Combined positron emission tomography and contrast enhanced CT (PET/CeCT) is a feasible single investigation in the staging of oesophagogastric cancers: single-centre pilot study experience during the COVID-19 pandemic.

INTRODUCTION: Staging of oesophagogastric (OG) cancers usually involves endoscopy (OGD), and separate visits for contrast enhanced computed tomography (CeCT) and positron emission tomography (PET/CT). At the height of the COVID-19 pandemic, some of our patients underwent single-visit combined staging with PET/CeCT. We compare this novel pathway with standard separate imaging in time to completion of staging, to start of treatment, and cost. METHODS: We identified all patients discussed at our OG multidisciplinary team (MDT) meeting in 2020. Clinical records revealed dates of investigations and treatments. Data were tabulated in Excel, with statistical analysis in SPSS. All patients followed the same MDT process and image reviewing criteria. Costs were compared using prices supplied by finance departments. RESULTS: A total of 211 new patients were discussed at our MDT in 2020. Of these, 48 patients had combined PET/CeCT staging, and 68 had separate scans. Median time (interquartile range) in days from OGD to final imaging was 9 (6-23) for the combined group versus 21 (16-28) for the separate group (p≤0.001). Median time (days) from OGD to treatment start was 37 (29-52) for combined versus 55 (40-71) for separate (p≤0.001). No combined scans were of insufficient diagnostic quality for the MDT. PET/CeCT had a potential cost saving of £113 per patient. CONCLUSIONS: PET/CeCT allows accurate radiological staging of OG cancers with a single scan. Patients completed staging and started treatment faster, with a potential saving of £10,509 in one year. PET/CeCT has become standard staging at our trust, and we aim to incorporate radiotherapy planning images too.

[Questionnaire for the utilization of the Emergency Department : Implications for the patient survey]. / Fragebogen zur Inanspruchnahme der Notaufnahmen : Implikationen für die Patientenbefragung.

BACKGROUND: For several years, Emergency Departments (ED) in Germany have observed increasing patient numbers, resulting in ED crowding. This leads to the question of whether patients with nonurgent conditions could also receive adequate treatment in primary care. Our objective was to develop a quantitative questionnaire to investigate in a larger patient group the reasons for this and to describe the implications for a patient survey in the ED. METHODS: The development of the questionnaire was based on a literature search and the results of the qualitative EPICS-2 study. Two pretest surveys were conducted in three EDs at the Charité - Universitätsmedizin Berlin. We included patients aged ≥ 18 years with outpatient treatment and the categories blue (nonurgent), green (standard), or yellow (urgent) according to the Manchester Triage System (MTS). RESULTS: In total, 189 patients were recruited in two surveys (pretest 1: n = 89, pretest 2 n = 100). The final questionnaire includes 24 items, which were evaluated and adapted during both pretests. The items evaluate basic clinical characteristics, reasons for choosing the ED, prior contacts in primary care, utilization of primary care after-hours services as well as sociodemographic characteristics. Data from the hospital information system were used to link the survey data with clinical characteristics. CONCLUSIONS: The questionnaire is based on reasons for ED utilization. We recommend the written, self-applied questionnaire for patient surveys with plausibility checks conducted by staff. It is necessary to consider the heterogenic study surroundings in the ED, which requires a lot of flexibility during data collection.

Endemic species may have complex histories: within-refugium phylogeography of an endangered Iberian vole.

Glacial refugia protected and promoted biodiversity during the Pleistocene, not only at a broader scale, but also for many endemics that contracted and expanded their ranges within refugial areas. Understanding the evolutionary history of refugial endemics is especially important in the case of endangered species to recognize the origins of their genetic structure and thus produce better informed conservation practices. The Iberian Peninsula is an important European glacial refugium, rich in endemics of conservation concern, including small mammals, such as the Cabrera vole (Microtus cabrerae). This near-threatened rodent is characterized by an unusual suite of genetic, life history and ecological traits, being restricted to isolated geographic nuclei in fast-disappearing Mediterranean subhumid herbaceous habitats. To reconstruct the evolutionary history of the Cabrera vole, we studied sequence variation at mitochondrial, autosomal and sex-linked loci, using invasive and noninvasive samples. Despite low overall mitochondrial and nuclear nucleotide diversities, we observed two main well-supported mitochondrial lineages, west and east. Phylogeographic modelling in the context of the Cabrera vole's detailed fossil record supports a demographic scenario of isolation of two populations during the Last Glacial Maximum from a single focus in the southern part of the Iberian Peninsula. In addition, our data suggest subsequent divergence within the east, and secondary contact and introgression of the expanding western population, during the late Holocene. This work emphasizes that refugial endemics may have a phylogeographic history as rich as that of more widespread species, and conservation of such endemics includes the preservation of that genetic legacy.

