Placing the keystone: the LIMBIC Military and Tactical Athlete Research Study.

OBJECTIVE: The LIMBIC Military and Tactical Athletic Research Study (MATARS) framework was established to confirm and extend understanding of concussion with initial studies driven by clinical data collected between 2015 and 2020 in a collegiate sports setting. The LIMBIC MATARS framework will be leveraged to apply gold-standard and innovative research designs to advance the science of concussion. This manuscript provides the background, methodology, and initial demographic data associated with the LIMBIC MATARS. METHODS: Consensus-based common data elements were used to conduct a retrospective chart review, specific to collegiate athletes diagnosed with concussions between 2015 and 2020 at 11 universities. RESULTS: A final sample of 1,311 (47.8% female) concussions were diagnosed during the five-year study period from athletes participating in a variety of National Collegiate Athlete Association (NCAA) sports. The LIMBIC MATARS demographic data, align with the NCAA and other pioneering multi-site concussion-related studies in terms of biological sex, race and ethnicity, and sport participation. CONCLUSION: This pragmatic, methodological approach was used to address several a priori hypotheses related to concussion, align with other multi-site studies of concussion, and establish a consortium for future investigations.

Lost in translation: the association of international status and native language on concussion in collegiate athletes in the United States.

OBJECTIVE: The purpose of this study was to characterize the associations of international student status and native language on time (in days) with the date of injury to (i) diagnosis, (ii) symptom resolution, and (iii) return to sport. METHODS: Utilizing data from a cross-sectional cohort of 1,044 concussion cases from LIMBIC MATARS member institutions (n = 11) in the US, we conducted two, matched case-control designs. Cases were divided into two groups: (i) international (n = 32) or domestic students (n = 32) and (ii) English as an Additional Language (EAL) speakers (n = 18) or Native English language speakers (n = 18). Both groups were individually matched to their respective controls based on gender, age, sport, and preexisting health conditions. RESULTS: There were no significant differences in days from injury to diagnosis (p = 0.94), symptom resolution (p = 0.64), or return to sport (p = 0.15) between international and domestic athletes. EAL speakers experienced symptom resolution approximately 7.5 days sooner (Md = 4.50; IQR = 4.00, 8.00) than Native English language speakers (Md = 12.00; IQR = 7.00, 21.00, p = 0.01). CONCLUSIONS: Our findings suggest that native language is associated with symptom resolution in collegiate athletes. Healthcare professionals should consider barriers related to native language that may impact symptom reporting and the overall injury experience of diverse collegiate athletes.

Racial identity and concussion diagnosis and recovery trajectories in collegiate athletes: a LIMBIC MATARS investigation.

OBJECTIVE: To determine if there were concussion diagnosis and recovery disparities between collegiate athletes with Black and White racial identities. DESIGN: Retrospective cohort study. METHODS: Concussion information was extracted from NCAA athlete medical files at LIMBIC MATARS member institutions from the 2015-16' to 2019-20' academic years. A total of 410 concussions from 9 institutions were included that provided all independent (i.e. racial identity of Black or White) and dependent variable information (i.e. dates of injury, diagnosis, symptom resolution, and return to sport) that were analyzed using Mann-Whitney U tests. The sample consisted of 114 (27.8%) concussions sustained by Black athletes and 296 (72.1%) sustained by White athletes. RESULTS: The overall sample had a median of 0 days between injury occurrence to diagnosis, 7 days to symptom resolution, and 12 days to return to sport. No significant timing differences were observed for concussion diagnosis (p = .14), symptom resolution (p = .39), or return to sport (p = 0.58) between collegiate athletes with Black versus White racial identities. CONCLUSIONS: These findings may reflect equitable access to onsite sports medicine healthcare resources that facilitate concussion management in the collegiate sport setting. Future work should explore these associations with a larger and more diverse sample of collegiate athletes.

Metal-Organic Frameworks for Drug Delivery: A Design Perspective.

The use of metal-organic frameworks (MOFs) in biomedical applications has greatly expanded over the past decade due to the precision tunability, high surface areas, and high loading capacities of MOFs. Specifically, MOFs are being explored for a wide variety of drug delivery applications. Initially, MOFs were used for delivery of small-molecule pharmaceuticals; however, more recent work has focused on macromolecular cargos, such as proteins and nucleic acids. Here, we review the historical application of MOFs for drug delivery, with a specific focus on the available options for designing MOFs for specific drug delivery applications. These options include choices of MOF structure, synthetic method, and drug loading. Further considerations include tuning, modifications, biocompatibility, cellular targeting, and uptake. Altogether, this Review aims to guide MOF design for novel biomedical applications.

