Donor noradrenaline use is associated with better allograft survival in recipients of pancreas transplantation.

INTRODUCTION: Outcomes following pancreas transplantation are suboptimal and better donor selection is required to improve this. Vasoactive drugs (VaD) are commonly used to correct the abnormal haemodynamics of organ donors in intensive care units. VaDs can differentially affect insulin secretion positively (dobutamine) or negatively (noradrenaline). The hypothesis was that some VaDs might induce beta-cell stress or rest and therefore impact pancreas transplant outcomes. The aim of the study was to assess relationships between VaD use and pancreas transplant graft survival. METHODS: Data from the UK Transplant Registry on all pancreas transplants performed between 2004 and 2016 with complete follow-up data were included. Univariable- and multivariable-adjusted Cox regression analyses determined risks of graft failure associated with VaD use. RESULTS: In 2,183 pancreas transplants, VaDs were used in the following numbers of donors: dobutamine 76 (3.5%), dopamine 84 (3.8%), adrenaline 161 (7.4%), noradrenaline 1,589 (72.8%) and vasopressin 1,219 (55.8%). In multivariable models, adjusted for covariates and the co-administration of other VaDs, noradrenaline use (vs non-use) was a strong predictor of better graft survival (hazard ratio [95% confidence interval] 0.77 [0.64-0.94], p = 0.01). CONCLUSIONS: Noradrenaline use was associated with better graft survival in models adjusted for donor and recipient variables - this may be related to inhibition of pancreatic insulin secretion initiating pancreatic beta-cell 'rest'. Further research is required to replicate these findings and establish whether relationships are causal. Identification of alternative methods of inducing beta-cell rest could be valuable in improving graft outcomes.

Early respiratory diagnosis: benefits of enhanced lung function assessment.

INTRODUCTION: The National Health Service for England Long Term Plan identifies respiratory disease as one of its priority workstreams. To assist with earlier and more accurate diagnosis of lung disease they recommend improvement in delivery of quality-assured spirometry. However, there is a likelihood that patients will present with abnormal gas exchange when spirometry results are normal and therefore there will be a proportion of patients whose time to diagnosis is still protracted. We wished to determine the incidence rate of this occurring within our Trust. METHODS: A retrospective review of all patients attending the lung function laboratory for their first pulmonary function assessment from June 2006 to December 2020 was undertaken. Forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) >-1.64 standardised residual (SR) was used to confirm no obstructive lung function abnormality and FVC >-1.64 SR to confirm no suggestion of a restrictive lung function abnormality. Lung gas transfer for carbon monoxide (TLCO) and transfer coefficient of the lung for carbon monoxide (KCO) <-1.64 SR confirmed the presence of a gas exchange abnormality. Spirometry and gas transfer reference values generated by the Global Lung Initiative were used to determine normality. RESULTS: Of 12 835 eligible first visits with normal FEV1/FVC and FVC, 4856 (37.8%) were identified as having an abnormally low TLCO and 3302 (25.7%) presenting with an abnormally low KCO. Of 3494 with FEV1/FVC SR <-1.64, 3316 also had a ratio of <0.70, meaning 178 (5%) of patients in this cohort would have been misclassified as having obstructive lung disease using the 0.70 cut-off recommended by the Global Initiative for Chronic Obstructive Lung Disease for diagnosing obstructive lung disease. DISCUSSION: In conclusion, to assist with ensuring more accurate and timely diagnosis of lung disease and enhance patients' diagnostic pathway, we recommend the performance of lung gas transfer measurements alongside spirometry in all healthcare settings. To assess and monitor gas transfer at the earliest opportunity we recommend this is implemented into new models being developed within community hubs. This will increase the identification of lung function abnormalities and provide patients with a definitive diagnosis earlier.

Safety and efficacy of teriparatide treatment for severe osteoporosis in patients with Duchenne muscular dystrophy.

