Conservative treatment for acute ankle sprain : a systematic review

The aim was to identify conservative treatments available for acute ankle sprain and to evaluate their effectiveness with respect to pain relief and short-term recovery of functional capacity. A systematic review of the relevant literature was conducted via a data search of the PROSPERO, PubMed, Scopus, CINAHL, PyscINFO and SPORTDiscus databases, from inception until December 2019, focusing on randomised control trial studies. Two of the authors independently assessed the quality of each study located and extracted the relevant data. The quality of each paper was assessed using the Cochrane risk of bias tool included in RevMan 5. In all, 20 studies met the inclusion criteria. In terms of absence of bias, only nine papers were classed as “high quality”. Studies (75%) were of low quality in terms of the blinding of participants and personnel and uncertainty in blinding of outcome assessment and all presented one or more other forms of bias. Despite the generally low quality of the studies considered, it can be concluded that conservative treatment for acute ankle sprain normally achieves pain relief and rapidly improved functionality. Research based on higher-quality study designs and procedures would enable more definitive conclusions to be drawn

Provision of care services for rheumatic and musculoskeletal diseases-related foot and ankle problems: a survey from sixteen european countries

DOI:10.1136/annrheumdis-2016-eular.4435Background: The increased prevalence of foot and ankle pathologies in Rheumatic and Musculoskeletal diseases (RMDs) is well documented1, however the provision of foot & ankle (F&A) healthcare services for people with RMDs in Europe has not been evaluated. Objectives: To assess the current healthcare systems for providing foot & ankle healthcare services for people with RMDs in Europe. Methods: A survey was undertaken to evaluate current provision of F&A health care services for people with RMDs across Europe. A questionnaire was distributed to all 22 country presidents representing HP associations within EULAR. The questionnaire used was developed and piloted (in 7 countries) by the EULAR F&A Study Group, and structured to capture the provision and type of F&A services for people with RMDs. When the HP presidents felt unable to answer specific questions they were encouraged to consult a colleague who may be better placed to provide the answers. Results: Sixteen questionnaires were completed (Norway, Ireland, Sweden, Hungary, Netherlands, UK, Denmark, Portugal, Italy, Switzerland, Austria, France, Czech Republic, Spain, Belgium, Malta). Of the 16, 13 respondents indicated provision of F&A health care services in their country, but only three countries had services specialising in RMD-related F&A problems (Netherlands, UK, Malta). The professions providing the care for patients with RMD-related F&A problems were different depending on the pathology and the country (Table1). Podiatrists provided care for F&A pain and deformity problems in 11 countries, but provided F&A ulcer care in only 8 countriesConclusions: Only 3 countries have F&A health care services specialised to the needs of people with RMDs. The professions providing the care varied between countries, and also depended on the F&A pathology. Interestingly, F&A healthcare services were provided by professions that do not solely specialised in F&A care. Further research is needed to assess the variation of F&A healthcare services between and within European countries and the impact on healthcare of various F&A healthcare service designs. References: Woodburn, J. & Helliwell, P. Foot problems in rheumatology. Rheumatology 36, 932-934 (1997).Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Homocitrullination of lysine residues mediated by myeloid derived suppressor cells in the tumour environment is a target for cancer immunotherapy

Background: Homocitrullination is the post translational modification of lysine that is recognized by T cells. Methods: This study identified homocitrullinated peptides from aldolase, enolase, cytokeratin and Bip and used HLA transgenic mice to assess immunogenicity by ELISpot assay. Vaccine efficacy was assessed in tumour therapy studies using HLA matched B16 melanoma expressing constitutive or IFNγ inducible MHC-II as represented by most human tumours. To determine the mechanism behind the therapy, immune cell infiltrates were analysed using flow cytometry and therapy studies in the presence of MPO inhibitor and T cell depletion performed. We assessed the T cell repertoire to homocitrullinated peptides in cancer patients and healthy donors using flow cytometry. Results: Homocitrulline peptide vaccination stimulated strong CD4 T cell responses and induced significant anti-tumour therapy in an established tumour model. The anti-tumour response was dependent upon CD4 T-cells and the effect was driven mainly via direct tumour recognition, as responses were only observed if the tumours were induced to express MHC-II. In vitro proliferation assays show that healthy donors and cancer patients have an oligoclonal CD4 T-cell repertoire recognizing homocitrullinated peptides. Inhibition of cyanate generation, which mediates homocitrullination, by myeloperoxidase (MPO) inhibition reduced tumour therapy by the vaccine induced T cells (P=0.0018). Analysis of the tumour microenvironment (TME) suggested that myeloid-derived suppressor cells (MDSCs) were a potential source of MPO. The selected B16 melanoma model showed MDSC infiltration. and was appropriate to see if the homocitrulline vaccine could overcome the immunosuppression associated with MDSCs. The vaccine was very effective (90% survival) as the induced CD4 T cells directly targeted the homocitrullinated tumour and likely reversed the immunosuppressive environment. Conclusion: We propose that MPO, potentially produced by MDSCs, catalyses the build-up of cyanate in the TME which diffuses into tumour cells causing homocitrullination of cytoplasmic proteins which are degraded and, in the presence of IFNγ, presented by MHC-II for direct CD4 T-cell recognition. Homocitrullinated proteins are a new target for cancer vaccines and may be particularly effective against tumours containing high levels of MPO expressing MDSCs

Preclinical and randomized phase I studies of plitidepsin in adults hospitalized with COVID-19

