165 research outputs found
Influences on User Trust in Healthcare Artificial Intelligence: A Systematic Review
BACKGROUND:
Artificial Intelligence (AI) is becoming increasingly prominent in domains such as healthcare. It is argued to be transformative through altering the way in which healthcare data is used. The realisation and success of AI depend heavily on peopleâs trust in its applications. Yet, influences on trust in healthcare AI (HAI) applications so far have been underexplored. The objective of this study was to identify aspects related to users, AI applications and the wider context influencing trust in HAI.
METHODS:
We performed a systematic review to map out influences on user trust in HAI. To identify relevant studies, we searched seven electronic databases in November 2019 (ACM digital library, IEEE Explore, NHS Evidence, ProQuest Dissertations & Thesis Global, PsycINFO, PubMed, Web of Science Core Collection). Searches were restricted to publications available in English and German. To be included studies had to be empirical; focus on an AI application (excluding robotics) in a health-related setting; and evaluate applications with regards to users.
RESULTS:
Three studies, one mixed-method and two qualitative studies in English were included. Influences on trust fell into three broad categories: human-related (knowledge, expectation, mental model, self-efficacy, type of user, age, gender), AI-related (data privacy and safety, operational safety, transparency, design, customizability, trialability, explainability, understandability, power-control-balance, benevolence) and context-related (AI company, media, usersâ social network). The factors resulted in an updated logic model illustrating the relationship between these aspects.
CONCLUSIONS:
Trust in HAI depends on a variety of factors, both external and internal to AI applications. This study contributes to our understanding of what influences trust in HAI by highlighting key influences, as well as pointing to gaps and issues in existing research on trust and AI. In so doing, it offers a starting point for further investigation of trust environments as well as trustworthy AI applications
Challenges and opportunities for non-antibody scaffold drugs
The first candidates from the promising class of small non-antibody protein scaffolds are now moving into clinical development and practice. Challenges remain, and scaffolds will need to be further tailored toward applications where they provide real advantages over established therapeutics to succeed in a rapidly evolving drug development landscape
The Human and Mouse Islet Peptidome: Effects of Obesity and Type 2 Diabetes, and Assessment of Intraislet Production of Glucagon-like Peptide-1.
To characterize the impact of metabolic disease on the peptidome of human and mouse pancreatic islets, LC-MS was used to analyze extracts of human and mouse islets, purified mouse alpha, beta, and delta cells, supernatants from mouse islet incubations, and plasma from patients with type 2 diabetes. Islets were obtained from healthy and type 2 diabetic human donors, and mice on chow or high fat diet. All major islet hormones were detected in lysed islets as well as numerous peptides from vesicular proteins including granins and processing enzymes. Glucose-dependent insulinotropic peptide (GIP) was not detectable. High fat diet modestly increased islet content of proinsulin-derived peptides in mice. Human diabetic islets contained increased content of proglucagon-derived peptides at the expense of insulin, but no evident prohormone processing defects. Diabetic plasma, however, contained increased ratios of proinsulin and des-31,32-proinsulin to insulin. Active GLP-1 was detectable in human and mouse islets but 100-1000-fold less abundant than glucagon. LC-MS offers advantages over antibody-based approaches for identifying exact peptide sequences, and revealed a shift toward islet insulin production in high fat fed mice, and toward proglucagon production in type 2 diabetes, with no evidence of systematic defective prohormone processing
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TNFR2 ligation in human T regulatory cells enhances IL2-induced cell proliferation through the non-canonical NF-ÎșB pathway.
