Genetic structure and climate niche differentiation among populations of Leopardus geoffroyi.

Geoffroy's cat (Leopardus geoffroyi) is a small-sized felid native to South America. Given the species' distribution covering a wide variety of habitats, and the presence of high levels of anthropization in part of its range, it is possible that genetically differentiated groups exist and that they occupy different climatic niches. We assessed patterns of contemporary genetic diversity and structure in the species across most of its range, characterizing each inferred genetic group based on ecological niche models. We genotyped 11 microsatellites for 142 samples covering most of Geoffroy's cat distribution, and investigated patterns of genetic structure and diversity, applying spatial and nonspatial Bayesian clustering methods and a spatial principal component analysis. We created ecological niche models for each genetic cluster, evaluating whether these clusters occupy different climatic spaces and display differences in the suitability of different values of the climatic variables analyzed. We identified two genetic clusters, one in the north-northeast and the other in the south-southwest of the species' distribution. These clusters showed moderate FST values between them and differences in dispersal/genetic diversity. We found isolation-by-distance patterns globally and within each cluster. We observed lower expected heterozygosity compared with other studies and a north-south gradient in allelic richness. The southern cluster showed lower genetic variability and a more restricted climatic niche suggesting that this group is more vulnerable to the effects of the current context of climate change. Individuals from the southern genetic cluster are under different pressures, likely a product of the particularly dry habitat they occupy. Climatic variables associated with habitat suitability suggest the southern cluster has affinity for the arid and semiarid conditions present in its distribution. Conservation measures should consider the genetic structure observed and differences in climatic spaces to maintain the evolutionary potential of the species.

Pneumonectomy following penetrating trauma with ECMO as postoperative support: case report - (Lung trauma and ECMO).

BACKGROUND: Penetrating thoracic injuries have a significant risk of morbi-mortality. Despite the advancements in damage control methods, a subset of patients with severe pulmonary vascular lesions and bronchial injuries persists. In some of these cases, post-traumatic pneumonectomy is required, and perioperative extracorporeal membrane oxygenation (ECMO) support may be required due to right ventricular failure and respiratory failure. CASE DESCRIPTION: A male was brought to the emergency department (ED) with a penetrating thoracic injury, presenting with massive right hemothorax and active bleeding that required ligation of the right pulmonary hilum to control the bleeding. Subsequently, he developed right ventricular dysfunction and ARDS, necessitating a dynamic hybrid ECMO configuration to support his condition and facilitate recovery. CONCLUSIONS: Penetrating thoracic injuries with severe pulmonary vascular lesions may need pneumonectomy to control bleeding. ECMO support reduces the associated mortality by decreasing the complications rate. A multidisciplinary team is essential to achieve good outcomes in severe compromised patients.

Neuropathological Lesions and Cognitive Abilities in Black and White Older Adults in Brazil.

