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Background Tracheal intubation carries an elevated risk of exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) due to the generation of aerosols containing high concentrations of the virus. An airway box was designed to mitigate the exposure of healthcare professionals performing intubations. Aim We evaluated usability and sustainability in the routine practice of the "airway box" as a protective device during high-risk airway procedures.  Materials and methods After institutional review board approval, clinicians were educated on using the device through simulation, intranet learning modules, and emailed resources. The airway box was made available in the emergency department, critical care units, perioperative area, and operating rooms. QR codes affixed to the box, emailed, and displayed in common areas provided easy access to complete a REDcap survey (Vanderbilt University Nashville, USA) eliciting providers' experience. Data was collected and analyzed between April 1 and July 31, 2020, on REDcap, and the results were analyzed. Results 687 emergent intubations took place. 232 were performed by anesthesiologists, 315 by emergency department providers, and 140 by critical care specialists. 39 surveys were completed, 29 from intubations in the operating room, three from the critical care units, five from interventional radiology suites, and two perioperatively. Providers found the device to be readily available, with a score of 4.51/5, and the majority of providers, 60%, found the device easy to use, rating it either a 4 or 5 out of 5. Providers acquired a mean Mallampati score of 1.75 and 1.40 mean laryngoscopic grade view. Conclusion Intubation boxes may effectively mitigate high-risk viral exposure during airway procedures. Survey responses show that devices were easy to use and did not significantly affect visualization of the airway. Similar to mask use, enclosure devices in clinical practice could become a vital part of medical protective equipment even after the SARS-CoV-2 pandemic if they are effectively implemented., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Ellison et al.)

Introduction: Traumatic injuries are preventable and understanding determinants of injury, such as socio-economic and environmental factors, is vital. This study evaluated traumatic injuries and identified areas of high trauma incidence., Methods: A retrospective review was conducted of all patients 14 years or older who were admitted with a traumatic injury to a Level I trauma center between 2016 and 2017. Descriptive analyses were presented and maps of high injury areas were generated., Results: The most frequent mechanisms of injury were falls (58.3%), motor vehicle crashes (22.3%), and motorcycle crashes (5.7%). Fall patients were more likely to be female (59.6%) and were the oldest age group (72.1 ± 17.2) compared to motor vehicle and motorcycle crash patients. Severe head (22.1%, p = 0.007) and extremity (35.7%, p = 0.001) injuries were most frequent among fall patients, however, more motorcycle crash patients required mechanical ventilation (16.1%, p < 0.001) and experienced the longest intensive care unit length of stay (5.3 ± 6.8 days, p < 0.001) and mechanical ventilation days (6.6 ± 8.5, p < 0.036). Motorcycle crash patients also had the greatest number of deaths (7.5%, p < 0.001). The generated maps of all traumas suggested that most injuries occur near our hospital and are located in several of the most population-dense zip codes., Conclusion: Patient demographics, injury severity, and hospital outcomes varied by mechanisms of injury. Traumatic injuries occurred near our hospital and were located in several of the most populationdense zip codes. Injury prevention efforts should target high incident areas., (© 2021 The University of Kansas Medical Center.)

The Pyruvate kinase isozymes M2 (PKM2) protein is a metabolic enzyme that regulates the final step of glycolysis. This enzyme is present in highly proliferating cells and is expressed in the placenta. We recently demonstrated upregulated placental PKM2 during human intrauterine growth restriction (IUGR). Our current objective was to determine PKM2 regulation of trophoblast invasion, trophoblast PKM2 localization as well as mTOR protein expression, and to determine effects of activation of PKM2 during IUGR. Human placental tissues were obtained and analyzed by immunohistochemistry and western blot. Trophoblast cells were cultured in normoxic and hypoxic conditions and real time cell invasion and PKM2 protein were determined during activation (Fructose-6-bisphosphate; FBP6) or inhibition (Shikonin) of PKM2. In vivo studies determined the effects of PKM2 activation on placental and fetal weights. IUGR samples had elevated levels of p-PKM2. Different trophoblast PKM2 localization and expression was observed during normoxia and hypoxia. Decreased trophoblast invasion and PKM2 expression was observed during mTOR inhibition. Protection from decreased placental and fetal weights was observed by PKM2 activation. We conclude that PKM2 regulates trophoblast cell invasion depending on its subcellular location. Our results suggest that PKM2 regulation in trophoblast cells is more directly affected during hypoxia and its expression is regulated by mTOR activity. Additionally, we conclude that activation of PKM2 could reverse and/or rescue the deceased placental and fetal weights observed during IUGR. These results suggest that PKM2 could be a mediator of trophoblast cell invasion and its abundance influences the development of complicated pregnancies like IUGR., Competing Interests: Declaration of competing interest None of the authors have any actual or potential competing financial or other interests with entities possibly interested in the subject matter., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Source Citation: Jones P, Lamdin R, Dalziel SR. Oral non-steroidal anti-inflammatory drugs versus other oral analgesic agents for acute soft tissue injury. Cochrane Database Syst Rev. 2020;8:CD007789. 32797734.

Dyskinesia induced by long-term L-Dopa (LID) therapy in Parkinson disease is associated with altered striatal function whose molecular bases remain unclear. Here, a transcriptomic approach was applied for comprehensive analysis of distinctively regulated genes in striatal tissue, their specific pathways, and functional- and disease-associated networks in a rodent model of LID. This approach has identified transforming growth factor beta type 1 (TGFβ1) as a highly upregulated gene in dyskinetic animals. TGFβ1 pathway is a top aberrantly regulated pathway in the striatum following LID development based on differentially expressed genes (> 1.5 fold change and P < 0.05). The induction of TGFβ1 pathway specific genes, TGFβ1, INHBA, AMHR2 and PMEPA1 was also associated with regulation of NPTX2, PDP1, SCG2, SYNPR, TAC1, TH, TNNT1 genes. Transcriptional network and upstream regulator analyses have identified AKT-centered functional and ERK-centered disease networks revealing the association of TGFβ1, IL-1β and TNFα with LID development. Therefore, results support that TGFβ1 pathway is a major contributor to the pathogenic mechanisms of LID., (© 2020 International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.)

The inhibition of acetylcholinesterase is regarded as the primary toxic mechanism of action for chemical warfare agents. Recently, there have been numerous reports suggesting that metabolic processes could significantly contribute to toxicity. As such, we applied a multi-omics pipeline to generate a detailed cascade of molecular events temporally occurring in guinea pigs exposed to VX. Proteomic and metabolomic profiling resulted in the identification of several enzymes and metabolic precursors involved in glycolysis and the TCA cycle. All lines of experimental evidence indicated that there was a blockade of the TCA cycle at isocitrate dehydrogenase 2, which converts isocitrate to α-ketoglutarate. Using a primary beating cardiomyocyte cell model, we were able to determine that the supplementation of α-ketoglutarate subsequently rescued cells from the acute effects of VX poisoning. This study highlights the broad impacts that VX has and how understanding these mechanisms could result in new therapeutics such as α-ketoglutarate.

