Automation can transform productivity in research activities that use liquid handling, such as organic synthesis, but it has made less impact in materials laboratories, which require sample ...preparation steps and a range of solid-state characterization techniques. For example, powder X-ray diffraction (PXRD) is a key method in materials and pharmaceutical chemistry, but its end-to-end automation is challenging because it involves solid powder handling and sample processing. Here we present a fully autonomous solid-state workflow for PXRD experiments that can match or even surpass manual data quality, encompassing crystal growth, sample preparation, and automated data capture. The workflow involves 12 steps performed by a team of three multipurpose robots, illustrating the power of flexible, modular automation to integrate complex, multitask laboratories.
This study presents a modular autonomous workflow for solid-state chemistry comprising three separate robots, allowing automated powder X-ray diffraction to underpin crystalline materials discovery.
The process characteristics of the synergic cold metal transfer (CMT) process have been examined for welding aluminium alloy. Utilising a simple backlighting system and through the arc monitoring the ...droplet transfer modes were identified. Whilst the modified short circuit mode was evident for the lower parameter range, a two part transfer mode based upon a combination of spray and short circuit transfer was observed for the mid to upper parameter range. The technology was also explored as a cladding process for applying to ternary alloyed (Al–Cu–Mg) aluminium plate. This alloy system is known to be susceptible to solidification cracking when MIG welded using the binary Al-2319 (Al–Cu) filler wire, this being due to the wide element freezing range of the weld resulting from mixing with the base material. Utilising this filler, weld dilution ratios for both CMT and pulsed welding were identified across the examined parameter range. The CMT process exhibited greater control of dilution that enabled deposition of a quasi-binary (Al–Cu) layer exhibiting a less crack susceptible composition. Onto this layer conventional MIG welding could be applied which could potentially eradicate cracking using a binary filler wire.
Diabetic foot ulcers portend an almost twofold increase in all-cause mortality compared with diabetes on its own.
To investigate the association between diabetic foot ulcers and risk of death.
We ...performed a meta-analysis of all observational studies investigating the association between diabetic foot ulcers and all-cause mortality. Risk ratios and risk differences were pooled in a random-effects model. The I
statistic was used to quantify heterogeneity between studies.
Altogether, we identified 11 studies that reported 84 131 deaths from any cause in 446 916 participants with diabetes during a total of 643 499 person-years of follow-up. The crude event rate for all-cause mortality in individuals with diabetes who did not develop foot ulceration was 22% lower at 181.5 deaths (per 1000 person-years) than in those who developed foot ulcers (230.8 per 1000 person-years). Diabetic foot ulceration was associated with an increased risk of all-cause mortality (pooled relative risk 2.45, 95% CI 1.85-2.85). We did not observe any tangible differences in risk of all-cause mortality from diagnosis in studies reporting a mean duration of follow-up of ≤3 years (relative risk 2.43, 95% CI 2.27-2.61) or >3 years (relative risk 2.26, 95% CI 2.13-2.40) years. Funnel plot inspection revealed no significant publication bias among studies included in this meta-analysis.
Our study shows an excess rate of all-cause mortality in people with diabetic foot ulceration when compared to those without foot ulceration. It is imperative that early interventions to prevent foot ulceration and modify cardiovascular disease risk factors are put in place to reduce excess mortality.
Summary
Background
Real‐world biologic drug survival is an important proxy measure for effectiveness. Predictors of drug survival may help patients with psoriasis choose between biologic therapies.
...Objectives
(i) To assess the relative drug survival of adalimumab, ustekinumab and secukinumab in patients with psoriasis. (ii) To investigate predictors of biologic drug survival.
Methods
A prospective cohort study was performed in the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR) between November 2007 and August 2019. We performed survival analysis and fitted a flexible parametric survival model for biologic discontinuation due to ineffectiveness.
Results
In total 9652 patients were included: 5543 starting on adalimumab (57·4%), 991 on secukinumab (10·3%) and 3118 on ustekinumab (32·3%). The overall drug survivals of adalimumab, secukinumab and ustekinumab in year 1 were 0·78 95% confidence interval (CI) 0·77–0·79, 0·88 (95% CI 0·86–0·91) and 0·88 (95% CI 0·87–0·89), respectively. The adjusted hazard ratios (adjHRs) for discontinuation of adalimumab and secukinumab compared with ustekinumab were 2·11 (95% CI 1·76–2·54) and 0·67 (95% CI 0·40–1·11), respectively. The presence of psoriatic arthritis predicted for survival in the adalimumab and secukinumab cohorts (adjHR 0·67, 95% CI 0·51–0·88 and 0·70, 95% CI 0·40–1·24, respectively), but for discontinuation in the ustekinumab cohort (adjHR 1·42, 95% CI 1·12–1·81). Previous exposure to biologic therapies predicted for discontinuation in the ustekinumab and secukinumab cohorts (adjHR 1·54, 95% CI 1·26–1·89 and 1·49, 95% CI 0·91–2·45, respectively) and for survival in the adalimumab cohort (adjHR 0·71, 95% CI 0·55–0·92).
