The effect of high-flow nasal oxygen flow rate on gas exchange in apnoeic patients: a randomised controlled trial.

High-flow nasal oxygen can be administered at induction of anaesthesia for the purposes of pre-oxygenation and apnoeic oxygenation. This intervention is claimed to enhance carbon dioxide elimination during apnoea, but the extent to which this occurs remains poorly quantified. The optimal nasal oxygen flow rate for gas exchange is also unknown. In this study, 114 patients received pre-oxygenation with high-flow nasal oxygen at 50 l.min-1. At the onset of apnoea, patients were allocated randomly to receive one of three nasal oxygen flow rates: 0 l.min-1; 70 l.min-1; or 120 l.min-1. After 4 minutes of apnoea, all oxygen delivery was ceased, tracheal intubation was performed, and oxygen delivery was recommenced when SpO2 was 92%. Mean (SD) PaCO2 rise during the first minute of apnoea was 1.39 (0.39) kPa, 1.41 (0.29) kPa, and 1.26 (0.38) kPa in the 0 l.min-1, 70 l.min-1 and 120 l.min-1 groups, respectively; p = 0.16. During the second, third and fourth minutes of apnoea, mean (SD) rates of rise in PaCO2 were 0.34 (0.08) kPa.min-1, 0.36 (0.06) kPa.min-1 and 0.37 (0.07) kPa.min-1 in the 0 l.min-1, 70 l.min-1 and 120 l.min-1 groups, respectively; p = 0.17. After 4 minutes of apnoea, median (IQR [range]) arterial oxygen partial pressures in the 0 l.min-1, 70 l.min-1 and 120 l.min-1 groups were 24.5 (18.6-31.4 [12.3-48.3]) kPa; 36.6 (28.1-43.8 [9.8-56.9]) kPa; and 37.6 (26.5-45.4 [11.0-56.6]) kPa, respectively; p < 0.001. Median (IQR [range]) times to desaturate to 92% after the onset of apnoea in the 0 l.min-1, 70 l.min-1 and 120 l.min-1 groups, were 412 (347-509 [190-796]) s; 533 (467-641 [192-958]) s; and 531 (462-681 [326-1007]) s, respectively; p < 0.001. In conclusion, the rate of carbon dioxide accumulation in arterial blood did not differ significantly between apnoeic patients who received high-flow nasal oxygen and those who did not.

Pre-oxygenation with facemask oxygen vs high-flow nasal oxygen vs high-flow nasal oxygen plus mouthpiece: a randomised controlled trial.

High-flow nasal oxygen used before and during apnoea prolongs time to desaturation at induction of anaesthesia. It is unclear how much oxygenation before apnoea prolongs this time. We randomly allocated 84 participants to 3 minutes of pre-oxygenation by one of three methods: 15 l.min-1 by facemask; 50 l.min-1 by high-flow nasal cannulae only; or 50 l.min-1 by high-flow nasal cannulae plus 15 l.min-1 by mouthpiece. We then anaesthetised and intubated the trachea of 79 participants and waited for oxygen saturation to fall to 92%. Median (IQR [range]) times to desaturate to 92% after pre-oxygenation with facemask oxygen, high-flow nasal oxygen only and high-flow nasal oxygen with mouthpiece, were: 309 (208-417 [107-544]) s; 344 (250-393 [194-585]) s; and 386 (328-498 [182-852]) s, respectively, p = 0.014. Time to desaturation after facemask pre-oxygenation was shorter than after combined nasal and mouthpiece pre-oxygenation, p = 0.006. We could not statistically distinguish high-flow nasal oxygen without mouthpiece from the other two groups for this outcome. Median (IQR [range]) arterial oxygen partial pressure after 3 minutes of pre-oxygenation by facemask, nasal cannulae and nasal cannulae plus mouthpiece, was: 49 (36-61 [24-66]) kPa; 57 (48-62 [30-69]) kPa; and 61 (55-64 [36-72]) kPa, respectively, p = 0.003. Oxygen partial pressure after 3 minutes of pre-oxygenation with nasal and mouthpiece combination was greater than after facemask pre-oxygenation, p = 0.002, and after high-flow nasal oxygen alone, p = 0.016. We did not reject the null hypothesis for the pairwise comparison of facemask pre-oxygenation and high-flow nasal pre-oxygenation, p = 0.14.

Radium-223 in the Treatment of Metastatic Castrate-Resistant Prostate Cancer.

