Evaluation of correlated studies using liquid cell and cryo-transmission electron microscopy: Hydration of calcium sulphate and the phase transformation pathways of bassanite to gypsum.

Insight into the nucleation, growth and phase transformations of calcium sulphate could improve the performance of construction materials, reduce scaling in industrial processes and aid understanding of its formation in the natural environment. Recent studies have suggested that the calcium sulphate pseudo polymorph, gypsum (CaSO4 ·2H2 O) can form in aqueous solution via a bassanite (CaSO4 ·0.5H2 O) intermediate. Some in situ experimental work has also suggested that the transformation of bassanite to gypsum can occur through an oriented assembly mechanism. In this work, we have exploited liquid cell transmission electron microscopy (LCTEM) to study the transformation of bassanite to gypsum in an undersaturated aqueous solution of calcium sulphate. This was benchmarked against cryogenic TEM (cryo-TEM) studies to validate internally the data obtained from the two microscopy techniques. When coupled with Raman spectroscopy, the real-time data generated by LCTEM, and structural data obtained from cryo-TEM show that bassanite can transform to gypsum via more than one pathway, the predominant one being dissolution/reprecipitation. Comparisons between LCTEM and cryo-TEM also show that the transformation is slower within the confined region of the liquid cell as compared to a bulk solution. This work highlights the important role of a correlated microscopy approach for the study of dynamic processes such as crystallisation from solution if we are to extract true mechanistic understanding.

Risk-mitigating behaviours in people with inflammatory skin and joint disease during the COVID-19 pandemic differ by treatment type: a cross-sectional patient survey.

BACKGROUND: Registry data suggest that people with immune-mediated inflammatory diseases (IMIDs) receiving targeted systemic therapies have fewer adverse coronavirus disease 2019 (COVID-19) outcomes compared with patients receiving no systemic treatments. OBJECTIVES: We used international patient survey data to explore the hypothesis that greater risk-mitigating behaviour in those receiving targeted therapies may account, at least in part, for this observation. METHODS: Online surveys were completed by individuals with psoriasis (globally) or rheumatic and musculoskeletal diseases (RMDs) (UK only) between 4 May and 7 September 2020. We used multiple logistic regression to assess the association between treatment type and risk-mitigating behaviour, adjusting for clinical and demographic characteristics. We characterized international variation in a mixed-effects model. RESULTS: Of 3720 participants (2869 psoriasis, 851 RMDs) from 74 countries, 2262 (60·8%) reported the most stringent risk-mitigating behaviour (classified here under the umbrella term 'shielding'). A greater proportion of those receiving targeted therapies (biologics and Janus Kinase inhibitors) reported shielding compared with those receiving no systemic therapy [adjusted odds ratio (OR) 1·63, 95% confidence interval (CI) 1·35-1·97]. The association between targeted therapy and shielding was preserved when standard systemic therapy was used as the reference group (OR 1·39, 95% CI 1·23-1·56). Shielding was associated with established risk factors for severe COVID-19 [male sex (OR 1·14, 95% CI 1·05-1·24), obesity (OR 1·37, 95% CI 1·23-1·54), comorbidity burden (OR 1·43, 95% CI 1·15-1·78)], a primary indication of RMDs (OR 1·37, 95% CI 1·27-1·48) and a positive anxiety or depression screen (OR 1·57, 95% CI 1·36-1·80). Modest differences in the proportion shielding were observed across nations. CONCLUSIONS: Greater risk-mitigating behaviour among people with IMIDs receiving targeted therapies may contribute to the reported lower risk of adverse COVID-19 outcomes. The behaviour variation across treatment groups, IMIDs and nations reinforces the need for clear evidence-based patient communication on risk-mitigation strategies and may help inform updated public health guidelines as the pandemic continues.

Clinical phenotypes and therapeutic responses in cutaneous-predominant sarcoidosis: 6-year experience in a tertiary referral service.

