The impact of COVID-19 on major trauma (ISS>15) in London, across its four Level 1 centres.

INTRODUCTION: The COVID-19 pandemic has led to reconfiguration of healthcare resources to manage increased demand for acute hospital beds and intensive care places. Concerns were raised regarding continuing provision of critical care for non-COVID patients during the pandemic. The aim of this study was to assess the impact of the COVID-19 pandemic on patients admitted with major trauma (Injury Severity Score >15) across the four Level 1 trauma centres in London. METHODS: Data were collected from all four major trauma centres (MTCs) in London using the Trauma Audit and Research Network database and from local databases at each centre. A 2-month period from 5 March to 5 May 2020 was selected and the same period during 2019 was used to compare changes due to the pandemic. RESULTS: There was a 31% decrease in overall number of patients presenting to the four MTCs during the COVID-19 period compared with 2019. There was no difference in patient demographics or mechanism of injury between the two periods. Sports-related injuries and proportion of self-presentation to hospital were reduced slightly during the pandemic, although the differences were not statistically significant. The mortality rate and association between mortality and injury severity were similar. Proportion of patients requiring intensive care unit facilities also did not change. CONCLUSION: Despite diversion of critical care resources to deal with COVID-related admissions, we did not observe a change in mortality rate or proportion of severely injured patients requiring critical care. Our results suggest London MTCs were able to provide their usual standard of care for critically injured major trauma (Injury Severity Score >15) patients during the pandemic.

The impact of Recovery Colleges on mental health staff, services and society.

AIMS: Recovery Colleges are opening internationally. The evaluation focus has been on outcomes for Recovery College students who use mental health services. However, benefits may also arise for: staff who attend or co-deliver courses; the mental health and social care service hosting the Recovery College; and wider society. A theory-based change model characterising how Recovery Colleges impact at these higher levels is needed for formal evaluation of their impact, and to inform future Recovery College development. The aim of this study was to develop a stratified theory identifying candidate mechanisms of action and outcomes (impact) for Recovery Colleges at staff, services and societal levels. METHODS: Inductive thematic analysis of 44 publications identified in a systematised review was supplemented by collaborative analysis involving a lived experience advisory panel to develop a preliminary theoretical framework. This was refined through semi-structured interviews with 33 Recovery College stakeholders (service user students, peer/non-peer trainers, managers, community partners, clinicians) in three sites in England. RESULTS: Candidate mechanisms of action and outcomes were identified at staff, services and societal levels. At the staff level, experiencing new relationships may change attitudes and associated professional practice. Identified outcomes for staff included: experiencing and valuing co-production; changed perceptions of service users; and increased passion and job motivation. At the services level, Recovery Colleges often develop somewhat separately from their host system, reducing the reach of the college into the host organisation but allowing development of an alternative culture giving experiential learning opportunities to staff around co-production and the role of a peer workforce. At the societal level, partnering with community-based agencies gave other members of the public opportunities for learning alongside people with mental health problems and enabled community agencies to work with people they might not have otherwise. Recovery Colleges also gave opportunities to beneficially impact on community attitudes. CONCLUSIONS: This study is the first to characterise the mechanisms of action and impact of Recovery Colleges on mental health staff, mental health and social care services, and wider society. The findings suggest that a certain distance is needed in the relationship between the Recovery College and its host organisation if a genuine cultural alternative is to be created. Different strategies are needed depending on what level of impact is intended, and this study can inform decision-making about mechanisms to prioritise. Future research into Recovery Colleges should include contextual evaluation of these higher level impacts, and investigate effectiveness and harms.

Second Blood Meal by Female Lutzomyia longipalpis: Enhancement by Oviposition and Its Effects on Digestion, Longevity, and Leishmania Infection.

Lutzomyia longipalpis is the main vector of visceral leishmaniasis (VL) in America. Physiological and molecular mechanisms of Leishmania infection in sand flies have been studied during the first gonotrophic cycle. There are few studies about these interactions during the second gonotrophic cycle mainly because of the difficulties maintaining sand flies through sequential feeds. Here we standardized conditions to perform the second blood feed efficiently, and our results show that oviposition is an essential factor for the success of multiple feeds. We evaluated the impact of the second blood meal on longevity, protein digestion, trypsin activity, and Leishmania mexicana development within L. longipalpis gut. Mortality of blood-fed females increases after second blood meal as compared to sugar-fed females. Trypsin activity was lower during the second gonotrophic cycle. However, no difference in protein intake was observed between blood meals. There was no difference in the population size of Leishmania in the gut after both blood meals. In this work, we presented an optimized protocol for obtaining sufficient numbers of sand fly females fed on a second blood meal, and we described some physiological and parasitological aspects of the second gonotrophic cycle which might influence the vectorial competence of sand flies.