Palmitate-Induced IRE1-XBP1-ZEB Signaling Represses Desmoplakin Expression and Promotes Cancer Cell Migration.

Elevated uptake of saturated fatty acid palmitate is associated with metastatic progression of cancer cells; however, the precise signaling mechanism behind the phenomenon is unclear. The loss of cell adhesion proteins, such as desmoplakin (DSP), is a key driving event in the transformation of cancer cells to more aggressive phenotypes. Here, we investigated the mechanism by which palmitate induces the loss of DSP in liver and breast cancer cells. We propose that palmitate activates the IRE1-XBP1 branch of the endoplasmic reticulum (ER) stress pathway to upregulate the ZEB transcription factor, leading to transcriptional repression of DSP. Using liver and breast cancer cells treated with palmitate, we found loss of DSP leads to increased cell migration independent of E-cadherin. We report that the ZEB family of transcription factors function as direct transcriptional repressors of DSP. CRISPR-mediated knockdown of IRE1 confirmed that the transcription of ZEB, loss of DSP, and enhanced migration in the presence of palmitate is dependent on the IRE1-XBP1 pathway. In addition, by analyzing the somatic expression and copy number variation profiles of over 11,000 tumor samples, we corroborate our hypothesis and establish the clinical relevance of DSP loss via ZEB in human cancers. IMPLICATIONS: Provides mechanistic link on palmitate-induced activation of IRE1α to cancer cell migration.

Modulating Polymer-siRNA Binding Does Not Promote Polyplex-Mediated Silencing.

The development of delivery vehicles for small interfering RNAs (siRNAs) remains a bottleneck to widespread clinical use. Cationic polymers represent an important class of potential delivery vehicles. In this study, we used alkyne-azide click chemistry to synthesize a variety of cationic poly(propargyl glycolide) backbone polymers to bind and deliver siRNAs. We demonstrated control over the binding interactions of these polymers and siRNAs by varying binding strength by more than three orders of magnitude. Binding strength was found to meet or exceed that of commercially available transfection agents. Our polymers effectively delivered siRNAs with no detectable cytotoxicity. Despite accumulation of siRNAs at levels comparable with commercial reagents, we did not observe silencing of the targeted protein. The implications of our results for future siRNA delivery vehicle design are discussed.

Kinetic analysis of the intracellular processing of siRNAs by confocal microscopy.

Here, we describe a method for tracking intracellular processing of small interfering RNA (siRNA) containing complexes using automated microscopy controls and image acquisition to minimize user effort and time. This technique uses fluorescence colocalization to monitor dual-labeled fluorescent siRNAs delivered by silica nanoparticles in different intracellular locations, including the early/late endosomes, fast/slow recycling endosomes, lysosomes and the endoplasmic reticulum. Combining the temporal association of siRNAs with each intracellular location, we reconstructed the intracellular pathways used in siRNA processing, and demonstrate how these pathways vary based on the chemical composition of the delivery vehicle.

Adjuvant statin therapy for oesophageal adenocarcinoma: the STAT-ROC feasibility study.

BACKGROUND: Statins inhibit proliferative signalling in oesophageal adenocarcinoma (OAC) and their use is associated with better survival in observational studies. The present study was undertaken to examine the feasibility of assessing adjuvant statin therapy in patients with operable OAC in a phase III RCT. METHODS: For this multicentre, double-blind, parallel-group, randomized, placebo-controlled feasibility trial, adults with OAC (including Siewert I-II lesions) who had undergone oesophagectomy were centrally allocated (1 : 1) to simvastatin 40 mg or matching placebo by block randomization, stratified by centre. Participants, clinicians and investigators were blinded to treatment allocation. Patients received treatment for up to 1 year. Feasibility outcomes were recruitment, retention, drug absorption, adherence, safety, quality of life, generalizability and survival. RESULTS: A total of 120 patients were assessed for eligibility at four centres, of whom 32 (26·7 per cent) were randomized, 16 in each group. Seven patients withdrew. Participants allocated to simvastatin had lower low-density lipoprotein cholesterol levels by 3 months (adjusted mean difference -0·83 (95 per cent c.i. -1·4 to -0·22) mmol/l; P = 0·009). Median adherence to medication was greater than 90 per cent between 3 and 12 months' follow-up. Adverse events were similar between the groups. Quality-of-life data were complete for 98·3 per cent of questionnaire items. Cardiovascular disease, diabetes and aspirin use were more prevalent in the non-randomized group, whereas tumour site, stage and grade were similar between groups. Survival estimates were imprecise. CONCLUSION: This RCT supports the conduct and informs the design considerations for a future phase III trial of adjuvant statin therapy in patients with OAC. Registration number: ISRCTN98060456 (www.isrctn/com).

