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.

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.

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.

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.

Multilevel principal components analysis of three-dimensional facial growth in adolescents.

BACKGROUND AND OBJECTIVES: The study of age-related facial shape changes across different populations and sexes requires new multivariate tools to disentangle different sources of variations present in 3D facial images. Here we wish to use a multivariate technique called multilevel principal components analysis (mPCA) to study three-dimensional facial growth in adolescents. METHODS: These facial shapes were captured for Welsh and Finnish subjects (both male and female) at multiple ages from 12 to 17 years old (i.e., repeated-measures data). 1000 "dense" 3D points were defined regularly for each shape by using a deformable template via "meshmonk" software. A three-level model was used here, namely: level 1 (sex/ethnicity); level 2, all "subject" variations excluding sex, ethnicity, and age; and level 3, age. The technicalities underpinning the mPCA method are presented in Appendices. RESULTS: Eigenvalues via mPCA predicted that: level 1 (ethnicity/sex) contained 7.9% of variation; level 2 contained 71.5%; and level 3 (age) contained 20.6%. The results for the eigenvalues via mPCA followed a similar pattern to those results of single-level PCA. Results for modes of variation made sense, where effects due to ethnicity, sex, and age were reflected in modes at appropriate levels of the model. Standardised scores at level 1 via mPCA showed much stronger differentiation between sex and ethnicity groups than results of single-level PCA. Results for standardised scores from both single-level PCA and mPCA at level 3 indicated that females had different average "trajectories" with respect to these scores than males, which suggests that facial shape matures in different ways for males and females. No strong evidence of differences in growth patterns between Finnish and Welsh subjects was observed. CONCLUSIONS: mPCA results agree with existing research relating to the general process of facial changes in adolescents with respect to age quoted in the literature. They support previous evidence that suggests that males demonstrate larger changes and for a longer period of time compared to females, especially in the lower third of the face. These calculations are therefore an excellent initial test that multivariate multilevel methods such as mPCA can be used to describe such age-related changes for "dense" 3D point data.

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.

Recipients' and providers' perspectives of obesity and potential barriers to weight management programmes in patients with Rheumatoid Arthritis (RA): a qualitative study.

BACKGROUND: The UK rheumatology community serves an ageing and ethnically diverse population, with a growing public health concern about obesity. Overweight and obesity contribute to 2.8 million preventable deaths annually. A raised Body Mass Index (BMI) in those with Rheumatoid Arthritis (RA) can have a significant negative impact on clinical outcomes. The aim of the study was to examine patients' and providers' perceptions of obesity and potential barriers to participation in a future weight management programme to contribute to an appropriate intervention design. METHOD: Qualitative semi-structured interviews were carried out with 11 patients with RA and one focus group was held with 8 members of a multi-disciplinary team working in one Rheumatology outpatient clinic. Framework analysis (FA) contributed to the inductive thematic analysis, and was employed to assist with the identification of the emergent codes and final themes. RESULTS: Three core themes were ascertained from the semi-structured interviews: i) The psychosocial impact of living with RA and obesity, ii) Challenges of living with RA and obesity and iii) Considerations for future weight management programmes. The Focus group analysis also identified three core themes: i) Micro-dynamics between patient and provider, ii) The relationship between the provider and the host institution in relation to the development of a future weight management programme and iii) The social and political context of obesity as a public health concern. CONCLUSION: Perceptions of obesity and weight gain and associated barriers to participating in weight management programmes, differ significantly between patients and providers. Patients, require a holistic approach to weight management by clinicians and the acknowledgement of the significant psychosocial impact of a dual diagnosis of RA and being overweight or obese. In contrast, providers seem reluctant to address weight increase with patients and require education and support at an individual and institutional level to integrate weight management into routine care.

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.

Using the zebrafish to understand tendon development and repair.

Tendons are important components of our musculoskeletal system. Injuries to these tissues are very common, resulting from occupational-related injuries, sports-related trauma, and age-related degeneration. Unfortunately, there are few treatment options, and current therapies rarely restore injured tendons to their original function. An improved understanding of the pathways regulating their development and repair would have significant impact in stimulating the formulation of regenerative-based approaches for tendon injury. The zebrafish provides an ideal system in which to perform genetic and chemical screens to identify new pathways involved in tendon biology. Until recently, there had been few descriptions of tendons and ligaments in the zebrafish and their similarity to mammalian tendon tissues. In this chapter, we describe the development of the zebrafish tendon and ligament tissues in the context of their gene expression, structure, and interactions with neighboring musculoskeletal tissues. We highlight the similarities with tendon development in higher vertebrates, showing that the craniofacial tendons and ligaments in zebrafish morphologically, molecularly, and structurally resemble mammalian tendons and ligaments from embryonic to adult stages. We detail methods for fluorescent in situ hybridization and immunohistochemistry as an assay to examine morphological changes in the zebrafish musculoskeleton. Staining assays such as these could provide the foundation for screen-based approaches to identify new regulators of tendon development, morphogenesis, and repair. These discoveries would provide new targets and pathways to study in the context of regenerative medicine-based approaches to improve tendon healing.

