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Vascular injury is a well-established, disease-modifying factor in acute respiratory distress syndrome (ARDS) pathogenesis. Recently, coronavirus disease 2019 (COVID-19)-induced injury to the vascular compartment has been linked to complement activation, microvascular thrombosis, and dysregulated immune responses. This study sought to assess whether aberrant vascular activation in this prothrombotic context was associated with the induction of necroptotic vascular cell death. To achieve this, proteomic analysis was performed on blood samples from COVID-19 subjects at distinct time points during ARDS pathogenesis (hospitalized at risk, N = 59; ARDS, N = 31; and recovery, N = 12). Assessment of circulating vascular markers in the at-risk cohort revealed a signature of low vascular protein abundance that tracked with low platelet levels and increased mortality. This signature was replicated in the ARDS cohort and correlated with increased plasma angiopoietin 2 levels. COVID-19 ARDS lung autopsy immunostaining confirmed a link between vascular injury (angiopoietin 2) and platelet-rich microthrombi (CD61) and induction of necrotic cell death [phosphorylated mixed lineage kinase domain-like (pMLKL)]. Among recovery subjects, the vascular signature identified patients with poor functional outcomes. Taken together, this vascular injury signature was associated with low platelet levels and increased mortality and can be used to identify ARDS patients most likely to benefit from vascular targeted therapies.

Mitochondria are well-known as organelles responsible for the maintenance of cellular bioenergetics through the production of ATP. While oxidative phosphorylation may be their most important function, mitochondria are also integral for the synthesis of metabolic precursors, calcium regulation, the production of reactive oxygen species, immune signaling, and apoptosis. Considering the breadth of their responsibilities, mitochondria are fundamental for cellular metabolism and homeostasis. Appreciating this significance, translational medicine has begun to investigate how mitochondrial dysfunction can represent a harbinger of disease. In this review, we provide a detailed overview of mitochondrial metabolism, cellular bioenergetics, mitochondrial dynamics, autophagy, mitochondrial damage-associated molecular patterns, mitochondria-mediated cell-death pathways, and how mitochondrial dysfunction at any of these levels is associated with disease pathogenesis. Mitochondria-dependent pathways may thereby represent an attractive therapeutic target for ameliorating human disease.

COVID-19-associated respiratory failure offers the unprecedented opportunity to evaluate the differential host response to a uniform pathogenic insult. Understanding whether there are distinct subphenotypes of severe COVID-19 may offer insight into its pathophysiology. Sequential Organ Failure Assessment (SOFA) score is an objective and comprehensive measurement that measures dysfunction severity of six organ systems, i.e., cardiovascular, central nervous system, coagulation, liver, renal, and respiration. Our aim was to identify and characterize distinct subphenotypes of COVID-19 critical illness defined by the post-intubation trajectory of SOFA score. Intubated COVID-19 patients at two hospitals in New York city were leveraged as development and validation cohorts. Patients were grouped into mild, intermediate, and severe strata by their baseline post-intubation SOFA. Hierarchical agglomerative clustering was performed within each stratum to detect subphenotypes based on similarities amongst SOFA score trajectories evaluated by Dynamic Time Warping. Distinct worsening and recovering subphenotypes were identified within each stratum, which had distinct 7-day post-intubation SOFA progression trends. Patients in the worsening suphenotypes had a higher mortality than those in the recovering subphenotypes within each stratum (mild stratum, 29.7% vs. 10.3%, p = 0.033; intermediate stratum, 29.3% vs. 8.0%, p = 0.002; severe stratum, 53.7% vs. 22.2%, p

