REGULATORY APPROVAL OF NEW MEDICAL DEVICES: A CROSS SECTIONAL STUDY

Objective To investigate the regulatory approval of new medical devices. Design Cross sectional study of new medical devices reported in the biomedical literature. Data sources PubMed was searched between 1 January 2000 and 31 December 2004 to identify clinical studies of new medical devices. The search was carried out during this period to allow time for regulatory approval. Eligibility criteria for study selection Articles were included if they reported a clinical study of a new medical device and there was no evidence of a previous clinical study in the literature. We defined a medical device according to the US Food and Drug Administration as an “instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article.” Main outcome measures Type of device, target specialty, and involvement of academia or of industry for each clinical study. The FDA medical databases were then searched for clearance or approval relevant to the device. Results 5574 titles and abstracts were screened, 493 full text articles assessed for eligibility, and 218 clinical studies of new medical devices included. In all, 99/218 (45%) of the devices described in clinical studies ultimately received regulatory clearance or approval. These included 510(k) clearance for devices determined to be “substantially equivalent” to another legally marketed device (78/99; 79%), premarket approval for high risk devices (17/99; 17%), and others (4/99; 4%). Of these, 43 devices (43/99; 43%) were actually cleared or approved before a clinical study was published. Conclusions We identified a multitude of new medical devices in clinical studies, almost half of which received regulatory clearance or approval. The 510(k) pathway was most commonly used, and clearance often preceded the first published clinical study

Skeletal muscle cells possess a 'memory' of acute early life TNF-α exposure: role of epigenetic adaptation.

Sufficient quantity and quality of skeletal muscle is required to maintain lifespan and healthspan into older age. The concept of skeletal muscle programming/memory has been suggested to contribute to accelerated muscle decline in the elderly in association with early life stress such as fetal malnutrition. Further, muscle cells in vitro appear to remember the in vivo environments from which they are derived (e.g. cancer, obesity, type II diabetes, physical inactivity and nutrient restriction). Tumour-necrosis factor alpha (TNF-α) is a pleiotropic cytokine that is chronically elevated in sarcopenia and cancer cachexia. Higher TNF-α levels are strongly correlated with muscle loss, reduced strength and therefore morbidity and earlier mortality. We have extensively shown that TNF-α impairs regenerative capacity in mouse and human muscle derived stem cells [Meadows et al. (J Cell Physiol 183(3):330-337, 2000); Foulstone et al. (J Cell Physiol 189(2):207-215, 2001); Foulstone et al. (Exp Cell Res 294(1):223-235, 2004); Stewart et al. (J Cell Physiol 198(2):237-247, 2004); Al-Shanti et al. (Growth factors (Chur, Switzerland) 26(2):61-73, 2008); Saini et al. (Growth factors (Chur, Switzerland) 26(5):239-253, 2008); Sharples et al. (J Cell Physiol 225(1):240-250, 2010)]. We have also recently established an epigenetically mediated mechanism (SIRT1-histone deacetylase) regulating survival of myoblasts in the presence of TNF-α [Saini et al. (Exp Physiol 97(3):400-418, 2012)]. We therefore wished to extend this work in relation to muscle memory of catabolic stimuli and the potential underlying epigenetic modulation of muscle loss. To enable this aim; C2C12 myoblasts were cultured in the absence or presence of early TNF-α (early proliferative lifespan) followed by 30 population doublings in the absence of TNF-α, prior to the induction of differentiation in low serum media (LSM) in the absence or presence of late TNF-α (late proliferative lifespan). The cells that received an early plus late lifespan dose of TNF-α exhibited reduced morphological (myotube number) and biochemical (creatine kinase activity) differentiation vs. control cells that underwent the same number of proliferative divisions but only a later life encounter with TNF-α. This suggested that muscle cells had a morphological memory of the acute early lifespan TNF-α encounter. Importantly, methylation of myoD CpG islands were increased in the early TNF-α cells, 30 population doublings later, suggesting that even after an acute encounter with TNF-α, the cells have the capability of retaining elevated methylation for at least 30 cellular divisions. Despite these fascinating findings, there were no further increases in myoD methylation or changes in its gene expression when these cells were exposed to a later TNF-α dose suggesting that this was not directly responsible for the decline in differentiation observed. In conclusion, data suggest that elevated myoD methylation is retained throughout muscle cells proliferative lifespan as result of early life TNF-α treatment and has implications for the epigenetic control of muscle loss

