First MTP joint injuries: MR imaging findings in surgically managed patients.

OBJECTIVES: Determine whether MR imaging findings or demographics predict surgical management in patients with first MTP joint injuries. MATERIALS AND METHODS: Retrospective study of 161 forefoot MRs for traumatic first MTP injury (M:F 92:69, mean age 33 ± 13 yrs.). Two radiologists reviewed imaging for ligamentous, osseous, and tendinous injuries. Ligaments and tendons were graded as 0:normal, 1:sprain or strain, 2:partial tear, 3:complete tear. Osseous injuries were classified as edema, fracture, or cartilage injury. Clinical data obtained included sex, age, injury acuity, sport participation, level of sport, and treatment. Imaging findings and demographic data were assessed to determine predictive factors for surgical management. Statistics included kappa, chi-squared, Fisher's exact, and logistic regression. RESULTS: Logistic regression (odds ratio [95% CI], p-value) showed that grade 2 or 3 injuries of the plantar ligamentous complex (2.87, [1.10, 7.48], p = 0.031), grade 2 or 3 injuries of the medial collateral ligament (3.24, [1.16, 9.08], p = 0.025), and participation in collegiate or professional sports (4.34 [1.64, 11.52], p = 0.003) were associated with an increased rate of surgical intervention. k = ligamentous injury (0.71-0.83), osseous trauma (0.88-0.95), and tendon injury (0.78). All other imaging findings and demographic factors were not significant predictors of surgery (p > 0.05). CONCLUSION: Participation in collegiate or professional sports and tears of the plantar ligamentous complex or medial collateral ligament predicted surgical management in patients with first MTP trauma.

Sampling implications of variation in daily activity of the sheep tick, Ixodes ricinus at a coastal grassland site in the U.K.

The sheep tick, Ixodes ricinus L. (Acari: Ixodidae), is an important vector of many pathogens of medical and veterinary significance. Determining vector abundance is a requisite of assessing potential vector-borne disease risk. Estimation of tick abundance is often conducted by blanket drag sampling a site, conducted at one time point during the day. The time of day chosen for sampling can vary, is not widely standardized and is often unreported by the investigator. This study investigated whether the time of day chosen for sampling had an effect on tick collection at an open grassland coastal site in North Devon, U.K., during May 2019 to July 2019. Tick abundance for both adults and nymphs in the evening period was more than twice that found in the mid-day sampling period. Overall abundance differed with site aspect, ground temperature and relative humidity. This study shows that for this open grassland recreational site, the time of day chosen for sampling has important implications for tick collection and the assessment of the relative risk of human exposure to ticks and tick-borne infections.

Cutaneous toxicities in patients with melanoma receiving checkpoint inhibitor therapy: a retrospective review. The experience of a single large specialist institution.

Checkpoint inhibitor (CPI) therapy has significantly improved overall survival for metastatic melanoma, and is now approved for use in the adjuvant setting. Modulating the immune system is recognized to cause cutaneous immune-related adverse events (irAEs). We conducted a retrospective observational cohort study of adult patients with melanoma at our tertiary referral centre, who received CPI therapy from 2006 to March 2018. This is the single largest study of cutaneous irAEs occurring on CPI therapy in patients with melanoma to date and encompasses 12 years. The results showed that cutaneous toxicity occurs in 24% of patients but is generally manageable, with < 5% patients discontinuing treatment.

AURIEL-PsO: a randomized, double-blind phase III equivalence trial to demonstrate the clinical similarity of the proposed biosimilar MSB11022 to reference adalimumab in patients with moderate-to-severe chronic plaque-type psoriasis.

