bluuebunny/crossref_metadata_2025 huggingface dataset:
Economies of Accomplishments
Authors: Goodman Glenda
Published: April 2020

Amateur music-making was often labeled a feminine “accomplishment”—a designation that carried ambivalent connotations. The extensive and contradictory prescriptive literature about accomplishments, and the broader discussion about women’s education of which it was a part, deemed musical ability at once essential and frivolous. The justifications for accomplishments cohered primarily around the theme of patriarchal authority: pleasing fathers and husbands and attracting potential mates. Warnings regarding accomplishments stemmed from scenarios where such justifications went awry (with foolish fathers and rakish suitors). Yet the lived experiences of amateur musicians show that young women took pleasure in the self-fashioning opportunities musical performances afforded. Moreover, in courtship and marriage, music served not simply to please and entertain others, but, as Sarah Brown’s experiences demonstrate, also was a critical mode through which family intimacy was built and maintained.
In Search of Guidance
Authors: Collis Robert , Bayer Natalie
Published: April 2020

This chapter examines the eleven-month residence of Tadeusz Grabianka in London, between December 1785 and November 1786. It undertakes an in-depth study of the extraordinary series of twelve meetings that took place during this time between Grabianka and Samuel Best, known as the so-called Shoreditch Prophet and Poor-Help. These encounters were noted down by Grabianka and provide a fascinating insight into both his and Best’s prophetic and millenarian mindsets. It also reveals the wider prevalence of millenarianism in London and beyond at the time and, moreover, illustrates Best’s pivotal role in fomenting this sentiment. The chapter also analyses the close ties between Grabianka, Best, and the burgeoning Swedenborgian milieu in the English capital in the 1780s. In large measure, these links were facilitated by Benedict Chastanier and William Bousie, who rank as two of the foremost Anglo-French illuminists of the era, and who both went on to join the Avignon Society in the late 1780s.
A Wolf in Sheep’s Clothing?
Authors: Collis Robert , Bayer Natalie
Published: April 2020

Chapter 4 focuses on the important, but highly controversial contribution to the religious and associational dynamic of the society of Ottavio Cappelli, who fashioned himself as a prophet able to communicate with the archangels Gabriel and Raphael. It places a particular emphasis on a crucial period between the end of 1789 and November 1791, a two-year time frame that takes in Cappelli’s apogee in Rome in early 1790, when he was feted by all within the society as a true prophet. The chapter analyses Cappelli’s contentious attempts in 1790 to reconfigure the Avignon Society as a more conventional Roman Catholic sect, which began to sow seeds of discord among Protestant initiates. It also examines the impact of his arrest by the papal authorities, in September 1790, on not only his personal fate, but also on the fortunes of the society as a whole. His fall, which was confirmed by a seven-year prison sentence in November 1791, played a key role in causing a schism in the Avignon Society that almost tore the group asunder.
Establishment of the Specialized Units in Liberia and Côte d’Ivoire
Authors: Medie Peace A.
Published: April 2020

Chapter 7 studies the implementation of the international women’s justice norm at the national level. It shows how pressure from the United Nations shaped the creation of the specialized units in Liberia and Côte d’Ivoire and thus the implementation of the international women’s justice norm. It draws on a range of interviews, including with personnel of the United Nations peacekeeping missions in Liberia and Côte d’Ivoire and the with women’s rights advocates, to demonstrate how this international pressure interacted with domestic pressure and conditions to produce varied implementation outcomes. While high international pressure was sufficient for the creation of the speicalized units, high domestic pressure and favorable political and institutional conditions were needed for rapid institutioanlization.
Just Add Water
Authors: Larson Rhett B.
Published: April 2020

Scientists have long been searching for a unified field theory—one answer to all of the questions about the physical universe. In Just Add Water: Solving the World’s Problems Using Its Most Precious Resource, I take a similar approach to social policy questions. What if we could find a unified social policy theory—the answer to every question, from how to prevent war to how to promote gender equality? Nearly all of our most serious global challenges are complex, multifaceted “wicked problems.” But perhaps the first step in solving wicked problems as seemingly distinct as racism and disease epidemics is the same: reform our laws, policies, and priorities to achieve global water security. Global water security means reasonable access for all people to water of acceptable quantity and quality with acceptable costs and risks. Just as the essential element to all life is water, so water is the essential element to solving life’s challenges. Virtually every major social challenge—including gender inequality, racial discrimination, terrorism, space exploration, global disease epidemics, mass migrations, and climate change—has a significant and underappreciated water component. Each chapter of this book takes one of these wicked problems, illustrates the role water plays in that problem, and proposes reforms to address the water aspect of that problem, with the aim of achieving global water security. My goal in this book is to convince the reader that the answer, or at least one part of the answer, to our most serious problems is the oft-repeated late-night infomercial exhortation: “Just add water.”
The Social Function of Corporate Law
Authors: Davies Paul
Published: April 2020

Since the financial crisis of 2007–09, the shareholder orientation of company law has come under increasing question. This chapter first sets out the social benefits potentially provided by a shareholder orientation and analyses the strategies available within the current company law framework to promote these potential benefits. It then moves on to consider more radical critiques of shareholder orientation. The first questions the capacity of non-shareholders to protect themselves via contract, outside company law. This issue is analysed mainly from the standpoint of employee contracting and employee representation within the corporate structure. The second section promotes the idea that companies should state a corporate purpose beyond profit making.
The Ghosts of Anticommunism and Neoliberalism
Authors: Bourdaghs Michael K.
Published: April 2020