Informed consent and the readability of the written consent form.

Introduction The aim of this study was to objectively ascertain the level of readability of standardised consent forms for orthopaedic procedures. Methods Standardised consent forms (both in summary and detailed formats) endorsed by the British Orthopaedic Association (BOA) were retrieved from orthoconsent.com and assessed for readability. This involved using an online tool to calculate the validated Flesch reading ease score (FRES). This was compared with the FRES for the National Health Service (NHS) Consent Form 1. Data were analysed and interpreted according to the FRES grading table. Results The FRES for Consent Form 1 was 55.6, relating to the literacy expected of an A level student. The mean FRES for the BOA summary consent forms (n=27) was 63.6 (95% confidence interval [CI]: 61.2-66.0) while for the detailed consent forms (n=32), it was 68.9 (95% CI: 67.7-70.0). All BOA detailed forms scored >60, correlating to the literacy expected of a 13-15-year-old. The detailed forms had a higher FRES than the summary forms (p<0.001). Conclusions This study demonstrates that the BOA endorsed standardised consent forms are much easier to read and understand than the NHS Consent Form 1, with the detailed BOA forms being the easiest to read. Despite this, owing to varying literacy levels, a significant proportion of patients may struggle to give informed consent based on the written information provided to them.

Species composition and population dynamics of phlebotomine sand flies in a Leishmania infected area of Chiang Mai, Thailand.

Phlebotomine sand flies are established vectors of leishmaniasis in humans. In Thailand, Leishmania martiniquensis and "Leishmania siamensis" have been described as causative agents of leishmaniasis. In this study, a survey of sand flies in the Leishmania infected area of Hang Dong district, Chiang Mai, Thailand was performed using CDC light traps for eight consecutive months, from January to August 2016. A total of 661 sand flies were collected, and of 280 female sand flies, four species of the genus Sergentomyia including Sergentomyia gemmea, S. barraudi, S. indica, and S. hivernus and one species of the genus Phlebotomus, Phlebotomus stantoni, were identified. S. gemmea and S. hivernus were found in Chiang Mai for the first time. The density of captured female sand flies was high in warm and humid periods from June to August, with temperatures of around 26°C and relative humidity about 74%. In addition, S. gemmea was the most predominant species in the area. Further studies as to whether or not these sand fly species could be a vector of Leishmaniasis in Thailand are required.

Didilia sp. infecting Phlebotomus stantoni in Thailand.

Nematode infection in wild caught Phlebotomine sand flies was investigated in Thailand. Light microscopy (LM) and scanning electron microscopy (SEM) were used to detect and morphologically characterize entomopathogenic nematodes that presented in the sand flies. Didilia sp. nematodes were found for the first time in the body cavity of wild caught male Phlebotomus stantoni sand flies. The Didilia sp. was identified based on the morphology of the adult nematodes, from their stylet and teeth at the anterior tip, body length, and egg shell sculpture. It was noted that every infected male sand fly had unrotated genitalia, which would not allow them to mate, thus leading to the loss of their offspring. This finding provided information that might lead to study on whether or not the Didilia sp. has the potential to control sand fly population.

Individual placement and support (IPS) for patients with offending histories: the IPSOH feasibility cluster randomised trial protocol.

INTRODUCTION: People with involvement in forensic psychiatric services face many obstacles to employment, arising from their offending, as well as their mental health problems. This study aims to assess the feasibility of conducting a randomised controlled trial (RCT) to evaluate the effectiveness of individual placement and support (IPS), in improving employment rates and associated psychosocial outcomes in forensic psychiatric populations. IPS has been found consistently to achieve employment rates above 50% in psychiatric patients without a history of involvement in criminal justice services. METHODS/DESIGN: This is a single-centre feasibility cluster RCT. Clusters will be defined according to clinical services in the community forensic services of Nottinghamshire Healthcare NHS Foundation Trust (NHCT). IPS will be implemented into 2 of the randomly assigned intervention clusters in the community forensic services of NHCT. A feasibility cluster RCT will estimate the parameters required to design a full RCT. The primary outcome is the proportion of people in open employment at 12-month follow-up. Secondary outcome measures will include employment, educational activities, psychosocial and economic outcomes, as well as reoffending rates. Outcome measures will be recorded at baseline, 6 months and 12 months. In accordance with the UK Medical Research Council guidelines on the evaluation of complex interventions, a process evaluation will be carried out; qualitative interviews with patients and staff will explore general views of IPS as well as barriers and facilitators to implementation. Fidelity reviews will assess the extent to which the services follow the principles of IPS prior, during and at the end of the trial. ETHICS AND DISSEMINATION: Ethical approval was obtained from the East Midlands Research Ethics Committee-Nottingham 1 (REC reference number 15/EM/0253). Final and interim reports will be prepared for project funders, the study sponsor and clinical research network. Findings will be disseminated through peer-reviewed journals, conferences and event presentations. TRIAL REGISTRATION NUMBER: NCT02442193; Pre-results.

