Manipulation du métabolisme énergétique dans les leucémies aiguës myéloïdes : mitochondrie, apoptose et mécanisme d'action de la metformine

La metformine, utilisée pour le traitement du diabète de type 2, a été décrite comme pouvant réduire le risque de cancer. Cependant, les mécanismes responsables de cette activité n'ont pas encore été élucidés. Nous avons ici décidé d'étudier les effets de la metformine dans les cellules de leucémie aiguë myéloïde (LAM). La metformine bloque la progression dans le cycle cellulaire, inhibe la prolifération et la formation de colonies in vitro. In vivo, un traitement quotidien à la metformine induit l'apoptose et réduit la progression tumorale. Toutefois, cette induction d'apoptose est variable en fonction des cellules leucémiques. La metformine induit une inhibition de mTORC1 indépendante de l'AMPK, qui peut être responsable des effets anti-tumoraux observés. Par ailleurs, la metformine réduit fortement l'activité du complexe I de la chaîne respiratoire, la consommation d'oxygène et la production d'ATP par la mitochondrie alors qu'elle stimule la glycolyse pour la production d'ATP et de lactate (effet Pasteur). Les cellules leucémiques avec une forte glycolyse ou activation d'AKT montrent une réduction significative de l'induction de l'effet Pasteur et de l'apoptose en réponse à la metformine. Ainsi, la déprivation en glucose ou un inhibiteur de la glycolyse ou d'AKT sensibilisent ces cellules à la metformine. Nous proposons que le mécanisme d'apoptose est bloqué par la phosphorylation et la translocation au pore mitochondrial VDAC1 de l'hexokinase-II en aval d'AKT. En conclusion, ces travaux ont permis de mieux caractériser la signalisation et le métabolisme impliqués dans la réponse anti-tumorale induite par la metformine dans des lignées cellulaires de LAM.Normoglycemic agent, metformin, decreases the risk of cancer in type 2 diabetics and inhibits cell growth in various cancers. Metformin activates AMPK and inhibits electron transport chain complex I (ETCI), but its mechanism of action in cancer cells is unknown. Thus, we investigated metformin's activity in human acute myeloid leukemia (AML) cells. Metformin significantly blocks cell cycle progression and inhibits cell proliferation and colony formation. However, the apoptotic response to metformin varies among AML cell types. Furthermore, daily treatment with metformin induces apoptosis and reduces tumor growth in vivo. Metformin induces an AMPK-independent inhibition of mTORC1, which could be responsible for metformin's anti-tumoral activities. Additionally, metformin decreases ETCI activity, oxygen consumption and mitochondrial ATP synthesis, while stimulating glycolysis for ATP and lactate production (so-called Pasteur Effect). AML cells with high basal AKT phosphorylation or glycolysis exhibit a markedly reduced induction of the Pasteur effect in response to metformin and are resistant to metformin-induced apoptosis. Accordingly, glucose starvation or treatment with deoxyglucose or an AKT inhibitor induces sensitivity to metformin. Thus, we propose that activation of AKT, which can phosphorylate hexokinase-II to induce its translocation to the mitochondrial outer membrane pore, VDAC1, blocks cytochrome c release and mitochondrial-induced apoptosis. Overall, this work has allowed us to decipher the role of certain signaling and metabolic pathways in the anti-tumoral response to metformin in AML

Cost of fertility treatment and live birth outcome in women of different ages and BMI

Acknowledgements We thank the Aberdeen Fertility Centre Database Committee and the Aberdeen Maternal and Neonatal Databank Committee for giving us approval to use their databases. We thank the Data Management Team for extracting the required information from these databases. The views expressed in this paper represent the views of the authors and not necessarily the views of the funding bodies. Funding This study was partly funded by an NHS endowment grant (Grant Number 12/48) and DM by a Chief Scientist Office Postdoctoral Fellowship (Ref PDF/12/06).Peer reviewedPostprin

Revising acute care systems and processes to improve breastfeeding and maternal postnatal health: a pre and post intervention study in one English maternity unit

