Dehydration mechanism of a small molecular solid: 5-nitrouracil hydrate

Previous studies of the dehydration of 5-nitrouracil (5NU) have resulted in it being classified as a ‘‘channel hydrate’’ in which dehydration proceeds principally by the exit of the water molecules along channels in the structure. We have re-examined this proposal and found that in fact there are no continuous channels in the 5NU structure that would contribute to such a mechanism. Product water molecules would be immediately trapped in unlinked voids in the crystal structure and would require some additional mechanism to break loose from the crystal. Through a detailed structural analysis of the macro and micro structure of the 5NU as it dehydrates, we have developed a model for the dehydration process based on the observed development of structural defects in the 5NU crystal and the basic crystallography of the material. The model was tested against standard kinetic measurements and found to present a satisfactory account of kinetic observations, thus defining the mechanism. Overall, the study shows the necessity of complementing standard kinetic studies with a parallel macro and micro examination of the dehydrating material when evaluating the mechanisms of dehydration and decomposition processes

DNA methylation partially mediates antidiabetic effects of metformin on HbA1c levels in individuals with type 2 diabetes

Aims: Despite metformin being used as first-line pharmacological therapy for type 2 diabetes, its underlying mechanisms remain unclear. We aimed to determine whether metformin altered DNA methylation in newlydiagnosed individuals with type 2 diabetes. Methods and Results: We found that metformin therapy is associated with altered methylation of 26 sites in blood from Scandinavian discovery and replication cohorts (FDR < 0.05), using MethylationEPIC arrays. The majority (88%) of these 26 sites were hypermethylated in patients taking metformin for ~ 3 months compared to controls, who had diabetes but had not taken any diabetes medication. Two of these blood-based methylation markers mirrored the epigenetic pattern in muscle and adipose tissue (FDR < 0.05). Four type 2 diabetes-associated SNPs were annotated to genes with differential methylation between metformin cases and controls, e.g., GRB10, RPTOR, SLC22A18AS and TH2LCRR. Methylation correlated with expression in human islets for two of these genes. Three metformin-associated methylation sites (PKNOX2, WDTC1 and MICB) partially mediate effects of metformin on follow-up HbA1c levels. When combining methylation of these three sites into a score, which was used in a causal mediation analysis, methylation was suggested to mediate up to 32% of metformin’s effects on HbA1c. Conclusion: Metformin-associated alterations in DNA methylation partially mediates metformin’s antidiabetic effects on HbA1c in newly-diagnosed individuals with type 2 diabetes

Key factors supporting implementation of a training program for neonatal family- centered care - a qualitative study

BackgroundTraditionally, the care of infants in neonatal care units has been professionally centered, paying less attention to family support. In recent years, many interventions have been developed to improve family-centered care and thereby parent and infant outcomes. Understanding the key factors of implementation of these interventions would help improve clinical practice. The aim of this study was to describe the staff's perceptions of the implementation of the Close Collaboration with Parents Training Program and to identify the barriers and facilitators of the implementation.MethodsA descriptive qualitative interview study was conducted in eight neonatal intensive care units in Finland. Nineteen unit managers and 32 nurses were interviewed after their unit had finished the 1.5-year training program. Data were analyzed using thematic content analysis.ResultsKey factors facilitating the implementation of the training program were multidisciplinary commitment and the staff's motivation to change their professional role to work as the parents' facilitator. Observable benefits promoted the implementation, as well as experiential learning as a facilitation method. The role of mentor was remarkable as a facilitator. In addition, contextual elements such as support from leadership and proper timing were important.ConclusionsImplementation of family-centered care is facilitated by staff who is prepared to accept parents as partners and adopt a new professional role. Enough time for preparation, readiness for the change, solid support from the leadership, and a multidisciplinary approach are needed as well. Mentoring was found to be one of the key factors facilitating the change.</p

Distribution and characteristics of newly-defined subgroups of type 2 diabetes in randomised clinical trials : Post hoc cluster assignment analysis of over 12,000 study participants

Publisher Copyright: © 2022Aims: Newly-defined subgroups of type 2 diabetes mellitus (T2DM) have been reported from real-world cohorts but not in detail from randomised clinical trials (RCTs). Methods: T2DM participants, uncontrolled on different pre-study therapies (n = 12.738; 82 % Caucasian; 44 % with diabetes duration > 10 years) from 14 RCTs, were assigned to new subgroups according to age at onset of diabetes, HbA1c, BMI, and fasting C-peptide using the nearest centroid approach. Subgroup distribution, characteristics and influencing factors were analysed. Results: In both, pooled and single RCTs, “mild-obesity related diabetes” predominated (45 %) with mean BMI of 35 kg/m2. “Severe insulin-resistant diabetes” was found least often (4.6 %) and prevalence of “mild age-related diabetes” (23.9 %) was mainly influenced by age at onset of diabetes and age cut-offs. Subgroup characteristics were widely comparable to those from real-world cohorts, but all subgroups showed higher frequencies of diabetes-related complications which were associated with longer diabetes duration. A high proportion of “severe insulin-deficient diabetes” (25.4 %) was identified with poor pre-study glycaemic control. Conclusions: Classification of RCT participants into newly-defined diabetes subgroups revealed the existence of a heterogeneous population of T2DM. For future RCTs, subgroup-based randomisation of T2DM will better define the target population and relevance of the outcomes by avoiding clinical heterogeneity.Peer reviewe