Vascular injury is a menacing element of acute respiratory distress syndrome (ARDS) pathogenesis. To better understand the role of vascular injury in COVID-19 ARDS, we used lung autopsy immunohistochemistry and blood proteomics from COVID-19 subjects at distinct timepoints in disease pathogenesis, including a hospitalized cohort at risk of ARDS development (“at risk”, N=59), an intensive care unit cohort with ARDS (“ARDS”, N=31), and a cohort recovering from ARDS (“recovery”, N=12). COVID-19 ARDS lung autopsy tissue revealed an association between vascular injury and platelet-rich microthrombi. This link guided the derivation of a protein signature in the at risk cohort characterized by lower expression of vascular proteins in subjects who died, an early signal of vascular limitation termed the maladaptive vascular response. These findings were replicated in COVID-19 ARDS subjects, as well as when bacterial and influenza ARDS patients (N=29) were considered, hinting at a common final pathway of vascular injury that is more disease (ARDS) then cause (COVID-19) specific, and may be related to vascular cell death. Among recovery subjects, our vascular signature identified patients with good functional recovery one year later. This vascular injury signature could be used to identify ARDS patients most likely to benefit from vascular targeted therapies.

BackgroundAlthough acute respiratory distress syndrome (ARDS) is associated with high mortality, its direct causal link with death is unclear. Clarifying this link is important to justify costly research on prevention of ARDS.ObjectiveTo estimate the attributable mortality, if any, of ARDS.DesignFirst, we performed a systematic review and meta-analysis of observational studies reporting mortality of critically ill patients with and without ARDS matched for underlying risk factor. Next, we conducted a survival analysis of prospectively collected patient-level data from subjects enrolled in three intensive care unit (ICU) cohorts to estimate the attributable mortality of critically ill septic patients with and without ARDS using a novel causal inference method.ResultsIn the meta-analysis, 44 studies (47 cohorts) involving 56 081 critically ill patients were included. Mortality was higher in patients with versus without ARDS (risk ratio 2.48, 95% CI 1.86 to 3.30; pConclusionsARDS has a direct causal link with mortality. Our findings provide information about the extent to which continued funding of ARDS prevention trials has potential to impart survival benefit.PROSPERO Registration NumberCRD42017078313

RationaleCOVID-19-associated respiratory failure offers the unprecedented opportunity to evaluate the differential host response to a uniform pathogenic insult. Prior studies of Acute Respiratory Distress Syndrome (ARDS) have identified subphenotypes with differential outcomes. Understanding whether there are distinct subphenotypes of severe COVID-19 may offer insight into its pathophysiology.ObjectivesTo identify and characterize distinct subphenotypes of COVID-19 critical illness defined by the post-intubation trajectory of Sequential Organ Failure Assessment (SOFA) score.MethodsIntubated COVID-19 patients at two hospitals in New York city were leveraged as development and validation cohorts. Patients were grouped into mild, intermediate, and severe strata by their baseline post-intubation SOFA. Hierarchical agglomerative clustering was performed within each stratum to detect subphenotypes based on similarities amongst SOFA score trajectories evaluated by Dynamic Time Warping. Statistical tests defined trajectory subphenotype predictive markers.Measurements and Main ResultsDistinct worsening and recovering subphenotypes were identified within each stratum, which had distinct 7-day post-intubation SOFA progression trends. Patients in the worsening suphenotypes had a higher mortality than those in the recovering subphenotypes within each stratum (mild stratum, 29.7% vs. 10.3%, p=0.033; intermediate stratum, 29.3% vs. 8.0%, p=0.002; severe stratum, 53.7% vs. 22.2%, pConclusionsThere are clear worsening and recovering subphenotypes of COVID-19 respiratory failure after intubation, which are more predictive of outcomes than baseline severity of illness. Organ dysfunction trajectory may be well suited as a surrogate for research in COVID-19 respiratory failure.At a Glance CommentaryScientific Knowledge on the SubjectCOVID-19 associated respiratory failure leads to a significant risk of morbidity and mortality. It is clear that there is heterogeneity in the viral-induced host response leading to differential outcomes, even amongst those treated with mechanical ventilation. There are many studies of COVID-19 disease which use intubation status as an outcome or an inclusion criterion. However, there is less understanding of the post intubation course in COVID-19.What This Study Adds to the FieldWe have developed and validated a novel subphenotyping model based on post-intubation organ dysfunction trajectory in COVID-19 patients. Specifically, we identified clear worsening and recovering organ dysfunction trajectory subphenotypes, which are more predictive of outcomes than illness severity at baseline. Dynamic inflammatory markers and ventilator variables rather than baseline severity of illness, demographics and comorbidities differentiate the worsening and recovering subphenotypes. Trajectory subphenotypes offer a potential road map for understanding the evolution of critical illness in COVID-19.