Importance: Race differences in dementia prevalence and incidence have previously been reported, with higher dementia burden in Black decedents. However, previous neuropathological studies were conducted mostly in convenience samples with White participants; conducting clinicopathological studies across populations is crucial for understanding the underlying dementia causes in individuals from different racial backgrounds. Objective: To compare the frequencies of neuropathological lesions and cognitive abilities between Black and White Brazilian adults in an autopsy study. Design, Setting, and Participants: This cross-sectional study used samples from the Biobank for Aging Studies, a population-based autopsy study conducted in Sao Paulo, Brazil. Participants were older adults whose family members consented to the brain donations; Asian participants and those with missing data were excluded. Samples were collected from 2004 to 2023. Neuropathologists were masked to cognitive outcomes. Exposure: Race as reported by the deceased's family member. Main Outcomes and Measures: The frequencies of neurodegenerative and cerebrovascular lesions were evaluated in 13 selected cerebral areas. Cognitive and functional abilities were examined with the Clinical Dementia Rating Scale. Results: The mean (SD) age of the 1815 participants was 74.0 (12.5) years, 903 (50%) were women, 617 (34%) were Black, and 637 (35%) had cognitive impairment. Small vessel disease (SVD) and siderocalcinosis were more frequent in Black compared with White participants (SVD: odds ratio [OR], 1.74; 95% CI, 1.29-2.35; P < .001; siderocalcinosis: OR, 1.70; 95% CI, 1.23-2.34; P = .001), while neuritic plaques were more frequent in White compared with Black participants (OR, 0.61; 95% CI, 0.44-0.83; P = .002). Likewise, Alzheimer disease neuropathological diagnosis was more frequent in White participants than Black participants (198 [39%] vs 77 [33%]), while vascular dementia was more common among Black participants than White participants (76 [32%] vs 121 [24%]). Race was not associated with cognitive abilities, nor did it modify the association between neuropathology and cognition. Conclusions and Relevance: In this cross-sectional study of Brazilian older adults, Alzheimer disease pathology was more frequent in White participants while vascular pathology was more frequent in Black participants. Further neuropathological studies in diverse samples are needed to understand race disparities in dementia burden.

Evaluating the Shock Index, Revised Assessment of Bleeding and Transfusion (RABT), Assessment of Blood Consumption (ABC) and novel PTTrauma score to predict critical transfusion threshold (CAT) in penetrating thoracic trauma.

The shock index (SI) has been associated with predicting transfusion needs in trauma patients. However, its utility in penetrating thoracic trauma (PTTrauma) for predicting the Critical Administration Threshold (CAT) has not been well-studied. This study aimed to evaluate the prognostic value of SI in predicting CAT in PTTrauma patients and compare its performance with the Assessment of Blood Consumption (ABC) and Revised Assessment of Bleeding and Transfusion (RABT) scores. We conducted a prognostic type 2, single-center retrospective observational cohort study on patients with PTTrauma and an Injury Severity Score (ISS) > 9. The primary exposure was SI at admission, and the primary outcome was CAT. Logistic regression and decision curve analysis were used to assess the predictive performance of SI and the PTTrauma score, a novel model incorporating clinical variables. Of the 620 participants, 53 (8.5%) had more than one CAT. An SI > 0.9 was associated with CAT (adjusted OR 4.89, 95% CI 1.64-14.60). The PTTrauma score outperformed SI, ABC, and RABT scores in predicting CAT (AUC 0.867, 95% CI 0.826-0.908). SI is a valuable predictor of CAT in PTTrauma patients. The novel PTTrauma score demonstrates superior performance compared to existing scores, highlighting the importance of developing targeted predictive models for specific injury patterns. These findings can guide clinical decision-making and resource allocation in the management of PTTrauma.

Prognostic value of liver metastases in colorectal cancer treated by systemic therapy: An ARCAD pooled analysis.

BACKGROUND: The liver is the most frequent site of metastases in colorectal cancer (CRC). This study aimed to assess the response rate and survival outcomes in metastatic CRC patients with non-liver metastases (NLM) compared to those with liver metastases (LM) across different lines of treatment. METHODS: A total of 17,924 mCRC patients included in 26 trials from the ARCAD CRC database were analyzed. The analysis was conducted based on the presence or absence of LM across different treatment groups: chemotherapy (CT) alone, CT + anti-VEGF, CT + anti-EGFR in KRAS wild-type tumors, within the first-line (1 L) and second-line (2 L), and patients enrolled in third-line (≥3 L) trials treated with trifluridine/tipiracil or regorafenib or placebo. The endpoints were overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). RESULTS: Out of the 17,924 patients, 14,066 had LM (30.6 % with only liver involvement and 69.4 % with liver and other metastatic sites), while 3858 patients had NLM. In the CT alone and CT + anti-VEGF subgroups, NLM patients showed better OS and PFS in the 1 L and 2 L settings. However, in the CT + anti-EGFR 1 L and 2 L subgroups, there was no significant difference in OS and PFS between NLM and LM patients. In the ≥ 3 L subgroups, better OS and PFS were observed in NLM patients. ORRs were higher in LM patients than in NLM patients across all cohorts treated in the 1 L and only in the anti-EGFR cohort in the 2 L. CONCLUSION: LM is a poor prognostic factor for mCRC increasing from 1 L to ≥ 3 L except for patients in 1 L and 2 L receiving CT+anti-EGFR. These data justify using LM as a stratification factor in future trials for patients with unresectable mCRC.