Demystifying damage control in musculoskeletal trauma.

Trauma care has evolved rapidly over the past decade. The benefits of operative fracture management in major trauma patients are well recognised. Concerns over early total care arose when applied broadly. The burden of additional surgical trauma could constitute a second hit, fuelling the inflammatory response and precipitating a decline into acute respiratory distress syndrome, sepsis and multiple organ dysfunction syndrome. Temporary external fixation aimed to deliver the benefits of fracture stabilisation without the risk of major surgery. This damage control orthopaedics approach was advocated for those in extremis and a poorly defined borderline group. An increasing understanding of the physiological response to major trauma means there is now a need to refine our treatment options. A number of large scale retrospective reviews indicate that early definitive fracture fixation is beneficial in the majority of major trauma patients. It is recommended that patients are selected appropriately on the basis of their response to resuscitation. The hope is that this approach (dubbed 'safe definitive fracture surgery' or 'early appropriate care') will herald an era when care is individualised for each patient and their circumstances. The novel Damage Control in Orthopaedic Trauma Surgery course at The Royal College of Surgeons of England aims to equip senior surgeons with the insights and mindset necessary to contribute to this key decision making process as well as also the technical skills to provide damage control interventions when needed, relying on the improved techniques of damage control resuscitation and advances in the understanding of early appropriate care.

Chronic generalized fibrotic skin lesions from disseminated leishmaniasis caused by Leishmania martiniquensis in two patients from northern Thailand infected with HIV.

BACKGROUND: Leishmaniasis is a newly emerging infection in Thailand. Most of the previous human cases have presented with the clinical features of visceral leishmaniasis and were mainly found in southern Thailand. Here we report the first two patients from northern Thailand presenting with disseminated cutaneous leishmaniasis. OBJECTIVES: To determine the nature of the infection of leishmaniasis and to identify the species of parasite responsible. METHODS: Clinical investigations included the taking of biopsy samples and histology. Parasitological diagnosis was performed by establishment of Leishmania promastigote cultures, and identification was performed by DNA sequencing of four independent gene loci (ribosomal RNA internal transcribed spacer 1; large subunit of RNA polymerase II; heat shock protein 70; RPL23a intergenic sequence). RESULTS: Both patients were infected with HIV, and had multiple cutaneous lesions and accompanying visceral leishmaniasis. They had similar cutaneous manifestations characterized by chronic generalized fibrotic lesions, which were more prominent on traumatic areas. In both patients the parasite was identified as Leishmania martiniquensis. This is a recently described species that is distinct and only distantly related to the classical agents of cutaneous leishmaniasis in Asia (Leishmania major and Leishmania tropica) or of visceral leishmaniasis (Leishmania donovani and Leishmania infantum). Each patient responded well to therapy with intravenous amphotericin B followed by oral itraconazole. CONCLUSIONS: Leishmania martiniquensis is a cause of cutaneous leishmaniasis in Thailand.

SETD2 loss-of-function promotes renal cancer branched evolution through replication stress and impaired DNA repair.

