Factors affecting turnaround time of SARS-CoV-2 sequencing for inpatient infection prevention and control decision making: analysis of data from the COG-UK HOCI study.

BACKGROUND: Barriers to rapid return of sequencing results can affect the utility of sequence data for infection prevention and control decisions. AIM: To undertake a mixed-methods analysis to identify challenges that sites faced in achieving a rapid turnaround time (TAT) in the COVID-19 Genomics UK Hospital-Onset COVID-19 Infection (COG-UK HOCI) study. METHODS: For the quantitative analysis, timepoints relating to different stages of the sequencing process were extracted from both the COG-UK HOCI study dataset and surveys of study sites. Qualitative data relating to the barriers and facilitators to achieving rapid TATs were included from thematic analysis. FINDINGS: The overall TAT, from sample collection to receipt of sequence report by infection control teams, varied between sites (median 5.1 days, range 3.0-29.0 days). Most variation was seen between reporting of a positive COVID-19 polymerase chain reaction (PCR) result to sequence report generation (median 4.0 days, range 2.3-27.0 days). On deeper analysis, most of this variability was accounted for by differences in the delay between the COVID-19 PCR result and arrival of the sample at the sequencing laboratory (median 20.8 h, range 16.0-88.7 h). Qualitative analyses suggest that closer proximity of sequencing laboratories to diagnostic laboratories, increased staff flexibility and regular transport times facilitated a shorter TAT. CONCLUSION: Integration of pathogen sequencing into diagnostic laboratories may help to improve sequencing TAT to allow sequence data to be of tangible value to infection control practice. Adding a quality control step upstream to increase capacity further down the workflow may also optimize TAT if lower quality samples are removed at an earlier stage.

Interdisciplinary working in public health research: a proposed good practice checklist.

Background: Guidance on how different disciplines from the natural, behavioural and social sciences can collaborate to resolve complex public health problems is lacking. This article presents a checklist to support researchers and principle investigators to develop and implement interdisciplinary collaborations. Methods: Fourteen individuals, representing 10 disciplines, participated in in-depth interviews to explore the strengths and challenges of working together on an interdisciplinary project to identify the determinants of substance use and gambling disorders, and to make recommendations for future interdisciplinary teams. Data were analysed thematically and a checklist was derived from insights offered by participants during interview and discussion among the authors on the implications of findings. Results: Participants identified 18 scientific, interactional and structural strengths and challenges of interdisciplinary research. These findings were used to develop an 18-item BASICS checklist to support future interdisciplinary collaborations. The five domains of the checklist are: (i) Blueprint, (ii) Attitudes, (iii) Staffing, (iv) Interactions and (v) Core Science. Conclusion: Interdisciplinary work has the potential to advance public health science but the numerous challenges should not be underestimated. Use of a checklist, such as BASICS, when planning and managing projects may help future collaborations to avoid some of the common pitfalls of interdisciplinary research.

Patient-driven hand hygiene audit process at a regional cancer center.

A patient-driven hand hygiene compliance audit strategy was piloted in a Canadian provincial cancer agency during routine provision of cancer outpatient care by health care providers (physicians, nurses, and health care aides) under conditions where the deployment of an independent external auditor was not feasible. The results of the audit suggest the feasibility of this approach as a routine institutional performance metric.

The Epidemiology of Staphylococcus aureus and Panton-Valentine Leucocidin (pvl) in Central Australia, 2006-2010.

BACKGROUND: The Central Australian Indigenous population has a high incidence of Staphylococcus aureus bacteremia (SAB) but little is known about the local molecular epidemiology. METHODS: Prospective observational study of bacteremic and nasal colonizing S.aureus isolates between June 2006 to June 2010. All isolates underwent single nucleotide polymorphism (SNP) genotyping and testing for the presence of the Panton-Valentine Leucocidin (pvl) gene. RESULTS: Invasive isolates (n = 97) were predominantly ST93 (26.6 %) and pvl positive (54.3 %), which was associated with skin and soft tissue infections (OR 4.35, 95 % CI 1.16, 16.31). Non-multiresistant MRSA accounted for 31.9 % of bacteremic samples and showed a trend to being healthcare associated (OR 2.16, 95 % CI 0.86, 5.40). Non-invasive isolates (n = 54) were rarely ST93 (1.9 %) or pvl positive (7.4 %). CONCLUSIONS: In Central Australia, ST93 was the dominant S.aureus clone, and was frequently pvl positive and associated with an aggressive clinical phenotype. Whether non-nasal carriage is more important with invasive clones or whether colonization occurs only transiently remains to be elucidated.