This chapter revisits the critiques of area studies carried out in the 1980s and the 1990s. Area studies programmes during the Cold War were dominated by social scientists, but today’s programmes are almost exclusively the domain of the humanities. The US government and allied foundations sharply reduced budgetary support for Asian studies, with the void being filled by state and state-related entities from East Asia pursuing so-called ‘soft power’ strategies. Today the majority of dissertations in the field claim some measure of critical politicality, whether in terms of postcolonialism, gender and sexuality studies, or environmentalism. Many of the direct targets of the original critique of area studies of the 1980s and the 1990s have seemingly dissolved—and yet area studies continues to thrive as an institution underwriting American power. The chapter explores how we can renew and reenergize the critique of area studies in its latest guise.
Imagine a Place
Authors: Martijn Marije
Published: April 2020

Proclus conceived of complex kinematic constructions in geometry as involving motions of points and lines that produced figures like conic sections within the phantasia (imagination) of the reasoner. He contended that in such constructions, the geometer projects various figures in three-dimensional space and not on a two-dimensional screen, as many commentators believe. Hence Proclus believes in what one might call the three-dimensionality of imagination. He also presents the remarkable argument that space should be understood as a kind of intelligible matter, where the latter is understood to be three-dimensional (not merely two-dimensional). Finally, the chapter discusses the extent to which Proclus foresees various early modern conceptions of space.
Space in Kantian Idealism
Authors: Friedman Michael
Published: April 2020

Kant’s conception of space can be understood only against the background of the famous debate between Leibniz and Newton in the early eighteenth century. Throughout his life, Kant sought a middle path between the philosophical extremes represented by Leibniz and Newton, but he eventually concluded that only transcendental idealism is able to explain the knowledge of nature expressed in Newton’s theory of universal gravitation, whose postulation of action at a distance among material bodies Kant embraced. Kant’s argument for transcendental idealism involves both his conception of geometry as providing synthetic a priori knowledge, but also his contention that the pure concepts of the understanding, such as substance and community, must be “schematized” or infused with spatiotemporal content if Newton’s science of nature is to be explained.
A Mathematical Sculptor’s Perspective on Space
Authors: Hart George
Published: April 2020

In this Reflection, a mathematician discusses four sculptures he created to express important aspects of various kinds of spaces, including ordinary Euclidean, hyperbolic space. The sculptures represent the transcription into physical objects of conceptual ideas concerning figures and the spaces they inhabit. Different sculptures exhibit various aspects of different spaces: e.g. whereas a handheld sculpture may lack orientation, thereby exhibiting an aspect of classic Euclidean space, a large sculpture fixed to the ground may have an orientation, thereby exhibiting an aspect of physical space.
A Rhetorical Political Analysis of Theresa May’s Statecraft on Brexit
Authors: Marlow-Stevens Samuel , Hayton Richard
Published: April 2020

By way of Rhetorical Political Analysis, this article argues that May’s rhetoric on Brexit undermined her statecraft and with it her capacity to deliver Britain’s departure from the European Union. Utilising Jim Bulpitt’s (1986) conception of statecraft, our analysis reveals how May’s rhetoric prioritised party management and the politics of support, but in so doing yielded political argument hegemony to Brexiteers, impeding the passing of her Brexit deal and damaging her capacity for governing competence. We evidence these arguments by analysing the appeals to ethos, pathos and logos in May’s key speeches between July 2016 and July 2019, ranging from her first as Prime Minister to her last.
Pepper CaMLO6 Negatively Regulates Ralstonia solanacearum Resistance and Positively Regulates High Temperature and High Humidity Responses
Authors: Yang Sheng , Shi Yuanyuan , Zou Longyun , Huang Jinfeng , Shen Lei , Wang Yuzhu , Guan Deyi , He Shuilin
Published: April 2020

Plant mildew-resistance locus O (MLO) proteins influence susceptibility to powdery mildew. However, their roles in plant responses to other pathogens and heat stress remain unclear. Here, we showed that CaMLO6, a pepper (Capsicum annuum) member of MLO clade V, is a protein targeted to plasma membrane and probably endoplasmic reticulum. The transcript expression level of CaMLO6 was upregulated in the roots and leaves of pepper plants challenged with high temperature and high humidity (HTHH) and was upregulated in leaves but downregulated in roots of plants infected with the bacterial pathogen Ralstonia solanacearum. CaMLO6 was also directly upregulated by CaWRKY40 upon HTHH but downregulated by CaWRKY40 upon R. solanacearum infection. Virus-induced gene silencing of CaMLO6 significantly decreased pepper HTHH tolerance and R. solanacearum susceptibility. Moreover, CaMLO6 overexpression enhanced the susceptibility of Nicotiana benthamiana and pepper plants to R. solanacearum and their tolerance to HTHH, effects that were associated with the expression of immunity- and thermotolerance-associated marker genes, respectively. These results suggest that CaMLO6 acts as a positive regulator in response to HTHH but a negative regulator in response to R. solanacearum. Moreover, CaMLO6 is transcriptionally affected by R. solanacearum and HTHH; these transcriptional responses are at least partially regulated by CaWRKY40.
Key Ethical Concepts and Their Application to COVID-19 Research
Authors: Dawson Angus , Emanuel Ezekiel J , Parker Michael , Smith Maxwell J , Voo Teck Chuan
Published: April 2020

