Apolipoprotein E controls Dectin-1-dependent development of monocyte-derived alveolar macrophages upon pulmonary ß-glucan-induced inflammatory adaptation.

The lung is constantly exposed to the outside world and optimal adaptation of immune responses is crucial for efficient pathogen clearance. However, mechanisms that lead to lung-associated macrophages' functional and developmental adaptation remain elusive. To reveal such mechanisms, we developed a reductionist model of environmental intranasal ß-glucan exposure, allowing for the detailed interrogation of molecular mechanisms of pulmonary macrophage adaptation. Employing single-cell transcriptomics, high-dimensional imaging and flow cytometric characterization paired with in vivo and ex vivo challenge models, we reveal that pulmonary low-grade inflammation results in the development of apolipoprotein E (ApoE)-dependent monocyte-derived alveolar macrophages (ApoE+CD11b+ AMs). ApoE+CD11b+ AMs expressed high levels of CD11b, ApoE, Gpnmb and Ccl6, were glycolytic, highly phagocytic and produced large amounts of interleukin-6 upon restimulation. Functional differences were cell intrinsic, and myeloid cell-specific ApoE ablation inhibited Ly6c+ monocyte to ApoE+CD11b+ AM differentiation dependent on macrophage colony-stimulating factor secretion, promoting ApoE+CD11b+ AM cell death and thus impeding ApoE+CD11b+ AM maintenance. In vivo, ß-glucan-elicited ApoE+CD11b+ AMs limited the bacterial burden of Legionella pneumophilia after infection and improved the disease outcome in vivo and ex vivo in a murine lung fibrosis model. Collectively these data identify ApoE+CD11b+ AMs generated upon environmental cues, under the control of ApoE signaling, as an essential determinant for lung adaptation enhancing tissue resilience.

Randomized crossover study comparing quantitative fit tests between Trident™ and 3M™ Aura™ N95/P2 respirators.

BACKGROUND: Various styles of N95/P2 filtering facepiece respirators (FFRs) have been used by Australian healthcare workers (HCWs) during the COVID-19 pandemic. This is usually driven by the national stockpile availability. Many studies demonstrate three-panel flat-fold N95/P2 FFRs have higher quantitative fit test (QNFT) pass rates than other FFR styles. This prospective randomized crossover study utilized QNFT to evaluate the performance of the new three-panel flat-fold FFR, the Trident™ P2 respirator compared to the previously most effective model, the 3M™ Aura™ 9320A + N95 respirator. METHODS: We recruited 500 participants who completed online training and QNFT on both respirators. The order of the respirator being examined first was randomly allocated. The primary outcome was the QNFT pass rate. Secondary outcomes included the overall fit factor, the individual fit factor for each exercise, and the first-attempt QNFT pass rate. RESULTS: We found that both the overall and first-attempt QNFT pass rates of the Trident P2 respirator were significantly higher than the 3M Aura (99.2% vs 92.6%, p < 0.001; and 92.6% vs 76.4%, p < 0.001 respectively). The overall fit factor and the individual fit factor were also significantly higher for the Trident FFR than the 3M Aura. CONCLUSIONS: This study is the first to report hospital-based QNFT results of the Trident FFR, demonstrating very high first-time and overall pass rates. Our findings are consistent with previous research showing very high QNFT pass rates with three-panel flat-fold FFRs. These findings are important for pandemic preparedness with respect to the stockpiling and safe utilization of N95/P2 respirators.

Multistate outbreaks of Salmonella infections linked to imported Maradol papayas - United States, December 2016-September 2017.