ANCA in patients with systemic lupus erythematosus. A cross sectional study in Brazilian patients and review of literature.

BACKGROUND: Antineutrophil cytoplasmatic antibodies (ANCA) have been detected in patients with systemic lupus erythematosus (SLE). In this study, we investigated the presence of ANCA in a sample of Brazilian SLE patients and its possible associations with clinical and serological outcomes. Additionally, we reviewed the literature of on ANCA in SLE. RESULTS: The presence of ANCA was detected in 130 patients using indirect immunofluorescence (IIF). The test was positive in 29.9% of the cases (17.6% pANCA and 11.5% cANCA). Male sex and peripheral vasculitis were more prevalent in the ANCA-positive sample. cANCA was associated with lupus anticoagulant and pANCA had a positive association with peripheral vasculitis and a negative association with anti- SSB/La antibodies. In the 22 studies included in the literature review, a wide range of ANCA positivity was found (13% to 81.1% by IIF and 0 to 22.2% by ELISA). ANCA was associated with renal damage in the Asian population. Although other associations have been found in isolated studies, they were not consistently reported. CONCLUSIONS: The ANCA prevalence found in this Brazilian sample was within the range reported in the literature and these autoantibodies were more frequent in males and in patients with vasculitis. The literature showed controversial results on the association between ANCA and SLE disease activity or clinical characteristics.

Oxaliplatin-Based Adjuvant Chemotherapy in Older Patients With Stage III Colon Cancer: An ACCENT/IDEA Pooled Analysis of 12 Trials.

PURPOSE: A number of studies suggest that older patients may have reduced or no benefit from the addition of oxaliplatin to fluoropyrimidines as adjuvant chemotherapy for stage III colon cancer (CC). MATERIALS AND METHODS: We studied the prognostic impact of age, as well as treatment adherence/toxicity patterns according to age, in patients with stage III CC who received 3 or 6 months of infusional fluorouracil, leucovorin, and oxaliplatin/capecitabine and oxaliplatin (CAPOX) on the basis of data collected from trials from the ACCENT and IDEA databases. Associations between age and time to recurrence (TTR), disease-free survival (DFS), overall survival (OS), survival after recurrence (SAR), and cancer-specific survival (CSS) were assessed by a Cox model or a competing risk model, stratified by studies and adjusted for sex, performance status, T and N stage, and year of enrollment. RESULTS: A total of 17,909 patients were included; 24% of patients were age older than 70 years (n = 4,340). Patients age ≥70 years had higher rates of early treatment discontinuation. Rates of grade ≥3 adverse events were similar between those older and younger than 70 years, except for diarrhea and neutropenia that were more frequent in older patients treated with CAPOX (14.2% v 11.2%; P = .01 and 12.1% v 9.6%; P = .04, respectively). In multivariable analysis, TTR was not significantly different between patients <70 years and those ≥70 years, but DFS, OS, SAR, and CSS were significantly shorter in those patients ≥70 years. CONCLUSION: In patients ≥70 years with stage III CC fit enough to be enrolled in clinical trials, oxaliplatin-based adjuvant chemotherapy was well tolerated and led to similar TTR compared with younger patients, suggesting similar efficacy. TTR may be a more appropriate end point for efficacy in this patient population.

Total Synthesis of Dragocins A-C through Electrochemical Cyclization.