During the WHO-GloPID COVID-19 Global Research and Innovation Forum meeting held in Geneva on the 11th and 12th of February 2020 a number of different ethical concepts were used. This paper briefly states what a number of these concepts mean and how they might be applied to discussions about research during the COVID-19 pandemic and related outbreaks. This paper does not seek to be exhaustive and other ethical concepts are, of course, relevant and important.
Do Minorities Pay More for Mortgages?
Authors: Bhutta Neil , Hizmo Aurel
Published: April 2020

We test for racial discrimination in the prices charged by mortgage lenders. We construct a unique data set from which we observe the three dimensions of a mortgage’s price: the interest rate, discount points, and fees. Although we find statistically significant gaps by race and ethnicity in interest rates, these gaps are offset by differences in discount points. We trace out point-rate schedules and show that minorities and whites face identical schedules, but sort to different locations on the schedule. Such sorting may reflect systematic differences in liquidity or preferences. Finally, we find no differences in total fees by race or ethnicity.
Inflammatory hallmarks of lesser prominence in psoriatic arthritis patients starting biologics: a Nordic population-based cohort study
Authors: Lund Hansen Rebekka , Schoedt Jørgensen Tanja , Dreyer Lene , Hetland Merete L , Glintborg Bente , Askling Johan , Di Giuseppe Daniela , Jacobsson Lennart T H , Wallman Johan K , Nordstrom Dan , Aaltonen Kalle , Kristianslund Eirik K , Kvien Tore K , Provan Sella A , Gudbjornsson Bjorn , Love Thorvadur J , Kristensen L E
Published: April 2020

Objectives

To assess secular trends in baseline characteristics of PsA patients initiating their first or subsequent biologic DMARD (bDMARD) therapy and to explore prescription patterns and treatment rates of bDMARDs from 2006 to 2017 in the Nordic countries.

Methods

PsA patients registered in the Nordic rheumatology registries initiating any treatment with bDMARDs were identified. The bDMARDs were grouped as original TNF inhibitor [TNFi; adalimumab (ADA), etanercept (ETN) and infliximab (IFX)]; certolizumab pegol (CZP) and golimumab (GOL); biosimilars and ustekinumab, based on the date of release. Baseline characteristics were compared for the five countries, supplemented by secular trends with R2 calculations and point prevalence of bDMARD treatment.

Results

A total of 18 089 patients were identified (Denmark, 4361; Iceland, 449; Norway, 1948; Finland, 1069; Sweden, 10 262). A total of 54% of the patients were female, 34.3% of patients initiated an original TNFi, 8% CZP and GOL, 7.5% biosimilars and 0.3% ustekinumab as a first-line bDMARD. Subsequent bDMARDs were 25.2% original TNFi, 9% CZP and GOL, 12% biosimilars and 2.1% ustekinumab. From 2015 through 2017 there was a rapid uptake of biosimilars. The total of first-line bDMARD initiators with lower disease activity increased from 2006 to 2017, where an R2 close to 1 showed a strong association.

Conclusion

Across the Nordic countries, the number of prescribed bDMARDs increased from 2006 to 2017, indicating a previously unmet need for bDMARDs in the PsA population. In recent years, PsA patients have initiated bDMARDs with lower disease activity compared with previous years, suggesting that bDMARDs are initiated in patients with a less active inflammatory phenotype.
Inhibitory Repetitive Transcranial Magnetic Stimulation to Treat Psychomotor Slowing: A Transdiagnostic, Mechanism-Based Randomized Double-Blind Controlled Trial
Authors: Walther Sebastian , Alexaki Danai , Schoretsanitis Georgios , Weiss Florian , Vladimirova Irena , Stegmayer Katharina , Strik Werner , Schäppi Lea
Published: April 2020

Psychomotor slowing is frequently distressing patients with depression and schizophrenia. Increased neural activity within premotor cortices is linked to psychomotor slowing. This transdiagnostic study tested whether add-on inhibitory repetitive transcranial magnetic stimulation (rTMS) of the supplementary motor area (SMA) may alleviate psychomotor slowing. Forty-five patients with severe psychomotor slowing (26 psychosis, 19 major depression) were randomized in this transdiagnostic, double-blind, parallel-group, sham-controlled trial of 15 daily sessions of add-on rTMS over 3 weeks. Treatment arms included inhibitory 1 Hz stimulation of the SMA, facilitatory intermittent theta burst stimulation (iTBS) of the SMA, facilitatory 15 Hz stimulation of the left dorsolateral prefrontal cortex (DLPFC), and sham stimulation of the occipital cortex. The primary outcome was response (>30% reduction from baseline) according to the Salpêtrière Retardation Rating Scale (SRRS). Secondary outcomes were course of SRRS and further symptom rating scales. Last-observation carried forward method was applied to all subjects with baseline data. Response rates differed between protocols: 82% with inhibitory 1 Hz rTMS of the SMA, 0% with facilitatory iTBS of the SMA, 30% with sham, and 33% with 15 Hz DLPFC rTMS (χ 2 = 16.6, P < .001). Dropouts were similarly distributed across protocols. Response rates were similar in the completer analysis. This transdiagnostic trial of rTMS demonstrates that inhibitory SMA stimulation may ameliorate psychomotor slowing in severely ill patients. It further provides proof-of-concept that motor inhibition is linked to increased neural activity in the SMA because the inhibitory protocol performed best in reducing symptoms.

