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BACKGROUND: Devastating cases of sepsis in previously healthy patients have received widespread attention and have helped to catalyze state and national mandates to improve sepsis detection and care. However, it is unclear what proportion of patients hospitalized with sepsis previously were healthy and how their outcomes compare with those of patients with comorbidities. RESEARCH QUESTION: Among adults hospitalized with community-onset sepsis, how many previously were healthy and how do their outcomes compare with those of patients with comorbidities? STUDY DESIGN AND METHODS: We retrospectively identified all adults with community-onset sepsis hospitalized in 373 US hospitals from 2009 through 2015 using clinical indicators of presumed infection and organ dysfunction (Centers for Disease Control and Prevention’s Adult Sepsis Event criteria). Comorbidities were identified using International Classification of Diseases, Ninth Revision, Clinical Modification codes. We applied generalized linear mixed models to measure the associations between the presence or absence of comorbidities and short-term mortality (in-hospital death or discharge to hospice), adjusting for severity of illness on admission. RESULTS: Of 6,715,286 hospitalized patients, 337,983 (5.0%) were hospitalized with community-onset sepsis. Most patients with sepsis (329,052 [97.4%]) had received a diagnosis of at least one comorbidity; only 2.6% previously were healthy. Patients with sepsis who previously were healthy were younger than those with comorbidities (mean age, 58.0 ± 19.8 years vs 67.0 ± 16.5 years), were less likely to require ICU care on admission (37.9% vs 50.5%), and were more likely to be discharged home (57.9% vs 45.6%), rather than to subacute facilities (16.3% vs 30.8%), but showed higher short-term mortality rates (22.8% vs 20.8%; P < .001 for all). The association between previously healthy status and higher short-term mortality persisted after risk adjustment (adjusted OR, 1.99; 95% CI, 1.87-2.13). INTERPRETATION: The vast majority of patients hospitalized with community-onset sepsis harbor pre-existing comorbidities. However, previously healthy patients may be more likely to die when they seek treatment at the hospital with sepsis compared with patients with comorbidities. These findings underscore the importance of early sepsis recognition and treatment for all patients.

Tympanic membrane (TM) perforations commonly occur as a result of chronic ear infections, direct trauma or blast injuries, as seen in military and civilian populations following terror attacks. TM perforations result in considerable morbidity, including hearing loss, pain, recurrent infections and decreased quality of life. Repair of chronic TM perforations is typically performed in the operating room under general anesthesia. Recently developed techniques for TM repair afford the option to manage patients in the clinic setting. Herein we describe our endoscopic approach for in-office, awake TM repair and review patient selection, instrumentation, technique and postoperative management. We also discuss outcomes from a cohort study including closure rates, hearing outcomes and patient reported outcome measures. Tympanic membrane perforation, tympanoplasty,in-office ear surgery, endoscopic ear surgery

In this paper, I discuss Newton's conception of body in De gravitatione and its relation to the legitimacy of action at a distance. Howard Stein has argued that such a conception privileges contact over distant action: by dint of being impenetrable, bodies must necessarily act through contact; yet there is no analogous property of which action at a distance is a consequence. This paper presents a challenge to Stein's reading. I begin by arguing that impenetrability cannot imply action through contact because such an implication hinges on one's laws of motion in three senses: it must be physically possible for contact to occur, the laws must make coherent the notion of a trajectory from which a body deviates, and the necessity of introducing collision dynamics renders impenetrability otiose. I then turn to a close reading of De gravitatione and consider whether Newton himself sees his account of body as establishing contact action as prior to distant action in any sense. Although Newton did see impenetrability as rendering bodily action intelligible, ample room remains for action at a distance once one takes into account certain textual ambiguities and the provisional character of the narrative. By way of substantiating this reading and answering an objection of Stein's, I pivot to Newton's remarks concerning the nature of gravity in his correspondence with Bentley. Although Newton is often held to reject essential gravity as being in conflict with his metaphysical commitments, I offer a more austere reading on which Newton is decrying a kind of action that is unmediated, or alleged to take place without a cause. By contrast, Newton carves out a place for action at a distance mediated by an immaterial agent as a perfectly acceptable explanation of natural phenomena.

Understanding the mechanisms of neural stimulation is necessary to improve the management of sensory disorders. Neurons can be artificially stimulated using electrical current, or with newer stimulation modalities, including optogenetics. Electrical stimulation forms the basis for all neuroprosthetic devices that are used clinically. Off-target stimulation and poor implant performance remain concerns for patients with electrically based neuroprosthetic devices. Optogenetic techniques may improve cranial nerve stimulation strategies used by various neuroprostheses and result in better patient outcomes. This article reviews the fundamentals of neural stimulation and provides an overview of recent major advancements in light-based neuromodulation."