An 'omics' approach towards the characterisation of laboratory scale anaerobic digesters treating municipal sewage sludge.

In this study, laboratory scale digesters were operated to simulate potential shocks to the Anaerobic Digestion (AD) process at a 350 ML/day wastewater treatment plant. The shocks included high (42 °C) and low (32 °C) temperature (either side of mesophilic 37 °C) and a 20% loading of fats, oil and grease (FOG; 20% w:v). These variables were explored at two sludge retention times (12 and 20 days) and two organic loading rates (2.0 and 2.5 kgTS/m(3)day OLR). Metagenomic and metabolomic approaches were then used to characterise the impact of operational shocks in regard to temperature and FOG addition, as determined through monitoring of biogas production, the microbial profile and their metabolism. Results showed that AD performance was not greatly affected by temperature shocks, with the biggest impact being a reduction in biogas production at 42 °C that persisted for 32 ± 1 days. The average biogas production across all digesters at the completion of the experiment was 264.1 ± 76.5 mL/day, with FOG addition observed to significantly promote biogas production (+87.8 mL/day). Metagenomic and metabolomic analyses of the digesters indicated that methanogens and methane oxidising bacteria (MOB) were low in relative abundance, and that the ratio of oxidising bacteria (methane, sulphide and sulphate) with respect to sulphate reducing bacteria (SRB) had a noticeable influence on biogas production. Furthermore, increased biogas production correlated with an increase in short chain fatty acids, a product of the addition of 20% FOG. This work demonstrates the application of metagenomics and metabolomics to characterise the microbiota and their metabolism in AD digesters, providing insight to the resilience of crucial microbial populations when exposed to operational shocks.

Adjacent Fe-Vacancy Interactions as the Origin of Room Temperature Ferromagnetism in (In(1-x)Fe(x))2O3.

Dilute magnetic semiconductors (DMSs) show great promise for applications in spin-based electronics, but in most cases continue to elude explanations of their magnetic behavior. Here, we combine quantitative x-ray spectroscopy and Anderson impurity model calculations to study ferromagnetic Fe-substituted In2O3 films, and we identify a subset of Fe atoms adjacent to oxygen vacancies in the crystal lattice which are responsible for the observed room temperature ferromagnetism. Using resonant inelastic x-ray scattering, we map out the near gap electronic structure and provide further support for this conclusion. Serving as a concrete verification of recent theoretical results and indirect experimental evidence, these results solidify the role of impurity-vacancy coupling in oxide-based DMSs.

Reversal of opioid-induced respiratory depression by BK-channel blocker GAL021: A pharmacokinetic-pharmacodynamic modeling study in healthy volunteers.

Opioid-induced respiratory depression (OIRD) is a serious and potentially life-threatening complication of opioid overdose, abuse, and misuse. An option to avert OIRD is to treat patients on strong opioids with respiratory stimulants that do not interact with the opioid system and consequently do not compromise opioid analgesic efficacy. The BK-channel blocker GAL021 is a respiratory stimulant acting at K(+) -channels expressed on type 1 carotid body cells. The authors performed a population pharmacokinetic-pharmacodynamic (PKPD) analysis on the ability of GAL021 to reverse alfentanil-induced respiratory depression in 12 male volunteers using an isohypercapnic experimental design. The analysis showed that (1) GAL021 interacts in a multiplicative fashion with alfentanil and GAL021, which predicts that GAL021 efficacy is reduced at low ventilation levels; (2) GAL021 has a rapid onset/offset with a blood-effect site equilibration half-life not different from zero; and (3) GAL021 displays ceiling in its efficacy to reverse OIRD.