Osteoporosis is a major concern in patients with Duchenne muscular dystrophy. In this novel study of teriparatide treatment in 6 patients with severe osteoporosis, bone health (fractures, vertebral morphometry, and DXA) remained stable, with no adverse events. These findings will help inform future osteoporosis research in this challenging population. INTRODUCTION: Despite standard therapy with vitamin D and bisphosphonates (BP), many patients with Duchenne muscular dystrophy (DMD) continue to sustain fragility fractures due to long-term glucocorticoid treatment and limited mobility. We aimed to evaluate the safety and efficacy of teriparatide for the treatment of severe osteoporosis in adolescent and young adult patients with DMD. METHODS: We prospectively treated 6 patients with DMD who had severe osteoporosis with teriparatide 20 mcg subcutaneously daily for 1-2 years. Inclusion criteria were long-term glucocorticoid therapy, and severe osteoporosis despite treatment with BP, or intolerance to BP. We examined long bone and vertebral fracture outcomes, including vertebral morphometry measures, bone mineral density and content, bone formation markers, safety indices, and adverse events. RESULTS: The mean age at teriparatide start was 17.9 years (range 13.9-22.1 years). All 6 patients were on daily glucocorticoids (mean ± SD; duration 10.9 ± 2.5 years) and 5 were non-ambulatory. Five patients had been treated with BP for 7.9 ± 4.2 years. All had vertebral and a history of long bone fragility fractures at baseline. Vertebral heights and Genant fracture grading remained stable. Long bone fracture rate appeared to decrease (from 0.84/year to 0.09/year); one patient sustained a long bone fracture at 6 months of treatment. Trajectories for change in bone mineral density and content were not different post- vs. pre-teriparatide. Procollagen type 1 amino-terminal propeptide (P1NP) increased, while laboratory safety indices remained stable and non-concerning. No adverse events were observed. CONCLUSION: In six patients with DMD treated with teriparatide for severe osteoporosis, we observed stable bone health and modest increases in P1NP, without safety concerns. Further studies are needed to better understand teriparatide efficacy for treatment of osteoporosis in patients with DMD.

Improving paediatric antimicrobial stewardship in hospital-based settings: why, where and how?

BACKGROUND: Antimicrobial resistance (AMR) is being recognized as a priority by healthcare organizations across the world. However, many children are managed on IV antimicrobials in hospital with very little consideration of antimicrobial stewardship issues. OBJECTIVES: A nurse-led paediatric ambulatory outpatient parenteral antimicrobial therapy (OPAT) service, managing children with common infections being ambulated on short courses of IV antimicrobials, was introduced within Southampton Children's Hospital in January 2018. We evaluated the impact of this service in terms of the quality of antimicrobial prescribing and timing of ambulation in children presenting with common infections. METHODS: All cases managed within the service were reviewed in two separate 2 month time periods: prior to introduction of the service (September-October 2016) and then prospectively after its introduction (September-October 2018). RESULTS: A total of 96% of IV antibiotic management decisions at 48 h were deemed appropriate in 2018, compared with 75% in 2016. A total of 64% of patients were ambulated on IV antibiotics at some point during their treatment course in 2018, compared with 19% in 2016. However, a significant proportion of antimicrobial decisions made at the point of presentation to hospital remained suboptimal in 2018. CONCLUSIONS: Children are commonly managed with IV antibiotics in hospital. We demonstrate marked improvements in appropriate antimicrobial use through the introduction of a nurse-led ambulatory OPAT service. In addition, such a service can promote a greater proportion of children being ambulated from hospital, freeing up valuable inpatient beds and potentially delivering cost savings that can be used to fund such services.

Risk of major cardiovascular events in patients with psoriasis receiving biologic therapies: a prospective cohort study.

