Perspectives on palliative oxygen for breathlessness: systematic review and meta-synthesis.

Oxygen therapy is frequently prescribed for the palliation of breathlessness, despite lack of evidence for its effectiveness in people who are not hypoxaemic. This study aimed to compare and contrast patients', caregivers' and clinicians' experiences of palliative oxygen use for the relief of chronic breathlessness in people with advanced life-limiting illnesses, and how this shapes prescribing.A systematic review and meta-synthesis of qualitative data was conducted. MEDLINE, CINAHL and PsycINFO were searched for peer-reviewed studies in English (2000-April 2019) reporting perspectives on palliative oxygen use for reducing breathlessness in people with advanced illnesses in any healthcare setting. After data extraction, thematic synthesis used line-by-line coding of raw data (quotes) to generate descriptive and analytical themes.Of 457 articles identified, 22 met the inclusion criteria by reporting perspectives of patients (n=337), caregivers (n=91) or clinicians (n=616). Themes common to these perspectives were: 1) benefits and burdens of palliative oxygen use, 2) knowledge and perceptions of palliative oxygen use beyond the guidelines, and 3) longitudinal trajectories of palliative oxygen use.There are differing perceptions regarding the benefits and burdens of using palliative oxygen. Clinicians should be aware that oxygen use may generate differing goals of therapy for patients and caregivers. These perceptions should be taken into consideration when prescribing oxygen for the symptomatic relief of chronic breathlessness in patients who do not quality for long-term oxygen therapy

Bioenergetic dysfunction in Huntington's disease human cybrids

In this work we studied the mitochondrial-associated metabolic pathways in Huntington's disease (HD) versus control (CTR) cybrids, a cell model in which the contribution of mitochondrial defects from patients is isolated. HD cybrids exhibited an interesting increase in ATP levels, when compared to CTR cybrids. Concomitantly, we observed increased glycolytic rate in HD cybrids, as revealed by increased lactate/pyruvate ratio, which was reverted after inhibition of glycolysis. A decrease in glucose-6-phosphate dehydrogenase activity in HD cybrids further indicated decreased rate of the pentose-phosphate pathway. ATP levels of HD cybrids were significantly decreased under glycolysis inhibition, which was accompanied by a decrease in phosphocreatine. Nevertheless, pyruvate supplementation could not recover HD cybrids' ATP or phosphocreatine levels, suggesting a dysfunction in mitochondrial use of that substrate. Oligomycin also caused a decrease in ATP levels, suggesting a partial support of ATP generation by the mitochondria. Nevertheless, mitochondrial NADH/NAD(t) levels were decreased in HD cybrids, which was correlated with a decrease in pyruvate dehydrogenase activity and protein expression, suggesting decreased tricarboxylic acid cycle (TCA) input from glycolysis. Interestingly, the activity of alpha-ketoglutarate dehydrogenase, a critical enzyme complex that links the TCA to amino acid synthesis and degradation, was increased in HD cybrids. In accordance, mitochondrial levels of glutamate were increased and alanine was decreased, whereas aspartate and glutamine levels were unchanged in HD cybrids. Conversely, malate dehydrogenase activity from total cell extracts was unchanged in HD cybrids. Our results suggest that inherent dysfunction of mitochondria from HD patients affects cellular bioenergetics in an otherwise functional nuclear background

Prediction of sarcomere mutations in subclinical hypertrophic cardiomyopathy.

BACKGROUND: Sarcomere protein mutations in hypertrophic cardiomyopathy induce subtle cardiac structural changes before the development of left ventricular hypertrophy (LVH). We have proposed that myocardial crypts are part of this phenotype and independently associated with the presence of sarcomere gene mutations. We tested this hypothesis in genetic hypertrophic cardiomyopathy pre-LVH (genotype positive, LVH negative [G+LVH-]). METHODS AND RESULTS: A multicenter case-control study investigated crypts and 22 other cardiovascular magnetic resonance parameters in subclinical hypertrophic cardiomyopathy to determine their strength of association with sarcomere gene mutation carriage. The G+LVH- sample (n=73) was 29 ± 13 years old and 51% were men. Crypts were related to the presence of sarcomere mutations (for ≥1 crypt, β=2.5; 95% confidence interval [CI], 0.5-4.4; P=0.014 and for ≥2 crypts, β=3.0; 95% CI, 0.8-7.9; P=0.004). In combination with 3 other parameters: anterior mitral valve leaflet elongation (β=2.1; 95% CI, 1.7-3.1; P<0.001), abnormal LV apical trabeculae (β=1.6; 95% CI, 0.8-2.5; P<0.001), and smaller LV end-systolic volumes (β=1.4; 95% CI, 0.5-2.3; P=0.001), multiple crypts indicated the presence of sarcomere gene mutations with 80% accuracy and an area under the curve of 0.85 (95% CI, 0.8-0.9). In this G+LVH- population, cardiac myosin-binding protein C mutation carriers had twice the prevalence of crypts when compared with the other combined mutations (47 versus 23%; odds ratio, 2.9; 95% CI, 1.1-7.9; P=0.045). CONCLUSIONS: The subclinical hypertrophic cardiomyopathy phenotype measured by cardiovascular magnetic resonance in a multicenter environment and consisting of crypts (particularly multiple), anterior mitral valve leaflet elongation, abnormal trabeculae, and smaller LV systolic cavity is indicative of the presence of sarcomere gene mutations and highlights the need for further study

