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1.
Cells ; 9(2)2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32046118

RESUMO

WNT5a is a mainly "non-canonical" WNT ligand whose dysregulation is observed in lung diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and asthma. Germline deletion of Wnt5a disrupts embryonic lung development. However, the temporal-specific function of WNT5a remains unknown. In this study, we generated a conditional loss-of-function mouse model (Wnt5aCAG) and examined the specific role of Wnt5a during the saccular and alveolar phases of lung development. The lack of Wnt5a in the saccular phase blocked distal airway expansion and attenuated differentiation of endothelial and alveolar epithelial type I (AT1) cells and myofibroblasts. Postnatal Wnt5a inactivation disrupted alveologenesis, producing a phenotype resembling human bronchopulmonary dysplasia (BPD). Mutant lungs showed hypoalveolization, but endothelial and epithelial differentiation was unaffected. The major impact of Wnt5a inactivation on alveologenesis was on myofibroblast differentiation and migration, with reduced expression of key regulatory genes. These findings were validated in vitro using isolated lung fibroblasts. Conditional inactivation of the WNT5a receptors Ror1 and Ror2 in alveolar myofibroblasts recapitulated the Wnt5aCAG phenotype, demonstrating that myofibroblast defects are the major cause of arrested alveologenesis in Wnt5aCAG lungs. Finally, we show that WNT5a is reduced in human BPD lung samples, indicating the clinical relevance and potential role for WNT5a in pathogenesis of BPD.

2.
BMJ Open ; 10(2): e032594, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32051304

RESUMO

OBJECTIVES: We developed a complex intervention called DECIDE (ComputeriseD dECisIonal support for suboptimally controlleD typE 2 Diabetes mellitus in Irish General Practice) which used a clinical decision support system to address clinical inertia and support general practitioner (GP) intensification of treatment for adults with suboptimally controlled type2 diabetes mellitus (T2DM). The current study explored the feasibility and potential impact of DECIDE. DESIGN: A pilot cluster randomised controlled trial. SETTING: Conducted in 14 practices in Irish General Practice. PARTICIPANTS: The DECIDE intervention was targeted at GPs. They applied DECIDE to patients with suboptimally controlled T2DM, defined as a glycated haemoglobin (HbA1c) ≥70 mmol/mol and/or blood pressure ≥150/95 mmHg. INTERVENTION: The intervention incorporated training and a web-based clinical decision support system which supported; (i) medication intensification actions; and (ii) non-pharmacological actions to support care. Control practices delivered usual care. PRIMARY AND SECONDARY OUTCOME MEASURES: Feasibility and acceptability was determined using thematic analysis of semi-structured interviews with GPs, combined with data from the DECIDE website. Clinical outcomes included HbA1c, medication intensification, blood pressure and lipids. RESULTS: We recruited 14 practices and 134 patients. At 4-month follow-up, all practices and 114 patients were followed up. GPs reported finding decision support helpful navigating increasingly complex medication algorithms. However, the majority of GPs believed that the target patient group had poor engagement with GP and hospital services for a range of reasons. At follow-up, there was no difference in glycaemic control (-3.6 mmol/mol (95% CI -11.2 to 4.0)) between intervention and control groups or in secondary outcomes including, blood pressure, total cholesterol, medication intensification or utilisation of services. Continuation criteria supported proceeding to a definitive randomised trial with some modifications. CONCLUSION: The DECIDE study was feasible and acceptable to GPs but wider impacts on glycaemic and blood pressure control need to be considered for this patient population going forward. TRIAL REGISTRATION NUMBER: ISRCTN69498919.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31771958