Human T regulatory cells (T regs) express high levels of TNF receptor 2 (TNFR2). Ligation of TNFR2 with TNF, which can recognise both TNFR1 and TNFR2, or with a TNFR2-selective binding molecule, DARPin 18 (D18) activates canonical NF-ÎșB signalling, assessed by IÎșBα degradation, and the magnitude of the response correlates with the level of TNFR2 expression. RNA-seq analysis of TNF- or D18-treated human T regs revealed that TNFR2 ligation induces transcription of NFKB2 and RELB, encoding proteins that form the non-canonical NF-ÎșB transcription factor. In combination with IL2, D18 treatment is specific for T regs in (1) stabilising NF-ÎșB-inducing kinase protein, the activator of non-canonical NF-ÎșB signalling, (2) inducing translocation of RelB from cytosol to nucleus, (3) increasing cell cycle entry, and (4) increasing cell numbers. However, the regulatory function of the expanded T regs is unaltered. Inhibition of RelB nuclear translocation blocks the proliferative response. We conclude that ligation of TNFR2 by D18 enhances IL2-induced T regs proliferation and expansion in cell number through the non-canonical NF-ÎșB pathway
Follicular helper T cell profiles predict response to costimulation blockade in type 1 diabetes
Follicular helper T (TFH) cells are implicated in type 1 diabetes (T1D), and their development has been linked to CD28 costimulation. We tested whether TFH cells were decreased by costimulation blockade using the CTLA-4âimmunoglobulin (Ig) fusion protein (abatacept) in a mouse model of diabetes and in individuals with new-onset T1D. Unbiased bioinformatics analysis identified that inducible costimulatory molecule (ICOS)+ TFH cells and other ICOS+ populations, including peripheral helper T cells, were highly sensitive to costimulation blockade. We used pretreatment TFH profiles to derive a model that could predict clinical response to abatacept in individuals with T1D. Using two independent approaches, we demonstrated that higher frequencies of ICOS+ TFH cells at baseline were associated with a poor clinical response following abatacept administration. Therefore, TFH analysis may represent a new stratification tool, permitting the identification of individuals most likely to benefit from costimulation blockade
Efficacy and safety of cotadutide, a dual glucagon-like peptide-1 and glucagon receptor agonist, in a randomized phase 2a study of patients with type 2 diabetes and chronic kidney disease
AIM: To assess the efficacy, safety and tolerability of cotadutide in patients with type 2 diabetes mellitus and chronic kidney disease. MATERIALS AND METHODS: In this phase 2a study (NCT03550378), patients with body mass index 25â45âkg/m(2), estimated glomerular filtration rate 30â59âml/min/1.73âm(2) and type 2 diabetes [glycated haemoglobin 6.5â10.5% (48â91âmmol/mol)] controlled with insulin and/or oral therapy combination, were randomized 1:1 to onceâdaily subcutaneous cotadutide (50â300âÎŒg) or placebo for 32âdays. The primary endpoint was plasma glucose concentration assessed using a mixedâmeal tolerance test. RESULTS: Participants receiving cotadutide (n = 21) had significant reductions in the mixedâmeal tolerance test area under the glucose concentrationâtime curve (â26.71% vs. +3.68%, pâ<â.001), more time in target glucose range on continuous glucose monitoring (+14.79% vs. â21.23%, p = .001) and significant reductions in absolute bodyweight (â3.41âkg vs. â0.13âkg, pâ<â.001) versus placebo (n = 20). In patients with baseline microâ or macroalbuminuria (n = 18), urinary albuminâtoâcreatinine ratios decreased by 51% at day 32 with cotadutide versus placebo (p = .0504). No statistically significant difference was observed in mean change in estimated glomerular filtration rate between treatments. Mild/moderate adverse events occurred in 71.4% of participants receiving cotadutide and 35.0% receiving placebo. CONCLUSIONS: We established the efficacy of cotadutide in this patient population, with significantly improved postprandial glucose control and reduced bodyweight versus placebo. Reductions in urinary albuminâtoâcreatinine ratios suggest potential benefits of cotadutide on kidney function, supporting further evaluation in larger, longerâterm clinical trials
Hospital admissions for severe infections in people with chronic kidney disease in relation to renal disease severity and diabetes status
Background: Immunosuppressive agents are being investigated for the treatment of
chronic kidney disease (CKD) but may increase risk of infection. This was a retrospective
observational study intended to evaluate the risk of hospitalized infection in
patients with CKD, by estimated glomerular filtration rate (eGFR) and proteinuria
status, aiming to identify the most appropriate disease stage for immunosuppressive
intervention.