The first total synthesis of dragocins A-C, remarkable natural products containing an unusual C4' oxidized ribose architecture bridged by a polyhydroxylated pyrrolidine, is presented through a route featuring a number of uncommon maneuvers. Several generations towards the target molecules are presented, including the spectacular failure of a key C-H oxidation on a late-stage intermediate. The final route features rapid, stereocontrolled access to a densely functionalized pyrrolidine and an unprecedented diastereoselective oxidative electrochemical cyclization to forge the hallmark 9-membered ring. Preliminary studies suggest this electrochemical oxidation protocol is generally useful.

Vascular access complications associated with resuscitative endovascular balloon occlusion of the aorta in adult trauma patients: A systematic review and meta-analysis.

BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is gaining popularity worldwide for managing hypotensive trauma patients. Vascular access complications related to REBOA placement have been reported, with some cases resulting in permanent morbidity. We aim to capitalize on the increase in literature to further describe and estimate the incidence of REBOA-associated vascular access complications in adult trauma patients. METHODS: We searched Medline, EMBASE, Scopus, and CINAHL for studies reporting vascular access complications of REBOA in adult trauma patients from inception to October 14, 2021. Studies reporting data from adult trauma patients who underwent REBOA insertion were eligible. Exclusion criteria included patients 15 years and younger, nontrauma patients, non-REBOA use, non-vascular access complications and patient duplication. Study data was abstracted using the PRISMA checklist and verified independently by three reviewers. Meta-analysis of proportions was performed using a random effects model with Freeman-Turkey double-arcsine transformation. Post hoc meta-regression by year of publication, sheath-size, and geographic region was also performed. The incidence of vascular access complications from REBOA insertion was the primary outcome of interest. Subgroup analysis was performed by degree of bias, sheath size, technique of vascular access, provider specialty, geographical region, and publication year. RESULTS: Twenty-four articles were included in the systematic review and the meta-analysis, for a total of 675 trauma patients who underwent REBOA insertion. The incidence of vascular access complications was 8% (95% confidence interval, 5%-13%). In post hoc meta-regression adjusting for year of publication and geographic region, the use of a smaller (7-Fr) sheath was associated with a decreased incidence of vascular access complications (odds ratio, 0.87; 95% confidence interval, 0.75-0.99; p = 0.046; R 2 = 35%; I 2 = 48%). CONCLUSION: This study provides a benchmark for quality of care in terms of vascular access complications related to REBOA insertion in adult trauma patients. Smaller sheath size may be associated with a decrease in vascular access complications. LEVEL OF EVIDENCE: Systematic Review and Meta-Analysis; Level III.

Critical systolic blood pressure threshold for endovascular aortic occlusion-A multinational analysis to determine when to place a REBOA.

BACKGROUND: Systolic blood pressure (SBP) is a potential indicator that could guide when to use a resuscitative endovascular balloon occlusion of the aorta (REBOA) in trauma patients with life-threatening injuries. This study aims to determine the optimal SBP threshold for REBOA placement by analyzing the association between SBP pre-REBOA and 24-hour mortality in severely injured hemodynamically unstable trauma patients. METHODS: We performed a pooled analysis of the aortic balloon occlusion (ABO) trauma and AORTA registries. These databases record the details related to the use of REBOA and include data from 14 countries worldwide. We included patients who had suffered penetrating and/or blunt trauma. Patients who arrived at the hospital with a SBP pre-REBOA of 0 mm Hg and remained at 0 mm Hg after balloon inflation were excluded. We evaluated the impact that SBP pre-REBOA had on the probability of death in the first 24 hours. RESULTS: A total of 1,107 patients underwent endovascular aortic occlusion, of these, 848 met inclusion criteria. The median age was 44 years (interquartile range [IQR], 27-59 years) and 643 (76%) were male. The median injury severity score was 34 (IQR, 25-45). The median SBP pre-REBOA was 65 mm Hg (IQR, 49-88 mm Hg). Mortality at 24 hours was reported in 279 (32%) patients. Math modeling shows that predicted probabilities of the primary outcome increased steadily in SBP pre-REBOA below 100 mm Hg. Multivariable mixed-effects analysis shows that when SBP pre-REBOA was lower than 60 mm Hg, the risk of death was more than 50% (relative risk, 1.5; 95% confidence interval, 1.17-1.92; p = 0.001). DISCUSSION: In patients who do not respond to initial resuscitation, the use of REBOA in SBPs between 60 mm Hg and 80 mm Hg may be a useful tool in resuscitation efforts before further decompensation or complete cardiovascular collapse. The findings from our study are clinically important as a first step in identifying candidates for REBOA. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level IV.