RESUMO

BACKGROUND: Understanding patient perceptions of their spiritual needs when approaching the end of life is essential to support the delivery of patient-centred care. AIM: To conduct a qualitative evidence synthesis on spirituality and spiritual care needs at the end of life in all healthcare settings from the patients' perspective. DESIGN: Studies were included where they were primary qualitative studies exploring spirituality in patients with a life expectancy of 12 months or less in any setting. Two reviewers independently screened titles, extracted data and conducted methodological quality appraisal. A thematic synthesis was conducted. Grading of Recommendations, Assessment, Development and Evaluation (GRADE) - Confidence in the Evidence from Reviews of Qualitative research (CERQual) was used to summarise the certainty of the evidence. DATA SOURCES: Six databases (Medline, Embase, Cochrane, CINAHL, PsycINFO, Applied Social Science Index and Abstracts) were searched from inception up to January 2019. RESULTS: Fifty papers (42 unique datasets), incorporating data from 710 patients were included. Studies recruited from a mix of inpatient, outpatient, hospice and community settings across 12 different countries. Three overarching themes were generated: the concept of spirituality, spiritual needs and distress, and spiritual care resources. Relationships were an intrinsic component of spirituality. CONCLUSION: Meeting patients' spiritual needs is an integral part of end-of-life care. This work emphasises that supporting relationships should be a central focus of spiritual care for patients at the end of life. PROSPERO REGISTRATION NUMBER: CRD42019122062.

4.
Alcohol ; 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31734307

RESUMO

Prenatal alcohol exposure (PAE) causes developmental abnormalities known as fetal alcohol spectrum disorder (FASD). Maternal iron status modulates the severity of these defects in the offspring. Because the placenta is central in supporting fetal development, we investigated if maternal iron status similarly modulates alcohol's effects in the placenta. We hypothesized that PAE causes placental insufficiency by decreasing placental weight and efficiency, and these are worsened by maternal iron deficiency (ID) and alleviated by dietary iron-fortification (IF). We also determined whether altered placental iron flux and inflammatory balance contribute to placental insufficiency. Pregnant Long-Evans rats consumed an ID (2-6 ppm), iron-sufficient (IS; 100 ppm), or IF (500 ppm) diet. Alcohol (5g/kg body weight) or isocaloric maltodextrin (MD) was gavaged daily from gestational day (GD) 13.5-19.5. Placental outcomes were evaluated on GD20.5. PAE reduced fetal weight (P < 0.0001), placental weight (P = 0.0324), and placental efficiency (P = 0.0043). PAE downregulated placental transferrin receptor (P = 0.0032); it also altered placental Il1b and Tnf expression and Il6:Il10 ratio (P = 0.0337, 0.0300 and 0.0034, respectively) to generate a response favoring inflammation. ID-PAE further reduced fetal growth and placental efficiency and induced a heightened pro-inflammatory placental profile. IF did not rescue the alcohol-reduced fetal weight, but it normalized placental efficiency and decreased placental inflammation. These placental cytokines correlated with fetal and placental growth, and explained 45% of variability in fetal weight and 20% of variability in placental efficiency. In summary, alcohol induces placental insufficiency and is associated with a pro-inflammatory cytokine profile exacerbated by maternal ID and mitigated by maternal IF. Because the placenta is closely linked to intrauterine growth, the placental insufficiency reported here may correlate with the lower birth weights in a subgroup of individuals who experienced PAE.