BACKGROUND: MSB11022 is a proposed adalimumab biosimilar. OBJECTIVES: To compare the efficacy, safety and immunogenicity of MSB11022 with reference adalimumab. METHODS: AURIEL-PsO was a double-blind randomized controlled equivalence trial, in which patients with moderate-to-severe chronic plaque-type psoriasis were randomized 1 : 1 to MSB11022 or reference adalimumab. The primary end point was ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) at week 16, with a prespecified equivalence interval of ± 18%. Patients with a ≥50% improvement in PASI at week 16 were eligible to enter a double-blind extension period: patients receiving MSB11022 continued treatment, and patients receiving reference adalimumab were rerandomized 1 : 1 either to continue reference adalimumab or to switch to MSB11022. Other efficacy end points and safety, immunogenicity and pharmacokinetic parameters were evaluated at scheduled visits up to weeks 52 (efficacy and immunogenicity), 54 and 66 (safety). RESULTS: In total, 443 patients were randomized. The difference in PASI 75 response rates at week 16 between the treatment arms was -1·9%, and the 95% confidence interval (-7·8% to 4·1%) was within the prespecified equivalence interval. No notable difference in the incidence of treatment-emergent adverse events was observed between treatment arms up to the end of the trial, and no new safety signals were observed. Following treatment switch at week 16, no clinically meaningful differences in safety or immunogenicity were seen between treatment arms through to the end of the observation period. CONCLUSIONS: Therapeutic equivalence between MSB11022 and reference adalimumab was demonstrated. AURIEL-PsO provides evidence to support the similarity of both products with regard to efficacy, safety and immunogenicity. What's already known about this topic? Adalimumab is a fully human antitumour necrosis factor-α monoclonal antibody, indicated for the treatment of multiple inflammatory disorders, including psoriasis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel diseases and ankylosing spondylitis. MSB11022 is a proposed adalimumab biosimilar that has shown structural and functional similarity to the reference product in an extensive analytical comparability exercise. MSB11022 has demonstrated bioequivalence and comparable safety and immunogenicity profiles in a phase I study in healthy volunteers. What does this study add? This phase III study confirmed equivalent efficacy for MSB11022 and reference adalimumab in patients without any immunomodulation comedication in moderate-to-severe chronic plaque-type psoriasis at week 16. The efficacy, safety and immunogenicity of MSB11022 and reference adalimumab were similar over the respective observation periods (week 52 for efficacy and immunogenicity, week 66 for safety). A switch from reference adalimumab to MSB11022 at week 16 did not impact efficacy, safety or immunogenicity.

The impact of BMI and smoking on risk of revision following knee and hip replacement surgery: evidence from routinely collected data.

OBJECTIVE: The aim of this study was to assess the association of body mass index (BMI) and smoking with risk of revision following total knee replacement (TKR) and total hip replacement (THR). DESIGN: Primary care data, from the Clinical Practice Research Datalink (CPRD), was linked to inpatient hospital records, from Hospital Episode Statistics Admitted Patient Care (HES APC), and covered 1997 to 2014. Parametric survival models, with BMI and smoking status included as explanatory variables, were estimated for 10-year risk of revision and mortality, and were extrapolated to estimate lifetime risk of revision. FINDINGS: TKR and THR cohorts included 10,260 and 10,961 individuals, respectively. For a change in BMI from 25 to 35, the 10-year risk of revision is expected change from 4.6% (3.3-6.4%) to 3.7% (2.6-5.1%) for TKR and 3.7% (2.8-5.1%) to 4.0% (2.8-5.7%) for THR for an otherwise average patient profile. Meanwhile, changing from a non-smoker to a current smoker is expected to change the risk of revision from 4.1% (3.1-5.5%) to 2.8% (1.7-4.7%) for TKR and from 3.8% (2.8-5.3%) to 2.9% (1.9-4.7%) for THR for an otherwise average patient profile. Estimates of lifetime risk were also similar for different values of BMI or smoking status. CONCLUSIONS: Obesity and smoking do not appear to have a meaningful impact on the risk of revision following TKR and THR.

Hydrogen sulphide production by Saccharomyces cerevisiae UCD 522 in a synthetic grape juice medium deficient of thiamin (vitamin B1 ) and/or pyridoxine (vitamin B6 ).

