Glycated haemoglobin, HOMA2-B, C-peptide to glucose ratio and type 2 diabetes clusters as predictors for therapy failure in individuals with type 2 diabetes without insulin therapy: A registry analysis.

AIM: Some people with type 2 diabetes mellitus (T2D) and declining ß-cell function do require insulin over time. Various laboratory parameters, indices of glucose metabolism or phenotypes of T2D (clusters) have been suggested, which might predict future therapy failure (TF), indicating the need for insulin therapy initiation. This analysis evaluated glycated haemoglobin (HbA1c), homeostatic model assessment (HOMA)2-B, C-peptide to glucose ratio (CGR) and diabetes clusters as predictive parameters for the occurrence of glycaemic TF in individuals diagnosed with T2D without previous insulin therapy. MATERIALS AND METHODS: In total, 159 individuals with T2D [41% female, median age 50 (IQR: 53-69) years, diabetes duration 9 (5-15) years], without insulin therapy were prospectively evaluated for the occurrence of a composite primary endpoint, including HbA1c increasing or remaining >8.0% (64 mmol/mol) 3 months after baseline on non-insulin glucose-lowering agents, insulin initiation or hospital admissions because of acute hyperglycaemic events. Diabetes clusters were formed according to previously described characteristics. Only severe autoimmune diabetes clusters were excluded because of a small amount of glutamate decarboxylase antibody-positive participants. The other clusters were distributed as mild age-related diabetes 33%; severe insulin-deficient diabetes 31%; mild obesity-related diabetes 20%; and severe insulin-resistant diabetes 15%. RESULTS: During a median observation of 57 months, higher tertiles of HbA1c at baseline, HOMA2-B, as well as a lower CGR were significantly predictive for the occurrence of the primary endpoint. The probability of meeting the primary endpoint was the highest for mild obesity-related diabetes [hazard ratio 3.28 (95% confidence interval 1.75-6.2)], followed by severe insulin-deficient diabetes [hazard ratio 2.03 (95% confidence interval 1.1-3.7)], mild age-related diabetes and the lowest for severe insulin-resistant diabetes. The best performance to predict TF with an area under the curve (AUC) of 0.77 was HbA1c at baseline, followed by HOMA2-B (AUC 0.69) and CGR (AUC 0.64). CONCLUSION: HbA1c, indices of insulin secretion capacity (HOMA2-B and CGR) and T2D clusters might be applicable tools to guide practitioners in the decision of whether insulin is required in people already diagnosed with T2D. These findings need to be validated in prospective studies.

Humoral immune response to COVID-19 vaccination in diabetes is age-dependent but independent of type of diabetes and glycaemic control: The prospective COVAC-DM cohort study.

AIMS: To investigate the seroconversion following first and second COVID-19 vaccination in people with type 1 and type 2 diabetes in relation to glycaemic control prior to vaccination and to analyse the response in comparison to individuals without diabetes. MATERIALS AND METHODS: This prospective, multicentre cohort study analysed people with type 1 and type 2 diabetes and a glycated haemoglobin level ≤58 mmol/mol (7.5%) or >58 mmol/mol (7.5%), respectively, and healthy controls. Roche's Elecsys anti-SARS-CoV-2 S immunoassay targeting the receptor-binding domain was used to quantify anti-spike protein antibodies 7 to 14 days after the first and 14 to 21 days after the second vaccination. RESULTS: A total of 86 healthy controls were enrolled in the study, as well as 161 participants with diabetes, of whom 150 (75 with type 1 diabetes and 75 with type 2 diabetes) were eligible for the analysis. After the first vaccination, only 52.7% of participants in the type 1 diabetes group and 48.0% of those in the type 2 diabetes group showed antibody levels above the cut-off for positivity. Antibody levels after the second vaccination were similar in participants with type 1 diabetes, participants with type 2 diabetes and healthy controls after adjusting for age, sex and multiple testing (P > 0.05). Age (r = -0.45, P < 0.001) and glomerular filtration rate (r = 0.28, P = 0.001) were significantly associated with antibody response. CONCLUSIONS: Anti-SARS-CoV-2 S receptor-binding domain antibody levels after the second vaccination were comparable in healthy controls and in participants with type 1 and type 2 diabetes, irrespective of glycaemic control. Age and renal function correlated significantly with the extent of antibody levels.

