bluuebunny/crossref_metadata_2025 huggingface dataset:
Silver chitosan nanocomposites as a potential treatment for superficial candidiasis
Authors: Artunduaga Bonilla Jhon Jhamilton , Honorato Leandro , Cordeiro de Oliveira Douglas Felipe , Araújo Gonçalves Rodrigo , Guimarães Allan , Miranda Kildare , Nimrichter Leonardo
Published: April 2021

Silver compounds are widely known for their antimicrobial activity, but can exert toxic effects to the host. Among the strategies to reduce its toxicity, incorporation into biopolymers has shown promising results. We investigated the green syntheses of silver nanoparticles (AgNPs) and their functionalization in a chitosan matrix (AgNPs@Chi) as a potential treatment against Candida spp. Inhibitory concentrations ranging between 0.06 and  1 μg/ml were observed against distinct Candida species. Nanocomposite-treated cells displayed cytoplasmic degeneration and a cell membrane and wall disruption. Silver nanocomposites in combination with fluconazole and amphotericin B showed an additive effect when analyzed by the Bliss method. The low cytotoxicity displayed in mammalian cells and in the Galleria mellonella larvae suggested their potential use in vivo. When tested as a topical treatment against murine cutaneous candidiasis, silver nanocomposites reduced the skin fungal burden in a dose-response behavior and favored tissue repair. In addition, the anti-biofilm effect of AgNPs@Chi in human nail model was demonstrated, suggesting that the polymeric formulation of AgNPs does not affect antifungal activity even against sessile cells. Our results suggest that AgNPs@Chi seems to be a less toxic and effective topical treatment for superficial candidiasis.

Lay Summary

This study demonstrated the efficacy of silver nanoparticles (AgNPs) in inhibiting the growth of Candida. AgNPs incorporated in chitosan displayed a reduced toxicity. Tests in infected mice showed the effectiveness of the treatment. AgNPs-chitosan could be an alternative to combat candidiasis.
Numerical simulations of macrospicule jets under energy imbalance conditions in the solar atmosphere
Authors: González-Avilés J J , Murawski K , Srivastava A K , Zaqarashvili T V , González-Esparza J A
Published: April 2021

Using numerical simulations, we study the effects of thermal conduction and radiative cooling on the formation and evolution of solar jets with some macrospicules features. We initially assume that the solar atmosphere is rarely in equilibrium through energy imbalance. Therefore, we test whether the background flows resulting from an imbalance between thermal conduction and radiative cooling influence the jets’ behaviour. In this particular scenario, we trigger the formation of the jets by launching a vertical velocity pulse localized at the upper chromosphere for the following test cases: (i) adiabatic case; (ii) thermal conduction case; (iii) radiative cooling case; and (iv) thermal conduction + radiative cooling case. According to the test results, the addition of the thermal conduction results in smaller and hotter jets than in the adiabatic case. On the other hand, the radiative cooling dissipates the jet after reaching the maximum height (≈5.5 Mm), making it shorter and colder than in the adiabatic and thermal conduction cases. Besides, the flow generated by the radiative cooling is more substantial than that caused by the thermal conduction. Despite the energy imbalance of the solar atmosphere background, the simulated jet shows morphological features of macrospicules. Furthermore, the velocity pulse steepens into a shock that propagates upward into a solar corona that maintains its initial temperature. The shocks generate the jets with a quasi-periodical behaviour that follows a parabolic path on time–distance plots consistent with macrospicule jets’ observed dynamics.
Evolution of primordial Kuiper belt binaries through a giant planet instability
Authors: Stone Lukas R , Kaib Nathan A
Published: April 2021

The non-resonant Kuiper belt objects between the 3:2 and 2:1 Neptunian mean motion resonances can be largely divided between a cold classical belt (CCB) and a hot classical belt (HCB). A notable difference between these two subpopulations is the prevalence of widely spaced, equal-mass binaries in the CCB, and a much smaller but non-zero number in the HCB. The primary reason for this difference in binary rate remains unclear. Here using N-body simulations we examine whether close encounters with the giant planets during an early outer Solar system instability may have disrupted primordial Kuiper belt binaries that existed within the primordial Kuiper belt before they attained HCB orbits. We find that such encounters are very effective at disrupting binaries down to separations of ∼ 1% of their Hill radius' (as measured in the modern Kuiper belt), potentially explaining the paucity of widely spaced, equal mass binaries in the modern HCB. Moreover, we find that the widest binaries observed in the modern HCB are quite unlikely to survive planetary encounters, but these same planetary encounters can widen a small subset of tighter binaries to give rise to the small population of very wide binaries seen in today's HCB.
Analysis of Deep Brain Stimulation Lead Targeting in the Stimulation of Anterior Nucleus of the Thalamus for Epilepsy Clinical Trial
Authors: Gross Robert E , Fisher Robert S , Sperling Michael R , Giftakis Jonathon E , Stypulkowski Paul H ,   on behalf of the SANTÉ Study Group
Published: April 2021

BACKGROUND

Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is an effective therapy for patients with drug-resistant focal epilepsy. Best practices for surgical targeting of the ANT can be refined as new information becomes available regarding effective stimulation sites.

OBJECTIVE

To conduct a retrospective analysis of the relationship between outcomes (seizure reduction during year 1) and DBS lead locations in subjects from the SANTÉ pivotal trial (Stimulation of ANT for Epilepsy) based upon recent clinical findings.

