Summary Background Lifestyle changes soon after diagnosis might improve outcomes in patients with type 2 diabetes mellitus, but no large trials have compared interventions. We investigated the ...effects of diet and physical activity on blood pressure and glucose concentrations. Methods We did a randomised, controlled trial in southwest England in adults aged 30–80 years in whom type 2 diabetes had been diagnosed 5–8 months previously. Participants were assigned usual care (initial dietary consultation and follow-up every 6 months; control group), an intensive diet intervention (dietary consultation every 3 months with monthly nurse support), or the latter plus a pedometer-based activity programme, in a 2:5:5 ratio. The primary endpoint was improvement in glycated haemoglobin A1c (HbA1c ) concentration and blood pressure at 6 months. Analysis was done by intention to treat. This study is registered, number ISRCTN92162869. Findings Of 593 eligible individuals, 99 were assigned usual care, 248 the diet regimen, and 246 diet plus activity. Outcome data were available for 587 (99%) and 579 (98%) participants at 6 and 12 months, respectively. At 6 months, glycaemic control had worsened in the control group (mean baseline HbA1c percentage 6·72, SD 1·02, and at 6 months 6·86, 1·02) but improved in the diet group (baseline-adjusted difference in percentage of HbA1c −0·28%, 95% CI −0·46 to −0·10; p=0·005) and diet plus activity group (−0·33%, −0·51 to −0·14; p<0·001). These differences persisted to 12 months, despite less use of diabetes drugs. Improvements were also seen in bodyweight and insulin resistance between the intervention and control groups. Blood pressure was similar in all groups. Interpretation An intensive diet intervention soon after diagnosis can improve glycaemic control. The addition of an activity intervention conferred no additional benefit. Funding Diabetes UK and the UK Department of Health.
L’article vise à étudier de quelle manière le jeu structurant des mouvements agressifs se trouve contrarié dans la relation fraternelle avec une personne autiste. Après un rappel théorique sur les ...distinctions entre violence et agressivité, nous montrons à partir d’exemples cliniques que la violence spécifique et inhérente à la pathologie autistique constitue parfois un obstacle à la création du lien fraternel, en suscitant chez les frères et sœurs des éprouvés qu’il leur est difficile d’admettre en eux. Ensuite, nous expliquons en quoi le processus d’identification, pivot de la construction du lien fraternel, est profondément perturbé par l’autisme, pathologie difficilement représentable : les frères et sœurs peinent à reconnaître en ce frère si étrange un semblable. Enfin, nous explorons l’intérêt d’un travail thérapeutique pour la fratrie.
The article aims at studying how the structuring game of aggressive movements is disturbed in the sibling relationship with an autistic person. After a theoretical reminder on the distinctions between violence and aggressiveness, we show from clinical examples which the violence specific and inherent to the autistic pathology constitutes sometimes an obstacle to the creation of the sibling link, by arousing at the siblings feelings that it is difficult to them to admit in them. Then, we explain in what the process of identification, pivot of the construction of the sibling link, is profoundly perturbed by the autism, pathology which is hardly representable: the siblings having difficulty in recognizing in this brother so strange a fellowman. Finally, we investigate the interest of a therapeutic work for the sibship.
Aims/hypothesis
We investigated whether objectively measured sedentary time and interruptions in sedentary time are associated with metabolic factors in people with type 2 diabetes.
Methods
We ...studied 528 adults (30–80 years) with newly diagnosed type 2 diabetes, who were participants in a diet and physical activity intervention. Waist circumference (WC), fasting HDL-cholesterol, insulin and glucose levels, HOMA of insulin resistance (HOMA-IR) and physical activity (accelerometer) were measured at baseline and at 6 months follow-up. Linear regression models were used to investigate cross-sectional and longitudinal associations of accelerometer-derived sedentary time and breaks in sedentary time (BST) with metabolic variables.