Despite advances in implant hardware, neuroprosthetic devices in otolaryngology have sustained evolutionary rather than revolutionary changes over the past half century. Although electrical stimulation has the capacity for facile activation of neurons and high temporal resolution, it has limited spatial selectivity. Alternative strategies for neuronal stimulation are being investigated to improve spatial resolution. In particular, light-based neuronal stimulation is a viable alternative and complement to electrical stimulation. This article provides a broad overview of light-based neuronal stimulation technologies. Specific examples of active research on light-based prostheses, including cochlear implants, auditory brainstem implants, retinal implants, and facial nerve implants, are reviewed.

Superior canal dehiscence (SCD) is a bony defect of the superior semicircular canal that is called SCD syndrome (SCDS) when associated with vestibular and auditory dysfunction. Surgical management of SCD is reserved for patients with intractable auditory and/or vestibular symptoms. As direct visualization of an arcuate eminence defect is most easily achieved from above, the majority of cases use a microscope-assisted middle fossa craniotomy. However, approximately 30% of SCD cases have a medial arcuate eminence defect along a downsloping tegmen. These defects can be difficult to visualize without a large cranial window, drilling down a prominent lateral skull base ridge, and/or prolonged brain retraction. In line with recent development of endoscopic ear surgery, the endoscope has been employed at our institution via a middle fossa craniotomy approach to repair a SCD. We believe that skull base endoscopy is a safe and effective way to identify and repair a medial or blue-lined SCD when used with a middle fossa craniotomy approach. The angled endoscope enhances visualization and transillumination of the SCD and reduces temporal lobe retraction. The following chapter highlights an endoscopic-assisted middle fossa craniotomy repair of SCD.

Patients with superior canal dehiscence syndrome may present with a myriad of auditory and/or vestibular complaints. Treatment of superior canal dehiscence syndrome depends on severity of symptoms and impact on quality of life. Surgery is recommended for patients with debilitating auditory and/or vestibular symptoms. The goal of surgery is to create a durable and watertight seal of the bony superior semicircular canal defect, thereby eliminating the “third window”. Repair involves either resurfacing and/or plugging of the dehiscent superior canal to eliminate the third window and reduce symptoms. Surgical options include middle fossa craniotomy or transmastoid (TM) approach. The main advantages of a TM approach includes (1) avoidance of a craniotomy, (2) lower risk of CSF leak, and (3) no brain retraction. The TM approach is ideal for superior petrosal sinus superior canal dehiscence cases as the defect is found medial along the skull base and can be isolated indirectly without direct manipulation of the brain and sinus. This chapter discusses the surgical technique of TM approach.

Airborne black carbon (BC) particles have serious implications for human health and climate change and thus represent a prime target for mitigation policies. The sources of BC include vehicles burning diesel fuel , which are common in urban areas in low-income countries. The objective of this study was to examine the possible relationship between traffic and airborne BC concentrations near roadways in Nairobi, Kenya. We measured personal exposure levels of BC in Nairobi in a field campaign in summer 2009, and subsequently confirmed our ability to estimate BC quantitatively by conducting a co-location experiment in Nairobi in the fall of 2011. The central business district of Nairobi recorded 11-h average daytime BC concentrations in the range 20–42 µg m −3 while the main highways feeding into Nairobi recorded BC levels of 17–79 µg m−3 . As far as we are aware, the data reported here include the highest multi-hour BC concentrations ever reported in Africa. Samples from gradient sampling showed rapid reduction of BC concentrations with distance away from traffic. The measured BC near the curbside of roadways was estimated to be in the range of 34–56% of PM 2.5, implying traffic was a dominant source of PM2.5 emissions in Nairobi. The high concentrations of BC that we observed raises concern regarding potential health threats to workers, residents, and visitors, and highlights the need for policies to address traffic-related air pollution in Nairobi.

Epstein-Barr Virus infection of B lymphocytes elicits diverse host responses via well-adapted transcriptional control dynamics. Consequently, this host-pathogen interaction provides a powerful system to explore fundamental processes leading to consensus fate decisions. Here we use single-cell transcriptomics to construct a genome-wide multistate model of B cell fates upon EBV infection. Additional single-cell data from human tonsils revealed correspondence of model states to analogous in vivo phenotypes within secondary lymphoid tissue, including a previously uncharacterized EBV(+) analog of multipotent activated precursors that can yield early memory B cells. These resources yield exquisitely detailed perspectives of the transforming cellular landscape during an oncogenic viral infection that simulates antigen-induced B cell activation and differentiation. Thus, they support investigations of state-specific EBV-host dynamics, effector B cell fates, and lymphomagenesis. To demonstrate this potential, we identify EBV infection dynamics in FCRL4(+) / TBX21(+) atypical memory B cells that are pathogenically associated with numerous immune disorders.