Trial registration: NCT03275766 (www.clinicaltrials.gov).
Ambiguity Coding Allows Accurate Inference of Evolutionary Parameters from Alignments in an Aggregated State-Space
Authors: Weber Claudia C , Perron Umberto , Casey Dearbhaile , Yang Ziheng , Goldman Nick
Published: April 2020

How can we best learn the history of a protein’s evolution? Ideally, a model of sequence evolution should capture both the process that generates genetic variation and the functional constraints determining which changes are fixed. However, in practical terms the most suitable approach may simply be the one that combines the convenience of easily available input data with the ability to return useful parameter estimates. For example, we might be interested in a measure of the strength of selection (typically obtained using a codon model) or an ancestral structure (obtained using structural modeling based on inferred amino acid sequence and side chain configuration).

But what if data in the relevant state-space are not readily available? We show that it is possible to obtain accurate estimates of the outputs of interest using an established method for handling missing data. Encoding observed characters in an alignment as ambiguous representations of characters in a larger state-space allows the application of models with the desired features to data that lack the resolution that is normally required. This strategy is viable because the evolutionary path taken through the observed space contains information about states that were likely visited in the “unseen” state-space. To illustrate this, we consider two examples with amino acid sequences as input. We show that $$\omega$$, a parameter describing the relative strength of selection on nonsynonymous and synonymous changes, can be estimated in an unbiased manner using an adapted version of a standard 61-state codon model. Using simulated and empirical data, we find that ancestral amino acid side chain configuration can be inferred by applying a 55-state empirical model to 20-state amino acid data. Where feasible, combining inputs from both ambiguity-coded and fully resolved data improves accuracy. Adding structural information to as few as 12.5% of the sequences in an amino acid alignment results in remarkable ancestral reconstruction performance compared to a benchmark that considers the full rotamer state information. These examples show that our methods permit the recovery of evolutionary information from sequences where it has previously been inaccessible. [Ancestral reconstruction; natural selection; protein structure; state-spaces; substitution models.]
Spatiotemporal clustering, social vulnerability and risk of congenital syphilis in northeast Brazil: an ecological study
Authors: de Souza Carlos D F , Machado Michael F , Correia Divanise S , do Carmo Rodrigo F , Cuevas Luis E , Santos Victor S
Published: April 2020

Background

To investigate the spatial distribution of congenital syphilis (CS) and its association to social vulnerability indexes in northeast Brazil.

Methods

This was an ecological study referring to all cases of CS and CS deaths recorded in the northeast region of Brazil from 2008 to 2015. Data were obtained from three Brazilian information systems. We examined statistical correlations between CS indicators by state and municipality and their socioeconomic and social vulnerability characteristics. We used Bayesian empirical local models to identify fluctuations of the indicators. Spatial statistical tests were used to identify spatial clusters and the municipalities at high risk of CS.

Results

The incidence of CS ranged from 2.1 cases/1000 live births (LB) in 2008 to 6.9/1000 LB in 2015, with an annual increase of 19.9% (p < 0.001). The mortality coefficient of CS ranged from 2.9/1000 LB in 2008 to 6.5/1000 LB in 2015, resulting in an annual increase of 15.1% (p < 0.001). Nine spatial clusters were identified. Cases of congenital syphilis occurred in well-defined spatiotemporal clusters and in areas with high levels of social vulnerability.

Conclusions

CS incidence is associated with social vulnerability. CS control programmes should target spatial clusters and populations with high levels of social vulnerability.
Cross-order host switches of hepatitis C-related viruses illustrated by a novel hepacivirus from sloths
Authors: Moreira-Soto Andres , Arroyo-Murillo Francisco , Sander Anna-Lena , Rasche Andrea , Corman Victor , Tegtmeyer Birthe , Steinmann Eike , Corrales-Aguilar Eugenia , Wieseke Nicolas , Avey-Arroyo Judy , Drexler Jan Felix
Published: April 2020

The genealogy of the hepatitis C virus (HCV) and the genus Hepacivirus remains elusive despite numerous recently discovered animal hepaciviruses (HVs). Viruses from evolutionarily ancient mammals might elucidate the HV macro-evolutionary patterns. Here, we investigated sixty-seven two-toed and nine three-toed sloths from Costa Rica for HVs using molecular and serological tools. A novel sloth HV was detected by reverse transcription polymerase chain reaction (RT-PCR) in three-toed sloths (2/9, 22.2%; 95% confidence interval (CI), 5.3–55.7). Genomic characterization revealed typical HV features including overall polyprotein gene structure, a type 4 internal ribosomal entry site in the viral 5′-genome terminus, an A–U-rich region and X-tail structure in the viral 3′-genome terminus. Different from other animal HVs, HV seropositivity in two-toed sloths was low at 4.5 per cent (3/67; CI, 1.0–12.9), whereas the RT-PCR-positive three-toed sloths were seronegative. Limited cross-reactivity of the serological assay implied exposure of seropositive two-toed sloths to HVs of unknown origin and recent infections in RT-PCR-positive animals preceding seroconversion. Recent infections were consistent with only 9 nucleotide exchanges between the two sloth HVs, located predominantly within the E1/E2 encoding regions. Translated sequence distances of NS3 and NS5 proteins and host comparisons suggested that the sloth HV represents a novel HV species. Event- and sequence distance-based reconciliations of phylogenies of HVs and of their hosts revealed complex macro-evolutionary patterns, including both long-term evolutionary associations and host switches, most strikingly from rodents into sloths. Ancestral state reconstructions corroborated rodents as predominant sources of HV host switches during the genealogy of extant HVs. Sequence distance comparisons, partial conservation of critical amino acid residues associated with HV entry and selection pressure signatures of host genes encoding entry and antiviral protein orthologs were consistent with HV host switches between genetically divergent mammals, including the projected host switch from rodents into sloths. Structural comparison of HCV and sloth HV E2 proteins suggested conserved modes of hepaciviral entry. Our data corroborate complex macro-evolutionary patterns shaping the genus Hepacivirus, highlight that host switches are possible across highly diverse host taxa, and elucidate a prominent role of rodent hosts during the Hepacivirus genealogy.
Cell‐Penetrating MK2 Inhibitory Peptide Blocks LPS‐Induced Expression of Proinflammatory Cytokines in HepG2 Hepatocytes
Authors: Kim Paul , Francis Tiffany , Dalrymple Durina , Yanamadala Yaswanthi , Carriere Victor M. , Poh Scott , Kim Audrey
Published: April 2020