Foodborne salmonellosis causes approximately 1 million illnesses annually in the United States. In the summer of 2017, we investigated four multistate outbreaks of Salmonella infections associated with Maradol papayas imported from four Mexican farms. PulseNet initially identified a cluster of Salmonella Kiambu infections in June 2017, and early interviews identified papayas as an exposure of interest. Investigators from Maryland, Virginia and Food and Drug Administration (FDA) collected papayas for testing. Several strains of Salmonella were isolated from papayas sourced from Mexican Farm A, including Salmonella Agona, Gaminara, Kiambu, Thompson and Senftenberg. Traceback from two points of service associated with illness sub-clusters in two states identified Farm A as a common source of papayas, and three voluntary recalls of Farm A papayas were issued. FDA sampling isolated four additional Salmonella strains from papayas sourced from Mexican Farms B, C and D. In total, four outbreaks were identified, resulting in 244 cases with illness onset dates from 20 December 2016 to 20 September 2017. The sampling of papayas and the collaborative work of investigative partners were instrumental in identifying the source of these outbreaks and preventing additional illnesses. Evaluating epidemiological, laboratory and traceback evidence together during investigations is critical to solving and stopping outbreaks.

A randomised controlled trial comparing fibreoptic-guided tracheal intubation through two supraglottic devices: Ambu® AuraGain™ laryngeal mask and LMA® Fastrach™.

The Ambu®AuraGain™ laryngeal mask (LM) (Ambu A/S, Ballerup, Denmark) is one of the few readily available second-generation supraglottic airway devices (SADs) that offer a conduit for fibreoptic-guided endotracheal intubation. We aimed to compare fibreoptic intubation through this device with the LMA® (laryngeal mask airway) Fastrach™ (Teleflex Medical, Co. Westmeath, Ireland), which has been a recommended dedicated rescue device for the management of the unanticipated difficult airway. This randomised controlled trial compared a previously described fibreoptic score in 116 patients with no known airway pathology, who had asleep fibreoptic endotracheal intubation via either the AuraGain LM or the LMA Fastrach. Time, ease and success rate of SAD and endotracheal tube (ETT) insertion and complications were recorded. The AuraGain LM demonstrated better laryngeal alignment with 29 out of 59 patients in the AuraGain LM (AG) group having a Grade 4 view (only vocal cords visible), compared to 20 out of 54 patients in the LMA Fastrach (FT) group (P=0.003). It allowed significantly quicker and easier ETT intubation when used as a conduit. The AuraGain LM was also quicker to insert compared to the Fastrach LMA. Similar rates of minor complications, such as sore throat and dysphonia occurred in both groups. Our study indicates that when used in patients with complete muscle relaxation and no known airway pathology, the AuraGain LM achieves better laryngeal alignment and quicker, easier and more successful fibreoptic-guided ETT intubation than the Fastrach LMA.

Optimising tear replacement rheology in canine keratoconjunctivitis sicca.

Dry eye is a substantial problem in a large number of human and canine patients. Numerous laboratory models for tear deficiency exist using genetically predisposed rodent models, animals treated with topical anti-muscarinics, or those kept in environments with increased air flow to produce the ocular surface changes seen in human patients. Canine keratoconjunctivitis sicca, seen in many thousands of dogs kept as companion animals, can provide a valuable spontaneous model for testing tear replacement medications that might better model disease in human patients, existing as it does in an outbred population that live in the same environments as their owners. Here the development of a crosslinked hyaluronic acid topical drop is described together with the results of trials on dogs with spontaneous keratoconjunctivitis sicca. Although hyaluronic acid in its native form in tear replacement drops shows a Newtonian rheology, the crosslinked product described here behaves in a non-Newtonian manner, with the same shear thinning shown by the tear film itself. The crosslinked product thus shows itself as a potentially valuable tear replacement medication for the human dry eye population as well as for dogs with the same condition.

Regenerating reptile retinas: a comparative approach to restoring retinal ganglion cell function.

Transection or damage to the mammalian optic nerve generally results in loss of retinal ganglion cells by apoptosis. This cell death is seen less in fish or amphibians where retinal ganglion cell survival and axon regeneration leads to recovery of sight. Reptiles lie somewhere in the middle of this spectrum of nerve regeneration, and different species have been reported to have a significant variation in their retinal ganglion cell regenerative capacity. The ornate dragon lizard Ctenophoris ornatus exhibits a profound capacity for regeneration, whereas the Tenerife wall lizard Gallotia galloti has a more variable response to optic nerve damage. Some individuals regain visual activity such as the pupillomotor responses, whereas in others axons fail to regenerate sufficiently. Even in Ctenophoris, although the retinal ganglion cell axons regenerate adequately enough to synapse in the tectum, they do not make long-term topographic connections allowing recovery of complex visually motivated behaviour. The question then centres on where these intraspecies differences originate. Is it variation in the innate ability of retinal ganglion cells from different species to regenerate with functional validity? Or is it variances between different species in the substrate within which the nerves regenerate, the extracellular environment of the damaged nerve or the supporting cells surrounding the regenerating axons? Investigations of retinal ganglion cell regeneration between different species of lower vertebrates in vivo may shed light on these questions. Or perhaps more interesting are in vitro studies comparing axon regeneration of retinal ganglion cells from various species placed on differing substrates.