[Exploring Patient Motives to Use Emergency Departments for Non-urgent Conditions: A Qualitative Study]. / Inanspruchnahme zentraler Notaufnahmen: Qualitative Erhebung der Motivation von Patientinnen und Patienten mit nichtdringlichem Behandlungsbedarf.

Background: The increasing utilization of Emergency Departments (ED) by outpatients with acute but non-urgent conditions contributes to ED crowding. This study aims to explore the motives of patients categorized as non-urgent for visiting the ED. Methods: A qualitative study based on semi-structured interviews was conducted at 2 ED's at Charité Berlin. A total of 40 patients categorized as non-urgent were interviewed. Data were analyzed using Qualitative Content Analysis. Results: In addition to unavailable appointments or having to wait a long time for an appointment with general practitioners and specialists, patients stated better time-flexibility, the University Hospital's quality of care and the availability of multidisciplinary care as reasons to seek medical care in the ED. Because of the 24/7 availability of EDs, some patients seem to make little effort to seek an appointment with a GP or a specialist outside the hospital. Conclusion: Our interview data indicate an independent function of EDs in outpatient care. It must be assumed that even a full coverage of service guarantee by the association of statuary health insurance physicians would not reduce ED utilization to cases of medical urgency only. To ensure sustainable medical quality for urgent as well as non-urgent medical care seekers, EDs need appropriate resources to cover the demand.

A voyage to Terra Australis: human-mediated dispersal of cats.

BACKGROUND: Cats have been transported as human commensals worldwide giving rise to many feral populations. In Australia, feral cats have caused decline and extinction of native mammals, but their time of introduction and origin is unclear. Here, we investigate hypotheses of cat arrival pre- or post-European settlement, and the potential for admixture between cats of different invasion events. We analyse the genetic structure and diversity of feral cats from six locations on mainland Australia, seven Australian islands and samples from Southeast Asia and Europe using microsatellite and mitochondrial DNA data. RESULTS: Our results based on phylogeographic model selection are consistent with a European origin of cats in Australia. We find genetic distinctiveness of Australian mainland samples compared with Dirk Hartog Island, Flinders Island, Tasman Island and Cocos (Keeling) Island samples, and genetic similarities between some of the island populations. Historical records suggest that introduction of cats to these islands occurred at the time of European exploration and/or in connection with the pearling, whaling and sealing trades early in the 19th century. On-going influx of domestic cats into the feral cat population is apparently causing the Australian mainland populations to be genetically differentiated from those island populations, which likely are remnants of the historically introduced cat genotypes. CONCLUSION: A mainly European origin of feral cats in Australia, with possible secondary introductions from Asia following the initial establishment of cats in Australia is reasonable. The islands surrounding Australia may represent founding populations and are of particular interest. The results of the study provide an important timeframe for the impact of feral cats on native species in Australia.

Building a sustainable clinical academic workforce to meet the future healthcare needs of Australia and New Zealand: report from the first summit meeting.

The delivery of healthcare that meets the requirements for quality, safety and cost-effectiveness relies on a well-trained medical workforce, including clinical academics whose career includes a specific commitment to research, education and/or leadership. In 2011, the Medical Deans of Australia and New Zealand published a review on the clinical academic workforce and recommended the development of an integrated training pathway for clinical academics. A bi-national Summit on Clinical Academic Training was recently convened to bring together all relevant stakeholders to determine how best to do this. An important part understood the lessons learnt from the UK experience after 10 years since the introduction of an integrated training pathway. The outcome of the summit was to endorse strongly the recommendations of the medical deans. A steering committee has been established to identify further stakeholders, solicit more information from stakeholder organisations, convene a follow-up summit meeting in late 2015, recruit pilot host institutions and engage the government and future funders.