METHODS

Postoperative images from SANTÉ subjects (n = 101) were evaluated with respect to lead trajectory relative to defined anatomic landmarks. A qualitative scoring system was used to rate each lead placement for proximity to an identified target region above the junction of the mammillothalamic tract with the ANT. Each subject was assigned a bilateral lead placement score, and these scores were then compared to clinical outcomes.

RESULTS

Approximately 70% of subjects had “good” bilateral lead placements based upon location with respect to the defined target. These subjects had a much higher probability of being a clinical responder (>50% seizure reduction) than those with scores reflecting suboptimal lead placements (43.5% vs 21.9%, P < .05).

CONCLUSION

Consistent with experience from more established DBS indications, our findings and other recent reports suggest that there may be specific sites within the ANT that are associated with superior clinical outcomes. It will be important to continue to evaluate these relationships and the evolution of other clinical practices (eg, programming) to further optimize this therapy.
Venous Anatomy Influence on the Approach Selection of a Petroclival Clear Cell Meningioma With Associated Multiple Spinal Meningiomas: 2-Dimensional Operative Video
Authors: Essayed Walid I B N , Mooney Michael A , Al-Mefty Ossama
Published: April 2021

Preoperative careful evaluation of the sigmoid transverse sinus and its tributary veins is paramount for the safe surgical planning of petroclival lesions.
1

,

2
When the vein of Labbé is running within the tentorium, classic petrosal approach involving transection of the tentorium is modified to avoid the risk of postoperative morbid temporal lobe venous infarcts.1–3
-

3
Thus, the surgical plan should be tailored to the specific patient anatomy as demonstrated in the presented case during which a transmastoid approach was followed, in the same surgical setting, by a middle fossa approach to resect a large petroclival clear cell meningioma with extension into Meckel cave. These meningiomas are WHO grade II tumors with a propensity to local recurrence and cerebrospinal fluid seeding.
4
SMARCE1 mutations define this subtype of meningioma, with frequent familial inheritance, and predispose patients to both skull base and spinal clear cell meningiomas.
5

,

6
Maximal surgical resection is the best initial treatment option allowing to withhold or delay the use of radiation in tumors frequently encountered in young patients.
7
In this report, we demonstrate the microsurgical techniques deployed to achieve maximal resection of a petroclival clear cell meningioma and associated lumbar and sacral spinal meningiomas in a 20-yr-old patient with a familial SMARCE1 mutation. The patient agreed to the surgical intervention and to the use of her image.
The Unique Fiber Anatomy of Middle Temporal Gyrus Default Mode Connectivity
Authors: Briggs Robert G , Tanglay Onur , Dadario Nicholas B , Young Isabella M , Fonseka R Dineth , Hormovas Jorge , Dhanaraj Vukshitha , Lin Yueh-Hsin , Kim Sihyong J , Bouvette Adam , Chakraborty Arpan R , Milligan Ty M , Abraham Carol J , Anderson Christopher D , O’Donoghue Daniel L , Sughrue Michael E
Published: April 2021

BACKGROUND

The middle temporal gyrus (MTG) is understood to play a role in language-related tasks such as lexical comprehension and semantic cognition. However, a more specific understanding of its key white matter connections could promote the preservation of these functions during neurosurgery.

OBJECTIVE

To provide a detailed description of the underlying white matter tracts associated with the MTG to improve semantic preservation during neurosurgery.

METHODS

Tractography was performed using diffusion imaging obtained from 10 healthy adults from the Human Connectome Project. All tracts were mapped between cerebral hemispheres with a subsequent laterality index calculated based on resultant tract volumes. Ten postmortem dissections were performed for ex vivo validation of the tractography based on qualitative visual agreement.

RESULTS

We identified 2 major white matter bundles leaving the MTG: the inferior longitudinal fasciculus and superior longitudinal fasciculus. In addition to long association fibers, a unique linear sequence of U-shaped fibers was identified, possibly representing a form of visual semantic transfer down the temporal lobe.

CONCLUSION

We elucidate the underlying fiber-bundle anatomy of the MTG, an area highly involved in the brain's language network. Improved understanding of the unique, underlying white matter connections in and around this area may augment our overall understanding of language processing as well as the involvement of higher order cerebral networks like the default mode network in these functions.
Optic Canal Decompression: Concepts and Techniques: 2-Dimensional Operative Video
Authors: Patra Devi P , Turcotte Evelyn L , Bendok Bernard R
Published: April 2021

The optic canal (OC) is a bony channel that transmits the optic nerve (ON) and ophthalmic artery (OphA) as they course through the lesser wing of the sphenoid bone to the orbital apex. The OC is involved in a variety of intracranial and extracranial pathologies,
1
and opening of the canal may be necessary in order to achieve adequate exposure, better disease control, and vision preservation.
2
Depending on the location of the pathology and its relationship with the optic nerve, the OC may be decompressed through an open transcranial approach or an endoscopic endonasal approach.
1,3
OC drilling can be tailored based on the location of the pathology and its extension. Anterior clinoid process and optic strut drilling can be added based on these factors as well.
4,5

In this video, we demonstrate the steps of OC drilling in both transcranial microscopic and endoscopic endonasal approaches through a combination of animated illustrations and operative videos. We present 4 cases, including 2 transcranial microscopic and 2 endoscopic endonasal approaches,
6
demonstrating OC decompression and its technical nuances. Each case was selected to represent the range of pathologies relevant to OC drilling to allow for a complete understanding of the techniques and concepts required for optimal treatment.