ANTECEDENTES: Las estatinas inhiben las señalizaciones proliferativas en el adenocarcinoma de esófago (oesophageal adenocarcinoma, OAC) y su uso se asocia con mejor supervivencia en estudios observacionales. El presente estudio se llevó a cabo para examinar la viabilidad de evaluar el tratamiento adyuvante con estatinas en pacientes con OAC operable en un ensayo aleatorizado y controlado de fase III. MÉTODOS: En este ensayo de viabilidad controlado por placebo, aleatorizado, de grupos paralelos, doble ciego y multicéntrico, los pacientes adultos con OAC (incluyendo lesiones Siewert I/II) que fueron sometidos a esofaguectomía se asignaron de forma centralizada (1:1) a tratamiento con simvastatina 40 mg o placebo equivalente mediante aleatorización en bloques, estratificados por centro. Los participantes, los clínicos y los investigadores desconocían la asignación del tratamiento. Los pacientes recibieron el tratamiento hasta un año. Los resultados de viabilidad fueron reclutamiento, retención, absorción del fármaco, adherencia, seguridad, calidad de vida, generalización, y supervivencia. RESULTADOS: Un total de 120 pacientes fueron evaluados para elegibilidad en 4 centros, de los cuales 32 (26,7%) fueron aleatorizados, 16 en cada grupo. Siete pacientes abandonaron el ensayo. Los pacientes asignados a tratamiento con simvastatina tenían niveles de colesterol LDL más bajos a los 3 meses (diferencia media ajustada, −0,83 mmol/L, i.c. del 95% −1,4 a −0,22, P = 0,009). La mediana de la adherencia a la medicación fue mayor del 90% entre los 3-12 meses de seguimiento. Los eventos adversos fueron similares entre los grupos. Los datos de calidad de vida estaban completos en el 98,3% de las preguntas del cuestionario. Enfermedad cardiovascular, diabetes y uso de aspirina eran más prevalentes en el grupo no aleatorizado, mientras que la localización del tumor, el estadio y el grado fueron similares entre los grupos. Las estimaciones de supervivencia fueron imprecisas. CONCLUSIÓN: Este RCT apoya la realización e informa de las consideraciones de diseño para un futuro ensayo de fase III de tratamiento adyuvante con estatinas en pacientes con OAC.

The 2020 International Alliance for the Control of Scabies Consensus Criteria for the Diagnosis of Scabies.

BACKGROUND: Scabies is a common parasitic skin condition that causes considerable morbidity globally. Clinical and epidemiological research for scabies has been limited by a lack of standardization of diagnostic methods. OBJECTIVES: To develop consensus criteria for the diagnosis of common scabies that could be implemented in a variety of settings. METHODS: Consensus diagnostic criteria were developed through a Delphi study with international experts. Detailed recommendations were collected from the expert panel to define the criteria features and guide their implementation. These comments were then combined with a comprehensive review of the available literature and the opinion of an expanded group of international experts to develop detailed, evidence-based definitions and diagnostic methods. RESULTS: The 2020 International Alliance for the Control of Scabies (IACS) Consensus Criteria for the Diagnosis of Scabies include three levels of diagnostic certainty and eight subcategories. Confirmed scabies (level A) requires direct visualization of the mite or its products. Clinical scabies (level B) and suspected scabies (level C) rely on clinical assessment of signs and symptoms. Evidence-based, consensus methods for microscopy, visualization and clinical symptoms and signs were developed, along with a media library. CONCLUSIONS: The 2020 IACS Criteria represent a pragmatic yet robust set of diagnostic features and methods. The criteria may be implemented in a range of research, public health and clinical settings by selecting the appropriate diagnostic levels and subcategories. These criteria may provide greater consistency and standardization for scabies diagnosis. Validation studies, development of training materials and development of survey methods are now required. What is already known about this topic? The diagnosis of scabies is limited by the lack of accurate, objective tests. Microscopy of skin scrapings can confirm the diagnosis, but it is insensitive, invasive and often impractical. Diagnosis usually relies on clinical assessment, although visualization using dermoscopy is becoming increasingly common. These diagnostic methods have not been standardized, hampering the interpretation of findings from clinical research and epidemiological surveys, and the development of scabies control strategies. What does this study add? International consensus diagnostic criteria for common scabies were developed through a Delphi study with global experts. The 2020 International Alliance for the Control of Scabies (IACS) Criteria categorize diagnosis at three levels of diagnostic certainty (confirmed, clinical and suspected scabies) and eight subcategories, and can be adapted to a range of research and public health settings. Detailed definitions and figures are included to aid training and implementation. The 2020 IACS Criteria may facilitate the standardization of scabies diagnosis.

