Identification of peptidomimetic telomere dysfunction inhibitor (TELODIN) through telomere dysfunction-induced foci (TIF) assay.

Telomere dysfunction-induced focus (TIF) assay allows efficient profiling of telomere dysfunctions in cells and tissues. Here, we describe the use of the TIF assay to screen synthetic peptides from E3 ubiquitin ligase FBW7, a tumor suppressor gene product, to prevent TIFs caused by environmental radiation stress. We demonstrate peptidomimetic telomere dysfunction inhibitor as a potentially intervening therapeutic drug candidate in aging-related diseases.

Respiratory support after delayed cord clamping: a prospective cohort study of at-risk births at ≥35 weeks gestation.

Objective: To identify risk factors associated with delivery room respiratory support in at-risk infants who are initially vigorous and received delayed cord clamping (DCC).

Design: Prospective cohort study.

Setting: Two perinatal centres in Melbourne, Australia.

Mechanisms of cancer stem cell senescence: Current understanding and future perspectives.

Cancer stem cells (CSCs) are a small population of heterogeneous tumor cells with the capacity of self-renewal and aberrant differentiation for immortality and divergent lineages of cancer cells. In contrast to bulky tumor cells, CSCs remain less differentiated and resistant to therapy even when targeted with tissue-specific antigenic markers. This makes CSCs responsible for not only tumor initiation, development, but also tumor recurrence.

What are the topics you care about making trials in lupus more effective? Results of an Open Space meeting of international lupus experts.

Despite promising candidates for new therapeutic options in the treatment of systemic lupus erythematosus (SLE), many clinical trials have failed in the past few years. The disappointing results have been at least partly be attributed to trial designs. With the aim of stimulating new developments in SLE trial design, an international open space meeting was held on occasion of the European Lupus Meeting 2018 in Duesseldorf, Germany about 'What are the topics you care about for making trials in lupus more effective?'.

Mental health after paediatric concussion: a systematic review and meta-analysis.

Objective: This systematic review and meta-analysis sought to rigorously examine mental health outcomes following paediatric concussion. To date, heterogeneous findings and methodologies have limited clinicians' and researchers' ability to meaningfully synthesise existing literature. In this context, there is a need to clarify mental health outcomes in a homogeneous sample, controlling for key methodological differences and applying a consistent definition of concussion across studies.

Is a nudge all we need to promote deliberate clinical inertia and thoughtful clinical decision making?

Deliberate clinical inertia is the art of doing nothing as a positive response. Individual clinicians can promote deliberate clinical inertia through teaching, re-framing the act of 'doing nothing' as 'doing something' and engaging in shared decision making. Behaviour change on a larger scale requires a systematic approach.

Genetic prion disease: D178N with 129MV disease modifying polymorphism-a clinical phenotype.

Background: Human prion diseases are a group of rare neurological diseases with a minority due to genetic mutations in the prion protein (PRNP) gene. The D178N mutation is associated with both Creutzfeldt-Jakob disease and fatal familial insomnia with the phenotype modified by a polymorphism at codon 129 with the methionine/valine (MV) polymorphism associated with atypical presentations leading to diagnostic difficulty.

Case: We present a case of fatal familial insomnia secondary to a PRNP D178N mutation with 129MV disease modifying polymorphism who had no family history, normal MRI, electroencephalography (EEG), cerebrospinal fluid (CSF) and positron emission tomography findings and a negative real-time quaking-induced conversion result.

Potential biomarkers and challenges in glioma diagnosis, therapy and prognosis.

Gliomas are the most common central nervous system malignancies and present with significant morbidity and mortality. Treatment modalities are currently limited to surgical resection, chemotherapy and radiotherapy. Increases in survival rate over the previous decades are negligible, further pinpointing an unmet clinical need in this field.

Hidden in Plain Sight: The Moral Imperatives of Hippocrates' First Aphorism.

This historiographic survey of extant English translations and interpretations of the renowned Hippocratic first aphorism has demonstrated a concerning acceptance and application of ancient deontological principles that have been used to justify a practice of medicine that has been both paternalistic and heteronomous. Such principles reflect an enduring Hippocratism that has perpetuated an insufficient appreciation of the moral nature of the aphorism's second sentence in the practice of the art of medicine. That oversight has been constrained by a philological discourse that has centred on the meanings of the aphorism's first sentence, while little consideration has been given to the more important ethical consideration within the second sentence's imperatives.

Pulmonary alveolar stem cells undergo senescence, apoptosis and differentiation by p53-dependent and -independent mechanisms in telomerase deficient mice.

Pulmonary senescence and fibrosis occur with deoxyribonucleic acid (DNA) damage response in the lungs deficient of telomerase. The molecular mechanism mediating pulmonary alveolar cell fates remains to be investigated. The present study shows that pulmonary alveolar epithelial type 2 cells (AEC2) (alveolar stem cells) undergo not only replicative senescence, but also apoptosis and differentiation in association with increased innate immune natural killer (NK) cells in telomerase knockout (KO) mice.

Assessing the impact of smoking on the health and productivity of the working-age Indonesian population using modelling.

Objectives: To estimate the impact of smoking in the working-age Indonesian population in terms of costs, years of life, quality-adjusted life years (QALYs) and productivity-adjusted life years (PALYs) lost.

