Impact of a hospice rapid response service on preferred place of death, and costs

Background: Many people with a terminal illness would prefer to die at home. A new palliative rapid response service (RRS) provided by a large hospice provider in South East England was evaluated (2010) to provide evidence of impact on achieving preferred place of death and costs. The RRS was delivered by a team of trained health care assistants and available 24/7. The purpose of this study was to (i) compare the characteristics of RRS users and non-users, (ii) explore differences in the proportions of users and non-users dying in the place of their choice, (iii) monitor the whole system service utilisation of users and non-users, and compare costs. Methods: All hospice patients who died with a preferred place of death recorded during an 18 month period were included. Data (demographic, preferences for place of death) were obtained from hospice records. Dying in preferred place was modelled using stepwise logistic regression analysis. Service use data (period between referral to hospice and death) were obtained from general practitioners, community providers, hospitals, social services, hospice, and costs calculated using validated national tariffs. Results: Of 688 patients referred to the hospice when the RRS was operational, 247 (35.9 %) used it. Higher proportions of RRS users than non-users lived in their own homes with a co-resident carer (40.3 % vs. 23.7 %); more non-users lived alone or in residential care (58.8 % vs. 76.3 %). Chances of dying in the preferred place were enhanced 2.1 times by being a RRS user, compared to a non-user, and 1.5 times by having a co-resident carer, compared to living at home alone or in a care home. Total service costs did not differ between users and non-users, except when referred to hospice very close to death (users had higher costs). Conclusions: Use of the RRS was associated with increased likelihood of dying in the preferred place. The RRS is cost neutral

Src Dependent Pancreatic Acinar Injury Can Be Initiated Independent of an Increase in Cytosolic Calcium

Several deleterious intra-acinar phenomena are simultaneously triggered on initiating acute pancreatitis. These culminate in acinar injury or inflammatory mediator generation in vitro and parenchymal damage in vivo. Supraphysiologic caerulein is one such initiator which simultaneously activates numerous signaling pathways including non-receptor tyrosine kinases such as of the Src family. It also causes a sustained increase in cytosolic calcium- a player thought to be crucial in regulating deleterious phenomena. We have shown Src to be involved in caerulein induced actin remodeling, and caerulein induced changes in the Golgi and post-Golgi trafficking to be involved in trypsinogen activation, which initiates acinar cell injury. However, it remains unclear whether an increase in cytosolic calcium is necessary to initiate acinar injury or if injury can be initiated at basal cytosolic calcium levels by an alternate pathway. To study the interplay between tyrosine kinase signaling and calcium, we treated mouse pancreatic acinar cells with the tyrosine phosphatase inhibitor pervanadate. We studied the effect of the clinically used Src inhibitor Dasatinib (BMS-354825) on pervanadate or caerulein induced changes in Src activation, trypsinogen activation, cell injury, upstream cytosolic calcium, actin and Golgi morphology. Pervanadate, like supraphysiologic caerulein, induced Src activation, redistribution of the F-actin from its normal location in the sub-apical area to the basolateral areas, and caused antegrade fragmentation of the Golgi. These changes, like those induced by supraphysiologic caerulein, were associated with trypsinogen activation and acinar injury, all of which were prevented by Dasatinib. Interestingly, however, pervanadate did not cause an increase in cytosolic calcium, and the caerulein induced increase in cytosolic calcium was not affected by Dasatinib. These findings suggest that intra-acinar deleterious phenomena may be initiated independent of an increase in cytosolic calcium. Other players resulting in acinar injury along with the Src family of tyrosine kinases remain to be explored. © 2013 Mishra et al

Variability of disk emission in pre-main sequence and related stars. II. Variability in the gas and dust emission of the Herbig Fe star SAO 206462

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.We present 13 epochs of near-infrared (0.8-5 μm) spectroscopic observations of the pre-transitional, "gapped" disk system in SAO 206462 (=HD 135344B). In all, six gas emission lines (Brα, Brγ, Paβ, Paγ, Paδ, Paepsilon, and the 0.8446 μm line of O I) along with continuum measurements made near the standard J, H, K, and L photometric bands were measured. A mass accretion rate of approximately 2 × 10–8 M ☉ yr–1 was derived from the Brγ and Paβ lines. However, the fluxes of these lines varied by a factor of over two during the course of a few months. The continuum also varied, but by only ~30%, and even decreased at a time when the gas emission was increasing. The H I line at 1.083 μm was also found to vary in a manner inconsistent with that of either the hydrogen lines or the dust. Both the gas and dust variabilities indicate significant changes in the region of the inner gas and the inner dust belt that may be common to many young disk systems. If planets are responsible for defining the inner edge of the gap, they could interact with the material on timescales commensurate with what is observed for the variations in the dust, while other disk instabilities (thermal, magnetorotational) would operate there on longer timescales than we observe for the inner dust belt. For SAO 206462, the orbital period would likely be 1-3 years. If the changes are being induced in the disk material closer to the star than the gap, a variety of mechanisms (disk instabilities, interactions via planets) might be responsible for the changes seen. The He I feature is most likely due to a wind whose orientation changes with respect to the observer on timescales of a day or less. To further constrain the origin of the gas and dust emission will require multiple spectroscopic and interferometric observations on both shorter and longer timescales that have been sampled so far.This work was supported by NASA ADP grants NNH06CC28C and NNX09AC73G, Hubble Space Telescope grants HST-GO-10764 and HST-GO-10864, Chilean National TAC grants CNTAC-010A-064