BACKGROUND: There is a limited evidence base for the treatment of cutaneous sarcoidosis. OBJECTIVE: To describe treatment modalities and responses in patients with predominantly cutaneous sarcoidosis, in addition to clinical characteristics and prevalence of systemic disease. METHODS: Data were prospectively collected over a 6-year period. The Cutaneous Sarcoidosis Activity and Morphology Index was used to assess treatment effectiveness. RESULTS: In total, 47 patients with biopsy-confirmed cutaneous sarcoidosis were identified. Morphologically, the most common lesions were papules (49%) and plaques (42.6%). The most commonly affected sites were the head and neck (79%); 89.4% had systemic as well as cutaneous disease; 77% received systemic corticosteroid therapy, while 87% required further steroid-sparing treatment; 40% achieved clinical remission with hydroxychloroquine (HCQ) and 88% achieved clinical remission with methotrexate (MTX). OR of achieving remission on MTX compared with HCQ was 9.8 (95% CI 2.4-40.4, P = 0.001). MTX was superior to both azathioprine (AZA) (OR = 22; 95% CI 1.7-285.9; P = 0.02) and mycophenolate mofetil (MMF) (OR = 22; 95% CI 1.7-285.9; P = 0.02) in achieving remission. CONCLUSION: HCQ is effective and well-tolerated. MTX was associated with significantly increased probability of achieving clinical remission compared with AZA and MMF.

Changing hospitalization trends for systemic lupus erythematosus and rheumatoid arthritis in England.

OBJECTIVES: Systemic lupus erythematosus (SLE) is a chronic, multisystemic, immune-mediated disorder associated with a substantial hospitalization risk. As a comparatively rare disease, there is a sparsity of research examining the burden of hospital admission in the contemporary era. We aim to describe national trends in hospitalization rates in England between 1998 and 2015 for SLE, using rheumatoid arthritis (RA) and general population rates as comparison cohorts for benchmarking. METHODS: Hospital admission rates, emergency and day-case admission rates, length of stay and bed days used were calculated using finished consultant episodes from Hospital Episode Statistics data. Cochran-Armitage tests and linear regression quantified the significance and magnitude of change over time. RESULTS: SLE admissions increased from 8.97 to 9.04 per 100,000 (p < 0.001) between 1998 and 2015. By comparison, RA admissions rose from 71.0 to 171.6 per 100,000 (p < 0.001) and all-cause admissions rose from 24,500 to 34,500 per 100,000 (p < 0.001). Emergency admissions decreased both for SLE (2.6 to 1.2 per 100,000) and RA (12.8 to 4.4 per 100,000) despite all-cause emergency admissions increasing from 9400 to 10,300 per 100,000. SLE and RA day cases increased, whilst median length of stay decreased. Despite increasing admissions, total bed days for SLE and RA fell by 60% and 90%, respectively. CONCLUSIONS: Whilst all-cause emergency admissions rose in the general population, those for SLE fell. Length of stay and bed days reduced and day cases increased, probably reflecting changing therapeutic strategies. This potentially large reduction in resource utilization warrants consideration when assessing the impact of new therapies.

Diagnostic yield of FDG-PET/CT in fever of unknown origin: a systematic review, meta-analysis, and Delphi exercise.

AIM: To perform a systematic review, meta-analysis and Delphi exercise to evaluate diagnostic yield of combined 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) positron-emission tomography and computed tomography (FDG-PET/CT) in fever of unknown origin (FUO). MATERIALS AND METHODS: Four databases were searched for studies of FDG-PET/CT in FUO 1/1/2000-1/12/2015. Exclusions were non-English language, case reports, non-standard FDG radiotracer, and significant missing data. Quality was assessed by two authors independently using a standardised tool. Pooled diagnostic yield was calculated using a random-effects model. An iterative electronic and face-to-face Delphi exercise generated interspeciality consensus. RESULTS: Pooled diagnostic yield was 56% (95% confidence interval [CI]: 50-61%, I2=61%) from 18 studies and 905 patients. Only five studies reported results of previous imaging, and subgroup analysis estimated diagnostic yield beyond conventional CT at 32% (95% CI: 22-44%; I2=66%). Consensus was established that FDG-PET/CT is increasingly available with an emerging role, but there is prevailing variability in practice. CONCLUSION: There is insufficient evidence to support the value of FDG-PET/CT in investigative algorithms of FUO. A paradigm shift in research is needed, involving prospective studies recruiting at diagnosis of FUO, with updated case definitions and hard outcome measures. Although these studies will be a significant undertaking with multicentre collaboration, their completion is vital for balancing both radiation exposure and costs against the possible benefits of utilising FDG-PET/CT.

Differences in disease phenotype and severity in SLE across age groups.