6.
Cartilage ; : 1947603519876354, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31578084

RESUMO

OBJECTIVE: Examination of intervertebral disc (IVD) regeneration in an ovine annular lesion model. HYPOTHESIS: Sulfation motifs are important functional determinants in glycosaminoglycans (GAGs). Previous studies have correlated 3-B-3(-) and 7-D-4 chondroitin sulfate (CS) motifs in tissues undergoing morphogenetic transition in development. We hypothesize that these motifs may also be expressed in degenerate IVDs and may represent a reparative response. DESIGN: Induction of disc degeneration by 5 mm or 6 × 20 mm lesions in the annulus fibrosus (AF) over 6 or 3 to 6 months postoperation (PO). Tissue sections were stained with toluidine blue-fast green, 3-B-3(-) and 7-D-4 CS-sulfation motifs were immunolocalized in 3-month PO 6 × 20 mm lesion IVDs. Sulfated glycosaminoglycan (GAG), 3-B-3(-), and 7-D-4 epitopes were quantitated by ELISIA (enzyme-linked immunosorbent inhibition assay) in extracts of AF (lesion site and contralateral half) and nucleus pulposus (NP) 0, 3, and 6 months PO. RESULTS: Collagenous overgrowth of lesions occurred in the outer AF. Chondroid metaplasia in ~20% of the 6 × 20 mm affected discs resulted in integration of an outgrowth of NP tissue with the inner AF lamellae preventing propagation of the lesion. 3-B-3(-) and 7-D-4 CS sulfation motifs were immunolocalized in this chondroid tissue. ELISIA quantified CS sulfation motifs demonstrating an increase 3 to 6 months PO in the AF lesion and a reduction in sulfated GAG not evident in the contralateral AF. CONCLUSIONS: (1) Outer annular lesions underwent spontaneous repair. (2) Chondroid metaplasia of the inner 6 × 20 mm defect prevented its propagation suggesting an apparent reparative response.

7.
Curr Pharm Teach Learn ; 11(9): 888-894, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31570125

RESUMO

INTRODUCTION: The purpose of this study was to evaluate the influence generational categories may have on commonalities among pharmacy students and their pharmacist preceptors during advanced pharmacy practice experiences (APPEs). METHODS: Multiple-choice surveys aimed at evaluating generational characteristics were sent to pharmacy students and their preceptors during the first three APPEs. Questions focused on six key areas: preferred learning/teaching style, view of career/work, communication style, view of technology, life outlook, and personal characteristics. Each response corresponded to a generational category (Veteran, Baby Boomer, Generation X, Millennial). Students and preceptors were instructed to apply each question to themselves; students then applied each question to their preceptor, while preceptors applied the questions to students. RESULTS: Twenty-six percent of students and 35% of preceptors completed at least one generational survey. Students selected the option that corresponded to their actual generational category significantly more often compared to preceptors (2.133 ±â€¯0.815 vs. 1.632 ±â€¯1.132, p = 0.007). Although none of the respondents belonged to the Veteran category, responses corresponding to this generation represented the second highest number of responses selected by students and preceptors alike. CONCLUSIONS: Students and preceptors identified with characteristics outside their actual generational category. In addition, both groups selected options such as working to make a difference that may correlate more with people who have chosen pharmacy as a profession. Pharmacist awareness of generational similarities may lead to a more successful student-preceptor relationship.

8.
Alcohol Clin Exp Res ; 43(11): 2332-2343, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31524964

RESUMO

BACKGROUND: Prenatal alcohol exposure (PAE) causes long-term growth and neurodevelopmental deficits that are worsened by maternal iron deficiency (ID). In our preclinical rat model, PAE causes fetal anemia, brain ID, and elevated hepatic iron via increased maternal and fetal hepcidin synthesis. These changes are normalized by a prenatal iron-fortified (IF) diet. Here, we hypothesize that iron status and PAE dysregulate the major upstream pathways that govern hepcidin production-EPO/BMP6/SMAD and IL-6/JAK2/STAT3. METHODS: Pregnant, Long Evans rat dams consumed ID (2 to 6 ppm iron), iron-sufficient (IS, 100 ppm iron), or IF (500 ppm iron) diets and received alcohol (5 g/kg) or isocaloric maltodextrin daily from gestational days (GD) 13.5 to 19.5. Protein and gene expression were quantified in the 6 experimental groups at GD 20.5. RESULTS: PAE did not affect Epo or Bmp6 expression, but reduced p-SMAD1/5/8/SMAD1/5/8 protein ratios in both IS and ID maternal and fetal liver (all p's < 0.01). In contrast, PAE stimulated maternal hepatic expression of Il-6 (p = 0.03) and elevated p-STAT3/STAT3 protein ratios in both IS and ID maternal and fetal liver (all p's < 0.02). PAE modestly elevated maternal Il-1ß, Tnf-α, and Ifn-γ. Fetal cytokine responses to PAE were muted compared with dams, and PAE did not affect hepatic Il-6 (p = 0.78) in IS and ID fetuses. Dietary iron fortification sharply attenuated Il-6 expression in response to PAE, with IF driving a 150-fold decrease (p < 0.001) in maternal liver and a 10-fold decrease (p < 0.01) in fetal liver. The IF diet also normalized p-STAT3/STAT3 ratios in both maternal and fetal liver. CONCLUSIONS: These findings suggest that alcohol-driven stimulation of the IL-6/JAK2/STAT3 pathway mediates the elevated hepcidin observed in the PAE dam and fetus. Normalization of these signals by IF suggests that dysregulated hepcidin is driven by alcohol's disruption of the IL-6/JAK2/STAT3 pathway. Prenatal dietary IF represents a potential therapeutic approach for PAE that warrants further investigation.