Background Most women in the UK give birth in a hospital labour ward, following which they are transferred to a postnatal ward and discharged home within 24 to 48 hours of the birth. Despite policy and guideline recommendations to support planned, effective postnatal care, national surveys of women’s views of maternity care have consistently found in-patient postnatal care, including support for breastfeeding, is poorly rated. Methods Using a Continuous Quality Improvement approach, routine antenatal, intrapartum and postnatal care systems and processes were revised to support implementation of evidence based postnatal practice. To identify if implementation of a multi-faceted QI intervention impacted on outcomes, data on breastfeeding initiation and duration, maternal health and women’s views of care, were collected in a pre and post intervention longitudinal survey. Primary outcomes included initiation, overall duration and duration of exclusive breastfeeding. Secondary outcomes included maternal morbidity, experiences and satisfaction with care. As most outcomes of interest were measured on a nominal scale, these were compared pre and post intervention using logistic regression. Results Data were obtained on 741/1160 (64%) women at 10 days post-birth and 616 (54%) at 3 months post-birth pre-intervention, and 725/1153 (63%) and 575 (50%) respectively postintervention. Post intervention there were statistically significant differences in the initiation (p = 0.050), duration of any breastfeeding (p = 0.020) and duration of exclusive breastfeeding to 10 days (p = 0.038) and duration of any breastfeeding to three months (p = 0.016). Post intervention, women were less likely to report physical morbidity within the first 10 days of birth, and were more positive about their in-patient care. Conclusions It is possible to improve outcomes of routine in-patient care within current resources through continuous quality improvement

Obeying the rules of the road: Procedural justice, social identity and normative compliance

Why do people comply with traffic laws and regulations? Road traffic policing tends to be premised on the idea that people comply when they are presented with a credible risk of sanction in the event of non-compliance. Such an instrumental model of compliance contrasts with the normative account offered by procedural justice theory, in which compliance is encouraged by legitimate legal authorities. Comparing these two accounts, we find evidence that both instrumental and normative factors explain variance in motorists’ self-reported propensity to offend. Extending the standard procedural justice account, we also find that it is social identity – not legitimacy – that forms the ‘bridge’ linking procedural fairness and compliance, at least according to a definition of legitimacy that combines felt obligation and moral endorsement. Fair treatment at the hands of police officers seems to enhance identification with the social group the police represent, and in turn, identification seems to motivate adherence to rules (laws) governing social behavior. These findings have implications not only for understandings of legal compliance, but also our understanding of why procedural justice motivates compliance, and the role of procedural justice in promoting social cohesion

The DUNDRUM Quartet: validation of structured professional judgement instruments DUNDRUM-3 assessment of programme completion and DUNDRUM-4 assessment of recovery in forensic mental health services

<p>Abstract</p> <p>Background</p> <p>Moving a forensic mental health patient from one level of therapeutic security to a lower level or to the community is influenced by more than risk assessment and risk management. We set out to construct and validate structured professional judgement instruments for consistency and transparency in decision making</p> <p>Methods</p> <p>Two instruments were developed, the seven-item DUNDRUM-3 programme completion instrument and the six item DUNDRUM-4 recovery instrument. These were assessed for all 95 forensic patients at Ireland's only forensic mental health hospital.</p> <p>Results</p> <p>The two instruments had good internal consistency (Cronbach's alpha 0.911 and 0.887). Scores distinguished those allowed no leave or accompanied leave from those with unaccompanied leave (ANOVA F = 38.1 and 50.3 respectively, p < 0.001). Scores also distinguished those in acute/high security units from those in medium or in low secure/pre-discharge units. Each individual item distinguished these levels of need significantly. The DUNDRUM-3 and DUNDRUM-4 correlated moderately with measures of dynamic risk and with the CANFOR staff rated unmet need (Spearman r = 0.5, p < 0.001).</p> <p>Conclusions</p> <p>The DUNDRUM-3 programme completion items distinguished significantly between levels of therapeutic security while the DUNDRUM-4 recovery items consistently distinguished those given unaccompanied leave outside the hospital and those in the lowest levels of therapeutic security. This data forms the basis for a prospective study of outcomes now underway.</p

Risk of COVID-19 hospitalizations among school-aged children in Scotland : a national incident cohort study