Defining mechanisms that generate intratumour heterogeneity and branched evolution may inspire novel therapeutic approaches to limit tumour diversity and adaptation. SETD2 (Su(var), Enhancer of zeste, Trithorax-domain containing 2) trimethylates histone-3 lysine-36 (H3K36me3) at sites of active transcription and is mutated in diverse tumour types, including clear cell renal carcinomas (ccRCCs). Distinct SETD2 mutations have been identified in spatially separated regions in ccRCC, indicative of intratumour heterogeneity. In this study, we have addressed the consequences of SETD2 loss-of-function through an integrated bioinformatics and functional genomics approach. We find that bi-allelic SETD2 aberrations are not associated with microsatellite instability in ccRCC. SETD2 depletion in ccRCC cells revealed aberrant and reduced nucleosome compaction and chromatin association of the key replication proteins minichromosome maintenance complex component (MCM7) and DNA polymerase δ hindering replication fork progression, and failure to load lens epithelium-derived growth factor and the Rad51 homologous recombination repair factor at DNA breaks. Consistent with these data, we observe chromosomal breakpoint locations are biased away from H3K36me3 sites in SETD2 wild-type ccRCCs relative to tumours with bi-allelic SETD2 aberrations and that H3K36me3-negative ccRCCs display elevated DNA damage in vivo. These data suggest a role for SETD2 in maintaining genome integrity through nucleosome stabilization, suppression of replication stress and the coordination of DNA repair.

Impact on outcome of a targeted performance improvement programme in haemodynamically unstable patients with a pelvic fracture.

We describe the impact of a targeted performance improvement programme and the associated performance improvement interventions, on mortality rates, error rates and process of care for haemodynamically unstable patients with pelvic fractures. Clinical care and performance improvement data for 185 adult patients with exsanguinating pelvic trauma presenting to a United Kingdom Major Trauma Centre between January 2007 and January 2011 were analysed with univariate and multivariate regression and compared with National data. In total 62 patients (34%) died from their injuries and opportunities for improved care were identified in one third of deaths. Three major interventions were introduced during the study period in response to the findings. These were a massive haemorrhage protocol, a decision-making algorithm and employment of specialist pelvic orthopaedic surgeons. Interventions which improved performance were associated with an annual reduction in mortality (odds ratio 0.64 (95% confidence interval (CI) 0.44 to 0.93), p = 0.02), a reduction in error rates (p = 0.024) and significant improvements in the targeted processes of care. Exsanguinating patients with pelvic trauma are complex to manage and are associated with high mortality rates; implementation of a targeted performance improvement programme achieved sustained improvements in mortality, error rates and trauma care in this group of severely injured patients.

Exsheathment and midgut invasion of nocturnally subperiodic Brugia malayi microfilariae in a refractory vector, Aedes aegypti (Thailand strain).

Exsheathment and midgut invasion of nocturnally subperiodic Brugia malayi microfilariae were analyzed using light and scanning electron microscopy in a refractory vector, Aedes aegypti (Thailand strain). Results showed that exsheathed microfilariae represented only approximately 1% of the total microfilaria midguts dissected at 5-min post-infected blood meal (PIBM). The percentage of exsheathed microfilariae found in midguts progressively increased to about 20, 60, 80, 90, and 100% at 1-, 2-5-, 6-12-, 18-36-, and 48-h PIBM, respectively. Importantly, all the microfilariae penetrating the mosquito midguts were exsheathed. Midgut invasion by the exsheathed microfilariae was observed between 2- and 48-h PIBM. SEM analysis revealed sheathed microfilariae surrounded by small particles and maceration of the microfilarial sheath in the midguts, suggesting that the midguts of the refractory mosquitoes might have protein(s) and/or enzyme(s) and/or factor(s) that induce and/or accelerate exsheathment. The microfilariae penetrated the internal face of the peritrophic matrix (PM) by their anterior part and then the midgut epithelium, before entering the hemocoel suggesting that PM was not a barrier against the microfilariae migrating towards the midgut. Melanized microfilariae were discovered in the hemocoel examined at 96-h PIBM suggesting that the refractory mosquitoes used melanization reactions against this parasite. This study provided evidence that A. aegypti (Thailand strain) has refractory mechanisms against B. malayi in both midgut and hemocoel.

The characterization of the Phlebotomus papatasi transcriptome.