An informed written consent has been obtained from each of the patients in this publication.

Video © Mayo Foundation for Medical Education and Research. All rights reserved.

Images at 1:03-1:10 © The Rhoton Collection.

Images at 3:56-4:07 Reprinted from World Neurosurgery, vol 124, Caporlingua et al,
3
Copyright 2019, with permission from Elsevier.

Images at 9:02-9:48 reprinted from Bendok et al,
6
by permission of the Congress of Neurological Surgeons.
Zygomatic Approach to Cavernous Sinus Chordoma: 2-Dimensional Operative Video
Authors: Aversa Antonio , Al-Mefty Ossama
Published: April 2021

Chordoma is not a benign disease. It grows invasively, has a high rate of local recurrence, metastasizes, and seeds in the surgical field.
1
Thus, chordoma should be treated aggressively with radical resection that includes the soft tissue mass and the involved surrounding bone that contains islands of chordoma.
2–5
High-dose radiation, commonly by proton beam therapy, is administered after gross total resection for long-term control. About half of chordoma cases occupy the cavernous sinus space and resecting this extension is crucial to obtain radical resection. Fortunately, the cavernous sinus proper extension is the easier part to remove and pre-existing cranial nerves deficit has good chance of recovery. As chordomas originate and are always present extradurally (prior to invading the dura), an extradural access to chordomas is the natural way for radical resection without brain manipulation. The zygomatic approach is key to the middle fossa, cavernous sinus, petrous apex, and infratemporal fossa; it minimizes the depth of field and is highly advantageous in chordoma located mainly lateral to the cavernous carotid artery.
6–12
This article demonstrates the advantages of this approach, including the mobilization of the zygomatic arch alleviating temporal lobe retraction, the peeling of the middle fossa dura for exposure of the cavernous sinus, the safe dissection of the trigeminal and oculomotor nerves, and total control of the petrous and cavernous carotid artery. Tumor extensions to the sphenoid sinus, sella, petrous apex, and clivus can be removed. The patient is a 30-yr-old who consented for surgery.
Concomitant Embolization and Microsurgical Resection of a Giant, Hypervascular Skull Base Meningioma: 2-Dimensional Operative Video
Authors: Mooney Michael A , Ibn Essayed Walid , Aziz-Sultan Mohammad Ali , Al-Mefty Ossama
Published: April 2021

Some skull base tumors can be extremely hypervascular, incorporating multiple vascular territories and demonstrating arteriovenous shunting. Devascularization is a critical step undertaken early in meningioma surgery, necessary before the debulking that is required in skull base tumors. While devascularization can often be achieved with appropriate approach selection, bony drilling, and microsurgical cautery, preoperative embolization of meningiomas has an invaluable role in selected cases.
1,2

 Embolization, however, does have added risk, magnified in large tumors by the potential infarction with subsequent edema that can potentially lead to acute deterioration and neurosurgical emergency. Hence, to achieve devascularization of an extremely vascular tumor, embolization and surgical resection should be performed concomitantly, as one operation, in which embolization might be the first stage, or might be performed after the craniotomy flap is raised, if necessary.
3
Naturally, this requires the multifaceted neurosurgical expertise of embolization and microsurgical resection, and the facility to perform such.

 We present a case of a giant, hypervascular, radiation-induced, skull base meningioma with internal and external carotid artery supply in a young patient with deteriorating vision in his only eye. Selective embolization of the internal maxillary, middle meningeal, and middle cerebral artery blood supplies was performed. Microsurgical interruption of the ethmoidal artery blood supply was then performed. This hybrid approach safely and effectively devascularized the tumor and allowed for a complete resection of this high-risk tumor
4
while minimizing risk to the ophthalmic artery and optic nerve.

 The patient was consented for surgery.
Using Administrative Records and Survey Data to Construct Samples of Tweeters and Tweets
Authors: Hughes Adam G , McCabe Stefan D , Hobbs William R , Remy Emma , Shah Sono , Lazer David M J
Published: April 2021

Social media data can provide new insights into political phenomena, but users do not always represent people, posts and accounts are not typically linked to demographic variables for use as statistical controls or in subgroup comparisons, and activities on social media can be difficult to interpret. For data scientists, adding demographic variables and comparisons to closed-ended survey responses have the potential to improve interpretations of inferences drawn from social media—for example, through comparisons of online expressions and survey responses, and by assessing associations with offline outcomes like voting. For survey methodologists, adding social media data to surveys allows for rich behavioral measurements, including comparisons of public expressions with attitudes elicited in a structured survey. Here, we evaluate two popular forms of linkages—administrative and survey—focusing on two questions: How does the method of creating a sample of Twitter users affect its behavioral and demographic profile? What are the relative advantages of each of these methods? Our analyses illustrate where and to what extent the sample based on administrative data diverges in demographic and partisan composition from surveyed Twitter users who report being registered to vote. Despite demographic differences, each linkage method results in behaviorally similar samples, especially in activity levels; however, conventionally sized surveys are likely to lack the statistical power to study subgroups and heterogeneity (e.g., comparing conversations of Democrats and Republicans) within even highly salient political topics. We conclude by developing general recommendations for researchers looking to study social media by linking accounts with external benchmark data sources.
Systematic study on the role of various higher-order processes in the breakup of weakly-bound projectiles
Authors: Singh Jagjit , Matsumoto Takuma , Ogata Kazuyuki
Published: April 2021

