Wounds research for patient benefit: a 5-year programme of research

Background Complex wounds are those that heal by secondary intention and include lower-limb ulcers, pressure ulcers and some surgical wounds. The care of people with complex wounds is costly, with care mainly being delivered by community nurses. There is a lack of current, high-quality data regarding the numbers and types of people affected, care received and outcomes achieved. Objectives To (1) assess how high-quality data about complex wounds can be captured effectively for use in both service planning and research while ensuring integration with current clinical data collection systems and minimal impact on staff time; (2) investigate whether or not a clinical register of people with complex wounds could give valid estimates of treatment effects, thus reducing dependence on large-scale randomised controlled trials (RCTs); (3) identify the most important research questions and outcomes for people with complex wounds from the perspectives of patients, carers and health-care professionals; (4) evaluate the potential contributions to decision-making of individual patient data meta-analysis and mixed treatment comparison meta-analysis; and (5) complete and update systematic reviews in topic areas of high priority. Methods To meet objectives 1 and 2 we conducted a prevalence survey and developed and piloted a longitudinal disease register. A consultative, deliberative method and in-depth interviews were undertaken to address objective 3. To address objectives 4 and 5 we conducted systematic reviews including mixed treatment comparison meta-analysis. Results From the prevalence survey we estimated the point prevalence of all complex wounds to be 1.47 per 1000 people (95% confidence interval 1.38 to 1.56 per 1000 people). Pressure ulcers and venous leg ulcers were the most common type of complex wound. A total of 195 people with a complex wound were recruited to a complex wounds register pilot. We established the feasibility of correctly identifying, extracting and transferring routine NHS data into the register; however, participant recruitment, data collection and tracking individual wounds in people with multiple wounds were challenging. Most patients and health professionals regarded healing of the wound as the primary treatment goal. Patients were greatly troubled by the social consequences of having a complex wound. Complex wounds are frequently a consequence of, and are themselves, a long-term condition but treatment is usually focused on healing the wound. Consultative, deliberative research agenda setting on pressure ulcer prevention and treatment with patients, carers and clinicians yielded 960 treatment uncertainties and a top 12 list of research priorities. Of 167 RCTs of complex wound treatments in a systematic review of study quality, 41% did not specify a primary outcome and the overall quality of the conduct and reporting of the research was poor. Mixed-treatment comparison meta-analysis in areas of high priority identified that matrix hydrocolloid dressings had the highest probability (70%) of being the most effective dressing for diabetic foot ulcers, whereas a hyaluronan fleece dressing had the highest probability (35%) of being the most effective dressing for venous ulcers; however, the quality of this evidence was low and uncertainty is high. Conclusions Complex wounds are common and costly with a poor evidence base for many frequent clinical decisions. There is little routine clinical data collection in community nursing. A prospective complex wounds register has the potential to both assist clinical decision-making and provide important research evidence but would be challenging to implement without investment in information technology in NHS community services. Future work should focus on developing insights into typical wound healing trajectories, identifying factors that are prognostic for healing and assessing the cost-effectiveness of selected wound treatments. Funding The National Institute for Health Research Programme Grants for Applied Research programme

Submillimetre compactness as a critical dimension to understand the main sequence of star-forming galaxies

We study the interstellar medium (ISM) properties as a function of the molecular gas size for 77 infrared-selected galaxies at z ∼ 1.3, having stellar masses 109.4 ≲ M⋆ ≲ 1012.0 M⊙ and star formation rates 12 ≲ SFRFIR ≲ 1000 M⊙ yr−1. Molecular gas sizes are measured on ALMA images that combine CO(2-1), CO(5-4), and underlying continuum observations, and include CO(4-3), CO(7-6) + [CI](3P2 − 3P1), [CI](3P1 − 3P0) observations for a subset of the sample. The ≳46 per cent of our galaxies have a compact molecular gas reservoir, and lie below the optical discs mass–size relation. Compact galaxies on and above the main sequence have higher CO excitation and star formation efficiency than galaxies with extended molecular gas reservoirs, as traced by CO(5-4)/CO(2-1) and CO(2-1)/LIR, SF ratios. Average CO + [CI] spectral line energy distributions indicate higher excitation in compacts relative to extended sources. Using CO(2-1) and dust masses as molecular gas mass tracers, and conversion factors tailored to their ISM conditions, we measure lower gas fractions in compact main-sequence galaxies compared to extended sources. We suggest that the submillimetre compactness, defined as the ratio between the molecular gas and the stellar size, is an unavoidable information to be used with the main sequence offset to describe the ISM properties of galaxies, at least above M⋆ ≥ 1010.6 M⊙, where our observations fully probe the main sequence scatter. Our results are consistent with mergers driving the gas in the nuclear regions, enhancing the CO excitation and star formation efficiency. Compact main-sequence galaxies are consistent with being an early post-starburst population following a merger-driven starburst episode, stressing the important role of mergers in the evolution of massive galaxies