During the last decade multiple mumps outbreaks have occurred in the U.S. despite high two dose MMR coverage with most cases detected among two dose MMR vaccine recipients. Waning immunity, the evolution of wild-type virus strains, and settings with intense exposure have contributed to the resurgence of mumps. Typically, mumps virus infections resolve without serious clinical sequelae; however, serious complications may occur among unvaccinated or severely immunocompromised individuals. Favipiravir (T-705) has been shown to have in vitro anti-viral activity against a broad range of positive and negative strand RNA viruses. Here, we demonstrate that T-705 inhibits the growth of wildtype and vaccine strains of mumps virus in vitro at low micro-molar concentrations (EC 50 8-10μM). We did not observe the development of resistance after five subsequent passages at low concentrations of drug. Both viral RNA and protein synthesis were selectively reduced compared to host mRNA and protein synthesis. Antiviral treatment options for mumps virus infection may be valuable, especially for areas with a high disease burden or for cases with severe complications. These results presented here suggest that further studies are warranted., (Copyright © 2020 Elsevier B.V. All rights reserved.)

While most testicular germ cell tumours (TGCTs) exhibit exquisite sensitivity to platinum chemotherapy, ~10% are platinum resistant. To gain insight into the underlying mechanisms, we undertake whole exome sequencing and copy number analysis in 40 tumours from 26 cases with platinum-resistant TGCT, and combine this with published genomic data on an additional 624 TGCTs. We integrate analyses for driver mutations, mutational burden, global, arm-level and focal copy number (CN) events, and SNV and CN signatures. Albeit preliminary and observational in nature, these analyses provide support for a possible mechanistic link between early driver mutations in RAS and KIT and the widespread copy number events by which TGCT is characterised.

The lipopolysaccharide biosynthesis pathway is considered an attractive drug target against the rising threat of multi-drug-resistant Gram-negative bacteria. Here, we report two novel small-molecule inhibitors (compounds 1 and 2 ) of the acyltransferase LpxA, the first enzyme in the lipopolysaccharide biosynthesis pathway. We show genetically that the antibacterial activities of the compounds against efflux-deficient Escherichia coli are mediated by LpxA inhibition. Consistently, the compounds inhibited the LpxA enzymatic reaction in vitro. Intriguingly, using biochemical, biophysical, and structural characterization, we reveal two distinct mechanisms of LpxA inhibition; compound 1 is a substrate-competitive inhibitor targeting apo LpxA, and compound 2 is an uncompetitive inhibitor targeting the LpxA/product complex. Compound 2 exhibited more favorable biological and physicochemical properties than compound 1 and was optimized using structural information to achieve improved antibacterial activity against wild-type E. coli . These results show that LpxA is a promising antibacterial target and imply the advantages of targeting enzyme/product complexes in drug discovery.

Ever since its development in the 1930's, the live-attenuated Yellow Fever virus vaccine YF-17D has been highly effective. Despite the increasing knowledge on the immune biology of the YF-17D vaccine, most studies have focused only on a few types of immune cells and pathways or mainly on the primary adaptive immune response to YF-17D vaccination. Here, we examined humoral, innate and adaptive cellular responses in a longitudinal YF-17D vaccination study in Switzerland, comparing both primary and booster vaccination. In contrast to the strong innate and adaptive immune response to the primary vaccination, we find that the response to boosting is much reduced. Our data show an inverse association of neutralizing antibodies at baseline with vaccine virus replication and with the immune response upon boosting. These results suggest that booster vaccination may not have major immunological effects when neutralizing antibodies are present. Importantly, our study population was healthy adults in a non-endemic country and ultimately booster vaccine requirement must be assessed based on additional epidemiological and public health considerations in endemic areas., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To determine radiologic preferences of practicing otolaryngologists regarding isolated nasal bone fractures., Study Design: An 8-question survey on isolated nasal bone fractures was designed., Setting: Surveys were sent to all otolaryngology residency program directors for distribution among residents and faculty. Additional surveys were distributed to private practice otolaryngology groups., Results: 140 physicians responded to the survey. 57% of the respondents were practicing otolaryngologists (75% with 10+ years of experience), while 43% of respondents were residents-in-training. 56% of respondents treated 1-5 nasal bone fractures per month. 80% of all respondents reported imaging being performed prior to consultation. If imaging was obtained before consultation, plain films and computed tomography (CT) maxillofacial/sinus scans were the most frequent modalities. 33% of residents and 70% of practicing otolaryngologists report imaging as 'rarely' or 'never' helpful in guiding management. 42% of residents and 20% of practicing otolaryngologists report asking for imaging when it wasn't already obtained. Decreased use of radiography was associated with greater years in practice and higher frequency of fractures treated., Conclusions and Relevance: Otolaryngologists seldom request imaging to evaluate and treat isolated nasal bone fractures. When ordered, imaging is utilized more often among residents-in-training and non-otolaryngology consulting physicians. This study highlights an opportunity to educate primary care and emergency room providers as well as otolaryngology residents on the value of comprehensive physical exam over radiographic imaging in the work-up of isolated nasal fractures. In addition, widespread adoption of a "no x-ray policy" in this setting may result in better resource utilization., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Statistics suggest that African Americans have a disproportionately high prevalence of Alzheimer disease (AD), yet are less likely to enroll in AD clinical trials than white individuals. Although research has previously identified various barriers to participation, relatively little is known about how to overcome these barriers and engage African American individuals in AD research. The purpose of this study is to better understand how African Americans conceptualize brain health and their ability to influence healthy brain aging., Methods: Three African American community advocates each facilitated a small group of African American participants over 8 to 10 sessions of a photovoice process involving discussion and sharing of images focused on brain health. Sessions were audiotaped and transcribed verbatim and photographs were uploaded., Findings: Participants recognized a diversity of what brain health can mean and indicated an interconnectedness between brain health and its influences. Key factors that were identified by group members as key to brain health included lifestyle factors, activity, and engagement and nature, resiliency, and positivity., Discussion: These emic insights into perceptions of brain health may represent important foci for targeted messaging strategies to promote brain health and research engagement within the African American population.

Ferredoxin5 (FDX5), a minor ferredoxin protein in the alga Chlamydomonas ( Chlamydomonas reinhardtii ), helps maintain thylakoid membrane integrity in the dark. Sulfur (S) deprivation has been used to achieve prolonged hydrogen production in green algae. Here, we propose that FDX5 is involved in algal responses to S-deprivation as well as to the dark. Specifically, we tested the role of FDX5 in both the initial aerobic and subsequent anaerobic phases of S-deprivation. Under S-deprived conditions, absence of FDX5 causes a distinct delay in achieving anoxia by affecting photosynthetic O 2 evolution, accompanied by reduced acetate uptake, lower starch accumulation, and delayed/lower fermentative metabolite production, including photohydrogen. We attribute these differences to transcriptional and/or posttranslational regulation of acetyl-CoA synthetase and ADP-Glc pyrophosphorylase, and increased stability of the PSII D1 protein. Interestingly, increased levels of FDX2 and FDX1 were observed in the mutant under oxic, S-replete conditions, strengthening our previously proposed hypothesis that other ferredoxins compensate in response to a lack of FDX5. Taken together, the results of our omics and pull-down experiments confirmed biochemical and physiological results, suggesting that FDX5 may have other effects on Chlamydomonas metabolism through its interaction with multiple redox partners., (© 2019 American Society of Plant Biologists. All Rights Reserved.)