Environmental signatures and effects of an oil and gas wastewater spill in the Williston Basin, North Dakota.

Wastewaters from oil and gas development pose largely unknown risks to environmental resources. In January 2015, 11.4ML (million liters) of wastewater (300g/L TDS) from oil production in the Williston Basin was reported to have leaked from a pipeline, spilling into Blacktail Creek, North Dakota. Geochemical and biological samples were collected in February and June 2015 to identify geochemical signatures of spilled wastewaters as well as biological responses along a 44-km river reach. February water samples had elevated chloride (1030mg/L) and bromide (7.8mg/L) downstream from the spill, compared to upstream levels (11mg/L and <0.4mg/L, respectively). Lithium (0.25mg/L), boron (1.75mg/L) and strontium (7.1mg/L) were present downstream at 5-10 times upstream concentrations. Light hydrocarbon measurements indicated a persistent thermogenic source of methane in the stream. Semi-volatile hydrocarbons indicative of oil were not detected in filtered samples but low levels, including tetramethylbenzenes and di-methylnaphthalenes, were detected in unfiltered water samples downstream from the spill. Labile sediment-bound barium and strontium concentrations (June 2015) were higher downstream from the Spill Site. Radium activities in sediment downstream from the Spill Site were up to 15 times the upstream activities and, combined with Sr isotope ratios, suggest contributions from the pipeline fluid and support the conclusion that elevated concentrations in Blacktail Creek water are from the leaking pipeline. Results from June 2015 demonstrate the persistence of wastewater effects in Blacktail Creek several months after remediation efforts started. Aquatic health effects were observed in June 2015; fish bioassays showed only 2.5% survival at 7.1km downstream from the spill compared to 89% at the upstream reference site. Additional potential biological impacts were indicated by estrogenic inhibition in downstream waters. Our findings demonstrate that environmental signatures from wastewater spills are persistent and create the potential for long-term environmental health effects.

Rheumatoid arthritis - an update for general dental practitioners.

Rheumatoid arthritis (RA) is a common chronic inflammatory autoimmune disorder which significantly impacts patients' lives and can lead to permanent disability. Inflammation in RA not only affects joints; but can affect organs including the heart and lungs. Early diagnosis, initiation of intensive drug therapy, and a multidisciplinary care approach have vastly improved the long-term prognosis for those living with the condition. However, RA patients often present with co-morbidities which add to the complexity of clinical management. Orofacial conditions associated with RA which dental professionals need to be aware of include periodontal disease, temporomandibular dysfunction and salivary gland dysfunction. In this article, we provide information on RA, oral health in RA and guidance on how best to manage patients with RA in general dental practice.

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.

Nano- and micro-patterning biotemplated magnetic CoPt arrays.

Patterned thin-films of magnetic nanoparticles (MNPs) can be used to make: surfaces for manipulating and sorting cells, sensors, 2D spin-ices and high-density data storage devices. Conventional manufacture of patterned magnetic thin-films is not environmentally friendly because it uses high temperatures (hundreds of degrees Celsius) and high vacuum, which requires expensive specialised equipment. To tackle these issues, we have taken inspiration from nature to create environmentally friendly patterns of ferromagnetic CoPt using a biotemplating peptide under mild conditions and simple apparatus. Nano-patterning via interference lithography (IL) and micro-patterning using micro-contact printing (µCP) were used to create a peptide resistant mask onto a gold surface under ambient conditions. We redesigned a biotemplating peptide (CGSGKTHEIHSPLLHK) to self-assemble onto gold surfaces, and mineralised the patterns with CoPt at 18 °C in water. Ferromagnetic CoPt is biotemplated by the immobilised peptides, and the patterned MNPs maintain stable magnetic domains. This bioinspired study offers an ecological route towards developing biotemplated magnetic thin-films for use in applications such as sensing, cell manipulation and data storage.

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.