Interaction between the obesity-risk gene FTO and the dopamine D2 receptor gene ANKK1/TaqIA on insulin sensitivity

Variations in FTO are the strongest common genetic determinants of adiposity, and may partly act by influencing dopaminergic signalling in the brain leading to altered reward processing that promotes increased food intake. Therefore, we investigated the impact of such an interaction on body composition, and peripheral and brain insulin sensitivity. Participants from the Tubingen Family study (n = 2245) and the Malmo Diet and Cancer study (n = 2921) were genotyped for FTO SNP rs8050136 and ANKK1 SNP rs1800497. Insulin sensitivity in the caudate nucleus, an important reward area in the brain, was assessed by fMRI in 45 participants combined with intranasal insulin administration. We found evidence of an interaction between variations in FTO and an ANKK1 polymorphism that associates with dopamine (D2) receptor density. In cases of reduced D2 receptor availability, as indicated by the ANKK1 polymorphism, FTO variation was associated with increased body fat and waist circumference and reduced peripheral insulin sensitivity. Similarly, altered central insulin sensitivity was observed in the caudate nucleus in individuals with the FTO obesity-risk allele and diminished D2 receptors. The effects of variations in FTO are dependent on dopamine D2 receptor density (determined by the ANKK1 polymorphism). Carriers of both risk alleles might, therefore, be at increased risk of obesity and diabetes.Peer reviewe

Smoking, use of smokeless tobacco, HLA genotypes and incidence of latent autoimmune diabetes in adults

Aims/hypotheses Smoking and use of smokeless tobacco (snus) are associated with an increased risk of type 2 diabetes. We investigated whether smoking and snus use increase the risk of latent autoimmune diabetes in adults (LADA) and elucidated potential interaction with HLA high-risk genotypes. Methods Analyses were based on Swedish case-control data (collected 2010-2019) with incident cases of LADA (n=593) and type 2 diabetes (n=2038), and 3036 controls, and Norwegian prospective data (collected 1984-2019) with incident cases of LADA (n=245) and type 2 diabetes (n=3726) during 1,696,503 person-years of follow-up. Pooled RRs with 95% CIs were estimated for smoking, and ORs for snus use (case-control data only). The interaction was assessed by attributable proportion (AP) due to interaction. A two-sample Mendelian randomisation (MR) study on smoking and LADA/type 2 diabetes was conducted based on summary statistics from genome-wide association studies. Results Smoking (RRpooled 1.30 [95% CI 1.06, 1.59] for current vs never) and snus use (OR 1.97 [95% CI 1.20, 3.24] for >= 15 box-years vs never use) were associated with an increased risk of LADA. Corresponding estimates for type 2 diabetes were 1.38 (95% CI 1.28, 1.49) and 1.92 (95% CI 1.27, 2.90), respectively. There was interaction between smoking and HLA high-risk genotypes (AP 0.27 [95% CI 0.01, 0.53]) in relation to LADA. The positive association between smoking and LADA/type 2 diabetes was confirmed by the MR study. Conclusions/interpretation Our findings suggest that tobacco use increases the risk of LADA and that smoking acts synergistically with genetic susceptibility in the promotion of LADA.Peer reviewe

Reply to : Proofreading deficiency in mitochondrial DNA polymerase does not affect total dNTP pools in mouse embryos

Non peer reviewe

Trends and patterns of antiseizure medication prescribing during pregnancy between 1995 and 2018 in the United Kingdom: A cohort study

OBJECTIVE: To examine antiseizure medication (ASM) prescription during pregnancy. DESIGN: Population-based drug utilisation study. SETTING: UK primary and secondary care data, 1995-2018, from the Clinical Practice Research Datalink GOLD version. POPULATION OR SAMPLE: 752 112 completed pregnancies among women registered for a minimum of 12 months with an 'up to standard' general practice prior to the estimated start of pregnancy and for the duration of their pregnancy. METHODS: We described ASM prescription across the study period, overall and by ASM indication, examined patterns of prescription during pregnancy including continuous prescription and discontinuation, and used logistic regression to investigate factors associated with those ASM prescription patterns. MAIN OUTCOME MEASURES: Prescription of ASMs during pregnancy and discontinuation of ASMs before and during pregnancy. RESULTS: ASM prescription during pregnancy increased from 0.6% of pregnancies in 1995 to 1.6% in 2018, driven largely by an increase in women with indications other than epilepsy. Epilepsy was an indication for 62.5% of pregnancies with an ASM prescription and non-epilepsy indications were present for 66.6%. Continuous prescription of ASMs during pregnancy was more common in women with epilepsy (64.3%) than in women with other indications (25.3%). Switching ASMs was infrequent (0.8% of ASM users). Factors associated with discontinuation included age ≥35, higher social deprivation, more frequent contact with the GP and being prescribed antidepressants or antipsychotics. CONCLUSIONS: ASM prescription during pregnancy increased between 1995 and 2018 in the UK. Patterns of prescription around the pregnancy period vary by indication and are associated with several maternal characteristics