Interaction Pattern of Arg 62 in the A-Pocket of Differentially Disease-Associated HLA-B27 Subtypes Suggests Distinct TCR Binding Modes

The single amino acid replacement Asp116His distinguishes the two subtypes HLA-B*2705 and HLA-B*2709 which are, respectively, associated and non-associated with Ankylosing Spondylitis, an autoimmune chronic inflammatory disease. The reason for this differential association is so far poorly understood and might be related to subtype-specific HLA:peptide conformations as well as to subtype/peptide-dependent dynamical properties on the nanoscale. Here, we combine functional experiments with extensive molecular dynamics simulations to investigate the molecular dynamics and function of the conserved Arg62 of the α1-helix for both B27 subtypes in complex with the self-peptides pVIPR (RRKWRRWHL) and TIS (RRLPIFSRL), and the viral peptides pLMP2 (RRRWRRLTV) and NPflu (SRYWAIRTR). Simulations of HLA:peptide systems suggest that peptide-stabilizing interactions of the Arg62 residue observed in crystal structures are metastable for both B27 subtypes under physiological conditions, rendering this arginine solvent-exposed and, probably, a key residue for TCR interaction more than peptide-binding. This view is supported by functional experiments with conservative (R62K) and non-conservative (R62A) B*2705 and B*2709 mutants that showed an overall reduction in their capability to present peptides to CD8+ T cells. Moreover, major subtype-dependent differences in the peptide recognition suggest distinct TCR binding modes for the B*2705 versus the B*2709 subtype

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Screening for psychological distress in patients with lung cancer: results of a clinical audit evaluating the use of the patient Distress Thermometer

Patients with lung cancer frequently suffer psychological distress and guidelines in the United Kingdom recommend screening of all cancer patients for this problem. The audit investigated use of the Distress Thermometer in terms of staff adherence to locally developed guidelines, patient willingness to use the tool, its impact on referral rates to clinical psychology services and concordance between the tool and the clinical assessment. Use of the Distress Thermometer was audited over a 3-month period in one lung cancer outpatient clinic. Referrals to clinical psychology services in response to clearly delineated referral indicators were assessed. Patient-reported outcomes were compared with practitioner assessment of need during clinical consultations to see whether the tool was measuring distress effectively. Thirty three of 34 patients used the Distress Thermometer during the audit period. Ten reported distress levels above 4 in the emotional or family problems domains. On ten occasions, the clinical interview identified problems not elicited by the Distress Thermometer. Guidelines were adhered to by staff, and patients were offered information about local support services and referral to clinical psychology services where indicated. Whilst all patients were happy to receive written information about further sources of support, none wanted to be referred to psychological services at that time. The Distress Thermometer is acceptable to patients with lung cancer in outpatient settings but it did not increase referrals for psychological support. Staff found it to be a useful tool in opening up communication about patient issues although it should not replace a comprehensive clinical interview

HLA-associated susceptibility to childhood B-cell precursor ALL: definition and role of HLA-DPB1 supertypes

Childhood B-cell precursor (BCP) ALL is thought to be caused by a delayed immune response to an unidentified postnatal infection. An association between BCP ALL and HLA class II (DR, DQ, DP) alleles could provide further clues to the identity of the infection, since HLA molecules exhibit allotype-restricted binding of infection-derived antigenic peptides. We clustered >30 HLA-DPB1 alleles into six predicted peptide-binding supertypes (DP1, 2, 3, 4, 6, and 8), based on amino acid di-morphisms at positions 11 (G/L), 69 (E/K), and 84 (G/D) of the DPβ1 domain. We found that the DPβ11-69-84 supertype GEG (DP2), was 70% more frequent in BCP ALL (n=687; P<10−4), and 98% more frequent in cases diagnosed between 3 and 6 years (P<10−4), but not <3 or >6 years, than in controls. Only one of 21 possible DPB1 supergenotypes, GEG/GKG (DP2/DP4) was significantly more frequent in BCP ALL (P=0.00004) than controls. These results suggest that susceptibility to BCP ALL is associated with the DP2 supertype, which is predicted to bind peptides with positively charged, nonpolar aromatic residues at the P4 position, and hydrophobic residues at the P1 and P6 positions. Studies of peptide binding by DP2 alleles could help to identify infection(s) carrying these peptides

Feeder layer- and animal product-free culture of neonatal foreskin keratinocytes: improved performance, usability, quality and safety

