Eculizumab as Salvage Treatment for Thrombotic Microangiopathy After Lung Transplantation.

BACKGROUND: Thrombotic microangiopathy (TMA) is a rare complication after lung transplantation (LT) that has seldom been characterized in detail. Recent evidence has linked TMA other than primary atypical hemolytic uremic syndrome (aHUS) with hyperactivation of the complement alternative pathway. The focus of this investigation was to analyze the treatment response with eculizumab in TMA after LT. METHODS: Case series where we have studied 11 patients with TMA after LT from 2 Spanish tertiary healthcare centers. Clinical data and response rates to eculizumab are provided. RESULTS: The main indication for lung transplant was chronic obstructive pulmonary disease (COPD) (36%) and most cases (82%) received bilateral LT. The median time to TMA diagnosis was 11.6 months (4.7-28.9) and the TMA trigger in the majority of cases (73%) was immunosuppressive drugs. Platelet and hemoglobin nadir were 58 × 103/µL (24-108) and 7.7 g/dL (7.1-7.9), respectively. All cases presented acute kidney injury (AKI) with a median creatinine of 4 mg/dL (3.2-4.8) and 54.5% required acute dialysis. Eculizumab was started after a median time of 8 days (6-14) with a median duration of 3 weeks (2-8). Complete TMA response was observed in 7 (63.6%) cases and hematologic response in 10 (90.9%). The time to hematologic and renal response was 23 days (13-29) and 28 days (14-46), respectively. CONCLUSIONS: TMA after LT is infrequent but potentially devastating. Our findings suggest that short cycles of eculizumab may be effective for severe TMA after LT.

Effects of Fructose and Palmitic Acid on Gene Expression in Drosophila melanogaster Larvae: Implications for Neurodegenerative Diseases.

One of the largest health problems worldwide is the development of chronic noncommunicable diseases due to the consumption of hypercaloric diets. Among the most common alterations are cardiovascular diseases, and a high correlation between overnutrition and neurodegenerative diseases has also been found. The urgency in the study of specific damage to tissues such as the brain and intestine led us to use Drosophila melanogaster to study the metabolic effects caused by the consumption of fructose and palmitic acid in specific tissues. Thus, third instar larvae (96 ± 4 h) of the wild Canton-S strain of D. melanogaster were used to perform transcriptomic profiling in brain and midgut tissues to test for the potential metabolic effects of a diet supplemented with fructose and palmitic acid. Our data infer that this diet can alter the biosynthesis of proteins at the mRNA level that participate in the synthesis of amino acids, as well as fundamental enzymes for the dopaminergic and GABAergic systems in the midgut and brain. These also demonstrated alterations in the tissues of flies that may help explain the development of various reported human diseases associated with the consumption of fructose and palmitic acid in humans. These studies will not only help to better understand the mechanisms by which the consumption of these alimentary products is related to the development of neuronal diseases but may also contribute to the prevention of these conditions.

COVID-19 in lung transplant recipients: A multicenter study.

This study describes the clinical presentation, treatment, and outcomes of SARS-CoV-2 infection in lung transplant recipients (LTRs). This is a multicenter, retrospective study of all adult LTRs with confirmed SARS-CoV-2 infection from March 4 until April 28, 2020 in six Spanish reference hospitals for lung transplantation. Clinical and radiological data, treatment characteristics, and outcomes were reviewed. Forty-four cases were identified in that period. The median time from transplantation was 4.2 (interquartile range: 1.11-7.3) years. Chest radiography showed acute parenchymal abnormalities in 32 (73%) cases. Hydroxychloroquine was prescribed in 41 (93%), lopinavir/ritonavir (LPV/r) in 14 (32%), and tocilizumab in 19 (43%) patients. There was a strong interaction between tacrolimus and LPV/r in all cases. Thirty-seven (84%) patients required some degree of respiratory support and/or oxygen therapy, and 13 (30%) were admitted to intermediate or intensive critical care units. Seventeen (39%) patients had died and 20 (45%) had been discharged at the time of the last follow-up. Deceased patients had a worse respiratory status and chest X-ray on admission and presented with higher D-dimer, interleukin-6, and lactate dehydrogenase levels. In this multicenter LTR cohort, SARS-CoV-2 presented with high mortality. Additionally, the severity of disease on presentation predicted subsequent mortality.