Electronic structure and spin trapping in LiMnAs and LiFeAs:Mn.

The electronic structure of insulating antiferromagnetic LiMnAs is investigated using soft x-ray spectroscopy and compared to the electronic structure of metallic LiFeAs. Our calculations support the experimentally observed insulating antiferromagnetic order in LiMnAs. The x-ray absorption and resonant inelastic x-ray scattering spectra in LiFeAs and LiMnAs are adequately explained by the electronic structure alone, although it is possible that LiMnAs has significant electronic correlations driven by Hund's J coupling. Finally, we show evidence of a possible spin trap in Li(Fe0.95Mn0.05)As.

GAL-021, a new intravenous BKCa-channel blocker, is well tolerated and stimulates ventilation in healthy volunteers.

BACKGROUND: Potassium-channels in the carotid body and the brainstem are important regulators of ventilation. The BKCa-channel contains response elements for CO, O2, and CO2. Its block increases carotid body signalling, phrenic nerve activity, and respiratory drive. GAL-021, a new BKCa-channel blocker, increases minute ventilation in rats and non-human primates. This study assessed the single-dose safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of GAL-021 in healthy volunteers. METHODS: Thirty subjects participated in a nine-period, randomized, double-blinded, placebo-controlled, crossover, ascending dose, first-in-human study with i.v. infusions of 0.1-0.96 mg kg(-1) h(-1) for 1 h and intermediate doses up to 4 h. RESULTS: Adverse event rates were generally similar among dose levels and between placebo- and GAL-021-treated subjects. At higher GAL-021 doses, a mild/moderate burning sensation at the infusion site occurred during the infusion. No clinically significant changes in vital signs or clinical chemistries were noted. Minute ventilation increased (AUE0-1 h ≈ 16%, P<0.05) and end-tidal carbon dioxide ([Formula: see text]) decreased (AUE0-1 h ≈ 6%, P<0.05) during the first hour at 0.96 mg kg(-1) h(-1) with 1/2-maximal [Formula: see text] and [Formula: see text]-change occurring by 7.5 min. Drug concentration rose rapidly during the infusion and decreased rapidly initially (distribution t1/2 of 30 min) and then more slowly (terminal t1/2 of 5.6 h). CONCLUSIONS: GAL-021 was safe and generally well tolerated with adverse events comparable with placebo except for an infusion site burning sensation. GAL-021 stimulated ventilation at the highest doses suggesting that greater infusion rates may be required for maximum PD effects. GAL-021 had PK characteristics consistent with an acute care medication.

Environmental determinants of Ixodes ricinus ticks and the incidence of Borrelia burgdorferi sensu lato, the agent of Lyme borreliosis, in Scotland.

Lyme borreliosis (LB) is the most common arthropod-borne disease of humans in the Northern hemisphere. In Europe, the causative agent, Borrelia burgdorferi sensu lato complex, is principally vectored by Ixodes ricinus ticks. The aim of this study was to identify environmental factors influencing questing I. ricinus nymph abundance and B. burgdorferi s.l. infection in questing nymphs using a large-scale survey across Scotland. Ticks, host dung and vegetation were surveyed at 25 woodland sites, and climatic variables from a Geographical Information System (GIS) were extracted for each site. A total of 2397 10 m2 transect surveys were conducted and 13 250 I. ricinus nymphs counted. Questing nymphs were assayed for B. burgdorferi s.l. and the average infection prevalence was 5·6% (range 0·8-13·9%). More questing nymphs and higher incidence of B. burgdorferi s.l. infection were found in areas with higher deer abundance and in mixed/deciduous compared to coniferous forests, as well as weaker correlations with season, altitude, rainfall and ground vegetation. No correlation was found between nymph abundance and infection prevalence within the ranges encountered. An understanding of the environmental conditions associated with tick abundance and pathogen prevalence may be used to reduce risk of exposure and to predict future pathogen prevalence and distributions under environmental changes.

Landscape genetics of a top neotropical predator.