Background: Nurses who volunteer in a nondisaster humanitarian surgical mission receive little attention in the research literature. Purpose: The purpose of this study was to explore how nurses involved in short-term nondisaster humanitarian care perceived and managed their experiences of working in a volunteer nursing capacity in a low- to middle-income country. Method: An immersive ethnographic method was used. Participants comprised 150 international registered nurses from 12 countries. Data collection incorporated 49 semistructured interviews and reflections on 1,500 hours of participant observation. Data were analysed using a thematic, inductive approach, following the consolidated criteria for reporting qualitative research guidelines. Results: The results of this qualitative enquiry revealed essential aspects of the nursing culture within a specific humanitarian nursing context—that is, promoting social justice and addressing health disparity through the delivery of compassionate surgical care. This paper presents data describing nurses’ motivations for participating as volunteers in humanitarian work. Discussion: Nurses are more likely to offer increased effort and enthusiasm when there is congruency between their beliefs, their professional identity, and their ability to enact on these. Understanding humanitarian nurses’ motivations gives guidance to leaders involved in managing, attracting, and retaining suitable nursing staff and orienting, debriefing, and supporting re-entry after withdrawing from short-term medical assignments that share a common imperative to care for the underserved.

Facial expressions are described traditionally as monolithic or unitary entities. However, humans have the capacity to produce facial blends of emotion in which the upper and lower face simultaneously display different expressions. Recent neuroanatomical studies in monkeys have demonstrated that there are separate cortical motor areas for controlling the upper and lower face in each hemisphere that, presumably, also occur in humans. Using high-speed videography, we began measuring the movement dynamics of spontaneous facial expressions, including facial blends, to develop a more complete understanding of the neurophysiology underlying facial expressions. In our part 1 publication in Cortex (2016), we found that hemispheric motor control of the upper and lower face is overwhelmingly independent; 242 (99%) of the expressions were classified as demonstrating independent hemispheric motor control whereas only 3 (1%) were classified as demonstrating dependent hemispheric motor control. In this companion paper (part 2), 251 unitary facial expressions that occurred on either the upper or lower face were analyzed. 164 (65%) expressions demonstrated dependent hemispheric motor control whereas 87 (35%) expressions demonstrated independent or dual hemispheric motor control, indicating that some expressions represent facial blends of emotion that occur across the vertical facial axis. These findings also support the concepts that 1) spontaneous facial expressions are organized predominantly across the horizontal facial axis and secondarily across the vertical facial axis and 2) facial expressions are complex, multi-component, motoric events. Based on the Emotion-type hypothesis of cerebral lateralization, we propose that facial expressions modulated by a primary-emotional response to an environmental event are initiated by the right hemisphere on the left side of the face whereas facial expressions modulated by a social-emotional response to an environmental event are initiated by the left hemisphere on the right side of the face.

The standard Monte Carlo (MC) k-eigenvalue algorithm involves iteratively converging the fission source distribution using a series of potentially time-consuming inactive cycles before quantities of interest can be tallied. One strategy for reducing the computational time requirements of these inactive cycles is the Sourcerer method, in which a deterministic eigenvalue calculation is performed to obtain an improved initial guess for the fission source distribution. This method has been implemented in the Exnihilo software suite within SCALE using the SP N or S N solvers in Denovo and the Shift MC code. The efficacy of this method is assessed with different Denovo solution parameters for a series of typical k-eigenvalue problems including small criticality benchmarks, full-core reactors, and a fuel cask. It is found that, in most cases, when a large number of histories per cycle are required to obtain a detailed flux distribution, the Sourcerer method can be used to reduce the computational time requirements of the inactive cycles.

Optogenetics is a transformative technology based on light-sensitive microbial proteins, known as opsins, that enable precise modulation of neuronal activity with pulsed radiant energy. Optogenetics has been proposed as a means to improve auditory implant outcomes by reducing channel interaction and increasing electrode density, but the introduction of opsins into cochlear spiral ganglion neurons (SGNs) in vivo has been challenging. Here we test opsin delivery using a synthetically developed ancestral adeno-associated virus (AAV) vector called Anc80L65. Wild-type C57BL/6 mouse pups were injected via the round window of cochlea with Anc80L65 carrying opsin Chronos under the control of a CAG promoter. Following an incubation of 6-22 weeks, pulsed blue light was delivered to cochlear SGNs via a cochleosotomy approach and flexible optical fiber. Optically evoked auditory brainstem responses (oABRs) and multiunit activity in inferior colliculus (IC) were observed. Post-experiment cochlear histology demonstrated opsin expression in SGNs (mean = 74%), with an even distribution of opsin along the cochlear basal/apical gradient. This study is the first to describe robust SGN transduction, opsin expression, and optically evoked auditory electrophysiology in neonatal mice. Ultimately, this work may provide the basis for a new generation of cochlear implant based on light.