Nonlinearity in a dynamo

Using a rotating flat layer heated from below as an example, we consider effects which lead to stabilizing an exponentially growing magnetic field in magnetostrophic convection in transition from the kinematic dynamo to the full non-linear dynamo. We present estimates of the energy redistribution over the spectrum and helicity quenching by the magnetic field. We also study the alignment of the velocity and magnetic fields. These regimes are similar to those in planetary dynamo simulations.Comment: Accepted to Geophys. Astrophys. Fluid Dyna

Uniformly Accelerated Observer in Moyal Spacetime

In Minkowski space, an accelerated reference frame may be defined as one that is related to an inertial frame by a sequence of instantaneous Lorentz transformations. Such an accelerated observer sees a causal horizon, and the quantum vacuum of the inertial observer appears thermal to the accelerated observer, also known as the Unruh effect. We argue that an accelerating frame may be similarly defined (i.e. as a sequence of instantaneous Lorentz transformations) in noncommutative Moyal spacetime, and discuss the twisted quantum field theory appropriate for such an accelerated observer. Our analysis shows that there are several new features in the case of noncommutative spacetime: chiral massless fields in $(1+1)$ dimensions have a qualitatively different behavior compared to massive fields. In addition, the vacuum of the inertial observer is no longer an equilibrium thermal state of the accelerating observer, and the Bose-Einstein distribution acquires $\theta$-dependent corrections.Comment: 19 pages. Typos correcte

Planning and developing a web-based intervention for active surveillance in prostate cancer: an integrated self-care programme for managing psychological distress

Objectives: To outline the planning, development and optimisation of a psycho-educational behavioural intervention for patients on active surveillance for prostate cancer. The intervention aimed to support men manage active surveillance-related psychological distress. / Methods: The person-based approach (PBA) was used as the overarching guiding methodological framework for intervention development. Evidence-based methods were incorporated to improve robustness. The process commenced with data gathering activities comprising the following four components: • A systematic review and meta-analysis of depression and anxiety in prostate cancer • A cross-sectional survey on depression and anxiety in active surveillance • A review of existing interventions in the field • A qualitative study with the target audience The purpose of this paper is to bring these components together and describe how they facilitated the establishment of key guiding principles and a logic model, which underpinned the first draft of the intervention. / Results: The prototype intervention, named PROACTIVE, consists of six Internet-based sessions run concurrently with three group support sessions. The sessions cover the following topics: lifestyle (diet and exercise), relaxation and resilience techniques, talking to friends and family, thoughts and feelings, daily life (money and work) and information about prostate cancer and active surveillance. The resulting intervention has been trialled in a feasibility study, the results of which are published elsewhere. / Conclusions: The planning and development process is key to successful delivery of an appropriate, accessible and acceptable intervention. The PBA strengthened the intervention by drawing on target-user experiences to maximise acceptability and user engagement. This meticulous description in a clinical setting using this rigorous but flexible method is a useful demonstration for others developing similar interventions. / Trial registration and Ethical Approval: ISRCTN registered: ISRCTN38893965. NRES Committee South Central – Oxford A. REC reference: 11/SC/0355

Using a Kinect Interface to Develop an Interactive 3D Tabletop Display

Since the release of the motion picture ’Minority Report’ in 2002, which depicts Tom Cruise interacting with a video display using only hand gestures, there has been a significant interest in the development of intelligent display technology, that users are able to interact with using gestures. In the real world it is common place for us to use gestures and body language to re-enforce our communication. It therefore becomes very natural for us to want to interact with our virtual media in the same way. Traditional methods for pose recognition involve using cameras to track the position of the user. However this can be very challenging to complete acurately in a variety of environments where camera can become occluded or the lighting conditions can change. In this research we prototyped a 3D tabletop display and explored the Kinect game controller as a possible solution to tracking the pose and gesture of a user whilst interacting with our display

Assessment of valley cold pools and clouds in a very high-resolution numerical weather prediction model

The formation of cold air pools in valleys under stable conditions represents an important challenge for numerical weather prediction (NWP). The challenge is increased when the valleys that dominate cold pool formation are on scales unresolved by NWP models, which can lead to substantial local errors in temperature forecasts. In this study a 2-month simulation is presented using a nested model con- figuration with a finest horizontal grid spacing of 100 m. The simulation is compared with observations from the recent COLd air Pooling Experiment (COLPEX) project and the model’s ability to represent cold pool formation, and the surface energy balance is assessed. The results reveal a bias in the model long-wave radiation that results from the assumptions made about the sub-grid variability in humidity in the cloud parametrization scheme. The cloud scheme assumes relative humidity thresholds below 100 % to diagnose partial cloudiness, an approach common to schemes used in many other models. The biases in radiation, and resulting biases in screen temperature and cold pool properties are shown to be sensitive to the choice of critical relative humidity, suggesting that this is a key area that should be improved for very high-resolution modeling

Longevity and skeletal muscle mass: the role of IGF signalling, the sirtuins, dietary restriction and protein intake.

