Management of everolimus-associated adverse events in patients with tuberous sclerosis complex: a practical guide

Tuberous sclerosis complex (TSC) is a genetic disorder characterised by highly variable comorbid dysfunction and subsequent morbidity. The mTOR inhibitor everolimus is indicated for the treatment of adult TSC patients with renal angiomyolipomas (AMLs) and for subependymal giant astrocytoma (SEGA) in both adults and children, based on data from the EXIST-1 and EXIST-2 trials. However, due to the historical predominance of everolimus in the oncology setting, some physicians who treat TSC patients may be unfamiliar with everolimus-associated adverse events (AEs) and appropriate management strategies. This article aims to serve as a resource for specialists including nephrologists, paediatricians, neurologists and geneticists who require practical guidance on the management of events such as non-infectious pneumonitis, rash, stomatitis, infections, and renal AEs. Additional consideration is given to drug interactions, hepatic impairment, fertility, and sexual maturation. Since patients with TSC receive clinical benefit from continued therapy, it is important that everolimus-related events are dealt with appropriately through strategies such as dose modification, interruption, the provision of supportive care, regular monitoring, and patient education

Selection Criteria for the Radical Treatment of Locally Advanced Rectal Cancer

There are over 14,000 newly diagnosed rectal cancers per year in the United Kingdom of which between 50 and 64 percent are locally advanced (T3/T4) at presentation. Pelvic exenterative surgery was first described by Brunschwig in 1948 for advanced cervical cancer, but early series reported high morbidity and mortality. This approach was later applied to advanced primary rectal carcinomas with contemporary series reporting 5-year survival rates between 32 and 66 percent and to recurrent rectal carcinoma with survival rates of 22–42%. The Swansea Pelvic Oncology Group was established in 1999 and is involved in the assessment and management of advanced pelvic malignancies referred both regionally and UK wide. This paper will set out the selection, assessment, preparation, surgery, and outcomes from pelvic exenterative surgery for locally advanced primary rectal carcinomas

The use of chilled condensers for the recovery of perfluorocarbon liquid in an experimental model of perfluorocarbon vapour loss during neonatal partial liquid ventilation

Background: Perfluorocarbon (PFC) vapour in the expired gases during partial liquid ventilation should be prevented from entering the atmosphere and recovered for potential reuse. This study aimed to determine how much PFC liquid could be recovered using a conventional humidified neonatal ventilator with chilled condensers in place of the usual expiratory ventilator circuit and whether PFC liquid could be recovered when using the chilled condensers at the ventilator exhaust outlet. Methods: Using a model lung, perfluorocarbon vapour loss during humidified partial liquid ventilation of a 3.5 kg infant was approximated. For each test 30 mL of FC-77 was infused into the model lung. Condensers were placed in the expiratory limb of the ventilator circuit and the amounts of PFC (FC-77) and water recovered were measured five times. This was repeated with the condensers placed at the ventilator exhaust outlet. Results: When the condensers were used as the expiratory limb, the mean (± SD) volume of FC77 recovered was 16.4 mL (± 0.18 mL). When the condensers were connected to the ventilator exhaust outlet the mean (± SD) volume of FC-77 recovered was 7.6 mL (± 1.14 mL). The volume of FC-77 recovered was significantly higher when the condenser was used as an expiratory limb. Conclusion: Using two series connected condensers in the ventilator expiratory line 55% of PFC liquid (FC-77) can be recovered during partial liquid ventilation without altering the function of the ventilator circuit. This volume of PFC recovered was just over twice that recovered with the condensers connected to the ventilator exhaust outlet

Municipal Ethical Standards: The Need for a New Approach Report

The New York State Commission on Government Integrity investigated numerous situations throughout the state that revealed just how bad the current law is. Our findings and a pro- posed municipal ethics act that we drafted to correct the law\u27s deficiencies are contained in the following report, Municipal Ethical Standards: The Need for a New Approach. Our pro- posed Act would set out the minimum ethical standards that should be observed in every municipality throughout the state. The premise here is that there are certain basic features to good government that make sense for all governments, no matter what their size or location - rural or suburban, upstate or downstate. If the proposed Act became law, localities would be able to enact more stringent regulations if they wanted to, but no local government could have standards that fell below the floor put in place by the Act. The Governor has had a bill introduced in the Legislature that is patterned after the law we proposed. The State Assembly has held public hearings on the bill and it is hopeful that in the 1990 legislative session, New Yorkers will get the strong municipal ethics law they need and deserve

Cooling of cryogenic electron bilayers via the Coulomb interaction

Heat dissipation in current-carrying cryogenic nanostructures is problematic because the phonon density of states decreases strongly as energy decreases. We show that the Coulomb interaction can prove a valuable resource for carrier cooling via coupling to a nearby, cold electron reservoir. Specifically, we consider the geometry of an electron bilayer in a silicon-based heterostructure, and analyze the power transfer. We show that across a range of temperatures, separations, and sheet densities, the electron-electron interaction dominates the phonon heat-dissipation modes as the main cooling mechanism. Coulomb cooling is most effective at low densities, when phonon cooling is least effective in silicon, making it especially relevant for experiments attempting to perform coherent manipulations of single spins.Comment: 9 pages, 5 figure

Reviews and contestability: new directions for Defence

Overview: The First Principles Review of Defence is arguably the most significant review of the defence establishment since the 1973 re-organisation led by Sir Arthur Tange. This Strategic Insights brings together a series of contributions to ASPI’s blog The Strategist written by ten experts with long experience and broad knowledge of Australia’s defence bureaucracy. They bring a wealth of different perspectives and point to significant challenges ahead for Defence if the reforms proposed by the First Principles Review are to succeed

Constructing a Geodynamic A Priori Seismic (GAPS) velocity model of upper mantle heterogeneity

Seismic studies of the deep mantle suffer from the fact that the probing seismic waves must traverse the highly heterogeneous and poorly resolved shallow structure. One potential way forward is to develop high-resolution models of the crust and upper mantle using other information. Here we describe the construction of a geodynamic a priori model of some aspects of upper mantle seismic velocity heterogeneity. It is based on an equal area tomographic grid and it has been produced at two scales, a 1° × 1° resolution at the equator, (i.e., each cell has an approximate dimension of 100 km by 100 km), and a 5° × 5° resolution at the equator. Both have a constant layer thickness of 100 km. Currently, the model accommodates the subducting lithosphere and global variation in continental crustal thickness and age of oceanic lithosphere. The shape of subducting oceanic lithosphere was derived from profiles through seismicity. The shape was combined with estimates of plate velocities and age of subducting lithosphere using an analytic solution of the thermal field to define the slab thermal anomaly. The temperature perturbation was converted to a slowness (1/velocity) perturbation. For oceanic lithosphere, a plate-cooling model was used to convert lithosphere age to slowness perturbation via a temperature perturbation. The variation in the thickness of continental crust, around a global average, formed the third element of the slowness perturbation model. This model has already been applied in a high-resolution mantle tomographic study of lower mantle heterogeneity