The virtual photon theory (VPT), which is based on first-order Coulomb dissociation restricted to the electric dipole (E1), has been successfully used to explain the breakup data for several cases. Our aim is to study the role of various higher-order processes that are ignored in the VPT, such as the nuclear breakup, interference between nuclear and Coulomb amplitudes, and multistep breakup processes mainly due to strong continuum-continuum couplings in the breakup of two-body projectiles on a heavy target at both intermediate and higher incident energies. For the purpose of numerical calculations, we employed eikonal version of three-body continuum-discretized coupled-channels (CDCC) reaction model. Our results for the breakup of 11Be and 17F on 208Pb target at 100, 250, and 520 MeV/A, show the importance of nuclear breakup contribution, and its significant role in the multistep processes. The multistep effect on Coulomb breakup for core-neutron projectile was found to be negligible, whereas it was important for core-proton projectile. Coulomb-nuclear interference (CNI) effect was also found to be non-negligible. Qantitatively, the multistep effects due to the nuclear breakup was found to depend on the incident energy through the energy dependence of the core-target and nucleon-target nuclear potentials. The nuclear breakup component, the CNI effect, and the multistep breakup processes are all found to be non-negligible; hence, the assumptions adopted in the VPT for the accurate description of breakup cross sections are not valid.
Can a CNN trained on the Ising model detect the phase transition of the q-state Potts model?
Authors: Fukushima Kimihiko , Sakai Kazumitsu
Published: April 2021

Employing a deep convolutional neural network (deep CNN) trained on spin configurations of the 2D Ising model and the temperatures, we examine whether the deep CNN can detect the phase transition of the 2D $q$-state Potts model. To this end, we generate binarized images of spin configurations of the $q$-state Potts model ($q\ge 3$) by replacing the spin variables $\{0,1,\ldots,\lfloor q/2\rfloor-1\}$ and $\{\lfloor q/2\rfloor,\ldots,q-1\}$ with $\{0\}$ and $\{1\}$, respectively. Then, we input these images to the trained CNN to output the predicted temperatures. The binarized images of the $q$-state Potts model are entirely different from Ising spin configurations, particularly at the transition temperature. Moreover, our CNN model is not trained on the information about whether phases are ordered/disordered but is naively trained by Ising spin configurations labeled with temperatures at which they are generated. Nevertheless, the deep CNN can detect the transition point with high accuracy, regardless of the type of transition. We also find that, in the high-temperature region, the CNN outputs the temperature based on the internal energy, whereas, in the low-temperature region, the output depends on the magnetization and possibly the internal energy as well. However, in the vicinity of the transition point, the CNN may use more general factors to detect the transition point.
Mortality Effects and Choice Across Private Health Insurance Plans
Authors: Abaluck Jason , Caceres Bravo Mauricio , Hull Peter , Starc Amanda
Published: April 2021

Competition in health insurance markets may fail to improve health outcomes if consumers are not able to identify high-quality plans. We develop and apply a novel instrumental variables framework to quantify the variation in causal mortality effects across plans and measure how much consumers attend to this variation. We first document large differences in the observed mortality rates of Medicare Advantage plans in local markets. We then show that when plans with high mortality rates exit these markets, enrollees tend to switch to more typical plans and subsequently experience lower mortality. We derive and validate a novel “fallback condition” governing the subsequent choices of those affected by plan exits. When the fallback condition is satisfied, plan terminations can be used to estimate the relationship between observed plan mortality rates and causal mortality effects. Applying the framework, we find that mortality rates unbiasedly predict causal mortality effects. We then extend our framework to study other predictors of plan mortality effects and estimate consumer willingness to pay. Higher-spending plans tend to reduce enrollee mortality, but existing quality ratings are uncorrelated with plan mortality effects. Consumers place little weight on mortality effects when choosing plans. Good insurance plans dramatically reduce mortality, and redirecting consumers to such plans could improve beneficiary health.
Policing and Punishing Illegal Gun Behavior: An Examination of Jail Detainee Experiences with Gun Law Enforcement In Los Angeles
Authors: Barragan Melissa
Published: April 2021

Drawing upon 140 interviews with individuals detained on gun-related charges, this article examines how participants’ experiences with gun-related policing and punishment shaped their beliefs and behaviors surrounding guns and gun violence. Findings suggest that respondents characterized many of their gun-related experiences as unjust. They argue that their policing encounters reinforced discriminatory practices and stereotypes, undermining a key feature of procedural and distributive justice – impartiality. Respondents’ experiences with police harassment and neglect attenuated their willingness to seek out and cooperate with the police by communicating that the law was not designed to serve marginalized groups, who often are treated as suspects first and victims second. By contrast, gang enhancements were key in shaping respondents’ perceptions of unjust punishment, as these severe penalties also revealed inequities by race/ethnicity, class, and other social characteristics. The legitimacy erosion and sense of failed protection by the state produced by these encounters ultimately helped to create a context whereby illegal gun carry was positioned as a necessary strategy. Findings from this study extend existing scholarship on justice perceptions by demonstrating how specific policing, punishment, and criminalization processes can damage the law’s legitimacy and inadvertently encourage the violence that the law was designed to deter.
External application of nitrogen alleviates toxicity of cadmium on poplars via starch and sucrose metabolism
Authors: He Fang , Zhao Qian , Huang Jin-Liang , Niu Meng-Xue , Feng Hua-Cong , Shi Yu-Jie , Zhao Kuang-Ji , Cui Xing-Lei , Wu Xiao-Lu , Mi Jia-Xuan , Zhong Yu , Liu Qing-Lin , Chen Liang-Hua , Wan Xue-Qin , Zhang Fan
Published: April 2021