Background Radium 223 (Ra-223) has been successfully utilised for the treatment of men with metastatic castrate resistant prostate cancer (mCRPC). To date, no real world outcomes from its use in the Irish population have been described. Methods All men referred to our institution for Ra-223 from September 2016 to March 2019 were included. Patient demographics, treatments received, toxicities and outcomes were recorded. Overall survival (OS) and progression free survival (PFS) were analysed using the Kaplan-Meier method. Results Complete data was available for 54 men. Median age was 75 years (range 61-86 years). The median number of prior systemic treatments for mCRPC was 2 (range 0-4). Median ECOG performance status was 1 at the start of treatment and 2 at completion. The median number of Ra-223 cycles received was 4 with 37%(n=20) completing all 6 planned cycles. The most common treatment-related toxicity was fatigue seen in 52% of patients ( n=28). Improved pain scores were documented in 76% of men requiring opioid analgesia at the start of treatment. The median OS was 7 months. A good ECOG performance status, fewer than 6 bone metastases, normal alkaline phosphatase level at start of treatment and chemotherapy naivety were associated with improved OS. Conclusions Ra-223 is a moderately well tolerated palliative treatment amongst Irish men with mCRPC.

Apnoeic oxygenation in paediatric anaesthesia: a narrative review.

Apnoeic oxygenation refers to oxygenation in the absence of any patient or ventilator effort to move the lungs. This phenomenon was first described in humans in the mid-20th century but has seen renewed interest in the last decade following the demonstration of apnoeic oxygenation with low-flow, and subsequently high-flow, nasal oxygen. This narrative review summarises our understanding of apnoeic oxygenation in the paediatric population. We examine the evidence supporting oxygenation via tracheal tube, modified laryngoscopes and nasal cannulae. The evidence for prolongation of safe apnoea time at induction of anaesthesia is also appraised. We explore the capacity for carbon dioxide clearance, flow rate selection with high-flow nasal oxygen and complications associated with the technique. It remains uncertain whether apnoeic oxygenation in paediatric patients results in a meaningful clinical benefit compared with standard care for outcomes such as the number of tracheal intubation attempts or the incidence of hypoxaemia. In particular, the role of apnoeic oxygenation in paediatric difficult airway management is unclear as this has not been the targeted focus of any published research to date.

Uses and mechanisms of apnoeic oxygenation: a narrative review.

Apnoeic oxygenation refers to oxygenation in the absence of spontaneous respiration or mechanical ventilation. It has been described in humans for over half a century and has seen a resurgence in interest given its potential to delay oxygen desaturation during airway management, especially with the advent of high-flow nasal cannulae. This narrative review summarises our current understanding of the mechanisms of gas exchange during apnoeic oxygenation and its diverse range of clinical applications, including its use at induction of anaesthesia and for the facilitation of 'tubeless anaesthesia'. Additional discussion covers use in critical care, obese, obstetric and paediatric sub-populations. The article also highlights current research efforts aiming to enhance the evidence base for the use of this technique.

The ophthalmic diagnosis and management of four siblings with Werner syndrome.

INTRODUCTION: Werner syndrome is a rare autosomal recessive disorder caused by mutations in the Werner syndrome WRN gene, on chromosome 8. Those affected manifest early the features of ageing. DISCUSSION: Cataract surgery is prone to post-operative complications in those with Werner syndrome. The development of cystoid macular oedema (CMO) is likely multifactorial. Patients with WS have diabetes mellitus type 2 which can contribute to macular oedema. There is a deposition of abnormal WRN proteins in the macula which also predisposes to macular oedema. The trauma of cataract surgery appears to be the main stimulus for the development of CMO. CMO may, as a result, be difficult to manage in Werner syndrome patients. CONCLUSION: Further study is needed to elucidate the precise role of retinal WRN protein expression in the development of CMO in those with Werner syndrome. A tailored and more successful approach to the treatment of CMO in such patients may result.

Validation of a Metastatic Assay using biopsies to improve risk stratification in patients with prostate cancer treated with radical radiation therapy.