Objective While hearing loss following temporal bone fracture is a well-described phenomenon, few data exist on auditory dysfunction in patients with traumatic brain injury (TBI) without temporal bone fracture. Herein, we aim to systematically review hearing loss after TBI without bony fracture and describe its etiologies. Data sources Pubmed, Embase, Cochrane databases. Review methods A systematic review of the literature from 1966 to January 2017 was performed using Preferred Reporting Items for Systematic Reviews and Meta-analyses recommendations. Data were obtained from studies that investigated hearing loss in TBI without skull fracture according to an a priori protocol with inclusion and exclusion criteria. Variables included type and severity of hearing loss, as well as pathophysiology of hearing loss. Results There were 13 studies with 773 patients that met study criteria. Overall, there was one prospective cohort study, four retrospective cohort studies, two case-control studies, and six case reports. The studies with the highest level of evidence report a change in hearing of at least 10–15 dB across a range of frequencies in as many as 58% percent of TBI patients without bony fracture, which was transient or chronic. The mechanism/severity of injury may impact the rate of hearing loss. Conclusions Hearing loss after TBI in the absence of bony injury appears to be a clinically significant but poorly characterized phenomenon.

The GPU solver within the Shift continuous-energy Monte Carlo neutron transport code has been extended to provide domain decomposition in addition to domain replication to enable the solution of problems with memory requirements exceeding the capacity of a single GPU. The strategy follows the Multiple Set, Overlapping Domain (MSOD) approach that is used in Shift’s CPU solver and integrates into the event-based algorithm used for Shift’s GPU solver. Furthermore, the ability to assign processors to spatial domains non-uniformly has been maintained. Two different approaches for communicating particle data between domains are considered, and multiple criteria for load balancing problems have been investigated. Numerical results are presented for both fresh and depleted small modular nuclear reactor (SMR) cores. A parallel efficiency of approximately 80% was achieved with up to 16 spatial domains measured relative to full domain replication. A scaling study on the Summit supercomputer demonstrates a weak scaling parallel efficiency of over 90% on over 24000 GPUs.

TOPIC: Critical Care TYPE: Original Investigations PURPOSE: Gasdermin-D (GSDMD) is a pore-forming molecule that serves as the final effector of pyroptosis (a form of inflammatory cell death) following activation of the cellular inflammasome in monocytes. Disulfiram (DSM), a drug used in the treatment of alcohol abuse, has recently been shown to inhibit GSDMD via disruption of pore formation after its cleavage by the inflammatory caspases (1, 4, and 5). The aim of this study was to elucidate the inhibitory effects of DSM on GSDMD-mediated pyroptosis and explore its role as a potential therapeutic agent in sepsis. METHODS: A series of experiments was conducted using THP1 cells (a human monocytic cell line) or purified human monocytes from the blood of healthy donors. Samples were pretreated with DSM in various concentrations 30 minutes prior to inflammasome activation with bacterial lipopolysaccharide (LPS). Cells were then assessed under light microscopy for swelling and fluorescent microscopy for the formation of ASC specks (activated oligomers of the adaptor protein required for caspase activation). Cell death was assessed using a lactate dehydrogenase (LDH) cytotoxicity assay. Interleukin-1-beta (IL1s) release was measured by ELISA. GSDMD cleavage, pro-IL1s synthesis, and caspase-1 cleavage were assessed using immunoblots. RESULTS: Unexpectedly, low dose DSM accentuated inflammasome activation. Dramatic inflammasome induction was observed at a concentration of 10uM, a dose associated with near peak inhibition in the prior study. However, higher doses of 50 to 100 uM suppressed pyroptosis as evidenced by loss of cell swelling and ASC speck formation, as well as LDH and IL-1s release. The DSM effect occurred downstream of caspase-1 activation as evidenced by preserved intracellular pro-IL1s synthesis and caspase-1 cleavage in the presence of DSM. Contrary to the prior report, GSDMD cleavage appeared to be inhibited at these higher doses. CONCLUSIONS: DSM unexpectedly exhibits upstream activation of the inflammasome at low doses but downstream inhibition at high doses. CLINICAL IMPLICATIONS: Although DSM's inhibitory effects on inflammasome function make it a promising agent for the future treatment of acute inflammatory conditions such as sepsis and covid-19, our results indicate that further study is needed to better characterize its possible activating effects at lower concentrations. DISCLOSURES: Collaboration via BARDA grant funding relationship with Beckman Coulter, Inc. Please note: 9/19/2019-8/31/2014 Added 04/27/2021 by Elliott Crouser, source=Web Response, value=Grant/Research Support No relevant relationships by Gregory Eisinger, source=Web Response No relevant relationships by Mikhail Gavrilin, source=Web Response No relevant relationships by Wissam Osman, source=Web Response No relevant relationships by Evan Prather, source=Web Response No relevant relationships by Mark Wewers, source=Web Response