Habitat loss and fragmentation as a consequence of human activities is a worldwide phenomenon and one of the major threats to global biodiversity. Habitat loss and fragmentation is particularly a concern in the biodiverse tropics, where deforestation is occurring at unprecedented rates. Although insects are one of the most diverse and functionally important groups in tropical ecosystems, the quantitative effect of landscape features on their gene flow remains unknown. Here, we used a robust landscape genetics approach to quantify the effect of ten landscape features (deforestation, mature forests, other forest types, the River Chagres, streams, stream banks, roads, sea, lakes and swamps) and interactions between them, on the gene flow of a neotropical forest keystone species, the army ant Eciton burchellii. The influence of landscape on E. burchellii's gene flow reflected the different dispersal capability of its sexes; aerial for males and pedestrian for females, and the different depths of population history inferred from microsatellites and mitochondrial DNA. In contrast to the gene flow-facilitating effect of mature forests, deforested areas were found to be strong barriers for E. burchellii's gene flow. Other forest types were found to be gene flow facilitators but only when interacting with mature secondary forests, therefore indicating the importance of mature forests for the survival of E. burchelii and its associate species. The River Chagres was identified as a major historical gene flow barrier for E. burchellii, suggesting that an important loss of connectivity may occur because of large artificial waterways such as the Panama Canal.

Effect of 3d doping on the electronic structure of BaFe2As2.

The electronic structure of BaFe(2)As(2) doped with Co, Ni and Cu has been studied by a variety of experimental and theoretical methods, but a clear picture of the dopant 3d states has not yet emerged. Herein we provide experimental evidence of the distribution of Co, Ni and Cu 3d states in the valence band. We conclude that the Co and Ni 3d states provide additional free carriers to the Fermi level, while the Cu 3d states are found at the bottom of the valence band in a localized 3d(10) shell. These findings help shed light on why superconductivity can occur in BaFe(2)As(2) doped with Co and Ni but not Cu.

Migration and multiple sclerosis in United Kingdom and Ireland immigrants to Australia: a reassessment. II. Characteristics of early (pre-1947) compared to later migrants.

In our recent reassessment we explored the risk of MS by age at immigration in 258 migrants from United Kingdom and Ireland (UKI) to four states of Australia (New South Wales, Queensland, South Australia, and Western Australia) in the period 1947-1981 (Group II). In the present report we have compared their characteristics with 44 cases who migrated before 1947 (Group I), divided into two subsets: Group Ia (15 cases) was rather similar to Group II in age at immigration (means of 20 and 23 years), age at onset (39 and 33 years), and duration from immigration to onset (19 and 10 years). Group Ib (29 cases) was significantly different from Group II, with mean ages of 4 years at immigration and 40 years at onset, for a mean interval of some 35 years between immigration and onset. All onsets in Group Ib occurred after 1947. We concluded that the Group Ib cases had most probably acquired their MS in Australia. Immigrants from high MS risk countries, including UKI, were modest in number before 1947, but some 770,000 entered from 1947-1981. They may have been the source of MS for the Group Ib migrants.

Benefits associated with a broad selection of dosage strengths for recombinant factor VIII products.

Factor VIII (FVIII) concentrates for haemophilia A patients are dosed according to body weight. This results in a continuous range of prescribed doses, which challenges pharmacies to find dosage strengths closest to the prescribed dose while utilizing the least number of vials. This study was conducted to determine whether a broader selection of FVIII dosage strengths results in improved dispensing accuracy and an increased number of single-vial users. This research retrospectively analyzed a US pharmacy database of prescriptions filled in 2008. Recombinant FVIII (rFVIII) therapies were classified by the range of dosage strengths offered in 2008: Group 1 had three dosage strengths; Group 2 had four dosage strengths; and Group 3 had six dosage strengths. A total of 76,584 dispensed doses of rFVIII for 1,244 patients were included in this analysis. Dispensing accuracy (calculated as both the absolute and relative difference between dispensed and prescribed dose) was significantly better for Group 3 (23.2 IU, 1.2%) than Groups 1 (33.5 IU, 1.6%) and 2 (50.2 IU, 2.4%) (both P < 0.01). In addition, the average number of unique actual rFVIII potencies dispensed per month was highly correlated (-0.977) with dispensing accuracy for each dosage strength group. Among Groups 1, 2 and 3, 23.0%, 44.9% and 73.4% of patients, respectively, had at least one single vial option dispensed (P < 0.0001). A broader selection of rFVIII dosage strengths and more actual rFVIII potencies were associated with improved dispensing accuracy and more single-vial users. This may translate into less waste, cost savings, increased convenience and improved adherence to physician-prescribed regimens.