Student attitudes regarding the educational value and welfare implications in the use of model eyes and live dogs in teaching practical fundus examination: evaluation of responses from 40 students.

This study sought to document student opinions on the educational value and welfare implications of use of artificial model eyes and live dogs in the training of veterinary students in examination of the canine fundus. Forty students who had undertaken a practical class on canine fundoscopy involving both use of artificial model eyes and live dogs were asked to complete a short questionnaire using a Likert scale to gauge their opinion on whether the use of live dogs and artificial eyes was very valuable (scoring 2), valuable (1), a neutral response (0), not particularly valuable (-1) or not at all valuable (-2) and to write a free text response on their views of the educational value and welfare implications of using artificial model eyes or live dogs in training for ophthalmic examination of the canine ocular fundus. Likert responses were 1.84±0.37 for using live greyhounds and 0.58±0.79 for using simulator eyes (p<0.0001). Thematic analysis of the written responses showed that while the artificial eyes were considered somewhat valuable in initial training, the live dogs were significantly preferred for their realism and the opportunity to examine the eye while handling a live animal. In conclusion, while model eyes are valuable initial training in use of the ophthalmoscope for funduscopic examination, students consider that examining the eye in the live dog is significantly more valuable and that the welfare of dogs thus used is not in their view unduly compromised.

Light and the evolution of vision.

It might seem a little ridiculous to cover the period over which vision evolved, perhaps 1.5 billion years, in only 3000 words. Yet, if we examine the photoreceptor molecules of the most basic eukaryote protists and even before that, in those of prokaryote bacteria and cyanobacteria, we see how similar they are to those of mammalian rod and cone photoreceptor opsins and the photoreceptive molecules of light sensitive ganglion cells. This shows us much with regard the development of vision once these proteins existed, but there is much more to discover about the evolution of even more primitive vision systems.

Oral infestation with leech Limnatis nilotica in two mixed-breed dogs.

Leeches are bloodsucking hermaphroditic parasites that attach to tissues using two muscular suckers, ingest large amounts of blood and may cause severe anaemia in the host. Two four-month-old mixed-breed dogs (one bitch and one male) were referred with anorexia, retching, hypersalivation and bleeding from the oral cavity. On physical examination, two live leeches were detected on the ventral aspect of the tongue of the bitch and one in a similar position in the male. The leeches were gently detached and removed using Adson tissue forceps after applying vinegar over the area. Microcytic hypochromic anaemia was detected in the bitch and mild leukocytosis in the dog. One month after treatment both animals were re-examined and a complete blood count was normal. Given that infestation with leeches as described here is associated with contaminated water, the use of clean and safe drinking water is recommended to avoid such diseases.

Home interventions are effective at decreasing indoor nitrogen dioxide concentrations.

