CTP:phosphoethanolamine cytidylyltransferase (ET), encoded by PCYT2, is the rate-limiting enzyme for phosphatidylethanolamine synthesis via the CDP-ethanolamine pathway. Phosphatidylethanolamine is ...one of the most abundant membrane lipids and is particularly enriched in the brain. We identified five individuals with biallelic PCYT2 variants clinically characterized by global developmental delay with regression, spastic para- or tetraparesis, epilepsy and progressive cerebral and cerebellar atrophy. Using patient fibroblasts we demonstrated that these variants are hypomorphic, result in altered but residual ET protein levels and concomitant reduced enzyme activity without affecting mRNA levels. The significantly better survival of hypomorphic CRISPR-Cas9 generated pcyt2 zebrafish knockout compared to a complete knockout, in conjunction with previously described data on the Pcyt2 mouse model, indicates that complete loss of ET function may be incompatible with life in vertebrates. Lipidomic analysis revealed profound lipid abnormalities in patient fibroblasts impacting both neutral etherlipid and etherphospholipid metabolism. Plasma lipidomics studies also identified changes in etherlipids that have the potential to be used as biomarkers for ET deficiency. In conclusion, our data establish PCYT2 as a disease gene for a new complex hereditary spastic paraplegia and confirm that etherlipid homeostasis is important for the development and function of the brain.
Aims
Genetic testing can be used to improve the safety and effectiveness of commonly prescribed medicines—a concept known as pharmacogenetics. This study aimed to quantify members of the UK public's ...preferences for a pharmacogenetic service to be delivered in primary care in the National Health Service.
Methods
Members of the UK population were surveyed via an online panel company. Respondents completed 1 of 2 survey versions, asking respondents to select their preferred pharmacogenetic testing service in the context of a presentation of low mood or pain. A conditional logit model was estimated, before the best functional form for the dataset was identified. Preference heterogeneity was identified via latent class analysis. Coefficients from the final selected models were used to estimate uptake in the context of different hypothetical pharmacogenetic services.
Results
Responses from 1993 individuals were included in the analysis. There were no differences observed in preference between the 2 clinical scenarios. Conditional logit analysis, using maximum likelihood estimation, indicated that respondents preferred to have noninvasive tests and wanted their data to be shared between different healthcare organizations to guide future prescribing. There was a preference for regional over national data sharing initiatives, and respondents preferred to have access to their data. Predicted uptake varied considerably, ranging from 51% to >99%, depending on design of the service.
Conclusion
This study identifies public preferences for a pharmacogenetic testing service and demonstrates how predicted uptake can be impacted by relatively minor adaptations. This highlights areas for prioritization during development of future pharmacogenetic services.
Understanding the effectiveness of infection control methods in reducing and preventing SARS-CoV-2 transmission in healthcare settings is of high importance. We sequenced SARS-CoV-2 genomes for ...patients and healthcare workers (HCWs) across multiple geographically distinct UK hospitals, obtaining 173 high-quality SARS-CoV-2 genomes. We integrated patient movement and staff location data into the analysis of viral genome data to understand spatial and temporal dynamics of SARS-CoV-2 transmission. We identified eight patient contact clusters (PCC) with significantly increased similarity in genomic variants compared to non-clustered samples. Incorporation of HCW location further increased the number of individuals within PCCs and identified additional links in SARS-CoV-2 transmission pathways. Patients within PCCs carried viruses more genetically identical to HCWs in the same ward location. SARS-CoV-2 genome sequencing integrated with patient and HCW movement data increases identification of outbreak clusters. This dynamic approach can support infection control management strategies within the healthcare setting.
Later chronotype has been associated with poorer glycemic control in type 2 diabetes. It is unclear whether this is a direct relationship, or if personality factors or social jetlag (SJL, ie, chronic ...circadian misalignment reflecting the discrepancy between the entrained phase of the circadian clock and socially-determined behavioural cycles) play a role. This study aimed to determine the relationships among chronotype, SJL, personality factors and glycemic control in type 2 diabetes, independently of sleep disturbances and daily caloric distribution.
In sum, 252 type 2 diabetes patients attending an annual review outpatients' clinic completed questionnaires, including the Munich Chronotype Questionnaire to assess chronotype and SJL, the Pittsburgh Sleep Quality index (PSQI), the Big Five Personality Inventory and the Center for Epidemiologic Studies Depression Scale. Chart review provided information on diabetes duration, Hemoglobin A1c (HbA1c), body mass index (BMI) and other clinical variables. Caloric intake was assessed via 24-h dietary recall.
Hierarchical linear regression revealed that SJL, but not chronotype or personality factors, was a significant predictor of HbA1c levels (β = 0.16, p < 0.05). There was a significant relationship between later chronotype and HbA1c levels, but only in patients who had more than 90 min SJL (r = 0.51, p = 0.002). Younger age was associated with a higher HbA1c (r = −0.23, p < 0.001), and this effect was partially mediated through SJL (Pm = 0.22).
We identify SJL as a novel factor that may impact on glycemic control in type 2 diabetes. Further study is needed to determine whether interventions aimed at reducing SJL may lead to improvements in glycemic control.
•Social jetlag predicted higher HbA1c levels in patients with type 2 diabetes.•This was independent of other sleep, personality and circadian variables.•Younger participants had higher HbA1c and greater social jetlag.•With greater social jetlag, later MSFsc was associated with higher HbA1c.
Asymptomatic coronary artery disease (CAD) is common in people with diabetes mellitus, but there is a lack of consensus regarding appropriate screening for the condition. We performed a 12-lead ...electrocardiogram (ECG) on 312 consecutive participants with diabetes mellitus attending for routine annual outpatient review in order to determine the effectiveness of a yearly ECG in screening people with diabetes for asymptomatic CAD.
Three of 312 participants (0.96%, 95% CI 0.2%-2.78%) had a newly identified ECG abnormality. One person had newly discovered atrial fibrillation. Two people had abnormalities which prompted further investigation for asymptomatic CAD. One of these participants underwent percutaneous coronary intervention. Seventeen further participants had abnormalities on ECG which had been previously documented, the majority having been present since their diagnosis of diabetes.
A low positive yield of routine annual ECG in our study does not support its use as a screening tool for asymptomatic CAD in diabetes. Our findings support advice to perform an ECG at diagnosis of diabetes and to repeat only if a person develops relevant symptoms.
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