OBJECTIVES: Significant differences have been reported in disease phenotype and severity of systemic lupus erythematosus (SLE) presenting in different age groups. Most indicate a more severe phenotype in juvenile-onset SLE (JSLE). There have been limited studies in older patients and no large studies looking at SLE across all age groups. METHODS: We assessed the effect of age of onset of SLE on the clinical phenotype by analysing data from two large UK cohorts (the UK JSLE Cohort and the UCLH SLE cohort). RESULTS: A total of 924 individuals were compared (413 JSLE, 511 adult-onset SLE). A female preponderance was present, but less pronounced at either end of the age spectrum. Arthritis was more common with advancing age (93% vs 72%, p < 0.001), whereas renal disease (44% vs 33%, p = 0.001), alopecia (47% vs 23%, p < 0.001) and aphthous ulcerations (39% vs 26%, p = 0.001) were more common in the young. Neuropsychiatric lupus was less common in mature-onset SLE (p < 0.01). JSLE was associated more commonly with thrombocytopenia (21% vs 15%, p = 0.01), haemolytic anaemia (20% vs 3%, p < 0.001), high anti-dsDNA (71% vs 63%, p = 0.009), Sm (22% vs 16%, p = 0.02) and RNP (36% vs 29%, p < 0.04) auto-antibodies. Leucopenia increased with advancing age (p < 0.001). Mortality has been declining over recent decades. However, death rates were substantially higher than the general population. The standardized mortality ratio was 18.3 in JSLE and 3.1 in adult-onset SLE. CONCLUSION: These data from the largest-ever direct comparison of JSLE with adult-onset SLE suggest an aggressive phenotype of disease with a worse outcome in patients with JSLE and emphasizes the importance of careful follow-up in this population.

Patients' and carers' views and expectations about intensive management for moderate rheumatoid arthritis: a qualitative study.

Intensive management for rheumatoid arthritis (RA) involves frequent hospital visits and adjusted doses or combinations of medication. Research is currently underway to test whether or not intensive management strategies are valuable in moderately active disease, however, patient views on intensive management in this disease group are unknown. The objectives of this study were to explore the views and expectations of patients with moderately active RA and of carers of patients with moderately active RA. We conducted focus groups and one-to-one interviews in 2014 with 14 participants (9 patients, 5 carers) from 4 rheumatology clinics across 3 London Hospital NHS Trusts. Non-English-speaking patients were included with the assistance of a professional translator. Focus groups and interviews were audio recorded and transcribed and transcripts analysed using a framework analysis approach. Four main themes were identified: 'Hopes and Expectations of Intensive Management', 'Acceptability of Intensive Management', 'Patient Education' and 'The Importance of Continuity of Care'. Our main findings were that attendance at frequent clinic appointments was largely acceptable to patients and carers. Views on taking higher doses of medication depended on how stable patients were on their current treatment regime. Continuity of care from the rheumatologist and the provision of written/verbal information about intensive management were important to patients and carers.

The first national clinical audit for rheumatoid arthritis.

The first national audit for rheumatoid and early inflammatory arthritis has benchmarked care for the first 3 months of follow-up activity from first presentation to a rheumatology service. Access to care, management of early rheumatoid arthritis and support for self care were measured against National Institute for Health and Care Excellence quality standards; impact of early arthritis and experience of care were measured using patient-reported outcome and experience measures. The results demonstrate delays in referral and accessing specialist care and the need for service improvement in treating to target, suppression of high levels of disease activity and support for self-care. Improvements in patient-reported outcomes within 3 months and high levels of overall satisfaction were reported but these results were affected by low response rates. This article presents a summary of the national data from the audit and discusses the implications for nursing practice.

Characterization and intervention for upper extremity exploration & reaching behaviors in infancy.

This article aims to: 1) highlight general exploration, reaching, and object exploration behaviors as key activities of daily living in infancy, 2) describe how knowledge of early warning signs for these behaviors may improve early assessment, and 3) discuss interventions that may advance performance of these behaviors. Early intervention should focus on improving performance of these behaviors because: a) these early, interrelated upper extremity behaviors serve an integral role in global learning and development in infancy, b) among at-risk populations, differences have been observed in the quantity and quality of performance of these behaviors and, in many cases, these differences are associated with related perceptual-motor and cognitive delays. This article highlights how early assessment and intervention can target these key early behaviors in populations at risk for upper extremity disabilities, such as those born preterm, with Down syndrome, brachial plexus palsy, or arthrogryposis multiplex congentia.

Does cardiovascular phenotype explain the association between diabetes and incident heart failure? The Strong Heart Study.