Background: Medical treatment for acute heart failure (AHF) has not changed substantially over the last four decades. Emergency department (ED)-based evidence for treatment is limited. Outcomes remain poor, with a 25% mortality or re-admission rate within 30days post discharge. Targeting pulmonary congestion, which can be objectively assessed using lung ultrasound (LUS), may be associated with improved outcomes., Methods: BLUSHED-AHF is a multicenter, randomized, pilot trial designed to test whether a strategy of care that utilizes a LUS-driven treatment protocol outperforms usual care for reducing pulmonary congestion in the ED. We will randomize 130 ED patients with AHF across five sites to, a) a structured treatment strategy guided by LUS vs. b) a structured treatment strategy guided by usual care. LUS-guided care will continue until there are ≤15 B-lines on LUS or 6h post enrollment. The primary outcome is the proportion of patients with B-lines ≤ 15 at the conclusion of 6 h of management. Patients will continue to undergo serial LUS exams during hospitalization, to better understand the time course of pulmonary congestion. Follow up will occur through 90days, exploring days-alive-and-out-of-hospital between the two arms. The study is registered on ClinicalTrials.gov (NCT03136198)., Conclusion: If successful, this pilot study will inform future, larger trial design on LUS driven therapy aimed at guiding treatment and improving outcomes in patients with AHF., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The frequency of knee arthroscopy procedures is increasing in pediatric and adolescent patients. In general, complications after these procedures in adolescents are uncommon. The purposes of this study are to report the incidence of venous thromboembolism (VTE) in adolescent patients after knee arthroscopy procedures, as well identify risk factors in this patient population., Methods: Medical records were reviewed in all pediatric and adolescent patients (≤19 y) who underwent an arthroscopic knee procedure from 2010 to 2014 and were diagnosed with a symptomatic VTE in the postoperative period. Demographic features were recorded, and included age, sex, body mass index, clinical characteristics (diagnosis, type of surgical intervention, tourniquet time), VTE risk factors [family history of VTE, obesity (body mass index >30), oral contraceptive use, and smoking use/exposure] and treatment (anticoagulation type/duration)., Results: Out of 2783 patients who underwent knee arthroscopy during the 5-year study period, 7 patients (3 males, 4 females, mean age, 16.9 y, range, 15 to 18) developed a symptomatic postoperative VTE (incidence, 0.25%, 95% confidence interval, 0.11%-0.54%). There were 6 unilateral deep venous thrombosis, and 1 bilateral deep venous thrombosis. Arthroscopic procedures performed in this cohort included anterior cruciate ligament reconstruction (3), isolated lateral release (1), meniscectomy (2), and patellar realignment with arthroscopic lateral release, open tibial tubercle osteotomy, and open proximal medial retinacular reefing (1). VTE was diagnosed an average of 9 days following surgery (range, 3 to 16). All patients were initially treated with low-molecular-weight heparin, and 2 were converted to warfarin. Mean duration of anticoagulation treatment was 64 days (range, 28 to 183). All patients had at least 1 identifiable medical or surgical risk factor, including oral contraceptive use (2), smoking (2), obesity (2), an arthroscopically assisted open procedure (4), or tourniquet time >60 minutes (3)., Conclusions: VTE after adolescent knee arthroscopy has not been well described. The incidence is ∼0.25%. Previously established risk factors for VTE were present in 100% of the affected population. Low-molecular-weight heparin was used to successfully treat this complication., Level of Evidence: Level IV.

Lyme arthritis (LA), a late disease manifestation of Borrelia burgdorferi infection, usually resolves with antibiotic therapy. However, some patients develop proliferative synovitis lasting months to several years after spirochetal killing, called postinfectious LA. In this study, we phenotyped haematopoietic and stromal cell populations in the synovial lesion ex vivo and used these findings to generate an in vitro model of LA using patient-derived fibroblast-like synoviocytes (FLS). Ex vivo analysis of synovial tissue revealed high abundance of IFNγ-producing T cells and NK cells. Similar to marked IFNγ responses in tissue, postinfectious LA synovial fluid also had high levels of IFNγ. HLA-DR-positive FLS were present throughout the synovial lesion, particularly in areas of inflammation. FLS stimulated in vitro with B. burgdorferi, which were similar to conditions during infection, expressed 68 genes associated primarily with innate immune activation and neutrophil recruitment. In contrast, FLS stimulated with IFNγ, which were similar to conditions in the postinfectious phase, expressed >2,000 genes associated with pathogen sensing, inflammation, and MHC Class II antigen presentation, similar to the expression profile in postinfectious synovial tissue. Furthermore, costimulation of FLS with B. burgdorferi and IFNγ induced greater expression of IL-6 and other innate immune response proteins and genes than with IFNγ stimulation alone. These results suggest that B. burgdorferi infection, in combination with IFNγ, initiates the differentiation of FLS into a highly inflammatory phenotype. We hypothesise that overexpression of IFNγ by lymphocytes within synovia perpetuates these responses in the postinfectious period, causing proliferative synovitis and stalling appropriate repair of damaged tissue., (© 2019 John Wiley & Sons Ltd.)

In this study, ozonation pretreatment of real distillery wastewater (DWW) for biodegradability enhancement was undertaken. Response surface methodology was used to model the value of effective parameters, including ozonation duration and initial chemical oxygen demand (COD) concentration, and to estimate linear interactions and quadratic effects. The analysis of variance confirmed the adequate description of all the responses by the quadratic model employed. During ozonation, the pH of the DWW increased in acidity from 4.53 to 4.05, indicating the formation of acidic intermediates. A 60% reduction in color was observed signifying the oxidation of the color causing biorecalcitrant aromatic compounds and confirmed by the reduction in ultraviolet absorbance at λ max of 254 nm. Moreover, an increase in change in oxidation state from -0.1 to 0.4 was attributed to the declined aromaticity and the formation of aliphatic structures. From the measurement of the ratio of biochemical: chemical oxygen demand (BOD 5 :COD), an increase from 0.48 to 0.72 confirmed improved biodegradability. Optimization studies aimed at achieving maximum improved biodegradability at maximum ozone transfer efficiency yielded optimum ozonation pretreatment parameters of initial COD of 4.1 g L -1 and duration of 64 min.

