55 research outputs found
Sacral nerve stimulation versus the magnetic sphincter augmentation device for adult faecal incontinence: the SaFaRI RCT
Background:
Preliminary studies using the FENIX™ (Torax Medical, Minneapolis, MN, USA) magnetic sphincter augmentation device suggest that it is safe to use for the treatment of adult faecal incontinence, but efficacy data are limited.
Objective:
To compare FENIX with sacral nerve stimulation for the treatment of adult faecal incontinence in terms of safety, efficacy, quality of life and cost-effectiveness.
Design, setting and participants:
Multicentre, parallel-group, unblinded, randomised trial comparing FENIX with sacral nerve stimulation in participants suffering moderate to severe faecal incontinence.
Interventions:
Participants were randomised on an equal basis to either sacral nerve stimulation or FENIX. Follow-up occurred 2 weeks postoperatively and at 6, 12 and 18 months post randomisation.
Main outcome and measure:
The primary outcome was success, defined as device in use and ≥ 50% improvement in Cleveland Clinic Incontinence Score at 18 months post randomisation. Secondary outcomes included complication rates, quality of life and cost-effectiveness. Between 30 October 2014 and 23 March 2017, 99 participants were randomised across 18 NHS sites (50 participants to FENIX vs. 49 participants to sacral nerve stimulation). The median time from randomisation to FENIX implantation was 57.0 days (range 4.0–416.0 days), and the median time from randomisation to permanent sacral nerve stimulation was 371.0 days (range 86.0–918.0 days). A total of 45 out of 50 participants underwent FENIX implantation and 29 out of 49 participants continued to permanent sacral nerve stimulation. The following results are reported, excluding participants for whom the corresponding outcome was not evaluable. Overall, there was success for 10 out of 80 (12.5%) participants, with no statistically significant difference between the two groups [FENIX 6/41 (14.6%) participants vs. sacral nerve stimulation 4/39 (10.3%) participants]. At least one postoperative complication was experienced by 33 out of 45 (73.3%) participants in the FENIX group and 9 out of 40 (22.5%) participants in the sacral nerve stimulation group. A total of 15 out of 50 (30%) participants in the FENIX group ultimately had to have their device explanted. Slightly higher costs and quality-adjusted life-years (incremental = £305.50 and 0.005, respectively) were observed in the FENIX group than in the sacral nerve stimulation group. This was reversed over the lifetime horizon (incremental = –£1306 and –0.23 for costs and quality-adjusted life-years, respectively), when sacral nerve stimulation was the optimal option (net monetary benefit = –£3283), with only a 45% chance of FENIX being cost-effective.
Limitations:
The SaFaRI study was terminated in 2017, having recruited 99 participants of the target sample size of 350 participants. The study is, therefore, substantially underpowered to detect differences between the treatment groups, with significant uncertainty in the cost-effectiveness analysis.
Conclusions:
The SaFaRI study revealed inefficiencies in the treatment pathways for faecal incontinence, particularly for sacral nerve stimulation. The success of both FENIX and sacral nerve stimulation was much lower than previously reported, with high postoperative morbidity in the FENIX group.
Future work:
Further research is needed to clarify the treatment pathways for sacral nerve stimulation and to determine its true clinical and cost-effectiveness.
Trial registration:
Current Controlled Trials ISRCTN16077538.