BACKGROUND: The cardiovascular safety profile of biologic therapies used for psoriasis is unclear. OBJECTIVES: To compare the risk of major cardiovascular events (CVEs; acute coronary syndrome, unstable angina, myocardial infarction and stroke) in patients with chronic plaque psoriasis treated with adalimumab, etanercept or ustekinumab in a large prospective cohort. METHODS: Prospective cohort study examining the comparative risk of major CVEs was conducted using the British Association of Dermatologists Biologics and Immunomodulators Register. The main analysis compared adults with chronic plaque psoriasis receiving ustekinumab with tumour necrosis-α inhibitors (TNFi: etanercept and adalimumab), whilst the secondary analyses compared ustekinumab, etanercept or methotrexate against adalimumab. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using overlap weights by propensity score to balance baseline covariates among comparison groups. RESULTS: We included 5468 biologic-naïve patients subsequently exposed (951 ustekinumab; 1313 etanercept; and 3204 adalimumab) in the main analysis. The secondary analyses also included 2189 patients receiving methotrexate. The median (p25-p75) follow-up times for patients using ustekinumab, TNFi, adalimumab, etanercept and methotrexate were as follows: 2.01 (1.16-3.21), 1.93 (1.05-3.34), 1.94 (1.09-3.32), 1.92 (0.93-3.45) and 1.43 (0.84-2.53) years, respectively. Ustekinumab, TNFi, adalimumab, etanercept and methotrexate groups had 7, 29, 23, 6 and 9 patients experiencing major CVEs, respectively. No differences in the risk of major CVEs were observed between biologic therapies [adjusted HR for ustekinumab vs. TNFi: 0.96 (95% CI 0.41-2.22); ustekinumab vs. adalimumab: 0.81 (0.30-2.17); etanercept vs. adalimumab: 0.81 (0.28-2.30)] and methotrexate against adalimumab [1.05 (0.34-3.28)]. CONCLUSIONS: In this large prospective cohort study, we found no significant differences in the risk of major CVEs between three different biologic therapies and methotrexate. Additional studies, with longer term follow-up, are needed to investigate the potential effects of biologic therapies on incidence of major CVEs.

Molecules with dipoles in periodic boundary conditions in a tetragonal cell.

When a system which contains a dipole, and whose dimensionality is less than three, is studied in a code which imposes periodic boundary conditions in all three dimensions, an artificial electric field arises which keeps the potential periodic. This has an impact on the total energy of the system, and on any other attribute which would respond to an electric field. Simple corrections are known for 0D systems embedded in a cubic geometry, and 2D slab systems. This paper shows how the 0D result can be extended to tetragonal geometries, and that for a particular c/a ratio the correction is zero. It also considers an exponential error term absent from the usual consideration of 2D slab geometries, and discusses an empirical form for this.

Long-Term Endurance and Power Training May Facilitate Motor Unit Size Expansion to Compensate for Declining Motor Unit Numbers in Older Age.

The evidence concerning the effects of exercise in older age on motor unit (MU) numbers, muscle fiber denervation and reinnervation cycles is inconclusive and it remains unknown whether any effects are dependent on the type of exercise undertaken or are localized to highly used muscles. MU characteristics of the vastus lateralis (VL) were assessed using surface and intramuscular electromyography in eighty-five participants, divided into sub groups based on age (young, old) and athletic discipline (control, endurance, power). In a separate study of the biceps brachii (BB), the same characteristics were compared in the favored and non-favored arms in eleven masters tennis players. Muscle size was assessed using MRI and ultrasound. In the VL, the CSA was greater in young compared to old, and power athletes had the largest CSA within their age groups. Motor unit potential (MUP) size was larger in all old compared to young (p < 0.001), with interaction contrasts showing this age-related difference was greater for endurance and power athletes than controls, and MUP size was greater in old athletes compared to old controls. In the BB, thickness did not differ between favored and non-favored arms (p = 0.575), but MUP size was larger in the favored arm (p < 0.001). Long-term athletic training does not prevent age-related loss of muscle size in the VL or BB, regardless of athletic discipline, but may facilitate more successful axonal sprouting and reinnervation of denervated fibers. These effects may be localized to muscles most involved in the exercise.

Assessing the severity of Type 2 diabetes using clinical data-based measures: a systematic review.