A paired trial comparing mononuclear cell collection in two machines for further inactivation through an inline or offline extracorporeal photopheresis procedure.

BACKGROUND: Extracorporeal photopheresis (ECP) is an effective treatment. However, protocols differ widely, and some questions, such as the number of cells to be collected or the number of ECP treatment days per treatment cycle, are still unsolved. The aim of this study was to compare a multistep (offline) (Spectra Optia and Macogenic G2) against an integrated (inline) ECP system (Therakos Cellex system) with respect to mononuclear cell (MNC) collection. STUDY DESIGN AND METHODS: The number and quality parameters of the MNC products collected were evaluated together with some machine parameters, such as collection time. Comparisons were made through paired sample analysis with the t test. RESULTS: Fourteen patients underwent 15 double-paired procedures using both ECP protocols. The average MNC collected in the multistep procedure was 77.4 × 108 , four times more than in the integrated procedure (18.5 × 108 ). MNC purity (84.4% vs. 63.8%) and enrichment (27.9 vs. 5.9) in the product collected were also higher in the multistep procedure. The whole ECP time was higher in the multistep than in the integrated procedure (272 vs. 106 min), but the calculated time to collect 25 × 108 MNCs in the multistep was shorter compared with the one-step procedure (77.8 vs. 172 min). All these differences between the two protocols were statistically significant. CONCLUSIONS: These two ECP protocols are different with respect to MNC collection and length of procedure. Some unresolved questions, such as the better MNC dose to inactivate or the number of consecutive days that ECP should be performed for optimal clinical efficacy, require further review.

Stress myocardial blood flow correlates with ventricular function and synchrony better than myocardial perfusion reserve: A Nitrogen-13 ammonia PET study.

BACKGROUND: Cardiac PET quantifies stress myocardial blood flow (MBF) and perfusion reserve (MPR), while ECG-gated datasets can measure components of ventricular function simultaneously. Stress MBF seems to outperform MPR in the detection of significant CAD. However, it is uncertain which perfusion measurement is more related to ventricular function. We hypothesized that stress MBF correlates with ventricular function better than MPR in patients studied for suspected myocardial ischemia. METHODS: We studied 248 patients referred to a rest and adenosine-stress Nitrogen-13 ammonia PET. We performed a multivariate analysis using systolic function (left ventricular ejection fraction, LVEF), diastolic function (mean filling rate in diastole, MFR/3), and synchrony (Entropy) as the outcome variables, and stress MBF, MPR, and relevant covariates as the predictors. Secondarily, we repeated the analysis for the subgroup of patients with and without a previous myocardial infarction (MI). RESULTS: 166 male and 82 female patients (mean age 63 ± 11 and 67 ± 11 year, respectively) were included. 60% of the patients presented hypertension, 57% dyslipidemia, 21% type 2 diabetes mellitus, 45% smoking, and 34.7% a previous MI. Mean stress MBF was 1.99 ± 0.75 mL/g/min, MPR = 2.55 ± 0.89, LVEF = 61.6 ± 15%, MFR/3 = 1.12 ± 0.38 EDV/s, and Entropy = 45.6 ± 11.3%. There was a significant correlation between stress MBF (P < .001) and ventricular function. This was stronger than the one for MPR (P = .063). Sex, age, diabetes, and extent of previous MI were also significant predictors. Results were similar for the analyses of the 2 subgroups. CONCLUSION: Stress MBF is better correlated with ventricular function than MPR, as evaluated by Nitrogen-13 ammonia PET, independently from other relevant cardiovascular risk factors and clinical covariates. This relationship between coronary vasodilatory capacity and ventricular function is sustained across groups with and without a previous MI.

Pharmacodynamic monitoring by residual gene expression of the nuclear factor of activated T cell-regulated genes in lung transplant recipients and its correlation with tacrolimus blood levels.