Background There is considerable policy, clinical and public interest about whether children should be vaccinated against SARS-CoV-2 and, if so, which children should be prioritised (particularly if vaccine resources are limited). To inform such deliberations, we sought to identify children and young people at highest risk of hospitalization from COVID-19. Methods We used the Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II) platform to undertake a national incident cohort analysis to investigate the risk of hospitalization among 5-17 years old living in Scotland in risk groups defined by the living risk prediction algorithm (QCOVID). A Cox proportional hazard model was used to derive hazard ratios (HR) and 95% confidence intervals (CIs) for the association between risk groups and COVID-19 hospital admission. Adjustments were made for age, sex, socioeconomic status, co-morbidity, and prior hospitalization. Results Between March 1, 2020 and November 22, 2021, there were 146 183 (19.4% of all 752 867 children in Scotland) polymerase chain reaction (PCR) confirmed SARS-CoV-2 infections among 5-17 years old. Of those with confirmed infection, 973 (0.7%) were admitted to hospital with COVID-19. The rate of COVID-19 hospitalization was higher in those within each QCOVID risk group compared to those without the condition. Similar results were found in age stratified analyses (5-11 and 12-17 years old). Risk groups associated with an increased risk of COVID-19 hospital admission, included (adjusted HR, 95% CIs): sickle cell disease 14.35 (8.48-24.28), chronic kidney disease 11.34 (4.61-27.87), blood cancer 6.32 (3.24-12.35), rare pulmonary diseases 5.04 (2.58-9.86), type 2 diabetes 3.04 (1.34-6.92), epilepsy 2.54 (1.69-3.81), type 1 diabetes 2.48 (1.47-4.16), Down syndrome 2.45 (0.96-6.25), cerebral palsy 2.37 (1.26-4.47), severe mental illness 1.43 (0.63-3.24), fracture 1.41 (1.02-1.95), congenital heart disease 1.35 (0.82-2.23), asthma 1.28 (1.06-1.55), and learning disability (excluding Down syndrome) 1.08 (0.82-1.42), when compared to those without these conditions. Although our Cox models were adjusted for a number of potential confounders, residual confounding remains a possibility. Conclusions In this national study, we observed an increased risk of COVID-19 hospital admissions among school-aged children with specific underlying long-term health conditions compared with children without these conditions

UK medical education on human trafficking: assessing uptake of the opportunity to shape awareness, safeguarding and referral in the curriculum.

BACKGROUND: Human trafficking is a serious violation of human rights, with numerous consequences for health and wellbeing. Recent law and policy reforms mean that clinicians now hold a crucial role in national strategies. 2015 research, however, indicates a serious shortfall in knowledge and confidence among healthcare professionals in the UK, leading potentially to failures in safeguarding and appropriate referral. Medical education is a central point for trafficking training. We ascertain the extent of such training in UK Medical Schools, and current curricular design. METHOD: We sent Freedom of Information requests to the 34 public UK medical schools, which included a preliminary question on education provision, supplemented with follow-up questions exploring the nature, delivery and format of any education, as well as future curriculum development. RESULTS: There was a response rate of 97%. A majority (72%) of the schools did not provide trafficking education. 13% of these did, however, offer opportunities outside the formal curriculum. 70% had no plans to implement any education opportunities. Among the 28% of schools providing teaching, 56% integrated this within the core curriculum. 56% only delivered this within a single year of the degree. 67% provided some form of teaching in-person, while 78% used a combination of methods. CONCLUSION: Medical education on trafficking in the UK is variable and often absent. To produce future clinicians who are competent and capable, there is a need for expanded education on trafficking and research into optimal curriculum design. The UK's new Independent Anti-Slavery Commissioner should work with medical schools to develop an educational strategy urgently to fulfil the UK Government's plans and commitments. Both in the UK and around the world, human trafficking education presents a critical opportunity to address human rights and safeguarding to a generation of new doctors

SDOCT Imaging to Identify Macular Pathology in Patients Diagnosed with Diabetic Maculopathy by a Digital Photographic Retinal Screening Programme

INTRODUCTION: Diabetic macular edema (DME) is an important cause of vision loss. England has a national systematic photographic retinal screening programme to identify patients with diabetic eye disease. Grading retinal photographs according to this national protocol identifies surrogate markers for DME. We audited a care pathway using a spectral-domain optical coherence tomography (SDOCT) clinic to identify macular pathology in this subset of patients. METHODS: A prospective audit was performed of patients referred from screening with mild to moderate non-proliferative diabetic retinopathy (R1) and surrogate markers for diabetic macular edema (M1) attending an SDOCT clinic. The SDOCT images were graded by an ophthalmologist as SDOCT positive, borderline or negative. SDOCT positive patients were referred to the medical retina clinic. SDOCT negative and borderline patients were further reviewed in the SDOCT clinic in 6 months. RESULTS: From a registered screening population of 17 551 patients with diabetes mellitus, 311 patients met the inclusion criteria between (March 2008 and September 2009). We analyzed images from 311 patients' SDOCT clinic episodes. There were 131 SDOCT negative and 12 borderline patients booked for revisit in the OCT clinic. Twenty-four were referred back to photographic screening for a variety of reasons. A total of 144 were referred to ophthalmology with OCT evidence of definite macular pathology requiring review by an ophthalmologist. DISCUSSION: This analysis shows that patients with diabetes, mild to moderate non-proliferative diabetic retinopathy (R1) and evidence of diabetic maculopathy on non-stereoscopic retinal photographs (M1) have a 42.1% chance of having no macular edema on SDOCT imaging as defined by standard OCT definitions of DME when graded by a retinal specialist. SDOCT imaging is a useful adjunct to colour fundus photography in screening for referable diabetic maculopathy in our screening population