Associations between respiratory symptoms, lung function and gastro-oesophageal reflux symptoms in a population-based birth cohort

BACKGROUND: Several studies have reported an association between asthma and gastro-oesophageal reflux, but it is unclear which condition develops first. The role of obesity in mediating this association is also unclear. We explored the associations between respiratory symptoms, lung function, and gastro-oesophageal reflux symptoms in a birth cohort of approximately 1000 individuals. METHODS: Information on respiratory symptoms, asthma, atopy, lung function and airway responsiveness was obtained at multiple assessments from childhood to adulthood in an unselected birth cohort of 1037 individuals followed to age 26. Symptoms of gastro-oesophageal reflux and irritable bowel syndrome were recorded at age 26. RESULTS: Heartburn and acid regurgitation symptoms that were at least "moderately bothersome" at age 26 were significantly associated with asthma (odds ratio = 3.2; 95% confidence interval = 1.6–6.4), wheeze (OR = 3.5; 95% CI = 1.7–7.2), and nocturnal cough (OR = 4.3; 95% CI = 2.1–8.7) independently of body mass index. In women reflux symptoms were also associated with airflow obstruction and a bronchodilator response to salbutamol. Persistent wheezing since childhood, persistence of asthma since teenage years, and airway hyperresponsiveness since age 11 were associated with a significantly increased risk of heartburn and acid regurgitation at age 26. There was no association between irritable bowel syndrome and respiratory symptoms. CONCLUSION: Reflux symptoms are associated with respiratory symptoms in young adults independently of body mass index. The mechanism of these associations remains unclear

Stabilizing entanglement autonomously between two superconducting qubits

Quantum error-correction codes would protect an arbitrary state of a multi-qubit register against decoherence-induced errors, but their implementation is an outstanding challenge for the development of large-scale quantum computers. A first step is to stabilize a non-equilibrium state of a simple quantum system such as a qubit or a cavity mode in the presence of decoherence. Several groups have recently accomplished this goal using measurement-based feedback schemes. A next step is to prepare and stabilize a state of a composite system. Here we demonstrate the stabilization of an entangled Bell state of a quantum register of two superconducting qubits for an arbitrary time. Our result is achieved by an autonomous feedback scheme which combines continuous drives along with a specifically engineered coupling between the two-qubit register and a dissipative reservoir. Similar autonomous feedback techniques have recently been used for qubit reset and the stabilization of a single qubit state, as well as for creating and stabilizing states of multipartite quantum systems. Unlike conventional, measurement-based schemes, an autonomous approach counter-intuitively uses engineered dissipation to fight decoherence, obviating the need for a complicated external feedback loop to correct errors, simplifying implementation. Instead the feedback loop is built into the Hamiltonian such that the steady state of the system in the presence of drives and dissipation is a Bell state, an essential building-block state for quantum information processing. Such autonomous schemes, broadly applicable to a variety of physical systems as demonstrated by a concurrent publication with trapped ion qubits, will be an essential tool for the implementation of quantum-error correction.Comment: 39 pages, 7 figure

Kinome rewiring reveals AURKA limits PI3K-pathway inhibitor efficacy in breast cancer.

Dysregulation of the PI3K-AKT-mTOR signaling network is a prominent feature of breast cancers. However, clinical responses to drugs targeting this pathway have been modest, possibly because of dynamic changes in cellular signaling that drive resistance and limit drug efficacy. Using a quantitative chemoproteomics approach, we mapped kinome dynamics in response to inhibitors of this pathway and identified signaling changes that correlate with drug sensitivity. Maintenance of AURKA after drug treatment was associated with resistance in breast cancer models. Incomplete inhibition of AURKA was a common source of therapy failure, and combinations of PI3K, AKT or mTOR inhibitors with the AURKA inhibitor MLN8237 were highly synergistic and durably suppressed mTOR signaling, resulting in apoptosis and tumor regression in vivo. This signaling map identifies survival factors whose presence limits the efficacy of targeted therapies and reveals new drug combinations that may unlock the full potential of PI3K-AKT-mTOR pathway inhibitors in breast cancer

GMOs: Non-Health Issues

The controversy over genetically modified [GM] organisms is often framed in terms of possible hazards for human health. Articles in a previous volume of this *Encyclopedia* give a general overview of GM crops [@Mulvaney2014] and specifically examine human health [@Nordgard2014] and labeling [@Bruton2014] issues surrounding GM organisms. This article explores several other aspects of the controversy: environmental concerns, political and legal disputes, and the aim of "feeding the world" and promoting food security. Rather than discussing abstract, hypothetical GM organisms, this article explores the consequences of the GM organisms that have actually been deployed in the particular contexts that they have been deployed, on the belief that there is little point in discussing GM organisms in an idealized or context-independent way

Rationale and design of the NODE-303 study: evaluating the safety of symptom-prompted, self-administered etripamil for paroxysmal supraventricular tachycardia episodes in real-world settings.