Introduction: Trough blood levels (C0) of tacrolimus are used to adjust drug dosage, but they do not consistently correlate with clinical outcomes. Measurement of residual gene expression of nuclear factor of activated T cell (NFAT)-regulated genes (NFAT-RGE) has been proposed as a pharmacodynamic biomarker to assess the degree of immunosuppression in certain solid organ transplantations, but little is known regarding lung transplant recipients (LTR). Our primary objective is to correlate tacrolimus blood levels with NFAT-RGE. Methods: NFAT-RGE and tacrolimus C0 and peak (C1.5) levels were determined in 42 patients at three, six and 12 months post-transplantation. Results: Tacrolimus C0 did not exhibit a correlation with NFAT-RGE, whereas C1.5 did. Besides, over 20% of measurements indicated high levels of immunosuppression based on the below 30% NFAT-RGE threshold observed in many studies. Among those measurements within the therapeutic range, 19% had an NFAT-RGE<30%. Conclusion: Consequently, a subset of patients within the tacrolimus therapeutic range may be more susceptible to infection or cancer, potentially benefiting from NFAT-RGE and tacrolimus peak level monitoring to tailor their dosage. Further quantitative risk assessment studies are needed to elucidate the relationship between NFAT-RGE and the risk of infection, cancer, or rejection.

Neutrophil-to-Lymphocyte Ratio and Cytokine Profiling as Predictors of Disease Severity and Survival in Unvaccinated COVID-19 Patients.

BACKGROUND: During the COVID-19 pandemic, identifying reliable biomarkers for predicting disease severity and patient outcomes in unvaccinated individuals is essential. This study evaluates the efficacy of key hematological markers, including leukocyte and neutrophil counts, Neutrophil-to-Lymphocyte Ratio (NLR), and cytokine profiles (IL-6, INF-γ, TNF-α, IL-17A, CCL2, and CXCL10) for predicting the necessity for mechanical ventilation and assessing survival probabilities. METHODS: We conducted an in-depth analysis on a cohort of COVID-19 patients, emphasizing the relationship between NLR, cytokine profiles, and clinical outcomes, utilizing routine leukocyte counting and cytokine quantification by flow cytometry. RESULTS: Elevated leukocyte and neutrophil counts, increased NLR, and significant cytokine elevations such as IL-6 and IL-10 were strongly associated with the need for mechanical ventilation, reflecting a pronounced systemic inflammatory response indicative of severe disease outcomes. CONCLUSION: Integrating hematological markers, particularly NLR and cytokine profiles, is crucial in predicting mechanical ventilation needs and survival in non-vaccinated COVID-19 patients. Our findings provide critical insights into the pathophysiology of COVID-19, supporting the development of more targeted clinical interventions and potentially informing future strategies for managing infectious disease outbreaks.

Surgical considerations in the resection of solitary fibrous tumors of the pleura.

Solitary fibrous tumors (SFTs) are rare mesenchymal pleural neoplasms with an overall good prognosis and low recurrence rate if completely resected and if degree of differentiation is favorable. Within the last decade, advances in research have led to more reliable methods of differentiating SFTs from other soft tissue tumors. Historically, several markers were used to distinguish SFTs from similar tumors, but these markers had poor specificity. Recent evidence showed NAB2-STAT6 fusion gene to be a distinct feature of SFTs with 100% specificity and sensitivity. Surgical resection, with an emphasis on obtaining negative margins, is the mainstay of treatment for SFTs. Preoperative planning with detailed imaging is imperative to delineate the extent of disease and vascular supply. One important radiologic distinction to aid delineation of a pleural-based tumor compared to a pulmonary parenchymal-based tumor is the angle that the tumor forms with the chest wall, which is obtuse for a pleural-based tumor, and acute for tumors of the lung parenchyma. Often, preoperative tissue diagnosis is not available, and surgery is both diagnostic and curative. Intraoperatively, emphasis should be on complete resection with negative margins. SFTs are resected via several approaches: thoracotomy, sternotomy with the option of hemi-clamshell extension, video-assisted thoracoscopic surgery, and robotic approach, which is increasingly being used and is our preference. We recommend a minimally invasive approach for most lesions, and have resected SFTs of the pleura that are up to 12 cm with the robotic approach. However, the current literature often cites 5 cm as the cut off for an open thoracotomy. Nevertheless, even with larger tumors, a minimally invasive robotic approach is our preference and practice. For giant SFTs (> 20 cm), an open approach may be preferable. Multiple thoracotomies and rib resection may be required to gain adequate exposure and ensure complete resection in these tumors. However, it is noteworthy that most of these tumors have a soft consistency and thus, once bagged, can easily be removed minimally invasively, and thus minimally invasive approach should not be completely ruled out. Recurrence in SFTs usually results from incomplete resection and redo surgery may portend a favorable prognosis.