UNLABELLED: Nitrogen dioxide (NO2 ), a by-product of combustion produced by indoor gas appliances such as cooking stoves, is associated with respiratory symptoms in those with obstructive airways disease. We conducted a three-armed randomized trial to evaluate the efficacy of interventions aimed at reducing indoor NO2 concentrations in homes with unvented gas stoves: (i) replacement of existing gas stove with electric stove; (ii) installation of ventilation hood over existing gas stove; and (iii) placement of air purifiers with high-efficiency particulate air (HEPA) and carbon filters. Home inspection and NO2 monitoring were conducted at 1 week pre-intervention and at 1 week and 3 months post-intervention. Stove replacement resulted in a 51% and 42% decrease in median NO2 concentration at 3 months of follow-up in the kitchen and bedroom, respectively (P = 0.01, P = 0.01); air purifier placement resulted in an immediate decrease in median NO2 concentration in the kitchen (27%, P < 0.01) and bedroom (22%, P = 0.02), but at 3 months, a significant reduction was seen only in the kitchen (20%, P = 0.05). NO2 concentrations in the kitchen and bedroom did not significantly change following ventilation hood installation. Replacing unvented gas stoves with electric stoves or placement of air purifiers with HEPA and carbon filters can decrease indoor NO2 concentrations in urban homes. PRACTICAL IMPLICATIONS: Several combustion sources unique to the residential indoor environment, including gas stoves, produce nitrogen dioxide (NO2), and higher NO2 concentrations, are associated with worse respiratory morbidity in people with obstructive lung disease. A handful of studies have modified the indoor environment by replacing unvented gas heaters; this study, to our knowledge, is the first randomized study to target unvented gas stoves. The results of this study show that simple home interventions, including replacement of an unvented gas stove with an electric stove or placement of HEPA air purifiers with carbon filters, can significantly decrease indoor NO2 concentrations.

Oxadiazole 2-oxides are toxic to the human hookworm, Ancylostoma ceylanicum, however glutathione reductase is not the primary target.

Hookworm disease, characterized by severe anemia and cognitive and growth delays, currently affects an estimated 740 million people worldwide. Despite the prevalence of this parasitic disease, few effective drug therapies are in use today, and the heavy reliance upon benzimidazoles highlights the need for the development of novel chemotherapies. Recent work with the trematode parasite Schistosoma mansoni has identified oxadiazole 2-oxides as effective antischistosomal compounds that function by targeting and inhibiting the antioxidant enzyme, thioredoxin glutathione reductase. In this study, a related enzyme, glutathione reductase, from the human hookworm Ancylostoma ceylanicum was identified and characterized, and its in vitro activity in the presence of the oxadiazole 2-oxides was analyzed. Ex vivo worm killing assays were also conducted to establish the relationship between a given compound's effect upon worm survival and inhibition of recombinant glutathione reductase (rAceGR). Finally, the in vivo anthelminthic efficacy of furoxan (Fx) was assessed in the hamster model of hookworm infection. The predicted amino acid sequence of AceGR contained a prototypical glutathione reductase active site sequence, but no thioredoxin reductase consensus sequences, suggesting that the glutathione and thioredoxin pathways of A. ceylanicum are distinct. Although ten of the forty-two oxadiazole 2-oxides tested inhibited rAceGR activity by at least fifty percent, and fifteen compounds were toxic to parasites ex vivo, little overlap existed between these two results. We therefore suggest that AceGR is not the primary target of the oxadiazole 2-oxides in effecting parasite death. Lastly, oral treatment of A. ceylanicuminfected hamsters with furoxan resulted in significantly improved weight gains and reduced intestinal worm burdens compared to vehicle treated controls, supporting continued development of this molecule as a novel anthelminthic.

Randomized controlled trial comparing the McGrath videolaryngoscope with the C-MAC videolaryngoscope in intubating adult patients with potential difficult airways.

BACKGROUND: Difficult and failed intubations, although rarely encountered, are major causes of morbidity and mortality in the current anaesthetic practice. To reduce the incidence of difficult and failed intubations, several devices including the recently developed videolaryngoscopes are available. This randomized controlled study aims to compare the use of the McGrath videolaryngoscope with the C-MAC videolaryngoscope in adult patients with potential difficult airways. METHODS: A total of 130 patients with the Mallampati grade of ≥3, requiring orotracheal intubation, were randomized to either having intubation with the McGrath videolaryngoscope or the C-MAC videolaryngoscope. The primary outcome was time to intubation. The laryngoscopic view, the number of intubation attempts, the proportion of intubation success, the ease of intubation, the haemodynamic responses to intubation, and the incidence of any complications were also recorded. RESULTS: Time to successful intubation with the C-MAC videolaryngoscope was shorter when compared with the McGrath videolaryngoscope {50 s [inter-quartile range (IQR) 38-70] vs 67 s (IQR 49-108), P<0.001}, despite the McGrath videolaryngoscope providing significantly more grade 1 laryngoscopic views. The C-MAC videolaryngoscope also resulted in significantly fewer intubation attempts and greater ease of intubation when compared with the McGrath videolaryngoscope. There were no statistically significant differences in the proportion of intubation success, the number of complications, and the changes in haemodynamic responses between the two videolaryngoscopes. CONCLUSIONS: The C-MAC videolaryngoscope allowed a quicker intubation time, fewer intubation attempts, and greater ease of intubation compared with the McGrath videolaryngoscope when used in patients with the Mallampati grade of ≥3.