BACKGROUND: Paroxysmal supraventricular tachycardia (PSVT) is a common episodic arrhythmia characterized by unpredictable onset and burdensome symptoms including palpitations, dizziness, chest pain, distress, and shortness of breath. Treatment of acute episodes of PSVT in the clinical setting consists of intravenous adenosine, beta-blockers, and calcium channel blockers (CCBs). Etripamil is an intranasally self-administered L-type CCB in development for acute treatment of AV-nodal dependent PSVT in a nonmedical supervised setting. METHODS: This paper summarizes the rationale and study design of NODE-303 that will assess the efficacy and safety of etripamil. In the randomized, double-blinded, placebo-controlled, Phase 3 RAPID trial, etripamil was superior to placebo in the conversion of single PSVT episodes by 30 minutes post initial dose when administered in the nonhealthcare setting; this study required a mandatory and observed test dosing prior to randomization. The primary objective of NODE-303 is to evaluate the safety of symptom-prompted, self-administered etripamil for multiple PSVT episodes in real-world settings, without the need for test dosing prior to first use during PSVT. Secondary endpoints include efficacy and disease burden. Upon perceiving a PSVT episode, the patient applies an electrocardiographic monitor, performs a vagal maneuver, and, if the vagal maneuver is unsuccessful, self-administers etripamil 70 mg, with an optional repeat dose if symptoms do not resolve within 10 minutes after the first dose. A patient may treat up to four PSVT episodes during the study. Adverse events are recorded as treatment-emergent if they occur within 24 hours after the administration of etripamil. RESULTS: Efficacy endpoints include time to conversion to sinus rhythm within 30 and 60 minutes after etripamil administration, and the proportion of patients who convert at 3, 5, 10, 20, 30, and 60 minutes. Patient-reported outcomes are captured by the Brief Illness Perception Questionnaire, the Cardiac Anxiety Questionnaire, the Short Form Health Survey 36, the Treatment Satisfaction Questionnaire for Medication and a PSVT survey. CONCLUSIONS: Overall, these data will support the development of a potentially paradigm-changing long-term management strategy for recurrent PSVT

Psychosocial impact of implantable cardioverter defibrillators (ICD) in young adults with Tetralogy of Fallot

Item does not contain fulltextOBJECTIVE: To investigate the psychosocial impact of having an implantable cardioverter defibrillator (ICD) in adults with Tetralogy of Fallot (ToF). METHODS: Included were 26 ToF-patients with an ICD (age 44 +/- 12 years), and two control groups consisting of 28 ToF-patients without an ICD (age 40 +/- 10 years) and a group of 35 ICD-patients of older age without ToF (age 72.0 +/- 8 years). This last control group was chosen to represent the "older general ICD population" with acquired heart disease seen at the out-patient clinic. Psychosocial functioning encompassed daily functioning, subjective health status, quality of life, anxiety, depression, coping and social support. RESULTS: ToF-patients with ICD showed diminished psychosocial functioning in comparison to ToF-patients without ICD. This was reflected by diminished subjectively perceived physical functioning (p = 0.01), general health perception (p < 0.01) and a lower satisfaction with life (p = 0.02). In comparison to older ICD-patients, ToF-patients with ICD showed less satisfaction with life (p = 0.03), experienced more anxiety (p = 0.01) and showed less favourable coping styles, although physical functioning was better for ToF-patients with ICD than for older ICD-patients (p = 0.01). More inappropriate shocks were found in ToF-patients with ICD compared to the older ICD-patients. CONCLUSION: In patients with ToF, ICD implantation had a major impact on psychosocial functioning which should be taken into account when considering ICD implantation in these young patients. To help improve psychosocial functioning, psychological counselling attuned to the specific needs of these patients may be useful.1 juli 201

Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD

Assessment of risk of insect-resistant transgenic crops to nontarget arthropods

An international initiative is developing a scientifically rigorous approach to evaluate the potential risks to nontarget arthropods (NTAs) posed by insect-resistant, genetically modified (IRGM) crops. It adapts the tiered approach to risk assessment that is used internationally within regulatory toxicology and environmental sciences. The approach focuses on the formulation and testing of clearly stated risk hypotheses, making maximum use of available data and using formal decision guidelines to progress between testing stages (or tiers). It is intended to provide guidance to regulatory agencies that are currently developing their own NTA risk assessment guidelines for IRGM crops and to help harmonize regulatory requirements between different countries and different regions of the world

Hypoxia and hypoxia inducible factor-1α are required for normal endometrial repair during menstruation

About a quarter of pre-menopausal women will suffer from heavy menstrual bleeding in their lives. Here, Maybin and colleagues show hypoxia and subsequent activation of HIF-1α during menses are required for normal endometrial repair, and identify pharmacological stabilisation of HIF-1α as a potential therapeutic strategy for this debilitating condition

Search for Gravitational Waves from Primordial Black Hole Binary Coalescences in the Galactic Halo

We use data from the second science run of the LIGO gravitational-wave detectors to search for the gravitational waves from primordial black hole (PBH) binary coalescence with component masses in the range 0.2--$1.0 M_\odot$. The analysis requires a signal to be found in the data from both LIGO observatories, according to a set of coincidence criteria. No inspiral signals were found. Assuming a spherical halo with core radius 5 kpc extending to 50 kpc containing non-spinning black holes with masses in the range 0.2--$1.0 M_\odot$, we place an observational upper limit on the rate of PBH coalescence of 63 per year per Milky Way halo (MWH) with 90% confidence.Comment: 7 pages, 4 figures, to be submitted to Phys. Rev.