Zearalenone Does Not Show Genotoxic Effects in the Drosophila melanogaster Wing Spot Test, but It Induces Oxidative Imbalance, Development, and Fecundity Alterations.

Zearalenone (ZEN) is a non-steroidal mycoestrogen produced by the Fusarium genus. ZEN and its metabolites compete with 17-beta estradiol for cytosolic estrogen receptors, causing reproductive alterations in vertebrates. ZEN has also been associated with toxic and genotoxic effects, as well as an increased risk for endometrial adenocarcinomas or hyperplasia, breast cancer, and oxidative damage, although the underlying mechanisms remain unclear. Previous studies have monitored cellular processes through levels of transcripts associated with Phase I Xenobiotic Metabolism (Cyp6g1 and Cyp6a2), oxidative stress (hsp60 and hsp70), apoptosis (hid, grim, and reaper), and DNA damage genes (Dmp53). In this study, we evaluated the survival and genotoxicity of ZEN, as well as its effects on emergence rate and fecundity in Drosophila melanogaster. Additionally, we determined levels of reactive oxygen species (ROS) using the D. melanogaster flare and Oregon R(R)-flare strains, which differ in levels of Cyp450 gene expression. Our results showed that ZEN toxicity did not increase mortality by more than 30%. We tested three ZEN concentrations (100, 200, and 400 µM) and found that none of the concentrations were genotoxic but were cytotoxic. Taking into account that it has previously been demonstrated that ZEN administration increased hsp60 expression levels and apoptosis gene transcripts in both strains, the data agree with an increase in ROS and development and fecundity alterations. Since Drosophila lacks homologous genes for mammalian estrogen receptors alpha and beta, the effects of this mycotoxin can be explained by a mechanism different from estrogenic activity.

Peripheral blood eosinophilia as a marker of acute cellular rejection in lung transplant recipients.

Previous studies in solid organ transplantation have shown a relationship between circulating eosinophil (EOS) counts and the presence of acute cellular rejection (ACR). However, the relationship between this potential biomarker and ACR in lung transplant (LTx) patients remains unclear. OBJECTIVE: To assess the association between EOS and the presence of acute cellular rejection in lung transplant recipients. MATERIALS AND METHODS: Retrospective study of 583 transbronchial biopsies (TBB) performed in 256 lung transplant patients between 2012 and 2018. We analyzed age, sex, underlying pathology, date of transplant, indications for TBB, presence and degree of ACR, and the simultaneous absolute and relative EOS. RESULTS: ACR were observed in 170 of 583 TBB (29.2%). EOS in patients with ACR were higher than in patients without ACR (203.6 ± 248/mm3 vs 103.1 ± 153/mm3; p < 0.001). High levels of both absolute and relative EOS were associated with the presence of ACR regardless of the underlying disease (odds ratio [OR] 1.003; 95% confidence interval [CI], 1.002-1.004; OR 1.226; 95% CI, 1.120-1.342) and time after transplant (OR 1.003; 95% CI, 1.002-1.004 and OR 1.239; 95% CI, 1.132-1.356). Moreover, both absolute and relative EOS were strongly associated with moderate and severe grades of ACR (OR 3.55; 95% CI, 3.00-4.10 and OR 3.56; 95% CI, 3.00-4.12). CONCLUSIONS: EOS are elevated in ACR, especially in moderate or severe ACR. Increased vigilance for ACR is therefore advisable in lung transplant recipients with elevated EOS.

Evaluation of Two Different CMV-Immunoglobulin Regimens for Combined CMV Prophylaxis in High-Risk Patients following Lung Transplant.

