Autism spectrum disorders (ASD) are characterized by a wide genetic and clinical heterogeneity. However, some biochemical impairments, including decreased melatonin (crucial for circadian regulation) ...and elevated platelet N-acetylserotonin (the precursor of melatonin) have been reported as very frequent features in individuals with ASD. To address the mechanisms of these dysfunctions, we investigated melatonin synthesis in post-mortem pineal glands - the main source of melatonin (9 patients and 22 controls) - and gut samples - the main source of serotonin (11 patients and 13 controls), and in blood platelets from 239 individuals with ASD, their first-degree relatives and 278 controls. Our results elucidate the enzymatic mechanism for melatonin deficit in ASD, involving a reduction of both enzyme activities contributing to melatonin synthesis (AANAT and ASMT), observed in the pineal gland as well as in gut and platelets of patients. Further investigations suggest new, post-translational (reduced levels of 14-3-3 proteins which regulate AANAT and ASMT activities) and post-transcriptional (increased levels of miR-451, targeting 14-3-3ζ) mechanisms to these impairments. This study thus gives insights into the pathophysiological pathways involved in ASD.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
This study aimed to gain a better understanding of nursing/midwifery students' perspectives on a pedagogy of caring and online learning during the COVID-19 pandemic. In addition, it aimed to ...determine if the COVID-19 pandemic impacted students' perceptions and experience of online learning and students' desire to enter the nursing/midwifery workforce.
Mixed methods.
A multi-centre cross-sectional survey of Australian nursing and midwifery students was undertaken to explore students' experience of learning during the COVID-19 pandemic.
There are several key findings from this study that may be relevant for the future delivery of undergraduate health education, students transitioning to practice and healthcare workforce retention. The study found that although students were somewhat satisfied with online learning during COVID-19, students reported significant issues with knowledge/skill acquisition and barriers to the learning process. The students reported feeling less prepared for practice and identified how clinical staff were unable to provide additional guidance and support due to increased workloads and stress. The textual responses of participants highlighted that connection/disconnection, empathy and engagement/disengagement had an impact on learning during COVID-19.
Connection, engagement and isolation were key factors that impacted nursing students' online learning experiences. In addition, graduates entering the workforce felt less prepared for entry into practice due to changes in education delivery during COVID-19 that they perceived impacted their level of clinical skills, confidence and ability to practice as new graduate nurses/midwives.
Not applicable.
Attention must be given to the transition of new graduate nurses and midwives whose education was impacted by pandemic restrictions, to support their professional career development and to ensure retention of future healthcare workforce. Connection, engagement and isolation were key factors that impacted nursing students' online learning experiences. Educators should consider how connection and engagement can be actively embedded in the online learning environment.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK, VSZLJ
Advances in high-throughput genotyping and the International HapMap Project have enabled association studies at the whole-genome level. We have constructed whole-genome genotyping panels of over ...550,000 (HumanHap550) and 650,000 (HumanHap650Y) SNP loci by choosing tag SNPs from all populations genotyped by the International HapMap Project. These panels also contain additional SNP content in regions that have historically been overrepresented in diseases, such as nonsynonymous sites, the MHC region, copy number variant regions and mitochondrial DNA. We estimate that the tag SNP loci in these panels cover the majority of all common variation in the genome as measured by coverage of both all common HapMap SNPs and an independent set of SNPs derived from complete resequencing of genes obtained from SeattleSNPs. We also estimate that, given a sample size of 1,000 cases and 1,000 controls, these panels have the power to detect single disease loci of moderate risk (lambda approximately 1.8-2.0). Relative risks as low as lambda approximately 1.1-1.3 can be detected using 10,000 cases and 10,000 controls depending on the sample population and disease model. If multiple loci are involved, the power increases significantly to detect at least one locus such that relative risks 20%-35% lower can be detected with 80% power if between two and four independent loci are involved. Although our SNP selection was based on HapMap data, which is a subset of all common SNPs, these panels effectively capture the majority of all common variation and provide high power to detect risk alleles that are not represented in the HapMap data.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
This paper presents a method for energy efficient weather routing of a ferry in Norway. Historical operational data from the ferry and environmental data are used to develop two models that ...predict the energy consumption. The first is a purely data-driven linear regression energy model, while the second is as a hybrid model, combining physical models with data-driven models using machine learning techniques. With an established energy model, it is possible to develop a route optimization that proposes efficient routes with less energy usage compared to fixed speed and heading control.
The kinase LKB1 is a critical tumor suppressor in sporadic and familial human cancers, yet the mechanisms by which it suppresses tumor growth remain poorly understood. To investigate the ...tumor-suppressive capacity of four canonical families of LKB1 substrates
, we used CRISPR/Cas9-mediated combinatorial genome editing in a mouse model of oncogenic KRAS-driven lung adenocarcinoma. We demonstrate that members of the SIK family are critical for constraining tumor development. Histologic and gene-expression similarities between LKB1- and SIK-deficient tumors suggest that SIKs and LKB1 operate within the same axis. Furthermore, a gene-expression signature reflecting SIK deficiency is enriched in
-mutant human lung adenocarcinomas and is regulated by LKB1 in human cancer cell lines. Together, these findings reveal a key LKB1-SIK tumor-suppressive axis and underscore the need to redirect efforts to elucidate the mechanisms through which LKB1 mediates tumor suppression. SIGNIFICANCE: Uncovering the effectors of frequently altered tumor suppressor genes is critical for understanding the fundamental driving forces of cancer growth. Our identification of the SIK family of kinases as effectors of LKB1-mediated tumor suppression will refocus future mechanistic studies and may lead to new avenues for genotype-specific therapeutic interventions.