Endocytosis Controls siRNA Efficiency: Implications for siRNA Delivery Vehicle Design and Cell-Specific Targeting.

While small interfering RNAs (siRNAs) are commonly used for laboratory studies, development of siRNA therapeutics has been slower than expected, due, in part, to a still limited understanding of the endocytosis and intracellular trafficking of siRNA-containing complexes. With the recent characterization of multiple clathrin-/caveolin-independent endocytic pathways, that is, those mediated by Graf1, Arf6, and flotillin, it has become clear that the endocytic mechanism influences subsequent intracellular processing of the internalized cargo. To explore siRNA delivery in light of these findings, we developed a novel assay that differentiates uptake by each of the endocytic pathways and can be used to determine whether endocytosis by a pathway leads to the initiation of RNA interference (RNAi). Using Lipofectamine 2000 (LF2K), we determined the endocytosis pathway leading to active silencing (whether by clathrin, caveolin, Arf6, Graf1, flotillin, or macropinocytosis) across multiple cell types (HeLa, H1299, HEK293, and HepG2). We showed that LF2K is internalized by Graf1-, Arf6-, or flotillin-mediated endocytosis for the initiation of RNAi, depending on cell type. In addition, we found that a portion of siRNA-containing complexes is internalized by pathways that do not lead to initiation of silencing. Inhibition of these pathways enhanced intracellular levels of siRNAs with concomitant enhancement of silencing.

Relative Quantification of siRNA Strand Loading into Ago2 for Design of Highly Active siRNAs.

In RNA interference (RNAi), silencing is achieved through the interaction of double-stranded small interfering RNAs (siRNAs) with essential RNAi pathway proteins, including Argonaute 2 (Ago2). Based on these interactions, one strand of the siRNA is loaded into Ago2 forming the active RNA-induced silencing complex (RISC). Optimal siRNAs maximize RISC activity against the intended target and minimize off-target silencing. To achieve the desired activity and specificity, selection of the appropriate siRNA strand for loading into Ago2 is essential. Here, we provide a protocol to quantify the relative loading of individual siRNA strands into Ago2, one factor in determining the capacity of a siRNA to achieve silencing activity and target specificity.

Vitrification of in vitro-derived bovine embryos: targeting enhancement of quality by refining technology and standardising procedures.

Bovine invitro fertilisation technology has been widely exploited in commercial settings. The majority of invitro-derived cattle embryos are transferred into recipient cows as recently collected (i.e. 'fresh') embryos due to the lack of a reliable cryopreservation method that results in favourable pregnancy rates following transfer of thawed embryos. This is a primary reason for the poor industry uptake of this extreme temperature freezing process. Numerous investigations into vitrification have revealed the importance of rapid cooling and warming rates, enhancing embryo viability after cryopreservation compared with conventional slow freezing. Those studies spawned a considerable assortment of cryovessels and diversity of procedures, delivering variable rates of success, which makes performing vitrification consistently a practical challenge. Hence, further research is required in order to both optimise and standardise vitrification methodology and to design a cryovessel that enables direct transfer of vitrified embryos to recipients after warming. In parallel with improvements in vitrification, it is important to continue to raise the quality of invitro-derived cattle embryos through modifications in laboratory culture techniques. The twin goals of methodology refinement and standardisation, leading to embryo quality enhancement, are each imperative if invitro fertilisation technology is to be adopted in the field.

Impact of prenatal and postnatal maternal environment on nephron endowment, renal function and blood pressure in the Lewis polycystic kidney rat.

