Design, Synthesis, and Biological Evaluation of a New Series of Carvedilol Derivatives That Protect Sensory Hair Cells from Aminoglycoside-Induced Damage by Blocking the Mechanoelectrical Transducer Channel.

Aminoglycosides (AGs) are broad-spectrum antibiotics used for the treatment of serious bacterial infections but have use-limiting side effects including irreversible hearing loss. Here, we assessed the otoprotective profile of carvedilol in mouse cochlear cultures and in vivo zebrafish assays and investigated its mechanism of protection which, we found, may be mediated by a block of the hair cell's mechanoelectrical transducer (MET) channel, the major entry route for the AGs. To understand the full otoprotective potential of carvedilol, a series of 18 analogues were prepared and evaluated for their effect against AG-induced damage as well as their affinity for the MET channel.

Alcohol Use Thresholds for Identifying Alcohol-related Problems Before and Following Roux-en-Y Gastric Bypass.

Objective: The aim of this study was to determine the sensitivity and specificity of potential thresholds of alcohol use for identifying alcohol-related problems in women post-Roux-en-Y gastric bypass (RYGB).

Background: Despite evidence that RYGB alters alcohol pharmacokinetics and is associated with an increased risk for alcohol-related problems, the level of alcohol use that should prompt further screening for alcohol-related problems following RYGB is unclear.

Methods: The Longitudinal Assessment of Bariatric Surgery-2 is a prospective cohort study.

Do Associations Between Alcohol Use and Alcohol Use Disorder Vary by Weight Status? Results From the National Epidemiologic Survey on Alcohol and Related Conditions-III.

Background: Understanding whether the associations between alcohol use and alcohol use disorder (AUD) differ by weight status may be useful in screening for AUD in populations where obesity is common. We aimed to determine whether the associations between alcohol use and AUD differ by weight status.

Methods: A total of 24,869 adult participants of the National Epidemiologic Survey on Alcohol and Related Conditions-III with a body mass index ≥18.

Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH): a stepped-wedge cluster-randomised trial.

Background: Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients.

Methods: We did a stepped-wedge cluster-randomised trial of patients aged 40 years or older undergoing emergency open major abdominal surgery.

Correction to: Which Costs Matter? Costs Included in Economic Evaluation and their Impact on Decision Uncertainty for Stable Coronary Artery Disease.

The original article can be found online.

Pharmacological clearance of senescent cells improves survival and recovery in aged mice following acute myocardial infarction.

Cardiovascular disease is the leading cause of death in individuals over 60 years old. Aging is associated with an increased prevalence of coronary artery disease and a poorer prognosis following acute myocardial infarction (MI). With age, senescent cells accumulate in tissues, including the heart, and contribute to age-related pathologies.

Creating sustainable health care systems.

Purpose: In order to create sustainable health systems, many countries are introducing ways to prioritise health services underpinned by a process of health technology assessment. While this approach requires technical judgements of clinical effectiveness and cost effectiveness, these are embedded in a wider set of social (societal) value judgements, including fairness, responsiveness to need, non-discrimination and obligations of accountability and transparency. Implementing controversial decisions faces legal, political and public challenge.

Human Cardiac-Mesenchymal Stem Cell-Like Cells, a Novel Cell Population with Therapeutic Potential.

Cardiac stem/progenitors are being used in the clinic to treat patients with a range of cardiac pathologies. However, improvements in heart function following treatment have been reported to be variable, with some showing no response. This discrepancy in response remains unresolved.

Cerebrovascular Smooth Muscle Cells as the Drivers of Intramural Periarterial Drainage of the Brain.

The human brain is the organ with the highest metabolic activity but it lacks a traditional lymphatic system responsible for clearing waste products. We have demonstrated that the basement membranes of cerebral capillaries and arteries represent the lymphatic pathways of the brain along which intramural periarterial drainage (IPAD) of soluble metabolites occurs. Failure of IPAD could explain the vascular deposition of the amyloid-beta protein as cerebral amyloid angiopathy (CAA), which is a key pathological feature of Alzheimer's disease.