Scalable Electrochemical Decarboxylative Olefination Driven by Alternating Polarity.

A mild, scalable (kg) metal-free electrochemical decarboxylation of alkyl carboxylic acids to olefins is disclosed. Numerous applications are presented wherein this transformation can simplify alkene synthesis and provide alternative synthetic access to valuable olefins from simple carboxylic acid feedstocks. This robust method relies on alternating polarity to maintain the quality of the electrode surface and local pH, providing a deeper understanding of the Hofer-Moest process with unprecedented chemoselectivity.

Multiple antiferromagnetic phases and magnetic anisotropy in exfoliated CrBr3 multilayers.

In twisted two-dimensional (2D) magnets, the stacking dependence of the magnetic exchange interaction can lead to regions of ferromagnetic and antiferromagnetic interlayer order, separated by non-collinear, skyrmion-like spin textures. Recent experimental searches for these textures have focused on CrI3, known to exhibit either ferromagnetic or antiferromagnetic interlayer order, depending on layer stacking. However, the very strong uniaxial anisotropy of CrI3 disfavors smooth non-collinear phases in twisted bilayers. Here, we report the experimental observation of three distinct magnetic phases-one ferromagnetic and two antiferromagnetic-in exfoliated CrBr3 multilayers, and reveal that the uniaxial anisotropy is significantly smaller than in CrI3. These results are obtained by magnetoconductance measurements on CrBr3 tunnel barriers and Raman spectroscopy, in conjunction with density functional theory calculations, which enable us to identify the stackings responsible for the different interlayer magnetic couplings. The detection of all locally stable magnetic states predicted to exist in CrBr3 and the excellent agreement found between theory and experiments, provide complete information on the stacking-dependent interlayer exchange energy and establish twisted bilayer CrBr3 as an ideal system to deterministically create non-collinear magnetic phases.

Magnetism-Induced Band-Edge Shift as the Mechanism for Magnetoconductance in CrPS4 Transistors.

Transistors realized on the 2D antiferromagnetic semiconductor CrPS4 exhibit large magnetoconductance due to magnetic-field-induced changes in the magnetic state. The microscopic mechanism coupling the conductance and magnetic state is not understood. We identify it by analyzing the evolution of the parameters determining the transistor behavior─carrier mobility and threshold voltage─with temperature and magnetic field. For temperatures T near the Néel temperature TN, the magnetoconductance originates from a mobility increase due to the applied magnetic field that reduces spin fluctuation induced disorder. For T ≪ TN, instead, what changes is the threshold voltage, so that increasing the field at fixed gate voltage increases the density of accumulated electrons. The phenomenon is explained by a conduction band-edge shift correctly predicted by the ab initio calculations. Our results demonstrate that the band structure of CrPS4 depends on its magnetic state and reveal a mechanism for magnetoconductance that had not been identified earlier.

Electronic Structure of Few-Layer Black Phosphorus from µ-ARPES.

