Fraziervance2667

To assess British doctors' work-life balance, home-life satisfaction and associated barriers.

We designed an online survey using Google Forms and distributed this via a closed social media group with 7031 members, exclusively run for British doctors. No identifiable data were collected and all respondents provided consent for their responses to be used anonymously. The questions covered demographic data followed by exploration of work-life balance and home-life satisfaction across a broad range of domains, including barriers thereto. Thematic analysis was performed for free-text responses.

417 doctors completed the survey (response rate 6%, typical for online surveys). Only 26% reported a satisfactory work-life balance; 70% of all respondents reported their work negatively affected their relationships and 87% reported their work negatively affected their hobbies. A significant proportion of respondents reported delaying major life events due to their working patterns 52% delaying buying a home, 40% delaprove the well-being of British doctors and improve retention of the current workforce.

Stromal barriers, such as the abundant desmoplastic stroma that is characteristic of pancreatic ductal adenocarcinoma (PDAC), can block the delivery and decrease the tumour-penetrating ability of therapeutics such as tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), which can selectively induce cancer cell apoptosis. This study aimed to develop a TRAIL-based nanotherapy that not only eliminated the extracellular matrix barrier to increase TRAIL delivery into tumours but also blocked antiapoptotic mechanisms to overcome TRAIL resistance in PDAC.

Nitric oxide (NO) plays a role in preventing tissue desmoplasia and could thus be delivered to disrupt the stromal barrier and improve TRAIL delivery in PDAC. We applied an

combinatorial phage display technique to identify novel peptide ligands to target the desmoplastic stroma in both murine and human orthotopic PDAC. We then constructed a stroma-targeted nanogel modified with phage display-identified tumour stroma-targeting peptides to co-deliver NO and TRAIL to PDAC and examined the anticancer effect in three-dimensional spheroid cultures

and in orthotopic PDAC models

.

The delivery of NO to the PDAC tumour stroma resulted in reprogramming of activated pancreatic stellate cells, alleviation of tumour desmoplasia and downregulation of antiapoptotic BCL-2 protein expression, thereby facilitating tumour penetration by TRAIL and substantially enhancing the antitumour efficacy of TRAIL therapy.

The co-delivery of TRAIL and NO by a stroma-targeted nanogel that remodels the fibrotic tumour microenvironment and suppresses tumour growth has the potential to be translated into a safe and promising treatment for PDAC.

The co-delivery of TRAIL and NO by a stroma-targeted nanogel that remodels the fibrotic tumour microenvironment and suppresses tumour growth has the potential to be translated into a safe and promising treatment for PDAC.Pathogenic variants in CKAP2L have previously been reported in Filippi Syndrome (FS), a rare autosomal recessive, craniodigital syndrome characterized by microcephaly, syndactyly, short stature, intellectual disability, and dysmorphic facial features. To date, fewer than ten patients with pathogenic variants in CKAP2L associated with FS have been reported. All of the previously reported probands have presumed loss-of-function variants (frameshift, canonical splice site, starting methionine) and all but one have been homozygous for a pathogenic variant. Here we describe two brothers who presented with microcephaly, micrognathia, syndactyly, dysmorphic features, and intellectual disability. Whole exome sequencing of the family identified a missense variant, c.2066G>A (p.Arg689His), in trans with a frameshift variant, c.1169_1173del (p.Ile390LysfsTer4), in CKAP2L. To our knowledge, these are the first patients with FS to be reported with a missense variant in CKAP2L and only the second family to be reported with two variants in trans.

There is currently a strong drive internationally towards creating digitally advanced healthcare systems through coordinated efforts at a national level. The English Global Digital Exemplar (GDE) programme is a large-scale national health information technology change programme aiming to promote digitally-enabled transformation in secondary healthcare provider organisations by supporting relatively digitally mature provider organisations to become international centres of excellence.

To qualitatively evaluate the impact of the GDE programme in promoting digital transformation in provider organisations that took part in the programme.

We conducted a series of in-depth case studies in 12 purposively selected provider organisations and a further 24 wider case studies of the remaining organisations participating in the GDE programme. Data collected included 628 interviews, non-participant observations of 190 meetings and workshops and analysis of 9 documents. We used thematic analysis aided by NVivo softwar, putting in place governance structures and leveraging reputational benefits for participating provider organisations, around a coherent vision of transformation.