Real-world data on metabolic effects of PCSK9 inhibitors in a tertiary care center in patients with and without diabetes mellitus.

BACKGROUND: The lipid-lowering and positive cardiovascular effect of proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors was shown in several studies, hence, they are more widely used in the lipid-lowering management of individuals with high cardiovascular risk. As real-world data are still scarce, specifically in patients with type 2 diabetes (T2D), the aim of this retrospective analysis was to investigate the efficacy of PCSK9 inhibitors in lowering low-density lipoprotein cholesterol (LDL-C) in an outpatient clinic of a tertiary care center in routine care. METHODS: A retrospective analysis of data extracted from the electronic patient record was performed. Patients who were routinely prescribed with PCSK9 inhibitor therapy (alirocumab or evolocumab) during the years 2016 and 2019 were included in the analysis. Characteristics of the patient population, the effects on LDL-C and HbA1c levels as well as subsequent cardiovascular events were assessed over an observation period of 18 months. RESULTS: We identified 237 patients treated with PCSK9 inhibitors between January 2016 and September 2019. Almost all patients (97.5%) received PCSK9 inhibitors for secondary prevention. 26.2% of the population had a concomitant diabetes diagnosis. Intolerance to statins (83.1%), ezetimibe (44.7%) or both agents (42.6%) was reported frequently. Three months after initiation of PCSK9 inhibitor therapy, 61.2% of the patients achieved LDL-C levels < 70 mg/dl, and 44.1% LDL-C levels < 55 mg/dl. The median LDL-C was lowered from 141 mg/dl at baseline, to 60 mg/dl after 3 months and 66 mg/dl after 12 months indicating a reduction of LDL-C as follows: 57.5% after 3 months and 53.6% after 12 months. After 3 months of observation, target achievement of LDL-C was higher in patients with T2D compared to non-diabetes patients; < 55 mg/dl: 51% vs. 41.5%; < 70 mg/dl 69.4 vs. 58.5%. After 12 months even more pronounced target LDL achievement in T2D was demonstrated < 55 mg/dl: 58.8% vs. 30.1%; < 70 mg/dl 70.6 vs. 49.6%. Patients with insufficiently controlled T2D (HbA1c > 54 mmol/mol) had a higher reduction in LDL-C but still were more likely to subsequent cardiovascular events. CONCLUSIONS: Significant reductions in LDL-C and a high percentage of patients achieving recommended treatment targets were observed. The percentage of patients with T2D meeting recommended LDL-C targets was higher than in those without T2D. Still some patients did not achieve LDL-C levels as recommended in current guidelines. Special attention to the characteristics of these patients is required in the future to enable achievement of treatment goals and avoid adverse cardiovascular outcomes.

Age differences in the prosocial influence effect.

Social influence occurs when an individual's thoughts or behaviours are affected by other people. There are significant age effects on susceptibility to social influence, typically a decline from childhood to adulthood. Most research has focused on negative aspects of social influence, such as peer influence on risky behaviour, particularly in adolescence. The current study investigated the impact of social influence on the reporting of prosocial behaviour (any act intended to help another person). In this study, 755 participants aged 8-59 completed a computerized task in which they rated how likely they would be to engage in a prosocial behaviour. Afterwards, they were told the average rating (in fact fictitious) that other participants had given to the same question, and then were asked to rate the same behaviour again. We found that participants' age affected the extent to which they were influenced by other people: children (8-11 years), young adolescents (12-14 years) and mid-adolescents (15-18 years) all significantly changed their ratings, while young adults (19-25 years) and adults (26-59 years) did not. Across the three youngest age groups, children showed the most susceptibility to prosocial influence, changing their reporting of prosocial behaviour the most. The study provides evidence that younger people's increased susceptibility to social influence can have positive outcomes.

Age-related differences in social influence on risk perception depend on the direction of influence.