Phytoremediation technology can help achieve moderate cost and considerable effect with respect to the remediation of heavy metal (HM) pollution in soil and water. Many previous studies have suggested the role of nitrogen (N) in the alleviation of effects of HM on plants. Herein, we sought to determine the molecular mechanisms by which additional N supplementation mitigates cadmium (Cd) toxicity in poplars using a combination of physiological, transcriptomic and phosphoproteomic analyses. The application of N can alleviate the toxicity of Cd to Populus by reducing chlorophyll degradation, maintaining the stability of ions inside and outside the cell membrane and increasing the soluble sugar content. Plant samples from the control, Cd stress and Cd_N treatments were used for an integrated analysis of the transcriptome, as well as for phosphoproteomics analysis. Moreover, 1314 differentially expressed genes and 119 differentially expressed kinase genes were discovered. Application of additional N under Cd stress promoted the phosphorylation process. Furthermore, 51 significantly enriched phosphorylated protein sites and 23 differentially expressed kinases were identified using phosphoproteomic and proteomic analyses. Importantly, transcriptomic and phosphoproteomic analyses jointly determined that the application of N could activate corresponding gene expression [UDP-glucose-dehydrogenase (UGD), GAUT, PME, pectin lyase, UDP-glucose-pyrophosphorylase 2 (UGP2), sucrose phosphate synthase (SPS), SUS and SPP2] and protein phosphorylation (UGP2 and SPS) in the sugar and starch synthesis pathways, which promoted the synthesis of sucrose and soluble sugar and subsequently alleviated the damage caused by Cd.
Population Structure of Pyrenophora teres f. teres Barley Pathogens from Different Continents
Authors: Dahanayaka Buddhika A. , Vaghefi Niloofar , Knight Noel L. , Bakonyi József , Prins Renée , Seress Diána , Snyman Lislé , Martin Anke
Published: April 2021

Net form net blotch disease, caused by Pyrenophora teres f. teres, results in significant yield losses to barley industries. Up-to-date knowledge of the genetic diversity and structure of pathogen populations is critical for elucidating the disease epidemiology and unraveling pathogen survival and dispersal mechanisms. Thus, this study investigated long-distance dispersal and adaptation by analyzing the genetic structure of 250 P. teres f. teres isolates collected from Australia, Canada, Hungary, and Republic of South Africa (RSA), and historical isolates from Canada, Denmark, Japan, and Sweden. The population genetic structure detected by discriminant analysis of principal components, with the use of 5,890 Diversity Arrays Technology markers, revealed the presence of four clusters. Two of these contained isolates from all regions, and all isolates from RSA were grouped in these two. Australia and Hungary showed three clusters each. One of the Australian clusters contained only Australian isolates. One of the Hungarian clusters contained only Hungarian isolates and one Danish isolate. STRUCTURE analysis indicated that some isolates from Australia and Hungary shared recent ancestry with RSA, Canada, and historical isolates and were thus admixed. Subdivisions of the neighbor joining network indicated that isolates from distinct countries were closely related, suggesting that multiple introduction events conferred genetic heterogeneity in these countries. Through a neighbor joining analysis and amplification with form-specific DNA markers, we detected two hybrid isolates, CBS 281.31 from Japan and H-919 from Hungary, collected in 1931 and 2018, respectively. These results provide a foundation for exploring improved management of disease incursions and pathogen control through strategic deployment of resistance.
Limiting Acute Kidney Injury Progression In Sepsis: Study Protocol and Trial Simulation*
Authors: Molinari Luca , Heskia Fabienne , Peerapornratana Sadudee , Ronco Claudio , Guzzi Louis , Toback Seth , Birch Robert , Beyhaghi Hadi , Kwan Thomas , Kampf J. Patrick , Yealy Donald M. , Kellum John A.
Published: April 2021

OBJECTIVES:

To describe study design considerations and to simulate a trial of biomarker-guided sepsis management aimed to reduce acute kidney injury (acute kidney injury). Tissue inhibitor of metalloproteinases-2 and insulin-like growth factor-binding protein 7, urinary biomarkers of cell-cycle arrest, and indicators of kidney stress can detect acute kidney injury before clinical manifestations. We sought to determine the event rates for acute kidney injury as a function of serial measurements of urinary (tissue inhibitor of metalloproteinases-2)•(insulin-like growth factor-binding protein 7) in patients at risk of sepsis-associated acute kidney injury, so that an escalating series of kidney-sparing sepsis bundles based on international guidelines could be applied.

DESIGN:

We described the study protocol of “Limiting acute kidney injury Progression In Sepsis,” a phase 4, multicenter, adaptive, randomized controlled trial. We performed simulations to estimate the rates for the trial’s primary endpoint using patient-level data from two previous studies (Sapphire and Protocolized Care for Early Septic Shock).

SETTING:

Academic and community ICUs.