Development of a broad spectrum polymer-released antimicrobial coating for the prevention of resistant strain bacterial infections.

More than 400,000 primary hip and knee replacement surgeries are performed each year in the United States. From these procedures, approximately 0.5-3% will become infected and when considering revision surgeries, this rate has been found to increase significantly. Antibiotic-resistant bacterial infections are a growing problem in patient care. This in vitro research investigated the antimicrobial potential of the polymer released, broad spectrum, Cationic Steroidal Antimicrobial-13 (CSA-13) for challenges against 5 × 10(8) colony forming units (CFU) of methicillin-resistant Staphylococcus aureus (MRSA). It was hypothesized that a weight-to-weight (w/w) concentration of 18% CSA-13 in silicone would exhibit potent bactericidal potential when used as a controlled release device coating. When incorporated into a polymeric device coating, the 18% (w/w) broad-spectrum polymer released CSA-13 antimicrobial eliminated 5 × 10(8) CFU of MRSA within 8 h. In the future, these results will be utilized to develop a sheep model to assess CSA-13 for the prevention of perioperative device-related infections in vivo.

The impact of pre-operative focused transthoracic echocardiography in emergency non-cardiac surgery patients with known or risk of cardiac disease.

This prospective observational study investigated the effect of focused transthoracic echocardiography in 99 patients who had suspected cardiac disease or were ≥ 65 years old, and were scheduled for emergency non-cardiac surgery. The treating anaesthetist completed a diagnosis and management plan before and after transthoracic echocardiography, which was performed by an independent operator. Clinical examination rated cardiac disease present in 75%; the remainder were asymptomatic. The cardiac diagnosis was changed in 67% and the management plan in 44% of patients after echocardiography. Cardiac disease was identified by echocardiography in 64% of patients, which led to a step-up of treatment in 36% (4% delay for cardiology referral, 2% altered surgery, 4% intensive care and 26% intra-operative haemodynamic management changes). Absence of cardiac disease in 36% resulted in a step-down of treatment in 8% (no referral 3%, intensive care 1% or haemodynamic treatment 4%). Pre-operative focused transthoracic echocardiography in patients admitted for emergency surgery and with known cardiac disease or suspected to be at risk of cardiac disease frequently alters diagnosis and management.

Cardiac output and propofol concentrations in prone surgical patients.

The aim of this study was to compare cardiac output and plasma propofol concentrations in the supine and prone positions in healthy adult patients presenting for lumbar spine surgery. Patients received propofol and remifentanil via effect-site steered target-controlled infusions. Cardiac output and plasma propofol concentration were compared during 20 minutes in the supine position and 20 minutes after positioning on a Wilson frame. Cardiac output did not change significantly over 20 minutes in either position (P = 0.37) and was similar at 20 minutes in the supine (6.1 [1.6] l/minute) and prone positions (6.1 [1.9] l/minute) (P = 0.87). Propofol concentrations were similar in the supine and prone positions at 20 minutes (2.55 [0.89] and 2.53 [0.90] microg/ml; P = 0.93). We conclude that prone positioning on the Wilson frame does not affect cardiac output or plasma propofol concentration.

Effect of intravenous parecoxib on post-craniotomy pain.