Mitogen‐activated protein kinase‐activated protein kinase 2 (MAPKAPK2) or MK2 is a downstream effector of the MAPK family member p38. The p38‐MK2 signaling axis is well known to regulate the inflammatory response, thus it is an important target of anti‐inflammatory drugs. For MK2, as with other intracellular targets, delivering the drug across the plasma membrane barrier represents a major challenge. Here we conjugate an anti‐inflammatory peptide (AIP‐1) selective for MK2 to a novel cell‐penetrating peptide (CPP‐AIP‐1) to enhance intracellular delivery. We evaluated the cytotoxicity, efficacy, and intracellular uptake of these therapeutic peptides in an in vitro model of liver inflammation using HepG2 human hepatoma cells challenged with lipopolysaccharides (LPS).

HepG2 cells were treated with 0.1–1000 μM AIP‐1 or CPP‐AIP‐1 for 24 hours to assess cytotoxicity. A significant decrease in cell viability was observed in response to 1000 μM CPP‐AIP‐1, whereas 1000 μM AIP‐1 had no significant effect on cell viability. Treatment with either peptide at 300 μM did not alter cell viability relative to untreated control. We selected the next highest noncytotoxic dose tested ‐ 100 μM ‐ as the therapeutic dose. HepG2 cells were treated for 24 hours with 1 ng/mL LPS to induce an inflammatory response and co‐incubated with 100 μM AIP‐1 or 100 μM CPP‐AIP‐1. We observed no changes in mRNA expression of the housekeeping genes ACTB, B2M, and RPLP0 under any of the treatment conditions.

We found that LPS significantly upregulated the mRNA expression of the proinflammatory cytokines CXCL8 and TNF, and that CPP‐AIP‐1 (but not AIP‐1) co‐incubation decreased expression to basal levels. Consistent with these mRNA expression data, LPS significantly increased CXCL8 secretion, and this was inhibited by CPP‐AIP‐1 only. Inflammation clearly plays an important role in the development and progression of many diseases. Our results demonstrate the functionality of a cell‐penetrating peptide in inhibiting the MK2‐mediated inflammatory response.

Support or Funding Information

Research reported in this abstract was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20 GM103424‐18, Louisiana Biomedical Research Network grant number LSU Subcontract No. PO‐0000002131 (formerly 99989), and Board of Regent – Research Competitiveness Subprogram grant number LEQSF(2018‐21)‐RD‐A‐13
Evaluation of pediatric distal femoral physeal fractures and the factors impacting poor outcome requiring further corrective surgery
Authors: Bellamy J. Taylor , Ward Laura A. , Fletcher Nicholas D.
Published: April 2020

Fractures of the distal femur carry a significant risk of physeal arrest and resulting growth complications which often require additional surgeries to correct the deformity. This study examines the risk of needing corrective procedures as a child approaches skeletal maturity. A retrospective analysis of patients treated at a single institution for distal femoral physeal fractures from 2000 to 2015 was performed. Association between sex, age, Salter–Harris (SH) class, and fracture displacement with the risk of physeal arrest were examined. Association between years of growth remaining to skeletal maturity and the risk of needing additional corrective surgery (defined by leg length difference >2 cm or angular deformity (>5°) was examined using a logistic regression model. One hundred one patients were available for review with an average age of 12.6 ± 3.2 years. Twenty-six patients (25.7%) developed a physeal arrest. Seventy-six percent of these required subsequent surgical intervention to address length and angular deformities Sex, age, and SH class were not significantly associated with physeal arrest (P > 0.05). Percent fracture displacement was significantly associated with physeal arrest (P = 0.02). Years of growth remaining to skeletal maturity were significantly associated with an increased risk of requiring corrective surgery for growth complications (odds ratio: 0.758; 95% confidence interval 0.587–0.979; P = 0.03), however, this association failed to persist when accounting for age. Years of growth remaining to skeletal maturity may predict the need for future interventions and should be accounted for when planning treatment of these challenging injuries.
Association of Hypoactive and Hyperactive Delirium With Cognitive Function After Critical Illness
Authors: Hayhurst Christina J. , Marra Annachiara , Han Jin H. , Patel Mayur B. , Brummel Nathan E. , Thompson Jennifer L. , Jackson James C. , Chandrasekhar Rameela , Ely E. Wesley , Pandharipande Pratik P. , Hughes Christopher G.
Published: April 2020

Objectives:

Delirium, a heterogenous syndrome, is associated with worse long-term cognition after critical illness. We sought to determine if duration of motoric subtypes of delirium are associated with worse cognition.