The impacts of thiamin and pyridoxine along with YAN on alcoholic fermentation and hydrogen sulphide production by Saccharomyces cerevisiae were studied. Using a synthetic grape juice medium, three fermentation trials were conducted; (i) 2 × 3 factorial design with thiamin (0, 0·2, or 0·5 mg l-1 ) and YAN (60 or 250 mg l-1 ) as variables, (ii) 2 × 3 factorial design with pyridoxine (0, 0·25, or 0·5 mg l-1 ) and YAN (60 or 250 mg l-1 ) as variables, and (iii) 3 × 3 factorial design with thiamin (0, 0·2 or 0·5 mg l-1 ) and pyridoxine (0, 0·25 or 0·5 mg l-1 ) as variables in media containing 60 mg l-1 YAN. Although the progress of fermentations was affected by thiamin or pyridoxine, YAN had a larger impact than either vitamin. H2 S production was significantly lower with increasing amounts of thiamin in those fermentations under low YAN (60 mg l-1 ) while even lower amounts (<30 µg l-1 ) were produced under high YAN (250 mg l-1 ) with or without the vitamin. The highest amounts of H2 S were synthesized in those fermentations without any pyridoxine (>110 µg l-1 ), with the lowest production in media with pyridoxine and high YAN (<20 µg l-1 ). SIGNIFICANCE AND IMPACT OF THE STUDY: Concentrations of thiamin, pyridoxine and yeast assimilable nitrogen (YAN) influenced the synthesis of hydrogen sulphide (H2 S) by Saccharomyces cerevisiae in a synthetic grape juice medium. With a few exceptions, an increase in the concentration of either vitamin or YAN resulted in less H2 S released. This is the first report to demonstrate that both thiamin and pyridoxine along with YAN affected H2 S production, emphasizing the need to assess yeast nutrients to lower risks of off-odours during fermentation.

Untangling Neolithic and Bronze Age mitochondrial lineages in South Asia.

Two key moments shaped the extant South Asian gene pool within the last 10 thousand years (ka): the Neolithic period, with the advent of agriculture and the rise of the Harappan/Indus Valley Civilisation; and Late Bronze Age events that witnessed the abrupt fall of the Harappan Civilisation and the arrival of Indo-European speakers. This study focuses on the phylogeographic patterns of mitochondrial haplogroups H2 and H13 in the Indian Subcontinent and incorporates evidence from recently released ancient genomes from Central and South Asia. It found signals of Neolithic arrivals from Iran and later movements in the Bronze Age from Central Asia that derived ultimately from the Steppe. This study shows how a detailed mtDNA phylogeographic approach, combining both modern and ancient variation, can provide evidence of population movements, even in a scenario of strong male bias such as in the case of the Bronze Age Steppe dispersals.

Interactive effects between total SO2 , ethanol and storage temperature against Brettanomyces bruxellensis.

Although Brettanomyces bruxellensis continues to be a problem during red winemaking due to formation of off-odours and flavours, few interactions between intrinsic and extrinsic conditions that would limit spoilage have been identified. Using a commercially prepared Merlot wine, a 3 × 2 × 2 complete factorial design was implemented with total SO2 (0, 60 or 100 mg l-1 ), ethanol (13% or 14·5% v v-1 ) and storage temperature (15° or 18°C) as variables. Populations of two strains of B. bruxellensis isolated from Washington wines (I1a and F3) were monitored for 100 days before concentrations of 4-ethylphenol, 4-ethylguaiacol and volatile acidity were measured. In wines with 13% v v-1 ethanol and stored at 15°C, addition of 100 mg l-1 total SO2 resulted in much longer lag phases (>40 days) compared with wines without sulphites. At 14·5% v v-1 ethanol, culturability did not recover from wines with 100 mg l-1 total SO2 regardless of the storage temperature (15° or 18°C). A few significant interactions were noted between these parameters which also affected synthesis of metabolites. Thus, SO2 , ethanol concentration and storage temperature should be together used as means to reduce infections by B. bruxellensis. SIGNIFICANCE AND IMPACT OF THE STUDY: The potential for utilizing SO2 along with the ethanol and storage temperature was studied to inhibit the spoilage yeast, Brettanomyces bruxellensis, during cellar ageing of red wines. This report is the first to identify the existence of interactions between these parameters that affect growth and/or metabolism of the yeast (i.e., synthesis of 4-ethylphenol, 4-ethylguaiacol and volatile acidity). Based on current and past findings, recommendations are presented related to the use of potential antimicrobial synergies between SO2 , ethanol concentration and storage temperatures.

A loss of host-derived MMP-7 promotes myeloma growth and osteolytic bone disease in vivo.