BACKGROUND AND AIMS: Diabetes remains a predictor of incident heart failure (HF), independent of intercurrent myocardial infarction (MI) and concomitant risk factors. Initial cardiovascular (CV) characteristics, associated with incident heart failure (HF) might explain the association of diabetes with incident HF. METHODS AND RESULTS: Participants to the 2nd Strong Heart Study exam, without prevalent HF or coronary heart disease, or glomerular filtration rate <30 mL/min/1.73 m(2), were analyzed (n = 2757, 1777 women, 1278 diabetic). Cox regression of incident HF (follow-up 8.91 ± 2.76 years) included incident MI censored as a competing risk event. Acute MI occurred in 96 diabetic (7%) and 84 non-diabetic participants (6%, p = ns). HF occurred in 156 diabetic (12%) and in 68 non-diabetic participants (5%; OR = 2.89, p < 0.001). After accounting for competing MI and controlling for age, gender, BMI, systolic blood pressure, smoking habit, plasma cholesterol, antihypertensive treatment, heart rate, fibrinogen and C-reactive protein, incident HF was predicted by greater LV mass index, larger left atrium, lower systolic function, greater left atrial systolic force and urinary albumin/creatinine excretion. Risk of HF was reduced with more rapid LV relaxation and anti-hypertensive therapy. Diabetes increases hazard of HF by 66% (0.02 < p < 0.001). The effect of diabetes could be explained by the level of HbA1c. CONCLUSIONS: Incident HF occurs more frequently in diabetes, independent of intercurrent MI, abnormal LV geometry, subclinical systolic dysfunction and indicators of less rapid LV relaxation, and is influenced by poor metabolic control. Identification of CV phenotype at high-risk for HF in diabetes should be advised.

Disrupting microtubule network immobilizes amoeboid chemotactic receptor in the plasma membrane.

Signaling cascades are initiated in the plasma membrane via activation of one molecule by another. The interaction depends on the mutual availability of the molecules to each other and this is determined by their localization and lateral diffusion in the cell membrane. The cytoskeleton plays a very important role in this process by enhancing or restricting the possibility of the signaling partners to meet in the plasma membrane. In this study we explored the mode of diffusion of the cAMP receptor, cAR1, in the plasma membrane of Dictyostelium discoideum cells and how this is regulated by the cytoskeleton. Single-particle tracking of fluorescently labeled cAR1 using Total Internal Reflection Microscopy showed that 70% of the cAR1 molecules were mobile. These receptors showed directed motion and we demonstrate that this is not because of tracking along the actin cytoskeleton. Instead, destabilization of the microtubules abolished cAR1 mobility in the plasma membrane and this was confirmed by Fluorescence Recovery after Photobleaching. As a result of microtubule stabilization, one of the first downstream signaling events, the jump of the PH domain of CRAC, was decreased. These results suggest a role for microtubules in cAR1 dynamics and in the ability of cAR1 molecules to interact with their signaling partners.

Risk of septic arthritis in patients with rheumatoid arthritis and the effect of anti-TNF therapy: results from the British Society for Rheumatology Biologics Register.

OBJECTIVES: To evaluate the risk of septic arthritis (SA) in patients with rheumatoid arthritis (RA) treated with anti-tumour necrosis factor (TNF) therapy. METHODS: Using data from the British Society for Rheumatology Biologics Register, a prospective observational study, the authors compared the risk of SA between 11 881 anti-TNF-treated and 3673 non-biological disease-modifying antirheumatic drug (nbDMARD)-treated patients. RESULTS: 199 patients had at least one episode of SA (anti-TNF: 179, nbDMARD: 20). Incidence rates were: anti-TNF 4.2/1000 patient years (pyrs) follow-up (95% CI 3.6 to 4.8), nbDMARD 1.8/1000 pyrs (95% CI 1.1 to 2.7). The adjusted HR for SA in the anti-TNF cohort was 2.3 (95% CI 1.2 to 4.4). The risk did not differ significantly between the three agents: adalimumab, etanercept and infliximab. The risk was highest in the early months of therapy. The patterns of reported organisms differed in the anti-TNF cohort. Prior joint replacement surgery was a risk factor for SA in all patients. The rate of postoperative joint infection (within 90 days of surgery) was 0.7%. This risk was not significantly influenced by anti-TNF therapy. CONCLUSIONS: Anti-TNF therapy use in RA is associated with a doubling in the risk of SA. Physicians and surgeons assessing the RA patient should be aware of this potentially life-threatening complication.

Saliva, diagnostics, and dentistry.

