL), we generated ventricle masks and dilated them by a voxel factor of 3. Lesions within the dilated ventricle margin were classified as periventricular. Cortical thinning was assessed by cortical mean thickness (CMT) and compared to data from 58 healthy controls (HCs; mean age: 29.1 ± 7.4 years). RESULTS: Compared to HC, CIS and (even more so) RRMS patients demonstrated significantly reduced CMT. Even after controlling for ventricular volume and total lesion load, increased periventricular lesion occupancy (percentage of PV-LL) significantly correlated with decreased CMT in RRMS (r = -0.295; p = 0.015), but not in CIS (r = 0.032; p = 0.768) patients. INTERPRETATION: The correlation between increased periventricular lesion burden and decreased CMT indicative of subpial cortical pathology supports the concept that common CSF-mediated factors might play a role in the accumulation of damage to gray and white matter in MS.

Use of bitemporal NACA score documentation in prehospital emergency medical services- a retrospective study.

BACKGROUND: The assessment of illness severity in the prehospital setting is essential for guiding appropriate medical interventions. The National Advisory Committee for Aeronautics (NACA) score is a validated tool commonly used for this purpose. However, the potential benefits of using bitemporal documentation of NACA scores to capture the dynamic changes in emergency situations remain uncertain. The objective of this study was to evaluate the potential benefit of bitemporal NACA score documentation in the prehospital setting, specifically in assessing the dynamic changes of emergencies and facilitating quality improvement through enhanced documentation practices. METHODS: In this retrospective study, data from prehospital emergency patients were analyzed who received care from the physician response unit between January 1, 2018, and May 31, 2021. Patient demographics, NACA scores, indications for emergency care, and changes in NACA scores were extracted from medical records. Statistical analyses were performed to examine the associations between NACA scores, emergency categories, indications, and changes in NACA scores. RESULTS: The study included 4005 patients, predominantly categorized as NACA III (33.7% at initial assessment, 41.8% at subsequent assessment) and NACA IV (31.6% at initial assessment, 22.4% at subsequent assessment). There was a significant improvement in NACA scores during the provision of prehospital care (p < 0.01). Notably, prehospital emergencies attributed to internal medical, neurological, traumatic, and paediatric causes demonstrated significant improvements in NACA scores (p < 0.01). Gender-specific differences were also observed. CONCLUSION: Our study suggests that the bitemporal documentation of NACA scores can be advantageous in the prehospital setting and may have implications for research, practice, and policy.

Hyperkalaemia in bleeding trauma patients: A potential marker of disease severity - A retrospective cohort study.

Background: Hyperkalaemia is a common electrolyte abnormality seen in critically ill patients. In haemorrhagic shock, it may contribute to cardiac arrest and has been identified as a potential marker for tissue hypoxia. However, the significance of its role in haemorrhagic shock and its contribution to mortality remains unclear. This study aimed to examine the potential underlying pathophysiology and evaluate the incidence and characteristics of patients with hyperkalaemia on hospital arrival in bleeding trauma patients before transfusions and its mortality. Methods: A retrospective cohort study was conducted on adult patients with traumatic bleeding admitted to a European Major Trauma Centre between January 2016 and December 2021. Patients were classified according to their serum potassium levels on arrival, and relevant clinical parameters between non-hyperkalaemic and hyperkalaemic patients were compared. Results: Among the 83 patients in this study, 8 (9.6 %) presented with hyperkalaemia on arrival. The median shock index showed a higher tendency in the hyperkalaemic group. Hyperkalaemia was found to be more common among younger patients who sustained penetrating trauma. Mortality rates were higher in the hyperkalaemic group, but the difference was not statistically significant. Conclusion: Our results suggest that hyperkalaemia occurs frequently in bleeding trauma patients on hospital arrival pre-transfusions, indicating a more severe illness. Our findings provide insights into the pathophysiology and characteristics of hyperkalaemia in bleeding trauma patients. Further studies are required to investigate the mechanisms by which hyperkalaemia contributes to mortality in haemorrhagic shock patients.

Evaluation of the T25FW in minimally disabled people with multiple sclerosis.