BACKGROUND: Pain management in craniotomy patients is challenging, with mild-to-moderate pain intensity, moderate-to-high risk of postoperative nausea and vomiting (PONV), and potentially catastrophic consequences of analgesic-related side-effects. The aim of this study was to determine whether i.v. parecoxib administered at dural closure during craniotomy decreased total morphine consumption and morphine-related side-effects compared with placebo. METHODS: One hundred adult patients presenting for supratentorial craniotomy under propofol/remifentanil anaesthesia were randomized to receive parecoxib, 40 mg i.v., or placebo in a double-blind manner. All patients received local anaesthetic scalp infiltration, regular i.v. paracetamol, nurse-administered morphine in the post-anaesthesia care unit (PACU) until verbal analogue pain scores were ≤4/10 and patient-controlled morphine thereafter. Morphine consumption, pain intensity, and analgesia-related side-effects were recorded during the first 24 h after operation. RESULTS: Ninety-six patients (49 control and 47 parecoxib) were included in the analyses. Fifty-nine (61%) patients received morphine in the PACU and only one patient (control) did not receive any morphine in the postoperative period. There were no significant differences between the two groups in morphine consumption [20 (range: 0-102) vs 16 (range: 1-92) mg; P=0.38], pain intensity [excellent/very good pain relief in 78% of parecoxib patients; 74% of control patients (P=0.72)] or analgesia-related side-effects (PONV in 51% of parecoxib patients; 56% of control patients; P=0.55) in the first 24 h after operation. No major morbidity was recorded. CONCLUSIONS: Our study demonstrated no clinical benefit to adding i.v. parecoxib to local anaesthetic scalp infiltration, i.v. paracetamol, and patient-controlled i.v. morphine after supratentorial craniotomy.

Predictors of airborne endotoxin concentrations in inner city homes.

Few studies have assessed in home factors which contribute to airborne endotoxin concentrations. In 85 inner city Baltimore homes, we found no significant correlation between settled dust and airborne endotoxin concentrations. Certain household activities and characteristics, including frequency of dusting, air conditioner use and type of flooring, explained 36-42% of the variability of airborne concentrations. Measurements of both airborne and settled dust endotoxin concentrations may be needed to fully characterize domestic exposure in epidemiologic investigations.

Periodic magnetic field as a polarized and focusing thermal neutron spectrometer and monochromator.

A novel periodic magnetic field (PMF) optic is shown to act as a prism, lens, and polarizer for neutrons and particles with a magnetic dipole moment. The PMF has a two-dimensional field in the axial direction of neutron propagation. The PMF alternating magnetic field polarity provides strong gradients that cause separation of neutrons by wavelength axially and by spin state transversely. The spin-up neutrons exit the PMF with their magnetic spins aligned parallel to the PMF magnetic field, and are deflected upward and line focus at a fixed vertical height, proportional to the PMF period, at a downstream focal distance that increases with neutron energy. The PMF has no attenuation by absorption or scatter, as with material prisms or crystal monochromators. Embodiments of the PMF include neutron spectrometer or monochromator, and applications include neutron small angle scattering, crystallography, residual stress analysis, cross section measurements, and reflectometry. Presented are theory, experimental results, computer simulation, applications of the PMF, and comparison of its performance to Stern-Gerlach gradient devices and compound material and magnetic refractive prisms.

Overexpression of vascular endothelial growth factor 165 (VEGF165) protects cardiomyocytes against doxorubicin-induced apoptosis.

Doxorubicin (Dox) has been employed in cancer chemotherapy for a few decades. However its clinical application became restricted because of dose-dependent cardiomyopathy. Recent studies suggest that Dox-induced cardiomyocyte apoptosis is a primary cause of cardiac damage. Vascular endothelial growth factor (VEGF) is a major factor for endothelial cell survival and angiogenesis. We have previously shown that VEGF165 significantly attenuates oxidative stress-induced cardiomyocytes apoptosis. We hypothesized that VEGF165 will protect the cardiomyocytes from Dox-induced apoptosis. to evaluate our hypothesis, we transfected cardiomyocytes H9c2 with adenovirus expressing VEGF165 24 hours before the cells were challenged with Dox at a concentration of 2 µm. Cardiomyocyte apoptosis was evaluated by Annexin V-FITC staining and by Western blot detection of cleaved caspase-3. The hypothesis was confirmed, and the protective mechanisms involve the inhibition of death receptor-mediated apoptosis and up-regulation of the prosurvival Akt/Nf-κb/bcl-2 signaling pathway.