9.
BMC Fam Pract ; 20(1): 131, 2019 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-31519171

RESUMO

BACKGROUND: Community pharmacy represents an important setting to identify patients who may benefit from an adherence intervention, however it remains unclear whether it would be feasible to monitor antihypertensive adherence within the workflow of community pharmacy. The aim of this study was to identify facilitators and barriers to monitoring antihypertensive medication adherence of older adults at the point of repeat dispensing. METHODS: We undertook a factorial survey of Irish community pharmacists, guided by a conceptual model adapted from the Theory of Planned Behaviour (TPB). Respondents completed four sections, 1) five factorial vignettes (clinical scenario of repeat dispensing), 2) a medication monitoring attitude measure, 3) subjective norms and self-efficacy questions, and 4) demographic and workplace questions. Barriers and facilitators to adherence monitoring behaviour were identified in factorial vignette analysis using multivariate multilevel linear modelling, testing the effect of both contextual factors embedded within the vignettes (section 1), and respondent-level factors (sections 2-4) on likelihood to perform three adherence monitoring behaviours in response to the vignettes. RESULTS: Survey invites (n = 1543) were sent via email and 258 completed online survey responses were received; two-thirds of respondents were women, and one-third were qualified pharmacists for at least 15 years. In factorial vignette analysis, pharmacists were more inclined to monitor antihypertensive medication adherence by examining refill-patterns from pharmacy records than asking patients questions about their adherence or medication beliefs. Pharmacists with more positive attitudes towards medication monitoring and normative beliefs that other pharmacists monitored adherence, were more likely to monitor adherence. Contextual factors also influenced pharmacists' likelihood to perform the three adherence monitoring behaviours, including time-pressures and the number of days late the patient collected their repeat prescription. Pharmacists' normative beliefs and the number of days late the patient collected their repeat prescription had the largest quantitative influence on responses. CONCLUSIONS: This survey identified that positive pharmacist attitudes and normative beliefs can facilitate adherence monitoring within the current workflow; however contextual time-barriers may prevent adherence monitoring. Future research should consider these findings when designing a pharmacist-led adherence intervention to be integrated within current pharmacy workflow.

10.
Birth Defects Res ; 111(16): 1234-1236, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31385457
11.
Pediatr Cardiol ; 40(8): 1633-1637, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31468061

RESUMO

We sought to assess acute hemodynamic changes after implementation of negative extrathoracic pressure (NEP) in spontaneously breathing ambulatory Fontan patients with symptomatic heart failure. We hypothesized that application of NEP would result in an acute decrease in pulmonary artery pressure. Ten patients with clinical evidence of Fontan failure underwent baseline hemodynamic catheterization while breathing spontaneously. Hemodynamic measurements were then repeated after 30 min of continuous NEP. After 30 min of continuous NEP, 4/10 patients had a decrease in their Fontan pressure by 2 mmHg and one patient had a decrease by 1 mmHg. There were three patients that had an increase in Fontan pressure by 2 mmHg. In 7/10 patients, indexed pulmonary vascular resistance decreased by an average of 31%. In symptomatic Fontan patients with a favorable hemodynamic response to NEP during catheterization, potential benefit of longer-term NEP to improve clinical status should be explored.