Funding:
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 18. See the NIHR Journals Library website for further project information
Diversity of Matriptase Expression Level and Function in Breast Cancer
Overexpression of matriptase has been reported in a variety of human cancers and is sufficient to trigger tumor formation in mice, but the importance of matriptase in breast cancer remains unclear. We analysed matriptase expression in 16 human breast cancer cell lines and in 107 primary breast tumors. The data revealed considerable diversity in the expression level of this protein indicating that the significance of matriptase may vary from case to case. Matriptase protein expression was correlated with HER2 expression and highest expression was seen in HER2-positive cell lines, indicating a potential role in this subgroup. Stable overexpression of matriptase in two breast cancer cell lines had different consequences. In MDA-MB-231 human breast carcinoma cells the only noted consequence of matriptase overexpression was modestly impaired growth in vivo. In contrast, overexpression of matriptase in 4T1 mouse breast carcinoma cells resulted in visible changes in morphology, actin staining and cell to cell contacts. This correlated with downregulation of the cell-cell adhesion molecule E-cadherin. These results suggest that the functions of matriptase in breast cancer are likely to be variable and cell context dependent
A state space approach to periodic convolutional codes
In this paper we study periodically time-varying convolutional
codes by means of input-state-output representations. Using these
representations we investigate under which conditions a given time-invariant
convolutional code can be transformed into an equivalent periodic
time-varying one. The relation between these two classes of convolutional
codes is studied for period 2. We illustrate the ideas presented in this
paper by constructing a periodic time-varying convolutional code from a
time-invariant one. The resulting periodic code has larger free distance
than any time-invariant convolutional code with equivalent parameters
Functional KV10.1 Channels Localize to the Inner Nuclear Membrane
Ectopically expressed human KV10.1 channels are relevant players in tumor biology. However, their function as ion channels at the plasma membrane does not totally explain their crucial role in tumors. Both in native and heterologous systems, it has been observed that a majority of KV10.1 channels remain at intracellular locations. In this study we investigated the localization and possible roles of perinuclear KV10.1. We show that KV10.1 is expressed at the inner nuclear membrane in both human and rat models; it co-purifies with established inner nuclear membrane markers, shows resistance to detergent extraction and restricted mobility, all of them typical features of proteins at the inner nuclear membrane. KV10.1 channels at the inner nuclear membrane are not all transported directly from the ER but rather have been exposed to the extracellular milieu. Patch clamp experiments on nuclei devoid of external nuclear membrane reveal the existence of channel activity compatible with KV10.1. We hypothesize that KV10.1 channels at the nuclear envelope might participate in the homeostasis of nuclear K+, or indirectly interact with heterochromatin, both factors known to affect gene expression
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Climate change and control of the southeastern Bering Sea pelagic ecosystem
We propose a new hypothesis, the Oscillating Control Hypothesis (OCH), which predicts that pelagic ecosystem function in the southeastern Bering Sea will alternate between primarily bottom-up control in cold regimes and primarily top-down control in warm regimes. The timing of spring primary production is determined predominately by the timing of ice retreat. Late ice retreat (late March or later) leads to an early, ice-associated bloom in cold water (e.g., 1995, 1997, 1999), whereas no ice, or early ice retreat before mid-March, leads to an open-water bloom in May or June in warm water (e.g., 1996, 1998, 2000). Zooplankton populations are not closely coupled to the spring bloom, but are sensitive to water temperature. In years when the spring bloom occurs in cold water, low temperatures limit the production of zooplankton, the survival of larval/juvenile fish, and their recruitment into the populations of species of large piscivorous fish, such as walleye pollock (Theragra chalcogramma), Pacific cod (Gadus macrocephalus) and arrowtooth flounder (Atheresthes stomias). When continued over decadal scales, this will lead to bottom-up limitation and a decreased biomass of piscivorous fish. Alternatively, in periods when the bloom occurs in warm water, zooplankton populations should grow rapidly, providing plentiful prey for larval and juvenile fish. Abundant zooplankton will support strong recruitment of fish and will lead to abundant predatory fish that control forage fish, including, in the case of pollock, their own juveniles. Piscivorous marine birds and pinnipeds may achieve higher production of young and survival in cold regimes, when there is less competition from large piscivorous fish for coldwater forage fish such as capelin (Mallotus villosus). Piscivorous seabirds and pinnipeds also may be expected to have high productivity in periods of transition from cold regimes to warm regimes, when young of large predatory species of fish are numerous enough to provide forage. The OCH predicts that the ability of large predatory fish populations to sustain fishing pressure will vary between warm and cold regimes. The OCH points to the importance of the timing of ice retreat and water temperatures during the spring bloom for the productivity of zooplankton, and the degree and direction of coupling between zooplankton and forage fish. Forage fish (e.g., juvenile pollock, capelin, Pacific herring [Clupea pallasii]) are key prey for adult pollock and other apex predators. In the southeastern Bering Sea, important changes in the biota since the mid-1970s include a marked increase in the biomass of large piscivorous fish and a concurrent decline in the biomass of forage fish, including age-1 walleye pollock, particularly over the southern portion of the shelf. Populations of northern fur seals (Callorhinus ursinus) and seabirds such as kittiwakes (Rissa spp.) at the Pribilof Islands have declined, most probably in response to a diminished prey base. The available evidence suggests that these changes are unlikely the result of a decrease in total annual new primary production, though the possibility of reduced post-bloom production during summer remains. An ecosystem approach to management of the Bering Sea and its fisheries is of great importance if all of the ecosystem components valued by society are to thrive. Cognizance of how climate regimes may alter relationships within this ecosystem will facilitate reaching that goal