Methods: Life table modelling of Indonesian smokers aged 15-54 years, followed up until 55 years (retirement age). Contemporary data on demographics, all-cause mortality, population attributable fractions and prevalence of smoking were derived from the Institute for Health Metrics and Evaluation.

Barriers and enablers to the implementation of multidisciplinary team meetings: a qualitative study using the theoretical domains framework.

Background: Evidence-based clinical practice guidelines recommend discussion by a multidisciplinary team (MDT) to review and plan the management of patients for a variety of cancers. However, not all patients diagnosed with cancer are presented at an MDT.

Objectives: (1) To identify the factors (barriers and enablers) influencing presentation of all patients to, and the perceived value of, MDT meetings in the management of patients with pancreatic cancer and; (2) to identify potential interventions that could overcome modifiable barriers and enhance enablers using the theoretical domains framework (TDF).

Associations of metabolic syndrome in SLE.

Objectives: To characterise the prevalence and associations of metabolic syndrome (MetS) in a multiethnic cohort of patients with SLE.

Methods: Using a standardised protocol, baseline demographics, per visit disease activity (Systemic Lupus Erythematosus Disease Activity Index-2K) and treatment data, and annual recording of organ damage accrual (Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC-ACR) Damage Index) were captured on patients with SLE from a single tertiary centre. The presence of MetS, defined using modified updated joint consensus criteria, was assessed at the final visit from patient records.

Efficacy and safety of expectant management in the treatment of tubal ectopic pregnancy: a systematic review and meta-analysis.

Study Question: Is expectant management (EM) of tubal ectopic pregnancy (EP) an effective and safe treatment strategy when compared to alternative interventions?

Summary Answer: There is insufficient evidence to conclude EM yields a difference in the resolution of tubal EP, the avoidance of surgery or time to resolution of tubal EP when compared to intramuscular methotrexate in stable patients with β-hCG <1500 IU/l.

What Is Already Known: The utilisation of medical and surgical management for EP is well established. EM aims to allow spontaneous resolution of the EP without intervention.

Insight Derived from Molecular Dynamics Simulation into the Selectivity Mechanism Targeting G-Quadruplex.

Stabilizing G-quadruplex (G4) structures formed in the oncogene promoter represents a fundamental strategy for cancer therapy. However, most G4 stabilizers lack selectivity over various G4s in the genomes. By investigating the binding characteristics of a conjugated imidazole/carbazole (IZCZ-3) molecule with the G4s of , and telomere through molecular docking and molecular dynamics simulations, the present study demonstrates that though the binding affinities between IZCZ-3 and the monomeric G4s are inconsistent with the experimental data, the dimeric and G4s can be targeted by IZCZ-3 through forming concomitant π-π stacking interactions with the intermolecular assembly producing significant contributions to the binding affinity.

FBW7 Mediates Senescence and Pulmonary Fibrosis through Telomere Uncapping.

Tissue stem cells undergo premature senescence under stress, promoting age-related diseases; however, the associated mechanisms remain unclear. Here, we report that in response to radiation, oxidative stress, or bleomycin, the E3 ubiquitin ligase FBW7 mediates cell senescence and tissue fibrosis through telomere uncapping. FBW7 binding to telomere protection protein 1 (TPP1) facilitates TPP1 multisite polyubiquitination and accelerates degradation, triggering telomere uncapping and DNA damage response.

Supraglottic airway devices for administration of surfactant to newborn infants with respiratory distress syndrome: a narrative review.

Surfactant is an effective treatment for respiratory distress syndrome, being particularly important for infants in whom continuous positive airway pressure (CPAP) provides insufficient support. Supraglottic airway devices present an attractive option for surfactant delivery, particularly as an alternative to methods dependent on direct laryngoscopy, a procedural skill that is both difficult to learn and in which to maintain competence. Published studies provide encouraging data that surfactant administration by supraglottic airway device can be performed with a high rate of success and may reduce the need for subsequent intubation compared with either continued CPAP or surfactant administration via endotracheal tube.

The effects of hedgehog ligand neutralising antibody 5E1 in a mouse model of endometriosis.

Objective: Endometriosis is a common and painful condition characterised by the formation of endometrial lesions within the peritoneal cavity. Previous studies have suggested a role for hedgehog signalling in the pathogenesis of endometriosis. We investigated the role of hedgehog signalling in the establishment of endometriosis lesions using 5E1, a hedgehog ligand neutralising antibody, and a mouse model of endometriosis.

Major GI bleeding in older persons using aspirin: incidence and risk factors in the ASPREE randomised controlled trial.

Objective: There is a lack of robust data on significant gastrointestinal bleeding in older people using aspirin. We calculated the incidence, risk factors and absolute risk using data from a large randomised, controlled trial.

Design: Data were extracted from an aspirin versus placebo primary prevention trial conducted throughout 2010-2017 ('ASPirin in Reducing Events in the Elderly (ASPREE)', n=19 114) in community-dwelling persons aged ≥70 years.

Australian women's understanding of menopause and its consequences: a qualitative study.

Background: This study was undertaken to determine women's knowledge of menopause and its consequences, and their menopause-related health-care experiences.

Methods: Participants were recruited to this cross-sectional qualitative study from a nationally, representative sample of Australian women. Recruitment was stratified by age to achieve groups of premenopausal (PRE), perimenopausal (PERI), early postmenopausal (E-POST), and late postmenopausal (L-POST) women.