Matrix metalloproteinases (MMPs) play a critical role in cancer pathogenesis, including tumor growth and osteolysis within the bone marrow microenvironment. However, the anti-tumor effects of MMPs are poorly understood, yet have significant implications for the therapeutic potential of targeting MMPs. Host derived MMP-7 has previously been shown to support the growth of bone metastatic breast and prostate cancer. In contrast and underscoring the complexity of MMP biology, here we identified a tumor-suppressive role for host MMP-7 in the progression of multiple myeloma in vivo. An increase in tumor burden and osteolytic bone disease was observed in myeloma-bearing MMP-7 deficient mice, as compared to wild-type controls. We observed that systemic MMP-7 activity was reduced in tumor-bearing mice and, in patients with multiple myeloma this reduced activity was concomitant with increased levels of the endogenous MMP inhibitor, tissue inhibitor of metalloproteinases-1 (TIMP-1). Our studies have identified an unexpected tumour-suppressive role for host-derived MMP-7 in myeloma bone disease in vivo, and highlight the importance of elucidating the effect of individual MMPs in a disease-specific context.

Tumour-derived alkaline phosphatase regulates tumour growth, epithelial plasticity and disease-free survival in metastatic prostate cancer.

BACKGROUND: Recent evidence suggests that bone-related parameters are the main prognostic factors for overall survival in advanced prostate cancer (PCa), with elevated circulating levels of alkaline phosphatase (ALP) thought to reflect the dysregulated bone formation accompanying distant metastases. We have identified that PCa cells express ALPL, the gene that encodes for tissue nonspecific ALP, and hypothesised that tumour-derived ALPL may contribute to disease progression. METHODS: Functional effects of ALPL inhibition were investigated in metastatic PCa cell lines. ALPL gene expression was analysed from published PCa data sets, and correlated with disease-free survival and metastasis. RESULTS: ALPL expression was increased in PCa cells from metastatic sites. A reduction in tumour-derived ALPL expression or ALP activity increased cell death, mesenchymal-to-epithelial transition and reduced migration. Alkaline phosphatase activity was decreased by the EMT repressor Snail. In men with PCa, tumour-derived ALPL correlated with EMT markers, and high ALPL expression was associated with a significant reduction in disease-free survival. CONCLUSIONS: Our studies reveal the function of tumour-derived ALPL in regulating cell death and epithelial plasticity, and demonstrate a strong association between ALPL expression in PCa cells and metastasis or disease-free survival, thus identifying tumour-derived ALPL as a major contributor to the pathogenesis of PCa progression.

Allocation to male vs female floral function varies by currency and responds differentially to density and moisture stress.

Allocation of finite resources to separate reproductive functions is predicted to vary across environments and affect fitness. Biomass is the most commonly measured allocation currency; however, in comparison with nutrients it may be less limited and express different environmental and evolutionary responses. Here, we measured carbon, nitrogen, phosphorus, and biomass allocation among floral whorls in recombinant inbred lines of Brassica rapa in multiple environments to characterize the genetic architecture of floral allocation, including its sensitivity to environmental heterogeneity and to choice of currency. Mass, carbon, and nitrogen allocation to female whorls (pistils and sepals) decreased under high density, whereas nitrogen allocation to male organs (stamens) decreased under drought. Phosphorus allocation decreased by half in pistils under drought, while stamen phosphorus was unaffected by environment. While the contents of each currency were positively correlated among whorls, selection to improve fitness through female (or male) function typically favored increased allocation to pistils (or stamens) but decreased allocation to other whorls. Finally, genomic regions underlying correlations among allocation metrics were mapped, and loci related to nitrogen uptake and floral organ development were located within mapped quantitative trait loci. Our candidate gene identification suggests that nutrient uptake may be a limiting step in maintaining male allocation. Taken together, allocation to male vs female function is sensitive to distinct environmental stresses, and the choice of currency affects the interpretation of floral allocation responses to the environment. Further, genetic correlations may counter the evolution of allocation patterns that optimize fitness through female or male function.

The prevalence of self-reported lower limb and foot health problems experienced by participants with systemic lupus erythematosus: Results of a UK national survey.

Objective The main aim of this survey was to determine the frequency of self-reported lower limb or foot and ankle complications experienced by participants with systemic lupus erythematosus (SLE). A secondary aim was to determine the frequency of treatments that have been received or that participants with SLE may like to receive if offered. Method A quantitative, cross-sectional, self-reported survey design was utilized. The developed survey was checked for face and content validity prior to patient partner cognitive debriefing in order to ensure usability, understanding of the process of completion and of the questions posed. The full protocol for survey development has been published previously. Results This is the first comprehensive national UK survey of lower limb and foot health problems reported by participants with SLE. A high prevalence of vascular, dermatological and musculoskeletal complications was reported by survey respondents. Additionally, whilst the relative prevalence of sensory loss was low, a quarter of people reported having had a fall related to changes in foot sensation demonstrating a previously unknown rate and cause of falls. Conclusion Complications related to vascular, dermatological and musculoskeletal health are identified as particularly prevalent in participants with SLE. Further, there is a suggestion that the provision of interventions to maintain lower limb health is highly varied and lacks national standardization, despite there being a strong indication of participant reported need. The findings of this work can be used to inform care guideline development in addition to identifying areas for future research.