Black phosphorus (BP) stands out among two-dimensional (2D) semiconductors because of its high mobility and thickness dependent direct band gap. However, the quasiparticle band structure of ultrathin BP has remained inaccessible to experiment thus far. Here we use a recently developed laser-based microfocus angle resolved photoemission (µ-ARPES) system to establish the electronic structure of 2-9 layer BP from experiment. Our measurements unveil ladders of anisotropic, quantized subbands at energies that deviate from the scaling observed in conventional semiconductor quantum wells. We quantify the anisotropy of the effective masses and determine universal tight-binding parameters, which provide an accurate description of the electronic structure for all thicknesses.

Determining spin-orbit coupling in graphene by quasiparticle interference imaging.

Inducing and controlling spin-orbit coupling (SOC) in graphene is key to create topological states of matter, and for the realization of spintronic devices. Placing graphene onto a transition metal dichalcogenide is currently the most successful strategy to achieve this goal, but there is no consensus as to the nature and the magnitude of the induced SOC. Here, we show that the presence of backscattering in graphene-on-WSe2 heterostructures can be used to probe SOC and to determine its strength quantitatively, by imaging quasiparticle interference with a scanning tunneling microscope. A detailed theoretical analysis of the Fourier transform of quasiparticle interference images reveals that the induced SOC consists of a valley-Zeeman (λvZ ≈ 2 meV) and a Rashba (λR ≈ 15 meV) term, one order of magnitude larger than what theory predicts, but in excellent agreement with earlier transport experiments. The validity of our analysis is confirmed by measurements on a 30 degree twist angle heterostructure that exhibits no backscattering, as expected from symmetry considerations. Our results demonstrate a viable strategy to determine SOC quantitatively by imaging quasiparticle interference.

Modified NEOMOD score as a neonatal mortality prediction tool in a medium-income country: A validation diagnostic test study.

Background and Aims: Multiple organ dysfunction (MOD) is a potentially reversible physiological disorder that involves two or more systems. Modified NEOMOD (Neonatal Multiple Organ Dysfunction score) scale could be a useful instrument to measure MOD and predict mortality. Our aim was to validate modified NEOMOD in patients from a neonatal intensive care unit (NICU) of a middle-income country. Methods: Diagnostic test study. Preterm newborns admitted NICU were included. Daily values were collected from birthday to Day 14. MOD was defined as at least one point in two or more systems. The lowest score is 0 and the maximum is 16. The outcome variable was mortality. Secondary outcomes were bronchopulmonary dysplasia, retinopathy of prematurity (ROP), late-onset neonatal sepsis (LONS), intraventricular hemorrhage (IVH) and length of hospital stay. Area under the curve (AUC) and Hosmer-Lemeshow test were calculated to evaluate scale discrimination and calibration. Logistic regression was used to estimate the association between daily modified NEOMOD score and death. Results: We included 273 patients who met the inclusion criteria. MOD incidence was 74.4%. The median gestational age in patients with MOD was 30 (interquartile range [IQR]: 27-33) and in patients without MOD it was 32 (IQR: 31-33) (p < 0.001). There were 40 deaths (14.6%), 38 (18.7%) from the MOD group and 2 (2.9%) from non-MOD group. On accumulated Day 7, AUC was 0.89 (95% confidence interval [CI]: 0.83-0.95). Modified NEOMOD had good calibration (X 2 = 2.94, p = 0.982). DBP (12.8% vs. 2.9%, p = 0.001), ROP (3.9% vs. 0%, p = 0.090), IVH (33% vs. 12.9%, p < 0.001), and LONS (36.5% vs. 8.6%, p < 0.001) frequency was higher in the MOD group than non-MOD group. Length of hospital stay also was higher in MOD group (median 21 days [IQR 7-44] vs. median 5 days [IQR 4-9], p = 0.004). Conclusion: Modified NEOMOD scale presents good discrimination and calibration for death in preterm children. This scale could help in clinical decision-making in real-time.

The vestibular calyceal junction is dismantled following subchronic streptomycin in rats and sensory epithelium stress in humans.