Bovine anaplasmosis (BA), caused by Anaplasma marginale, is an economically important tick-borne disease of cattle in the United States (U.S.) and worldwide. Anecdotally, Veterinary Feed Directive prescriptions in the southeastern U.S. are written mostly for treatment/prevention of BA. However, there are no recent temporal seroprevalence estimates of BA in Texas (TX). Thus, this study was aimed at determining the seroprevalence of and factors associated with BA in TX. Data were obtained from an active slaughter survey (n = 215) performed between August and December 2014 as well as from reviewing Texas A&M Veterinary Medical Diagnostic Laboratories (TVMDLs) records of specimens submitted for BA testing from January 2002 to June 2012 (n = 15,460). Irrespective of the assay used, the overall apparent seroprevalence of BA in TX between 2002 and 2012 was 15.91% (95% CI: 15.34 - 16.50%) and the yearly increase in seroprevalence followed a significant trend (P < .0001). With cELISA, the apparent seroprevalence of BA was 13.49% (95% CI: 9.56 - 18.7%) and 13.02% (95% CI: 9.74 - 17.18%) for the slaughter survey and TVMDLs records between October and December 2011, respectively. Whereas the estimated true seroprevalence for the same period was 12.35% (95% CI: 8.04 - 18.05%) and 12.78% (95% CI: 9.19 - 17.30%), respectively. Factors associated with positive BA results were age, breed, diagnostic assay used, year and quarter of the year the specimens were submitted. The odds of the outcome were 1.5 times as high when cattle were adults (vs juvenile). In comparison to other breeds, the odds of the outcome were 11.57, 7.16, and 2.5 times higher in Hereford, Angus, and mixed breeds, respectively. When compared to 2003, the odds of the diagnosis of BA was approximately 2 times as high in 2010 but 3 times as high in 2002, 2005, and 2011 and approximately 4 times as high in 2006 and 2007. In comparison to the duration from October to December, the odds of the outcome were approximately 1.5 as high from January to March and from July to September durations. Counties with specimen submissions for BA testing had a significantly greater cattle population (p = .0061) and number of cattle farms (p < .001) than counties without specimen submissions. Subsequent prevention and control measures for BA should target these factors and should prioritize on counties with higher cattle population in the eastern part of TX. Furthermore, TVMDLs records appear sufficient for the surveillance of BA in TX., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Currently, all assays measuring acetylcholinesterase (AChE) activity following a suspected nerve agent exposure leverage methodologies that fail to identify the agent. This limits the overall effectiveness and ability to administer proper countermeasures. As such, there is an urgent need to identify novel, rapid, and more comprehensive approaches to establish AChE activity, including identification of the toxicant. Paper spray mass spectrometry was used to monitor the activity of acetylcholinesterase, both in-solution and on modified hydrophobic paper surface. Hydrophobic paper surfaces were prepared using vaporized trichloro(3,3,3-trifluoropropyl)silane. In both approaches, mixtures of diluted human whole blood with and without VX were mixed with a non-endogenous AChE specific substrate, 1,1-dimethyl-4-acetylthiomethylpiperidinium (MATP+). Formation of the cleaved MATP+ product was monitored over time and compared to MATP+ to determine relative AChE activity. This on-substrate assay was effective at determining AChE activity and identifying the toxicant; however, determination of AChE activity in-solution proceeded at a slower rate. The on-substrate assay serves as a pioneering example of an enzymatic reaction occurring on the surface of a paper spray ionization ticket. This work broadens the range of applications relating to paper spray ionization-based clinical diagnostic assays. Graphical Abstract ᅟ.

Nearly 85% of acute heart failure (AHF) patients who present to the emergency department (ED) with acute heart failure are hospitalized. Once hospitalized, within 30 days post-discharge, 27% of patients are re-hospitalized or die. Attempts to improve outcomes with novel therapies have all failed. The evidence for existing AHF therapies are poor: No currently used AHF treatment is known to improve long-term outcomes. ED treatment is largely the same today as 40 years ago. Admitting patients who could have avoided hospitalization may contribute to adverse outcomes. Hospitalization is not benign; patients enter a vulnerable phase post-discharge, at increased risk for morbidity and mortality. When hospitalization is able to be shortened or avoid completely, certain risks can be mitigated, including risk of medication errors, in-hospital falls, delirium, nosocomial infections, and other iatrogenic complications. Additionally, patients would prefer to be home, not hospitalized. Furthermore, hospitalization and re-hospitalization for AHF predominantly affects patients of lower socioeconomic status (SES). Avoiding hospitalization in patients who do not require admission may improve outcomes and quality of life, while reducing costs. Short stay unit (SSU: <24 h, also referred to as an 'observation unit') management of AHF may be effective for lower risk patients. However, to date there have only been small studies or retrospective analyses on the SSU management for AHF patients. In addition, SSU management has been considered 'cheating' for hospitals trying to avoid 30-day readmission penalties, as SSUs or observation units do not count as an admission. However, more recent analyses demonstrate differential use of observation status has not led to decreases in re-admission, suggesting this concern may be misplaced. Thus, we propose a robust clinical effectiveness trial to demonstrate the effectiveness of this patient-centered strategy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Worldwide, nearly two million children are infected with human immunodeficiency virus (HIV), with breastfeeding accounting for the majority of contemporary HIV transmissions. Antiretroviral therapy (ART) has reduced HIV-related morbidity and mortality but is not curative. The main barrier to a cure is persistence of latent HIV in long-lived reservoirs. However, our understanding of the cellular and anatomic sources of the HIV reservoir during infancy and childhood is limited. Here, we developed a pediatric model of ART suppression in orally simian immunodeficiency virus (SIV)-infected rhesus macaque (RM) infants, with measurement of virus persistence in blood and tissues after 6 to 9 months of ART. Cross-sectional analyses were conducted to compare SIV RNA and DNA levels in adult and infant RMs naive to treatment and on ART. We demonstrate efficient viral suppression following ART initiation in SIV-infected RM infants with sustained undetectable plasma viral loads in the setting of heterogeneous penetration of ART into lymphoid and gastrointestinal tissues and low drug levels in the brain. We further show reduction in SIV RNA and DNA on ART in lymphoid tissues of both infant and adult RMs but stable (albeit low) levels of SIV RNA and DNA in the brains of viremic and ART-suppressed infants. Finally, we report a large contribution of naive CD4 + T cells to the total CD4 reservoir of SIV in blood and lymph nodes of ART-suppressed RM infants that differs from what we show in adults. These results reveal important aspects of HIV/SIV persistence in infants and provide insight into strategic targets for cure interventions in a pediatric population. IMPORTANCE While antiretroviral therapy (ART) can reduce HIV replication, the virus cannot be eradicated from an infected individual, and our incomplete understanding of HIV persistence in reservoirs greatly complicates the generation of a cure for HIV infection. Given the immaturity of the infant immune system, it is critically important to study HIV reservoirs specifically in this population. Here, we established a pediatric animal model to simulate breastfeeding transmission and study SIV reservoirs in rhesus macaque (RM) infants. Our study demonstrates that ART can be safely administered to infant RMs for prolonged periods and that it efficiently controls viral replication in this model. SIV persistence was shown in blood and tissues, with similar anatomic distributions of SIV reservoirs in infant and adult RMs. However, in the peripheral blood and lymph nodes, a greater contribution of the naive CD4 + T cells to the SIV reservoir was observed in infants than in adults., (Copyright © 2018 American Society for Microbiology.)

To investigate iliotibial band (ITB) diameter thickness at the greater trochanter in patients requiring iliotibial band release who have failed conservative modalities, in comparison to an asymptomatic patient population. A total of 68 subjects were selected to be reviewed using T2 axial plane MRI. The ITB diameter thickness was measured in 34 subjects who underwent surgical ITB release, and compared with a match-paired asymptomatic hip cohort consisting of 34 subjects. ITB diameter thickness was measured at the thickest location for each subject twice by two different examiners. Inter/intra class correlation coefficient was determined for ITB measurement technique accuracy, and the presence of recalcitrant proximal hip pain was evaluated. Interclass correlation coefficient with 95% confidence was measured to be 0.953. The average thickness for ITB surgical release subjects was measured to be 5.61 ± 2.10 mm, and for asymptomatic subjects 3.77 ± 0.79 mm ( P  < 0.001). The results of this study demonstrate a statistically significant positive relationship of an increased diameter thickness in the ITB in symptomatic patients who failed conservative therapy and underwent surgical intervention for treatment.