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We aimed to investigate community first responders’ contribution to emergency care provision in terms of number, rate, type, and location of calls and characteristics of patients attended.
We used a ...retrospective observational design analyzing routine data from electronic clinical records from 6 of 10 ambulance services in the United Kingdom during 2019. Descriptive statistics, including numbers and frequencies, were used to illustrate characteristics of incidents and patients that the community first responders attended first in both rural and urban areas.
The data included 4.5 million incidents during 1 year. The community first responders first attended a higher proportion of calls in rural areas compared with those in urban areas (3.90% versus 1.48 %). In rural areas, the community first responders also first attended a higher percentage of the most urgent call categories, 1 and 2. The community first responders first attended more than 9% of the total number of category 1 calls and almost 5% of category 2 calls. The community first responders also attended a higher percentage of the total number of cardiorespiratory and neurological/endocrine conditions. They first attended 6.5% of the total number of neurological/endocrine conditions and 5.9% of the total number of cardiorespiratory conditions. Regarding arrival times in rural areas, the community first responders attended higher percentages (more than 6%) of the total number of calls that had arrival times of less than 7 minutes or more than 60 minutes.
In the United Kingdom, community first responders contribute to the delivery of emergency medical services, particularly in rural areas and especially for more urgent calls. The work of community first responders has expanded from their original purpose—to attend to out-of-hospital cardiac arrests. The future development of community first responders’ schemes should prioritize training for a range of conditions, and further research is needed to explore the contribution and potential future role of the community first responders from the perspective of service users, community first responders’ schemes, ambulance services, and commissioners.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Results of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects.
FOCUS was a pragmatic, ...multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762.
Between Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 95% CI 0·839–1·079; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 13·43% patients vs 269 17·21%; difference 3·78% 95% CI 1·26–6·30; p=0·0033), but they had more bone fractures (45 2·88% vs 23 1·47%; difference 1·41% 95% CI 0·38–2·43; p=0·0070). There were no significant differences in any other event at 6 or 12 months.
Fluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function.
UK Stroke Association and NIHR Health Technology Assessment Programme.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Late-stage isolated medial knee osteoarthritis can be treated with total knee replacement (TKR) or partial knee replacement (PKR). There is high variation in treatment choice and little robust ...evidence to guide selection. The Total or Partial Knee Arthroplasty Trial (TOPKAT) therefore aims to assess the clinical effectiveness and cost-effectiveness of TKR versus PKR in patients with medial compartment osteoarthritis of the knee, and this represents an analysis of the main endpoints at 5 years.
Our multicentre, pragmatic randomised controlled trial was done at 27 UK sites. We used a combined expertise-based and equipoise-based approach, in which patients with isolated osteoarthritis of the medial compartment of the knee and who satisfied general requirements for a medial PKR were randomly assigned (1:1) to receive PKR or TKR by surgeons who were either expert in and willing to perform both surgeries or by a surgeon with particular expertise in the allocated procedure. The primary endpoint was the Oxford Knee Score (OKS) 5 years after randomisation in all patients assigned to groups. Health-care costs (in UK 2017 prices) and cost-effectiveness were also assessed. This trial is registered with ISRCTN (ISRCTN03013488) and ClinicalTrials.gov (NCT01352247).
Between Jan 18, 2010, and Sept 30, 2013, we assessed 962 patients for their eligibility, of whom 431 (45%) patients were excluded (121 13% patients did not meet the inclusion criteria and 310 32% patients declined to participate) and 528 (55%) patients were randomly assigned to groups. 94% of participants responded to the follow-up survey 5 years after their operation. At the 5-year follow-up, we found no difference in OKS between groups (mean difference 1·04, 95% CI −0·42 to 2·50; p=0·159). In our within-trial cost-effectiveness analysis, we found that PKR was more effective (0·240 additional quality-adjusted life-years, 95% CI 0·046 to 0·434) and less expensive (−£910, 95% CI −1503 to −317) than TKR during the 5 years of follow-up. This finding was a result of slightly better outcomes, lower costs of surgery, and lower follow-up health-care costs with PKR than TKR.
Both TKR and PKR are effective, offer similar clinical outcomes, and result in a similar incidence of re-operations and complications. Based on our clinical findings, and results regarding the lower costs and better cost-effectiveness with PKR during the 5-year study period, we suggest that PKR should be considered the first choice for patients with late-stage isolated medial compartment osteoarthritis.
National Institute for Health Research Health Technology Assessment Programme.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Investigations into stem cell-fueled renewal of an organ benefit from an inventory of cell type-specific markers and a deep understanding of the cellular diversity within stem cell niches. Using the ...adult mouse incisor as a model for a continuously renewing organ, we performed an unbiased analysis of gene co-expression relationships to identify modules of co-expressed genes that represent differentiated cells, transit-amplifying cells, and residents of stem cell niches. Through in vivo lineage tracing, we demonstrated the power of this approach by showing that co-expression module members
and
define populations of incisor epithelial and mesenchymal stem cells. We further discovered that two adjacent mesenchymal tissues, the periodontium and dental pulp, are maintained by distinct pools of stem cells. These findings reveal novel mechanisms of incisor renewal and illustrate how gene co-expression analysis of intact biological systems can provide insights into the transcriptional basis of cellular identity.
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