The GDE programme has been successful in accelerating digital transformation in participating provider organisations. Large-scale digital transformation programmes in healthcare can stimulate local progress through protected funding, putting in place governance structures and leveraging reputational benefits for participating provider organisations, around a coherent vision of transformation.LPS binding protein (LBP) is an important innate sensor of microbial cell wall structures. Frequent functionally relevant mutations exist and have been linked to influence susceptibility to and course of bacterial infections. We examined functional properties of a single nucleotide polymorphism resulting in an exchange of phenylalanine to leucine at position 436 of LBP (rs2232618) and compared the frequent variant of the molecule with the rare one in ligand binding experiments. We then stimulated RAW cells with bacterial ligands in the presence of serum obtained from individuals with different LBP genotypes. We, furthermore, determined the potential effects of structural changes in the molecule by in silico modeling. Finally, we analyzed 363 surgical patients for this genetic variant and examined incidence and course of sepsis following surgery. We found that binding of LBP to bacterial ligands was reduced, and stimulation of RAW cells resulted in an increased release of TNF when adding serum from individuals carrying the F436L variant as compared with normal LBP. In silico analysis revealed structural changes of LBP, potentially explaining some of the effects observed for the LBP variant. Finally, patients carrying the F436L variant were found to be similarly susceptible for sepsis. However, we observed a more favorable course of severe infections in this cohort. Our findings reveal new insights into LPS recognition and the subsequent activation of the innate immune system brought about by LBP. The identification of a genetic variant of LBP influencing the course of sepsis may help to stratify individuals at risk and thus reduce clinical complications of patients.

The aim of this study was to identify dietary patterns in a Czech pregnancy cohort established in the early postcommunist era and investigate associations between dietary patterns, maternal characteristics and birth outcomes.

Pregnant women were recruited for the Czech part of the European Longitudinal Study of Pregnancy and Childhood. A self-reported questionnaire answered in late pregnancy was used to assess information about the weekly intake of 43 food items. Information about birth outcomes (birth weight, height, ponderal index, head circumference, cephalisation index, gestational length and Apgar score) was obtained from the National Registry of Newborns. Complete details on diet and birth outcomes were available for 4320 mother-infant pairs.

The food items were aggregated into 28 variables and used for extraction of two dietary patterns by principal component factor analysis. The patterns were denoted 'unhealthy' and 'healthy/traditional' based on the food items with the highest factor loadings o highest factor loadings on each pattern. The 'unhealthy' pattern had high positive loadings on meat, processed food and confectionaries. In contrast, the 'healthy/traditional' pattern had high positive loadings on vegetables, dairy, fruits and wholemeal bread. Following adjustment for covariates, we found that high adherence to the unhealthy pattern (expressed as beta for 1 unit increase in pattern score), that is, the higher consumption of less healthy foods, was associated with lower birth weight -23.8 g (95% CI -44.4 to -3.2) and length -0.10 cm (95% CI -0.19 to -0.01) and increased cephalisation index 0.91 μm/g (95% CI 0.23 to 1.60). The 'healthy/traditional' pattern was not associated with any birth outcomes. This study supports the recommendation to eat a healthy and balanced diet during pregnancy.Noise introduced in the human nervous system from cellular to systems levels can have a major impact on signal processing. Using transcranial stimulation, electrical noise can be added to cortical circuits to modulate neuronal activity and enhance function in the healthy brain and in neurologic patients. Transcranial random noise stimulation (tRNS) is a promising technique that is less well understood than other non-invasive neuromodulatory methods. The aim of the present scoping review is to collate published evidence on the effects of electrical noise at the cellular, systems, and behavioral levels, and discuss how this emerging method might be harnessed to augment perceptual and motor functioning of the human nervous system. Online databases were used to identify papers published in 2008-2021 using tRNS in humans, from which we identified 70 publications focusing on sensory and motor function. Additionally, we interpret the existing evidence by referring to articles investigating the effects of noise stimulation in animal and subcellular models. We review physiological and behavioral findings of tRNS-induced offline after-effects and acute online benefits which manifest immediately when tRNS is applied to sensory or motor cortices. We link these results to evidence showing that activity of voltage-gated sodium ion channels might be an important cellular substrate for mediating these tRNS effects. We argue that tRNS might make neural signal transmission and processing within neuronal populations more efficient, which could contribute to both (1) offline after-effects in the form of a prolonged increase in cortical excitability and (2) acute online noise benefits when computations rely on weak inputs.People with diabetes are more likely to require surgical intervention than those without and have an increased risk of developing postoperative complications. learn more The Highs and lows review from the National Confidential Enquiry into Patient Outcome and Death reported on inadequate diabetes care in the perioperative period. As a result, the Centre for Perioperative Care has published guidance on perioperative management of diabetes recently.Early identification and glucose optimisation pre-operatively is key, and assists in formulating an individualised plan for diabetes care during admission, surgery and postoperatively. The plan will include dose adjustments of diabetes medication, and use of variable rate insulin infusion or continuous subcutaneous insulin infusion where applicable. The guideline also highlights the importance of improved communication between healthcare teams involved in the perioperative pathway in order to improve outcomes and care.