Study Design: Mapping Review., Objective: The objective of this study was to map out and characterize the quantity and quality of all published spinal cord injury (SCI) randomized controlled trials (RCTs) with respect to number, sample size, and methodological quality between January 1970 and December 2016., Setting: Not applicable., Methods: A literature search of multiple research databases was conducted. Studies adhering to the following criteria were included: the research design was an RCT; written in English; participants were >18 years; and the sample was >50% SCI. Data were extracted pertaining to author(s), year of publication, country of origin, initial and final sample size, intervention, and control. Methodological quality was assessed using the Physiotherapy Evidence Database (PEDro) tool. Data was assessed overall and by each year of publication., Results: In total, 466 RCTs were published 1971-2016 on 29 primary topic areas, with Bladder (n = 78, 16.7%) most common, followed by Pain (n = 54, 11.6%), and Lower Limb (n = 45, 9.7%). Studies were published in 172 unique journals, with the most common being Spinal Cord (n = 68, 14.6%). The most common producer of studies was the United States (n = 191, 41.0%). RCT publications increased linearly until 2012 when the rate tripled, resulting in 40.8% published 2012-2016. A total of 247 (59.4%) RCTs had <30 subjects; there was no change in sample size over time (p = 0.770). The overall mean PEDro score was 5.56 (1.68); scores improved from 5.0 (1.4) in 1976 to 6.3 (1.9) in 2016 (F = 2.230, p < 0.001)., Conclusions: The number of SCI RCTs and their associated sample size remains low; however, methodological quality has improved over time.

Bovine anaplasmosis (BA) is tick-borne disease of cattle caused by Anaplasma marginale and it remains an economically important disease in the United States (U.S.). We have anecdotal information that Veterinary Feed Directive prescriptions in Kentucky (KY) are written most often for treatment and prevention of BA. However, there are no recent prevalence estimates of this disease in KY. Thus, this study was aimed at determining the seroprevalence of and factors associated with BA in KY. Data were obtained from an active slaughter survey (n = 232) performed between May and July 2013 as well as from reviewing The University of Kentucky Veterinary Diagnostic Laboratory (UKVDL) records of specimens submitted for BA testing from 2002-2012 (n = 2,573). With competitive ELISA, the apparent prevalence of BA in KY was 10.78% (95% CI: 7.41-15.42%) and 11.58% (95% CI: 10.31-12.98%) for the slaughter survey and laboratory records, respectively. Whereas the estimated true prevalence was 9.44% (95% CI: 5.65-14.48%) and 10.3% (95% CI: 8.92-11.8%), respectively. From the laboratory records, factors associated with positive BA results were age, breed, whether specimens were submitted singularly or as a group, year and quarter of the year the specimens were submitted. The odds of the outcome were 5 times as high when cattle were adults (vs juvenile) and almost 4 times as high when specimens were submitted singularly (vs group). In comparison to Holstein breed, the odds of the outcome were 3.5 and 2.5 times higher in Angus and mixed breeds, respectively. The odds of a diagnosis of BA varied in an undulating pattern by year of sample submission. When compared to 2011, the odds of a diagnosis of BA was approximately 3 times as high in 2005, 2008, and 2009 and approximately 5 times as high in 2004, 2006, and 2012. In comparison to the duration from January to March, the odds of the outcome were almost 20 times as high from July to September but 10 times as high from October to December durations. Counties with specimen submissions for BA testing had a significantly greater cattle population and number of cattle farms than counties without specimen submissions. Future prevention and control measures for BA should target these factors and should be weighted more on counties with higher cattle population. Furthermore, current records from the UKVDL appear sufficient for the surveillance of BA in KY., (Published by Elsevier B.V.)

Background: Valid patient-reported outcomes (PROs) for the shoulder and elbow do not exist for children. We assessed children's comprehension of the Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) questionnaire and the American Shoulder and Elbow Surgeons (ASES) standardized shoulder assessment form, identified response errors, and modified items to create a new pediatric shoulder and elbow PRO., Methods: We recruited 50 children (aged 10-18 years) with shoulder or elbow disorders from a children's hospital-based orthopedic clinic for this qualitative study. A trained researcher conducted cognitive interviews to identify children's comprehension of PROs. In phase 1, 40 children were purposefully sampled on the basis of age and gender, interviewed, and audiotaped. A behavioral scientist analyzed transcripts, modified items, and created the Pediatric and Adolescent Shoulder and Elbow Survey (Pedi-ASES). In phase 2, 10 children were interviewed to gather feedback on and to refine the Pedi-ASES., Results: The average interview time was 25 minutes (range, 17-44 minutes). There were 242 comments generated about the QuickDASH; 51% of children struggled with complex terminology, and 35% did not understand "tingling." Children generated 309 comments about the ASES, primarily associated with narcotic medications (65%) and shoulder instability (42%). Time frame and format issues were noted. In phase 2, children found the new PRO easier to comprehend and answer., Conclusions: Modifications were needed in general instruction, language, format, and response mapping in the original PROs. Children had few difficulties with the Pedi-ASES. Designing PROs that are specific to children will enable researchers and clinicians to more accurately assess health status and clinical outcomes., (Copyright © 2017 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Pulmonary atresia with intact ventricular septum and congenital left ventricular aneurysms are both rare, representing <1 and <0.1% of CHD, respectively. The association of left ventricular aneurysms and pulmonary atresia with intact ventricular septum has been documented in the literature, but all the previous case reports have involved children with acquired left ventricular aneurysms. We report an interesting case of a child with both pulmonary atresia with intact ventricular septum and a congenital left ventricular aneurysm. The combination of these two lesions ultimately affected the course of clinical care for the patient.

Objective: The objective of this study was to evaluate patients' braking performance using a modern driving simulator after undergoing a right hip arthroscopy., Design: This prospective study included 5 total driving sessions at which measurements were taken., Setting: The study was conducted at an academic medical center., Patients: A total of 14 patients scheduled to undergo a right hip arthroscopy were enrolled and compared with a control group of 17 participants to account for a potential learning phenomenon., Interventions: Patients drove in the simulator preoperatively to establish a baseline, and then drove again at 2, 4, 6, and 8 weeks postoperatively. The control group did not undergo any type of surgical procedure. The main independent variable was time from surgery., Main Outcome Measures: A modern driving simulator was used to measure initial reaction time (IRT), throttle release time (TRT), foot movement time (FMT), and brake travel time (BTT). The braking reaction time (BRT) was calculated as the sum of IRT + TRT + FMT, and the total braking time (TBT) was calculated as the sum of BRT + BTT., Results: The experimental group showed no significant changes in BTT (P = 0.11, (Equation is included in full-text article.)= 0.04) nor TBT (P = 0.20, (Equation is included in full-text article.)= 0.03) over the duration of 8 weeks. Although the experimental group did exhibit significant improvements in IRT (P = 0.002), TRT (P < 0.0001), FMT (P < 0.0001), and BRT (P = 0.0002) between preoperative and 2 weeks postoperative driving sessions, there were no significant changes thereafter. The mean preoperative TBT and 2 weeks postoperative TBT for the experimental group were 3.07 seconds (SD = 0.50) and 2.97 seconds (SD = 0.57), respectively. No learning phenomenon was observed in the control group., Conclusions: This study's findings suggest that patients may return to driving 2 weeks postoperatively from a right-sided hip arthroscopy procedure.