BACKGROUND: The clinical benefits of the common off-label use of cytomegalovirus (CMV)-specific immunoglobulin (CMV-Ig) combined with antivirals in organ transplantation have not been previously assessed. The objective was to compare the risk of CMV infection and other post-transplantation outcomes between two CMV-Ig prophylaxis regimens in lung transplant recipients; Methods: Retrospective study of 124 donor CMV positive/recipient negative (D+/R-) patients receiving preventive ganciclovir/valganciclovir for 12 months, of whom 62 received adjunctive CMV-Ig as per label indication (short regimen [SR-Ig]; i.e., 7 doses over 2.5 months) and were compared to 62 who received an extended off-label regimen (ER-Ig) consisting of 17 doses over one year after transplantation. RESULTS: The incidence of CMV infection or disease, acute rejection, chronic lung allograft dysfunction, and survival did not differ between the two CMV-Ig schedules. Although the time to the first CMV infection after transplantation was shorter in the ER-Ig than in the SR-Ig adjunctive group (log-rank: p = 0.002), the risk was independently predicted by antiviral cessation (odds ratio = 3.74; 95% confidence interval = 1.04-13.51; p = 0.030), whereas the CMV-Ig schedule had no effect. CONCLUSIONS: Extending the adjunctive CMV-Ig prophylaxis beyond the manufacturer's recommendations up to one year does not confer additional clinical benefits regarding lung post-transplantation outcomes.

High baseline expression of IL-6 and IL-10 decreased CCR7 B cells in individuals with previous SARS-CoV-2 infection during BNT162b2 vaccination.

The current pandemic generated by SARS-CoV-2 has led to mass vaccination with different biologics that have shown wide variations among human populations according to the origin and formulation of the vaccine. Studies evaluating the response in individuals with a natural infection before vaccination have been limited to antibody titer analysis and evaluating a few humoral and cellular response markers, showing a more rapid and intense humoral response than individuals without prior infection. However, the basis of these differences has not been explored in depth. In the present work, we analyzed a group of pro and anti-inflammatory cytokines, antibody titers, and cell populations in peripheral blood of individuals with previous SARS-CoV-2 infection using BNT162b2 biologic. Our results suggest that higher antibody concentration in individuals with an earlier disease could be generated by higher production of plasma cells to the detriment of the presence of memory B cells in the bloodstream, which could be related to the high baseline expression of cytokines (IL-6 and IL-10) before vaccination.

From Modern Planetary Health to Decolonial Promotion of One Health of Peripheries.

The concept of Planetary Health has recently emerged in the global North as a concern with the global effects of degraded natural systems on human health. It calls for urgent and transformative actions. However, the problem and the call to solve it are far from new. Planetary health is a colonial approach that disregards alternative knowledge that over millennia have accumulated experiences of sustainable and holistic lifestyles. It reinforces the monolog of modernity without realizing that threats to "planetary health" reside precisely in its very approach. It insists on imposing its recipes on political, epistemological, and ontological peripheries created and maintained through coloniality. The Latin American decolonial turn has a long tradition in what could be called a "transformative action," going beyond political and economic crises to face a more fundamental crisis of civilization. It deconstructs, with other decolonial movements, the fallacy of a dual world in which the global North produces epistemologies, while the rest only benefit from and apply those epistemologies. One Health of Peripheries is a field of praxis in which the health of multispecies collectives and the environment they comprise is experienced, understood, and transformed within symbolic and geographic peripheries, ensuing from marginalizing apparatuses. In the present article, we show how the decolonial promotion of One Health of Peripheries contributes to think and advance decentralized and plural practices to attend to glocal realities. We propose seven actions for such promotion.

Variation in resistance to oxidative stress in Oregon-(R)R-flare and Canton-S strains of Drosophila melanogaster.

All aerobic organisms are susceptible to damage by reactive oxygen species (ROS). ROS-induced damage has been associated with aging and diseases such as metabolic syndrome and cancer. However, not all organisms develop these diseases, nor do they age at the same rate; this is partially due to resistance to oxidative stress, a quantitative trait attributable to the interaction of factors including genetics and environmental. Drosophila melanogaster represents an ideal system to study how genetic variation can affect resistance to oxidative stress. In this work, oxidative stress (total and mitochondrial ROS), antioxidant response, and Cap 'n' collar isoform C and Spineless gene expression, one pesticide resistant (Oregon R(R)-flare) and wild-type (Canton-S) strains of D. melanogaster, were analyzed to test resistance to basal oxidative stress. ROS, catalase, and superoxide dismutase were determined by flow cytometry, and Cap 'n' collar isoform C and Spineless expression by qRT-PCR. The intensity of oxidative stress due to the pro-oxidant zearalenone in both was evaluated by flow cytometry. Data confirm expected differences in oxidative stress between strains that differ in Cyp450s levels. The Oregon (R)R-flare showed greater ROS, total and mitochondrial, compared to Canton-S. Regarding oxidative stress genes expression Cap 'n' collar isoform C and Spineless (Ss), Oregon R(R)-flare strain showed higher expression. In terms of response to zearalenone mycotoxin, Canton-S showed higher ROS concentration. Our data show variation in the resistance to oxidative stress among these strains of D. melanogaster.