12.
Proc Natl Acad Sci U S A ; 116(38): 18951-18961, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31462498

RESUMO

The hydrophobic gasket (HG), a ring of hydrophobic amino acids in the voltage-sensing domain of most voltage-gated ion channels, forms a constriction between internal and external aqueous vestibules. Cationic Arg or Lys side chains lining the S4 helix move through this "gating pore" when the channel opens. S4 movement may occur during gating of the human voltage-gated proton channel, hHV1, but proton current flows through the same pore in open channels. Here, we replaced putative HG residues with less hydrophobic residues or acidic Asp. Substitution of individuals, pairs, or all 3 HG positions did not impair proton selectivity. Evidently, the HG does not act as a secondary selectivity filter. However, 2 unexpected functions of the HG in HV1 were discovered. Mutating HG residues independently accelerated channel opening and compromised the closed state. Mutants exhibited open-closed gating, but strikingly, at negative voltages where "normal" gating produces a nonconducting closed state, the channel leaked protons. Closed-channel proton current was smaller than open-channel current and was inhibited by 10 µM Zn2+ Extreme hyperpolarization produced a deeper closed state through a weakly voltage-dependent transition. We functionally identify the HG as Val109, Phe150, Val177, and Val178, which play a critical and exclusive role in preventing H+ influx through closed channels. Molecular dynamics simulations revealed enhanced mobility of Arg208 in mutants exhibiting H+ leak. Mutation of HG residues produces gating pore currents reminiscent of several channelopathies.

13.
Development ; 146(15)2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31331942

RESUMO

Postnatal alveolar formation is the most important and the least understood phase of lung development. Alveolar pathologies are prominent in neonatal and adult lung diseases. The mechanisms of alveologenesis remain largely unknown. We inactivated Pdgfra postnatally in secondary crest myofibroblasts (SCMF), a subpopulation of lung mesenchymal cells. Lack of Pdgfra arrested alveologenesis akin to bronchopulmonary dysplasia (BPD), a neonatal chronic lung disease. The transcriptome of mutant SCMF revealed 1808 altered genes encoding transcription factors, signaling and extracellular matrix molecules. Elastin mRNA was reduced, and its distribution was abnormal. Absence of Pdgfra disrupted expression of elastogenic genes, including members of the Lox, Fbn and Fbln families. Expression of EGF family members increased when Tgfb1 was repressed in mouse. Similar, but not identical, results were found in human BPD lung samples. In vitro, blocking PDGF signaling decreased elastogenic gene expression associated with increased Egf and decreased Tgfb family mRNAs. The effect was reversible by inhibiting EGF or activating TGFß signaling. These observations demonstrate the previously unappreciated postnatal role of PDGFA/PDGFRα in controlling elastogenic gene expression via a secondary tier of signaling networks composed of EGF and TGFß.

14.
CMAJ ; 191(18): E489-E490, 2019 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-31061073
15.
PLoS Comput Biol ; 15(4): e1006937, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30973878