As important vectors of human disease, phlebotomine sand flies are of global significance to human health, transmitting several emerging and re-emerging infectious diseases. The most devastating of the sand fly transmitted infections are the leishmaniases, causing significant mortality and morbidity in both the Old and New World. Here we present the first global transcriptome analysis of the Old World vector of cutaneous leishmaniasis, Phlebotomus papatasi (Scopoli) and compare this transcriptome to that of the New World vector of visceral leishmaniasis, Lutzomyia longipalpis. A normalized cDNA library was constructed using pooled mRNA from Phlebotomus papatasi larvae, pupae, adult males and females fed sugar, blood, or blood infected with Leishmania major. A total of 47 615 generated sequences was cleaned and assembled into 17 120 unique transcripts. Of the assembled sequences, 50% (8837 sequences) were classified using Gene Ontology (GO) terms. This collection of transcripts is comprehensive, as demonstrated by the high number of different GO categories. An in-depth analysis revealed 245 sequences with putative homology to proteins involved in blood and sugar digestion, immune response and peritrophic matrix formation. Twelve of the novel genes, including one trypsin, two peptidoglycan recognition proteins (PGRP) and nine chymotrypsins, have a higher expression level during larval stages. Two novel chymotrypsins and one novel PGRP are abundantly expressed upon blood feeding. This study will greatly improve the available genomic resources for P. papatasi and will provide essential information for annotation of the full genome.

Interpretation of pediatric lung function: impact of ethnicity.

RATIONALE: To evaluate the appropriateness of spirometric and plethysmographic reference equations in healthy young children according to ethnic origin. METHODS: Spirometry data were collated in 400 healthy children (214 Black and 186 White) aged 6-12 years. Of these children, 68 Black and 115 White children also undertook plethysmography. Results were expressed as percent predicted according to commonly used equations for spirometry and plethysmography. RESULTS: Black children had lower lung function for a given height compared to White children. The magnitude and direction of these differences varied according to specific outcome. In the studied age range (6-12 years) the ethnic-specific Wang equations were adequate for spirometry (mean results approximating 100% predicted in both ethnic groups). By contrast, significant differences were found between observed and % predicted plethysmographic lung volumes according to published equations derived from White children: Among the Black children, function residual capacity (FRC) and total lung capacity (TLC) were on average, 14 and 6% lower than predicted, whereas mean residual volume (RV) and RV/TLC were 4 and 10% higher. Among White children, the Rosenthal equations gave the best fit, with the exception of FRC which was, on average, 9% lower than predicted. CONCLUSION: Spirometry equations may suffice in Black children; however, interpretation of static lung volumes in Black children is limited due to inappropriate reference equations. More appropriate plethysmographic reference equations that are applicable to all ethnic groups across the entire age range are urgently needed.

High-average-power, carrier-envelope phase-stable, few-cycle pulses at 2.1 µm from a collinear BiB3O6 optical parametric amplifier.

We generate self-carrier-to-envelope phase-stable, 630 µJ pulses, centered at 2.1 µm, with 42 fs (6 cycle) duration based on collinear optical parametric amplification in BiB(3)O(6) at 3 kHz. These pulses are generated through a traveling wave amplifier scheme, and the bandwidth supports 28 fs (4 cycle) pulse duration. Carrier-to-envelope phase stability was measured to be 410 mrad over 10 min or 260 mrad over 35 s.

Wavelength dependence of the suppressed ionization of molecules in strong laser fields.

We study ionization of molecules by an intense laser field over a broad wavelength regime, ranging from 0.8 to 1.5 µm experimentally and from 0.6 to 10 µm theoretically. A reaction microscope is combined with an optical parametric amplifier to achieve ionization yields in the near-infrared wavelength regime. Calculations are done using the strong-field S-matrix theory and agreement is found between experiment and theory, showing that ionization of many molecules is suppressed compared to the ionization of atoms with identical ionization potentials at near-infrared wavelengths at around 0.8 µm, but not at longest wavelengths (10 µm). This is due to interference effects in the electron emission that are effective at low photoelectron energies but tend to average out at higher energies. We observe the transition between suppression and nonsuppression of molecular ionization in the near-infrared wavelength regime (1-5 µm).

Sub-250-mrad, passively carrier-envelope-phase-stable mid-infrared OPCPA source at high repetition rate.

An all-optical and passively carrier-to-envelope-phase-stabilized (CEP-stabilized) optical parametric chirped pulse amplification (OPCPA) system is demonstrated with sub-250-mrad CEP stability over 11 min and better than 100 mrad over 11 s. This is achieved without any electronic CEP stabilization loop for 160 kHz pulse repetition rate in the few cycle regime.

Few-cycle pulse characterization with an acousto-optic pulse shaper.

An acousto-optic pulse shaper has been used to characterize few-cycle pulses generated in a hollow-core fiber. A grism pair precompensates for the dispersion of the acousto-optic crystal, allowing the full pulse-shaping window to be used for replica generation rather than self-compensation. A 9.4 fs pulse was measured, the shortest ever measured with an acousto-optic pulse shaper, to our knowledge.