Pathogenic human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infection of humans and rhesus macaques (RMs) induces persistently high production of type I interferon (IFN-I), which is thought to contribute to disease progression. To elucidate the specific role of interferon alpha (IFN-α) in SIV pathogenesis, 12 RMs were treated prior to intravenous (i.v.) SIV mac239 infection with a high or a low dose of an antibody (AGS-009) that neutralizes most IFN-α subtypes and were compared with six mock-infused, SIV-infected controls. Plasma viremia was measured postinfection to assess the effect of IFN-α blockade on virus replication, and peripheral blood and lymphoid tissue samples were analyzed by immunophenotypic staining. Consistent with the known antiviral effect of IFN-I, high-dose AGS-009 treatment induced a modest increase in acute-phase viral loads versus controls. Four out of 6 RMs receiving a high dose of AGS-009 also experienced an early decline in CD4 + T cell counts that was associated with progression to AIDS. Interestingly, 50% of the animals treated with AGS-009 (6/12) developed AIDS within 1 year of infection compared with 17% (1/6) of untreated controls. Finally, blockade of IFN-α decreased the levels of activated CD4 + and CD8 + T cells, as well as B cells, as measured by PD-1 and/or Ki67 expression. The lower levels of activated lymphocytes in IFN-α-blockaded animals supports the hypothesis that IFN-α signaling contributes to lymphocyte activation during SIV infection and suggests that this signaling pathway is involved in controlling virus replication during acute infection. The potential anti-inflammatory effect of IFN-α blockade should be explored as a strategy to reduce immune activation in HIV-infected individuals. IMPORTANCE Interferon alpha (IFN-α) is a member of a family of molecules (type I interferons) that prevent or limit virus infections in mammals. However, IFN-α production may contribute to the chronic immune activation that is thought to be the primary cause of immune decline and AIDS in HIV-infected patients. The study presented here attempts to understand the contribution of IFN-α to the natural history and progression of SIV infection of rhesus macaques, the primary nonhuman primate model system for testing hypotheses about HIV infection in humans. Here, we show that blockade of IFN-α action promotes lower chronic immune activation but higher early viral loads, with a trend toward faster disease progression. This study has significant implications for new treatments designed to impact the type I interferon system., (Copyright © 2018 American Society for Microbiology.)

The ability of nanotechnology-enabled consumer sprays to inactivate bacteria has direct health implications. This research investigated the ability of six nanosilver-based consumer sprays to inactivate bacteria. We determined the minimal inhibitory concentrations (MICs) of the products by an agar dilution method, collected particles released from sprays onto bacterial films using impactors, and determined metal concentrations in the products using ICPMS. Also, the size of silver nanoparticles in the products' suspensions was determined using single particle (sp)ICPMS. Two of the six nanoproducts inhibited growth of Escherichia coli and Bacillus atrophaeus bacteria (MICs of 40,000 and 160,000 ppm). Collection of particles aerosolized from these two products onto films of the same bacteria inhibited bacterial growth; however, the mass concentration deposited onto bacterial films was lower than the MICs. Furthermore, these two nanoproducts had the lowest silver concentrations compared to the other four nanosilver products. Yet, they had the smallest nanosilver particles: mean size of ~20 to 30 nm vs. ~45 nm for the other products. Their suspensions were more acidic (pH ~3-5) and had higher concentrations of zinc and magnesium compared to other products. This research illustrates that some consumer nanoproducts have antibacterial potential and may affect our microbiota. Yet, the inactivation potential cannot solely be presumed based on the nanosilver presence and concentration in the product; the final nanoproduct's form, including its matrix, must be considered. As nanomaterials are increasingly incorporated into consumer goods, this research highlights the need to investigate final-form consumer nanoproducts and their potential to affect our microbial environment., Competing Interests: Conflicts of Interest Statement: There are no conflicts to declare.

This study evaluated the photocatalytic activity of polyaniline (PANI)-capped titanium dioxide and zinc oxide (TiO 2 /ZnO) hybrid, for the degradation of P-Cresol. The hybrid was synthesized by precipitating ZnO on the surface of commercial TiO 2 . An "in situ" chemical oxidative polymerization method was used to prepare the PANI capped hybrid (TiO 2 /ZnO/PANI). The photocatalysts were characterized by powder X-ray diffraction (XRD), a Brunauer Emmett Teller (BET) analyzer, Fourier-transform infrared (FTIR) and photoluminescence spectroscopies, high resolution-transmission electron microscopy (HR-TEM) and thermogravimetric analysis (TGA). During photodegradation under ultraviolet (UV) irradiation, ZnO, TiO 2 , TiO 2 /ZnO hybrid and TiO 2 /ZnO/PANI composite had P-Cresol removal of 43%, 50%, 61% and 99%, respectively. The higher activity of the TiO 2 /ZnO hybrid as compared to TiO 2 and ZnO was attributed to a reduced electron-hole pair recombination. The recombination was further significantly reduced upon introduction of PANI; hence, the highest activity observed with TiO 2 /ZnO/PANI. The initial reaction rate constant for TiO 2 /ZnO/PANI (0.9679 min -1 ) was more than twice compared to that for TiO 2 /ZnO hybrid (0.1259 min -1 ). A synergistic effect between PANI and TiO 2 /ZnO resulted in a highly efficient charge separation caused by the transfer of photogenerated holes from the hybrid to highest occupied molecular orbitals (HOMO) of PANI. The best TiO 2 /ZnO/PANI (PANI to TiO 2 /ZnO) ratio observed was 0.5:2 for the photodegradation of P-Cresol. Total organic carbon (TOC) analysis indicated a 97.4% mineralization of P-Cresol with PANI/TiO 2 /ZnO.

Organophosphorus (OP) nerve agents continue to be a threat at home and abroad during the war against terrorism. Human exposure to nerve agents such as VX results in a cascade of toxic effects relative to the exposure level including ocular miosis, excessive secretions, convulsions, seizures, and death. The primary mechanism behind these overt symptoms is the disruption of cholinergic pathways. While much is known about the primary toxicity mechanisms of nerve agents, there remains a paucity of information regarding impacts on other pathways and systemic effects. These are important for establishing a comprehensive understanding of the toxic mechanisms of OP nerve agents. To identify novel proteins that interact with VX, and that may give insight into these other mechanisms, we used activity-based protein profiling (ABPP) employing a novel VX-probe on lysates from rat heart, liver, kidney, diaphragm, and brain tissue. By making use of a biotin linked VX-probe, proteins covalently bound by the probe were isolated and enriched using streptavidin beads. The proteins were then digested, labeled with isobarically distinct tandem mass tag (TMT) labels, and analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Quantitative analysis identified 132 bound proteins, with many proteins found in multiple tissues. As with previously published ABPP OP work, monoacylglycerol lipase associated proteins and fatty acid amide hydrolase (FAAH) were shown to be targets of VX. In addition to these two and other predicted neurotransmitter-related proteins, a number of proteins involved with energy metabolism were identified. Four of these enzymes, mitochondrial isocitrate dehydrogenase 2 (IDH2), isocitrate dehydrogenase 3 (IDH3), malate dehydrogenase (MDH), and succinyl CoA (SCS) ligase, were assayed for VX inhibition. Only IDH2 NADP+ activity was shown to be inhibited directly. This result is consistent with other work reporting animals exposed to OP compounds exhibit reduced IDH activity. Though clearly a secondary mechanism for toxicity, this is the first time VX has been shown to directly interfere with energy metabolism. Taken together, the ABPP work described here suggests the discovery of novel protein-agent interactions, which could be useful for the development of novel diagnostics or potential adjuvant therapeutics.

