Structure-Enabled Discovery of a Stapled Peptide Inhibitor to Target the Oncogenic Transcriptional Repressor TLE1.

TLE1 is an oncogenic transcriptional co-repressor that exerts its repressive effects through binding of transcription factors. Inhibition of this protein-protein interaction represents a putative cancer target, but no small-molecule inhibitors have been published for this challenging interface. Herein, the structure-enabled design and synthesis of a constrained peptide inhibitor of TLE1 is reported. The design features the introduction of a four-carbon-atom linker into the peptide epitope found in many TLE1 binding partners. A concise synthetic route to a proof-of-concept peptide, cycFWRPW, has been developed. Biophysical testing by isothermal titration calorimetry and thermal shift assays showed that, although the constrained peptide bound potently, it had an approximately five-fold higher Kd than that of the unconstrained peptide. The co-crystal structure suggested that the reduced affinity was likely to be due to a small shift of one side chain, relative to the otherwise well-conserved conformation of the acyclic peptide. This work describes a constrained peptide inhibitor that may serve as the basis for improved inhibitors

Women's Perceptions of the Hypertensive Disorders of Pregnancy in Nigeria, Mozambique, Pakistan, and India: A Qualitative Evidence Synthesis of Primary Data From the Community-Level Interventions for Pre-Eclampsia (CLIP) Feasibility Study

This presentation will explore a crosscutting theme ‘‘changed medical mind-set,’’ emerging from a series of studies into mentoring for U.K. doctors undertaken by the author over more than a decade. Whilst there are many types of mentoring, the approach used in the initiatives studied is based upon the Egan skilled helper model and does not rest on notions of a senior-protege relationship. Although not the focus of these studies, participants have consistently and spontaneously reported changes in their way of thinking—some expressing this as life changing and profound; some as a moment of pause and reflection, a relearning of forgotten skills; and others as prompting reflection on a medical culture (and discourse) which perpetuates a certain way of thinking and being. The studies included qualitative and mixed methods explorations and evaluations of the perceived benefits of involvement in mentoring (2004), mentoring schemes (2008), mentor development initiatives and courses (2015), and an ongoing British Medical Association–funded study into the relationships between mentoring activities and Doctors’ Health and Wellbeing. The studies have drawn on social constructionism (Gergen, 1999) and been based in the view that, like education and learning, mentoring is a set of complex social processes which is individual, socially negotiated, and context bound. The methodologies employed draw on grounded theory, illuminative evaluation, and latterly elements of realistic evaluation. Thus, it seems engagement in Egan style mentoring activities (learning about mentoring, doing mentoring, using mentoring skills) has an impact on medical mind-sets and potentially on medical culture

Potential for task-sharing to Lady Health Workers for identification and emergency management of pre-eclampsia at community level in Pakistan.

BACKGROUND: An estimated 276 Pakistani women die for every 100,000 live births; with eclampsia accounting for about 10 % of these deaths. Community health workers contribute to the existing health system in Pakistan under the banner of the Lady Health Worker (LHW) Programme and are responsible to provide a comprehensive package of antenatal services. However, there is a need to increase focus on early identification and prompt diagnosis of pre-eclampsia in community settings, since women with mild pre-eclampsia often present without symptoms. This study aims to explore the potential for task-sharing to LHWs for the community-level management of pre-eclampsia and eclampsia in Pakistan. METHODS: A qualitative exploratory study was undertaken February-July 2012 in two districts, Hyderabad and Matiari, in the southern province of Sindh, Pakistan. Altogether 33 focus group discussions (FGDs) were conducted and the LHW curriculum and training materials were also reviewed. The data was audio-recorded, then transcribed verbatim for thematic analysis using QSR NVivo-version10. RESULTS: Findings from the review of the LHW curriculum and training program describe that in the existing community delivery system, LHWs are responsible for identification of pregnant women, screening women for danger signs and referrals for antenatal care. They are the first point of contact for women in pregnancy and provide nutritional counselling along with distribution of iron and folic acid supplements. Findings from FGDs suggest that LHWs do not carry a blood pressure device or antihypertensive medications; they refer to the nearest public facility in the event of a pregnancy complication. Currently, they provide tetanus toxoid in pregnancy. The health advice provided by lady health workers is highly valued and accepted by pregnant women and their families. Many Supervisors of LHWs recognized the need for increased training regarding pre-eclampsia and eclampsia, with a focus on identifying women at high risk. The entire budget of the existing lady health worker Programme is provided by the Government of Pakistan, indicating a strong support by policy makers and the government for the tasks undertaken by these providers. CONCLUSION: There is a potential for training and task-sharing to LHWs for providing comprehensive antenatal care; specifically for the identification and management of pre-eclampsia in Pakistan. However, the implementation needs to be combined with appropriate training, equipment availability and supervision. TRIAL REGISTRATION: ClinicalTrial.gov, NCT01911494