Background: The main clinical manifestations of coronavirus disease 2019 (COVID-19) onset are respiratory symptoms, including cough, sputum and dyspnea. However, a significant proportion of patients initially manifested extra-respiratory symptoms, such as fever, myalgia and diarrhea. Here we compared the different characteristics and outcomes between the patients with respiratory symptoms and extra-respiratory symptoms at illness onset.Methods: The patients admitted to the respiratory departments from eight hospitals out of Wuhan with nucleic acid-positive of severe acute respiratory syndrome coronavirus (SARS-CoV-2) were recruited. Epidemiological information, clinical manifestations, laboratory findings, and radiological characteristics, treatment regimens and outcomes data were recorded and analyzed.Results: The median age of the recruited 541 subjects was 43 years (IQR, 33-55). Of the 541 subjects, 404 (74.5%) subjects had initial symptom that were respiratory, while 137 (25.5%) subjects had extra-respiratory symptoms. Respiratory COVID-19 subjects had more secondary bacterial infections (pp = 0.01) dyspnea (OR = 4.91, p < 0.001) and secondary bacterial infection (OR = 19.8, p < 0.001) were independently associated with development of ARDS among COVID-19 patients.Conclusion: we identify COVID-19 subjects with dyspnea at disease onset have worse prognosis. We also demonstrate age and secondary bacterial infections to be independently associated with ARDS development in subjects with COVID-19.

Necroptosis is a genetically regulated form of necrotic cell death that has emerged as an important pathway in human disease. The necroptosis pathway is induced by a variety of signals, including death receptor ligands, and regulated by receptor-interacting protein kinases 1 and 3 (RIPK1 and RIPK3) and mixed-lineage kinase domain–like pseudokinase (MLKL), which form a regulatory necrosome complex. RIPK3-mediated phosphorylation of MLKL executes necroptosis. Recent studies, using animal models of tissue injury, have revealed that RIPK3 and MLKL are key effectors of injury propagation. This Review explores the functional roles of RIPK3 and MLKL as crucial pathogenic determinants and markers of disease progression and severity in experimental models of human disease, including acute and chronic pulmonary diseases; renal, hepatic, cardiovascular, and neurodegenerative diseases; cancer; and critical illness.

BACKGROUND. In sepsis, there may be dysregulation in programed cell death pathways, typified by apoptosis and necroptosis. Programmed cell death pathways may contribute to variability in the immune response. TRAIL is a potent inducer of apoptosis. Receptor-interacting serine/threonine protein kinase-3 (RIPK3) is integral to the execution of necroptosis. We explored whether plasma TRAIL levels were associated with in-hospital mortality, organ dysfunction, and septic shock. We also explored the relationship between TRAIL and RIPK3. METHODS. We performed an observational study of critically ill adults admitted to intensive care units at 3 academic medical centers across 2 continents, using 1 as derivation and the other 2 as validation cohorts. Levels of TRAIL were measured in the plasma of 570 subjects by ELISA. RESULTS. In all cohorts, lower (