Is observation for traumatic hemothorax safe?

BACKGROUND: Eastern Association for the Surgery of Trauma guidelines suggest tube thoracostomy (TT) be considered for all traumatic hemothoraces. However, previous research has suggested that some traumatic hemothoraces may be observed safely. We sought to (1) determine the safety of selective observation for traumatic hemothorax and (2) identify predictors of failed observation. METHODS: All patients with traumatic hemothorax from 2000 to 2014 at a Level I trauma center were identified and categorized by size as small (<300 cc) or large (≥300 cc) based on chest computed tomography (CT) scan measurements. Patients with no CT or with TT placement before CT were excluded. Patients were categorized into four intervention groups: (i) early TT (<24 hours after CT), (ii) failed observation (TT ≥24 hours after CT), (iii) successful observation (no TT), and (iv) inevaluable due to early mortality (no TT but died within 7 days). Univariate analyses compared outcomes between groups. Multivariate analyses identified independent predictors of failed observation. RESULTS: Three hundred forty patients met the inclusion criteria. 156 (46%) patients received early TT. Of the 184 patients that were initially observed, 121 (66%) were successfully observed, 53 (29%) failed observation, and 10 (5%) were inevaluable due to early mortality. Most of the successfully observed hemothoraces were small (119/121, 98%). Four independent predictors of failed observation were identified: older age, fewer ventilation-free days, large hemothorax, concurrent pneumothorax. Patients, who received TT were more likely than non-TT patients to receive tissue plasminogen activator, develop an empyema, have fewer hospital-free days, and are discharged to rehabilitation rather than home. When compared to early TT, failed observation was associated with a higher likelihood of discharge to rehabilitation but no difference in mortality, hospital-free days, or rate of empyema. CONCLUSION: Initial observation in select patients is safe and may result in better outcomes. The identified predictors of failed observation can help in clinical decision making regarding the need for TT in patients with traumatic hemothorax. LEVEL OF EVIDENCE: Therapeutic/care management, level IV.

Mortality after emergent trauma laparotomy: A multicenter, retrospective study.

BACKGROUND: Two decades ago, hypotensive trauma patients requiring emergent laparotomy had a 40% mortality. In the interim, multiple interventions to decrease hemorrhage-related mortality have been implemented but few have any documented evidence of change in outcomes for patients requiring emergent laparotomy. The purpose of this study was to determine current mortality rates for patients undergoing emergent trauma laparotomy. METHODS: A retrospective cohort of all adult, emergent trauma laparotomies performed in 2012 to 2013 at 12 Level I trauma centers was reviewed. Emergent trauma laparotomy was defined as emergency department (ED) admission to surgical start time in 90 minutes or less. Hypotension was defined as arrival ED systolic blood pressure (SBP) ≤90 mm Hg. Cause and time to death was also determined. Continuous data are presented as median (interquartile range [IQR]). RESULTS: One thousand seven hundred six patients underwent emergent trauma laparotomy. The cohort was predominately young (31 years; IQR, 24-45), male (84%), sustained blunt trauma (67%), and with moderate injuries (Injury Severity Score, 19; IQR, 10-33). The time in ED was 24 minutes (IQR, 14-39) and time from ED admission to surgical start was 42 minutes (IQR, 30-61). The most common procedures were enterectomy (23%), hepatorrhaphy (20%), enterorrhaphy (16%), and splenectomy (16%). Damage control laparotomy was used in 38% of all patients and 62% of hypotensive patients. The Injury Severity Score for the entire cohort was 19 (IQR, 10-33) and 29 (IQR, 18-41) for the hypotensive group. Mortality for the entire cohort was 21% with 60% of deaths due to hemorrhage. Mortality in the hypotensive group was 46%, with 65% of deaths due to hemorrhage. CONCLUSION: Overall mortality rate of a trauma laparotomy is substantial (21%) with hemorrhage accounting for 60% of the deaths. The mortality rate for hypotensive patients (46%) appears unchanged over the last two decades and is even more concerning, with almost half of patients presenting with an SBP of 90 mm Hg or less dying.