AIMS: To identify and critically appraise measures that use clinical data to grade the severity of Type 2 diabetes. METHODS: We searched MEDLINE, Embase and PubMed between inception and June 2018. Studies reporting on clinical data-based diabetes-specific severity measures in adults with Type 2 diabetes were included. We excluded studies conducted solely in participants with other types of diabetes. After independent screening, the characteristics of the eligible measures including design and severity domains, the clinical utility of developed measures, and the relationship between severity levels and health-related outcomes were assessed. RESULTS: We identified 6798 studies, of which 17 studies reporting 18 different severity measures (32 314 participants in 17 countries) were included: a diabetes severity index (eight studies, 44%); severity categories (seven studies, 39%); complication count (two studies, 11%); and a severity checklist (one study, 6%). Nearly 89% of the measures included diabetes-related complications and/or glycaemic control indicators. Two of the severity measures were validated in a separate study population. More severe diabetes was associated with increased healthcare costs, poorer cognitive function and significantly greater risks of hospitalization and mortality. The identified measures differed greatly in terms of the included domains. One study reported on the use of a severity measure prospectively. CONCLUSIONS: Health records are suitable for assessment of diabetes severity; however, the clinical uptake of existing measures is limited. The need to advance this research area is fundamental as higher levels of diabetes severity are associated with greater risks of adverse outcomes. Diabetes severity assessment could help identify people requiring targeted and intensive therapies and provide a major benchmark for efficient healthcare services.

Impact of social deprivation, demographics and centre on HbA1c outcomes with continuous subcutaneous insulin infusion.

AIMS: To assess the impact of social deprivation, demographics and centre on HbA1c outcomes with continuous subcutaneous insulin infusion (CSII) in adults with Type 1 diabetes. METHODS: Demographic data, postcode-derived English Index of Multiple Deprivation data and 12-month average HbA1c (mmol/mol) pre- and post-CSII were collated from three diabetes centres in the north west of England, University Hospital of South Manchester (UHSM), Salford Royal Foundation Hospital (SRFT) and Manchester Royal Infirmary (MRI). Univariable and multivariable regression models explored relationships between demographics, Index of Multiple Deprivation, centre and HbA1c outcomes. RESULTS: Data were available for 693 (78%) individuals (UHSM, n = 90; SRFT, n = 112; and MRI, n = 491) of whom 59% were women. Median age at CSII start was 39 (IQR 29.5-49.0) years and median diabetes duration was 20 (11-29) years. Median Index of Multiple Deprivation was 15 193 (6313-25 727). Overall median HbA1c improved from 69 to 64 mmol/mol (8.5% to 8.0%) within the first year of CSII. In multivariable analysis, higher pre-CSII HbA1c was significantly associated with higher deprivation (P = 0.036), being female (P < 0.001), and centre (MRI; P = 0.005). Following pre-CSII HbA1c adjustment, post-CSII HbA1c or HbA1c change were not related to demographic factors and deprivation, but remained significantly related to the centre; UHSM and SRFT had larger reductions in HbA1c with CSII compared with MRI [median -7.0 (-0.6%) vs. -6.0 (-0.55%) vs. -4.5 (-0.45%) mmol/mol; P = 0.005]. CONCLUSIONS: Higher pre-CSII HbA1c levels were associated with higher deprivation and being female. CSII improves HbA1c irrespective of social deprivation and demographics. Significant differences in HbA1c improvements were observed between centres. Further work is warranted to explain these differences and minimize variation in clinical outcomes with CSII.

Developing a foot ulcer risk model: what is needed to do this in a real-world primary care setting?

AIM: To determine how routinely collected data can inform a risk model to predict de novo foot ulcer presentation in the primary care setting. METHODS: Data were available on 15 727 individuals without foot ulcers and 1125 individuals with new foot ulcers over a 12-year follow-up in UK primary care. We examined known risk factors and added putative risk factors in our logistic model. RESULTS: People with foot ulcers were 4.2 years older (95% CI 3.1-5.2) than those without, and had higher HbA1c % (mean 7.9 ± 1.9 vs 7.5 ± 1.7) / HbA1c mmol/mol (63 ± 21 vs 59 ± 19) (p<0.0001) concentration [+0.45 (95% CI 0.33-0.56), creatinine level [+6.9 µmol/L (95% CI 4.1-9.8)] and Townsend score [+0.055 (95% CI 0.033-0.077)]. Absence of monofilament sensation was more common in people with foot ulcers (28% vs 21%; P<0.0001), as was absence of foot pulses (6.4% vs 4.8%; P=0.017). There was no difference between people with or without foot ulcers in smoking status, gender, history of stroke or foot deformity, although foot deformity was extremely rare (0.4% in people with foot ulcers, 0.6% in people without foot ulcers). Combining risk factors in a single logistic regression model gave modest predictive power, with an area under the receiver-operating characteristic curve of 0.65 (95% CI 0.62-0.67). The prevalence of ulceration in the bottom decile of risk was 1.8% and in the top decile it was 13.4% (compared with an overall prevalence of 6.5%); thus, the presence of all six risk factors gave a relative risk of 7.4 for development of a foot ulcer over 12 years. CONCLUSION: We have made some progress towards defining a variable set that can be used to create a foot ulcer prediction model. More accurate determination of foot deformity/pedal circulation in primary care may improve the predictive value of such a future risk model, as will identification of additional risk variables.