Carbamazepine reduces memory induced activation of mesial temporal lobe structures: a pharmacological fMRI-study

BACKGROUND AND PURPOSE: It is not known whether carbamazepine (CBZ; a drug widely used in neurology and psychiatry) influences the blood oxygenation level dependent (BOLD) contrast changes induced by neuronal activation and measured by functional MRI (fMRI). We aimed to investigate the influence of CBZ on memory induced activation of the mesial temporal lobes in patients with symptomatic temporal lobe epilepsy (TLE). MATERIAL AND METHODS: Twenty-one individual patients with refractory symptomatic TLE with different CBZ serum levels and 20 healthy controls were studied using BOLD fMRI. Mesial temporal lobe (MTL) activation was induced by a task that is based on the retrieval of individually familiar visuo-spatial knowledge. The extent of significant MTL fMRI activation was measured and correlated with the CBZ serum level. RESULTS: In TLE patients, the extent of significant fMRI activation over both MTL was negatively correlated to the CBZ serum level (Spearman r = -0.654, P < 0.001). Activation over the supposedly normal MTL, i.e. contralateral to the seizure onset of TLE patients, was smaller than the averaged MTL activation in healthy controls (P < 0.005). Age, duration of epilepsy, side of seizure onset, and intelligence were not correlated to the extent of the significant BOLD-response over both MTL in patients with TLE. CONCLUSIONS: In TLE patients, carbamazepine reduces the fMRI-detectable changes within the mesial temporal lobes as induced by effortful memory retrieval. FMRI appears to be suitable to study the effects of chronic drug treatment in patients with epilepsy

Endogenous cholinergic inputs and local circuit mechanisms govern the phasic mesolimbic dopamine response to nicotine

Nicotine exerts its reinforcing action by stimulating nicotinic acetylcholine receptors (nAChRs) and boosting dopamine (DA) output from the ventral tegmental area (VTA). Recent data have led to a debate about the principal pathway of nicotine action: direct stimulation of the DAergic cells through nAChR activation, or disinhibition mediated through desensitization of nAChRs on GABAergic interneurons. We use a computational model of the VTA circuitry and nAChR function to shed light on this issue. Our model illustrates that the α4β2-containing nAChRs either on DA or GABA cells can mediate the acute effects of nicotine. We account for in vitro as well as in vivo data, and predict the conditions necessary for either direct stimulation or disinhibition to be at the origin of DA activity increases. We propose key experiments to disentangle the contribution of both mechanisms. We show that the rate of endogenous acetylcholine input crucially determines the evoked DA response for both mechanisms. Together our results delineate the mechanisms by which the VTA mediates the acute rewarding properties of nicotine and suggest an acetylcholine dependence hypothesis for nicotine reinforcement.Peer reviewe

Marginal Level Dystrophin Expression Improves Clinical Outcome in a Strain of Dystrophin/Utrophin Double Knockout Mice

Inactivation of all utrophin isoforms in dystrophin-deficient mdx mice results in a strain of utrophin knockout mdx (uko/mdx) mice. Uko/mdx mice display severe clinical symptoms and die prematurely as in Duchenne muscular dystrophy (DMD) patients. Here we tested the hypothesis that marginal level dystrophin expression may improve the clinical outcome of uko/mdx mice. It is well established that mdx3cv (3cv) mice express a near-full length dystrophin protein at ∼5% of the normal level. We crossed utrophin-null mutation to the 3cv background. The resulting uko/3cv mice expressed the same level of dystrophin as 3cv mice but utrophin expression was completely eliminated. Surprisingly, uko/3cv mice showed a much milder phenotype. Compared to uko/mdx mice, uko/3cv mice had significantly higher body weight and stronger specific muscle force. Most importantly, uko/3cv outlived uko/mdx mice by several folds. Our results suggest that a threshold level dystrophin expression may provide vital clinical support in a severely affected DMD mouse model. This finding may hold clinical implications in developing novel DMD therapies

Should Research Ethics Encourage the Production of Cost-Effective Interventions?