PATIENTS:

Critically ill patients with sepsis or septic shock, without evidence of stage 2/3 acute kidney injury at enrollment.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

Our primary endpoint is progression of two or more stages of acute kidney injury, death, or dialysis within 72 hours after enrollment. In the Sapphire simulation, 45 of 203 patients (22%) with sepsis met the endpoint. In Protocolized Care for Early Septic Shock, 144 of 607 patients (24%) with septic shock met the endpoint. In both simulations, (tissue inhibitor of metalloproteinases-2)•(insulin-like growth factor-binding protein 7) patterns, suggested by Limiting acute kidney injury Progression In Sepsis protocol, stratified the risk for the endpoint from 6% (three negative tests) to 41% (for patients eligible for the highest level of kidney-sparing sepsis bundle) in Sapphire, and 14% (two negative tests) to 46% (for the highest level of kidney-sparing sepsis bundle) in Protocolized Care for Early Septic Shock.

CONCLUSIONS:

Findings of our Limiting acute kidney injury Progression In Sepsis trial simulation confirmed that (tissue inhibitor of metalloproteinases-2)•(insulin-like growth factor-binding protein 7) could identify patients with different rates of progression to moderate/severe acute kidney injury, death, or dialysis in 72 hours. The Limiting acute kidney injury Progression In Sepsis protocol algorithm is therefore feasible in terms of identifying suitably high-risk individuals for kidney-sparing sepsis bundle.
Association Between Lack of Blinding and Mortality Results in Critical Care Randomized Controlled Trials: A Meta-Epidemiological Study*
Authors: Martin Guillaume L. , Trioux Théo , Gaudry Stéphane , Tubach Florence , Hajage David , Dechartres Agnès
Published: April 2021

OBJECTIVES:

To investigate whether intervention effect estimates for mortality differ between blinded and nonblinded randomized controlled trials conducted in critical care. We used a meta-epidemiological approach, comparing effect estimates between blinded and nonblinded randomized controlled trials for the same research question.

DATA SOURCES:

Systematic reviews and meta-analyses of randomized controlled trials evaluating a therapeutic intervention on mortality in critical care, published between January 2009 and March 2019 in high impact factor general medical or critical care journals and by Cochrane.

DATA EXTRACTION:

For each randomized controlled trial included in eligible meta-analyses, we evaluated whether the trial was blinded (i.e., double-blinded and/or reporting adequate methods) or not (i.e., open-label, single-blinded, or unclear). We collected risk of bias evaluated by the review authors and extracted trial results.

DATA SYNTHESIS:

Within each meta-analysis, we compared intervention effect estimates between blinded and nonblinded randomized controlled trials by using a ratio of odds ratio (< 1 indicates larger estimates in nonblinded than blinded randomized controlled trials). We then combined ratio of odds ratios across meta-analyses to obtain the average relative difference between nonblinded and blinded trials. Among 467 randomized controlled trials included in 36 meta-analyses, 267 (57%) were considered blinded and 200 (43%) nonblinded. Intervention effect estimates were statistically significantly larger in nonblinded than blinded trials (combined ratio of odds ratio, 0.91; 95% CI, 0.84–0.99). We found no heterogeneity across meta-analyses (p = 0.72; I
2 = 0%; τ2 = 0). Sensitivity analyses adjusting the main analysis on risk of bias items yielded consistent results.

CONCLUSIONS:

Intervention effect estimates of mortality were slightly larger in nonblinded than blinded randomized controlled trials conducted in critical care, but confounding cannot be excluded. Blinding of both patients and personnel is important to consider when possible in critical care trials, even when evaluating mortality.
ICU Memories and Patient Outcomes in a Low Middle–Income Country: A Longitudinal Cohort Study
Authors: Tripathy Swagata , Kar Nilamadhab , Acharya Swati P. , Singh Santosh Kumar
Published: April 2021

OBJECTIVES:

To study memories of ICU following discharge, their associations, and impact on mental health and quality of life in a low- and middle-income country.

DESIGN:

Prospective observational cohort; data on memories (pain, fear, nightmare, factual), clinical and demographic variables, anxiety-depression, posttraumatic stress symptoms, and quality of life were collected 0, 7, 14, 30, 90, and 180 days post discharge. Home visits for assessment minimized loss to follow-up. Linear mixed-models and regression analyses were used to estimate adjusted effects of memories controlling for age, sex, time, and severity of illness.

SETTING:

Twenty-five bedded ICU of a tertiary care center in East India.

PATIENTS:

Adult ICU survivors between January 2017 and July 2018 able to communicate their memories.

INTERVENTIONS:

Not applicable.

MEASUREMENTS AND MAIN RESULTS:

Final sample consisted of 322 patients who completed 180 days follow-up. Pain, fear, factual, and nightmare memories dropped from 85%, 56%, 55%, and 45% at discharge to less than or equal to 5% at 180 days. Patients with gaps in ICU memory had worse anxiety-depression, posttraumatic stress symptoms, and quality of life at all follow-up points. Sedation (odds ratio, 0.54; CI, 0.4–0.7), steroids (odds ratio, 0.47; CI, 0.3–0.8), benzodiazepines (odds ratio, 1.74; CI, 1–3.04), and mechanical ventilation (odds ratio, 0.43; CI, 0.2–0.8) were independently associated with gaps in memory. Non-ICU factor such as substance addiction (odds ratio, 5.38; CI, 2–14) was associated with memories affecting mental health and quality of life.