Variations in the management of significant polyps and early colorectal cancer: results from a multicentre observational study of 383 patients.

AIM: The concept of significant polyps and early colorectal cancer (SPECC) encompasses complex polyps not amenable to routine snare polypectomy or where malignancy cannot be excluded. Surgical resection (SR) offers definitive treatment, but is overtreatment for the majority which are benign and amenable to less invasive endoscopic resection (ER). The aim of this study was to investigate variations in the management and outcomes of significant colorectal polyps. METHOD: This was a retrospective observational study of significant colorectal polyps, defined as nonpedunculated lesions of ≥ 20 mm size, diagnosed across nine UK hospitals in 2014. Inclusion criteria were endoscopically or histologically benign polyps at biopsy. RESULTS: A total of 383 patients were treated by primary ER (87.2%) or SR (12.8%). Overall, 108/383 (28%) polyps were detected in the Bowel Cancer Screening Programme (BCSP). Primary SR was associated with a significantly longer length of stay and major complications (P < 0.01). Of the ER polyps, 290/334 (86.8%) patients were treated without undergoing surgery. The commonest indication for secondary surgery was unexpected polyp cancer, and of these cases 60% had no residual cancer in the specimen. Incidence of unexpected cancer was 10.7% (n = 41) and was similar between ER and SR groups (P = 0.11). On multivariate analysis, a polyp size of > 30 mm and non-BCSP status were independent risk factors for primary SR [OR 2.51 (95% CI 1.08-5.82), P = 0.03]. CONCLUSION: ER is safe and feasible for treating significant colorectal polyps. Robust accreditation within the BCSP has led to improvements in management, with lower rates of SR compared with non-BCSP patients. Standardization, training in polyp assessment and treatment within a multidisciplinary team may help to select appropriate treatment strategies and improve outcomes.

Failure to expand the motor unit size to compensate for declining motor unit numbers distinguishes sarcopenic from non-sarcopenic older men.

KEY POINTS: The age-related loss of muscle mass is related to the loss of innervating motor neurons and denervation of muscle fibres. Not all denervated muscle fibres are degraded; some may be reinnervated by an adjacent surviving neuron, which expands the innervating motor unit proportional to the numbers of fibres rescued. Enlarged motor units have larger motor unit potentials when measured using electrophysiological techniques. We recorded much larger motor unit potentials in relatively healthy older men compared to young men, but the older men with the smallest muscles (sarcopenia) had smaller motor unit potentials than healthy older men. These findings suggest that healthy older men reinnervate large numbers of muscle fibres to compensate for declining motor neuron numbers, but a failure to do so contributes to muscle loss in sarcopenic men. ABSTRACT: Sarcopenia results from the progressive loss of skeletal muscle mass and reduced function in older age. It is likely to be associated with the well-documented reduction of motor unit numbers innervating limb muscles and the increase in size of surviving motor units via reinnervation of denervated fibres. However, no evidence exists to confirm the extent of motor unit remodelling in sarcopenic individuals. The aim of the present study was to compare motor unit size and number between young (n = 48), non-sarcopenic old (n = 13), pre-sarcopenic (n = 53) and sarcopenic (n = 29) men. Motor unit potentials (MUPs) were isolated from intramuscular and surface EMG recordings. The motor unit numbers were reduced in all groups of old compared with young men (all P < 0.001). MUPs were higher in non-sarcopenic and pre-sarcopenic men compared with young men (P = 0.039 and 0.001 respectively), but not in the vastus lateralis of sarcopenic old (P = 0.485). The results suggest that extensive motor unit remodelling occurs relatively early during ageing, exceeds the loss of muscle mass and precedes sarcopenia. Reinnervation of denervated muscle fibres probably expands the motor unit size in the non-sarcopenic and pre-sarcopenic old, but not in the sarcopenic old. These findings suggest that a failure to expand the motor unit size distinguishes sarcopenic from pre-sarcopenic muscles.