Relationship between wild greylag and European domestic geese based on mitochondrial DNA.

The origins of the European domestic goose are uncertain. The available information comes from archaeological findings and historical literature, but genetic evidence has hitherto been scarce. The domestic goose in Europe is derived from the greylag goose (Anser anser), but it is not known where the initial domestication took place and which of the two subspecies of greylag goose was ancestral. We aimed to determine the amount and geographical distribution of genetic diversity in modern populations of greylag geese as well as in different breeds of the domestic goose to make inferences about goose domestication. We studied DNA sequence variation in the mitochondrial control region of greylag geese from multiple populations across Europe and western Asia as well as specimens of domestic geese representing 18 modern breeds and individuals not belonging to any recognised breed. Our results show notable differences in genetic diversity between different greylag goose populations and the presence of six mitochondrial haplogroups which show a degree of geographical partitioning. The genetic diversity of the domestic goose is low, with 84% of sampled individuals having one of two major closely related haplotypes, suggesting that modern European domestic geese may derive from a narrow genetic base. The site of domestication remains unresolved, but domestic geese in Turkey were unusually diverse, indicating the importance of further sampling in the vicinity of the eastern Mediterranean and the Near East. There appears to be past or ongoing hybridisation between greylags and domestic geese in particular areas, consistent with field observations.

The effect of chemotherapy on health-related quality of life in mesothelioma: results from the SWAMP trial.

BACKGROUND: The effect of chemotherapy on health-related quality of life (HRQoL) in malignant pleural mesothelioma (MPM) is poorly understood. Patient-individualised prognostication and prediction of treatment response from chemotherapy is useful but little evidence exists to guide practice. METHOD: Consecutive patients with MPM who were fit for first-line chemotherapy with pemetrexed and cisplatin\carboplatin were recruited and followed up for a minimum of 12 months. This study focussed on the HRQoL outcomes of these patients using the EQ-5D, EORTC QLQ-C30 and LC13. RESULTS: Seventy-three patients were recruited of which 58 received chemotherapy and 15 opted for best supportive care (BSC). Compliance with HRQoL questionnaires was 98% at baseline. The chemotherapy group maintained HRQoL compared with the BSC group whose overall HRQoL fell (P=0.006) with worsening dyspnoea and pain. The impact of chemotherapy was irrespective of histological subtype although those with non-epithelioid disease had worse HRQoL at later time points (P=0.012). Additionally, those with a falling mesothelin or improvement on modified-RECIST CT at early follow-up had a better HRQoL at 16 weeks. CONCLUSIONS: HRQoL was maintained following chemotherapy compared with a self-selected BSC group. Once chemotherapy is initiated, a falling mesothelin or improved RECIST CT findings infer a quality-of-life advantage.

The South West Area Mesothelioma and Pemetrexed trial: a multicentre prospective observational study evaluating novel markers of chemotherapy response and prognostication.

BACKGROUND: Robust markers that predict prognosis and detect early treatment response in malignant pleural mesothelioma (MPM) would enhance patient care. METHODS: Consecutive patients with MPM who were considered fit for first-line chemotherapy were prospectively recruited. Patients of similar performance status opting for best supportive care were included as a comparator group. Baseline and interval CT, PET-CT and serum markers (mesothelin, fibulin-3 and neutrophil-lymphocyte ratio (NLR)) were obtained, and patients followed up for a minimum 12 months. FINDINGS: Seventy-three patients were recruited (58 chemotherapy/15 comparator arm). Baseline TGV (total glycolytic volume on PET-CT) was an independent predictor of worse overall survival (OS) (P=0.001). Change in interval TGV(baseline/after two cycles of chemotherapy) did not predict OS or chemotherapy response on CT. Baseline NLR<4 was an independent predictor of better OS (median survival 453 (IQR 272-576) days vs NLR⩾4, 257 (IQR 147-490), P=0.002). Although baseline serum mesothelin did not predict OS, a falling level at 8 weeks significantly predicted longer time to progression (TTP) (P<0.001). INTERPRETATION: Neutrophil-lymphocyte ratio and baseline TGV predict prognosis in malignant pleural mesothelioma (MPM), but PET-CT is unhelpful in monitoring chemotherapy response. Serum mesothelin is a useful early treatment response marker when measured serially during chemotherapy and may have a role in evaluating patients' treatment response.