CONCLUSIONS:

Gaps in memory and various memory types were common after ICU admission, whose prevalence waned over time. Compared with nightmares and fearful memories, gaps in memories were most strongly associated with poor mental health and quality of life. Identifying patients with gaps in memories might be an objective way of planning interventions to improve their long-term outcomes.
Discriminating Bacterial and Viral Infection Using a Rapid Host Gene Expression Test*
Authors: Tsalik Ephraim L. , Henao Ricardo , Montgomery Jesse L. , Nawrocki Jeff W. , Aydin Mert , Lydon Emily C. , Ko Emily R. , Petzold Elizabeth , Nicholson Bradly P. , Cairns Charles B. , Glickman Seth W. , Quackenbush Eugenia , Kingsmore Stephen F. , Jaehne Anja K. , Rivers Emanuel P. , Langley Raymond J. , Fowler Vance G. , McClain Micah T. , Crisp Robert J. , Ginsburg Geoffrey S. , Burke Thomas W. , Hemmert Andrew C. , Woods Christopher W.
Published: April 2021

OBJECTIVES:

Host gene expression signatures discriminate bacterial and viral infection but have not been translated to a clinical test platform. This study enrolled an independent cohort of patients to describe and validate a first-in-class host response bacterial/viral test.

DESIGN:

Subjects were recruited from 2006 to 2016. Enrollment blood samples were collected in an RNA preservative and banked for later testing. The reference standard was an expert panel clinical adjudication, which was blinded to gene expression and procalcitonin results.

SETTING:

Four U.S. emergency departments.

PATIENTS:

Six-hundred twenty-three subjects with acute respiratory illness or suspected sepsis.

INTERVENTIONS:

Forty-five–transcript signature measured on the BioFire FilmArray System (BioFire Diagnostics, Salt Lake City, UT) in ~45 minutes.

MEASUREMENTS AND MAIN RESULTS:

Host response bacterial/viral test performance characteristics were evaluated in 623 participants (mean age 46 yr; 45% male) with bacterial infection, viral infection, coinfection, or noninfectious illness. Performance of the host response bacterial/viral test was compared with procalcitonin. The test provided independent probabilities of bacterial and viral infection in ~45 minutes. In the 213-subject training cohort, the host response bacterial/viral test had an area under the curve for bacterial infection of 0.90 (95% CI, 0.84–0.94) and 0.92 (95% CI, 0.87–0.95) for viral infection. Independent validation in 209 subjects revealed similar performance with an area under the curve of 0.85 (95% CI, 0.78–0.90) for bacterial infection and 0.91 (95% CI, 0.85–0.94) for viral infection. The test had 80.1% (95% CI, 73.7–85.4%) average weighted accuracy for bacterial infection and 86.8% (95% CI, 81.8–90.8%) for viral infection in this validation cohort. This was significantly better than 68.7% (95% CI, 62.4–75.4%) observed for procalcitonin (p < 0.001). An additional cohort of 201 subjects with indeterminate phenotypes (coinfection or microbiology-negative infections) revealed similar performance.

CONCLUSIONS:

The host response bacterial/viral measured using the BioFire System rapidly and accurately discriminated bacterial and viral infection better than procalcitonin, which can help support more appropriate antibiotic use.
A Phase I Study of an IDO-1 Inhibitor (LY3381916) as Monotherapy and in Combination With an Anti-PD-L1 Antibody (LY3300054) in Patients With Advanced Cancer
Authors: Kotecki Nuria , Vuagnat Perrine , O’Neil Bert H. , Jalal Shadia , Rottey Sylvie , Prenen Hans , Benhadji Karim A. , Xia Meng , Szpurka Anna M. , Saha Abhijoy , Wallin Johan , Suriyapperuma Subha , Galvao Violeta R. , Geeganage Sandaruwan , Doman Thompson N. , Gandhi Leena , Xu Xiaojian , Bendell Johanna
Published: April 2021

LY3381916 is an orally available, highly selective, potent inhibitor of indoleamine 2,3-dioxygenase 1. This study explored the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of LY3381916 monotherapy and in combination with a programmed death-ligand 1 (PD-L1) inhibitor (LY3300054) in patients with advanced solid tumors. During dose escalation, patients received escalating doses of LY3381916 at 60–600 mg once daily (qd) and 240 mg twice daily in monotherapy (n=21) and in combination with PD-L1 inhibitor at 700 mg every 2 weeks (n=21). A modified toxicity probability interval method was used to guide dose escalation. Dose-limiting toxicities occurred in 3 patients; 1 at LY3381916 240 mg twice daily (alanine aminotransferase/aspartate aminotransferase increase and systemic inflammatory response syndrome) and 2 at LY3381916 240 mg qd in combination with PD-L1 inhibitor (fatigue and immune-related hepatitis). LY3381916, at the recommended phase II dose, 240 mg qd, in combination with PD-L1 inhibitor, produced maximal inhibition of indoleamine 2,3-dioxygenase 1 activity in plasma and tumor tissue, and led to an increase of CD8 T cells in tumor tissue. In the combination dose expansion cohorts, 14 triple-negative breast cancer and 4 non–small cell lung cancer patients were enrolled. Treatment-related liver toxicity (grade ≥2 alanine aminotransferase/aspartate aminotransferase increase or immune-related hepatitis) was the most prominent adverse event in triple-negative breast cancer patients (n=5, 35.7%). Best response was stable disease. These preliminary data suggest an alternative dose level of LY3381916 is needed for the combination with PD-L1 inhibitor. The combination clinical activity was limited in this study.
Profiloplasty in One Session Versus Single Treatment Areas
Authors: Romeo Francesco
Published: April 2021

BACKGROUND

Fillers have been widely used to improve facial profile, and a better result is obtained if the entire profile is treated at the same time.