Adolescents are particularly susceptible to social influence. Here, we investigated the effect of social influence on risk perception in 590 participants aged eight to fifty-nine-years tested in the United Kingdom. Participants rated the riskiness of everyday situations, were then informed about the rating of these situations from a (fictitious) social-influence group consisting of teenagers or adults, and then re-evaluated the situation. Our first aim was to attempt to replicate our previous finding that young adolescents are influenced more by teenagers than by adults. Second, we investigated the social-influence effect when the social-influence group's rating was more, or less, risky than the participants' own risk rating. Younger participants were more strongly influenced by teenagers than by adults, but only when teenagers rated a situation as more risky than did participants. This suggests that stereotypical characteristics of the social-influence group - risk-prone teenagers - interact with social influence on risk perception.

A Window of Opportunity for Cognitive Training in Adolescence.

In the current study, we investigated windows for enhanced learning of cognitive skills during adolescence. Six hundred thirty-three participants (11-33 years old) were divided into four age groups, and each participant was randomly allocated to one of three training groups. Each training group completed up to 20 days of online training in numerosity discrimination (i.e., discriminating small from large numbers of objects), relational reasoning (i.e., detecting abstract relationships between groups of items), or face perception (i.e., identifying differences in faces). Training yielded some improvement in performance on the numerosity-discrimination task, but only in older adolescents or adults. In contrast, training in relational reasoning improved performance on that task in all age groups, but training benefits were greater for people in late adolescence and adulthood than for people earlier in adolescence. Training did not increase performance on the face-perception task for any age group. Our findings suggest that for certain cognitive skills, training during late adolescence and adulthood yields greater improvement than training earlier in adolescence, which highlights the relevance of this late developmental stage for education.

Social influence on risk perception during adolescence.

Adolescence is a period of life in which peer relationships become increasingly important. Adolescents have a greater likelihood of taking risks when they are with peers rather than alone. In this study, we investigated the development of social influence on risk perception from late childhood through adulthood. Five hundred and sixty-three participants rated the riskiness of everyday situations and were then informed about the ratings of a social-influence group (teenagers or adults) before rating each situation again. All age groups showed a significant social-influence effect, changing their risk ratings in the direction of the provided ratings; this social-influence effect decreased with age. Most age groups adjusted their ratings more to conform to the ratings of the adult social-influence group than to the ratings of the teenager social-influence group. Only young adolescents were more strongly influenced by the teenager social-influence group than they were by the adult social-influence group, which suggests that to early adolescents, the opinions of other teenagers about risk matter more than the opinions of adults.

Expression of gemcitabine metabolizing enzymes and stromal components reveal complexities of preclinical pancreatic cancer models for therapeutic testing.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) poorly responds to antineoplastic agents. Discrepancies between preclinical success and clinical failure of compounds has been a continuous challenge and major obstacle in PDAC research. AIM: To investigate the association of the tumor microenvironment (TME) composition and gemcitabine metabolizing enzyme (GME) expression in vitro and several in vivo models. METHODS: mRNA expression and protein levels of GME (cytosolic 5'-nucleotidase 1 A; NT5C1A, cytidine deaminase; CDA, deoxycytidine kinase; DCK), gemcitabine transporters (ENT1, ENT2, RRM1, RRM2) and stromal components (hyaluroninc acid, podoplanin, masson trichrome, picrosirius) were assessed by qRT-PCR and immunohistochemistry in murine LSL-KrasG12D/+;LSL-Trp53R172 H/+; Pdx-1-Cre (KPC), orthotopically transplanted mice (OTM), human primary resected PDAC tissue (hPRT), corresponding patient-derived xenograft (PDX) mice, and KPC-SPARC-/- mice. mRNA expression of GME was analyzed in PDAC cell lines (Panc-1, MIA PaCa, BXPC3 and L3.6) upon incubation on collagen or pancreatic stellate cell (PSC) conditioned media by qRT-PCR. RESULTS: Endogenous KPC tumors exhibited significantly higher levels of GME compared to OTM. However, GME levels did not differ between hPRT and corresponding PDX mice. Using Kendalls Tau correlation coefficient we did not show a significant correlation of GME and components of the TME except for NT5C1A and hyaluronic acid in PDX mice (p=0.029). GME were not significantly altered upon SPARC depletion in vivo, and upon treatment with PSC-conditioned media or incubation on collagen plated dishes in vitro. CONCLUSIONS: Our findings suggest that the expression of GME is independent from the deposition of stromal components. KPC mice are most appropriate to study stromal composition whereas PDX mice maintain GME expression of the corresponding hPRT and could be best suited for pharmacokinetic studies.