This project considers whether and how research ethics can contribute to the provision of cost-effective medical interventions. Clinical research ethics represents an underexplored context for the promotion of cost-effectiveness. In particular, although scholars have recently argued that research on less-expensive, less-effective interventions can be ethical, there has been little or no discussion of whether ethical considerations justify curtailing research on more expensive, more effective interventions. Yet considering cost-effectiveness at the research stage can help ensure that scarce resources such as tissue samples or limited subject popula- tions are employed where they do the most good; can support parallel efforts by providers and insurers to promote cost-effectiveness; and can ensure that research has social value and benefits subjects. I discuss and rebut potential objections to the consideration of cost-effectiveness in research, including the difficulty of predicting effectiveness and cost at the research stage, concerns about limitations in cost-effectiveness analysis, and worries about overly limiting researchers’ freedom. I then consider the advantages and disadvantages of having certain participants in the research enterprise, including IRBs, advisory committees, sponsors, investigators, and subjects, consider cost-effectiveness. The project concludes by qualifiedly endorsing the consideration of cost-effectiveness at the research stage. While incorporating cost-effectiveness considerations into the ethical evaluation of human subjects research will not on its own ensure that the health care system realizes cost-effectiveness goals, doing so nonetheless represents an important part of a broader effort to control rising medical costs

Patient-rated health status predicts prognosis following percutaneous coronary intervention with drug-eluting stenting

Purpose: In patients treated with percutaneous coronary intervention (PCI) with the paclitaxel-eluting stent, we examined whether patient-rated health status predicts adverse clinical events. Methods: Consecutive PCI patients treated with drug-eluting stenting (N = 870; 72.2% men; mean age = 62.6 ± 11.5) completed the EQ-5D post-PCI. The EQ-5D levels were dichotomized into 'no problems' (level 1) versus 'problems' (levels 2, 3); the visual analogue scale (VAS) was dichotomized using the 25th percentile (cut-off ≤60) indicating poor health status. Patients were followed up for 1-year clinical events (death or non-fatal myocardial infarction (MI)). Results: There were 53 deaths/MIs at follow-up. The EQ-5D health status dimensions mobility (HR:2.23; 95% CI:1.25-3.97), self-care (HR:3.09; 95% CI:1.54-6.20), and self-reported health status as measured with the EQ-VAS (HR:2.94; 95% CI:1.65-5.25) were independent predictors of death/MI and added to the predictive value of a model comprised of demographic and clinical characteristics. The EQ-5D dimensions usual activities, pain/discomfort, and anxiety/depression were not associated with adverse clinical events in adjusted analysis. Conclusions: Patient-rated health status predicted adverse clinical events at 1-year follow-up in PCI patients treated with drug-eluting stenting, with the risk being more than 2-fold indepe

Women and postfertilization effects of birth control: consistency of beliefs, intentions and reported use

BACKGROUND: This study assesses the consistency of responses among women regarding their beliefs about the mechanisms of actions of birth control methods, beliefs about when human life begins, the intention to use or not use birth control methods that they believe may act after fertilization or implantation, and their reported use of specific methods. METHODS: A questionnaire was administered in family practice and obstetrics and gynecology clinics in Salt Lake City, Utah, and Tulsa, Oklahoma. Participants included women ages 18–50 presenting for any reason and women under age 18 presenting for family planning or pregnancy care. Analyses were based on key questions addressing beliefs about whether specific birth control methods may act after fertilization, beliefs about when human life begins, intention to use a method that may act after fertilization, and reported use of specific methods. The questionnaire contained no information about the mechanism of action of any method of birth control. Responses were considered inconsistent if actual use contradicted intentions, if one intention contradicted another, or if intentions contradicted beliefs. RESULTS: Of all respondents, 38% gave consistent responses about intention to not use or to stop use of any birth control method that acted after fertilization, while 4% gave inconsistent responses. The corresponding percentages for birth control methods that work after implantation were 64% consistent and 2% inconsistent. Of all respondents, 34% reported they believed that life begins at fertilization and would not use any birth control method that acts after fertilization (a consistent response), while 3% reported they believed that life begins at fertilization but would use a birth control method that acts after fertilization (inconsistent). For specific methods of birth control, less than 1% of women gave inconsistent responses. A majority of women (68% or greater) responded accurately about the mechanism of action of condoms, abstinence, sterilization, and abortion, but a substantial percentage of women (between 19% and 57%) were uncertain about the mechanisms of action of oral contraceptives, intrauterine devices (IUDs), Depo-Provera, or natural family planning. CONCLUSION: Women who believe that life begins at fertilization may not intend to use a birth control method that could have postfertilization effects. More research is needed to understand the relative importance of postfertilization effects for women in other populations, and in relation to other properties of and priorities for birth control methods. However, many women were uncertain about the mechanisms of action of specific methods. To respect the principles of informed consent, some women may need more education about what is known and not known about the mechanisms of action of birth control methods