Characteristics and outcomes of heart failure hospitalization before implementation of a heart failure clinic: The PRECIC study

Objective: This study aims to characterize patients hospitalized for acute heart failure (HF) in an internal medicine department and their one-year mortality and rate of rehospitalization for decompensated HF. Methods: This retrospective observational study enrolled all patients discharged in 2012 after hospitalization for acute HF. Discharge summaries, clinical records and telephone interviews were analysed. The data reports to the year before implementation of a heart failure clinic. Results: Four hundred and twenty-nine patients were enrolled, with a mean age of 79 years, 62.5% female. The most prevalent comorbidity and etiology was hypertension (86.7%) and the most frequent decompensation trigger was infection. HF with preserved ejection fraction (HFpEF) was present in 70.5%. In-hospital mortality was 7.9%. At discharge more than half of the patients were prescribed beta-blockers (52.8%) and angiotensin-converting enzyme inhibitors (52%). Women presented a significantly higher proportion of HFpEF than men (75.3% vs. 62.7%, p=0.01). Patients with diabetes and those with ischemic etiology had significantly higher pro-portions of HF with reduced ejection fraction (HFrEF) (34.8% vs. 24.3% in non-diabetic patients,p=0.027, and 56.2% vs. 15.6% for other etiologies, p<0.001). The HFrEF group were more fre-quently discharged under beta-blockers and spironolactone (75.2% vs. 46.4% in the HFpEF group,p<0.001 and 31.2% vs. 12.6% in the HFpEF group, p<0.001, respectively). Mortality was 34.3%and rehospitalization for HF was 30.5% in one-year follow-up.Conclusions: The population characterized is an elderly one, mainly female and with HFpEF.Nearly a third of patients died and/or were rehospitalized in the year following discharge

Social and economic value of Portuguese community pharmacies in health care

Background: Community pharmacies are major contributors to health care systems across the world. Several studies have been conducted to evaluate community pharmacies services in health care. The purpose of this study was to estimate the social and economic benefits of current and potential future community pharmacies services provided by pharmacists in health care in Portugal. Methods: The social and economic value of community pharmacies services was estimated through a decision-model. Model inputs included effectiveness data, quality of life (QoL) and health resource consumption, obtained though literature review and adapted to Portuguese reality by an expert panel. The estimated economic value was the result of non-remunerated pharmaceutical services plus health resource consumption potentially avoided. Social and economic value of community pharmacies services derives from the comparison of two scenarios: "with service" versus "without service". Results: It is estimated that current community pharmacies services in Portugal provide a gain in QoL of 8.3% and an economic value of 879.6 million euros (Msic), including 342.1 Msic in non-remunerated pharmaceutical services and 448. 1 Msic in avoided expense with health resource consumption. Potential future community pharmacies services may provide an additional increase of 6.9% in QoL and be associated with an economic value of 144.8 Msic: 120.3 Msic in non-remunerated services and 24.5 Msic in potential savings with health resource consumption. Conclusions: Community pharmacies services provide considerable benefit in QoL and economic value. An increase range of services including a greater integration in primary and secondary care, among other transversal services, may add further social and economic value to the society

Combination of cyclic nucleotide modulators with P2Y12 receptor antagonists as anti-platelet therapy

"This is the peer reviewed version of the following article: Armstrong, PC, Ferreira, PM, Chan, MV, et al. Combination of cyclic nucleotide modulators with P2Y12 receptor antagonists as anti‐platelet therapy. J Thromb Haemost. 2020 https://doi.org/10.1111/jth.14826 which has been published in final form at   https://doi.org/10.1111/jth.14826BACKGROUND: Endothelium-derived prostacyclin and nitric oxide elevate platelet cyclic nucleotide levels and maintain quiescence. We previously demonstrated that a synergistic relationship exists between cyclic nucleotides and P2Y12 receptor inhibition. A number of clinically approved drug classes can modulate cyclic nucleotide tone in platelets including activators of NO-sensitive guanylyl cyclase (GC) and phosphodiesterase (PDE) inhibitors. However, the doses required to inhibit platelets produce numerous side effects including headache. OBJECTIVE: We investigated using GC-activators in combination with P2Y12 receptor antagonists as a way to selectively amplify the anti-thrombotic effect of both drugs. METHODS: In vitro light transmission aggregation and platelet adhesion under flow were performed on washed platelets and platelet rich plasma. Aggregation in whole blood and a ferric chloride-induced arterial thrombosis model were also performed. RESULTS: The GC-activator BAY-70 potentiated the action of the P2Y12 receptor inhibitor prasugrel active metabolite in aggregation and adhesion studies and was associated with raised intra-platelet cyclic nucleotide levels. Furthermore, mice administered sub-maximal doses of the GC activator cinaciguat together with the PDE inhibitor dipyridamole and prasugrel, showed significant inhibition of ex vivo platelet aggregation and significantly reduced in vivo arterial thrombosis in response to injury without alteration in basal carotid artery blood flow. CONCLUSIONS: Using in vitro, ex vivo, and in vivo functional studies, we show that low dose GC activators synergize with P2Y12 inhibition to produce powerful anti-platelet effects without altering blood flow. Therefore, modulation of intra-platelet cyclic nucleotide levels alongside P2Y12 inhibition can provide a strong, focused anti-thrombotic regimen while minimizing vasodilator side effects