Methods: Routine UK primary-care
and linked secondary-care
data were extracted
from the Clinical Practice Research Datalink. Patients with a record of CKD were
identified and grouped into type 2, type 1 and nondiabetes cohorts. Time-dependent,
Cox proportional hazard models were used to determine the likelihood of hospitalized
infection.
Results: We identified 97 839 patients with a record of CKD, of these 11 719 (12%)
had type 2 diabetes. In these latter patients, the adjusted hazard ratios (aHR) were
1.00 (95% CI: 0.80-1.25),
1.00, 1.03 (95% CI: 0.92-1.15),
1.36 (95% CI: 0.20-1.54),
1.82 (95% CI: 1.54-2.15)
and 2.41 (95% CI: 1.60-3.63)
at eGFR stages G1, G2 (reference),
G3a, G3b, G4 and G5, respectively; and 1.00, 1.45 (95% CI: 1.29-1.63)
and 1.91
(95% CI: 1.67-2.20)
at proteinuria stages A1 (reference), A2 and A3, respectively. All
aHRs (except G1 and G3a) were significant, with similar patterns observed within the
non-DM
and overall cohorts.
Conclusions: eGFR and degree of albuminuria were independent markers of hospitalized
infection in both patients with and without diabetes. The same patterns of
hazard ratios of eGFR and proteinuria were seen in CKD patients regardless of diabetes
status, with the risk of each outcome increasing with a decreasing eGFR and increasing
proteinuria. Infection risk increased significantly from eGFR stage G3b and
proteinuria stage A2 in type 2 diabetes. Treating type 2 DM patients with CKD at
eGFR stages G1-G3a
with immunosuppressive therapy may therefore provide a favourable
risk-benefit
ratio (G1-G3a
in type 2 diabetes; G1-G2
in nondiabetes and
overall cohorts) although the degree of proteinuria needs to be considered
Hospital admissions for severe infections in people with chronic kidney disease in relation to renal disease severity and diabetes status
Background: Immunosuppressive agents are being investigated for the treatment of
chronic kidney disease (CKD) but may increase risk of infection. This was a retrospective
observational study intended to evaluate the risk of hospitalized infection in
patients with CKD, by estimated glomerular filtration rate (eGFR) and proteinuria
status, aiming to identify the most appropriate disease stage for immunosuppressive
intervention.
Methods: Routine UK primary-care
and linked secondary-care
data were extracted
from the Clinical Practice Research Datalink. Patients with a record of CKD were
identified and grouped into type 2, type 1 and nondiabetes cohorts. Time-dependent,
Cox proportional hazard models were used to determine the likelihood of hospitalized
infection.
Results: We identified 97 839 patients with a record of CKD, of these 11 719 (12%)
had type 2 diabetes. In these latter patients, the adjusted hazard ratios (aHR) were
1.00 (95% CI: 0.80-1.25),
1.00, 1.03 (95% CI: 0.92-1.15),
1.36 (95% CI: 0.20-1.54),
1.82 (95% CI: 1.54-2.15)
and 2.41 (95% CI: 1.60-3.63)
at eGFR stages G1, G2 (reference),
G3a, G3b, G4 and G5, respectively; and 1.00, 1.45 (95% CI: 1.29-1.63)
and 1.91
(95% CI: 1.67-2.20)
at proteinuria stages A1 (reference), A2 and A3, respectively. All
aHRs (except G1 and G3a) were significant, with similar patterns observed within the
non-DM
and overall cohorts.