Despite extensive research and development, new nano-based diagnostic contrast agents have faced major barriers in gaining regulatory approval due to their potential systemic toxicity and prolonged retention in vital organs. Here we use five independent biodistribution techniques to demonstrate that oral ingestion of one such agent, gold-silica Raman nanoparticles, results in complete clearance with no systemic toxicity in living mice. The oral delivery mimics topical administration to the oral cavity and gastrointestinal (GI) tract as an alternative to intravenous injection. Biodistribution and clearance profiles of orally (OR) vs. intravenously (IV) administered Raman nanoparticles were assayed over the course of 48 h. Mice given either an IV or oral dose of Raman nanoparticles radiolabeled with approximately 100 μCi (3.7MBq) of 64Cu were imaged with dynamic microPET immediately post nanoparticle administration. Static microPET images were also acquired at 2 h, 5 h, 24 h and 48 h. Mice were sacrificed post imaging and various analyses were performed on the excised organs to determine nanoparticle localization. The results from microPET imaging, gamma counting, Raman imaging, ICP-MS, and hyperspectral imaging of tissue sections all correlated to reveal no evidence of systemic distribution of Raman nanoparticles after oral administration and complete clearance from the GI tract within 24 h. Paired with the unique signals and multiplexing potential of Raman nanoparticles, this approach holds great promise for realizing targeted imaging of tumors and dysplastic tissues within the oral cavity and GI-tract. Moreover, these results suggest a viable path for the first translation of high-sensitivity Raman contrast imaging into clinical practice.

Depending on a subject’s attentional bias, robust changes in emotional perception occur when facial blends (different emotions expressed on upper/lower face) are presented tachistoscopically. If no instructions are given, subjects overwhelmingly identify the lower facial expression when blends are presented to either visual field. If asked to attend to the upper face, subjects overwhelmingly identify the upper facial expression in the left visual field but remain slightly biased to the lower facial expression in the right visual field. The current investigation sought to determine whether differences in initial saccadic targets could help explain the perceptual biases described above. Ten subjects were presented with full and blend facial expressions under different attentional conditions. No saccadic differences were found for left versus right visual field presentations or for full facial versus blend stimuli. When asked to identify the presented emotion, saccades were directed to the lower face. When asked to attend to the upper face, saccades were directed to the upper face. When asked to attend to the upper face and try to identify the emotion, saccades were directed to the upper face but to a lesser degree. Thus, saccadic behavior supports the concept that there are cognitive-attentional pre-attunements when subjects visually process facial expressions. However, these pre-attunements do not fully explain the perceptual superiority of the left visual field for identifying the upper facial expression when facial blends are presented tachistoscopically. Hence other perceptual factors must be in play, such as the phenomenon of virtual scanning.

Superior canal dehiscence (SCD) is a bony defect of the superior semicircular canal. SCD syndrome occurs when vestibular or auditory dysfunction accompanies SCD. Although not all patients with SCD are symptomatic, surgical repair is an option in patients with incapacitating symptoms and are unresponsive to conservative treatment. Traditionally, repair of SCD when involving the arcuate eminence can be achieved using a middle fossa craniotomy approach. However, approximately 30% of SCD cases have a medial arcuate eminence defect along a downsloping tegmen, making the defect difficult to visualize with the binocular microscope without a large craniotomy, extensive temporal lobe retraction, and drilling of the skull base. As complete visualization of an arcuate eminence defect is essential for successful repair, we describe an operative approach to visualize the SCD that combines a small middle fossa craniotomy and rigid endoscopy. The wide-field view and superior transillumination with skull base endoscopy can be achieved with a minimal access skin incision, small bony window, less dural dissection, and reduced brain retraction, resulting in unequivocal identification of the entire arcuate eminence defect.