Saliva, a scientific and clinical entity familiar to every oral health researcher and dental practitioner, has emerged as a translational and clinical commodity that has reached national visibility at the National Institutes of Health and the President's Office of Science and Technology. "Detecting dozens of diseases in a sample of saliva" was issued by President Obama as one of the 14 Grand Challenges for biomedical research in the 21(st) Century (National Economic Council, 2010). In addition, NIH's 2011 Government Performance Report Act (GPRA) listed 10 initiatives in the high-risk long-term category (Collins, 2011). The mandate is to determine the efficacy of using salivary diagnostics to monitor health and diagnose at least one systemic disease by 2013. The stage is set for the scientific community to capture these national and global opportunities to advance and substantiate the scientific foundation of salivary diagnostics to meet these goals. A specific calling is to the oral, dental, and craniofacial health community. Three areas will be highlighted in this paper: the concept of high-impact diagnostics, the role of dentists in diagnostics, and, finally, an infrastructure currently being developed in the United Kingdom--The UK Biobank--which will have an impact on the translational and clinical utilizations of saliva.

An exploration of adolescent facial shape changes with age via multilevel partial least squares regression.

BACKGROUND AND OBJECTIVES: Multilevel statistical models represent the existence of hierarchies or clustering within populations of subjects (or shapes in this work). This is a distinct advantage over single-level methods that do not. Multilevel partial-least squares regression (mPLSR) is used here to study facial shape changes with age during adolescence in Welsh and Finnish samples comprising males and females. METHODS: 3D facial images were obtained for Welsh and Finnish male and female subjects at multiple ages from 12 to 17 years old. 1000 3D points were defined regularly for each shape by using "meshmonk" software. A three-level model was used here, including level 1 (sex/ethnicity); level 2, all "subject" variations excluding sex, ethnicity, and age; and level 3, age. The mathematical formalism of mPLSR is given in an Appendix. RESULTS: Differences in facial shape between the ages of 12 and 17 predicted by mPLSR agree well with previous results of multilevel principal components analysis (mPCA); buccal fat is reduced with increasing age and features such as the nose, brow, and chin become larger and more distinct. Differences due to ethnicity and sex are also observed. Plausible simulated faces are predicted from the model for different ages, sexes and ethnicities. Our models provide good representations of the shape data by consideration of appropriate measures of model fit (RMSE and R2). CONCLUSIONS: Repeat measures in our dataset for the same subject at different ages can only be modelled indirectly at the lowest level of the model at discrete ages via mPCA. By contrast, mPLSR models age explicitly as a continuous covariate, which is a strong advantage of mPLSR over mPCA. These investigations demonstrate that multivariate multilevel methods such as mPLSR can be used to describe such age-related changes for dense 3D point data. mPLSR might be of much use in future for the prediction of facial shapes for missing persons at specific ages or for simulating shapes for syndromes that affect facial shape in new subject populations.

Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register (BSRBR).

BACKGROUND: The risk of tuberculosis (TB) in patients with rheumatoid arthritis (RA) is thought to be increased following anti-tumour necrosis factor (anti-TNF) therapy, with a proposed differential risk between the anti-TNF drugs etanercept (ETA), infliximab (INF) and adalimumab (ADA). OBJECTIVE: To compare directly the risk between drugs, to explore time to event, site of infection and the role of ethnicity. METHODS: Data from the British Society for Rheumatology Biologics Register (BSRBR), a national prospective observational study, were used to compare TB rates in 10 712 anti-TNF treated patients (3913 ETA, 3295 INF, 3504 ADA) and 3232 patients with active RA treated with traditional disease-modifying antirheumatic drugs. RESULTS: To April 2008, 40 cases of TB were reported, all in the anti-TNF cohort. The rate of TB was higher for the monoclonal antibodies ADA (144 events/100,000 person-years) and INF (136/100,000 person-years) than for ETA (39/100,000 person-years). After adjustment, the incidence rate ratio compared with ETA-treated patients was 3.1 (95% CI 1.0 to 9.5) for INF and 4.2 (1.4 to 12.4) for ADA. The median time to event was lowest for INF (5.5 months) compared with ETA (13.4 months) and ADA (18.5 months). 13/40 cases occurred after stopping treatment. 25/40 (62%) cases were extrapulmonary, of which 11 were disseminated. Patients of non-white ethnicity had a sixfold increased risk of TB compared with white patients treated with anti-TNF therapy. CONCLUSION: The rate of TB in patients with RA treated with anti-TNF therapy was three- to fourfold higher in patients receiving INF and ADA than in those receiving ETA.