Results
In cross-sectional analyses each hour of sedentary time was associated with larger WC (unstandardised regression coefficient
B
95% CI 1.89 cm 0.94, 2.83;
p
< 0.001), higher insulin (
B
= 8.22 pmol/l 2.80, 13.65;
p
= 0.003) and HOMA-IR (
B
= 0.42 0.14, 0.70;
p
= 0.004), and lower HDL-cholesterol (
B
= −0.04 mmol/l −0.06, −0.01;
p
= 0.005). Adjustment for WC attenuated all associations. Each BST was associated with lower WC (
B
= −0.15 cm − 0.24, −0.05;
p
= 0.003) and there was evidence of a weak linear association with HDL-cholesterol, but no association with insulin levels or HOMA-IR. Volume of sedentary time at baseline predicted HDL-cholesterol (
B
= −0.05 mmol/l −0.08, −0.01;
p
= 0.007), insulin levels (
B
= 8.14 pmol/l 0.1.51, 14.78;
p
= 0.016) and HOMA-IR (
B
= 0.49 0.08, 0.90;
p
= 0.020) at 6 months, though not WC. Baseline BST did not substantially predict any metabolic variables at follow-up. No change was seen in sedentary time or BST between baseline and 6 months follow-up.
Conclusions/interpretation
Higher sedentary time is associated with a poorer metabolic profile in people with type 2 diabetes.
Immunotherapy for type 1 diabetes Allen, L A; Dayan, C M
British medical bulletin,
12/2021, Letnik:
140, Številka:
1
Journal Article
Recenzirano
Despite advances in technology including the development of more sophisticated methods of monitoring blood glucose and delivering insulin, many individuals with type 1 diabetes continue to experience ...significant challenges in optimizing glycaemic control. Alternative treatment approaches to insulin are required. Increasing efforts have focused on developing treatments aimed at targeting the underlying disease process to modulate the immune system, maximize beta cell function and enhance endogenous insulin production and action.
Literature searches with keywords 'Type 1 diabetes and immunotherapy', publications relating to clinical trials of immunotherapy in type 1 diabetes.
Insulin therapy is insufficient to achieve optimal glycaemic control in many individuals with type 1 diabetes, and new treatment approaches are required. Studies have showed promising results for the use of immunotherapy as a means of delaying disease onset and progression.
The optimal way of identifying individuals most likely to benefit from immunotherapies.
A better understanding of the natural history of type 1 diabetes has made it possible to identify individuals who have developed autoimmunity but have not yet progressed to clinical diabetes, offering opportunities not only to develop treatments that delay disease progression, but prevent its development in the first place. A consensus on how to identify individuals who may benefit from immunotherapy to prevent disease onset is needed.
The development of optimal strategies for preventing and delaying progression of type 1 diabetes, and monitoring the response to immunointervention.
Background
Primary hypothyroidism affects about 3% of the general population in Europe. In most cases people with hypothyroidism are treated with levothyroxine. In the context of the 2023 British ...Thyroid Association guidance and the 2020 Competitions and Marketing Authority (CMA) ruling, we examined prescribing data for levothyroxine, Natural desiccated thyroid (NDT) and liothyronine by dose, regarding changes over the years 2016–2022.
Design
Monthly primary care prescribing data for each British National Formulary code were analysed for levothyroxine, liothyronine and NDT.
Patients and Measurements
The rolling 12‐month total/average of cost or prescribing volume was used to identify the moment of change. Results included number of prescriptions, the actual costs, and the cost/prescription/mcg of drug.
Results
Liothyronine: In 2016 94% of the total 74,500 prescriptions were of the 20 mcg dose. In 2020 the percentage prescribed in the 5 mcg and 10 mcg doses started to increase so that by 2022 each reached nearly 27% of total liothyronine prescribing. The average cost/prescription in 2016 of 20 mcg was £404/prescription and this fell by 80% to £101 in 2022; while the 10 mcg cost of £348/prescription fell by only 35% to £255 and the 5 mcg cost of £355/prescription fell by 38% to £242/prescription. The total prescriptions of liothyronine in 2016 were 74,605, falling by 30% up to 2019 when they started to grow again ‐ most recently at 60,990−15% lower than the 2016 figure, with the result that total costs fell by 70% to £9 m/year.