Of mice and the 'Age of Discovery': the complex history of colonization of the Azorean archipelago by the house mouse (Mus musculus) as revealed by mitochondrial DNA variation.

Humans have introduced many species onto remote oceanic islands. The house mouse (Mus musculus) is a human commensal and has consequently been transported to oceanic islands around the globe as an accidental stowaway. The history of these introductions can tell us not only about the mice themselves but also about the people that transported them. Following a phylogeographic approach, we used mitochondrial D-loop sequence variation (within an 849- to 864-bp fragment) to study house mouse colonization of the Azores. A total of 239 sequences were obtained from all nine islands, and interpretation was helped by previously published Iberian sequences and 66 newly generated Spanish sequences. A Bayesian analysis revealed presence in the Azores of most of the D-loop clades previously described in the domesticus subspecies of the house mouse, suggesting a complex colonization history of the archipelago as a whole from multiple geographical origins, but much less heterogeneity (often single colonization?) within islands. The expected historical link with mainland Portugal was reflected in the pattern of D-loop variation of some of the islands but not all. A more unexpected association with a distant North European source area was also detected in three islands, possibly reflecting human contact with the Azores prior to the 15th century discovery by Portuguese mariners. Widening the scope to colonization of the Macaronesian islands as a whole, human linkages between the Azores, Madeira, the Canaries, Portugal and Spain were revealed through the sharing of mouse sequences between these areas. From these and other data, we suggest mouse studies may help resolve historical uncertainties relating to the 'Age of Discovery'.

Prevalence of dysglycemia in Calabar: a cross-sectional observational study among residents of Calabar, Nigeria.

OBJECTIVE: Population data on dysglycemia are scarce in West Africa. This study aimed to determine the pattern of dysglycemia in Calabar city in South East Nigeria. DESIGN: This was a cross-sectional observational study. METHODS: 1134 adults in Calabar were recruited. A multistage sampling method randomly selected 4 out of 22 wards, and 50 households from each ward. All adults within each household were recruited and an oral glucose tolerance test was performed. Dysglycemia was defined as any form of glucose intolerance, including: impaired fasting glucose (blood glucose level 110-125 mg/dL), impaired glucose tolerance (blood glucose level ≥140 mg/dL 2 h after consuming 75 g of glucose), or diabetes mellitus (DM), as defined by fasting glucose level ≥126 mg/dL, or a blood glucose level ≥200 mg/dL, 2 h after a 75 g glucose load. RESULTS: Mean values of fasting plasma glucose were 95 mg/dL (95% CI 92.1 to 97.5) for men and 96 mg/dL (95% CI 93.2 to 98.6) for women. The overall prevalence of dysglycemia was 24%. The prevalence of impaired fasting glucose was 9%, the prevalence of impaired glucose tolerance 20%, and the prevalence of undiagnosed DM 7%. All values were a few percentage points higher for men than women. CONCLUSIONS: The prevalence of undiagnosed DM among residents of Calabar is similar to studies elsewhere in Nigeria but much higher than the previous national prevalence survey, with close to a quarter of the adults having dysglycemia and 7% having undiagnosed DM. This is a serious public health problem requiring a programme of mass education and case identification and management in all health facilities. TRIAL REGISTRATION NUMBER: CRS/MH/CR-HREC/020/Vol.8/43.

[Point-of-care testing in preclinical emergency medicine]. / Point-of-care-Testung in der präklinischen Notfallmedizin.