Conclusions
Secukinumab and ustekinumab have similar sustained drug survival, while adalimumab has a lower drug survival in patients with psoriasis. Psoriatic arthritis and previous biologic experience were predictors with differential effects between the biologic therapies.
What is already known about this topic?
There is conflicting evidence over the real‐world drug survival of secukinumab in patients with psoriasis.
Data from registries to date suggest that secukinumab has a lower drug survival than that reported from clinical trials.
What does this study add?
This study found that secukinumab and ustekinumab had similar sustained drug survival in the real world, while the drug survival of adalimumab was lower, suggesting that the real‐world drug survival of secukinumab is higher than previously reported.
We found that psoriatic arthritis and previous biologic experience had differential effects on drug discontinuation in the three biologic cohorts. These predictors may help patients and clinicians choose the most appropriate biologic therapy.
Linked Comment: Veysey. Br J Dermatol 2020; 183:204–205.
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).
To compare directly the risk between drugs, to explore time to event, site of infection and the role of ethnicity.
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.
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.
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.
Factorisation (also known as “factor separation”) is widely used in the analysis of numerical simulations. It allows changes in properties of a system to be attributed to changes in multiple ...variables associated with that system. There are many possible factorisation methods; here we discuss three previously proposed factorisations that have been applied in the field of climate modelling: the linear factorisation, the Stein and Alpert (1993) factorisation, and the Lunt et al. (2012) factorisation. We show that, when more than two variables are being considered, none of these three methods possess all four properties of “uniqueness”, “symmetry”, “completeness”, and “purity”. Here, we extend each of these factorisations so that they do possess these properties for any number of variables, resulting in three factorisations – the “linear-sum” factorisation, the “shared-interaction” factorisation, and the “scaled-residual” factorisation. We show that the linear-sum factorisation and the shared-interaction factorisation reduce to be identical in the case of four or fewer variables, and we conjecture that this holds for any number of variables. We present the results of the factorisations in the context of three past studies that used the previously proposed factorisations.
Summary
Background
Psoriasis is associated with risk factors for serious infections, but the independent relationship between psoriasis and serious infection is as yet unclear.
Objectives
To ...determine whether people with psoriasis have a higher risk of hospitalization due to any infection, respiratory infections, soft‐tissue and skin infections, or a higher risk of death due to infection.
Methods
We conducted a cohort study of people (≥ 18 years) with psoriasis using the UK Clinical Practice Research Datalink (CPRD GOLD) linked to Hospital Episode Statistics (HES) and Office for National Statistics (ONS) mortality records between 1 April 2003 and 31 December 2016, and matched with up to six comparators on age, sex and general practice. Hospitalization was ascertained from HES records; death was ascertained from ONS mortality records. Stratified Cox proportional hazard models were estimated, with stepwise adjustment in different models for potential confounders or mediators between psoriasis and serious infection.
Results
There were 69 315 people with psoriasis and 338 620 comparators who were followed up for a median (interquartile range) of 4·9 (5·9) and 5·1 (6·3) years, respectively. People with psoriasis had a higher incidence rate of serious infection 20·5 per 1000 person‐years, 95% confidence interval (CI) 20·0–21·0, n = 7631 compared with those without psoriasis (16·1 per 1000 person‐years, 95% CI 15·9–16·3, n = 30 761). The fully adjusted hazard ratio for the association between psoriasis and serious infection was 1·36 (95% CI 1·31–1·40), with similar results across the other outcomes.
Conclusions
Psoriasis is associated with a small increase in the risk of serious infection. Further research is needed to understand how psoriasis predisposes to a higher risk of infection.
What is already known about this topic?
Several studies have shown that people with psoriasis have a higher risk of hospitalization due to infection, but these studies are limited by residual confounding for lifestyle factors or underestimation of the true incidence of hospital admissions from primary care electronic health records.
What does this study add?
Using a large primary care database linked with secondary care Hospital Episode Statistics, we found that, after adjusting for potential confounders and mediators, the hazard ratio for the association between psoriasis and the development of serious infection was 1·36 (95% confidence interval 1·31–1·40).
In summary, we show that having psoriasis is independently associated with a small but increased risk of serious infection.
Linked Comment: Naldi. Br J Dermatol 2021; 184:6.
Plain language summary available online
To use general practice-level data for England, available through the National Diabetes Audit, and primary care prescribing data to identify prescription treatment factors associated with variations ...in achieved glucose control (HbA
).