Design:

Secondary analysis of prospective multicenter cohort study.

Setting:

Academic, community, and Veteran Affairs hospitals.

Patients:

Five-hundred eighty-two survivors of respiratory failure or shock.

Interventions:

We assessed delirium and level of consciousness using the Confusion Assessment Method-ICU and Richmond Agitation Sedation Scale daily during hospitalization. We defined a day with hypoactive delirium as a day with positive Confusion Assessment Method-ICU and corresponding Richmond Agitation Sedation Scale score less than or equal to 0 and a day with hyperactive delirium as a day with positive Confusion Assessment Method-ICU and corresponding Richmond Agitation Sedation Scale score greater than 0. At 3 and 12 months, we assessed global cognition with the Repeatable Battery for the Assessment of Neurologic Status and executive function with the Trail Making Test Part B. We used multivariable regression to examine the associations between days of hypoactive and hyperactive delirium with cognition outcomes. We allowed for interaction between days of hypoactive and hyperactive delirium and adjusted for baseline and in-hospital covariates.

Measurements and Results:

Hypoactive delirium was more common and persistent than hyperactive delirium (71% vs 17%; median 3 vs 1 d). Longer duration of hypoactive delirium was associated with worse global cognition at 3 (–5.13 [–8.75 to –1.51]; p = 0.03) but not 12 (–5.76 [–9.99 to –1.53]; p = 0.08) months and with worse executive functioning at 3 (–3.61 [–7.48 to 0.26]; p = 0.03) and 12 (–6.22 [–10.12 to –2.33]; p = 0.004) months; these associations were not modified by hyperactive delirium. Hyperactive delirium was not associated with global cognition or executive function in this cohort.

Conclusions:

Longer duration of hypoactive delirium was independently associated with worse long-term cognition. Assessing motoric subtypes of delirium in the ICU might aid in prognosis and intervention allocation. Future studies should consider delineating motoric subtypes of delirium.
Ketamine Use for Tracheal Intubation in Critically Ill Children Is Associated With a Lower Occurrence of Adverse Hemodynamic Events
Authors: Conway J. Arden , Kharayat Priyanka , Sanders Ronald C. , Nett Sholeen , Weiss Scott L. , Edwards Lauren R. , Breuer Ryan , Kirby Aileen , Krawiec Conrad , Page-Goertz Christopher , Polikoff Lee , Turner David A. , Shults Justine , Giuliano John S. , Orioles Alberto , Balkandier Sylvain , Emeriaud Guillaume , Rehder Kyle J. , Kian Boon Joel Lim , Shenoi Asha , Vanderford Paula , Nuthall Gabrielle , Lee Anthony , Zeqo Jonida , Parsons Simon J. , Furlong-Dillard Jamie , Meyer Keith , Harwayne-Gidansky Ilana , Jung Philipp , Adu-Darko Michelle , Bysani G. Kris , McCarthy Melissa A. , Shlomovich Mark , Toedt-Pingel Iris , Branca Aline , Esperanza Maria Christina , Al-Subu Awni M. , Pinto Matthew , Tallent Sarah , Shetty Rakshay , Thyagarajan Sujatha , Ikeyama Takanari , Tarquinio Keiko M. , Skippen Peter , Kasagi Mioko , Howell Joy D. , Nadkarni Vinay M. , Nishisaki Akira
Published: April 2020

Objectives:

Tracheal intubation in critically ill children with shock poses a risk of hemodynamic compromise. Ketamine has been considered the drug of choice for induction in these patients, but limited data exist. We investigated whether the administration of ketamine for tracheal intubation in critically ill children with or without shock was associated with fewer adverse hemodynamic events compared with other induction agents. We also investigated if there was a dose dependence for any association between ketamine use and adverse hemodynamic events.

Design:

We performed a retrospective analysis using prospectively collected observational data from the National Emergency Airway Registry for Children database from 2013 to 2017.

Setting:

Forty international PICUs participating in the National Emergency Airway Registry for Children.

Patients:

Critically ill children 0–17 years old who underwent tracheal intubation in a PICU.

Interventions:

None.

Measurements and Main Results:

The association between ketamine exposure as an induction agent and the occurrence of adverse hemodynamic events during tracheal intubation including dysrhythmia, hypotension, and cardiac arrest was evaluated. We used multivariable logistic regression to account for patient, provider, and practice factors with robust ses to account for clustering by sites. Of 10,750 tracheal intubations, 32.0% (n = 3,436) included ketamine as an induction agent. The most common diagnoses associated with ketamine use were sepsis and/or shock (49.7%). After adjusting for potential confounders and sites, ketamine use was associated with fewer hemodynamic tracheal intubation associated adverse events compared with other agents (adjusted odds ratio, 0.74; 95% CI, 0.58–0.95). The interaction term between ketamine use and indication for shock was not significant (p = 0.11), indicating ketamine effect to prevent hemodynamic adverse events is consistent in children with or without shock.