Background: Radiotherapy is an effective treatment of intermediate/high-risk locally advanced prostate cancer, however, >30% of patients relapse within 5 years. Clinicopathological parameters currently fail to identify patients prone to systemic relapse and those whom treatment intensification may be beneficial. The purpose of this study was to independently validate the performance of a 70-gene Metastatic Assay in a cohort of diagnostic biopsies from patients treated with radical radiotherapy and androgen deprivation therapy. Patients and methods: A bridging cohort of prostate cancer diagnostic biopsy specimens was profiled to enable optimization of the Metastatic Assay threshold before further independent clinical validation in a cohort of diagnostic biopsies from patients treated with radical radiotherapy and androgen deprivation therapy. Multivariable Cox proportional hazard regression analysis was used to assess assay performance in predicting biochemical failure-free survival (BFFS) and metastasis-free survival (MFS). Results: Gene expression analysis was carried out in 248 patients from the independent validation cohort and the Metastatic Assay applied. Ten-year MFS was 72% for Metastatic Assay positive patients and 94% for Metastatic Assay negative patients [HR = 3.21 (1.35-7.67); P = 0.003]. On multivariable analysis the Metastatic Assay remained predictive for development of distant metastases [HR = 2.71 (1.11-6.63); P = 0.030]. The assay retained independent prognostic performance for MFS when assessed with the Cancer of the Prostate Assessment Score (CAPRA) [HR = 3.23 (1.22-8.59); P = 0.019] whilst CAPRA itself was not significant [HR = 1.88, (0.52-6.77); P = 0.332]. A high concordance [100% (61.5-100)] for the assay result was noted between two separate foci taken from 11 tumours, whilst Gleason score had low concordance. Conclusions: The Metastatic Assay demonstrated significant prognostic performance in patients treated with radical radiotherapy both alone and independent of standard clinical and pathological variables. The Metastatic Assay could have clinical utility when deciding upon treatment intensification in high-risk patients. Genomic and clinical data are available as a public resource.

Apnoeic oxygenation with high-flow nasal oxygen for laryngeal surgery: a case series.

Surgery under apnoeic conditions with the use of high-flow nasal oxygen is novel. Between November 2016 and May 2017, 28 patients underwent tubeless laryngeal or tracheal surgery under apnoeic conditions with high-flow nasal oxygen as the sole method of gas exchange. Patients received total intravenous anaesthesia and neuromuscular blocking agents for the duration of their surgery. The median (IQR [range]) apnoea time was 19 (15-24 [9-37]) min. Four patients experienced an episode of oxygen desaturation to a value between 85% and 90%, lasting less than 2 min in each case. Median (IQR [range]) end-tidal carbon dioxide (ETCO2 ) level following apnoea was 8.2 (7.2-9.4 [5.8-11.8]) kPa. The mean (SD) rate of ETCO2 increase was 0.17 (0.07) kPa.min-1 from an approximated baseline value of 5.00 kPa. Venous blood sampling from 19 patients demonstrated a mean (SD) partial pressure of carbon dioxide (PV CO2 ) of 6.29 (0.71) kPa at baseline and 9.44 (1.12) kPa after 15 min of apnoea. This equates to a mean (SD) PV CO2 rise of 0.21 (0.08) kPa.min-1 during this period. Mean (SD) pH was 7.40 (0.03) at baseline and 7.23 (0.04) after 15 min of apnoea. Mean (SD) standard bicarbonate was 26.7 (1.8) mmol.l-1 at baseline and 25.4 (1.8) mmol.l-1 at 15 min. We conclude that high-flow nasal oxygen under apnoeic conditions can provide satisfactory gas exchange in order to allow tubeless anaesthesia for laryngeal surgery.

I Still Haven't Found What I'm Looking For... Bono, Google and Glaucoma Awareness.

The effect of celebrity diagnosis on public awareness of health conditions has already been well documented. In October 2014, Bono, the lead singer with U2, revealed publicly for the first time that he has glaucoma. This study aimed to analyze the impact of Bono's announcement on public awareness of glaucoma using Google Search trends as an indicator of public interest in the disease. Google Trends was used to examine Google Search activity for the term 'Glaucoma' between 2009 and 2015 in both Ireland and the United Kingdom. Trend analyses were performed using Microsoft Excel Version 14.3.5. Increased Google Search activity for 'Glaucoma' in October 2014 was found in both Ireland and the United Kingdom. A five-fold increase from the mean Google Search activity for this term was found in Ireland and a two-fold increase from the mean Google Search activity for this term was found in the United Kingdom. No such increase in Google Search activity occurred during each country's 2014 Glaucoma Awareness week. Google Trends is useful in medical research as a means of assessing public awareness of, and/or interest in, health related topics. Current approaches to glaucoma related health promotion in both Ireland and the United Kingdom have failed to yield an increase in on-line Google Search activity. While there was an increase in interest in glaucoma it is unclear whether this led to an increase in health seeking behaviour.