BACKGROUND: Measurement of biological signals directly at the patient (point-of-care testing, POCT) is an established standard in emergency medicine when test results are needed quickly and within a reliable time frame or if external testing requires a disproportionate effort. OBJECTIVES: Currently, the rapid test for ß-HCG in urine and POCT measurement of lactate, blood gases, cardiac tropinin, haemoglobin, and hematocrit are well established in emergency medicine. POCT of copeptin, fatty acid-binding proteins (FABP), procalcitonin, coagulation values, natriuretic peptides, D-dimer, and toxicological substances are of future interest. In this article, the appropriate use of point-of-care testing in prehospital emergency medicine is discussed. RESULTS: Application of POCT is dependent of the underlying conditions, the availability of appropriate devices, and of suitable reference methods in a central laboratory. In addition, economical and quality aspects play an important role. CONCLUSION: In emergency departments, POCT is currently developing into a standard measuring method for a number of markers because hospital laboratories are increasingly being merged and consequently reduce their emergency-analytic services. In countries with a high density of hospitals, however, preclinical POCT should be reduced to the minimum necessary.

Relaxed functional constraints on triplicate α-globin gene in the bank vole suggest a different evolutionary history from other rodents.

Gene duplication plays an important role in the origin of evolutionary novelties, but the mechanisms responsible for the retention and functional divergence of the duplicated copy are not fully understood. The α-globin genes provide an example of a gene family with different numbers of gene duplicates among rodents. Whereas Rattus and Peromyscus each have three adult α-globin genes (HBA-T1, HBA-T2 and HBA-T3), Mus has only two copies. High rates of amino acid evolution in the independently derived HBA-T3 genes of Peromyscus and Rattus have been attributed to positive selection. Using RACE PCR, reverse transcription-PCR (RT-PCR) and RNA-seq, we show that another rodent, the bank vole Clethrionomys glareolus, possesses three transcriptionally active α-globin genes. The bank vole HBA-T3 gene is distinguished from each HBA-T1 and HBA-T2 by 20 amino acids and is transcribed 23- and 4-fold lower than HBA-T1 and HBA-T2, respectively. Polypeptides corresponding to all three genes are detected by electrophoresis, demonstrating that the translated products of HBA-T3 are present in adult erythrocytes. Patterns of codon substitution and the presence of low-frequency null alleles suggest a postduplication relaxation of purifying selection on bank vole HBA-T3.

Genetic identification of Iberian rodent species using both mitochondrial and nuclear loci: application to noninvasive sampling.

Species identification through noninvasive sampling is increasingly used in animal conservation genetics, given that it obviates the need to handle free-living individuals. Noninvasive sampling is particularly valuable for elusive and small species such as rodents. Although rodents are not usually assumed to be the most obvious target for conservation, of the 21 species or near-species present in Iberia, three are considered endangered and declining, while several others are poorly studied. Here, we develop a genetic tool for identifying all rodent species in Iberia by noninvasive genetic sampling. To achieve this purpose, we selected one mitochondrial gene [cytochrome b (cyt-b)] and one nuclear gene [interphotoreceptor retinoid-binding protein (IRBP)], which we first sequenced using tissue samples. Both genes allow for the phylogenetic distinction of all species except the sibling species Microtus lusitanicus and Microtus duodecimcostatus. Overall, cyt-b showed higher resolution than IRBP, revealing a clear barcoding gap. To allow these markers to be applied to noninvasive samples, we selected a short highly diagnostic fragment from each gene, which we used to obtain sequences from faeces and bones from owl pellets. Amplification success for the cyt-b and IRBP fragment was 85% and 43% in faecal and 88% and 64% in owl-pellet DNA extractions, respectively. The method allows the unambiguous identification of the great majority of Iberian rodent species from noninvasive samples, with application in studies of distribution, spatial ecology and population dynamics, and for conservation.

Origin of the chromosomal radiation of Madeiran house mice: a microsatellite analysis of metacentric chromosomes.

Chromosome races of Mus musculus domesticus are characterised by particular sets of metacentric chromosomes formed by Robertsonian fusions and whole-arm reciprocal translocations. The Atlantic island of Madeira is inhabited by six chromosome races of house mice with 6-9 pairs of metacentric chromosomes. Three of these races are characterised by the metacentric 3.8 also found elsewhere in the distribution of M. m. domesticus, including Denmark and Spain. We investigated the possibility that metacentric 3.8 was introduced to Madeira during the initial colonisation, as this could have 'seeded' the cascade of chromosomal mutation that is the basis of the extraordinary chromosomal radiation observed on the island. Variation at 24 microsatellite loci mapping to three different chromosomal regions (proximal, interstitial and distal) of mouse chromosomes 3 and 8 was investigated in 179 mice from Madeira, Denmark, Portugal, Spain, Italy and Scotland. Analyses of microsatellite loci closely linked to the centromeres of these chromosomes ('proximal loci') do not support a common evolutionary origin of metacentric 3.8 among Madeiran, Danish and Spanish mouse populations. Our results suggest that Madeiran mice are genetically more similar to standard karyotype mice from Portugal than to metacentric mice from elsewhere. There is expected to be an interruption to gene flow between hybridising metacentric races on Madeira, particularly in the chromosomal regions close to the rearrangement breakpoints. Consistent with this, relating to differentiation involving chromosomes 3 and 8 on Madeira, we found greater genetic structure among races for proximal than interstitial or distal loci.