Objective: The aim of the study was to evaluate the image quality of a photostimulable phosphor (PSP) plate system to determine if image degradation has occurred after a number of clinical uses., Study Design: Twenty DIGORA Optime PSP plates (Soredex Orion Corp., Helsinki, Finland) were imaged throughout clinical use. Image quality was assessed by using spatial and contrast resolution through the use of the dental radiographic phantom designed for the Nationwide Evaluation of X-Ray Trends surveys of 1993 and 1999. Spatial resolution was summarized in line pairs per millimeter. The paired t test was used to analyze the contrast wells. The contrast-to-noise ratio (CNR) was calculated to determine the signal-to-noise ratio as another measure of contrast. Descriptive statistics were used to summarize the CNR ratios., Results: Spatial resolution decreased after 48 clinical uses. No significant differences were found for the pairwise comparisons of the contrast wells. No CNR varied by more than two-tenths' value difference., Conclusions: Digora Optime PSP plates displayed unaffected image quality up to 48 clinical uses. Additional studies are needed to confirm these results and to establish guidelines for appropriate replacement intervals for PSP plates., (Copyright © 2016 Elsevier Inc. All rights reserved.)

We tested, in rhesus macaques, the effects of a 500-fold range of an admixed recombinant modified vaccinia Ankara (MVA) expressing rhesus GM-CSF (MVA/GM-CSF) on the immunogenicity and protection elicited by an MVA/SIV macaque 239 vaccine. High doses of MVA/GM-CSF did not affect the levels of systemic envelope (Env)-specific Ab, but it did decrease the expression of the gut-homing receptor α4β7 on plasmacytoid dendritic cells (p < 0.01) and the magnitudes of Env-specific IgA (p = 0.01) and IgG (p < 0.05) in rectal secretions. The protective effect of the vaccine was evaluated using 12 weekly rectal challenges in rhesus macaques subgrouped by tripartite motif-containing protein 5α (TRIM5α) genotypes that are restrictive or permissive for infection by the challenge virus SIVsmE660. Eight of nine TRIM5α-restrictive animals receiving no or the lowest dose (1 × 10 5 PFU) of MVA/GM-CSF resisted all 12 challenges. In the comparable TRIM5α-permissive group, only 1 of 12 animals resisted all 12 challenges. In the TRIM5α-restrictive animals, but not in the TRIM5α-permissive animals, the number of challenges to infection directly correlated with the magnitudes of Env-specific rectal IgG (r = +0.6) and IgA (r = +0.6), the avidity of Env-specific serum IgG (r = +0.5), and Ab dependent cell-mediated virus inhibition (r = +0.6). Titers of neutralizing Ab did not correlate with protection. We conclude that 1) protection elicited by MVA/SIVmac239 is strongly dependent on the presence of TRIM5α restriction, 2) nonneutralizing Ab responses contribute to protection against SIVsmE660 in TRIM5α-restrictive animals, and 3) high doses of codelivered MVA/GM-CSF inhibit mucosal Ab responses and the protection elicited by MVA expressing noninfectious SIV macaque 239 virus-like particles., (Copyright © 2016 by The American Association of Immunologists, Inc.)

Unlabelled: Simian immunodeficiency virus (SIV)-infected sooty mangabeys (SMs) do not develop AIDS despite high levels of viremia. Key factors involved in the benign course of SIV infection in SMs are the absence of chronic immune activation and low levels of infection of CD4(+) central memory (TCM) and stem cell memory (TSCM) T cells. To better understand the role of virus replication in determining the main features of SIV infection in SMs, we treated 12 SMs with a potent antiretroviral therapy (ART) regimen for 2 to 12 months. We observed that ART suppressed viremia to <60 copies/ml of plasma in 10 of 12 animals and induced a variable decrease in the level of cell-associated SIV DNA in peripheral blood (average changes of 0.9-, 1.1-, 1.5-, and 3.7-fold for CD4(+) transitional memory [TTM], TCM, effector memory [TEM], and TSCM cells, respectively). ART-treated SIV-infected SMs showed (i) increased percentages of circulating CD4(+) TCM cells, (ii) increased levels of CD4(+) T cells in the rectal mucosa, and (iii) significant declines in the frequencies of HLA-DR(+) CD8(+) T cells in the blood and rectal mucosa. In addition, we observed that ART interruption resulted in rapid viral rebound in all SIV-infected SMs, indicating that the virus reservoir persists for at least a year under ART despite lower infection levels of CD4(+) TCM and TSCM cells than those seen in pathogenic SIV infections of macaques. Overall, these data indicate that ART induces specific immunological changes in SIV-infected SMs, thus suggesting that virus replication affects immune function even in the context of this clinically benign infection., Importance: Studies of natural, nonpathogenic simian immunodeficiency virus (SIV) infection of African monkeys have provided important insights into the mechanisms responsible for the progression to AIDS during pathogenic human immunodeficiency virus (HIV) infection of humans and SIV infection of Asian macaques. In this study, for the first time, we treated SIV-infected sooty mangabeys, a natural host for the infection, with a potent antiretroviral therapy (ART) regimen for periods ranging from 2 to 12 months and monitored in detail how suppression of virus replication affected the main virological and immunological features of this nonpathogenic infection. The observed findings provide novel information on both the pathogenesis of residual immunological disease under ART during pathogenic infection and the mechanisms involved in virus persistence during primate lentiviral infections., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

The integrated stress response (ISR) is a homeostatic mechanism by which eukaryotic cells sense and respond to stress-inducing signals, such as amino acid starvation. General controlled non-repressed (GCN2) kinase is a key orchestrator of the ISR, and modulates protein synthesis in response to amino acid starvation. Here we demonstrate in mice that GCN2 controls intestinal inflammation by suppressing inflammasome activation. Enhanced activation of ISR was observed in intestinal antigen presenting cells (APCs) and epithelial cells during amino acid starvation, or intestinal inflammation. Genetic deletion of Gcn2 (also known as Eif2ka4) in CD11c(+) APCs or intestinal epithelial cells resulted in enhanced intestinal inflammation and T helper 17 cell (TH17) responses, owing to enhanced inflammasome activation and interleukin (IL)-1β production. This was caused by reduced autophagy in Gcn2(-/-) intestinal APCs and epithelial cells, leading to increased reactive oxygen species (ROS), a potent activator of inflammasomes. Thus, conditional ablation of Atg5 or Atg7 in intestinal APCs resulted in enhanced ROS and TH17 responses. Furthermore, in vivo blockade of ROS and IL-1β resulted in inhibition of TH17 responses and reduced inflammation in Gcn2(-/-) mice. Importantly, acute amino acid starvation suppressed intestinal inflammation via a mechanism dependent on GCN2. These results reveal a mechanism that couples amino acid sensing with control of intestinal inflammation via GCN2.

Phosgene (CG), a toxic inhalation and industrial hazard, causes bronchoconstriction, vasoconstriction and associated pathological effects that could be life threatening. Ion channels of the transient receptor potential (TRP) family have been identified to act as specific chemosensory molecules in the respiratory tract in the detection, control of adaptive responses and initiation of detrimental signaling cascades upon exposure to various toxic inhalation hazards (TIH); their activation due to TIH exposure may result in broncho- and vasoconstriction. We studied changes in the regulation of intracellular free Ca(2+) concentration ([Ca(2+)]i) in cultures of human bronchial smooth muscle cells (BSMC) and human pulmonary microvascular endothelial cells (HPMEC) exposed to CG (16ppm, 8min), using an air/liquid interface exposure system. CG increased [Ca(2+)]i (p<0.05) in both cell types, The CG-induced [Ca(2+)]i was blocked (p<0.05) by two types of TRP channel blockers, SKF-96365, a general TRP channel blocker, and RR, a general TRPV (vanilloid type) blocker, in both BSMC and HPMEC. These effects correlate with the in vivo efficacies of these compounds to protect against lung injury and 24h lethality from whole body CG inhalation exposure in mice (8-10ppm×20min). Thus the TRP channel mechanism appears to be a potential target for intervention in CG toxicity., (Published by Elsevier Ireland Ltd.)