The relationship between neuromuscular blocking agents and neuromuscular dysfunction acquired in critical illness remains unclear. We examined the association between neuromuscular blocking agents and ICU-acquired weakness, critical illness polyneuropathy, and critical illness myopathy.PubMed, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, Cumulative Index of Nursing and Allied Health Literature, and bibliographies of included studies were searched from database inception until September 24, 2015.Randomized controlled trials and prospective observational studies examining the association between neuromuscular blocking agents and ICU-acquired weakness, critical illness polyneuropathy, or critical illness myopathy.One author screened titles/abstracts. Two authors independently reviewed full text and extracted data from included studies. Meta-analysis was performed using the DerSimonian-Laird random effects model (OpenMetaAnalyst 10.10 for OS.X). We assessed reporting bias with funnel plots and heterogeneity with the I statistic.Of 2,170 titles/abstracts screened, 99 full texts were selected for review, yielding one randomized controlled trial and 18 prospective observational studies, for a total of 2,254 patients. The randomized controlled trial did not show an association between neuromuscular blocking agents and neuromuscular dysfunction acquired in critical illness (odds ratio, 1.21; 95% CI, 0.67-2.19), but pooled data from all included studies suggested a modest association (odds ratio, 1.25; 95% CI, 1.06-1.48; I = 16%). Funnel plots suggested reporting bias, and sensitivity analyses showed a disproportionate contribution from critical illness polyneuropathy/critical illness myopathy and severe sepsis/septic shock studies.This meta-analysis suggests a modest association between neuromuscular blocking agents and neuromuscular dysfunction acquired in critical illness; limitations include studies with a high risk of bias and a disproportionate contribution from studies examining patients for critical illness polyneuropathy/critical illness myopathy and those with severe sepsis/septic shock.

BackgroundAcute respiratory distress syndrome (ARDS) is heterogeneous. As an indication of the heterogeneity of ARDS, there are patients whose syndrome improves rapidly (i.e., within 24 hours), others whose hypoxemia improves gradually and still others whose severe hypoxemia persists for several days. The latter group of patients with persistent severe ARDS poses challenges to clinicians. We attempted to assess the baseline characteristics and outcomes of persistent severe ARDS and to identify which variables are useful to predict it.MethodsA secondary analysis of patient-level data from the ALTA, EDEN and SAILS ARDSNet clinical trials was conducted. We defined persistent severe ARDS as a partial pressure of arterial oxygen to fraction of inspired oxygen ratio (PaO2:FiO2) of equal to or less than 100 mmHg on the second study day following enrollment. Regularized logistic regression with an L1 penalty [Least Absolute Shrinkage and Selection Operator (LASSO)] techniques were used to identify predictive variables of persistent severe ARDS.ResultsOf the 1531 individuals with ARDS alive on the second study day after enrollment, 232 (15%) had persistent severe ARDS. Of the latter, 100 (43%) individuals had mild or moderate hypoxemia at baseline. Usage of vasopressors was greater [144/232 (62%) versus 623/1299 (48%); pConclusionsPatients with persistent severe ARDS have distinct baseline characteristics and poor prognosis. Identifying such patients at enrollment may be useful for the prognostic enrichment of trials.

This essay which analyses the contribution made by Malthus opens by describing the intellectual context offered by the late 18th and early 19th centuries when scientific discoveries and technological advances inspired some thinkers to envision utopia. Malthus wrote his first treatise on population to further a debate with his father. In his essay Malthus elaborated on the ideas of other thinkers about the limits of subsistence and population increase to reveal their socioeconomic implications. Malthus could envision no human means that would prevent population from growing faster than its means of subsistence and he disputed the perfectibility of man or human society. Because of his essay Malthus was appointed professor of political economy at a college in Hertfordshire and spent the rest of his life revising his first effort and publishing another major work. Malthus believed that charity could have a detrimental effect on poverty and that the impoverished would be better served if they were given an opportunity to work or an education. He argued that initiatives to alleviate a problem could exacerbate it if they were based on an inadequate understanding. Malthus affected other thinkers such as Darwin and Wallace Herbert Spencer and Marx (who deplored Malthuss ideas) and blazed a trail of influence into the 20th century. The continued existence of the two opposing views that science can solve all problems and that poverty can not be eliminated may reflect a difference of predisposition rather than the force of reason. The impending crisis caused by unchecked consumption of nonrenewable resources and population growth is of such magnitude today that few are willing to accept its inevitability.