Live attenuated Francisella novicida vaccine protects against Francisella tularensis pulmonary challenge in rats and non-human primates.

Francisella tularensis causes the disease tularemia. Human pulmonary exposure to the most virulent form, F. tularensis subsp. tularensis (Ftt), leads to high morbidity and mortality, resulting in this bacterium being classified as a potential biothreat agent. However, a closely-related species, F. novicida, is avirulent in healthy humans. No tularemia vaccine is currently approved for human use. We demonstrate that a single dose vaccine of a live attenuated F. novicida strain (Fn iglD) protects against subsequent pulmonary challenge with Ftt using two different animal models, Fischer 344 rats and cynomolgus macaques (NHP). The Fn iglD vaccine showed protective efficacy in rats, as did a Ftt iglD vaccine, suggesting no disadvantage to utilizing the low human virulent Francisella species to induce protective immunity. Comparison of specific antibody profiles in vaccinated rat and NHP sera by proteome array identified a core set of immunodominant antigens in vaccinated animals. This is the first report of a defined live attenuated vaccine that demonstrates efficacy against pulmonary tularemia in a NHP, and indicates that the low human virulence F. novicida functions as an effective tularemia vaccine platform.

Amino Acid Specific Stable Nitrogen Isotope Values in Avian Tissues: Insights from Captive American Kestrels and Wild Herring Gulls.

Through laboratory and field studies, the utility of amino acid compound-specific nitrogen isotope analysis (AA-CSIA) in avian studies is investigated. Captive American kestrels (Falco sparverius) were fed an isotopically characterized diet and patterns in δ15N values of amino acids (AAs) were compared to those in their tissues (muscle and red blood cells) and food. Based upon nitrogen isotope discrimination between diet and kestrel tissues, AAs could mostly be categorized as source AAs (retaining baseline δ15N values) and trophic AAs (showing 15N enrichment). Trophic discrimination factors based upon the source (phenylalanine, Phe) and trophic (glutamic acid, Glu) AAs were 4.1 (muscle) and 5.4 (red blood cells), lower than those reported for metazoan invertebrates. In a field study involving omnivorous herring gulls (Larus argentatus smithsonianus), egg AA isotopic patterns largely retained those observed in the laying female's tissues (muscle, red blood cells, and liver). Realistic estimates of gull trophic position were obtained using bird Glu and Phe δ15N values combined with ß values (difference in Glu and Phe δ15N in primary producers) for aquatic and terrestrial food webs. Egg fatty acids were used to weight ß values for proportions of aquatic and terrestrial food in gull diets. This novel approach can be applied to generalist species that feed across ecosystem boundaries.

The Influence of Insecticide Resistance, Age, Sex, and Blood Feeding Frequency on Thermal Tolerance of Wild and Laboratory Phenotypes of Anopheles funestus (Diptera: Culicidae).

Resistance to insecticides is a global phenomenon and is increasing at an unprecedented rate. How resistant and susceptible strains of malaria vectors might differ in terms of life history and basic biology is often overlooked, despite the potential importance of such information in light of changing climates. Here, we investigated the upper thermal limits (ULT50) of wild and laboratory strains of Anopheles funestus Giles mosquitoes, including resistance status, sex, age, and blood feeding status as potential factors influencing ULT50. No significant differences in ULT50 were observed between strains displaying different resistance patterns, nor was there a significant difference between wild and laboratory strains. In some instances, strains showed a senescence response, displaying decreased ULT50 with an increase in age, and differences between males and females (females displaying higher ULT50 than males). Blood feeding did not seem to influence ULT50 in any way. For An. funestus, it seems evident that there is no cost to resistance despite what is displayed in other anopheline species. This could have significant impacts for vector control, with resistant populations of An. funestus performing just as well, if not better, than susceptible strains, especially under changing environmental conditions such as those expected to occur with climate change.

Bacillus anthracis Overcomes an Amino Acid Auxotrophy by Cleaving Host Serum Proteins.