Plitidepsin, a marine-derived cyclic-peptide, inhibits SARS-CoV-2 replication at nanomolar concentrations by targeting the host protein eukaryotic translation elongation factor 1A. Here, we show that plitidepsin distributes preferentially to lung over plasma, with similar potency against across several SARS-CoV-2 variants in preclinical studies. Simultaneously, in this randomized, parallel, open-label, proof-of-concept study (NCT04382066) conducted in 10 Spanish hospitals between May and November 2020, 46 adult hospitalized patients with confirmed SARS-CoV-2 infection received either 1.5 mg (n = 15), 2.0 mg (n = 16), or 2.5 mg (n = 15) plitidepsin once daily for 3 d. The primary objective was safety; viral load kinetics, mortality, need for increased respiratory support, and dose selection were secondary end points. One patient withdrew consent before starting procedures; 45 initiated treatment; one withdrew because of hypersensitivity. Two Grade 3 treatment-related adverse events were observed (hypersensitivity and diarrhea). Treatment-related adverse events affecting more than 5% of patients were nausea (42.2%), vomiting (15.6%), and diarrhea (6.7%). Mean viral load reductions from baseline were 1.35, 2.35, 3.25, and 3.85 log10 at days 4, 7, 15, and 31. Nonmechanical invasive ventilation was required in 8 of 44 evaluable patients (16.0%); six patients required intensive care support (13.6%), and three patients (6.7%) died (COVID-19-related). Plitidepsin has a favorable safety profile in patients with COVID-19

Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial

Background: Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. Methods: We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov, NCT04327388; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021. Findings: Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 [20%]), sarilumab 200 mg (n=159 [38%]), or sarilumab 400 mg (n=173 [42%]). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days [95% CI 9·0 to 15·0]) and sarilumab 200 mg (10·0 days [9·0 to 12·0]; hazard ratio [HR] 1·03 [95% CI 0·75 to 1·40]; log-rank p=0·96) or sarilumab 400 mg (10·0 days [9·0 to 13·0]; HR 1·14 [95% CI 0·84 to 1·54]; log-rank p=0·34), or in proportions of patients alive (77 [92%] of 84 patients in the placebo group; 143 [90%] of 159 patients in the sarilumab 200 mg group; difference −1·7 [−9·3 to 5·8]; p=0·63 vs placebo; and 159 [92%] of 173 patients in the sarilumab 400 mg group; difference 0·2 [−6·9 to 7·4]; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% [95% CI −7·7 to 25·5]; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 11% (17 of 159) were in the sarilumab 200 mg group, and 10% (18 of 173) were in the sarilumab 400 mg group. Interpretation: This trial did not show efficacy of sarilumab in patients admitted to hospital with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19. Funding: Sanofi and Regeneron Pharmaceuticals

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Aetiology of acute respiratory infection in preschool children requiring hospitalisation in Europe-results from the PED-MERMAIDS multicentre case-control study.

BACKGROUND: Both pathogenic bacteria and viruses are frequently detected in the nasopharynx (NP) of children in the absence of acute respiratory infection (ARI) symptoms. The aim of this study was to estimate the aetiological fractions for ARI hospitalisation in children for respiratory syncytial virus (RSV) and influenza virus and to determine whether detection of specific respiratory pathogens on NP samples was associated with ARI hospitalisation. METHODS: 349 children up to 5 years of age hospitalised for ARI (following a symptom-based case definition) and 306 hospital controls were prospectively enrolled in 16 centres across seven European Union countries between 2016 and 2019. Admission day NP swabs were analysed by multiplex PCR for 25 targets. RESULTS: RSV was the leading single cause of ARI hospitalisations, with an overall population attributable fraction (PAF) of 33.4% and high seasonality as well as preponderance in younger children. Detection of RSV on NP swabs was strongly associated with ARI hospitalisation (OR adjusted for age and season: 20.6, 95% CI: 9.4 to 45.3). Detection of three other viral pathogens showed strong associations with ARI hospitalisation: influenza viruses had an adjusted OR of 6.1 (95% CI: 2.5 to 14.9), parainfluenza viruses (PIVs) an adjusted OR of 4.6 (95% CI: 1.8 to 11.3) and metapneumoviruses an adjusted OR of 4.5 (95% CI: 1.3 to 16.1). Influenza viruses had a PAF of 7.9%, PIVs of 6.5% and metapneumoviruses of 3.0%. In contrast, most other pathogens were found in similar proportions in cases and controls, including Streptococcus pneumoniae, which was weakly associated with case status, and endemic coronaviruses. CONCLUSION: RSV is the predominant cause of ARI hospitalisations in young children in Europe and its detection, as well as detection of influenza virus, PIV or metapneumovirus, on NP swabs can establish aetiology with high probability. PAFs for RSV and influenza virus are highly seasonal and age dependent

Translucency of Graphene to van der Waals Forces Applies to Atoms/Molecules with Different Polar Character

Graphene has been proposed to be either fully transparent to van der Waals interactions to the extent of allowing switching between hydrophobic and hydrophilic behavior, or partially transparent (translucent), yet there has been considerable debate on this topic, which is still ongoing. In a combined experimental and theoretical study we investigate the effects of different metal substrates on the adsorption energy of atomic (argon) and molecular (carbon monoxide) adsorbates on high-quality epitaxial graphene. We demonstrate that while the adsorption energy is certainly affected by the chemical composition of the supporting substrate and by the corrugation of the carbon lattice, the van der Waals interactions between adsorbates and the metal surfaces are partially screened by graphene. Our results indicate that the concept of graphene translucency, already introduced in the case of water droplets, is found to hold more generally also in the case of single polar molecules and atoms, which are apolar