This article describes decision making leadership and political organization among the indigenous Nambiquara of Brazil. The author describes the Nambiquara before their contact with Western civilization. The Nambiquara live in western Brazil near the Bolivian border. Their habitat was discovered around 1910 and then ignored until around 1960 when a road was built parallel to the old telegraph lines. The region is a mix of savanna and forest. Villages are comprised of two or three thatched houses of related kin. Trees are felled for gardens and left in place before burning which provides the soil with nutrients before the bush takes over. Gardens include staples such as corn and manioc as well as beans peppers tobacco cotton yams and sweet potatoes. The Nambiquara move away after all the good gardening places are used up. Meat is obtained by men hunting with bows and arrows. Animals are only raised as pets. Women are responsible for gardening. The associations of men with animals and women with plants is captured in the symbolism of songs the shape of rituals and the meaning of their myths. Sharing is a basic value. Although there is no word for "generosity" there is a word for "stinginess." Important decisions are made by consensus even though this is a slow process. Men are the political authorities. When a member of the group is unwilling to maintain the group norms he leaves to live elsewhere. The Nambiquara identify the village as their social group and recognize one leader ("a capable one") per village. Leaders must be hunters and gardeners generous wise and not bossy. The relationship between leaders and followers is influence and not authority. Political life is a balance of individualism and equality and shaped by abundance.

Hypocalcaemia is a rare complication of calcium channel blocker overdose, having been reported only once previously (J Toxicol Clin Toxicol, 1992, 30, 309). In this article, we report a case of a 37-year-old woman who developed hypocalcaemia after a verapamil overdose, review the literature and propose a mechanism for this rare finding.

Life on Earth is driven by energy. Autotrophs take it from solar radiation and heterotrophs take it from autotrophs. Energy captured slowly by photosynthesis is stored up, and as denser reservoirs of energy have come into being over the course of Earth's history, heterotrophs that could use more energy evolved to exploit them.Homo sapiens is such a heterotroph; indeed, the ability to use energy extra-somatically (outside the body) enables human beings to use far more energy than any other heterotroph that has ever evolved. The control of fire and the exploitation of fossil fuels have made it possible forHomo sapiens to release, in a short time, vast amounts of energy that accumulated long before the species appeared. By using extrasomatic energy to modify more and more of its environment to suit human needs, the human population effectively expanded its resource base so that for long periods it has exceeded contemporary requirements. This allowed an expansion of population similar to that of species introduced into extremely propitious new habitats, such as rabbits in Australia or Japanese beetles in the United States. The world's present population of over 5.5 billion is sustained and continues to grow through the use of extrasomatic energy. But the exhaustion of fossil fuels, which supply three quarters of this energy, is not far off, and no other energy source is abundant and cheap enough to take their place. A collapse of the earth's human population cannot be more than a few years away. If there are survivors, they will not be able to carry on the cultural traditions of civilization, which require abundant, cheap energy. It is unlikely, however, that the species itself can long persist without the energy whose exploitation is so much a part of itsmodus vivendi. The human species may be seen as having evolved in the service of entropy, and it cannot be expected to outlast the dense accumulations of energy that have helped define its niche. Human beings like to believe they are in control of their destiny, but when the history of life on Earth is seen in perspective, the evolution ofHomo sapiens is merely a transient episode that acts to redress the planet's energy balance.

Neuromuscular blocking agents (NMBAs), or “paralytics,” often are deployed in the sickest patients in the intensive care unit (ICU) when usual care fails. Despite the publication of guidelines on the use of NMBAs in the ICU in 2002, clinicians have needed more direction to determine which patients would benefit from NMBAs and which patients would be harmed. Recently, new evidence has shown that paralytics hold more promise when used in carefully selected lung injury patients for brief periods of time. When used in early acute respiratory distress syndrome (ARDS), NMBAs assist to establish a lung protective strategy, which leads to improved oxygenation, decreased pulmonary and systemic inflammation, and potentially improved mortality. It also is increasingly recognized that NMBAs can cause harm, particularly critical illness polyneuromyopathy (CIPM), when used for prolonged periods or in septic shock. In this review, we address several practical considerations for clinicians who use NMBAs in their practice. Ultimately, we conclude that NMBAs should be considered a lung protective adjuvant in early ARDS and that clinicians should consider using an alternative NMBA to the aminosteroids in septic shock with less severe lung injury pending further studies.