Conclusions:

Ketamine use for tracheal intubation is associated with fewer hemodynamic tracheal intubation–associated adverse events.
Continuous Versus Intermittent Infusion of Vancomycin and the Risk of Acute Kidney Injury in Critically Ill Adults: A Systematic Review and Meta-Analysis*
Authors: Flannery Alexander H. , Bissell Brittany D. , Bastin Melissa Thompson , Morris Peter E. , Neyra Javier A.
Published: April 2020

Objectives:

Critically ill patients routinely receive vancomycin as empiric antibiotic therapy. A continuous infusion administration strategy may be superior to intermittent infusion by minimizing peak concentrations and variability thereby optimizing safety. We performed a systematic review and meta-analysis to investigate the impact of vancomycin infusion strategy on acute kidney injury in critically ill adults.

Data Sources:

A systematic search of MEDLINE, CINAHL, Web of Science, International Pharmaceutical Abstracts, and Google Scholar was undertaken.

Study Selection:

We included randomized controlled trials and observational studies evaluating acute kidney injury in critically ill adults comparing vancomycin administered by intermittent and continuous infusion. Secondary outcomes included mortality and pharmacokinetic target attainment.

Data Extraction:

Eleven studies were identified for analysis with baseline demographics, endpoints, protocol definitions, and outcomes extracted.

Data Synthesis:

When compared with intermittent infusion, continuous infusion was associated with a reduction in acute kidney injury in critically ill adults (odds ratio, 0.47; 95% CI, 0.34–0.65) and a 2.6 greater odds of pharmacokinetic target attainment (odds ratio, 2.63; 95% CI, 1.52–4.57). No difference in mortality was observed (odds ratio, 1.04; 95% CI, 0.80–1.35).

Conclusions:

When administered via a continuous infusion, vancomycin is associated with a 53% reduction in the odds of acute kidney injury and a 2.6-fold higher odds of pharmacokinetic target attainment when compared with intermittent infusion without influencing overall mortality.
Adverse Events After Transition From ICU to Hospital Ward: A Multicenter Cohort Study*
Authors: Sauro Khara M. , Soo Andrea , de Grood Chloe , Yang Michael M. H. , Wierstra Benjamin , Benoit Luc , Couillard Philippe , Lamontagne François , Turgeon Alexis F. , Forster Alan J. , Fowler Robert A. , Dodek Peter M. , Bagshaw Sean M. , Stelfox Henry T.
Published: April 2020

Objectives:

To examine adverse events and associated factors and outcomes during transition from ICU to hospital ward (after ICU discharge).

Design:

Multicenter cohort study.

Setting:

Ten adult medical-surgical Canadian ICUs.

Patients:

Patients were those admitted to one of the 10 ICUs from July 2014 to January 2016.

Interventions:

None.

Measurements and Main Results:

Two ICU physicians independently reviewed progress and consultation notes documented in the medical record within 7 days of patient’s ICU discharge date to identify and classify adverse events. The adverse event data were linked to patient characteristics and ICU and ward physician surveys collected during the larger prospective cohort study. Analyses were conducted using multivariable logistic regression. Of the 451 patients included in the study, 84 (19%) experienced an adverse event, the majority (62%) within 3 days of transfer from ICU to hospital ward. Most adverse events resulted only in symptoms (77%) and 36% were judged to be preventable. Patients with adverse events were more likely to be readmitted to the ICU (odds ratio, 5.5; 95% CI, 2.4–13.0), have a longer hospital stay (mean difference, 16.1 d; 95% CI, 8.4–23.7) or die in hospital (odds ratio, 4.6; 95% CI, 1.8-11.8) than those without an adverse event. ICU and ward physician predictions at the time of ICU discharge had low sensitivity and specificity for predicting adverse events, ICU readmissions, and hospital death.

Conclusions:

Adverse events are common after ICU discharge to hospital ward and are associated with ICU readmission, increased hospital length of stay and death and are not predicted by ICU or ward physicians.
Clinician Recognition of the Acute Respiratory Distress Syndrome: Risk Factors for Under-Recognition and Trends Over Time*
Authors: Schwede Matthew , Lee Robert Y. , Zhuo Hanjing , Kangelaris Kirsten N. , Jauregui Alejandra , Vessel Kathryn , Belzer Annika , Deiss Thomas , Matthay Michael A. , Liu Kathleen D. , Calfee Carolyn S.
Published: April 2020

Objectives:

The acute respiratory distress syndrome is common in critically ill patients. Recognition is crucial because acute respiratory distress syndrome is associated with a high mortality rate, and low tidal volume ventilation improves mortality. However, acute respiratory distress syndrome often goes unrecognized. Risk factors for under-recognition and trends over time have not been fully described.

Design:

Retrospective chart review of patients with acute respiratory distress syndrome from a prospective cohort study of critically ill patients. For each patient’s ICU stay, we searched the chart for terms that indicated that acute respiratory distress syndrome was diagnosed, in the differential diagnosis, or treated with low tidal volume ventilation.

Setting:

ICUs at a tertiary hospital at the University of California, San Francisco between 2008 and 2016.

Patients:

Critically ill patients with acute respiratory distress syndrome.

Interventions:

None.