Length-independent telomere damage drives post-mitotic cardiomyocyte senescence.

Ageing is the biggest risk factor for cardiovascular disease. Cellular senescence, a process driven in part by telomere shortening, has been implicated in age-related tissue dysfunction. Here, we address the question of how senescence is induced in rarely dividing/post-mitotic cardiomyocytes and investigate whether clearance of senescent cells attenuates age-related cardiac dysfunction.

Beliefs and attitudes regarding prenatal marijuana use: Perspectives of pregnant women who report use.

Objective: With the increasingly permissive legal and social environments regarding marijuana, it is important to understand prenatal marijuana use from the perspective of women who use marijuana. Our objective was to qualitatively describe the marijuana use experiences, beliefs, and attitudes of women who used marijuana during pregnancy.

Methods: We conducted semi-structured interviews with pregnant women who had either reported current marijuana use or had urine testing positive for marijuana.

Spontaneous Otoacoustic Emissions in Mice Reflect Changes in Cochlear Amplification and How It Is Controlled by the Tectorial Membrane.

Spontaneous otoacoustic emissions (SOAEs) recorded from the ear canal in the absence of sound reflect cochlear amplification, an outer hair cell (OHC) process required for the extraordinary sensitivity and frequency selectivity of mammalian hearing. Although wild-type mice rarely emit, those with mutations that influence the tectorial membrane (TM) show an incidence of SOAEs similar to that in humans. In this report, we characterized mice with a missense mutation in a gene required for the formation of the striated-sheet matrix within the core of the TM.

Hair-Bundle Links: Genetics as the Gateway to Function.

Up to five distinct cell-surface specializations interconnect the stereocilia and the kinocilium of the mature hair bundle in some species: kinocilial links, tip links, top connectors, shaft connectors, and ankle links. In developing hair bundles, transient lateral links are prominent. Mutations in genes encoding proteins associated with these links cause Usher deafness/blindness syndrome or nonsyndromic (isolated) forms of human hereditary deafness, and mice with constitutive or conditional alleles of these genes have provided considerable insight into the molecular composition and function of the different links.

Enhancing Social-Emotional Health and Wellbeing in the Early Years (E-SEE): a study protocol of a community-based randomised controlled trial with process and economic evaluations of the incredible years infant and toddler parenting programmes, delivered in a proportionate universal model.

Introduction: Behavioural and mental disorders have become a public health crisis and by 2020 may surpass physical illness as a major cause of disability. Early prevention is key. Two Incredible Years (IY) parent programmes that aim to enhance child well-being and development, IY Infant and IY Toddler, will be delivered and evaluated in a proportionate universal intervention model called Enhancing Social-Emotional Health and Wellbeing in the Early Years (E-SEE) Steps.

Quantifying the impact of partial measurement invariance in diagnostic research: An application to addiction research.

Establishing measurement invariance, or that an instrument measures the same construct(s) in the same way across subgroups of respondents, is crucial in efforts to validate social and behavioral instruments. Although substantial previous research has focused on detecting the presence of noninvariance, less attention has been devoted to its practical significance and even less has been paid to its possible impact on diagnostic accuracy. In this article, we draw additional attention to the importance of measurement invariance and advance diagnostic research by introducing a novel approach for quantifying the impact of noninvariance with binary items (e.

Rapamycin improves healthspan but not inflammaging in nfκb1 mice.

Increased activation of the major pro-inflammatory NF-κB pathway leads to numerous age-related diseases, including chronic liver disease (CLD). Rapamycin, an inhibitor of mTOR, extends lifespan and healthspan, potentially via suppression of inflammaging, a process which is partially dependent on NF-κB signalling. However, it is unknown if rapamycin has beneficial effects in the context of compromised NF-κB signalling, such as that which occurs in several age-related chronic diseases.

A Risk Assessment Framework for the Socioeconomic Impacts of Electricity Transmission Infrastructure Failure Due to Space Weather: An Application to the United Kingdom.