Preschool children's interpretation of object-initial sentences: neural correlates of their behavioral performance.

The acquisition of the function of case-marking is a key step in the development of sentence processing for German-speaking children since case-marking reveals the relations between sentential arguments. In this study, we investigated the development of the processing of case-marking and argument structures in children at 3, 4;6 and 6 years of age, as well as its processing in adults. Using EEG, we measured event-related potentials (ERPs) in response to object-initial compared to subject-initial German sentences including transitive verbs and case-marked noun phrases referring to animate arguments. We also tested children's behavioral competence in a sentence-picture matching task. Word order and case-marking were manipulated in German main clauses. Adults' behavioral performance was close to perfect and their ERPs revealed a negativity for the processing of the topicalized accusative marked noun phrase (NP1) and no effect for the second NP (NP2) in the object-initial structure. Children's behavioral data showed a significant above-chance outcome in the subject-initial condition for all age groups, but not for the object-initial condition. In contrast to adults, the ERPs of 3-year-olds showed a positivity at NP1, indicating difficulties in processing the non-canonical object-initial structures. Children at the age of 4;6 did not differ in the processing patterns of object-initial vs. subject-initial sentences at NP1 but showed a slight positivity at NP2. This positivity at NP2, which implies syntactic integration difficulties, is more pronounced in 6-year-olds but is absent in adults. At NP1, however, 6-year-olds show the same negativity as adults. In sum, the behavioral and electrophysiological findings demonstrate that children in each age group use different strategies, which are indicative of their developmental stage. While 3-year-olds merely detect differences in the two sentence structures without being able to use this information for sentence comprehension, 4;6-year-olds proceed to use mainly a word-order strategy, processing NP1 in both conditions in the same manner, which leads to processing difficulties upon detecting case-marking cues at NP2. At the age of 6, children are able to use case-marking cues for comprehension but still show enhanced effort for correct thematic-role assignment.

The matrix reasoning item bank (MaRs-IB): novel, open-access abstract reasoning items for adolescents and adults.

Existing non-verbal ability tests are typically protected by copyright, preventing them from being freely adapted or computerized. Working towards an open science framework, we provide 80 novel, open-access abstract reasoning items, an online implementation and item-level data from 659 participants aged between 11 and 33 years: the matrix reasoning item bank (MaRs-IB). Each MaRs-IB item consists of an incomplete matrix containing abstract shapes. Participants complete the matrices by identifying relationships between the shapes. Our data demonstrate age differences in non-verbal reasoning accuracy, which increased during adolescence and stabilized in early adulthood. There was a slight linear increase in response times with age, resulting in a peak in efficiency (i.e. a measure combining speed and accuracy) in late adolescence. Overall, the data suggest that the MaRs-IB is sensitive to developmental differences in reasoning accuracy. Further psychometric validation is recommended.

Adolescence as a Sensitive Period of Brain Development.

Most research on sensitive periods has focussed on early sensory, motor, and language development, but it has recently been suggested that adolescence might represent a second 'window of opportunity' in brain development. Here, we explore three candidate areas of development that are proposed to undergo sensitive periods in adolescence: memory, the effects of social stress, and drug use. We describe rodent studies, neuroimaging, and large-scale behavioural studies in humans that have yielded data that are consistent with heightened neuroplasticity in adolescence. Critically however, concrete evidence for sensitive periods in adolescence is mostly lacking. To provide conclusive evidence, experimental studies are needed that directly manipulate environmental input and compare effects in child, adolescent, and adult groups.