Patients' experiences of lupus-related foot problems: a qualitative investigation.

Background Systemic lupus erythematosus (SLE) can present with a variety of symptoms. Previous research has shown there is a high prevalence of lower limb and foot problems in patients with SLE associated with the musculoskeletal, vascular and neurological changes. Furthermore, there is a high prevalence of infections affecting the feet and a range of common skin and nail problems. However, it is not known how these foot problems impact upon people's lives. Therefore, we aimed to explore this using a qualitative approach. Method Following ethical approval, 12 participants were recruited who had a diagnosis of SLE, current and/or past experience of foot problems and were over 18 years in age. Following consent, interviews were carried out with an interpretivist phenomenological approach to both data collection and analysis. Results Seven themes provide insight into: foot problems and symptoms; the impact of these foot problems and symptoms on activities; disclosure and diagnosis of foot problems; treatment of foot problems and symptoms; perceived barriers to professional footcare; unanswered questions about feet and footcare; and identification of the need for professional footcare and footcare advice. Conclusion These participants tend to "self-treat" rather than disclose that they may need professional footcare. A lack of focus upon foot health within a medical consultation is attributed to the participant's belief that it is not within the doctor's role, even though it is noted to contribute to reduced daily activity. There is a need for feet to be included as a part of patient monitoring and for foot health management to be made accessible for people with SLE.

Role of polysaccharides in food, digestion, and health.

Polysaccharides derived from plant foods are major components of the human diet, with limited contributions of related components from fungal and algal sources. In particular, starch and other storage carbohydrates are the major sources of energy in all diets, while cell wall polysaccharides are the major components of dietary fiber. We review the role of these components in the human diet, including their structure and distribution, their modification during food processing and effects on functional properties, their behavior in the gastrointestinal tract, and their contribution to healthy diets.

Exploring pressures, tissue reperfusion and body positioning: a pilot evaluation.

OBJECTIVE: To assess the relationship in healthy adults and critically ill patients between: patient position, body mass index (BMI), patient body temperature, interface pressure (IP) and tissue reperfusion (TR). Also to determine the relationship in critically ill patients between: Sequential Organ Failure Assessment (SOFA) score, Braden Scale score for predicting pressure injury risk, Acute Physiology and Chronic Health Evaluation II (APACHE II) severity of disease classification score, IP and TR. METHODS: This study took place in a 27-bed intensive care unit (ICU) of an Australian tertiary hospital. IP and TR outcomes were measured at the sacrum and greater trochanter. Repeated measures analyses of variance (ANOVAs) and doubly multivariate repeated measures ANOVAs were conducted using peak pressure index (PPI), peak time (PT), settled time constant (STC) and normalised hyperaemic area (NHA) measures of TR as outcomes. Participant type, body mass index (BMI), Braden and APACHE II scores and patient body temperature were considered as between-groups factors and covariates. RESULTS: We recruited 23 low- and high-acuity ICU patients and nine healthy adult volunteers. Not all IP readings could be obtained from ICU patients. TR readings were collected from all recruited patients, but not all TR measurements were mutually uncorrelated. Controlling for age, PPI readings differed between participant types (p=0.093), with the highest values associated with high-acuity patients and the lowest with healthy adults; the association was not substantive when controlling for age and BMI. Age was a significant variable (p=0.008), with older participants having higher scores than younger ones. No statistically significant associations between any measured parameter and TR variables were observed. However, temperature was revealed to be related to TR (p=0.091). CONCLUSIONS: Although not powered to detect significant effects, this pilot analysis has determined several associations of importance, with differences in outcomes observed between low- and high-acuity ICU patients; and between ICU patients and healthy volunteers.

Erythema action spectrum of topical 8-methoxypsoralen-sensitized skin re-evaluated: implications for routine clinical practice.