UNLABELLED: Bacteria sustain an infection by acquiring nutrients from the host to support replication. The host sequesters these nutrients as a growth-restricting strategy, a concept termed "nutritional immunity." Historically, the study of nutritional immunity has centered on iron uptake because many bacteria target hemoglobin, an abundant circulating protein, as an iron source. Left unresolved are the mechanisms that bacteria use to attain other nutrients from host sources, including amino acids. We employed a novel medium designed to mimic the chemical composition of human serum, and we show here that Bacillus anthracis, the causative agent of anthrax disease, proteolyzes human hemoglobin to liberate essential amino acids which enhance its growth. This property can be traced to the actions of InhA1, a secreted metalloprotease, and extends to at least three other serum proteins, including serum albumin. The results suggest that we must also consider proteolysis of key host proteins to be a way for bacterial pathogens to attain essential nutrients, and we provide an experimental framework to determine the host and bacterial factors involved in this process. IMPORTANCE: The mechanisms by which bacterial pathogens acquire nutrients during infection are poorly understood. Here we used a novel defined medium that approximates the chemical composition of human blood serum, blood serum mimic (BSM), to better model the nutritional environment that pathogens encounter during bacteremia. Removing essential amino acids from BSM revealed that two of the most abundant proteins in blood-hemoglobin and serum albumin-can satiate the amino acid requirement for Bacillus anthracis, the causative agent of anthrax. We further demonstrate that hemoglobin is proteolyzed by the secreted protease InhA1. These studies highlight that common blood proteins can be a nutrient source for bacteria. They also challenge the historical view that hemoglobin is solely an iron source for bacterial pathogens.

IgG subclass and heavy chain domains contribute to binding and protection by mAbs to the poly γ-D-glutamic acid capsular antigen of Bacillus anthracis.

Bacterial capsules are common targets for antibody-mediated immunity. The capsule of Bacillus anthracis is unusual among capsules because it is composed of a polymer of poly-γ-d-glutamic acid (γdPGA). We previously generated murine IgG3 monoclonal antibodies (mAbs) to γdPGA that were protective in a murine model of pulmonary anthrax. IgG3 antibodies are characteristic of the murine response to polysaccharide antigens. The goal of the present study was to produce subclass switch variants of the γdPGA mAbs (IgG3 → IgG1 → IgG2b → IgG2a) and assess the contribution of subclass to antibody affinity and protection. Subclass switch antibodies had identical variable regions but differed in their heavy chains. The results showed that a switch from the protective IgG3 to IgG1, IgG2b or IgG2a was accompanied by i) a loss of protective activity ii) a change in mAb binding to the capsular matrix, and iii) a loss of affinity. These results identify a role for the heavy chain constant region in mAb binding. Hybrid mAbs were constructed in which the CH1, CH2 or CH3 heavy chain constant domains from a non-protective, low binding IgG2b mAb were swapped into the protective IgG3 mAb. The IgG3 mAb that contained the CH1 domain from IgG2b showed no loss of affinity or protection. In contrast, swapping the CH2 or CH3 domains from IgG2b into IgG3 produced a reduction in affinity and a loss of protection. These studies identify a role for the constant region of IgG heavy chains in affinity and protection against an encapsulated bacterial pathogen.

Lethal factor, but not edema factor, is required to cause fatal anthrax in cynomolgus macaques after pulmonary spore challenge.

Inhalational anthrax is caused by inhalation of Bacillus anthracis spores. The ability of B. anthracis to cause anthrax is attributed to the plasmid-encoded A/B-type toxins, edema toxin (edema factor and protective antigen) and lethal toxin (lethal factor and protective antigen), and a poly-d-glutamic acid capsule. To better understand the contribution of these toxins to the disease pathophysiology in vivo, we used B. anthracis Ames strain and isogenic toxin deletion mutants derived from the Ames strain to examine the role of lethal toxin and edema toxin after pulmonary spore challenge of cynomolgus macaques. Lethal toxin, but not edema toxin, was required to induce sustained bacteremia and death after pulmonary challenge with spores delivered via bronchoscopy. After intravenous challenge with bacilli to model the systemic phase of infection, lethal toxin contributed to bacterial proliferation and subsequent host death to a greater extent than edema toxin. Deletion of protective antigen resulted in greater loss of virulence after intravenous challenge with bacilli than deletion of lethal toxin or edema toxin alone. These findings are consistent with the ability of anti-protective antigen antibodies to prevent anthrax and suggest that lethal factor is the dominant toxin that contributes to the escape of significant numbers of bacilli from the thoracic cavity to cause anthrax after inhalation challenge with spores.