Maternal insufficiency during fetal development can have long-lasting effects on the offspring, most notably on nephron endowment. In polycystic kidney disease (PKD), variability in severity of disease is observed and maternal environment may be a modifying factor. In this study, we first established that in a rodent model of PKD, the Lewis polycystic kidney (LPK) rat's nephron numbers are 25% lower compared with wildtype animals. We then investigated the effects of prenatal and postnatal maternal environment on phenotype and nephron number. LPK pups born from and raised by homozygous LPK dams (control) were compared with LPK pups cross-fostered onto heterozygous LPK dams to improve postnatal environment; with LPK pups born from and raised by heterozygous LPK dams to improve both prenatal and postnatal environment and with LPK pups born from and raised by Wistar Kyoto-LPK heterozygous dams to improve both prenatal and postnatal environment on a different genetic background. Improvement in both prenatal and postnatal environment improved postnatal growth, renal function and reduced blood pressure, most notably in animals with different genetic background. Animals with improved postnatal environment only showed improved growth and blood pressure, but to a lesser extent. All intervention groups showed increased nephron number compared with control LPK. In summary, prenatal and postnatal environment had significant effect in delaying progression and reducing severity of PKD, including nephron endowment.

Infliximab is associated with an increased risk of serious infection in patients with psoriasis in the U.K. and Republic of Ireland: results from the British Association of Dermatologists Biologic Interventions Register (BADBIR).

BACKGROUND: Patients with psoriasis and clinicians are concerned that infliximab may be associated with a risk of serious infections. OBJECTIVES: To compare the risk of serious infections associated with infliximab in patients with chronic plaque psoriasis against a cohort on nonbiologic systemic therapies. METHODS: A prospective cohort study was performed using data from the British Association of Dermatologists Biologic Interventions Register (BADBIR). Infliximab was compared with nonbiologic systemic therapies, inclusive of any exposure to methotrexate, ciclosporin, acitretin, fumaric acid esters, psoralen-ultraviolet A or hydroxycarbamide. Serious infections were those associated with hospitalization, the use of intravenous antimicrobial therapy and/or those that led to death. Propensity score inverse probability treatment weights were used to adjust for potential confounding from a priori identified covariates. Cox proportional hazards models were calculated to obtain hazard ratios (HRs). RESULTS: In total, 3843 participants were included for analysis up to October 2016. The incidence rates were significantly higher in the infliximab cohort (47·8 per 1000 person-years) [95% confidence interval (CI) 35·7-64·0], compared with 14·2 per 1000 person-years (95% CI 11·5-17·4) in the nonbiologic systemic cohort. Infliximab was associated with an overall increase in the risk of serious infection compared with nonbiologics [adjusted HR (adjHR) 1·95, 95% CI 1·01-3·75] and methotrexate only (adjHR 2·96, 95% CI 1·58-5·57) and a higher risk of serious infection in the first 6 months of therapy (adjHR 3·49, 95% CI 1·14-10·70). CONCLUSIONS: Infliximab is associated with an increased risk of serious infections compared with nonbiologic systemic therapies in patients with psoriasis in the U.K. and the Republic of Ireland.

Does the Addition of Salubrinal to in vitro Maturation Medium Enhance Bovine Blastocyst Yields and Embryo Cryotolerance?

BACKGROUND: Modifications to in vitro maturation (IVM) media are made to improve rates of blastocyst formation and quality of mammalian embryos. Embryo quality is an important factor in the viability of embryos following cryopreservation. Salubrinal is a specific inhibitor of endoplasmic reticulum stress-induced apoptosis in eukaryotic cells. Here, it was added to IVM medium in an attempt to increase blastocyst formation and to enhance embryo quality in cattle. OBJECTIVE: To assess the effect on blastocyst formation and cryotolerance of the supplementation of salubrinal to bovine IVM medium. MATERIALS AND METHODS: Cumulus-oocyte complexes (COCs) collected from slaughterhouse ovaries were assigned randomly to two groups, either cultured in IVM medium that was supplemented with 400 mM salubrinal (treated, 262 COCs) or that was not supplemented (control, 263 COCs). All oocytes of the matured COCs were fertilized in vitro with sperm from the same proven bull and cultured for 6-7 d. At the time of blastocyst collection, expanded blastocysts were chosen for cryopreservation, while early, hatching and hatched blastocysts and those of poor quality were not used. There were 83 expanded blastocysts classified to be of good quality in both the control and salubrinal-treated groups that were subjected to vitrification. After 5 to 10 months of cold storage, the embryos were warmed and cultured in vitro for 24 h to assess the survival rate and for 48 h to assess the hatching rate. RESULTS: The blastocyst developmental rate in the salubrinal-treated group was similar to that in the control group, 61.5% compared with 62.7% (P > 0.05). The survival rate of blastocysts after vitrification was also similar, at or very close to 100%. In addition, there was no statistically significant difference in the hatching rate of expanded blastocysts derived from the COCs cultured with (treated) and without (control) addition of salubrinal to the IVM medium (91.6% compared with 85.5%; P > 0.05). CONCLUSION: Supplementation of salubrinal to the IVM medium neither improved nor reduced rates of bovine blastocyst formation and of embryo cryotolerance as determined by post-warming viability.