RESUMO

Gestational alcohol exposure causes fetal alcohol spectrum disorder (FASD) and is a prominent cause of neurodevelopmental disability. Whole transcriptome sequencing (RNA-Seq) offer insights into mechanisms underlying FASD, but gene-level analysis provides limited information regarding complex transcriptional processes such as alternative splicing and non-coding RNAs. Moreover, traditional analytical approaches that use multiple hypothesis testing with a false discovery rate adjustment prioritize genes based on an adjusted p-value, which is not always biologically relevant. We address these limitations with a novel approach and implemented an unsupervised machine learning model, which we applied to an exon-level analysis to reduce data complexity to the most likely functionally relevant exons, without loss of novel information. This was performed on an RNA-Seq paired-end dataset derived from alcohol-exposed neural fold-stage chick crania, wherein alcohol causes facial deficits recapitulating those of FASD. A principal component analysis along with k-means clustering was utilized to extract exons that deviated from baseline expression. This identified 6857 differentially expressed exons representing 1251 geneIDs; 391 of these genes were identified in a prior gene-level analysis of this dataset. It also identified exons encoding 23 microRNAs (miRNAs) having significantly differential expression profiles in response to alcohol. We developed an RDAVID pipeline to identify KEGG pathways represented by these exons, and separately identified predicted KEGG pathways targeted by these miRNAs. Several of these (ribosome biogenesis, oxidative phosphorylation) were identified in our prior gene-level analysis. Other pathways are crucial to facial morphogenesis and represent both novel (focal adhesion, FoxO signaling, insulin signaling) and known (Wnt signaling) alcohol targets. Importantly, there was substantial overlap between the exomes themselves and the predicted miRNA targets, suggesting these miRNAs contribute to the gene-level expression changes. Our novel application of unsupervised machine learning in conjunction with statistical analyses facilitated the discovery of signaling pathways and miRNAs that inform mechanisms underlying FASD.


Assuntos
Éxons/genética , Transtornos do Espectro Alcoólico Fetal/genética , MicroRNAs/genética , Aprendizado de Máquina não Supervisionado , Animais , Big Data , Embrião de Galinha , Análise por Conglomerados , Biologia Computacional , Bases de Dados de Ácidos Nucleicos/estatística & dados numéricos , Modelos Animais de Doenças , Etanol/toxicidade , Feminino , Perfilação da Expressão Gênica/estatística & dados numéricos , Humanos , Gravidez , Análise de Componente Principal , Aprendizado de Máquina não Supervisionado/estatística & dados numéricos
16.
J Mol Histol ; 50(3): 285-294, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30993430

RESUMO

The aim of this study was to ascertain whether, like many cell types in cartilaginous tissues if type XI collagen was a pericellular component of annulus fibrosus (AF) cells and chondrocytes. Fine fibrillar networks were visualised which were perlecan, HS (MAb 10E4) and type XI collagen positive. Heparitinase-III pre-digestion abolished the type XI collagen and 10E4 localisation in these fibrillar assemblies demonstrating a putative HS mediated interaction which localised the type XI collagen. Type XI collagen was confirmed to be present in the Heparitinase III treated AF monolayer media samples by immunoblotting. Heparitinase-III generated ΔHS stub epitopes throughout these fibrillar networks strongly visualised by MAb 3-G-10. Monolayers of murine hip articular chondrocytes from C57BL/6 and Hspg2 exon 3 null mice also displayed pericellular perlecan localisations, however type XI collagen was only evident in the Wild type mice. Perlecan was also immunolocalised in control and murine knee articular cartilage from the two mouse genotypes subjected to a medial meniscal destabilisation procedure which induces OA. This resulted in a severe depletion of perlecan levels particularly in the perlecan exon 3 null mice and was consistent with OA representing a disease of the pericellular matrix. A model was prepared to explain these observations between the NPP type XI collagen domain and HS chains of perlecan domain-I in the pericellular matrix of AF cells which likely contributed to cellular communication, tissue stabilization and the regulation of extracellular matrix homeostasis.