Conclusions
Liothyronine costs fell after the CMA ruling but remain orders of magnitude higher than for levothyroxine. The remaining 0.2% of patients with liothyronine treated hypothyroidism are still absorbing 16% of medication costs. The lower liothyronine 5cmg and 10 mcg doses as recommended by BTA are 240% the costs of the 20 mcg dose. Thus, following latest BTA guidance which recommends the lower liothyronine doses still incurs substantial additional costs vs the prescribing liothyronine in the no longer recommended treatment regime. High drug price continues to impact clinical decisions, potentially limiting liothyronine therapy availability to a considerable number of patients who could benefit from this treatment.
Aims
Phase III DEFEND‐2 investigated whether otelixizumab (3.1 mg over 8 days) preserved C‐peptide secretion in patients with new‐onset Type 1 diabetes, focusing on adolescents (12–17 years).
Methods
...One hundred and seventy‐nine patients (54 adolescents) were randomized to otelixizumab or placebo. The primary endpoint was change in 2‐h mixed‐meal‐stimulated C‐peptide area under the curve at month 12. Enrolment was suspended in April 2011 following negative efficacy results from DEFEND‐1. DEFEND‐2 terminated early after 12 months' efficacy and safety follow‐up.
Results
Change from baseline C‐peptide was not significantly different ∆ = –0.09 nmol/l (95% CI –0.17 to 0; P = 0.051). No differential C‐peptide effect was seen for otelixizumab in adolescents and more adverse events were reported.
Conclusions
Efficacy and tolerability of otelixizumab was similar to DEFEND‐1. The 3.1‐mg dose was non‐efficacious in adults and adolescents. Further investigation of the mechanism of action seen at higher doses and therapeutic window is required.
Clinical Trials Registry No: NCT 00763451
What's new?
DEFEND‐2 was intended as a confirmatory study to DEFEND‐1, which tested the efficacy and safety of low‐dose otelixizumab (3.1 mg) in 281 adolescents and adults with new‐onset Type 1 diabetes; DEFEND‐2 studied this dose in a population enriched with adolescents.
Following lack of efficacy in DEFEND–1, enrolment of new subjects to DEFEND‐2 was suspended; analysis of 6‐month data also showed no efficacy advantage of otelixizumab, but reaffirmed the safety of this dose.
These results are important to further understanding of Type 1 diabetes; additional research is needed to establish the optimal dose of otelixizumab.
Abstract
A novel approach for high-performance gecko-inspired adhesives for strong and reversible adhesion to smooth surfaces is proposed. The composite patterns comprising elastomeric ...mushroom-shaped microfibers decorated with an extremely soft and thin terminal layer of pressure sensitive adhesive. Through the optimal tip shape and improved load sharing, the adhesion performance was greatly enhanced. A high adhesion strength of 300 kPa together with superior durability on smooth surfaces are achieved, outperforming monolithic fibers by 35 times. Our concept of composite microfibrillar adhesives provides significant benefits for real world applications including wearable medical devices, transfer printing systems, and robotic manipulation.
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Antigen specific immunotherapy aims to tolerise patients to specific autoantigens that are responsible for the pathology of an autoimmune disease. Immune tolerance is generated in ...conditions where the immune response is suppressed and thus gold nanoparticles (AuNPs) are an attractive drug delivery platform due to their anti-inflammatory effects and their potential to facilitate temporal and spatial delivery of a peptide autoantigen in conjunction with pro-tolerogenic elements. In this study we have covalently attached an autoantigen, currently under clinical evaluation for the treatment of type 1 diabetes (PIC19-A3 peptide), to AuNPs to create nanoscale (<5 nm), negatively charged (−40 to −60 mV) AuNP-peptide complexes for immunotherapy. We also employ a clinically approved microneedle delivery system, MicronJet600, to facilitate minimally-invasive intradermal delivery of the nanoparticle constructs to target skin-resident antigen presenting cells, which are known to be apposite target cells for immunotherapy. The AuNP-peptide complexes remain physically stable upon extrusion through microneedles and when delivered into ex vivo human skin they are able to diffuse rapidly and widely throughout the dermis (their site of deposition) and, perhaps more surprisingly, the overlying epidermal layer. Intracellular uptake was extensive, with Langerhans cells proving to be the most efficient cells at internalising the AuNP-peptide complex (94% of the local population within the treated region of skin). In vitro studies showed that uptake of the AuNP-peptide complexes by dendritic cells reduced the capacity of these cells to activate naïve T cells. This indicator of biological functionality encourages further development of the AuNP-peptide formulation, which is now being evaluated in clinical trials.