Retrospective analysis of differences in annual factor VIII utilization among haemophilia A patients.

Finding differences in drug utilization patterns within rare patient populations is challenging without access to a large sample. Our objective was to identify patient and treatment-related factors associated with differences in annual recombinant factor VIII (rFVIII) utilization in a large cohort of haemophilia A patients. This retrospective analysis utilized a large, US specialty pharmacy dispensing database from January 2006 to September 2009. Differences in median annual FVIII utilization (IU kg(-1) year(-1)) by age, severity, treatment regimen, rFVIII product type and health insurance plan were tested using non-parametric statistics and regression analysis. A total of 1011 haemophilia A patients were included in the overall analysis. Severe haemophilia patients had higher median annual FVIII utilization than mild/moderate patients (P < 0.0001). Median annual FVIII utilization was also significantly different between treatment regimens (episodic = 1429 IU kg(-1) year(-1) vs. prophylaxis = 3993 IU kg(-1) year(-1) for severe patients, P < 0.0001). Children (0-12 years old), adolescents (13-18 years old) and adults (19+ years old) with severe haemophilia A receiving prophylaxis utilized 4588, 4082 and 3223 IU kg(-1) year(-1) (P < 0.0001). After controlling for age, severity, treatment regimen and insurance type, regression analysis revealed B domain-deleted recombinant FVIII (BDD-rFVIII) was associated with 33% higher FVIII consumption compared with full-length recombinant FVIII (FL-rFVIII) (P = 0.0172). Similar results were also seen when matching BDD-rFVIII and FL-rFVIII patients. Health insurance type was not associated with annual FVIII utilization. As expected, age, severity and treatment regimen were significantly associated with FVIII utilization. After controlling for confounders, patients receiving FL-rFVIII prophylactically were associated with lower annual FVIII utilization compared with patients receiving BDD-rFVIII prophylactically.

The electronic structure of lithium metagallate.

Herein we present a study of the electronic structure of lithium metagallate (LiGaO(2)), a material of interest in the field of optoelectronics. We use soft x-ray spectroscopy to probe the electronic structure of both the valence and conduction bands and compare our measurements to ab initio density functional theory calculations. We use several different exchange-correlation functionals, but find that no single theoretical approach used herein accurately quantifies both the band gap and the Ga 3d(10) states in LiGaO(2). We derive a band gap of 5.6 eV, and characterize electron hybridization in both the valence and conduction bands. Our study of the x-ray spectra may prove useful in analysing spectra from more complicated LiGaO(2) heterostructures.

Inter-laboratory study of the in vitro dendritic cell migration assay for identification of contact allergens.

The aim of this study was to investigate the transferability of technology and reproducibility of MUTZ-3 derived Langerhans Cell (MUTZ-LC) migration assay. The protocol was transferred from the NL-lab to two Sens-it-iv project partners (UK-lab, Italy-lab). Intra- and inter-laboratory variation with regards to MUTZ-3 progenitor culture, differentiation to MUTZ-LC, maturation and migration assay were investigated. In the transwell-migration-assay, preferential migration of sensitizer-exposed MUTZ-LC towards CXCL12 was observed (three sensitizers), whereas non-sensitizer-exposed MUTZ-LC only migrated towards CCL5 (two non-sensitizers). Four pre-pro-haptens were also identified by UK-lab. When taking the arbitrary criteria of at least two of three independent repetitions per laboratory having to have a CXCL12/CCL5 ratio>1.1 for classification as a sensitizer, all sensitizers tested in all labs were easily distinguished from all non-sensitizers. The number of repetitions giving false negative or false positive was very low (only 7 out of a total of 54 repetitions), indicating that both intra- and inter-laboratory variation was extremely low. Even though only a few chemicals were tested in this study, we show clearly that the in vitro DC migration assay is transferable between laboratories. The results were consistent between the laboratories, and the dose response data were reproduced in the three laboratories.