Cryptic speciation in the field vole: a multilocus approach confirms three highly divergent lineages in Eurasia.

Species are generally described from morphological features, but there is growing recognition of sister forms that show substantial genetic differentiation without obvious morphological variation and may therefore be considered 'cryptic species'. Here, we investigate the field vole (Microtus agrestis), a Eurasian mammal with little apparent morphological differentiation but which, on the basis of previous sex-linked nuclear and mitochondrial DNA (mtDNA) analyses, is subdivided into a Northern and a Southern lineage, sufficiently divergent that they may represent two cryptic species. These earlier studies also provided limited evidence for two major mtDNA lineages within Iberia. In our present study, we extend these findings through a multilocus approach. We sampled 163 individuals from 46 localities, mainly in Iberia, and sequenced seven loci, maternally, paternally and biparentally inherited. Our results show that the mtDNA lineage identified in Portugal is indeed a distinct third lineage on the basis of other markers as well. In fact, multilocus coalescent-based methods clearly support three separate evolutionary units that may represent cryptic species: Northern, Southern and Portuguese. Divergence among these units was inferred to have occurred during the last glacial period; the Portuguese lineage split occurred first (estimated at c. 70 000 bp), and the Northern and Southern lineages separated at around the last glacial maximum (estimated at c. 18 500 bp). Such recent formation of evolutionary units that might be considered species has repercussions in terms of understanding evolutionary processes and the diversity of small mammals in a European context.

Fellow travellers: a concordance of colonization patterns between mice and men in the North Atlantic region.

BACKGROUND: House mice (Mus musculus) are commensals of humans and therefore their phylogeography can reflect human colonization and settlement patterns. Previous studies have linked the distribution of house mouse mitochondrial (mt) DNA clades to areas formerly occupied by the Norwegian Vikings in Norway and the British Isles. Norwegian Viking activity also extended further westwards in the North Atlantic with the settlement of Iceland, short-lived colonies in Greenland and a fleeting colony in Newfoundland in 1000 AD. Here we investigate whether house mouse mtDNA sequences reflect human history in these other regions as well. RESULTS: House mice samples from Iceland, whether from archaeological Viking Age material or from modern-day specimens, had an identical mtDNA haplotype to the clade previously linked with Norwegian Vikings. From mtDNA and microsatellite data, the modern-day Icelandic mice also share the low genetic diversity shown by their human hosts on Iceland. Viking Age mice from Greenland had an mtDNA haplotype deriving from the Icelandic haplotype, but the modern-day Greenlandic mice belong to an entirely different mtDNA clade. We found no genetic association between modern Newfoundland mice and the Icelandic/ancient Greenlandic mice (no ancient Newfoundland mice were available). The modern day Icelandic and Newfoundland mice belong to the subspecies M. m. domesticus, the Greenlandic mice to M. m. musculus. CONCLUSIONS: In the North Atlantic region, human settlement history over a thousand years is reflected remarkably by the mtDNA phylogeny of house mice. In Iceland, the mtDNA data show the arrival and continuity of the house mouse population to the present day, while in Greenland the data suggest the arrival, subsequent extinction and recolonization of house mice--in both places mirroring the history of the European human host populations. If house mice arrived in Newfoundland with the Viking settlers at all, then, like the humans, their presence was also fleeting and left no genetic trace. The continuity of mtDNA haplotype in Iceland over 1000 years illustrates that mtDNA can retain the signature of the ancestral house mouse founders. We also show that, in terms of genetic variability, house mouse populations may also track their host human populations.