BACKGROUND: Published methodology used to determine psoralen plus ultraviolet A (PUVA) erythemal action spectrum does not reflect current clinical practice for psoralen sensitization. We re-evaluated the PUVA action spectrum using aqueous 8-methoxypsoralen (8-MOP) 2·6 mg L(-1) as used routinely in current clinical practice. OBJECTIVES: To determine the UVA erythema action spectrum of topical 8-MOP-sensitized normal skin. METHODS: Twenty healthy volunteers with skin phototypes I-V were recruited. Forearms were psoralen-sensitized at 37 °C for 10 min. Six UVA irradiations at 10-nm intervals between 325 and 375 nm were randomly allocated to forearm sites and were applied using a 10-nm bandwidth irradiation monochromator. The visual minimal phototoxic dose (MPD) was recorded on each site at 96 h. RESULTS: Volunteer Boston phototypes were: I, n = 2; II, n = 6; III, n = 6; IV, n = 5 and V, n = 1. The mean MPD (J cm(-2) ) for all subjects at each wavelength was as follows: 325 nm, 0·64 (SD 0·37); 335 nm, 0·80 (SD 0·58); 345 nm, 0·96 (SD 0·55); 355 nm, 1·50 (SD 0·85); 365 nm, 2·19 (SD 0·90); and 375 nm, 2·89 (SD 1·06). Therefore, the relative sensitization at each wavelength (erythemal action spectrum) was: 1, 0·83, 0·67, 0·43, 0·29 and 0·22. There were significant differences between the PUVA erythemal effectiveness at different wavelengths but none between skin types. CONCLUSIONS: This study has established the erythemal action spectrum for bath/soak PUVA therapy as is currently performed. In all volunteers, the peak sensitivity was at 325 nm. All volunteers showed a similar trend across the wavelengths studied irrespective of skin type. The determination of the action spectrum for PUVA-induced erythema is important as it permits reliable estimates of erythemal efficacy of any UVA source where the emission spectrum of the lamp is known or can be measured.

Randomized trial of a dual-hormone artificial pancreas with dosing adjustment during exercise compared with no adjustment and sensor-augmented pump therapy.

AIMS: To test whether adjusting insulin and glucagon in response to exercise within a dual-hormone artificial pancreas (AP) reduces exercise-related hypoglycaemia. MATERIALS AND METHODS: In random order, 21 adults with type 1 diabetes (T1D) underwent three 22-hour experimental sessions: AP with exercise dosing adjustment (APX); AP with no exercise dosing adjustment (APN); and sensor-augmented pump (SAP) therapy. After an overnight stay and 2 hours after breakfast, participants exercised for 45 minutes at 60% of their maximum heart rate, with no snack given before exercise. During APX, insulin was decreased and glucagon was increased at exercise onset, while during SAP therapy, subjects could adjust dosing before exercise. The two primary outcomes were percentage of time spent in hypoglycaemia (<3.9 mmol/L) and percentage of time spent in euglycaemia (3.9-10 mmol/L) from the start of exercise to the end of the study. RESULTS: The mean (95% confidence interval) times spent in hypoglycaemia (<3.9 mmol/L) after the start of exercise were 0.3% (-0.1, 0.7) for APX, 3.1% (0.8, 5.3) for APN, and 0.8% (0.1, 1.4) for SAP therapy. There was an absolute difference of 2.8% less time spent in hypoglycaemia for APX versus APN (p = .001) and 0.5% less time spent in hypoglycaemia for APX versus SAP therapy (p = .16). Mean time spent in euglycaemia was similar across the different sessions. CONCLUSIONS: Adjusting insulin and glucagon delivery at exercise onset within a dual-hormone AP significantly reduces hypoglycaemia compared with no adjustment and performs similarly to SAP therapy when insulin is adjusted before exercise.

Needle-free nasal delivery of glucagon for treatment of diabetes-related severe hypoglycemia: toxicology of polypropylene resin used in delivery device.