Assuntos
Anel Fibroso/efeitos dos fármacos , Colágeno Tipo XI/genética , Proteoglicanas de Heparan Sulfato/genética , Animais , Anel Fibroso/metabolismo , Anel Fibroso/patologia , Cartilagem Articular/crescimento & desenvolvimento , Cartilagem Articular/metabolismo , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Éxons/genética , Matriz Extracelular/genética , Proteínas da Matriz Extracelular/genética , Homeostase/genética , Disco Intervertebral/crescimento & desenvolvimento , Disco Intervertebral/metabolismo , Camundongos , Polissacarídeo-Liase/farmacologia
17.
Int J Pharm Pract ; 27(5): 459-467, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30968988

RESUMO

AIMS: Methods that enable targeting and tailoring of adherence interventions may facilitate implementation in clinical settings. We aimed to determine whether community pharmacy refill-adherence metrics are useful to identify patients at higher risk of healthcare utilisation due to low antihypertensive adherence, who may benefit from an adherence intervention. METHODS: We conducted a prospective cohort study, recruiting participants (n = 905) from 106 community pharmacies across the Republic of Ireland. Participants completed a structured interview at baseline and 12 months. Antihypertensive medication adherence was evaluated from linked pharmacy records using group-based trajectory modelling (GBTM) and proportion of days covered (PDC). Healthcare utilisation included self-reported number of hospital visits (emergency department visits and inpatient admissions) and general practitioner (GP) visits, over a 6-month period. Separate regression models were used to estimate the association between adherence and number of hospital/GP visits. The relative statistical fit of each model using different adherence metrics was determined using the Bayesian information criterion (BIC). RESULTS: For the number of hospital visits, significant associations were observed only for PDC but not for GBTM. Each 10% increase in refill-adherence by PDC was significantly associated with a 16% lower rate of hospital visits (adjusted incidence rate ratio 0.84, 95% CI 0.72-0.98, P = 0.036). Poorer adherence using both measures was associated with higher GP visits. Improvements in BIC favoured models using PDC. CONCLUSIONS: Medication refill-adherence, measured using PDC in community pharmacy settings, could be used to recognise poor antihypertensive adherence to enable effective targeting of clinical interventions to improve hypertension management and outcomes.

18.
Birth Defects Res ; 111(12): 686-699, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31021056

RESUMO

BACKGROUND: Prenatal alcohol exposure causes distinctive craniofacial anomalies that arise, in part, from the apoptotic elimination of neural crest (NC) progenitors that form the face. This vulnerability of NC to alcohol is puzzling as they normally express the transcriptional repressor Snail1/2 (in chick Snai2), which suppresses apoptosis and promotes their migration. Here, we investigate alcohol's impact upon Snai2 function. METHODS: Chick cranial NC cells were treated with acute alcohol (52 mM, 2 hr). We evaluated NC migration, gene expression, proliferation, and apoptosis thereafter. RESULTS: Transient alcohol exposure induced Snai2 (191% ± 23%; p = .003) and stimulated NC migration (p = .0092). An alcohol-induced calcium transient mediated this Snai2 induction, and BAPTA-AM blocked whereas ionomycin mimicked these pro-migratory effects. Alcohol suppressed CyclinD1 protein content (59.1 ± 12%, p = .007) and NC proliferation (19.7 ± 5.8%, p < .001), but these Snai2-enriched cells still apoptosed in response to alcohol. This was explained because alcohol induced p53 (198 ± 29%, p = .023), and the p53 antagonist pifithrin-α prevented their apoptosis. Moreover, alcohol counteracted Snai2's pro-survival signals, and Bcl2 was repressed (68.5 ± 6.0% of controls, p = .016) and PUMA was not induced, while ATM (1.32-fold, p = .01) and PTEN (1.30-fold, p = .028) were elevated. CONCLUSIONS: Alcohol's calcium transient uncouples the Snai2/p53 regulatory loop that normally prevents apoptosis during EMT. This represents a novel pathway in alcohol's neurotoxicity, and complements demonstrations that alcohol suppresses PUMA in mouse NC. We propose that the NCs migratory behavior, and their requirement for Snai2/p53 co-expression, makes them vulnerable to stressors that dysregulate Snai2/p53 interactions, such as alcohol.