Prospective study in bullous pemphigoid: association of high serum anti-BP180 IgG levels with increased mortality and reduced Karnofsky score.

BACKGROUND: Bullous pemphigoid (BP) is a subepidermal blistering disease characterized by autoantibodies against the two hemidesmosomal proteins, BP180 (type XVII collagen) and BP230. The multicentre prospective BLISTER (Bullous Pemphigoid Steroids and Tetracyclines) trial randomized 253 patients with BP to compare the benefits and harms between initial treatment with doxycycline or prednisolone. OBJECTIVES: To analyse distinct autoantibody profiles for the prediction of the disease course in a well-characterized cohort of BP sera. METHODS: One hundred and forty-three patients of the BLISTER trial consented to participate in this serological study. Sera taken at baseline were analysed by (i) indirect immunofluorescence, (ii) anti-BP180 NC16A (16th noncollagenous domain) and anti-BP230 enzyme-linked immunosorbent assay and (iii) immunoblotting with various substrates. Results were then linked with clinical parameters including age, Karnofsky score, number of blisters, related adverse events and mortality. RESULTS: Disease activity correlated with immunoglobulin (Ig)G anti-BP180 levels but not with levels of anti-BP230 IgG and anti-BP180 IgE. High levels of both anti-BP180 IgG and anti-BP230 IgG were associated with a low Karnofsky score. The presence of anti-BP230 IgG was more frequent in older patients. Those with higher total IgE serum levels suffered from fewer adverse events. Higher IgG anti-BP180 levels were associated with an increased 1-year mortality rate. CONCLUSIONS: Analysis of the autoantibody profile is not only of diagnostic relevance but may also be helpful in predicting the course of the disease.

Urological sequelae of desmoids associated with familial adenomatous polyposis.

The aim of this retrospective cohort study was to review urological complication rates arising from familial adenomatous polyposis associated desmoid tumours and their management. All patients over a 35-year period were identified from a prospectively maintained polyposis registry database and had an intra-abdominal desmoid tumour. Those without ureteric complications (n = 118, group A) were compared to those that developed ureteric obstruction (n = 40, group B) for demographics, treatment interventions and survival outcomes. 158 (56% female) patients were identified. Median age at diagnosis was 31 years and desmoids typically occurred 3.6 years after colectomy for familial adenomatous polyposis. Ureteric obstruction secondary to tumour growth occurred in 25% of cases. There was no significant difference in gender distribution or overall age at desmoid diagnosis between the two groups. In group B, the median age at desmoid diagnosis was significantly younger in women compared to men (25 and 43 years, respectively) (p = 0.01). Thirty-eight percent of patients already had ureteric obstruction at desmoid diagnosis, the remainder occurred after 48.6 months, but 20 years in two cases. Seventy-three percent (29/40) had ureteric stenting, a long-term requirement for most. Permanent renal injury occurred in six cases but survival between the two groups was not significantly different. Ureteric obstruction occurs frequently in patients with familial adenomatous polyposis and an intra-abdominal desmoid tumour. Those most at risk are the young following colectomy. Clinicians should actively survey the renal tract at regular intervals after a diagnosis of an intra-abdominal desmoid tumour as complications can arise insidiously, at any stage.

Doxycycline compared with prednisolone therapy for patients with bullous pemphigoid: cost-effectiveness analysis of the BLISTER trial.