Mitochondrial-dependent apoptosis in Huntington's disease human cybrids

We investigated the involvement of mitochondrial-dependent apoptosis in Huntington's disease (HD) vs. control (CTR) cybrids, obtained from the fusion of human platelets with mitochondrial DNA-depleted NT2 cells, and further exposed to 3-nitropropionic acid (3-NP) or staurosporine (STS). Untreated HD cybrids did not exhibit significant modifications in the activity of mitochondrial respiratory chain complexes I-IV or in mtDNA sequence variations suggestive of a primary role in mitochondrial susceptibility in the subpopulation of HD carriers studied. However, a slight decrease in mitochondrial membrane potential and increased formation of intracellular hydroperoxides was observed in HD cybrids under basal conditions. Furthermore, apoptotic nuclei morphology and a moderate increase in caspase-3 activation, as well as increased levels of superoxide ions and hydroperoxides were observed in HD cybrids upon 3-NP or STS treatment. 3-NP-evoked apoptosis in HD cybrids involved cytochrome c and AIF release from mitochondria, which was associated with mitochondrial Bax translocation. CTR cybrids subjected to 3-NP showed increased mitochondrial Bax and Bim levels and the release of AIF, but not cytochrome c, suggesting a different mode of cell death, linked to the loss of membrane integrity. Additionally, increased mitochondrial Bim and Bak levels, and a slight release of cytochrome c in untreated HD cybrids may help to explain their moderate susceptibility to mitochondrial-dependent apoptosi

Effect of band anisotropy on electronic structure of PbS, PbSe, and PbTe quantum dots

We have calculated the electronic structure of spherical PbS, PbSe, and PbTe quantum dots using a four-band envelope-function formalism that accounts for band anisotropy. By comparing our results with an analytical calculation that assumes a spherical approximation of the (k) over right arrow.(p) over right arrow Hamiltonian, we show that the effects of band anisotropy are more pronounced for the excited states and increase with the confinement. We also show how the same technique can be applied to ellipsoidal quantum dots.62117357736

In vitro and in vivo characterization of PLLA-316L stainless steel electromechanical devices for bone tissue engineering—A preliminary study

Bone injuries represent a major social and financial impairment, commonly requiring surgical intervention due to a limited healing capacity of the tissue, particularly regarding critical-sized defects and non-union fractures. Regenerative medicine with the application of bone implants has been developing in the past decades towards the manufacturing of appropriate devices. This work intended to evaluate medical 316L stainless steel (SS)-based devices covered by a polymer poly (L-lactic acid) (PLLA) coating for bone lesion mechanical and functional support. SS316L devices were subjected to a previously described silanization process, following a three-layer PLLA film coating. Devices were further characterized and evaluated towards their cytocompatibility and osteogenic potential using human dental pulp stem cells, and biocompatibility via subcutaneous implantation in a rat animal model. Results demonstrated PLLA-SS316L devices to present superior in vitro and in vivo outcomes and suggested the PLLA coating to provide osteo-inductive properties to the device. Overall, this work represents a preliminary study on PLLA-SS316L devices’ potential towards bone tissue regenerative techniques, showing promising outcomes for bone lesion support.This work was developed within the scope of the project CICECO-Aveiro Institute of Materials, FCT Ref. UID/CTM/50011/2019, financed by national funds through the FCT/MCTES and when appropriate co-financed by FEDER under the PT2020 Partnership Agreement. This work was also financed by Portugal 2020 through the European Regional Development Fund (ERDF), in the frame of Operational Competitiveness and Internationalization Programme (POCI), in the scope of the project “Advanced BioMEMs for tissue engineering: Applications in hard tissue (BioMEMs)”, POCI-01-0145-FEDER-032095. Mariana Vieira Branquinho (SFRH/BD/146172/2019), Ana Catarina Sousa (SFRH/BD/146689/2019), and Rui Damásio Alvites (SFRH/BD/116118/2016), acknowledge FCT, for financial support