A 44-year-old African-American woman was admitted with four months of intermittent “shock-like” sensations in her chest radiating to both arms; she developed left arm weakness just prior to admission. A cervical spine magnetic resonance imaging (MRI) demonstrated intramedullary enhancement from C1 to T1 (Fig. 1 Panel a). Figure 1. Cervical spine magnetic resonance imaging (MRI) of a 44-year-old African-American woman. Panel a: MRI with gadolinium contrast 3 weeks prior to admission. Panel b: MRI with gadolinium contrast after 8 weeks of corticosteroid therapy. Neurologic examination showed 4/5 strength of left wrist flexors and extensors, decreased bilateral light touch and pinprick sensation from C5 to T5, and hyperalgesia bilaterally from T1 to T3. Chest x-ray showed hilar adenopathy. Serum angiotensin converting enzyme level was 191 U/L (normal 9–67). Lumbar puncture was remarkable for a protein of 54 mg/dl (normal 15–45) and glucose of 30 mg/dl (normal 45–80; serum glucose 106). Transbronchial biopsy showed non-caseating granulomas. Sarcoidosis is an idiopathic inflammatory disease characterized by non-caseating granulomas affecting any organ. Neurologic involvement occurs in 5–17 % of sarcoidosis patients, with 0.43 % having spinal cord involvement.1 The most common cerebrospinal fluid findings are elevated protein and hypoglycorrhachia, presumably a manifestation of chronic meningeal inflammation.2 Owing to the invasive nature of spinal cord biopsy, neurosarcoidosis is often diagnosed with extraneural tissue and the appropriate clinical syndrome.3,4 Treatment generally includes immunosuppressive agents. This patient’s neurological deficits and radiographic abnormalities improved with corticosteroids (Fig. ​(Fig.11 Panel b).

[reaction: see text] High-level theoretical methods are applied to calculate the 13C NMR chemical shifts of three isomers of [10]annulene. Comparison with experiment clearly shows that the carrier of NMR signals of the so-called B form is the "twist" isomer. The results of this study strongly support predictions of relative energies of mono-trans [10]annulene isomers at the CCSD(T) level, which in turn are in qualitative disagreement with DFT and MP2 calculations.

[reaction: see text] Both DFT and CCSD and CCSD(T) computational methods indicate that 1-fluorocyclopropene can undergo an unprecedented "electrocyclic" automerization process involving a full 180 degrees rotation of its methylene group, without the formation of an intermediate carbene or diradical.

I was surprised that Wittenberg did not mention the use of ultrasound in anaesthesia and critical care.1 Ever since the National Institute for Health and Care Excellence advocated the use of ultrasound for central venous access in 2002, every anaesthetic department has been obliged to purchase an …

Technologies the U.S. military depends on are at risk of failing during the on-going transformation of the joint force. Driving forces behind how the military transforms its forces include: societal desire for, and belief in, technological solutions; political impetus to develop and field increasingly complex technologies; a constrained top-line budget forcing zero-sum decisions within the government; market forces resulting in the world-wide proliferation of technology; and competent adversaries who will create a technology-hostile battlespace. Complicating the transformation process are elements, which, if left unattended, lead to critical vulnerabilities. These include human-technology relationships, logistic support, interoperability, training and budget decisions. The warfighting CinCs can mitigate the risks of technology failure associated with transformation with an approach that includes: preventing the premaure deployment of weapon systems; training assigned forces for general technology failure; and reorganization of the command and control structure to support decentralized execution and self- synchronization.

Resource Management In Amazonia: Indigenous and Folk Strategies. Darrell A. Posey and William Balee. editors. Advances in Economic Botany, Volume 7. New York: The New York Botanical Garden, 1989. vll. 304 pp. $59.00 (paper). ISBN 0-89327-340-6.

As expected, the PPVT and various forms of the Quick Test, all tests of receptive vocabulary, overestimated the three IQs of the WAIS—R, often by more than half a standard deviation for a small sample (N = 30) of psychiatric in-patients. A restricted range of scores may have contributed to spuriously high correlations among the various measures of IQ.

For 30 patients high correlations among scores on Quick Test forms and between scores on Quick Test forms and WAIS scores are as expected from prior work. Premorbid scores were higher than current scores. Range was restricted (IQs of 50 to 127), variances heterogeneous as expected.