BACKGROUND: Bullous pemphigoid (BP) is an autoimmune blistering skin disorder associated with significant morbidity and mortality. Doxycycline and prednisolone to treat bullous pemphigoid were compared within a randomized controlled trial (RCT). OBJECTIVES: To compare the cost-effectiveness of doxycycline-initiated and prednisolone-initiated treatment for patients with BP. METHODS: Quality-of-life (EuroQoL-5D-3L) and resource data were collected as part of the BLISTER trial: a multicentre, parallel-group, investigator-blinded RCT. Within-trial analysis was performed using bivariate regression of costs and quality-adjusted life-years (QALYs), with multiple imputation of missing data, informing a probabilistic assessment of incremental treatment cost-effectiveness from a health service perspective. RESULTS: In the base case, there was no robust difference in costs or QALYs per patient at 1 year comparing doxycycline- with prednisolone-initiated therapy [net cost £959, 95% confidence interval (CI) -£24 to £1941; net QALYs -0·024, 95% CI -0·088 to 0·041]. However, the findings varied by baseline blister severity. For patients with mild or moderate blistering (≤ 30 blisters) net costs and outcomes were similar. For patients with severe blistering (> 30 blisters) net costs were higher (£2558, 95% CI -£82 to £5198) and quality of life poorer (-0·090 QALYs, 95% CI -0·22 to 0·042) for patients starting on doxycycline. The probability that doxycycline would be cost-effective for those with severe pemphigoid was 1·5% at a willingness to pay of £20 000 per QALY. CONCLUSIONS: Consistently with the clinical findings of the BLISTER trial, patients with mild or moderate blistering should receive treatment guided by the safety and effectiveness of the drugs and patient preference - neither strategy is clearly a preferred use of National Health Service resources. However, prednisolone-initiated treatment may be more cost-effective for patients with severe blistering.

The electronic and optical properties of the sulvanite compounds: a many-body perturbation and time-dependent density functional theory study.

We have studied, by means of first-principles calculations, the electronic and optical properties of the sulvanite family: Cu3MX4 (M = V, Nb, Ta and X = S, Se), which, due to its broad range of gaps and chemical stability, have emerged as promising materials for technological applications such as photovoltaics and transparent conductivity. To address the reliability of those properties we have used semi-local and hybrid functionals (PBEsol, HSE06), many-body perturbation theory (G0W0 approximation and Bethe-Salpeter equation), and time-dependent density functional theory (revised bootstrap kernel) to calculate the quasi-particle dispersion relation, band gaps, the imaginary part of the macroscopic dielectric function and the absorption coefficient. The calculated valence band maximum and the conduction band minimum are located at the R and X-points, respectively. The calculated gaps using PBEsol are between 0.81 and 1.88 eV, with HSE06 into 1.73 and 2.94 eV, whereas the G0W0 values fall into the 1.91-3.19 eV range. The calculated dielectric functions and absorption coefficients show that all these compounds present continuous excitonic features when the Bethe-Salpeter equation is used. Contrarily, the revised bootstrap kernel is incapable of describing the excitonic spectra. The calculated optical spectra show that Cu3VS4 and Cu3MSe4 have good absorption in the visible, whereas Cu3NbS4 and Cu3TaS4 have it on the near ultraviolet.

Generating new evidence, improving clinical practice and developing research capacity: the benefits of recruiting to the U.K. Dermatology Clinical Trials Network's STOP GAP and BLISTER trials.

Clinical trials may benefit clinical practice in three ways: firstly, clinicians may change their practice according to the new trial evidence; secondly, clinical processes can improve when working on a trial; and thirdly, research capacity is increased. We held a meeting to present and discuss the results of two large multicentre randomized controlled trials delivered through the U.K. Dermatology Clinical Trials Network. Investigators gave reflections on how the trials had changed their clinical practice. The STOP GAP trial showed that prednisolone and ciclosporin are equally effective as first-line systemic treatment for pyoderma gangrenosum. The final decision of which treatment to use should be based on the different adverse event profiles of the two drugs in relation to comorbidities, along with age, disease severity and patient preference. The BLISTER trial showed that starting people with pemphigoid on doxycycline produces acceptable short-term effectiveness and a superior safety profile to oral corticosteroids. Recruiting to these trials has led to the development of new specialist clinics with improved documentation. It has increased the profile of participating departments and embedded research in the department's activities. Helping to design and run these trials has also allowed trial staff to develop new skills in research design, which has been beneficial for career development. These and other benefits of recruiting to the trials are summarized here. We hope that these reflections will inspire wider involvement in clinical research.