A new look at the supposed risks of early institutional rearing.

The main focus is on the assessment of the effects of early institutional care and compares three longitudinal studies from Romania, Greece and Hong Kong/China. The findings have been strikingly contrasting. The review asks if the risks are dependent on whether or not the institutional rearing is accompanied by gross pervasive deprivation (as it was in Romania) and investigates the methodological issues to explore the causal influence of the outcomes. Evidence is considered on changing institutional practices and the benefits of doing so. Comparison is made between institutions with major deprivation and those without global deprivation. A small number of studies are discussed that look at direct comparisons between institutional and community care. The empirical and conceptual implications of the findings are discussed.

Comparison of different insulin pump makes under routine care conditions in adults with Type 1 diabetes.

AIMS: To compare long-term HbA1c changes associated with different insulin pumps during routine care in a large cohort of adults with Type 1 diabetes representative of other clinic populations. METHODS: Observational, retrospective study of 508 individuals starting pump therapy between 1999 and 2014 (mean age, 40 years; 55% women; diabetes duration, 20 years; 94% Type 1 diabetes; median follow-up, 3.7 years). Mixed linear models compared covariate-adjusted HbA1c changes associated with different pump makes. RESULTS: The pumps compared were: 50% Medtronic, 24% Omnipod, 14% Roche and 12% Animas. Overall HbA1c levels improved and improvements were maintained during a follow-up extending to 10 years (HbA1c : pre-continuous subcutaneous insulin infusion (pre-CSII) vs. 12 months post CSII, 71 (61, 82) vs. 66 (56, 74) mmol/mol; 8.7 (7.7, 9.6) vs. 8.2 (7.3, 8.9)%; P < 0.0001). The percentage of individuals with HbA1c ≥ 64 mmol/mol (8.0%) reduced from a pre-CSII level of 68% to 55%. After adjusting for baseline confounders, there were no between-pump differences in HbA1c lowering (P = 0.44), including a comparison of patch pumps with traditional catheter pumps (P = 0.63). There were no significant (P < 0.05) between-pump differences in HbA1c lowering in pre-specified subgroups stratified by pre-pump HbA1c , age or diabetes duration. HbA1c lowering was positively related to baseline HbA1c (P < 0.001) and diabetes duration (P = 0.017), and negatively related to the number of years of CSII use (P = 0.024). CONCLUSIONS: Under routine care conditions, there were no covariate-adjusted differences in HbA1c lowering when comparing different pump makes, including a comparison of patch pumps vs. traditional catheter pumps. Therefore, the choice of CSII make should not be influenced by the desired degree of HbA1c lowering.

Fitness effects of mutation: testing genetic redundancy in Arabidopsis thaliana.

Screens of organisms with disruptive mutations in a single gene often fail to detect phenotypic consequences for the majority of mutants. One explanation for this phenomenon is that the presence of paralogous loci provides genetic redundancy. However, it is also possible that the assayed traits are affected by few loci, that effects could be subtle or that phenotypic effects are restricted to certain environments. We assayed a set of T-DNA insertion mutant lines of Arabidopsis thaliana to determine the frequency with which mutation affected fitness-related phenotypes. We found that between 8% and 42% of the assayed lines had altered fitness from the wild type. Furthermore, many of these lines exhibited fitness greater than the wild type. In a second experiment, we grew a subset of the lines in multiple environments and found whether a T-DNA insert increased or decreased fitness traits depended on the assay environment. Overall, our evidence contradicts the hypothesis that genetic redundancy is a common phenomenon in A. thaliana for fitness traits. Evidence for redundancy from prior screens of knockout mutants may often be an artefact of the design of the phenotypic assays which have focused on less complex phenotypes than fitness and have used single environments. Finally, our study adds to evidence that beneficial mutations may represent a significant component of the mutational spectrum of A. thaliana.