Post-modernism's use and abuse of Nietzsche

I focus on Nietzsche's architectural metaphor of self-construction in arguing for the claim that postmodern readings of Nietzsche misunderstand his various attacks on dogmatic philosophy as paving the way for acceptance of a self characterized by fundamental disunity. Nietzsche's attack on essentialist dogmatic metaphysics is a call to engage in a purposive self-creation under a unifying will, a will that possesses the strength to reinterpret history as a pathway to "the problem that we are". Nietzsche agrees with the postmodernists that unity is not a pre-given, however he would disavow their rejection of unity as a goal. Where the postmodernists celebrate "the death of the subject" Nietzsche rejects this valorization of disunity as a form of Nihilism and prescribes the creation of a genuine unified subjectivity to those few capable of such a goal. Postmodernists are nearer Nietzsche's idea of the Last Man than his idea of the Overman.Articl

Basic Cyber Hygiene:Does It Work?

A number of security certifications for small- and medium-size enterprises have been proposed, but how effective are these schemes? We evaluated the effectiveness of Cyber Essentials and found that its security controls work well to mitigate threats that exploit vulnerabilities remotely with commodity-level tools

Causes and circumstances of maternal death: A secondary analysis of the community-level Interventions for pre-eclampsia (CLIP) trials cohort

Background: Incomplete vital registration systems mean that causes of death during pregnancy and childbirth are poorly understood in low-income and middle-income countries. To inform global efforts to reduce maternal mortality, we compared physician review and computerised analysis of verbal autopsies (interpreting verbal autopsies [InterVA] software), to understand their agreement on maternal cause of death and circumstances of mortality categories (COMCATs) in the Community-Level Interventions for Pre-eclampsia (CLIP) cluster randomised trials.Methods: The CLIP trials took place in India, Pakistan, and Mozambique, enrolling pregnant women aged 12-49 years between Nov 1, 2014, and Feb 28, 2017. 69 330 pregnant women were enrolled in 44 clusters (36 008 in the 22 intervention clusters and 33 322 in the 22 control clusters). In this secondary analysis of maternal deaths in CLIP, we included women who died in any of the 22 intervention clusters or 22 control clusters. Trained staff administered the WHO 2012 verbal autopsy after maternal deaths. Two physicians (and a third for consensus, if needed) reviewed trial surveillance data and verbal autopsies, and, in intervention clusters, community health worker-led visit data. They determined cause of death according to the WHO International Classification of Diseases-Maternal Mortality (ICD-MM). Verbal autopsies were also analysed by InterVA computer models (versions 4 and 5) to generate cause of death. COMCAT analysis was provided by InterVA-5 and, in India, by physician review of Maternal Newborn Health Registry data. Causes of death and COMCATs assigned by physician review, Inter-VA-4, and InterVA-5 were compared, with agreement assessed with Cohen\u27s κ coefficient.Findings: Of 61 988 pregnancies with successful follow-up in the CLIP trials, 143 maternal deaths were reported (16 deaths in India, 105 in Pakistan, and 22 in Mozambique). The maternal death rate was 231 (95% CI 193-268) per 100 000 identified pregnancies. Most deaths were attributed to direct maternal causes (rather than indirect or undetermined causes as per ICD-MM classification), with fair to good agreement between physician review and InterVA-4 (κ=0·56 [95% CI 0·43-0·66]) or InterVA-5 (κ=0·44 [0·30-0·57]), and InterVA-4 and InterVA-5 (κ=0·72 [0·60-0·84]). The top three causes of death were the same by physician review, InterVA-4, and InterVA-5 (ICD-MM categories obstetric haemorrhage, non-obstetric complications, and hypertensive disorders); however, attribution of individual patient deaths to obstetric haemorrhage varied more between methods (physician review, 38 [27%] deaths; InterVA-4, 69 [48%] deaths; and InterVA-5, 82 [57%] deaths), than did attribution to non-obstetric causes (physician review, 39 [27%] deaths; InterVA-4, 37 [26%] deaths; and InterVA-5, 28 [20%] deaths) or hypertensive disorders (physician review, 23 [16%] deaths; InterVA-4, 25 [17%] deaths; and InterVA-5, 24 [17%] deaths). Agreement for all nine ICD-MM categories was fair for physician review versus InterVA-4 (κ=0·48 [0·38-0·58]), poor for physician review versus InterVA-5 (κ=0·36 [0·27-0·46]), and good for InterVA-4 versus InterVA-5 (κ=0·69 [0·59-0·79]). The most commonly assigned COMCATs by InterVA-5 were emergencies (68 [48%] of 143 deaths) and health systems (62 [43%] deaths), and by physician review (India only) were health systems (seven [44%] of 16 deaths) and inevitability (five [31%] deaths); agreement between InterVA-5 and physician review (India data only) was poor (κ=0·04 [0·00-0·15]).Interpretation: Our findings indicate that InterVA-5 is less accurate than InterVA-4 at ascertaining causes and circumstances of maternal death, when compared with physician review. Our results suggest a need to improve the next iteration of InterVA, and for researchers and clinicians to preferentially use InterVA-4 when recording maternal deaths.Funding: University of British Columbia (grantee of the Bill & Melinda Gates Foundation)

Oral antihypertensive therapy for severe hypertension in pregnancy and postpartum: a systematic review.