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Climate change and control of the southeastern Bering Sea pelagic ecosystem
We propose a new hypothesis, the Oscillating Control Hypothesis (OCH), which predicts that pelagic ecosystem function in the southeastern Bering Sea will alternate between primarily bottom-up control in cold regimes and primarily top-down control in warm regimes. The timing of spring primary production is determined predominately by the timing of ice retreat. Late ice retreat (late March or later) leads to an early, ice-associated bloom in cold water (e.g., 1995, 1997, 1999), whereas no ice, or early ice retreat before mid-March, leads to an open-water bloom in May or June in warm water (e.g., 1996, 1998, 2000). Zooplankton populations are not closely coupled to the spring bloom, but are sensitive to water temperature. In years when the spring bloom occurs in cold water, low temperatures limit the production of zooplankton, the survival of larval/juvenile fish, and their recruitment into the populations of species of large piscivorous fish, such as walleye pollock (Theragra chalcogramma), Pacific cod (Gadus macrocephalus) and arrowtooth flounder (Atheresthes stomias). When continued over decadal scales, this will lead to bottom-up limitation and a decreased biomass of piscivorous fish. Alternatively, in periods when the bloom occurs in warm water, zooplankton populations should grow rapidly, providing plentiful prey for larval and juvenile fish. Abundant zooplankton will support strong recruitment of fish and will lead to abundant predatory fish that control forage fish, including, in the case of pollock, their own juveniles. Piscivorous marine birds and pinnipeds may achieve higher production of young and survival in cold regimes, when there is less competition from large piscivorous fish for coldwater forage fish such as capelin (Mallotus villosus). Piscivorous seabirds and pinnipeds also may be expected to have high productivity in periods of transition from cold regimes to warm regimes, when young of large predatory species of fish are numerous enough to provide forage. The OCH predicts that the ability of large predatory fish populations to sustain fishing pressure will vary between warm and cold regimes. The OCH points to the importance of the timing of ice retreat and water temperatures during the spring bloom for the productivity of zooplankton, and the degree and direction of coupling between zooplankton and forage fish. Forage fish (e.g., juvenile pollock, capelin, Pacific herring [Clupea pallasii]) are key prey for adult pollock and other apex predators. In the southeastern Bering Sea, important changes in the biota since the mid-1970s include a marked increase in the biomass of large piscivorous fish and a concurrent decline in the biomass of forage fish, including age-1 walleye pollock, particularly over the southern portion of the shelf. Populations of northern fur seals (Callorhinus ursinus) and seabirds such as kittiwakes (Rissa spp.) at the Pribilof Islands have declined, most probably in response to a diminished prey base. The available evidence suggests that these changes are unlikely the result of a decrease in total annual new primary production, though the possibility of reduced post-bloom production during summer remains. An ecosystem approach to management of the Bering Sea and its fisheries is of great importance if all of the ecosystem components valued by society are to thrive. Cognizance of how climate regimes may alter relationships within this ecosystem will facilitate reaching that goal
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Anomalous conditions in the south-eastern Bering Sea, 1997: Nutrients, phytoplankton and zooplankton
Anomalies in the regional weather over the southeastern Bering Sea during spring and summer of 1997 resulted in significant differences in nutrient availability, phytoplankton species composition, and zooplankton abundance over the continental shelf as compared with measurements in the 1980s. Calm winds and the reduction of cloud cover in spring and summer produced a very shallow mixed layer in which nitrate and silicate were depleted after an April diatom bloom. High submarine light levels allowed subsequent phytoplankton growth below the pycnocline and eventual depletion of nitrate from the water column to depths of 70 m or more. Thus, total new production during 1997 may have exceeded that of previous years when nitrate was not depleted below the pycnocline. A bloom of the coccolithophorid, Emiliania huxleyi, was observed in early July in the warm, nutrient-depleted waters over the middle and inner shelf. Emiliania huxleyi concentrations reached 4.5 × 106 cells L-1 by September, and the bloom persisted through the autumn. There was evidence for increased abundance of some species of copepods in 1997 as compared with data from the middle domain in June 1981. The abundance of adult and juvenile euphausiids in 1997 was statistically similar to values measured in 1980 and 1981. However, near-surface swarms were rarely observed on the inner shelf in August-September 1997. Lack of euphausiid availability in the upper water column may partially explain the August-September mass mortality of planktivorous short-tailed shearwaters (Puffinus tenuirostris) observed on the inner shelf
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