CONTEXT: The intranasal route is a promising route of administration for several emergency rescue drugs including naloxone and glucagon. Glucagon nasal powder (GNP) is a novel, needle-free delivery system for intranasal administration of glucagon for the treatment of severe hypoglycemia, an infrequent but serious complication of insulin use in patients with diabetes. The GNP delivery device is a compact, highly portable, single-use nasal powder dosing device constructed of polypropylene that allows for simple, single-step administration. OBJECTIVE: To evaluate the toxicological profile of the polypropylene resin used in the actuator part of the delivery device that will contact skin and nasal mucosal membranes of the patient, we performed an in vitro cytotoxicity study, a skin sensitization study and an irritation (intracutaneous reactivity) study in animal models. METHODS: Extracts of the actuator of the GNP device were generated from HAM F12 medium with 10% fetal bovine serum, 0.9% sodium chloride (NaCl) or sesame oil. The in vitro cytotoxicity test was performed in cultured L929 mouse fibroblasts. Skin sensitization analysis was performed in 10 guinea pigs according to the Magnusson-Kligman method, using a maximization method with Freund's Complete Adjuvant. Irritation following intracutaneous/intradermal treatment with device extracts (NaCl and sesame oil extractants) was assessed in three New Zealand White rabbits. RESULTS: In vitro cytotoxicity test: Both undiluted and diluted extract showed no toxicity (i.e. no abnormal morphology, cell death or cell lysis) toward L929 fibroblasts (cytotoxicity grade 0). Sensitization test in guinea pigs: Challenge with device extracts did not evoke positive responses in test animals previously induced with device extracts. The net response value represented an incidence rate of 0% and a net dermal irritation score value of 0.00. Irritation (intracutaneous/intradermal) test in New Zealand White rabbits: Device extracts and corresponding vehicle controls caused similar irritation reactions. The difference between the mean scores for the device extracts and the corresponding vehicle controls was less than 1.0. CONCLUSIONS: Extracts of the polypropylene resin of the GNP delivery device are not cytotoxic, do not result in dermal sensitization and do not cause irritation when applied topically or intracutaneously. Given the infrequent use and very short duration of exposure to the nasal mucosa during administration of GNP, the polypropylene resin of the GNP device actuator will likely not cause adverse dermal sensitization effects or irritation effects in humans and can, therefore, be considered for use as a delivery device in clinical trials assessing the efficacy and safety of GNP for the treatment of insulin-using patients experiencing episodes of severe hypoglycemia.

EULAR-PReS points to consider for the use of imaging in the diagnosis and management of juvenile idiopathic arthritis in clinical practice.

To develop evidence based points to consider the use of imaging in the diagnosis and management of juvenile idiopathic arthritis (JIA) in clinical practice. The task force comprised a group of paediatric rheumatologists, rheumatologists experienced in imaging, radiologists, methodologists and patients from nine countries. Eleven questions on imaging in JIA were generated using a process of discussion and consensus. Research evidence was searched systematically for each question using MEDLINE, EMBASE and Cochrane CENTRAL. Imaging modalities included were conventional radiography, ultrasound, MRI, CT, scintigraphy and positron emission tomography. The experts used the evidence obtained from the relevant studies to develop a set of points to consider. The level of agreement with each point to consider was assessed using a numerical rating scale. A total of 13 277 references were identified from the search process, from which 204 studies were included in the systematic review. Nine points to consider were produced, taking into account the heterogeneity of JIA, the lack of normative data and consequent difficulty identifying pathology. These encompassed the role of imaging in making a diagnosis of JIA, detecting and monitoring inflammation and damage, predicting outcome and response to treatment, use of guided therapies, progression and remission. Level of agreement for each proposition varied according to the research evidence and expert opinion. Nine points to consider and a related research agenda for the role of imaging in the management of JIA were developed using published evidence and expert opinion.

What is the risk of having a total hip or knee replacement for patients with lupus?

Individuals with systemic lupus erythematosus (SLE) frequently have arthralgia but joint damage leading to surgery is thought to be less common. In addition to inflammatory damage, other reasons like avascular necrosis (AVN), which is often associated with steroid use, excessive alcohol intake and antiphospholipid syndrome (APS), may increase the likelihood of large joint failure. In this study we aimed to determine the likelihood of having a total hip replacement (THR) or total knee replacement (TKR) for individuals with SLE compared to those without lupus, by performing a retrospective matched case control study of all THRs and TKRs that were performed between 1991 and 2011 and recorded in the General Practice Research Database (GPRD). Individuals with inflammatory arthritis due to any other causes were excluded and the results were adjusted for steroid use, alcohol consumption (drinking status) and APS. The results show that patients with lupus who had a THR or TKR were younger than their peers without lupus. In addition, they appeared to have a significantly increased risk of TKR but the increased risk of THR did not remain after adjustment for steroid use, alcohol consumption and APS.