Space weather phenomena have been studied in detail in the peer-reviewed scientific literature. However, there has arguably been scant analysis of the potential socioeconomic impacts of space weather, despite a growing gray literature from different national studies, of varying degrees of methodological rigor. In this analysis, we therefore provide a general framework for assessing the potential socioeconomic impacts of critical infrastructure failure resulting from geomagnetic disturbances, applying it to the British high-voltage electricity transmission network.

Economic Evaluation of Environmental Interventions: Reflections on Methodological Challenges and Developments.

Evaluation of the costs and outcomes associated with environmental policies and interventions is often required to inform public policy and allocate scarce resources. Methods to conduct assessments of cost-effectiveness have been developed in the context of pharmaceuticals, but have more recently been applied in public health, diagnostics, and other more complex interventions. The suitability of existing economic evaluation methodology has been explored in many contexts, however, this is yet to be undertaken for interventions and policies pertaining to the natural environment, such as urban green spaces and strategies to reduce indoor and outdoor air pollution.

Prenatal alcohol exposure and offspring alcohol use and misuse at 22 years of age: A prospective longitudinal study.

Studies have shown that prenatal alcohol exposure (PAE) is related to drinking problems during adulthood, but the level of prenatal exposure associated with young adults' quantity and frequency of alcohol use and drinking problems has not yet been established. The relation between PAE and offspring levels of alcohol use and alcohol abuse/dependency was examined in 608 22-year-olds. Mothers were recruited in early pregnancy and maternal alcohol use data were collected for each trimester of pregnancy.

The Role of CD38 on the Function of Regulatory B Cells in a Murine Model of Lupus.

Previous work from our group has shown that mice develop a milder pristane-induced lupus disease than WT or counterparts, demonstrating a new role for CD38 in promoting aberrant inflammation and lupus-like autoimmunity via a Transient Receptor Potential Melastatin 2 (TRPM2)-dependent apoptosis-driven mechanism. In this study we asked whether CD38 may play a role in the expression and function of regulatory B cells (IL-10-producing B cells or B10 cells). In pristane-treated mice the frequency of spleen CD19⁺CD1dCD5⁺ B cells, which are highly enriched in B10 cells, was significantly increased in splenocytes compared to WT, while the frequency of peritoneal plasmacytoid dendritic cells (pDCs), which are major type I Interferon (IFN) producers, was greatly diminished.

Establishing Heat Alert Thresholds for the Varied Climatic Regions of British Columbia, Canada.

Following an extreme heat event in 2009, a Heat Alert and Response System (HARS) was implemented for the greater Vancouver area of British Columbia (BC), Canada. This system has provided a framework for guiding public health interventions and assessing population response and adaptation to extreme heat in greater Vancouver, but no other parts of BC were covered by HARS. The objective of this study was to identify evidence-based heat alert thresholds for the Southwest, Southeast, Northwest, and Northeast regions to facilitate the introduction of HARS across BC.

Chemotherapy and biologic use in the routine management of metastatic colorectal cancer in Australia: is clinical practice following the evidence?

Background: Emerging evidence on the optimal use of chemotherapy and biologics in patients with metastatic colorectal cancer should impact management in routine care. Recent studies have demonstrated benefits for initial triplet chemotherapy (5-fluorouracil, oxaliplatin and irinotecan, FOLFOXIRI) and for initial treatment with an epidermal growth factor receptor inhibitor (EGFRi) in patients with a RAS wild-type tumour and a left-sided primary tumour.

Aim: To explore evolving pattern of metastatic colorectal cancer care over time in Australia.

Trajectories of pre- and postnatal co-use of cannabis and tobacco predict co-use and drug use disorders in adult offspring.

Co-use of cannabis and tobacco is increasingly common among women and is associated with tobacco and cannabis dependence and poorer cessation outcomes. However, no study has examined maternal patterns of co-use over time, or the impact of maternal co-use on co-use and drug problems in adult offspring. Pregnant women (M age = 23, range = 18-42; 52% African American, 48% White) were asked about substance use during each trimester of pregnancy, and at 8 and 18 months, 3, 6, 10, 14, 16, and 22 years postpartum.