Conclusions: eGFR and degree of albuminuria were independent markers of hospitalized
infection in both patients with and without diabetes. The same patterns of
hazard ratios of eGFR and proteinuria were seen in CKD patients regardless of diabetes
status, with the risk of each outcome increasing with a decreasing eGFR and increasing
proteinuria. Infection risk increased significantly from eGFR stage G3b and
proteinuria stage A2 in type 2 diabetes. Treating type 2 DM patients with CKD at
eGFR stages G1-G3a
with immunosuppressive therapy may therefore provide a favourable
risk-benefit
ratio (G1-G3a
in type 2 diabetes; G1-G2
in nondiabetes and
overall cohorts) although the degree of proteinuria needs to be considered
Phenotypic screening reveals TNFR2 as a promising target for cancer immunotherapy.
Antibodies that target cell-surface molecules on T cells can enhance anti-tumor immune responses, resulting in sustained immune-mediated control of cancer. We set out to find new cancer immunotherapy targets by phenotypic screening on human regulatory T (Treg) cells and report the discovery of novel activators of tumor necrosis factor receptor 2 (TNFR2) and a potential role for this target in immunotherapy. A diverse phage display library was screened to find antibody mimetics with preferential binding to Treg cells, the most Treg-selective of which were all, without exception, found to bind specifically to TNFR2. A subset of these TNFR2 binders were found to agonise the receptor, inducing iÎș-B degradation and NF-ÎșB pathway signalling in vitro. TNFR2 was found to be expressed by tumor-infiltrating Treg cells, and to a lesser extent Teff cells, from three lung cancer patients, and a similar pattern was also observed in mice implanted with CT26 syngeneic tumors. In such animals, TNFR2-specific agonists inhibited tumor growth, enhanced tumor infiltration by CD8+ T cells and increased CD8+ T cell IFN-Îł synthesis. Together, these data indicate a novel mechanism for TNF-α-independent TNFR2 agonism in cancer immunotherapy, and demonstrate the utility of target-agnostic screening in highlighting important targets during drug discovery.GW, BM, SG, JC-U, AS, AG-M, CB, JJ, RL, AJL, SR, RS, LJ, VV-A, RM and RWW were funded by MedImmune; JP and VB were funded by AstraZeneca PLC; JW, RSA-L and JB were funded by NIHR Cambridge Biomedical Research Centre and Kidney Research UK; JS and JF were funded by Retrogenix Ltd
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Development and validation of an LC-MS/MS method for detection and quantification of in vivo derived metabolites of [Pyr 1 ]apelin-13 in humans
Abstract: [Pyr1]apelin-13 is the predominant apelin peptide isoform in the human cardiovascular system and plasma. To date, few studies have investigated [Pyr1]apelin-13 metabolism in vivo in rats with no studies examining its stability in humans. We therefore aimed to develop an LC-MS/MS method for detection and quantification of intact [Pyr1]apelin-13 and have used this method to identify the metabolites generated in vivo in humans. [Pyr1]apelin-13 (135 nmol/min) was infused into six healthy human volunteers for 120 minutes and blood collected at time 0 and 120 minutes after infusion. Plasma was extracted in the presence of guanidine hydrochloride and analysed by LC-MS/MS. Here we report a highly sensitive, robust and reproducible method for quantification of intact [Pyr1]apelin-13 and its metabolites in human plasma. Using this method, we showed that the circulating concentration of intact peptide was 58.3 ± 10.5 ng/ml after 120 minutes infusion. We demonstrated for the first time that in humans, [Pyr1]apelin-13 was cleaved from both termini but the C-terminal was more susceptible to cleavage. Consequently, of the metabolites identified, [Pyr1]apelin-13(1â12), [Pyr1]apelin-13(1â10) and [Pyr1]apelin-13(1â6) were the most abundant. These data suggest that apelin peptides designed for use as cardiovascular therapeutics, should include modifications that minimise C-terminal cleavage
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