BACKGROUND: Walking impairment is one of the most prevalent symptoms in people with multiple sclerosis (pwMS). In this study, we aimed to explore the usefulness of a simple walking test, the Timed 25 Foot Walk (T25FW), in detecting subtle differences in "fully ambulatory" pwMS compared to HC. METHODS: We therefore investigated retrospective data from a clinical real-life cohort of 650 pwMS. We first analyzed the amount of patients showing clinically relevant impairment in the T25FW (T25FW > 6 s) within different levels of disability according to the Expanded Disability Status Scale (EDSS). For detailed analysis in "fully ambulatory" pwMS, we formed four groups according to the respective levels of disability (EDSS 0, EDSS 1, EDSS 1.5-2, EDSS 2.5-3), and compared their walking speed to age- and sex-matched healthy controls (HC). RESULTS: In our cohort, the number of patients showing clinically relevant slowing in the T25FW ranged from 15% in "fully ambulatory" patients (EDSS 0-3) to 69% in patients with moderate (EDSS 3.5-5.5) and 100% in patients with severe impairment (EDSS ≥6). Further analyses in "fully ambulatory" patients revealed that all EDSS-subgroups showed significant slowing compared to HC. The mean difference to walking speed of HC became gradually more pronounced from 0.15 m/s in asymptomatic patients (EDSS 0) to 0.5 m/s in patients with EDSS 2.5-3. CONCLUSION: These findings underline the ability of the T25FW to detect slowing even in patients with minimal disability. While the difference to HC was slightly below clinical relevance in asymptomatic patients (EDSS 0), slowing gradually worsened from EDSS 1 onwards and exceeded published thresholds for clinical meaningfulness.

Hyperactive STAT5 hijacks T cell receptor signaling and drives immature T cell acute lymphoblastic leukemia.

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive immature T cell cancer. Mutations in IL7R have been analyzed genetically, but downstream effector functions such as STAT5A and STAT5B hyperactivation are poorly understood. Here, we studied the most frequent and clinically challenging STAT5BN642H driver in T cell development and immature T cell cancer onset and compared it with STAT5A hyperactive variants in transgenic mice. Enhanced STAT5 activity caused disrupted T cell development and promoted an early T cell progenitor-ALL phenotype, with upregulation of genes involved in T cell receptor (TCR) signaling, even in absence of surface TCR. Importantly, TCR pathway genes were overexpressed in human T-ALL and mature T cell cancers and activation of TCR pathway kinases was STAT5 dependent. We confirmed STAT5 binding to these genes using ChIP-Seq analysis in human T-ALL cells, which were sensitive to pharmacologic inhibition by dual STAT3/5 degraders or ZAP70 tyrosine kinase blockers in vitro and in vivo. We provide genetic and biochemical proof that STAT5A and STAT5B hyperactivation can initiate T-ALL through TCR pathway hijacking and suggest similar mechanisms for other T cell cancers. Thus, STAT5 or TCR component blockade are targeted therapy options, particularly in patients with chemoresistant clones carrying STAT5BN642H.

PerIoperative iNflammatory reSponse assessment In hiGH-risk patienTs undergoing non-cardiac surgery (INSIGHT): study protocol of a prospective non-interventional observational study.

INTRODUCTION: Increased inflammatory processes after non-cardiac surgery are very common. The association between postoperative inflammation and the occurrence of cardiovascular complications after non-cardiac surgery are still not entirely clear. Therefore, we will evaluate the association between postoperative inflammation and the occurrence of major cardiovascular complications in patients at-risk for cardiovascular complications undergoing non-cardiac surgery. We will further evaluate the association of postoperative inflammation and days-at-home within 30 days after surgery (DAH30), the incidence of acute kidney injury, postoperative N-terminal probrain natriuretic peptide (NT-proBNP) concentrations and neurocognitive decline. METHODS AND ANALYSIS: In this multicentre study, we will include 1400 patients at-risk for cardiovascular complications undergoing non-cardiac surgery. Our primary aim is to evaluate the association of postoperative maximum C-reactive protein concentration and the occurrence of a composite of five major cardiovascular complications (myocardial infarction, myocardial injury after non-cardiac surgery, new onset of atrial fibrillation, stroke and death) within 30 days after surgery using a Mann-Whitney-U test as well as a logistic regression model. As our secondary aim, we will evaluate the association of a composite of three inflammatory biomarkers (interleukin 6, procalcitonin and copeptin) on the occurrence of our composite of five cardiovascular complications within 30 days and 1 year after surgery, acute kidney injury, DAH30 and NT-proBNP concentrations using linear or logistic regression models. We will measure inflammatory biomarkers before surgery, and on the first, second, third and fifth postoperative day. We will check medical records and conduct a telephone survey 30 days and 1 year after surgery. We evaluate neurocognitive function, using a Montreal Cognitive Assessment, before and 1 year after surgery. ETHICS AND DISSEMINATION: This study was approved by the ethics committees at the Medical University of Vienna (2458/2020) and at the Medical University of Graz (33-274 ex 20/21). TRIAL REGISTRATION NUMBER: NCT04753307.