Oncomodulin (Ocm), a member of the parvalbumin family of calcium binding proteins, is expressed predominantly by cochlear outer hair cells in subcellular regions associated with either mechanoelectric transduction or electromotility. Targeted deletion of Ocm caused progressive cochlear dysfunction. Although sound-evoked responses are normal at 1 month, by 4 months, mutants show only minimal distortion product otoacoustic emissions and 70-80 dB threshold shifts in auditory brainstem responses. Thus, Ocm is not critical for cochlear development but does play an essential role for cochlear function in the adult mouse., Significance Statement: Numerous proteins act as buffers, sensors, or pumps to control calcium levels in cochlear hair cells. In the inner ear, EF-hand calcium buffers may play a significant role in hair cell function but have been very difficult to study. Unlike other reports of genetic disruption of EF-hand calcium buffers, deletion of oncomodulin (Ocm), which is predominately found in outer hair cells, leads to a progressive hearing loss after 1 month, suggesting that Ocm critically protects hearing in the mature ear., (Copyright © 2016 the authors 0270-6474/16/361631-05$15.00/0.)

Objective: The objective of this study was to evaluate the safety and performance of the artificial pancreas (AP) in adolescents with type 1 diabetes (T1D) following insulin omission for food., Research Design and Methods: In a randomized, cross-over trial, adolescents with T1D aged 13-18 yr were enrolled in a randomized, cross-over trial. On separate days, received either usual care (UC) through their home insulin pump or used an AP system (Diabetes Assistant platform, continuous glucose monitor, and insulin pump). Approximately 1 h after admission, participants in both groups received an unannounced snack of 30 g carbohydrate, and 4 h later they received an 80 g lunch, for which both groups only received 75% of the calculated insulin dose to cover carbohydrates. On the UC day (but not the AP day), they received their full high blood glucose (BG) correction factor at lunch. Each admission lasted approximately 8 h., Results: A total of 16 participants completed the trial. On the AP day (compared to UC), mean BG was lower (197 ± 10 vs. 235 ± 14 mg/dL) and time in range 70-180 mg/dL was higher (43% ± 7 vs. 19% ± 7) (both p < 0.05) overall; these results held in the time following the snack and meal (also p < 0.05). During the trial, there were no differences between groups in the rate of hypoglycemia <70 mg/dL., Conclusions: The AP provided improvements in short-term glycemic control without increases in hypoglycemia following missed insulin for food in adolescents. Thus, the AP partly compensates for missed insulin boluses for food, a common occurrence in adolescent diabetes care. Further testing is needed in longer-term settings., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Persistent primitive hepatic venous plexus is an anomaly of the systemic venous return characterised by postnatal persistence of the foetal intrahepatic venous drainage. Scimitar syndrome is a condition that consists of partial anomalous pulmonary venous return of the right pulmonary venous drainage into the systemic veins, associated with pulmonary artery hypoplasia with the underdeveloped right lung, pulmonary sequestration, and cardiac malposition. Both conditions are rare and together have been rarely described in the literature. We report the first case of this combination of lesions imaged by cardiac magnetic resonance imaging with a three-dimensional reconstruction and reviewed the literature to characterise this uncommon combination.

Background: Many trauma care providers often disregard the abdominal clinical examination in the presence of extra-abdominal distracting injuries and mandate abdominal computed tomographic scan in these patients. Ignoring the clinical examination may incur undue expense and radiation exposure. The purpose of this study was to assess the efficacy of abdominal clinical examination in patients with distracting injuries., Methods: During a 1-year period, all awake and alert blunt trauma patients with Glasgow Coma Scale (GCS) score of 14 or 15 were entered into a prospective study. Abdominal clinical examination was performed and documented prospectively on all patients. Abdominal clinical examination included four-quadrant anterior abdominal palpation, flank palpation, lower thoracic palpation, pelvis examination, and palpation of the thoracolumbar spine. Following examination documentation, all patients underwent computed tomographic scan of the abdomen and pelvis with intravenous contrast., Results: A total of 803 patients were enrolled: 451 patients had distracting injuries, and 352 patients did not. Of the 352 patients without distracting injuries, 19 (5.4%) had intra-abdominal injuries, of whom 2 (10.5%) had negative clinical examination result. Of the 451 patients with distracting injuries, 48 (10.6%) were diagnosed with intra-abdominal injury, of whom 5 (10.4%) had negative clinical examination result. All five missed injuries in patients with distracting injuries were solid organ injuries, none of which required surgical intervention or blood transfusion. The sensitivity and negative predictive value of abdominal examination for patients with distracting injuries were 90.0% and 97.0%, respectively. The sensitivity and negative predictive value of abdominal examination for surgically significant and transfusion-requiring injuries were both 100%., Conclusion: Distracting injuries do not seem to diminish the efficacy of clinical abdominal examination for the diagnosis of clinically significant abdominal injury. These data suggest that clinical examination of the abdomen is valid in awake and alert blunt trauma patients, regardless of the presence of other injuries., Level of Evidence: Diagnostic study, level III.

HIV-1 infection is characterized by varying degrees of chronic immune activation and disruption of T-cell homeostasis, which impact the rate of disease progression. A deeper understanding of the factors that influence HIV-1-induced immunopathology and subsequent CD4(+) T-cell decline is critical to strategies aimed at controlling or eliminating the virus. In an analysis of 127 acutely infected Zambians, we demonstrate a dramatic and early impact of viral replicative capacity (vRC) on HIV-1 immunopathogenesis that is independent of viral load (VL). Individuals infected with high-RC viruses exhibit a distinct inflammatory cytokine profile as well as significantly elevated T-cell activation, proliferation, and CD8(+) T-cell exhaustion, during the earliest months of infection. Moreover, the vRC of the transmitted virus is positively correlated with the magnitude of viral burden in naive and central memory CD4(+) T-cell populations, raising the possibility that transmitted viral phenotypes may influence the size of the initial latent viral reservoir. Taken together, these findings support an unprecedented role for the replicative fitness of the founder virus, independent of host protective genes and VL, in influencing multiple facets of HIV-1-related immunopathology, and that a greater focus on this parameter could provide novel approaches to clinical interventions.

CD8 T cells are a potent tool for eliminating intracellular pathogens and tumor cells. Thus, eliciting robust CD8 T-cell immunity is the basis for many vaccines under development. However, the relationship between antigen load and the magnitude of the CD8 T-cell response is not well-described in a human immune response. Here we address this issue by quantifying viral load and the CD8 T-cell response in a cohort of 80 individuals immunized with the live attenuated yellow fever vaccine (YFV-17D) by sampling peripheral blood at days 0, 1, 2, 3, 5, 7, 9, 11, 14, 30, and 90. When the virus load was below a threshold (peak virus load < 225 genomes per mL, or integrated virus load < 400 genome days per mL), the magnitude of the CD8 T-cell response correlated strongly with the virus load (R(2) ∼ 0.63). As the virus load increased above this threshold, the magnitude of the CD8 T-cell responses saturated. Recent advances in CD8 T-cell-based vaccines have focused on replication-incompetent or single-cycle vectors. However, these approaches deliver relatively limited amounts of antigen after immunization. Our results highlight the requirement that T-cell-based vaccines should deliver sufficient antigen during the initial period of the immune response to elicit a large number of CD8 T cells that may be needed for protection.