Measurements and Main Results:

Acute respiratory distress syndrome was recognized in 70% of patients, and recognition increased from 60% in 2008–2009 to 92% in 2016 (p = 0.004). Use of tidal volumes less than 6.5 mL/kg also increased (p < 0.001) from 20% to 92%. Increased acute respiratory distress syndrome severity (p = 0.01) and vasopressor use (p = 0.04) were associated with greater recognition. Clinician diagnosis of acute respiratory distress syndrome and inclusion of acute respiratory distress syndrome in the differential diagnosis were associated with tidal volumes less than 6.5 mL/kg (51% use of tidal volume ≤ 6.5 mL/kg if acute respiratory distress syndrome recognized vs 15% if not recognized; p = 0.002). Diagnosing acute respiratory distress syndrome was associated with lower tidal volume in multivariate analysis.

Conclusions:

Although acute respiratory distress syndrome recognition and low tidal volume ventilation use have increased over time, they remain less than universal. Clinician recognition of acute respiratory distress syndrome is associated with both systemic and respiratory severity of illness and is also associated with use of low tidal volume ventilation.
Factors Disrupting Melatonin Secretion Rhythms During Critical Illness
Authors: Maas Matthew B. , Lizza Bryan D. , Abbott Sabra M. , Liotta Eric M. , Gendy Maged , Eed John , Naidech Andrew M. , Reid Kathryn J. , Zee Phyllis C.
Published: April 2020

Objectives:

The circadian system modulates many important physiologic processes, synchronizing tissue-specific functions throughout the body. We sought to characterize acute alterations of circadian rhythms in critically ill patients and to evaluate associations between brain dysfunction, systemic multiple organ dysfunction, environmental stimuli that entrain the circadian rhythm (zeitgebers), rest-activity rhythms, and the central circadian rhythm-controlled melatonin secretion profile.

Design:

Prospective study observing a cohort for 24–48 hours beginning within the first day of ICU admission.

Setting:

Multiple specialized ICUs within an academic medical center.

Patients:

Patients presenting from the community with acute onset of either intracerebral hemorrhage as a representative neurologic critical illness or sepsis as a representative systemic critical illness. Healthy control patients were studied in using modified constant routine in a clinical research unit.

Interventions:

None.

Measurements and Main Results:

Light, feeding, activity, medications, and other treatment exposures were evaluated along with validated measures of encephalopathy (Glasgow Coma Scale), multiple organ system function (Sequential Organ Failure Assessment score), and circadian rhythms (profiles of serum melatonin and its urinary metabolite 6-sulphatoxymelatonin). We studied 112 critically ill patients, including 53 with sepsis and 59 with intracerebral hemorrhage. Environmental exposures were abnormal, including light (dim), nutritional intake (reduced or absent and mistimed), and arousal stimuli (increased and mistimed). Melatonin amplitude and acrophase timing were generally preserved in awake patients but dampened and delayed with increasing encephalopathy severity. Melatonin hypersecretion was observed in patients exposed to catecholamine vasopressor infusions, but unaffected by sedatives. Change in vasopressor exposure was the only factor associated with changes in melatonin rhythms between days 1 and 2.

Conclusions:

Encephalopathy severity and adrenergic agonist medication exposure were the primary factors contributing to abnormal melatonin rhythms. Improvements in encephalopathy and medical stabilization did not rapidly normalize rhythms. Urinary 6-sulphatoxymelatonin is not a reliable measure of the central circadian rhythm in critically ill patients.
Stress-Induced Behavioral Quiescence and Abnormal Rest-Activity Rhythms During Critical Illness
Authors: Maas Matthew B. , Lizza Bryan D. , Kim Minjee , Abbott Sabra M. , Gendy Maged , Reid Kathryn J. , Zee Phyllis C.
Published: April 2020

Objectives:

To characterize acute alterations of circadian and ultradian rest-activity rhythms in critically ill patients and their association with brain dysfunction, systemic multiple organ dysfunction, and melatonin rhythms.

Design:

Prospective study observing a cohort for 48 hours beginning within the first day of ICU admission.

Setting:

ICUs within an academic medical center.

Patients:

Patients presenting from the community with acute onset of either intracerebral hemorrhage or sepsis as representative neurologic and systemic critical illnesses. Healthy control patients were studied in the community, during hospital bedrest, and during sleep deprivation.

Interventions:

None.

Measurements and Main Results:

Circadian and ultradian characteristics of rest-activity patterns were measured by wrist actigraphy, severity of neurologic and systemic illness by Glasgow Coma Scale and Sequential Organ Failure Assessment, and central circadian rhythm by melatonin profile. We studied 112 critically ill patients, including 53 with sepsis and 59 with intracerebral hemorrhage, along with 53 control participants. Total daily activity was markedly reduced and rest-activity rhythmicity was undetectable, neither of which was replicated by hospital bedrest in healthy controls. Circadian rest-activity rhythm fragmentation and attenuation and ultradian disorganization was associated with Glasgow Coma Scale and Sequential Organ Failure Assessment in adjusted models. Rest-activity rhythms showed no detectable phase coherence with melatonin rhythms.

Conclusions:

Critically ill patients rapidly enter a state of behavioral quiescence proportionate to their illness severity with concomitant disturbance of circadian and ultradian rest-activity rhythms and loss of phase coherence with the melatonin rhythm. Quiescence characteristics in rest-activity rhythms were not different in patients with and without delirium, suggesting them to be distinct phenomena. Animal models of severe physiologic stress have shown that specific neural pathway separate from the sleep-wake regulatory pathway induce behavioral quiescence and rest-activity arrhythmia, and facilitate recovery of cellular homeostasis. Whether quiescence is a conserved protective response pathway in humans is not yet understood.