Women with breast cancer (BC) and antithyroid peroxidase (TPO) autoantibodies (TPOAb) have a better prognosis than women lacking TPOAb. Sera from women with TPOAb displayed immunoreactivity to BC ...tissue by immunofluorescence that was not apparent in women without TPOAb. We hypothesize a BC/thyroid shared antigen that provides a target for humoral or cell‐mediated immune activity; candidates include the sodium/iodide symporter (expressed in thyroid and BC), cross‐reacting epitopes in TPO and lactoperoxidase (LPO) or TPO itself. As the association is with TPOAb, we investigated TPO expression in BC, breast peritumoral tissue (PT), other tissues (tumoral and not) and thyroid as positive control. Transcripts for known and novel TPO isoforms were detected in BC (n = 8) and PT (n = 8) but at approximately 104‐fold lower than in thyroid while in non‐BC tumors (n = 5) they were at the limit of detection. TPO was expressed also in adipose tissue (n = 17), 103‐fold lower than in thyroid. Full length TPO (Mr 105–110 kDa) was detected in Western blots in the majority of examined tissues; preabsorption of the TPO antibody with recombinant TPO (but not LPO) reduced the signal, indicating specificity. The same occurred with some lower molecular weight bands, which could correspond to smaller TPO transcript isoforms, present in all samples. In conclusion, TPO is weakly expressed in BC and other tissues; this could partly explain the high frequency and protective role of TPOAb in BC patients. Further studies will investigate tissue specificity, function and immunogenicity of the novel TPO variants (some BC‐specific) identified.
What's new?
Women with breast cancer who have antibodies against the enzyme thyroid peroxidase (TPO) have a better prognosis than those without the antibodies. This study showed that TPO mRNAs and proteins can be found in breast cancer tissue. They found several novel isoforms of TPO in the breast cancer samples, suggesting that these tissue‐specific isoforms could be useful in diagnosis.
Microneedle devices have been proposed as a minimally invasive delivery system for the intradermal administration of nucleic acids, both plasmid DNA (pDNA) and siRNA, to treat localised disease or ...provide vaccination. Different microneedle types and application methods have been investigated in the laboratory, but limited and irreproducible levels of gene expression have proven to be significant challenges to pre-clinical to clinical progression. This study is the first to explore the potential of a hollow microneedle device for the delivery and subsequent expression of pDNA in human skin. The regulatory approved MicronJet600® (MicronJet hereafter) device was used to deliver reporter plasmids (pCMVβ and pEGFP-N1) into viable excised human skin. Exogenous gene expression was subsequently detected at multiple locations that were distant from the injection site but within the confines of the bleb created by the intradermal bolus. The observed levels of gene expression in the tissue are at least comparable to that achieved by the most invasive microneedle application methods e.g. lateral application of a microneedle. Gene expression was predominantly located in the epidermis, although also evident in the papillary dermis. Optical coherence tomography permitted real time visualisation of the sub-surface skin architecture and, unlike a conventional intradermal injection, MicronJet administration of a 50μL bolus appears to create multiple superficial microdisruptions in the papillary dermis and epidermis. These were co-localised with expression of the pCMVβ reporter plasmid. We have therefore shown, for the first time, that a hollow microneedle device can facilitate efficient and reproducible gene expression of exogenous naked pDNA in human skin using volumes that are considered to be standard for intradermal administration, and postulate a hydrodynamic effect as the mechanism of gene delivery.
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