BACKGROUND: Pregnant and postpartum women with severe hypertension are at increased risk of stroke and require blood pressure (BP) reduction. Parenteral antihypertensives have been most commonly studied, but oral agents would be ideal for use in busy and resource-constrained settings. OBJECTIVES: To review systematically, the effectiveness of oral antihypertensive agents for treatment of severe pregnancy/postpartum hypertension. SEARCH STRATEGY: A systematic search of MEDLINE, EMBASE and the Cochrane Library was performed. SELECTION CRITERIA: Randomised controlled trials in pregnancy and postpartum with at least one arm consisting of a single oral antihypertensive agent to treat systolic BP ≥ 160 mmHg and/or diastolic BP ≥ 110 mmHg. DATA COLLECTION AND ANALYSIS: Cochrane RevMan 5.1 was used to calculate relative risk (RR) and weighted mean difference by random effects. MAIN RESULTS: We identified 15 randomised controlled trials (915 women) in pregnancy and one postpartum trial. Most trials in pregnancy compared oral/sublingual nifedipine capsules (8-10 mg) with another agent, usually parenteral hydralazine or labetalol. Nifedipine achieved treatment success in most women, similar to hydralazine (84% with nifedipine; relative risk [RR] 1.07, 95% confidence interval [95% CI] 0.98-1.17) or labetalol (100% with nifedipine; RR 1.02, 95% CI 0.95-1.09). Less than 2% of women treated with nifedipine experienced hypotension. There were no differences in adverse maternal or fetal outcomes. Target BP was achieved ~ 50% of the time with oral labetalol (100 mg) or methyldopa (250 mg) (47% labetelol versus 56% methyldopa; RR 0.85 95% CI 0.54-1.33). CONCLUSIONS: Oral nifedipine, and possibly labetalol and methyldopa, are suitable options for treatment of severe hypertension in pregnancy/postpartum

“Like works of our hands are giving testimony!” A qualitative study on kangaroo mother care and health worker empowerment in southern Malawi

The purpose of this paper is to explore health worker perspectives of empowerment associated with kangaroo mother care in southern Malawi. We conducted a secondary analysis of 27 in-depth interviews collected between May-Aug 2019 at a large Malawian tertiary hospital and three rural referral hospitals. Data was analyzed using a thematic approach with NVivo 12 software (QSR International, Melbourne, Australia). Health workers reported positive perceptions of kangaroo mother care because it helped save the lives of preterm and low birthweight infants who previously did not frequently survive. This gave them hope due to increased capacity to care for low birthweight infants and subsequently increased job satisfaction. Experiences of success supported workplace morale and strengthened commitment to their clinical roles. This study suggests that kangaroo mother care may support health worker empowerment and resilience in their work.   Cet article-ci se prend pour son objectif d'explorer les perspectives de l'autonomie associée avec les soins maternels kangourous implémentés aux cliniques médicales dans le sud du Malawi. Les perspectives de l'autonomie dont on parle ici appartiennent aux travailleurs de la santé. Nous avons effectué une analyse secondaire de vingt-sept entrevues collectionnées entre les mois mai et août en 2019 au Malawi à une hôpital de soins tertiaires et aux trois hôpitaux d'aiguillage ruraux. Les données ont été analysées en utilisant l'approche thématique avec le logiciel NVivo 12 (QSR International, Melbourne, Australia). Les travailleurs de la santé ont communiqué les perceptions positives des soins maternels kangourous parce que ceux-ci les ont aidé à sauver les vies des nourrissons prématurés et de faible poids de naissance qui autrefois souvent n'avaient pas survécu. Ceci leur a donné de l'espoir parce que leur capacité de prendre soin des nourrissons de faible poids de naissance est accrue et ensuite leur satisfaction au travail a augmenté aussi. Ces expériences de succès ont soutenu leur morale au travail et ont renforcé leur engagement envers leur rôles cliniques. Cette étude-ci suggère que les soins maternels kangourou peuvent promouvoir l'autonomie des travailleurs de la santé et leur résilience dans leur travail. &nbsp

Measurement of residual stresses in rails using Rayleigh waves

This paper presents a new nondestructive approach for evaluating the residual longitudinal stresses in rails. The developed approach utilises the acoustoelastic effect to infer the longitudinal stress from the measured speed of Rayleigh waves propagating along the longitudinal direction. The measured Rayleigh wave speed along the longitudinal direction is shown to vary significantly across the height of the rail section, which can be directly correlated to the residual stress profile in the rail section. Unlike existing residual stress measurement techniques, such as hole-drilling or sectioning, the developed approach can be potentially applied for the in-situ residual stress measurement, without taking the rail out of service.James Martin Hughes, James Vidler, Aditya Khanna, Munawwar Mohabuth, Andrei Kotousov and Ching-Tai N