General practice-level National Diabetes Audit data on Type 1 diabetes, including details of population characteristics, services, proportion of people achieving target glycaemic control HbA
≤58 mmol/mol (7.5%) and proportion of people at high glycaemic risk HbA
>86 mmol/ml (10%), were linked to 2013-2016 primary care diabetes prescribing data on insulin types and blood glucose monitoring for all people with diabetes.
A wide variation was found between the 10
percentile and the 90
percentile of general practices in both target glycaemic control (15.6% to 44.8%, respectively) and high glycaemic risk (4.8% to 28.6%, respectively). Our analysis suggests that, given the extrapolated total of 280 000 people with Type 1 diabetes in the UK, there may be the potential to increase the number of those within target glycaemic control from 80 000 to 101 000; 53% of this increase (11 000 people) would result from service improvements and 47% (10 000 people) from medication and technology changes. The same improvements would also provide the opportunity to reduce the number of people at high glycaemic risk from 42 000 to 26 500. A key factor associated with practice-level target HbA
achievement would be greater use of insulin pumps for up to an additional 56 000 people.
If the HbA
achievement rates in service provision, medication and use of technology currently seen in practices in the 90
percentile were to be matched with regard to HbA
achievement rates in all general practices, glycaemic control might be improved for 36 500 people, with all the attendant health benefits.
Objective
To examine mortality rates in UK patients with early rheumatoid arthritis (RA) from 1990–2011 and compare with population trends.
Methods
The Norfolk Arthritis Register (NOAR) recruited ...adults with ≥2 swollen joints for ≥4 weeks: cohort 1 (1990–1994), cohort 2 (1995–1999), and cohort 3 (2000–2004). At baseline, serum rheumatoid factor and anti–citrullinated protein antibody were measured and the 2010 American College of Rheumatology/European League Against Rheumatism RA classification criteria were applied. Patients were followed for 7 years, until emigration or death. The UK Office for National Statistics notified the NOAR of the date and cause of deaths, and provided mortality rates for the Norfolk population. All‐cause and cardiovascular‐specific standardized mortality ratios (SMRs) were calculated. Poisson regression was used to compare mortality rate ratios (MRRs) between cohorts and then, with cubic splines, to model rates by calendar year. Analyses were performed in patients 1) with early inflammatory arthritis, 2) classified as having RA, and 3) autoantibody positive.
Results
A total of 2,517 patients were included, with 1,639 women (65%) and median age 55 years, and 1,419 (56%) fulfilled the 2010 RA criteria. All‐cause and cardiovascular‐specific SMRs were significantly elevated in the antibody‐positive groups. There was no change in mortality rates over time after accounting for changes in the population rates. In RA patients, all‐cause MRRs, compared to cohort 1, were 1.13 (95% confidence interval 95% CI 0.84–1.52) and 1.00 (95% CI 0.70–1.43) in cohorts 2 and 3, respectively.
Conclusion
Mortality rates were increased in patients with RA and SMRs were particularly elevated in those who were autoantibody positive. Compared to the general population, mortality rates have not improved over the past 20 years.
Background: There is increased cardiovascular disease mortality in rheumatoid arthritis. This may reflect an increased prevalence of cardiovascular disease or an increased case fatality in patients ...with rheumatoid arthritis. Objectives: To examine whether rheumatoid patients with disease onset in the 1980s–1990s have increased mortality, and to compare cardiovascular admission rates in rheumatoid patients with those of the general population. Methods: An inception cohort of 1010 rheumatoid patients attending Stockport rheumatology clinics between 1981 and 1996 was followed up to December 2002 through the Office for National Statistics. Standardised mortality ratios (SMR) were calculated for all-cause and cause specific mortality, using the population of Stockport as reference. Cardiovascular disease admission rates were ascertained for a subgroup of patients using national hospital episode statistics; standardised cardiovascular disease admission rates (SAR) and SMRs were calculated for this subgroup. Results: 470 patients (48%) died during a median follow up of 11.4 years. All-cause mortality was increased in men (SMR = 1.45 (95% confidence interval, 1.22 to 1.71)) and women (SMR = 1.84 (1.64 to 2.05)), as was cardiovascular disease mortality in men (SMR = 1.36 (1.04 to 1.75) and women (SMR = 1.93 (1.65 to 2.26)). No difference in cardiovascular disease admission rates was observed in men (SAR 1.20 (0.89 to 1.58) or women (SAR = 1.10 (0.88 to 1.36)), despite excess cardiovascular disease mortality in this subgroup. Conclusions: Patients with rheumatoid arthritis have reduced life expectancy and excess cardiovascular disease mortality. Nevertheless, standardised admission rates for cardiovascular disease were not raised. This suggests either that cardiovascular disease in rheumatoid arthritis has a higher case fatality than in the general population or that it often goes unrecognised before the fatal event.
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