Advancing age is associated with a progressive loss of skeletal muscle (SkM) mass and function. Given the worldwide aging demographics, this is a major contributor to morbidity, escalating socio-economic costs and ultimately mortality. Previously, it has been established that a decrease in regenerative capacity in addition to SkM loss with age coincides with suppression of insulin/insulin-like growth factor signalling pathways. However, genetic or pharmacological modulations of these highly conserved pathways have been observed to significantly enhance life and healthspan in various species, including mammals. This therefore provides a controversial paradigm in which reduced regenerative capacity of skeletal muscle tissue with age potentially promotes longevity of the organism. This paradox will be assessed and considered in the light of the following: (i) the genetic knockout, overexpression and pharmacological models that induce lifespan extension (e.g. IRS-1/s6K KO, mTOR inhibition) versus the important role of these signalling pathways in SkM growth and adaptation; (ii) the role of the sirtuins (SIRTs) in longevity versus their emerging role in SkM regeneration and survival under catabolic stress; (iii) the role of dietary restriction and its impact on longevity versus skeletal muscle mass regulation; (iv) the crosstalk between cellular energy metabolism (AMPK/TSC2/SIRT1) and survival (FOXO) versus growth and repair of SkM (e.g. AMPK vs. mTOR); and (v) the impact of protein feeding in combination with dietary restriction will be discussed as a potential intervention to maintain SkM mass while increasing longevity and enabling healthy aging

Testosterone enables growth and hypertrophy in fusion impaired myoblasts that display myotube atrophy: deciphering the role of androgen and IGF-I receptors

We have previously highlighted the ability of testosterone to improve differentiation and myotube hypertrophy in fusion impaired myoblasts that display reduced myotube hypertrophy at 72hrs (after transfer to low serum media) via multiple population doublings (PD) vs. their parental controls (CON); an observation which is abrogated via PI3K/Akt inhibition (Deane et al. 2013). However, whether the most predominant molecular mechanism responsible for T induced hypertrophy occurs directly via androgen receptor or indirectly via IGF-IR/PI3K/Akt pathway is currently debated. PD and CON C2C12 muscle cells were exposed to low serum conditions in the presence or absence of T (100 nM) ± inhibitors of AR (flutamide/F, 40 μm) and IGF-IR (Picropodophyllin/PPP, 150 nM) for 72 hrs and 7 days (early/late muscle differentiation respectively). T increased AR and Akt abundance, myogenin expression, and myotube hypertrophy, but not ERK1/2 activity in both CON and PD cell types. Akt activity was not increased significantly in either cell type with T. Testosterone was unable to promote early differentiation in the presence of IGF-IR inhibitor (PPP) yet still able to promote appropriate later increases in myotube hypertrophy and AR abundance despite IGF-IR inhibition. The addition of the AR inhibitor powerfully attenuated all T induced increases in differentiation and myotube hypertrophy with corresponding reductions in AR abundance, phosphorylated Akt, ERK1/2 and gene expression of IGF-I, myoD and myogenin with increases in myostatin mRNA both cell types. Interestingly, despite basally reduced differentiation and myotube hypertrophy, PD cells showed larger increased in AR abundance vs. CON cells, a response abrogated in the presence of AR but not IGF-IR inhibitors. Furthermore, T induced increases in Akt abundance were sustained despite the presence of IGF-IR inhibition in PD cells only. However, flutamide alone reduced IGF-IR mRNA in both cell types across time points, with an observed reduction in activity of ERK and Akt, perhaps suggesting that IGF-IR was transcriptionally regulated by AR. However, where testosterone increased AR protein content there was no increases observed in IGF-IR gene expression. Overall, this suggested that sufficient AR was important to enable normal gene expression of IGF-IR and downstream signalling, yet elevated levels of AR due to testosterone had no further effect on IGF-IR, despite testosterone increasing Akt abundance in the presence of IGF-IR inhibitor. In conclusion, testosterones ability to improve differentiation and myotube hypertrophy occurred predominately via increases in AR and Akt abundance in both CON and PD cells, with fusion impaired cells (PD) showing an increased responsiveness to T induced AR levels. Finally, T induced increases in myotube hypertrophy (but not early differentiation) occurred independently of upstream IGF-IR input, however it appears that normal AR function in basal conditions is required for adequate IGF-IR gene expression and downstream Akt abundance