Since 1987, keratinocytes have been cultured at the Queen Astrid Military Hospital. These keratinocytes have been used routinely as auto and allografts on more than 1,000 patients, primarily to accelerate the healing of burns and chronic wounds. Initially the method of Rheinwald and Green was used to prepare cultured epithelial autografts, starting from skin samples from burn patients and using animal-derived feeder layers and media containing animal-derived products. More recently we systematically optimised our production system to accommodate scientific advances and legal changes. An important step was the removal of the mouse fibroblast feeder layer from the cell culture system. Thereafter we introduced neonatal foreskin keratinocytes (NFK) as source of cultured epithelial allografts, which significantly increased the consistency and the reliability of our cell production. NFK master and working cell banks were established, which were extensively screened and characterised. An ISO 9001 certified Quality Management System (QMS) governs all aspects of testing, validation and traceability. Finally, as far as possible, animal components were systematically removed from the cell culture environment. Today, quality controlled allograft production batches are routine and, due to efficient cryopreservation, stocks are created for off-the-shelf use. These optimisations have significantly increased the performance, usability, quality and safety of our allografts. This paper describes, in detail, our current cryopreserved allograft production process

'Care and Prevent': rationale for investigating skin and soft tissue infections and AA amyloidosis among people who inject drugs in London.

BACKGROUND: Skin and soft tissue infections (SSTIs) are a leading cause of morbidity and mortality among people who inject drugs (PWID). International data indicate up to one third of PWID have experienced an SSTI within the past month. Complications include sepsis, endocarditis and amyloid A (AA) amyloidosis. AA amyloidosis is a serious sequela of chronic SSTI among PWID. Though there is a paucity of literature reporting on AA amyloidosis among PWID, what has been published suggests there is likely a causal relationship between AA amyloidosis and injecting-related SSTI. If left untreated, AA amyloidosis can lead to renal failure; premature mortality among diagnosed PWID is high. Early intervention may reverse disease. Despite the high societal and individual burden of SSTI among PWID, empirical evidence on the barriers and facilitators to injecting-related SSTI prevention and care or the feasibility and acceptability of AA amyloidosis screening and treatment referral are limited. This study aims to fill these gaps and assess the prevalence of AA amyloidosis among PWID. METHODS: Care and Prevent is a UK National Institute for Health Research-funded mixed-methods study. In five phases (P1-P5), we aim to assess the evidence for AA amyloidosis among PWID (P1); assess the feasibility of AA amyloidosis screening, diagnostic and treatment referral among PWID in London (P2); investigate the barriers and facilitators to AA amyloidosis care (P3); explore SSTI protection and risk (P4); and co-create harm reduction resources with the affected community (P5). This paper describes the conceptual framework, methodological design and proposed analysis for the mixed-methods multi-phase study. RESULTS: We are implementing the Care and Prevent protocol in London. The systematic review component of the study has been completed and published. Care and Prevent will generate an estimate of AA amyloidosis prevalence among community recruited PWID in London, with implications for the development of screening recommendations and intervention implementation. We aim to recruit 400 PWID from drug treatment services in London, UK. CONCLUSIONS: Care and Prevent is the first study to assess screening feasibility and the prevalence of positive proteinuria, as a marker for AA amyloidosis, among PWID accessing drug treatment services. AA amyloidosis is a serious, yet under-recognised condition for which early intervention is available but not employed

DNA topoisomerase I and II expression in drug resistantgerm cell tumours

A small number of testicular germ cell tumours are refractory to current chemotherapy regimens. DNA topoisomerase I is the target for several new drugs and a potential candidate treatment for chemorefractory germ cell tumours. DNA topoisomerase IIα is the target for etoposide, which is currently used regularly in germ cell tumour treatment. The expression of DNA topoisomerase I and IIα were therefore assessed immunohistochemically in a range of testicular tumours, especially those with persistent malignant elements on retroperitoneal lymph node dissection. Pre-chemotherapy orchidectomy specimens were matched with post-chemotherapy retroperitoneal lymph node dissections to examine changes in expression. There was considerable variation in the expression of topoisomerase I in different tumour types. Both yolk sac tumours and teratoma, mature showed universal expression of topoisomerase I, while 38% of seminomas and 30% of embryonal carcinomas were positive. Strong topoisomerase IIα expression was found in embryonal carcinoma. There was a negative correlation between topoisomerase I and IIα expression (P=0.004) and downregulation of topoisomerase IIα after chemotherapy (P=0.02). Topoisomerase I expression appears to increase in those cases with residual teratoma, mature, but is largely unchanged in those cases remaining as embryonal carcinoma. These results suggest that topoisomerase I inhibitors may be useful in chemorefractory germ cell tumours, especially yolk sac tumours and where there are unresectable residual teratoma, mature deposits