Investigation of the presence of ghrelin in the central nervous system of the rat and mouse.

Ghrelin and ghrelin receptor agonist have effects on central neurons in many locations, including the hypothalamus, caudal brain stem, and spinal cord. However, descriptions of the distributions of ghrelin-like immunoreactivity in the CNS in published work are inconsistent. We have used three well-characterized anti-ghrelin antibodies, an antibody to the unacylated form of ghrelin, and a ghrelin peptide assay in rats, mice, ghrelin knockout mice, and ghrelin receptor reporter mice to re-evaluate ghrelin presence in the rodent CNS. The stomach served as a positive control. All antibodies were effective in revealing gastric endocrine cells. However, no specific staining could be found in the brain or spinal cord. Concentrations of antibody 10 to 30 times those effective in the stomach bound to nerve cells in rat and mouse brain, but this binding was not reduced by absorbing concentrations of ghrelin peptide, or by use of ghrelin gene knockout mice. Concentrations of ghrelin-like peptide, detected by enzyme-linked immunosorbent assay in extracts of hypothalamus, were 1% of gastric concentrations. Ghrelin receptor-expressing neurons had no adjacent ghrelin immunoreactive terminals. It is concluded that there are insignificant amounts of authentic ghrelin in neurons in the mouse or rat CNS and that ghrelin receptor-expressing neurons do not receive synaptic inputs from ghrelin-immunoreactive nerve terminals in these species.

Migration and multiple sclerosis in immigrants to Australia from United Kingdom and Ireland: a reassessment. I. Risk of MS by age at immigration.

A previous study of the prevalence of multiple sclerosis (MS) in 1981 among immigrants from the United Kingdom and Ireland to Australia found that the prevalence for those with age at immigration (AAI) under 15 years of age did not differ from the older immigrants. We have reanalysed the original materials as well as census data for 1901-1981 for UKI and other high MS risk country immigrants. There was a highly significant trend in the prevalence rates of all Australians from New South Wales (NSW) to South Australia (SA) to Western Australia (WA) to Queensland (QLD). Rates by state among the Australian-born were almost identical to these, but there was no prevalence gradient for the UKI-born. The denominator population at risk of MS by AAI was calculated from special census tables of length of residence in Australia by age 0-79 in 1981 for UKI immigrants 1947-1981. The numerator was limited to the subset of 258 MS (Group II) also immigrating in 1947 and later, and age 0-79 in 1981. The absolute risk of MS for these migrants to the four states entering at age 0-14 was 22/100,000, significantly less than for all older age groups; age 15-39 immigrants had a risk of 54/100,000. Similar risk ratios for 0-14 versus 15-39 by state were 31 versus 61 (NSW), 29 versus 44 (QLD), 11 versus 50 (SA), 15 versus 51 (WA).

The role of trauma scoring in developing trauma clinical governance in the Defence Medical Services.

This paper discusses mathematical models of expressing severity of injury and probability of survival following trauma and their use in establishing clinical governance of a trauma system. There are five sections: (i) Historical overview of scoring systems--anatomical, physiological and combined systems and the advantages and disadvantages of each. (ii) Definitions used in official statistics--definitions of 'killed in action' and other categories and the importance of casualty reporting rates and comparison across conflicts and nationalities. (iii) Current scoring systems and clinical governance--clinical governance of the trauma system in the Defence Medical Services (DMS) by using trauma scoring models to analyse injury and clinical patterns. (iv) Unexpected outcomes--unexpected outcomes focus clinical governance tools. Unexpected survivors signify good practice to be promulgated. Unexpected deaths pick up areas of weakness to be addressed. Seventy-five clinically validated unexpected survivors were identified over 2 years during contemporary combat operations. (v) Future developments--can the trauma scoring methods be improved? Trauma scoring systems use linear approaches and have significant weaknesses. Trauma and its treatment is a complex system. Nonlinear methods need to be investigated to determine whether these will produce a better approach to the analysis of the survival from major trauma.