Hair cell (HC) loss by epithelial extrusion has been described to occur in the rodent vestibular system during chronic 3,3'-iminodipropionitrile (IDPN) ototoxicity. This is preceded by dismantlement of the calyceal junction in the contact between type I HC (HCI) and calyx afferent terminals. Here, we evaluated whether these phenomena have wider significance. First, we studied rats receiving seven different doses of streptomycin, ranging from 100 to 800 mg/kg/day, for 3-8 weeks. Streptomycin caused loss of vestibular function associated with partial loss of HCI and decreased expression of contactin-associated protein (CASPR1), denoting calyceal junction dismantlement, in the calyces encasing the surviving HCI. Additional molecular and ultrastructural data supported the conclusion that HC-calyx detachment precede HCI loss by extrusion. Animals allowed to survive after the treatment showed functional recuperation and rebuilding of the calyceal junction. Second, we evaluated human sensory epithelia obtained during therapeutic labyrinthectomies and trans-labyrinthine tumour excisions. Some samples showed abnormal CASPR1 label strongly suggestive of calyceal junction dismantlement. Therefore, reversible dismantlement of the vestibular calyceal junction may be a common response triggered by chronic stress, including ototoxic stress, before HCI loss. This may partly explain clinical observations of reversion in function loss after aminoglycoside exposure.

Immediate Norepinephrine in Endotoxic Shock: Effects on Regional and Microcirculatory Flow.

OBJECTIVES: To investigate the effects of immediate start of norepinephrine versus initial fluid loading followed by norepinephrine on macro hemodynamics, regional splanchnic and intestinal microcirculatory flows in endotoxic shock. DESIGN: Animal experimental study. SETTING: University translational research laboratory. SUBJECTS: Fifteen Landrace pigs. INTERVENTIONS: Shock was induced by escalating dose of lipopolysaccharide. Animals were allocated to immediate start of norepinephrine (i-NE) ( n = 6) versus mandatory 1-hour fluid loading (30 mL/kg) followed by norepinephrine (i-FL) ( n = 6). Once mean arterial pressure greater than or equal to 75 mm Hg was, respectively, achieved, successive mini-fluid boluses of 4 mL/kg of Ringer Lactate were given whenever: a) arterial lactate greater than 2.0 mmol/L or decrease less than 10% per 30 min and b) fluid responsiveness was judged to be positive. Three additional animals were used as controls (Sham) ( n = 3). Time × group interactions were evaluated by repeated-measures analysis of variance. MEASUREMENTS AND MAIN RESULTS: Hypotension was significantly shorter in i-NE group (7.5 min [5.5-22.0 min] vs 49.3 min [29.5-60.0 min]; p < 0.001). Regional mesenteric and microcirculatory flows at jejunal mucosa and serosa were significantly higher in i-NE group at 4 and 6 hours after initiation of therapy ( p = 0.011, p = 0.032, and p = 0.017, respectively). Misdistribution of intestinal microcirculatory blood flow at the onset of shock was significantly reversed in i-NE group ( p < 0.001), which agreed with dynamic changes in mesenteric-lactate levels ( p = 0.01) and venous-to-arterial carbon dioxide differences ( p = 0.001). Animals allocated to i-NE showed significantly higher global end-diastolic volumes ( p = 0.015) and required significantly less resuscitation fluids ( p < 0.001) and lower doses of norepinephrine ( p = 0.001) at the end of the experiment. Pulmonary vascular permeability and extravascular lung water indexes were significantly lower in i-NE group ( p = 0.021 and p = 0.004, respectively). CONCLUSIONS: In endotoxemic shock, immediate start of norepinephrine significantly improved regional splanchnic and intestinal microcirculatory flows when compared with mandatory fixed-dose fluid loading preceding norepinephrine. Immediate norepinephrine strategy was related with less resuscitation fluids and lower vasopressor doses at the end of the experiment.