OBJECTIVE

To compare the outcomes of 2 groups of patients: the former undergoing a treatment in a single area to improve the facial profile, and the latter undergoing a total profiloplasty reharmonization in 1 session.

MATERIALS AND METHODS

The outcomes of this study have been evaluated using both the angle of convexity and the Global Aesthetic Improvement Scale method.

RESULTS

This study demonstrates that the approval rating increases by 56.3% for patients, 81.3% for the practitioner, and 76.3% for an independent practitioner when a synchronous treatment is used to improve the facial profile as compared with a single treatment of 1 profile area.

CONCLUSION

The profiloplasty treatment in 1 session allows the achievement of a more harmonic facial profile and increases the patient's approval as compared with treatments of a single facial area.
Estimating the Effectiveness of Rotavirus Vaccine Schedules
Authors: Butler Anne M. , Breskin Alexander , Sahrmann John M. , Brookhart M. Alan
Published: April 2021

Background:

Important questions exist regarding the comparative effectiveness of alternative childhood vaccine schedules; however, optimal approaches to studying this complex issue are unclear.

Methods:

We applied methods for studying dynamic treatment regimens to estimate the comparative effectiveness of different rotavirus vaccine (RV) schedules for preventing acute gastroenteritis-related emergency department (ED) visits or hospitalization. We studied the effectiveness of six separate protocols: one- and two-dose monovalent rotavirus vaccine (RV1); one-, two-, and three-dose pentavalent rotavirus vaccine (RV5); and no RV vaccine. We used data on all infants to estimate the counterfactual cumulative risk for each protocol. Infants were censored when vaccine receipt deviated from the protocol. Inverse probability of censoring-weighted estimation addressed potentially informative censoring by protocol deviations. A nonparametric group-based bootstrap procedure provided statistical inference.

Results:

The method yielded similar 2-year effectiveness estimates for the full-series protocols; weighted risk difference estimates comparing unvaccinated children to those adherent to either full-series (two-dose RV1, three-dose RV5) corresponded to four fewer hospitalizations and 12 fewer ED visits over the 2-year period per 1,000 children. We observed dose–response relationships, such that additional doses further reduced risk of acute gastroenteritis. Under a theoretical intervention to fully vaccinate all children, the 2-year risk differences comparing full to observed adherence were 0.04% (95% CI = 0.03%, 0.05%) for hospitalizations and 0.17% (95% CI = 0.14%, 0.19%) for ED visits.

Conclusions:

The proposed approach can generate important evidence about the consequences of delaying or skipping vaccine doses, and the impact of interventions to improve vaccine schedule adherence.
Perimesencephalic Subarachnoid Hemorrhage in Pregnancy: A Case Report
Authors: Ruggieri Stefania , Gatto Maurizia , Gentile Maria Annunziata , D’Oria Salvatore , Tamma Filippo , Caringella Domenico , Giocolano Alessandra , Taccaliti Chiara , Guido Maurizio
Published: April 2021

Perimesencephalic subarachnoid hemorrhage (P-SAH) is a benign subset of subarachnoid hemorrhage. Only two cases of P-SAH during pregnancy have been reported in the literature. We describe a case of P-SAH detected at 29 weeks’ gestation, arose with severe bilateral frontal headache, neck rigidity, and vomiting. A diagnosis of P-SAH was confirmed on magnetic resonance angiography with no evidence of vascular malformation or bleeding sources and conservatively treated. Hemorrhage, vasospasm, and cerebellar edema observed on initial magnetic resonance angiography resolved after two months. The clinical course of P-SAH during pregnancy appears to be favorable. Our case shows for the first time in literature that magnetic resonance angiography is a valid diagnostic test for P-SAH during pregnancy that circumvents radiological risk associated with conventional imaging.
Improvement of Vision and Ocular Surface Symptoms With a Scleral Lens After Microbial Keratitis
Authors: Macedo-de-Araújo Rute J. , McAlinden Colm , van der Worp Eef , González-Méijome José M.
Published: April 2021

A 38-year-old woman, previous daily disposable soft contact lens wearer, reported an episode of microbial keratitis positive for Pseudomonas aeruginosa 11 months before contacting the investigators. After acute treatment, she was left with a degree of opacity in the pupillary area, corneal scar, and an irregular corneal profile, with a best spectacle visual acuity of +0.48 logarithm of the minimum angle of resolution. A scleral lens was able to mask those corneal sequelae and, even considering the corneal opacity, the visual acuity recovered to +0.06 logarithm of the minimum angle of resolution. The patient was fitted with a 16.4-mm scleral lens and attended several appointments over a 12-month follow-up period. After 12 months of scleral lens wear, the improvement of both high-contrast and low-contrast visual acuities remained stable and a clearing of the corneal opacity was observed. The comfort was assessed with the Ocular Surface Disease Index questionnaire, which depicted a comfort enhancement from 75.0 to 47.9 over the short term. The Quality of Vision questionnaire was also administrated and showed an improvement on frequency, severity, and bothersome of the vision-related symptoms over time. Scleral lens may be a good option to improve vision, comfort, and restore the ocular surface function in patients with corneal scars and opacities secondary to microbial keratitis.