19.
Br J Gen Pract ; 69(683): e373-e380, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31015226

RESUMO

BACKGROUND: Changes in clinical guidelines for primary prevention of cardiovascular disease (CVD) have widened eligibility for statin therapy. AIM: To illustrate the potential impacts of changes in clinical guidelines. DESIGN AND SETTING: Modelling the impacts of seven consecutive European guidelines based on a cohort of people aged ≥50 years from the Irish Longitudinal Study on Ageing. METHOD: The eligibility for statin therapy of a sample of people without a history of CVD was established, according to changing guideline recommendations and modelled associated potential costs. The authors calculated the numbers needed to treat (NNT) to prevent one major vascular event in patients at the lowest baseline risk for which each of the seven guidelines recommended treatment, and for those at low, medium, high, and very-high risk according to 2016 guidelines. These were compared with the NNT that patients reported as required to justify taking a daily medicine. RESULTS: The proportion of patients eligible for statins increased from approximately 8% in 1987 to 61% in 2016; associated costs rose from €13.9 million to €107.1 million per annum. The NNT for those at the lowest risk for which each guideline recommended treatment rose from 40 to 400. By 2016, the NNT for low-risk patients was 400 compared to ≤25 very-high risk patients. The proportion of patients eligible for statins achieving NNT levels that patients regarded as justified to taking a daily medicine fell as guidelines changed over time. CONCLUSION: Increased eligibility for statin therapy impacts large proportions of the present population and healthcare budgets. Decisions to take and reimburse statins should be considered on the basis of expected cost-effectiveness and acceptability to patients.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Idoso , Doenças Cardiovasculares/etiologia , Estudos de Coortes , Definição da Elegibilidade , Feminino , Humanos , Irlanda , Masculino , Pessoa de Meia-Idade , Preferência do Paciente , Seleção de Pacientes , Guias de Prática Clínica como Assunto , Prevenção Primária , Fatores de Risco
20.
BMJ Open ; 9(4): e023085, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015265

RESUMO

OBJECTIVE: To synthesise evidence from exclusively primary prevention data on the effectiveness of statins for prevention of cardiovascular disease (CVD), including stroke, and outcomes stratified by baseline risk and gender. DESIGN: Overview of systematic reviews (SRs) using Revised-AMSTAR approach to assess quality. DATA SOURCES: Cochrane Database of Systematic Reviews, MEDLINE, Embase, PubMed, Scopus and PROSPERO to June 2017. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: SRs of randomised control trials (RCTs) or individual patient data (IPD) from RCTs, examining the effectiveness of statins versus placebo or no treatment on all-cause mortality, coronary heart disease, CVD (including stroke) and composite endpoints, with stratification by baseline risk and gender. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted data and assessed methodological quality. A narrative synthesis was conducted. RESULTS: Three SRs were included. Quality of included SRs was mixed, and none reported on the risk of bias of included trials.We found trends towards reduced all-cause mortality in all SRs (RR 0.91 [95% CI 0.85 to 0.97]), (RR 0.91 [95% CI 0.83 to 1.01]) and (RR 0.78 [95% CI 0.53 to 1.15]) though it was not statistically significant in two SRs. When stratified by baseline risk, the effect on all-cause mortality was no longer statistically significant except in one medium risk category. One review reported significant reductions (RR 0.85 [95% CI 0.77 to 0.95]) in vascular deaths and non-significant reductions in non-vascular deaths (RR 0.97 [95% CI 0.88 to 1.07]). There were significant reductions in composite outcomes overall, but mixed results were reported in these when stratified by baseline risk. These reviews included studies with participants considered risk equivalent to those with established CVD. CONCLUSIONS: There is limited evidence on the effectiveness of statins for primary prevention with mixed findings from studies including participants with widely ranging baseline risks. Decision making for the use of statins should consider individual baseline risk, absolute risk reduction and whether risk reduction justifies potential harms and taking a daily medicine for life. TRIAL REGISTRATION NUMBER: CRD42017064761.

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